functional neurology, rehabilitation, and ergonomics

FUNCTIONAL NEUROLOGY, REHABILITATION, AND ERGONOMICS Volume 6, Number 3, 2016

TABLE OF CONTENTS From the Editor-in-Chief Gerry Leisman

151

Editorial - Landmine Injuries: Treatment and Rehabilitation Seema Biswas, Kobi Peleg, Morgan Clond, Irina Radomislensky, Harald Veen, Miklosh Bala, Alexander Izakson, Evgeny Solomonov, and Alexander Lerner

153

Scientific Papers Cognitive-Motor Integration in Normal Aging and Preclinical Alzheimer’s Disease: Neural Correlates and Early Detection Kara M. Hawkins, Lauren E. Sergio, and Aman I. Goyal

169

What Functional Neurology Can Offer the Treatment of Developmental Disabilities Gerry Leisman and Robert Melillo

233

Cortical Asymmetry and the Optimization of Learning Gerry Leisman and Robert Melillo

283

Clinical Papers A Retrospective Risk Prediction of Other-Directed Aggression and Violence in a Patient with Mixed Dementia Samuel T. Gontkovsky

309

Cognitive Gains after Vestibular and Balance Therapy in a Patient with Progressive Balance Dysfunction Subsequent to Ependymoma Radiation Therapy Michael S. Trayford

319

The Clinical Relevance of CNS Injury-Induced Immune Deficiency Syndrome (CIDS) in Functional Neurology Practice Samuel Yanuck

325

ii

Contents

Abstracts from the 2016 IAFNR Conference A Multimodal Approach to Care of an Adolescent Male with Absence Seizures Joseph Coppus, Michael Longyear, and Michael Hall

331

Cognitive Improvements in a Teenage Male with Post-Concussive Syndrome Following Functional Neurology Intervention Dominic Fetterly, Rachel Abbott, and Michael Hall

333

Adolescent Learning Disability, Functional Neurological Management in a 13-Year-Old Female Brittany Forrester, Michael Longyear, and Michael Hall

335

Cervical-Ocular-Vestibular Therapy and Functional Neurology in a Concussed Collegiate Male Wrestler Katherine E. Leonardis, Jonathan Vestal, and Michael Hall

337

Improved Sensory Perception, Fine Motor Coordination and Balance in Patient with Brain Injury Following Lifting Event Paula Rhodes and Jon Eberle

339

Learning Disability and Reading Difficulty in a 12-Year-Old Male Rachel Smith, Michael Longyear, and Michael Hall

341

Letter to the Editor - The Effects of Stress and Chiropractic Adjustments on Neural Regulation Richard G. Barwell and Jonathan Vestal

343

IAFNR News and Events

351

Literature Calling

367

New York

Journal of

Functional Neurology, Rehabilitation, and Ergonomics The Official Journal of the International Association of Functional Neurology and Rehabilitation The aim of this interdisciplinary journal is to provide a forum for the fields of Biomedical and Rehabilitation Engineering, Neuropsychology, Clinical Neurology, Human Factors and Ergonomics, and vocational assessment and training to present critical ideas, theories, proof-ofconcept for technology solutions, and data-based evaluative research to facilitate return to work or more effective functional development in children and adults. Functional Neurology, Rehabilitation, and Ergonomics is published quarterly by Nova Science Publishers, Inc. 400 Oser Avenue, Suite 1600 Hauppauge, New York 11788, USA E-mail: [email protected] Web: www.novapublishers.com ISSN: 2156-941X Institutional Subscription Rates per Volume Print: $350

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Additional color graphics might be available in the e-version of this journal. Copyright © 2016 by Nova Science Publishers, Inc. All rights reserved. Printed in the United States of America. No part of this Journal may be reproduced, stored in a retrieval system, or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical, photocopying, recording, or otherwise without permission from the Publisher. The Publisher assumes no responsibility for any statements of fact or opinion expressed in the published papers.

Editor-in-Chief Gerry Leisman Nazareth, Israel Co-Editor-in-Chief Robert Melillo Rockville Centre, NY USA Assistant Editor - Production Janet Groschel Gilbert, AZ USA

Shashank Agarwal New York, NY, USA

Editorial Board Members Mario Estévez-Báez Havana, Cuba

Rabiul Ahasan Kuala Terengganu, Malaysia

Newton Howard Cambridge, MA, USA

Randy Beck Perth, Australia

Megan L. Hudson West Springfield, MA, USA

Eti Ben-Simon Tel-Aviv, Israel

Efraim Jaul Jerusalem, Israel

Paul Berger-Gross Bayside, NY, USA

Datis Kharrazian Carlspoor, CA, USA

John A. Brabyn San Francisco, CA, USA

Samuel Landsberger Los Angeles, CA, USA

Orit Braun-Benjamin Karmiel, Israel

Seung Won Lee Seoul, Korea

Lynn M. Carlson W. Springfield, MA, USA

Joy MacDermid Hamilton, Ontario, CA

Eliezer Carmeli Haifa, Israel

Calixto Machado Havana, Cuba

Emmanuel Donchin Tampa, FL, USA

Joav Merrick Jerusalem, Israel

Andrew L. Egel College Park, MD, USA

Raed Mualem Nazareth, Israel

Khosrow Eghtesadi W. Palm Beach, FL, USA

Paul Noone Hampton East Victoria, Australia Jackie Oldham Manchester, UK Chandler Phillips Dayton, OH, USA Rafael Rodríguez-Rojas Madrid, Spain Anthony L. Rosner Boston, MA, USA Thomas Schack Bielfeld, Germany Fredric Schiffer Boston, MA, USA Peter Scire Peachtree City, GA, USA Suryakumar Shah Scottsdale, AZ, USA Joseph Weisberg Great Neck, NY, USA Leslie Weiser Boston, MA, USA

Funct Neurol Rehabil Ergon 2016;6(3):151

ISSN: 2156-941X © 2016 Nova Science Publishers, Inc.

From the Editor-in-Chief Gerry Leisman* Editor-in-Chief, FNRE The National Institute for Brain and Rehabilitation Sciences, Nazareth, Israel Universidad de Ciencias Médicas de la Habana, Facultad Manuel Fajardo

Now in the middle of our sixth year of publication, each of the twenty-two issues of our journal Functional Neurology, Rehabilitation and Ergonomics have had an editorial dealing with, within and external to the practice of Functional Neurology. Each, written by me, has attempted to focus on different life, practice, and social issues that either directly affect the clinical practice or involve world-wide issues that should have us raising voices loudly in protest of what clinicians and scientists oftentimes regard as being irrelevant. I have asked the editorialist of the current issue, Seema Biswas, to report on issues important to her. Dr. Biswas is the Editor-in-Chief of the esteemed British Medical Journal, Clinical Reports, is an experienced battlefield surgeon and has recently been introduced to Functional Neurology. She is supported by the International Red Cross and is currently located at Ziv Hospital’s Department of Surgery in Sefad, Israel. Ms. Biswas is completing her PhD from Ben Gurion University of the Negev in Medical Anthropology and is truly a Renaissance person, despite jokes about surgeons. Out of her interest in our “goings on,” she will be visiting and lecturing at our laboratories and clinics in Cuba with myself and Dr. Calixto Machado. I urge you to take her editorial and research report seriously and advocate for change in government policies in this regard. I on behalf of the IAFNR membership welcome her to our pages and, as usual, welcome comments from FNRE’s readers about her report. I also look forward to joint projects between our journal FNRE and the BMJ.

*

[email protected]

Funct Neurol Rehabil Ergon 2016;6(3):153-165

ISSN: 2156-941X © Nova Science Publishers, Inc.

Editorial Landmine Injuries: Treatment and Rehabilitation Seema Biswas1,2,3,*, Kobi Peleg5, Morgan Clond6, Irina Radomislensky5, Harald Veen3, Miklosh Bala7, Alexander Izakson8, Evgeny Solomonov2, and Alexander Lerner9,10 1

Editor-in-Chief British Medical Journal, Case Reports 2 Department of Surgery Ziv Medical Center, Sefad, Israel 3 International Committee of the Red Cross, Geneva, Switzerland 4 The National Institute for Brain and Rehabilitation Sciences, Nazareth, Israel 5 Israeli National Center for Trauma and Emergency Medicine Research. The Gertner Institute, Tel Hashomer, Israel 6 School of Medicine, Ben Gurion University, Beer Sheva, Israel 7 Trauma Department, Hadassah Hospital Hebrew University School of Medicine, Ein Kerem, Jerusalem Israel 8 Department of Anesthesiology, Ziv Medical Center, Safed, Israel 9 Department of Orthopaedic Surgery, Ziv Medical Center, Safed, Israel 10 Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel

Abstract Background: Although landmines are considered important for border defense, they pose considerable danger to unintended targets, especially civilians living in conflict and post-conflict zones. Civilian facilities are, therefore, increasingly seeing patients presenting with landmine injuries. Method: The number of patients with landmine injuries treated across Israel was identified by searching the records of the Israeli National Center for Trauma and Emergency Medicine Research at the Gertner Institute. Clinical data of patients with landmine injury treated at Ziv Medical Center were analyzed. Results: ITNR for landmine injuries managed in Israeli health facilities from 1997 to 2013 show that in that period 23 patients were admitted to hospitals across the country. Almost all injuries were to the limbs. Only 4 patients were transferred to dedicated rehabilitation centers. Guidelines on the management of landmine injuries were put together from the over 30 years’ experience in dealing with war related injuries at Ziv Medical center and our case series of patients with landmine injuries. Conclusions: The number of civilians with mine injuries is significant in both conflict and post-conflict areas. Expertise is needed in the management of these complex injuries in both civilian and military facilities. Clinical relevance: By studying cases of landmine injuries across the country and drawing up management guidelines appropriate to civilian centers, war surgery expertise may be shared with those working in civilian rehabilitation facilities. Keywords’ landmines, blast injury, debridement, limb salvage, rehabilitation, amputation

*

Email: [email protected]

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Seema Biswas, Kobi Peleg, Morgan Clond et al.

Introduction Landmine explosions are an ongoing global health problem, and present a daily risk to unintended targets in agricultural and residential areas in conflict and post-conflict zones. According to the 2014 Monitor Report, [1] landmines contaminate 56 countries and four territories, and were responsible for at least 3,308 casualties worldwide in 2013 alone. Civilians accounted for 79% of the casualties, security forces for 18%, and professionals dismantling the mines accounted for 3% [2-4]. Forty six percent of civilian casualties worldwide were children1 who exhibit a natural curiosity toward these devices [5] and suffer a higher prevalence of upper limb injury [2, 6]. In Turkey, injury prevented children from returning to school in all but five of 23 cases [2]. International Mine Action Standards (IMAS), describe mine action in terms of five complementary activities: a) mine-risk

(A)

awareness; b) humanitarian demining, i.e., mine and unexploded ordnance survey, mapping, marking and, when necessary, clearance; c) victim assistance, including rehabilitation and reintegration; d) stockpile destruction; and e) advocacy against the use of anti-personnel mines. [7, 8]. The International Committee of the Red Cross, ICRC, has been a major force for mine action. [9] The ICRC categorizes three patterns of landmine injury. Pattern 1 injuries are those that result from stepping on the landmine, and predominantly involve injuries to the lower extremities (see Figure 1). Pattern 2 injuries result from being near the explosive at the time of detonation. These injuries are characterized by penetrating injuries due to fragments and other projectiles, as well as exposure to the blast wave. Pattern 3 injuries are seen as a result of tampering with or handling the device, and are characterized by injuries to the face, eyes, and upper extremities [4].

(B)

(C)

Figure 1. ICRC surgeons consider landmine injuries to be amongst the most difficult to treat because of the extent of the operative care and coordinated multidisciplinary approach required. A) Diagram showing how an injury, apparently confined to the foot, is associated with proximal compartmental muscle damage. B) Diagram of explosive injury with traumatic amputation of the lower leg. The mechanism of proximal compartmental injury with skin and gastrocnemius preservation is shown. C) Diagram showing how, when the skin has returned to position, the extent of proximal damage is hidden. Figure illustrated by Robin Coupland. Adapted with permission from International Committee of the Red Cross [9].

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Editorial The majority of Israel's mine fields are located in the border area of the Golan Heights. [10]. Although Israel has begun dismantling mine fields, [11, 12] some of the mines remain active and may migrate as a result of the area’s propensity to soil erosion. The only prior research available on the Golan Heights is from a self-published survey conducted by the Al-Haq group in 2000, which reported 66 injuries amongst Golan residents since 1967, including 16 deaths. Forty-three of the survivors (86%) and eight of the deaths (50%) were under the age of 18 at the time of injury [5]. They suggest that the high proportion of children amongst those injured may be due to their traditional roles in cattle grazing and farming [3, 13, 14]. In the Negev, 50% of those injured by ordnance amongst the Bedouin were under the age of 16 [15]. We here provide a countrywide analysis of landmine casualties in Israel, based on the National Trauma Registry and experience of dealing with landmine injuries in a civilian hospital treating casualties of the Syrian civil war. As mine injuries continue to present to civilian health facilities across the country, there is a growing need among surgeons to manage patients in a manner that optimizes anatomical and functional recovery, and addresses physical and mental rehabilitation. It is for this reason that Functional Neurologists and rehabilitationists have been recruited to provide creative ideas for speedy solutions for restoration of function.

2008 up to a further ten hospitals have been included. With institutional ethics committee approval, clinical data of casualties from the Syrian civil war were collected from the orthopedic department of Ziv Medical Center. Of the thirteen cases presented from Ziv, five fall within the 2013 Gertner dataset.

Results INTR Data INTR data for landmine injuries across Israel from 1997 to 2013 show that 23 patients were admitted to hospitals with landmine injuries. No data for fatalities at the scene are available. Table I. (A) Gender distribution of patients injured by landmines (B) Age distribution of patients injured by landmines, (C) Population group that injured patients identified themselves within (A)

Gender

Number of patients

Percentage

Female

1

4.35

Male

22

95.65 (B)

Materials and Methods

Population Group

Number of Percentage patients

The number of landmine injuries treated in hospitals in Israel was identified by searching the records of the Israel National Trauma Registry (ITNR) of the Gertner Institute, which collects data from hospitals across the country. Between 1997 and 2007, only between six and ten hospitals were within the registry (six of which are level 1 Trauma Centers). Since

Israeli citizen

6

26.09

Non-Israeli citizen

4

17.39

IDF soldier

7

30.43

Foreign worker

1

4.35

Syrian citizen

5

21.74

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Ziv Data

(C)

ISS

Number of patients

Percentage

1-8

5

21.74

9-14

14

60.87

16-24

1

4.35

25-75

3

13.04

Since February 2013, 13 of 434 patients from Syria admitted to Ziv Medical Center suffered trauma consistent with mine injury (See Table IV).

Guidelines for the Management of Mine Injuries to Limbs

Tables Ia, b and c show the demographic characteristics of the patients. Over half of the patients (up to 52%) were young adults, mostly men (96%). Table II shows the severity of injuries. Almost all injuries were to the limbs but sites of injury are presented separately, irrespective of multiple trauma. Table 3 shows that four patients were transferred to dedicated rehabilitation centers. Table II. Injury Severity Score

Injury sites Number of patients*

Percentage

Head and Neck

9

39.13

Spine

1

4.35

Torso

8

34.78

Extremities

22

95.65

* Casualties had multiple injuries.

Table III. Destination after hospital discharge

Destination after hospital discharge Destination

Number of patients

Percentage

Another Hospital

6

26.09

Home

13

56.52

Rehabilitation

4

17.39

Anti-personnel mine injury inflicts extensive local and systemic damage that requires a comprehensive approach to treatment from emergency surgery to rehabilitation back into society. Sepsis may be secondary to deep-seated tissue necrosis and contamination from multiple fragments, which, in contrast to civilian causes of trauma, may not be immediately visible. Personal and cultural attitudes towards radical debridement and amputation are important and require discussion with the patient (and their family, or even community members, in certain circumstances) for informed consent. X-ray is mandatory to investigate fractures, dislocations, foreign bodies and gas within bone and soft tissues. Computer tomography angiography (CTA) may be available in civilian hospitals and is a non-invasive and rapid method for the evaluation of associated vascular injury. Copious irrigation, active and/or passive immunization against tetanus, and antibiotic cover of aerobic and anaerobic bacteria are essential [16, 17]. The risk of infection increases with failure of early and correct antibiotic prescription, delayed or inadequate wound irrigation and debridement, the presence of Clostridium perfringens in the wound, unstable fracture fixation, primary wound closure, positive bacterial cultures after surgical procedures, the development of bacterial resistance and extensive soft tissue damage [18, 19]. Also associated with the risk of sepsis are the physiological insults of multiple-trauma, hemodynamic shock, malnutrition and underlying medical comorbidities [20].

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Editorial

Table IV. Clinical characteristics of patients treated in Ziv Medical Center with mine injuries in 2013 and 2014 (n = 13) Patient

Age

Gender

Injury description

Surgical Intervention in Detail

1

Adult

Male

Multiple fractures and dislocations of right foot with bone and soft tissue loss

DBR (3), NPWT, Spanning trans-ankle Ex Fix

Female

Right traumatic AKA, left open tibial fracture with bone and soft tissue loss

DBR, completion right AKA. DBR (3). Acute shortening left tibia. Tubular Ex Fix followed by conversion to Illizarov frame

2

Child

Left foot and ankle destructionmassive soft tissue loss. Open left humerus fracture with radial nerve palsy Traumatic amputation right forefoot, right ankle fracture, multiple fragment wounds to both lower limbs Traumatic left BKA, right foot fracture, multiple fragment wounds entire body

3

Child

Male

4

Adult

Female

5

Child

Male

6

Child

Male

Traumatic right BKA and left AKA

7

Adult

Male

Bilateral tibia/fibula fractures with extensive soft tissue loss

8

Child

Male

High traumatic left AKA, traumatic amputation right forefoot, right leg bone and soft tissue loss, traumatic trans-metacarpal amputation left hand, open left humerus fracture Right femur fracture, traumatic right foot amputation and soft tissue loss distal leg, open left tibial fracture with extensive bone and soft tissue loss, burns to both lower limbs Open right foot fractures with extensive bone and soft tissue loss

9

Adult

Male

10

Adult

Male

11

Adult

Male

Left hind and mid foot destruction, left tibial fracture with massive bone and soft tissue loss

12

Adult

Male

13

Adult

Male

Outcome BKA due to tissue necrosis. Walking with crutches within 3 weeks Walking FWB both lower limbs with right leg prosthesis within 4 weeks Left tibial fracture healed after 5 months of external fixation.

DBR and Ex Fix left humerus. DBR (4) left lower limb, BKA, revised to AKA due to extensive tissue necrosis

Walking with prosthesis within 6 weeks

DBR (2), NPWT, spanning trans-ankle Ex Fix, SSG

Walking with crutches within 6 weeks

DBR (3), completion left BKA, NPWT, SSG

Walking with prosthesis in 6 weeks

DBR (2), completion of bilateral lower limb amputations DBR (5) and bilateral Spanning trans-ankle external fixation, bilateral BKA due to extensive tissue necrosis DBR (7), completion left AKA, spanning right trans-ankle Ex Fix, left humerus Ex Fix. Right BKA due to local and generalized sepsis, NPWT DBR (2), right BKA, Ex Fix right femur. DBR (4) left leg, Ex Fix with acute shortening, conversion to Ilizarov circular fixation

Walking with prosthesis in 6 weeks Walking with prosthesis in 6 weeks Walking with prosthesis within 9 weeks Walking FWB both lower limbs with right leg prosthesis within 6 weeks

Spanning trans-ankle Ex Fix, DBR (5), NPWT, SSG DBR (2), spanning hybrid Ex Fix with ring for foot elevation (relief of pressure). Left AKA due to extensive tissue necrosis

Walking with crutches after 6 weeks

Left hind and midfoot destruction, massive soft tissue loss, right leg soft tissue loss, right forearm fracture, burns

DBR (3), spanning trans-ankle Ex Fix, left BKA due to septic necrosis. Right forearm Ex Fix


Traumatic right AKA, left foot destruction, left tibial fracture

DBR (3), completion right AKA, left BKA


* exact age not given for reasons of confidentiality (all Syrian patients are anonymous). DBR – debridement () numbers in brackets refer to number of DBR procedures. NPWT – negative pressure wound therapy. Ex-fix – external fixation of fractures. AKA – above knee amputation. BKA – below knee amputation. SSG – split skin graft. FWB – full weight bearing.


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Acute compartment syndrome, subsequent myoneural fibrosis, joint stiffness and contractures, chronic infection, including osteomyelitis, chronic pain syndromes and limb loss are common potential complications [2123]. Patients should undergo primary surgery as soon as they are hemodynamically stable after initial resuscitation. Badly mangled non-viable limbs should be amputated immediately. Mass casualty situations and limited medical resources may preclude reconstruction of still viable but badly damaged and ischemic limbs. The surgeon will ultimately tailor the operation to the resources available and familiarity with orthopedic fixation, but, treatment should, ideally, consist of the following steps (see Figure 2):  

 





Transfer the patient to the Operating Theatre as soon as possible; Proceed with wound lavage and debridement of all devascularized muscle, skin, fascia, subcutaneous tissue, fat, and bone. Remove all foreign material; Extend wounds to identify all areas of devitalized tissue; Perform fasciotomy in patients with vascular trauma or undergoing vascular reperfusion procedures, in patients with acute compartment syndrome and in patients where compartment syndrome is anticipated; Dislocations and severely displaced fractures of the foot and ankle should be reduced and fixed using minimally invasive fracture stabilization techniques (pinning or spanning external fixation). Avoid additional unnecessary soft tissue damage during reduction and fixation. Stabilization methods should allow access to wounds for assessment and dressing (Figure 3); Minimally invasive tubular external fixation frames (Figure 4) should be used for rapid, effective primary fracture stabilization, avoiding











additional trauma and devascularization of the injured limb, and facilitating transfer of the patient. Trans-articular bridging in patients with intra- and periarticular fractures, or in patients with extensive soft tissue damage around joints is an effective damage control technique; [24] Leave the wound open initially with a bulky absorptive dressing that does not constrict blood supply to the limb. In austere environments, ICRC practice is to perform an initial thorough debridement and lavage, apply a bulky absorptive dressing and leave the wound untouched until the patient returns for delayed primary closure (most often 5 days later). Provided that the first debridement was radical, delayed primary closure of the wound is usually possible at 5 days and repeated debridement is not required in most patients. Although external fixation and attempts at limb reconstruction in austere environments are possible, these environments do not permit a course of limb salvage and inevitably, the incidence of amputation for direct landmine limb injury is close to 100% in these circumstances [25, 26]; Peripheral nerve blocks provide reliable post-operative pain relief, support early mobilization and reduce the need for opiate analgesia; Topical negative pressure wound management is useful where there is tissue loss and in limb salvage; [27,29] Serial debridement and irrigation remain the practice in military and wellresourced civilian medical centers, [30] and should be continued every 24-72 hours, in an effort to establish a clean and stable wound bed for subsequent skin graft and limb reconstruction; Continue antibiotics for at least 72 hours and check microbiological culture and sensitivities;

159

Editorial 







Large bone defects may be temporarily filled with antibiotic laden cement spacers; Early plastic reconstruction to cover exposed bone ends and neurovascular structures may be not be possible if the patient’s general condition remains unstable or if local tissues remain friable. Acute temporary malposition (limb shortening or shortening with angulation (Figure 3) may minimize tissue defects without the need for complex plastic procedures. Final realignment and elongation should begin only after soft tissue healing overlying the fracture; Bilateral lower limb injury with loss of one limb is relatively common in mine injury. Late elongation of the salvaged leg may be avoided through appropriate fitting of a prosthesis and length compensation on the contra-lateral side; Three-dimensional circular external fixation frames provide sufficient stability to permit early functional





loading, including full weight bearing, even for patients with bilateral lower limbs injuries. These ring frames also serve to prevent pressure to the posterior aspect of the limbs (reducing the incidence of pressure necrosis) and facilitating the management of circumferential wounds (see Figure 3); In the case of unsalvageable limbs or post-traumatic limb loss: the level of amputation should be considered carefully as increased energy requirements for mobilization may cause patients to discontinue efforts at walking in spite of good prostheses. Every attempt should, therefore, be made to preserve the knee joint. While no specific reference exists regarding the likely outcome of severe, closed, mid foot, and/or hind foot fractures, overall function is usually poor. A stiff, painless ankle and foot may act as a biological prosthesis, but if severe pain prevents walking, ankle and/or subtalar arthrodesis is indicated.

ED – Emergency Department OR – Operating Room CTA – Computer Tomography Angiogram NWPT – Negative Pressure Wound Therapy Figure 2. Schematic of Management of Mine Injuries

160


(A)

(B)

(C)

Figure 3. Extensive foot destruction after mine blast injury. (A) Radiological image demonstrating multiple foot fractures and dislocations with bone loss; (B) Massive wound irrigation in the Operating Theatre; (C) Post-operative radiological image demonstrates re-alignment and primary skeletal stabilization using thin wires and tubular external fixation frame.

(A)

(B)

(C)

Figure 4. A 15 year old girl suffered a mine blast resulting in bilateral lower limb injury – traumatic right above knee amputation and open left tibial fracture with extensive bone and soft tissue loss. (A) Clinical picture demonstrates primary skeletal stabilization of the left leg using unilateral external fixation frame after debridement and acute limb shortening (damage control procedure); (B) Two weeks later conversion to three-dimensional Ilizarov frame; (C) Four weeks after injury – prosthetic fitting to right lower limb, early walking with full weight bearing to both lower limbs.

Editorial

Post-Operative Recovery, Rehabilitation and Early Mobilization Salvaged limbs: An established rehabilitation protocol is key in the postoperative period, especially after peri-articular reconstruction. Rehabilitation should take place within a supportive environment and take into account other physical injuries and psychosocial trauma. Physiotherapy should begin immediately, and include muscle strengthening exercises, and active and passive mobilization of injured joints, including the joints above and below the injury, especially the hand and fingers. Active mobilization of the injured limb should commence as soon as soft tissue cover, a priority, is achieved [31]. The circular Ilizarov fixator aids early mobilization through threedimensional fracture stability, stabilization of multiple bone fragments, controlled axial micromotion, and early joint movement of intraarticular fractures. Accurately placed hinges allow early controlled motion. Controlled loading of a healing fracture stimulates callus formation and remodeling, and accelerates the restoration of bone strength [32, 33]. The stability of fixation in the hybrid or circular Ilizarov frames is sufficient in bilateral lower limb injuries to allow weight bearing with crutches. In the treatment of patients with more distal fractures, in whom rigid fixation of the foot in the external fixation frame is required, partial weight bearing may be achieved by attaching a thick elastic sole to the external fixation ring. After the healing of soft tissue wounds patients may be discharged and return on an outpatient basis for long term rehabilitation therapy including gradual realignment of bone fragments or elongation procedures. Amputated limbs: In spite of efforts at limb salvage, in a cohort of patients, amputation remains a reality of limb injury from landmines. Where there is limb loss, early fitting of prostheses is crucial. Prostheses should be fitted as soon as the amputation wound is healed. Both physical and mental adjustment to the prosthesis

161

is necessary in the immediate post-operative period and through longer-term rehabilitation and support. Early weight bearing and ambulation prevents deterioration of postural reflexes and permits shaping of the stump for definitive prosthetic fitting [34].

Discussion Limb Salvage and Limb Loss In the case series described above, 10 of 13 patients (77%) suffered limb loss. A study in Iraq reported that 72% of patients required amputations after landmine injury (58.6% lower limb and 13.3% upper limb). [6] In Afghanistan, the most densely mined nation in the world, 47.5% of the survivors suffered traumatic limb amputations [3]. In Greece, mortality due to landmines between the years 1998 and 2003 was 52.5%, and amputation among survivors occurred in 37% [35]. Thus, where limb salvage is compromised by sepsis, amputation should be performed promptly and not be regarded as a failure.

Rehabilitation as a Priority The Syrian casualties treated in Ziv Medical Center undergo a period of physical and occupational therapy with early mobilization and prosthetic fitting. Physical and psychosocial rehabilitation must be appropriate to the environment of the patient, and support must be available long after the physical injuries have healed. One patient learning to use toilet facilities in the hospital after amputation had never previously had access to indoor plumping. What support is available within Syria is difficult to ascertain, and amplifies the need to become mobile, independent and confident early. It is obvious that in their anxiety to return to Syria, some patients opted for amputation rather than staged care with limb salvage that patients tried to mobilize on painful stumps, and that addressing their psychosocial needs within

162


the hospital environment through social workers, psychiatrists and even medical clowns was only partially beneficial. Children who suffered amputation or blindness as a result of blast injury insisted on returning to their families rather than prolonging their separation in favor of further rehabilitation. There is no question that rehabilitation must proceed in an environment where patients feel the least anxiety. This may explain why, in Israel, longterm rehabilitation almost always takes place at home [36]. The ICRC describes physical rehabilitation in terms of the provision of prostheses, orthoses, wheel chairs, walking aids and ongoing therapy so that patients with disabilities may remain active and become financially reintegrated and participative within society - maintaining the highest level of independence and quality of life. Real support, in terms of mobility assistance, but, crucially, also in terms of the development of infrastructure, well after the physical wounds have healed is, therefore, a concern. Since 1979, the ICRC rehabilitation unit has supported over 180 projects in 48 countries. [37] Their physical rehabilitation program incorporates four activities towards long term rehabilitation needs: improving accessibility, enhancing quality in multi-disciplinary management; ensuring sustainability and strengthening capacity in local environments; and, promoting full-inclusion and participation within society. Deepening the commitment of local governments to patients with disabilities in observance of the UN Convention on the Rights of People with Disabilities remains important [7].

Reintegration into Society Reintegration into society remains an enormous challenge. Anxiety, depression, and post-traumatic stress disorder (PTSD) are common and influence quality of life, resumption of normal activity, and the perception of pain. [38-41]. Amongst survivors in Sri Lanka, 80% suffered from anxiety, 73% from depression, and 72% from PTSD. [42]

Patients in Cambodia reported anxiety in 62%, depression in 74%, and PTSD in 34% [43]. In Laos and Iran, 82% and 69% of survivors, respectively, reported anxiety or depression [40] - with symptoms more common amongst patients who were older, more recently injured, and who underwent amputation. Self-care, mobility, and return to work are particularly difficult after upper limb amputation. [40]. In Sri Lanka 50% of patients lost their earning capacity after upper limb amputation. [42] Women may be abandoned by their husbands or be unable to marry [44]. Sixty percent of injured women in Sri Lanka remained unmarried [42]. Under Taliban law when a man is killed or disabled, his wife is forbidden to work [45]. The effects of stigmatization, abandonment by family, loss of a meaningful role in society, and loss of earning potential are harder to cope with in conflict zones. Long-term rehabilitation teams in conflict zones have few professionals available and few resources to support them [46] - most people in need of rehabilitation services do not receive adequate care [47]. According to the World Health Organization, 80% of people with disabilities live in low-income countries, and fewer than 2% of the injured are able to access rehabilitation services. [41] In 2005 there were 24 prosthetic and orthotic schools in developing countries, graduating 400 practitioners a year. The World Health Organization recommends that this number should be significantly increased in order to meet community needs [48]. Amongst the patients in the case series presented above, there was no mortality, but the presumption is that patients with lethal injuries in Syria did not survive the journey to definitive care. The Gertner Trauma Registry has no record of the number of people fatally injured at the scene of mine explosions. As the institute was established in 1997, data prior to this date are not within the registry and substantiated comment about prior incidence of landmine injuries and disability is not possible. In spite of this, however, our epidemiological and clinical findings contribute to a universal understanding of the scale of the problem, the clinical

Editorial challenges in the management of complex, disabling injuries and the need for quality rehabilitation services. Resources must be available for long-term care and reintegration into society.

[3]

[4]

Conclusion Landmines injuries are a global problem. Landmines remain problematic in both conflict and post-conflict environments. Crucial to the protection of civilians is the identification, marking and dismantling of minefields. Priority should be given for the management of patients with landmine injuries in units where there is expertise in limb salvage. Patients suffering amputation need support in early mobilization and rehabilitation. The psychosocial morbidity of disability associated with the inability to return to school or work, and a dependence on others must be addressed in effective rehabilitation programs. The analysis of outcomes for landmine injury survivors is essential to determining the adequacy of injury prevention measures, access to high quality healthcare resources, and the identification of subpopulations especially vulnerable to injury, poor outcomes and in need of lifelong support.

[5]

Acknowledgments

[11]

The authors wish to thank Dr. Amram Hadary, Mr. David Fuchs, Mrs. Shlomit Dahan and Mrs Merav Kadosh for their assistance in sourcing data at Ziv Medical Center, Sefad, Israel.

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Scientific Papers



Cognitive-Motor Integration in Normal Aging and Preclinical Alzheimer’s Disease: Neural Correlates and Early Detection Kara M. Hawkins*

SECTION I

Toronto Rehabilitation Institute, UHN Toronto, ON, Canada

Abstract

*

Correspondence: Toronto Rehabilitation Institute, UHN, 550 University Ave., Toronto, ON, Canada. Email: [email protected]

The objectives of these studies were to characterize how the ability to integrate cognition into action is disrupted by both normal and pathological aging, to evaluate the effectiveness of kinematic measures in discriminating between individuals who are and are not at increased Alzheimer’s disease (AD) risk, and to examine the structural and functional neural correlates of cognitive-motor impairment in individuals at increased AD risk. The underlying hypothesis, based on previous research, is that measuring visuomotor integration under conditions that place demands on visual-spatial and cognitivemotor processing may provide an effective al means for the early detection of brain alterations associated with AD risk. To this end, the first study involved testing participants both with and without AD risk factors on visuomotor tasks using a dualtouchscreen tablet. Comparisons between high AD risk participants (n = 22; mean age = 67.7 +/- 11.3) and both young (n = 22; mean age = 26.4 +/- 4.1) and old (n = 22 mean age = 64.3 +/- 10.1) healthy control groups revealed significant performance disruptions in at-risk participants in the most cognitively demanding task. Furthermore, a stepwise discriminant analysis was able to distinguish between high and low AD risk participants with a classification accuracy of 86.4% (sensitivity: 81.8%, specificity: 90.9%). Based on the prediction that the impairments observed in high AD risk participants reflect disruption to the intricate reciprocal communication between

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hippocampal, parietal, and frontal brain regions required to successfully prepare and update complex reaching movements, the second and third studies were designed to examine the underlying structural and functional connectivity associated with cognitive-motor performance. Young adult (n = 10; mean age = 26.6 +/- 2.7), and both low AD risk (n = 10; mean age = 58.7 +/- 5.6) and high AD risk (n = 10; mean age = 58.5+/-6.9) older adult participants underwent anatomical, diffusion-weighted, and resting-state functional connectivity scans. These data revealed significant age-related declines in white matter integrity that were more pronounced in the high AD risk group. Decreased functional connectivity in the default mode network (DMN) was also found in high AD risk participants. Furthermore, measures of white matter integrity and restingstate functional connectivity with DMN seedregions were significantly correlated with task performance. These data support our hypothesis that disease-related disruptions in visuomotor control are associated with identifiable brain alterations, and thus all assessments incorporating both cognition and action together may be useful in identifying individuals at increased AD risk. Keywords: Alzheimer’s disease, Visual-spatial processing, Cognitive-motor interaction, Functional connectivity This work was supported by a Canadian Institutes of Health Research Banting and Best Canadian Graduate Scholarship, Institute of Aging Special Recognition Award, and Ontario Women’s Health Scholars Award. © Kara Hawkins, 2015

Introduction The underlying theory guiding this work is that different types of visuomotor compatibility are processed in separate, but overlapping, parietofrontal networks, and that these separate networks are affected differently in healthy aging versus disease. Generally when reaching for an object in the environment the visual stimulus and its required motor action are in alignment. However, the evolution of the

capacity for tool-use in primates has resulted in situations where the correspondence between vision and action is not direct. A common example is the use of a computer mouse to move a cursor on a monitor, which involves a decoupling, or dissociation, between the spatial location of the visual target and the spatial location of the movement goal. Such learned sensory- and/or cognitive-motor transformations underlie much of our everyday activities (including driving), yet the basic cortical mechanisms responsible for these s remain unknown. Following damage to the cerebral cortex (e.g., neurodegeneration, stroke, traumatic brain injury), these complex visuomotor transformations may become impaired, and, in turn, the pattern of impairment may provide insight into the underlying neural mechanisms involved in this. The research projects presented here were designed to 1) characterize how the ability to integrate cognition into action is disrupted by Alzheimer’s disease (AD) in its early stages, 2) to determine the predictive potential of kinematic measures in discriminating between high and low AD risk older adults, and 3) to examine the structural and functional neural correlates of cognitive-motor integration in healthy aging and preclinical AD. While the ability to directly interact with objects does not appear to be impaired in early AD relative to healthy aging, performance decrements have been observed when patients perform motor control tasks under conditions in which direct visual feedback is not provided [1– 6]. It has been suggested that these disruptions may result from functional (i.e., hypometabolism / hypoperfusion) and structural (i.e., grey matter atrophy) alterations in posterior parietal association areas, which have been documented in preclinical AD [7,8]. We further suggest that impairment in cognitive-motor integration may reflect early brain alterations disrupting the intricate reciprocal communication between hippocampal, parietal and frontal brain regions involved in successfully preparing, executing, and updating complex reaching s. In support of this prediction, recent diffusion tensor imaging (DTI) studies in mild cognitive impairment

Cognitive-Motor Integration in Normal Aging and Preclinical Alzheimer’s Disease (MCI) and AD have revealed disruption to the integrity of prominent parietal-frontal white matter tracts [9], as well as projections from the hippocampus to the inferior parietal cortex [10]. Ultimately, the projects described here are designed to demonstrate that using kinematic measures to evaluate cognitive - motor performance in older adults may provide a novel, simplified, and objective al means through which to detect underlying brain alterations associated with increased AD risk.

Visuomotor compatibility and visuallyguided movements Most reaching movements performed in daily life are referred to as standard visuomotor transformations. In this type of reach, the eyes are directed towards an object of interest and the hand moves to the same location in space as that acquired by the eyes. Many of the movements that we learn to perform, however, require nonstandard visuomotor transformations, in which the motor system must integrate some form of cognitive information (e.g., visual-spatial, memory, rule-based, semantic) into the motor program. In a non-standard transformation the end effector must move to a spatial location that is not directly aligned with the location of the visual target. Two forms of non-standard transformational mapping have been described in the literature [11]. The first form is referred to as a sensorimotor recalibration or spatial realignment. One situation in which this form of transformation is required is when the physical location of the visual stimulus is in a different plane relative to the movement required by the limb (e.g., moving a computer mouse or laparoscopic surgery). In this situation both vision and proprioception must be used to remap the visual location of the target and representation of the hand in one plane, onto the true location of the hand and target in the other plane [12–14]. Furthermore, in order to sustain the motor plan throughout the course of the movement, the current position of the actual hand relative to the actual reach target (both of which the eyes are not looking at) must be

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continuously updated. The second form is called strategic control; this occurs when a cognitive strategy is used to realign the required limb movement relative to the spatial location of the target [15,16]. For example, strategic control is required for anti-reaching tasks in which participants are asked to move in the opposite direction of a visual target, which is similar to incorporating the rule that moving a rudder to the left will move a boat to the right.

Parietofrontal networks for sensorimotor transformations In order to reach accurately for an object one must transform sensory signals into a complex pattern of muscle activity, a process known as sensorimotor transformation. The neurological computations underlying this seemingly straightforward task are not yet completely understood. Reaching movements to visual targets rely on sensory information that is initially represented in retinocentric or eyecentered coordinates (i.e., the location of the target in space is internally represented in the brain using its position on the retina; [17]). In order to specify the kinematics and kinetics of the motor program, the retinocentric signal must be transformed into motor coordinates imposed by the joints and muscles of the arm. The cortical control of reaching movements has been described as a sequence of coordinate transformations from retinocentric, to headcentered, then to body-, or shoulder-, centered coordinates by combining sensory signals in a serial manner, and comparing each with the body-centered location of the arm [18]. Numerous cortical areas appear to combine visual, proprioceptive, attentional, and biomechanical information. In particular, interconnected neuronal populations from parietal, premotor, and primary motor areas perform transformations from extrinsic spatial representations to intrinsic joint and muscle representations necessary for the generation of an accurate motor output [19–28]. Much current research seeks to characterize the role of different frontoparietal networks in

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sensory-guided reaching, with an emphasis on the connectivity between these areas. However, there has been relatively little research on the neurophysiology of cognitive-motor integration, where rules dictate the relationship between perception and action [29–31]. Studies suggest that both superior and inferior parietal lobules (SPL, IPL) are involved in the early processing of sensory input for movement guidance. Neurons in the posterior parietal cortex discharge in response to both sensation and movement, and are thus considered crucial in the transformation of visual information needed for motor s [32–34]. Further, cell activity in SPL, IPL, and the parietal-occipital junction is affected by attention, gaze, and tool use [20, 35– 49], which are all relevant to cognitive-motor integration. While the contribution of postcentral cortical areas to rule-based nonstandard sensorimotor mapping is an open area of research, it is well known that higher cognitive functions are related to activity in frontal areas. Many studies have examined the degree to which cell activity in different frontal lobe regions covaries with the attributes of sensory input, motor output, and their various integrated combinations [50–55]. These characteristics of cells in parietal and frontal regions suggest relevance to the processing of visual input and the planning of limb movements requiring the integration of task-specific rules. Previous neurophysiological research in our lab has specifically examined the involvement of parietal and premotor regions, at the single cell and cell assembly (local field potential - LFP) levels, during performance of standard relative to non-standard visuomotor transformation tasks [56–58]. The tasks used in these studies were similar to the dual touchscreen cognitive-motor assessment tasks developed for the aging and AD work described herein. Using single cell recordings in the SPL of rhesus macaque monkeys, we found a temporal activation profile supporting the role of the SPL in visually-guided reach planning and online monitoring, as well as significant differences in cell activation profiles during standard relative to non-standard task performance [56]. These findings were taken to

suggest that the SPL is involved in processing the non-standard nature of a motor task and contributes to the reciprocal parietal-frontal communication required to accurately transform incongruent sensory inputs into an appropriate motor action. Further support for the involvement of the SPL in non-standard visuomotor transformations was also found when analyzing LFPs within this region [58]. Specifically, the onset of coordinated cell assembly oscillations within the beta range (1020 Hz) occurred later in the planning phase of a non-standard relative to standard task. Furthermore, upon movement initiation, oscillations within both the low frequency (5-10 Hz) and gamma (30-40 Hz) ranges dominated during non-standard but not standard task performance. These results were interpreted as reflecting a delay in top-down control over movement planning and increased reliance on proprioceptive inputs and online control mechanisms during non-standard reaching. Single cell and LFP recordings within the dorsal premotor cortex also revealed task-related differences in neural activation, including greater involvement of the rostral portion of the dorsal premotor cortex during rule integration and greater involvement of the caudal portion of the dorsal premotor cortex during online updating when performing a non-standard reaching task [57]. These fundamental studies have provided novel insight into our understanding of how the brain transforms visual information into an accurate motor output, specifically under conditions in which the correspondence between vision and action is not direct. Not only is this research relevant to the development of brain machine interfaces, it also supports the notion that manipulating visuomotor compatibility results in differential activation within parietofrontal visuomotor networks. Furthermore, these findings have laid the foundation for our applied work, leading to the development of the hypothesis that the parieto-frontal networks underlying cognitive-motor integration are affected differently in healthy aging versus AD.

Cognitive-Motor Integration in Normal Aging and Preclinical Alzheimer’s Disease

The Effects of Healthy Aging on Sensorimotor Control Changes in sensorimotor control with age have been well documented and involve alterations in both upper and lower limb function. Declines with age often include increased variability, as well as slower reaction and movement times [59–61], irregular visually guided reach trajectories [62], and decreased postural stability and locomotor function [63,64]. Such well-established age-related psychomotor slowing also contributes to less efficient movement planning [65–67] and online updating [68]. Studies examining the control of arm movements in older adults demonstrate increased reliance on visual feedback, which is often interpreted as compensation for deficiencies in central motor planning [65– 67,69]. For example, Haaland et al. [65] examined aiming movements with and without visual feedback in young and elderly adults. In doing so, they found that as target distance (i.e., movement amplitude) and size increased, older adults did not scale the velocity and distance of their initial movement to the same magnitude as young adults. Older adults were also less accurate at the end of the deceleration phase of the initial movement. Furthermore, older adults demonstrated larger increases in absolute error with increasing target distance in the non-visual condition. Based on these results, the authors suggest that the movement plans of older adults may be imprecise or incomplete, especially when movements are longer, thus resulting in increased reliance on visual feedback. On the other hand, some studies have also demonstrated that online corrective mechanisms may be less efficient in older individuals [68,70]. For example, Sarlegna [70] compared the use of visual feedback regarding target position for the online correction of movement trajectories between young and older adults. Targets were either stationary or displaced at movement onset (so-called “double-step” paradigm), thus requiring efficient use of online visual feedback to adjust movement trajectories

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during trials in which target displacement occurred. Older adults displayed significantly later and less accurate trajectory corrections compared to young adults on target-jump trials. The authors suggest that the efficient use of visual information (either perceived, or not – e.g., when target jumps occur during saccadic suppression) for large online corrections, such as those required in a double-step task, likely involves the posterior parietal cortex (PPC). Evidence for the role of PPC in online updating comes from studies in which PPC activity is disrupted through transcranial magnetic stimulation (TMS) or lesion. Both of these manipulations result in impairment to the trajectory corrections normally observed during visual target displacement tasks [71,72]. Thus, age-related declines in information processing speed, particularly in posterior parietal regions responsible for the integration of somatosensory information into movements [73–76], may result in delayed online updating in older individuals. Similar age-related changes as those involved in the planning and online correction of arm movements have also been observed in the planning and guidance of foot placement during locomotion. Specifically, when stepping over obstacles or onto targets, older individuals fixate the target earlier and longer than young individuals before initiating their step [77–79]. Thus, there appears to be a common age-related increase in the reliance on visual information for both upper and lower limb motor control. To examine the use of vision by young and older adults during locomotion, Chapman and Hollands [78] experimentally controlled for the availability of visual information during the stance and swing phases of the step cycle. In this study, the authors demonstrated that older participants exhibit significantly larger foot placement errors when vision is unavailable during both the stance and swing phases, while young adults are not affected by the visual manipulations. These results were taken to suggest that older adults have a reduced ability to efficiently use vision for feed-forward planning during locomotion.

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The complex inter-limb coordination patterns required for locomotion have also been examined in older adults [80,81]. Using cyclical flexion-extension movements of the right wrist and ankle, that were either isodirectional (both limb segments moved in the same direction) or non-isodirectional (both segments moved in opposite directions), Heuninckx et al. [80] have demonstrated that coordination performance is less stable in older adults, even after correcting for task difficulty by slowing the cycling frequency. Using functional magnetic resonance imaging (fMRI), these authors have also shown that in both isodirectional and non-isodirectional coordination tasks elderly participants exhibit additional activation of brain areas involved in sensory processing and integration (including the supramarginal gyrus, secondary somatosensory area, precuneus, frontal operculum, and anterior insula), as well as cognitive monitoring of motor performance (including the pre-supplementary motor area, pre-dorsal motor areas, prefrontal cortex and rostral cingulate). Furthermore, during the more complex non-isodirectional task, elderly participants exhibited additional activation of brain regions known to be involved in inhibitory control and the suppression of prepotent responses (i.e., the anterior rostral cingulate and the dorsolateral prefrontal cortex). These results, along with the finding that increased activation is associated with improved performance in the elderly [81], suggest that additional recruitment in the aging brain is compensatory in nature. In other words, enhanced attentional deployment and cognitive monitoring may reconcile agerelated deficits in more automatic sensorimotor processing [82].

Visuomotor Deficits in Alzheimer’s Disease and Lesion Studies Although AD is most commonly associated with memory and other cognitive impairments, deficits in purposeful movements (i.e., apraxia) have been identified later in the course of the disease [83]. Furthermore, recent studies have

demonstrated subtle deteriorations in the performance of non-standard sensorimotor transformation tasks in early AD [1–6]. These studies have shown increases in reaction time, movement time, and task performance errors in AD patients compared to age-match controls when they are required to perform reaching tasks that do not allow for continuous visual monitoring of the hand. Standard reaches, on the other hand, do not show impairment in patient groups [4]. The authors of these studies suggest that structural degradation of parietal and prefrontal areas, as well as the cortico-cortical connections between them [2, 84], may be responsible for the observed impairments in nonstandard visuomotor transformations. Ghilardi and colleagues [1] suggest that the increased movement times and fragmented velocity profiles observed in their study indicate a strong reliance on continuous visual monitoring of the moving hand in AD patients. Furthermore, better accuracy in initial movement direction, relative to end point accuracy, suggests that these patients can generate a motor plan, but are unable to sustain the motor plan throughout the course of the movement. In other words, the internal feedback loop required to update the current location of the hand relative to the position of the target, which relies on intact parietal-frontal connections, may be disrupted in these patients. Based on the observation that hypoperfusion of parietal areas correlates with clinical evidence of apraxia in AD patients [85], it has also been suggested that visuomotor transformation deficits observed in early AD may reflect early deterioration of the neural networks involved in praxic functions. Although clinically obvious apraxia is often not present until the later stages of AD, subtle apraxic deficits have been observed early in the disease process, and may actually be an early feature of the disease [86–91]. Research into the neural basis of praxic function suggests an important role for inferior parietal-frontal regions. A recent lesion subtraction analysis compared left braindamaged patients with impaired purposeful limb movements (i.e., ideomotor limb apraxia), to left

Cognitive-Motor Integration in Normal Aging and Preclinical Alzheimer’s Disease brain-damaged patients without these impairments [92]. The results suggested that limb apraxia is associated with lesions to the inferior parietal cortex, as well as the inferior frontral gyrus extending into ventral premotor cortex (PMv) (i.e., an inferior parietal-frontal network). Lesion studies by Buxbaum and colleagues [93–95] have presented similar findings. These studies have demonstrated that left hemisphere patients who exhibit apraxic deficits (such as abnormal hand posture responses to meaningful objects/tools, impaired object recognition, and/or impaired functional hand-object interactions) present with lesions including Brodmann areas (BA) 39 and/or 40 (i.e., angular and supramarginal gyri of the IPL), whereas lesions in patients who do not exhibit apraxia rarely include inferior parietal regions. Based on these findings, Buxbaum et al. [95] have suggested that the IPL maps between representations of object identity processed by the ventral stream (i.e., in the nearby temporal lobe) and spatial representations of the body processed by the dorsal stream (i.e., in the nearby SPL), thus allowing for the integration of object-based knowledge and action representations, which can then be transformed into a motor program by premotor cortex. Interestingly, Buxbaum et al. [93] have also demonstrated that apraxic patients are able to perform normally at recognizing appropriate hand postures for interacting with novel objects. Thus, these authors have suggested that intact superior parietal-frontal pathways concerned with spatial-to-motor computations that do not require access to stored representations may mediate motor responses to novel objects. It has been suggested that these superior networks may be mainly responsible for processing more rapid, online visuomotor transformations [96]. Accordingly, damage to superior parietal areas results in a different neurological impairment known as optic ataxia. Optic ataxia is defined as a disorder affecting the accuracy and co-ordination of rapidly executed reaching and grasping movements under visual control, especially when the target object is in peripheral vision

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[43]. This disorder is not related to visual acuity or motor execution deficits, that is, patients can perceive objects and produce movements, but they exhibit difficulty formulating accurate visually guided limb trajectories. Using a lesion subtraction method, Karnath and Perenin [43] compared a group of patients who sustained parietal damage and exhibited optic ataxia, with a group of patients who sustained similar parietal damage, but did not exhibit optic ataxia. Their lesion overlap findings revealed that optic ataxia appears to be associated with lesions close to the parieto-occipital junction, centering on the precuneus at the medial cortical aspect of the hemisphere. These patient studies illustrate the important role of the posterior parietal cortex in visuomotor control, and support the notion of two functionally distinct parietal-frontal streams [97]: the so-called “dorsal-dorsal” stream responsible for the online control of motor actions, and the so-called “ventral-dorsal” stream subserving space perception, action organization and action understanding. When lesions are relatively isolated to one stream or the other they result in the ideomotor apraxia/optic ataxia dichotomy described above. The visuomotor deficits observed in early AD, however, are less well understood. Recently, studies using brain-imaging techniques to examine the functional and structural changes associated with AD (see section on neural correlates of preclinical and prodromal Alzheimer’s disease below) have provided some insight into this. Specifically, these studies have demonstrated that along with structural hippocampal atrophy, compromised parietalfrontal and cingulum bundle white matter tracts, as well as posterior parietal hypometabolism/hypoperfusion and reduced resting-state functional connectivity in early AD may lead to disruption in hippocampal-parietal and parietal-frontal visuospatial and visuomotor networks. In other words, disconnection across cortical regions, as oppose to isolated atrophy within specific brain regions, may underlie the observed visuomotor deficits in early AD.

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Typical Clinical Manifestation of Alzheimer’s Disease and Biomarkers for Early Detection The major neuropathological changes associated with AD have been identified (i.e., amyloid-beta accumulation and neurofibrillary tangles), however the underlying cause is largely unknown. Typically, the initial clinical manifestation of AD dementia involves shortterm memory deficits, which eventually progress and are accompanied by more global and pronounced cognitive impairments. A diagnosis of probable AD involves several steps to rule out other potential causes of dementia, including evaluation of mental status, medical history, clinical examination, and laboratory tests. While AD is the most common cause of dementia (5060% of cases), there are many other disorders that can simulate or cause dementia, some of which are responsive to treatment (e.g., depression, medication-induced dementia and nutritional / metabolic / endocrine / systemic disorders, such as hypothyroidism, B12 deficiency and systemic infections). Dementia is defined as a syndrome that is characterized by multiple cognitive deficits including memory impairment and at least one other cognitive disturbance, such as impaired executive function, aphasia, agnosia or apraxia. Activities of daily living (e.g., social and occupational function) are also impaired (Diagnostic and Statistical Manual of Mental Disorders IV – DSM-IV; American Psychiatric Association). Other causes of dementia include vascular dementia (approximately 20% of cases), hydrocephalus, tumors, and hematoma [98]. The National Institute of Neurological and communicative Disorders and Stroke and Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria for diagnosis of probable AD includes: 1) Dementia established by objective testing, 2) deficits in two or more cognitive areas, 3) progressive worsening of memory and other cognitive functions, 4) no disturbance in consciousness, 5) onset between ages 40 and 90 and 6) absence of other brain diseases or systemic disorders that

could account for the deficits in memory and cognition [99]. Cases that involve atypical cognitive symptoms and progression are often referred to specialists for assessment and may result in diagnosis of a rarer neurodegenerative diseases such as frontotemporal lobar dementia, corticobasal degeneration, dementia with Lewy bodies or progressive supranuclear palsy. Importantly, by the time the manifestation of AD is ally observable, significant damage to the brain is already present and is likely irreversible [100], with a reported hippocampal volume loss of approximately 20% at the mild stages of AD dementia [101]. Thus, in order to develop effective treatments that may terminate or slow the neurodegenerative process, early detection prior to the onset of symptoms is essential. Recent structural and functional neuroimaging studies in cognitively healthy older adults at increased genetic risk for AD and in those diagnosed with MCI offer promising evidence for the potential value of brain imaging biomarkers in the early detection of AD pathology. In recent years, apolipoprotein E epsilon 4 (ApoE4) genotyping (a genetic risk factor for sporadic AD), amyloid-beta (Aβ) imaging and neuropsychological tests of subtle cognitive (generally episodic/working memory) changes have been used to identify individuals at increased risk for AD [100]. ApoE is a cholesterol carrying lipoprotein that supports injury repair and lipid transport in the brain. For lipid delivery, ApoE binds to cell-surface receptors, including Aβ peptides. The regulation of Aβ aggregation and clearance in the brain depends on the APOE isoform. Specifically, the ApoE4 allele has been associated with late-onset AD, amyloid deposits in the walls of cerebral blood vessels and cognitive decline in normal aging [102]. Aβ imaging involves measuring the level of amyloid deposition in the brain using Clabeled Pittsburgh Compound-B (PiB), a radiotracer that binds to Aβ, in positron emission tomography (PET) scans. A high level of PiB binding in cognitively healthy individuals is associated with increase AD risk and future declines in episodic and working memory [103].

Cognitive-Motor Integration in Normal Aging and Preclinical Alzheimer’s Disease MCI involves a clinical diagnosis of subtle cognitive changes (often involving episodic memory impairment). The clinical criteria for MCI includes a decline in memory (amnestic MCI) or other cognitive domains (non-amnestic MCI), as well as subjective cognitive complaints corroborated by a relative, however social functioning and instrumental activities of daily living remain intact [104]. Individuals who meet the diagnostic criteria for MCI (especially amnestic MCI) are at increased risk of progressing to AD dementia [105]. By comparing neuroimaging measures in preclinical (i.e., no cognitive symptoms, but at increased risk due to ApoE4 genotype, family history and/or high Aβ deposition) and prodromal (i.e., MCI) groups relative to cognitively healthy lowrisk groups, recent studies have provided important insight into early brain changes that may prove useful as biomarkers for the early detection of AD pathology and the prediction of dementia before the onset of clinical symptoms.

Neural Correlates of Preclinical and Prodromal Alzheimer’s Disease Over the past several years many brainimaging studies have investigated the neural underpinnings of AD. In 2009, a meta-analysis of these studies revealed that, aside from the commonly known structural atrophy in transentorhinal and hippocampal regions, hypometabolism and hypoperfusion in the IPL and precuneus (i.e., medial SPL) are also prevalent features of early AD [8]. Furthermore, functional alterations in the left IPL and precuneus (BA 7/31/39/40) distinguished between MCI converters and non-converters [8]. Disruption to these brain regions, which have been shown to be involved in visuo-spatial processing and spatially guided [106], may underlie the early visuomotor impairments observed in AD. It has been suggested that these parietal alterations may be caused by regional amyloid deposits [84, 107–109] and/or hippocampal-parietal disconnection (diaschisis

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hypothesis) via disruption of the cingulum bundle [10]. Villain and colleagues [10] found support for the diaschisis hypothesis using whole-brain voxel-based correlations to assess the relationships between hippocampal atrophy, white matter integrity, and grey matter metabolism. Their results revealed that hippocampal atrophy is specifically related to cingulum bundle disruption, which is in turn highly correlated with hypometabolism of the posterior cingulate cortex, middle cingulate gyrus, thalamus, mammillary bodies, parahippocampal gyrus, and right temporoparietal association cortex. With regards to visuomotor control, inputs from hippocampus to IPL likely play an important role in the integration of memory into spatial processing and the establishment of maps of extrapersonal space [110]. Many of the more recent neuroimaging studies in MCI and AD have employed DTI to examine the integrity of white matter (WM) tracts connecting various regions of the brain. Using multiple DTI measure, Bosch and colleagues [9] found that many WM changes in the brains of MCI and AD patients were secondary to grey matter atrophy. However, radial diffusivity (DR) increases independent of grey matter atrophy were observed in amnestic MCI participants in the posterior parts of the inferior fronto-occipital and longitudinal fasciculi (IFOF and ILF). These results may reflect early WM compromise (i.e., demyelination) in prodromal AD affecting the WM tracts forming parietal- and occipitalfrontal connections. Others have reported similar disruption to the integrity of association fibre tracts in early AD, generally including the IFOF, ILF, superior longitudinal fasciculus (SLF), corpus callosum (CC), and cingulum bundle (CG) [111–113]. These findings provide support for the “retrogenesis model” of AD, suggesting that WM degeneration occurs in a reverse pattern to myelogenesis. Stricker and colleagues [113] have specifically demonstrated lower fractional anisotropy (FA), reflecting impaired WM integrity, in late-myelinating but not earlymyelinating tracts in AD patients compared to

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healthy older adults. It has been suggested that, since late-differentiating oligodendrocytes ensheath many more axons and have different lipid properties, late-myelinating regions (e.g., parietal, prefrontal, temporal) may be particularly vulnerable to the myelin breakdown that occurs in aging and AD [112]. The observation of WM alterations in prodromal AD (i.e., MCI) in the above studies suggests that disruption to the integrity of association fibre tracts takes place at an early stage of disease progression [9,111]. These results are consistent with earlier studies in which PET was used to examine glucose metabolism in the brains of ApoE4 carriers over the age of 50 with AD affected relatives (114,115). These at-risk participants (i.e., with no cognitive symptoms) showed reduced parietal glucose metabolism, and follow-up assessments showed that cognitive decline after 2 years was greatest in those ApoE4 carriers with the lowest metabolism in parietal and temporal regions at baseline [116]. More recently these studies have been supported, and expanded upon, by PET and magnetic resonance imaging (MRI) studies finding that individuals with a maternal family history of AD are particularly susceptibility to glucose metabolism and grey matter volume alterations [117,118]. Compared with both no family history and paternal family history groups, participants with a maternal family history of AD were found to have reduced cerebral metabolic rate of glucose in the posterior cingulate cortex / precuneus, parietotemporal cortex, frontal cortex, and medial temporal lobe [118]. Lower grey matter volumes were also observed in AD-vulnerable brain regions, as well as progressive grey matter atrophy overtime in the precuneus and parahippocampal gyrus, in individuals with a maternal family history of AD [117]. Recent DTI studies have also found microstructural changes in cognitively normal women at increased risk of AD due to family history and carrying one or more ApoE4 allele [119,120]. The brains of these women showed decreased microstructural integrity in WM tracts with

direct and secondary connections to the medial temporal lobe (e.g., the fornix, CG, ILF and IFOF), years before the expected onset of cognitive symptoms. Several studies using resting-state functional magnetic resonance imaging (rs-fMRI) have also demonstrated reduced functional connectivity across interconnected cortical regions (including the precuneus, lateral parietal, lateral temporal, and medial prefrontal cortices), known as the default mode network (DMN), that are normally active in correlation with each other during rest [121–126]. These studies have shown that cognitively normal individuals with high amyloid burden, as well as ApoE4 carriers, exhibit significantly reduced functional connectivity within brain regions of the default network, and that these regions of reduced functional connectivity overlap strongly with regional glucose hypometabolism. Taken together, the above studies indicate that disconnection between the medial temporal lobe and neocortex, as well as between parietal and frontal regions, may occur very early in the course of AD.

Brief Overview of Projects Project 1) Visuomotor impairments in older adults at increased Alzheimer's disease risk. In this first project we asked if a new approach can be used to sensitively detect early AD. In other words, can kinematic measures provide a al means through which to identify individuals at increased AD risk? We have found, as the current neurological assessments typically find, that reaching and gross motor movements made under direct conditions (congruent gaze and object location, like reaching to pick up a cup of coffee) are not generally impaired in early AD and MCI relative to healthy aging. Significantly, however, as soon as an element of dissociation is introduced into a reaching task (e.g., the guiding visual information is dissociated from the required motor act, such as using a computer mouse), the performance of patients with early AD declines precipitously [1, 3–6]. Recent

Cognitive-Motor Integration in Normal Aging and Preclinical Alzheimer’s Disease results suggest that adults with MCI also show a decline in performance, albeit less dramatically [89]. Based on these initial findings, we hypothesized that there would be a measurable decline in the brain’s ability to integrate visualspatial and cognitive information with action in going from healthy aging, to increased genetic risk, to MCI. The objectives of this project were 1) to collect normative data from young, low AD risk, and high AD risk populations and perform between group comparisons, and 2) to determine the predictive potential of kinematic outcome measures using a discriminant analysis to separate between high and low AD risk groups. Project 2) Diffusion tensor imaging correlates of cognitive-motor decline in normal aging and increased Alzheimer’s disease risk, and project 3) Adults at increased Alzheimer’s disease risk display cognitive-motor integration impairment associated with changes in restingstate functional connectivity. The aim of these projects was to expand upon project #1 by examining the underlying structural and functional connectivity in relation to AD risk and cognitive-motor integration performance. Taken together, recent neuroimaging and motor control studies in early AD suggest that functional alterations in parietal areas associated with hippocampal-parietal and parietal-frontal disconnection may underlie early AD-associated motor control deficits. Thus, in projects 2 and 3 we propose that comparing DTI and resting-state functional connectivity measures between individuals at increased AD risk and both agematched and young healthy controls may provide insight into the very early structural and functional changes associated with AD pathology, and may correlate with disruptions observed on our cognitive-motor assessment. Specifically, we hypothesized that white matter tracts connecting posterior and anterior brain regions (e.g., SLF, ILF, IFOF), as well as projecting from hippocampal to neocortical regions (e.g., CG), and resting-state functional connectivity within the DMN would be compromised in individuals at increased genetic risk of AD, and would be associated with the

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cognitive-motor deficits observed in project 1. The objectives of these projects were 1) to compare hippocampal volume, DTI, and resting state functional connectivity measures between healthy aging and increased AD-risk populations, and 2) to correlate DTI and resting state functional connectivity measures with the kinematic measures reflecting poorer cognitivemotor performance in high AD risk relative to healthy control participants in project #1.

Summary and Knowledge Dissemination The work expands upon previous studies examining cognitive-motor integration deficits in dementia patients, and advances our understanding of the brain mechanisms underlying these deficits. Three manuscripts have been published in the Journal of Alzheimer’s disease. Our findings have also been presented at the Society for the Neural Control of Movement, the Canadian Association of Neuroscience, the Canadian Association on Gerontology, and the Society for Neuroscience annual meetings, as well as at invited talks in the community (the Integrated Partnership for Seniors North York, York Region Healthy Aging Working Group, and Southlake Regional Health Center hospital rounds). The findings described are informative for clinicians in the field (through assessment tool development), caregivers and community-based practitioners (through advancing our knowledge of the everyday functional limitations of AD patients), and neuroscientists (through description of the underlying neural correlates of). The purpose of this research is to understand how the brain’s ability to incorporate visual-spatial and cognitive information into a motor act, which is essential to our everyday function, is disrupted by early AD-related brain alterations. The clinical and fundamental projects described here also advance our understanding of how we interact with objects in nd dressing (Figure

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Kara M. Hawkins and Lauren E. Sergio

SECTION II Visuomotor Impairments in Older Adults at Increased Alzheimer’s Disease Risk Kara M. Hawkins1 and Lauren E. Sergio2 1

Toronto Rehabilitation Institute, UHN Toronto, ON, Canada 2 Graduate Program in Kinesiology and Health Science, York University, Toronto, ON, Canada

Abstract Background: Recent evidence suggests that visuomotor s may be disrupted in the very early stages of Alzheimer’s disease. Here we propose that using kinematic measures under conditions that place demands on visualspatial and cognitive-motor processing may provide an effective al means to detect subtle changes associated with Alzheimer’s disease risk. Methods: To this end, we have tested 22 young adults (mean age = 26.4 +/- 4.1), 22 older adults (mean age = 64.3 +/- 10.1) at low Alzheimer’s disease risk, and 22 older adults (mean age = 67.7 +/- 11.3) at high Alzheimer’s disease risk (i.e., strong family history or diagnosis of mild cognitive impairment). Kinematic measures were acquired on four visuomotor transformation tasks (standard, feedback reversal, plane dissociated, and plane dissociated + feedback reversal) using a dual-touchscreen tablet. Results: Comparing participants at increased Alzheimer’s disease risk with both young and old healthy control groups revealed significant performance disruptions in at-risk individuals as task demands increased. Furthermore, we were able to discriminate between individuals at high and low Alzheimer’s disease risk with a classification accuracy of 86.4% (sensitivity: 81.8%, specificity: 90.9%). Conclusion: We suggest that the impairments observed in individuals at increased Alzheimer’s disease risk may reflect inherent brain alteration and/or early neuropathology disrupting the reciprocal communication between hippocampal, parietal, and frontal brain

regions required to successfully prepare and update complex reaching movements. Such impairment has the potential to affect activities of daily living, and may serve as a sensitive measure of functional ability in at-risk adults. Keywords: Alzheimer’s disease, Visual-spatial processing, Cognitive-motor interaction, Functional connectivity, ADL Reprinted from the Journal of Alzheimer’s Disease, 42(2), Hawkins KM & Sergio LE, Visuomotor impairments in older adults at increased Alzheimer’s disease risk, 607-621, Copyright (2014), with permission from IOS Press [127]. This work was supported by a Canadian Institutes of Health Research Banting and Best Canadian Graduate Scholarship, Institute of Aging Special Recognition Award, and Ontario Women’s Health Scholars Award. © Kara Hawkins, 2015.

Introduction Alzheimer’s disease (AD) is the most common form of dementia, affecting approximately 13% of individuals aged 65 years and older, and 40-50% of individuals aged 80 years and older [98]. Typically, the initial clinical manifestation of AD involves short-term memory deficits, which eventually progress and are accompanied by more global and pronounced cognitive impairments. By the time this ally noticeable manifestation of the disease occurs, significant damage to the brain is already present and may be irreversible [100]. In order to develop effective treatments that may terminate or slow the neurodegenerative process, recent reports emphasize the importance of developing better tools for assessing impairments in the early stages of AD before substantial neurodegeneration occurrs [128]. While AD is typically associated with hippocampal atrophy and memory deficits, research has also demonstrated that functional and structural alterations involving posterior parietal association areas are present in the very early stages of the disease [8,129]. Posterior

Visuomotor Impairments in Older Adults at Increased Alzheimer’s Disease Risk parietal cortex (PPC) plays an important role in transforming visual-spatial information into goal-directed actions [130]. In particular, reciprocal parietal-frontal networks involving interconnected neuronal populations are required to transform extrinsic spatial representations into intrinsic joint and muscle representations necessary for the generation of an accurate motor output [19, 21, 24, 27, 130]. Disruption to these parietal-frontal networks in early stages of AD may result in impaired visuomotor control. In a typical or “standard” reach, the eyes are directed towards an object of interest then the hand moves to that same location in space. Many of the movements we learn to perform, however, require more complex sensorimotor transformations in which the motor system must integrate some form of cognitive information (e.g., visual-spatial, memorized, rule-based, semantic) into the motor program. In these learned “non-standard” sensorimotor transformations the end effector must move to a spatial location that is not directly aligned with the location of the visual target. These indirect visuomotors rely on the brain’s ability to either recalibrate the sensory-motor relationship or use a cognitive strategy to realign the required limb movement relative to the spatial location of the target [11]. E.g., guiding a computer mouse relies on the ability to incorporate visual and proprioceptive signals into the remapping of the visual location of the target and representation of the hand (i.e., cursor) in one plane, onto the true location of the target and hand in the other plane [131]. Furthermore, in order to sustain the motor plan throughout the course of the movement, the current position of the actual hand relative to the actual reach target (both of which the eyes are not looking at) must be continuously updated. On the other hand, when asked to integrate a specific rule into a movement, such as moving in the opposite direction of a visual target, the brain develops a cognitive strategy to generate the desired motor output [15]. While the neurological computations underlying the integration of cognition into action remain to be fully elucidated, it is likely that this relies on the recruitment of additional

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neural networks [132], which may be more vulnerable to AD pathology than the primary sensorimotor networks known to be preserved until the later stages of the disease [133]. Stereotyped motor actions, such as interacting directly with an object, do not appear to be impaired in early AD relative to healthy aging however performance decrements have been observed under conditions in which direct visual feedback is not provided [1–5, 134, 135]. Similar impairments under indirect visuomotor conditions have also been observed in premanifest Huntington’s disease [131]. These visuomotor deficits may reflect posterior parietal damage and/or white matter compromise in parietal-frontal networks. Traditionally, motor control deficits (e.g., apraxia) have mainly been identified later on in the course of AD [83]. However, recent observations of visuomotor deficits under cognitively demanding task conditions in early AD suggest that deterioration of the neural networks involved in praxic function may occur early in the disease process, and could serve as an early identifying feature of the disease [86– 91, 134–136]. Thus, we hypothesized that using kinematic measures to quantify visuomotor performance under cognitively demanding conditions may successfully identify individuals at increased AD risk due to family history or a diagnosis of mild cognitive impairment (MCI). Both MCI and AD family history are known risk factors for the development of AD [98]. Diagnosis of MCI typically includes the presence of memory complaints corroborated by a family member when possible, performance of at least 1.5 standard deviations below the normal age-standardized mean on standardized memory tests such as the Montreal Cognitive Assessment (MoCA), absence of dementia based on clinical evaluation, and absence of significant impairment in functional independence based on clinical judgement [104]. Increased risk due to family history includes the rare familial form of the disease resulting in early-onset AD [98], as well as late-onset AD in immediate family members [137–139], especially if multiple family members are affected [140]. Our Specific predictions, based on pilot data, were that

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movement accuracy and precision would be disproportionately compromised as task demands increased in participants at high AD risk. Furthermore, we predicted that psychomotor slowing would be observed with normal aging, but would be exacerbated by AD risk. We also predicted that increasing the cognitive load by combining visual-spatial recalibration and strategic control demands would provide a more sensitive measure for separation between groups.

Materials and Methods Participants This study included 66 participants: 22 older adults at high AD risk, 22 older adults at low AD risk, and 22 young adults (see Table 1 for demographic statistics). Older adults were recruited in collaboration with the Canadian Association of Retired People, Southlake Regional Health Center, and Mackenzie Richmond Hill Hospital (MRHH). Individuals were classified as high AD risk based on AD family history (n=14) or diagnosis of MCI (n=8) using the Petersen criteria [104] at the MRHH geriatric outpatient clinic. Individuals classified as family history positive scored at or above ageand education-adjusted norms on the MoCA and

reported either a maternal (n = 6), multiple (n = 6) or early-onset (n = 2) family history of AD. Paternal family history alone was not included in the high AD risk classification based on recent evidence that paternal history may not carry the same increased risk as maternal history [118,141,142]. Individuals classified as low AD risk reported no dementia of any type within their known family history, scored at or above age- and education-adjusted norms on the MoCA, and expressed no memory complaints beyond normal expectations for their age. Exclusion criteria included vision or upper-limb impairments, medical conditions that would hinder task performance (e.g., severe arthritis), neurological or psychiatric illnesses (e.g., schizophrenia, depression, alcoholism, epilepsy, Parkinson’s disease), and history of stroke or severe head injury. For comparison between low and high AD risk older adults, cognitive (MoCA – version 7.1), computer, and touchscreen experience data are recorded in Table I. Computer and touchscreen experience were assessed with a frequency of use rating scale (i.e., how frequently do you use a computer or touchscreen? 0=never, 1=rarely, 2=occasionally, 3=often). The study protocol was approved by the Human Participants Review Sub-Committee, York University’s Ethics Review Board, and conforms to the standards of the Canadian TriCouncil Research Ethics guidelines.

Table I. Summary of participant information Young Low AD Risk High AD Risk n 22 22 22 Age (SD) 26.4 (4.1)* 64.3 (10.1) 67.7 (11.3) Range 21-34 54-84 54-91 High AD risk subgroups FH+: 60.8 (5.4), MCI: 79.8 (8.2)* Sex (% female) 50% 50% 77.3%* High AD risk subgroups FH+: 86%*, MCI: 62.5% Handedness (% right) 90.9% 90.9% 90.9% Years of education (SD) NA 15.8 (3.5) 14.6 (5.2) High AD risk subgroups FH+: 17.4 (0.9), MCI: 9.8 (1.4)* MoCA score (SD) NA 27.6 (1.6) 25.8 (4.3) Range 25-30 12-30 High AD risk subgroups FH+: 27.3 (2.3), MCI: 22.9 (5.5)* Computer experience (SD) NA 2.3 (0.8) 2.1 (1.2) High AD risk subgroups FH+: 2.9 (0.1), MCI: 0.9 (0.4)* Touchscreen experience (SD) NA 1.0 (0.8) 1.3 (1.2) High AD risk subgroups FH+: 1.7 (0.3), MCI: 0.5 (0.4)* NA: not applicable; AD: Alzheimer’s disease; FH+: family history positive; MCI: mild cognitive impairment; SD: standard deviation. Asterisks denote significant difference from the other groups or, in the case of the sex variable, a significantly greater proportion of female participants at p < .05.

Visuomotor Impairments in Older Adults at Increased Alzheimer’s Disease Risk

Experimental Task All participants were tested on four visuomotor transformation tasks similar to those used previously by Tippett et al. [3–5] and Salek et al. [89]. These tasks were presented on an Acer Iconia 6120 dual-touchcreen tablet: One standard (direct) task in which the spatial location of the viewed target and the required movement were the same, and three nonstandard (indirect) tasks (feedback reversal, plane dissociated, and plane dissociated + feedback reversal) in which the location of the viewed target was dissociated from the required movement (Fig. 1A). Task conditions were presented in randomized blocks consisting of five pseudo-randomly presented trials to each of four peripheral targets (from a common central ‘home’ target), for a total of 20 trials per condition and 80 trials per participant. To ensure task comprehension each participant was given two practice trials per target prior to each condition. Throughout the experiment a webcam was used to monitor eye movements. If incorrect eye movements were made, participants were reminded to always look towards the target and not at their hands. The peripheral targets were colored red and presented directly to the left, right, above, or

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below the home target. Each peripheral target was centerd on a point 75 mm from the middle of the home target (i.e., center of the monitor). The size (20 mm diameter), position, and color of the targets were consistent across all conditions. To maintain a consistent visual border around the peripheral targets, the task was displayed on a 170 x 170 mm black square with the surrounding background colored grey. The trial timing and participant responses consisted of the following: 1) a green colored home target was presented on the vertical tablet, 2) participants touched the home target (either directly or with the cursor using the horizontal tablet), which changed its color to yellow indicating that they had acquired the home target, 3) after holding the home target for a center hold time (CHT) of 4000 ms a red peripheral target was presented and the home target disappeared, serving as a ‘go-signal’ for participants to look towards the visual target and slide their fingers along the touchscreen in order to direct the cursor to the target, 4) once the peripheral target was acquired and held for a target hold time (THT) of 500 ms it disappeared and the trial ended, 5) the next trial began with the presentation of the home target after an inter trial interval of 2000 ms (Fig. 1B).

Figure 1. (A) Schematic drawing of the four experimental conditions. Light grey circle, eye, and hand symbols denote the starting position for each trial (i.e., the home target). Dark grey eye and hand symbols denote the instructed eye and hand movements for each task. Dark grey circle denotes the peripheral target, presented randomly in one of four locations. White square denotes the cursor feedback provided during each condition. (B). Trial timing. Open circles denote nonilluminated target locations. Disappearance of the home target (which occurred at the same time as presentation of the peripheral target) served as the “go-signal” to initiate movement. CHT: center hold time, RT: reaction time, MT: movement time, THT: target hold time.

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In all conditions, participants were instructed to move as quickly and accurately as possible. In the standard (S) condition, participants were asked to slide their finger directly to the targets on the vertical tablet (i.e., the cursor was under their finger). In the feedback reversal (FR) condition, the cursor moved in the opposite direction of the participant’s finger movements, requiring them to slide their finger away from the visual target in order to direct the cursor towards it. In the plane dissociated (PD) condition, participants slid their finger along the horizontal tablet in order to direct the cursor towards visual targets in the vertical plane. And finally, when feedback reversal (PD+FR) was added, movements in the opposite direction of the visual targets, as well as in a different spatial plane, were required. In all conditions participants were instructed to look at the location of the presented target, regardless of whether their finger was sliding to that target or in a different direction/spatial plane. Thus, in all but the standard condition the final spatial locations of gaze and hand were decoupled.

Data Processing Timing, finger position (x, y coordinates; 60 Hz sampling rate), and error data were recorded for each trial and converted into MATLAB readable format using a custom written C++ application. Unsuccessful trials were coded by the software and resulted in trial termination if the finger left the home target too early (10000 ms). Velocity profiles were computed for each successful trial and displayed alongside a Cartesian plot illustrating finger position data and target locations using a custom-written analysis program (MATLAB). Movement onsets and offsets for the first ballistic movement (i.e., the initial muscular impulse) were scored as 10% peak velocity then verified visually to ensure that computed offsets appropriately reflected the first point at which movements

stopped or slowed significantly (i.e., the end of the first ballistic movement before any corrective movements). Total movement offsets were identified visually as the point at which velocity reached a final zero-crossing and position data plateaued (i.e., stopping the cursor inside the peripheral target). In the feedback reversal conditions, trials in which the first ballistic movement exited the boundaries of the home target in the wrong direction (i.e., moving the finger towards as oppose to away from the visual target) were coded as direction reversal errors and eliminated from further trajectory endpoint analyses. These processed data were then loaded into a custom written analysis program to compute accuracy, precision and timing outcome measures, as well as generate velocity and trajectory plots.

Dependent Measures The dependent measures of interest in this study were on- and off-axis constant errors, variable error, corrective path length, reaction time, total movement time, and direction reversal errors. Accuracy of the first ballistic movement was determined by computing the absolute on-axis (i.e., distance) and off-axis (i.e., direction) constant errors (CE) which reflect components of reaching accuracy that have been shown to be controlled independently by the motor system [143]. CEs were calculated as the average distance between the actual target position (defined as the coordinates at the center of the target) and the on- or off-axis ballistic movement offset for that target (t) [Σ( xi-t)/n or Σ(yi-t/n)]. Absolute on- and off-axis CEs were then averaged across targets, resulting in single measures that reflected the magnitude of distance and direction errors for each condition. Precision was determined by computing the variable error (VE), which is the standard deviation (i.e., variation from the mean) of the ballistic movement offsets [√Σ( xi-μ)2/n, √Σ( yiμ)2/n]. The pythagorean resultant VE (i.e., √VEx2 + VEy2) was then averaged across targets to generate a single measure for each condition. Corrective movements were quantified by

Visuomotor Impairments in Older Adults at Increased Alzheimer’s Disease Risk subtracting the ballistic path length from the total path length, resulting in a measure of corrective path length (CPL). Reaction time (RT) was calculated as the time between disappearance of the home target (i.e., the ‘go signal’) and movement onset. Total movement time (TMT) was calculated as the time between movement onset and the total movement offset upon positioning the cursor inside the peripheral target. Direction reversals (only applicable in the feedback reversal conditions) were recorded as a percentage of completed trials.

Statistical Analysis Partial correlations were used to examine the relationship between our task outcome measures and MoCA scores, while controlling for age, in the older adult groups. To determine significant differences in demographic variables between groups, one-way analysis of variance (ANOVA) tests were used to compare means (i.e., age, years of education, MoCA scores, computer experience, touchscreen experience) and Chi-squared tests were used to compare proportions (i.e., sex; Table I). While most of the potentially confounding demographic characteristics were not significantly different between the young, low AD risk and high AD risk groups, a significantly larger proportion of the high AD risk group was female, thus sex was included as a covariate in the mixed-design analysis of covariance (ANCOVA) tests that were used to compare our dependent measures across the four task conditions (repeated), and between the three experimental groups (young, low AD risk and high AD risk). Percent direction reversals in the FR and PD+FR conditions were compared between groups using a one-way ANOVA. To overcome violations of the sphericity assumption, Greenhouse-Geisser correction was applied, altering the degrees of freedom and producing an F-ratio where the Type I error rate was reduced. When there were significant main or interaction effects, post hoc analyses were adjusted for multiple comparisons using Bonferroni correction. Dependent

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measures from the most cognitively demanding task, which demonstrated the strongest predictive potential based on the ANCOVA results, were entered as predictor variables in a stepwise discriminant analysis comparing low and high AD risk groups. MoCA scores were also included as a potential predictor in this stepwise discriminant analysis in order to compare discriminability between high and low AD risk groups based on visuomotor versus cognitive measures. Applying this discriminant analysis to our data allowed us to identify the weighted linear combination of task outcome variables that contributed maximally to the separation between low and high AD risk groups, and provided estimates of sensitivity, specificity, and overall classification accuracy. In order to demonstrate that this separation between low and high AD risk participants based on cognitive-motor performance exists for both family history positive (FH+) and MCI subgroups, we also conducted separate stepwise discriminant analyses comparing the low AD risk group to each subgroup. Statistical significance levels were set to 0.05. All statistical analyses were carried out using SPSS statistical software.

Results Significant negative correlations between MoCA scores and visuomotor performance in older adults were mainly found in the plane dissociated condition (Table II). These correlations indicate that older adult participants with lower cognitive scores (i.e., those diagnosed with MCI) exhibit greater impairments in visuomotor control under spatially dissociated conditions. The lack of significant correlations between MoCA scores and all but one performance measure in the most cognitively-demanding condition, suggests that the performance decrements observed on this task in the high AD risk group may be independent of more global impairments in cognition detected by standardized cognitive tests.

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Kara M. Hawkins and Lauren E. Sergio Table II. Significant correlations between MoCA scores and kinematic measures

Kinematic Measures R On-axis constant error (PD condition) - 0.399 On-axis constant error (PD+FR condition) - 0.345 Variable error (PD condition) - 0.336 Corrective path length (PD condition) - 0.379 Reaction time (PD condition) - 0.429 Total movement time (PD condition) - 0.393 PD: plane dissociated; PD+FR: plane dissociated + feedback reversal.

As predicted, a marked deterioration in movement control was observed in high AD risk participants as the cognitive demands of the task increased. The mean ballistic trajectories plotted in Figure 2 illustrate a pronounced disruption in the performance (i.e., larger variability and endpoint errors) of high AD risk participants, including both FH+ and MCI subgroups, during the most cognitively demanding PD+FR condition. Example full trajectories from the PD+FR condition are also displayed in Figure 2 in order to demonstrate the typical trajectory deviations observed in the high AD risk group. Figure 3 illustrates mean velocity profiles across task conditions for young, low AD risk, FH+ and MCI participants. Again, performance disruptions in high AD risk participants, including both FH+ and MCI subgroups, were most pronounced in the PD+FR condition. Figure 3 also demonstrates that the performance of MCI patients was affected at lower levels of cognitive demand (i.e., in the FR and PD conditions) than FH+ participants. Our ANCOVA tests resulted in significant condition by group interactions for all dependent measures (on-axis CE: F(3.9,122) = 14.78, p < .001, ηp2 = .323; off-axis CE: F(4.5,141) = 10.06, p < .001, ηp2 = .245; VE: F(3.8,116) = 8.02, p < .001, ηp2 = .206; CPL: F(2.8,85.6) = 24.79, p < .001, ηp2 = .444; RT: F(3.5,110) = 8.59, p < .001, ηp2 = .217; TMT: F(2.9,91) = 11.61, p < .001, ηp2 = .272), indicating impairments in performance with increasing task difficulty that were influenced primarily by the high AD risk group. Figure 4 illustrates these interaction effects with the high AD risk group subdivided into FH+ and MCI subgroups. Displaying these subgroups separately demonstrates that the impairment in performance observed in the conditions with

r2 0.159 0.119 0.113 0.144 0.184 0.154

p-value 0.008 0.024 0.028 0.012 0.004 0.009

only one level of dissociation (i.e., FR and PD) were mainly influenced by MCI participants, while the pronounced performance disruptions observed when combining spatial dissociation and feedback reversal (i.e., in the PD+FR condition) were influenced by both FH+ and MCI participants within the high AD risk group. Group means in each condition for all dependent variables and effect sizes reflecting the effect of group within each condition are listed in Table III. Post-hoc analyses revealed significantly larger on-axis constant errors in the high AD risk group relative to both the young and low AD risk groups during the PD and PD+FR conditions. On-axis constant errors were also significantly larger in both older adult groups relative to the young group in the standard condition (Figure 4A). Significantly larger off-axis constant errors were observed in the high AD risk group relative to both the young and low AD risk groups in the PD+FR condition, and relative to the young group only in the PD condition (Figure 4B). Performance variability (i.e., variable error) and corrective path length were significantly increased in the high AD risk group relative to the low AD risk group for the FR condition and relative to both the young and low AD risk groups for the PD and PD+FR conditions (Figure 4C-D). Post-hoc analyses of the timing outcome variables also revealed effects of AD risk, however effects of normal aging were also clearly present. Reaction time was significantly longer in high AD risk participants relative to young participants in all task conditions. However, reaction time was also significantly longer in low AD risk participants relative to young participants in the FR and PD+FR conditions. Reaction time was only significantly different between high and low AD

Visuomotor Impairments in Older Adults at Increased Alzheimer’s Disease Risk risk groups in the FR condition (Figure 4E). Lastly, movement time was significantly longer in high AD risk relative to young participants in all task conditions, as well as in low AD risk relative to young participants in the non-standard conditions. Movement time was only significantly different between high and low AD risk groups in the PD+FR condition (Figure 4F). The one-way ANOVA tests for differences in the percentage of direction reversals between groups for the FR and PD+FR conditions were not significant. Notably, however, we did observe that within the high AD risk group, individuals diagnosed with MCI tended to commit more direction reversal errors. In order to test this observation, we separated the high AD risk group into FH+ and MCI subgroups and compared percent DR between MCI, FH+, low AD risk, and young groups in the FR and

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PD+FR conditions using non-parametric Kruskal-Wallis tests. The omnibus KruskalWallis test revealed no significant differences in direction reversal errors between groups in the FR condition (young: M = 1.39 +/- 0.6; low AD risk: M = 2.73 +/- 0.91; FH+: M = 1.79 +/- 1; MCI: M = 11.25 +/- 9.29), however in the PD+FR condition, the percentage of direction reversal errors was significantly different between groups (p = .042). Specifically, posthoc analyses revealed that in the PD+FR condition, percentage of direction reversals was significantly higher in the MCI group relative to the young group (p = .006), as well as relative to the low AD risk group with marginal significance (p = .056; young: M = 3.91 +/1.86; low AD risk: M = 6.31 +/- 2.28; FH+: M = 7.62 +/- 2.45; MCI: M = 19.04 +/- 7.35).

Figure 2. Left panel: mean ballistic trajectories (+/-SD) in the standard and plane dissociated + feedback reversal (PD+FR) conditions across groups: (A) Young, (B) Low Alzheimer’s disease (AD) risk, (C) Family history positive (FH+) and (D) Mild cognitive impairment (MCI). Crosshairs reflect variability in reach performance, calculated as the standard deviation (SD) at ten equal points along the reach trajectory. Right panel: examples of the typical full reach trajectories observed during the plane dissociated + feedback reversal (PD+FR) condition in each group (note the pronounce trajectory deviations in the high AD risk participants).

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Figure 3. Mean velocity profiles (filtered using a 10 Hz low pass Butterworth filter) across task conditions for each group: (A) Young, (B) Low Alzheimer’s disease (AD) risk, (C) Family history positive (FH+) and (D) Mild cognitive impairment (MCI). Shading represents standard deviation. FR: feedback reversal, PD: plane dissociated, PD+FR: plane dissociated + feedback reversal, m/s: meters per second.

In order to determine the predictive potential of kinematic measures from a cognitively demanding visuomotor task in discriminating between high and low AD risk participants, the dependent measures from the PD+FR condition, along with MoCA scores, were entered into a stepwise discriminant analysis. The minimum partial F for entrance into the discriminant analysis was 3.84 and the maximum partial F for removal was 2.71. The most correlated, and thus first predictor variable entered into the analysis by the stepwise program, was corrective path length, next was variable error, and the last

variable adding significant predictive power to the canonical R squared was off-axis constant error. In a fourth and final step, corrective path length was removed from the analysis with an F to remove value of 2.51. The resulting discriminant function was significant (Wilks’ Lambda = .468, p < .001), with a canonical correlation of .73. The structure matrix indicated that off-axis constant error was the strongest predictor (r = .73), next was variable error (r = .64), followed by corrective path length (r = .53) and on-axis constant error (r = .34). The correlation between MoCA scores and the

Visuomotor Impairments in Older Adults at Increased Alzheimer’s Disease Risk standardized canonical discriminant function (r = .06) indicated that cognitive scores were not useful in predicting group membership. The resulting canonical discriminant function was: D = (.453 x off-axis constant error) + (.168 x variable error) - 3.614. The grouping of cases resulted in an overall classification accuracy of 86.4%, with a sensitivity of 81.8% and specificity of 90.9%. The discriminant analyses conducted separately on the high AD risk subgroups also demonstrated good separation from the low AD risk group (FH+: Wilks’ Lambda = .474, p < .001, canonical correlation = .73; MCI: Wilks’ Lambda = .344, p < .001, canonical correlation = .81). The predictors included in the discriminant function classifying FH+ versus low AD risk participants were corrective path length (r = .89) and variable error (r = .68) [D = (.131 x variable error) + (.067 x corrective path length) – 2.67]. Again, MoCA scores were not useful in predicting group membership in this analysis

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(r = .16). However, in the discriminant function classifying MCI versus low AD risk participants, MoCA scores did add significant predictive power, as would be expected since impaired MoCA performance was one of the diagnostic criteria for MCI classification. Importantly, several kinematic measures were also significant predictors and were better than or as good as MoCA scores at predicting group membership, including off-axis constant error (r = .65), corrective path length (r = .62), on-axis constant error (r = .57), and variable error (r = .51). MoCA scores were negatively correlated with the discriminant function (r = -.52), reflecting lower scores in the MCI group. The predictors included in the discriminant function were offaxis constant error, variable error, and MoCA score [D = (.534 x off-axis constant error) + (.145 x variable error) – (.149 x MoCA score) .745]. These discriminant analysis classification results are summarized in Table IV.

Table III. Group means and effect sizes for kinematic measures in each condition* Group Means (SE)

ηp2 Low AD Risk High AD Risk Standard 3.85 (.39) 5.57 (.39) 5.66 (.40) .176 FR 7.13 (.69) 6.36 (.69) 8.33 (.71) .059 On-axis constant error PD 7.19 (.96) 7.18 (.96) 11.06 (.98) .142 PD+FR 7.69 (1.46) 11.45 (1.46) 22.23 (1.49) .450 Standard 1.97 (.15) 1.76 (.15) 1.77 (.15) .021 FR 2.15 (.19) 1.99 (.19) 2.41 (.19) .038 Off-axis constant error PD 1.48 (.19) 1.74 (.19) 2.15 (.19) .090 PD+FR 2.81 (.33) 2.43 (.33) 5.16 (.34) .376 Standard 3.73 (.27) 3.26 (.27) 4.03 (.28) .060 FR 6.01 (.47) 4.92 (.47) 7.09 (.48) .141 Variable error PD 5.92 (.50) 5.66 (.50) 7.69 (.50) .131 PD+FR 7.41 (.79) 8.63 (.79) 14.02 (.81) .376 Standard 2.92 (.29) 2.99 (.29) 3.67 (.29) .059 FR 6.49 (.70) 5.14 (.70) 8.46 (.72) .148 Corrective path length PD 6.72 (.90) 6.10 (.90) 10.03 (.92) .143 PD+FR 7.97 (2.16) 10.65 (2.16) 31.49 (2.20) .519 Standard 460 (28) 549 (28) 613 (28) .191 FR 587 (42) 823 (42) 982 (43) .411 Reaction time PD 493 (37) 563 (37) 670 (38) .152 PD+FR 636 (79) 1044 (79) 1239 (80) .325 Standard 509 (43) 609 (43) 676 (43) .109 FR 718 (65) 996 (65) 1093 (67) .218 Total movement time PD 728 (102) 1089 (102) 1196 (104) .154 PD+FR 929 (212) 1666 (212) 2665 (216) .342 * Partial eta-squared (η 2) effect sizes reflect the effect of group within each condition and are based on the linearly p independent pairwise comparisons among the estimated marginal means. AD: Alzheimer’s disease; SE: standard error; FR: feedback reversal; PD: plane dissociated. Kinematic Measures

Condition

Young

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Figure 4. A-F. Results of group (young: light grey bars, low AD risk: medium grey bars, FH+: dark grey bars, MCI: black bars) by condition (S: standard, FR: feedback reversal, PD: plane dissociated, PD+FR: plane dissociated + feedback reversal) mixed ANCOVAs on task dependent measures. Means +/- 1 standard error of the mean, * = < .05, ** = < .001. AD: Alzheimer’s disease; FH+: family history positive; MCI: mild cognitive impairment.

Table IV. Classification results of stepwise discriminant analyses Predicted Group Membership Total Low AD Risk High AD Risk Low AD Risk 20 2 22 Count High AD Risk 4 18 22 Classificationa Low AD Risk 90.9 9.1 100.0 % High AD Risk 18.2 81.8 100.0 Low AD Risk FH+ Total Low AD Risk 20 2 22 Count FH+ 3 11 14 Classificationb Low AD Risk 90.9 9.1 100.0 % FH+ 21.4 78.6 100.0 Low AD Risk MCI Total Low AD Risk 21 1 22 Count MCI 2 6 8 c Classification Low AD Risk 95.5 4.5 100.0 % MCI 25 75 100.0 Each case in the analysis is classified by the functions derived from all cases other than that case. a. 86.4% of cases correctly classified. b. 86.1% of cases correctly classified. c. 90% of cases correctly classified. AD: Alzheimer’s disease; FH+: family history positive; MCI: mild cognitive impairment. Group

Visuomotor Impairments in Older Adults at Increased Alzheimer’s Disease Risk

Discussion The results of the present study demonstrate a striking impairment of visuomotor integration under cognitively demanding task conditions in high AD risk older adults relative to both low AD risk and young participants. Specifically, we found that when performing the PD+FR task, participants at increased AD risk, due to both family history and MCI, demonstrated significant impairments on measures of accuracy, consistency and timing. Furthermore, we demonstrated that these kinematic measures are useful in discriminating between older adults who are and are not at increased AD risk. Visuomotor impairment in MCI and AD populations has received little study to date, thus the present state of knowledge in this area is low. Most research involving the assessment of AD in its early stages is cognitive based, and only recently has it been recognized that complex movements may also be affected [86,87,89,135]. The results of the current study indicate that measurable impairments in visuomotor control are already present in individuals at increased risk of developing AD. We suggest that these impairments may reflect inherent brain alterations and/or early neuropathology disrupting the connectivity between hippocampal, parietal and frontal brain regions required to successfully control complex reaching s. In support of this prediction, recent diffusion tensor imaging (DTI) studies in MCI and early AD have revealed disruption to the integrity of prominent association fibre tracts, including parietal-frontal connections [9,111] and projections from the hippocampus to inferior parietal regions [10]. Furthermore, DTI studies in cognitively normal participants at increased AD risk due to family history and carrying one or more apolipoprotein E epsilon 4 allele have shown decreased microstructural integrity in WM tracts with direct and secondary connections to the medial temporal lobes, years before the expected onset of cognitive symptoms [119,120]. Taken together the above findings indicate that disconnection between the medial temporal

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lobes and neocortex, as well as between parietal and frontal cortex, may occur very early in the course of AD. In order to investigate whether or not these brain alterations are responsible for the visuomotor impairments observed in this study, our lab is currently using MRI techniques to correlate anatomical and functional connectivity with visuomotor performance in individuals at increased AD risk.

Interpretation of Visuomotor Deficits Associated with Alzheimer’s Disease Risk Our results suggest that visuomotor networks involved in both visual-spatial recalibration and strategic control may be compromised in individuals at increased AD risk. Specifically, we found that the performance of MCI patients was impacted at lower levels of cognitive demand when either strategic control (FR condition) or visual-spatial recalibration (PD condition) were required, whereas performance impairments in FH+ participants only became apparent at higher levels of cognitive demand when both strategic control and visual-spatial recalibration were required at the same time (i.e., PD+FR condition). Furthermore, MCI patients showed direction reversal errors in the feedback reversal conditions reflecting impaired inhibition of prepotent responses, as well as overall slowing in reaction and movement times across task conditions that were not present in FH+ participants. These findings suggest that visuomotor tasks with increasing levels of cognitive demand may be useful not only in detecting AD risk before cognitive declines on standardized tests are present, but also in monitoring disease progression from preclinical to MCI stages. We propose three putative mechanisms (which are not mutually exclusive) to account for the visuomotor deficits observed in high AD risk participants in the current study. First, increased ballistic endpoint errors may reflect disruption to motor programming, and thus more reliance on online sensory feedback. In turn,

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these corrective mechanisms may also be disrupted or delayed, resulting in trajectory deviations and extended corrective path lengths. In other words, the internal feedback loop required to update the current location of the hand relative to the position of the target, which relies on intact parietal-frontal connections [144], may be disrupted. Studies examining the control of arm movements in older adults have demonstrated that increased reliance on visual feedback is present in normal healthy aging, which is often interpreted as compensation for deficiencies in central motor planning. [65– 67,69] Furthermore, online corrective mechanisms have been shown to be less efficient in older individuals [68,70]. Our results suggest that these changes associated with normal aging may be exacerbated in individuals at increased AD risk. Second, disruption to attentional control networks [145,146] may also play a role in the errors and slowed performance observed under indirect task conditions. Such disruption would impair the ability to inhibit stereotyped eye-hand coupling and divide attention (i.e., neural resources) between incongruent eye and hand movements. Baddeley and colleagues [145,146] have demonstrated that individuals in the early stages of AD exhibit substantial impairment in the ability to combine performance on two simultaneous tasks, indicating that an attentional processing deficit exists in early AD. Lastly, poorer accuracy and precision under conditions of spatial dissociation may also be explained by disruption to hippocampal-parietal processing, which is required for the integration of visual-spatial information into a motor program [110].

Study Limitations Considering the relatively small sample size used in the present study, future research is required in order to determine the generalizability of our results and to apply appropriate cross-validation to the discriminant analyses. Furthermore, longitudinal studies are

required in order to fully elucidate the predictive potential of kinematic measures in identifying individuals who will later go on to develop Alzheimer’s disease. Lastly, while there were similarities between the FH+ and MCI participants combined to form the high AD risk group in the present study, there were also important differences that could not be fully examined statistically due to the small number of MCI participants included. These MCI patients were also older, less educated, and had less computer/touchscreen experience than the other study participants, adding potential confounds that may have exacerbated their impaired performance. Again, future studies with larger sample sizes and better separation between different levels of risk would clarify this issue.

Conclusions and Clinical Implications Based on the findings of the current and previous research from our lab, clinical assessment tools incorporating cognition and action together would be useful not only in providing information about the functional abilities of a patient, but also in alerting clinicians to increased dementia risk before cognitive symptoms are consistently present. Furthermore, we speculate that the early detection of visuomotor deficits may serve to identify individuals at increased risk for subsequent clinical decline in areas such as balance and gait [146,147], driving, and activities of daily living. Several studies have demonstrated an association between motor symptoms and adverse health effects in old age [134], thus assessments that employ motor measures may provide more accurate identification of individuals at increased disease risk. Importantly, our results provide strong evidence that the integration of cognition and movement control can provide valuable, clinically-relevant information that may be more useful than measuring performance in either of these domains in isolation.

Diffusion Tensor Imaging Correlates of Cognitive-Motor Decline in Normal Aging and … 193

SECTION III Diffusion Tensor Imaging Correlates of Cognitive-Motor Decline in Normal Aging and Increased Alzheimer’s Disease Risk Kara M. Hawkins1, Aman I. Goyal2, and Lauren E. Sergio3 1

Toronto Rehabilitation Institute, UHN Toronto, ON, Canada 2 Neuroimaging Laboratory York University, Toronto Ontario Canada 3 Graduate Program in Kinesiology and Health Science, York University, Toronto, Ontario, Canada

Abstract Alzheimer’s disease (AD) is typically associated with impairments in memory and other aspects of cognition, while deficits in complex movements are commonly observed later in the course of the disease. Recent studies, however, have indicated that subtle deteriorations in visuomotor control under cognitively demanding conditions may in fact be an early identifying feature of AD. Our previous work has shown that the ability to perform visuomotor tasks that rely on visualspatial and rule-based transformations is disrupted in prodromal and preclinical AD. Here, in a sample of 30 female participants (10 young: mean age = 26.6 +/- 2.7, 10 low AD risk: mean age = 58.7 +/- 5.6, and 10 high AD risk: mean age = 58.5 +/- 6.9), we test the hypothesis that these cognitive-motor impairments are associated with early ADrelated brain alterations. Using diffusionweighted magnetic resonance imaging, we assessed the relationship between normal aging, increased AD risk, cognitive-motor performance, and the underlying white matter (WM) integrity of the brain. Our whole-brain analysis revealed significant age-related declines in WM integrity, which were more widespread in high relative to low AD risk participants. Furthermore, analysis of mean diffusivity measures within isolated WM

clusters revealed a stepwise decline in WM integrity across young, low AD risk, and high AD risk groups. In support of our hypothesis, we also observed that lower WM integrity was associated with poorer cognitive-motor performance. These results are the first to demonstrate a relationship between ADrelated WM alterations and impaired cognitive-motor control. The application of these findings may provide a novel clinical strategy for the early detection of individuals at increased AD risk. Keywords: Alzheimer’s disease, Visual-spatial processing, Cognitive-motor interaction, Functional connectivity, White mater integrity This work was supported by a Canadian Institutes of Health Research Banting and Best Canadian Graduate Scholarship, Institute of Aging Special Recognition Award, and Ontario Women’s Health Scholars Award. © Kara Hawkins, 2015 Reprinted from the Journal of Alzheimer’s Disease, 44(3), Hawkins KM, Goyal AI & Sergio LE, Diffusion tensor imaging correlates of cognitive-motor decline in normal aging and Increased Alzheimer’s Disease Risk, 867878. Copyright (2015), with permission from IOS Press [148]

Introduction Over the past several years many brainimaging studies have investigated the neural underpinnings of Alzheimer’s disease (AD). In 2009, a meta-analysis of these studies revealed that, aside from the commonly known structural atrophy in trans-entorhinal and hippocampal regions, hypometabolism and hypoperfusion in the inferior parietal lobule (IPL) and precuneus are also prevalent features of early AD [8]. Furthermore, recent neuroimaging studies employing diffusion tensor imaging (DTI) in mild cognitive impairment (MCI) and AD have reported white matter (WM) compromise affecting several major fiber tracts forming parietal-frontal, interhemispheric, and hippocampal-cortical connections, including the inferior fronto-occipital fasciculus (IFOF),

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Kara M. Hawkins, Aman I. Goyal, and Lauren E. Sergio

inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus (SLF), corpus callosum (CC), and cingulum (CG) bundle [9, 111–113]. Microstructural declines in the CG, ILF, and IFOF have also been found in cognitively normal women at increased risk of AD due to family history and apolipoprotein E4 (ApoE4) genotype, years before the expected onset of cognitive symptoms [119, 120]. While AD dementia is typically associated with declines in cognition and short-term memory resulting from hippocampal atrophy [101], these clinical symptoms only present themselves after significant damage to the brain has already occurred [100]. Thus, neuroimaging studies including individuals in the preclinical (i.e., increased genetic risk) and prodromal (i.e., MCI) stages of AD are essential for the development of early detection strategies. Notably, the alterations in parietal areas and declines in WM integrity that have been observed in these preclinical / prodromal studies provide insight into other behaviors that may be affected even earlier in the disease process. Specifically, parietal cortex plays an important role in transforming visual-spatial information into goal-directed actions [19, 56, 58, 130]. Further, WM tracts forming hippocampalparietal and parietal-frontal connections are required to successfully transform spatial representations and contextual information into accurate motor outputs [21, 24, 110]. These observations suggest that early neurodegeneration may have an impact on rulebased motor control. Accordingly, impairments in visuomotor control under non-standard conditions, in which the correspondence between vision and action is not direct [11], have been observed in early and preclinical AD [1–5,89,127,135,149]. Given the potential impact of AD-related brain alteration on motor control and the close relationship between cognition and action [30], the aim of the present study is to examine the underlying structural connectivity associated with impaired cognitivemotor performance observed in individuals at increased AD risk. Using DTI and highresolution magnetic resonance imaging (MRI),

we test the hypothesis that kinematic measures from a cognitively demanding visuomotor task are associated with identifiable brain alterations similar to those observed in early AD, and thus may be useful in identifying individuals at increased AD risk.

Materials and Methods Participants Thirty right-handed female participants were included in this study: 10 healthy young adults (mean age = 26.6+/-2.7), 10 low AD risk older adults (mean age = 58.7 +/-5.6), and 10 high AD risk older adults (mean age = 58.5+/-6.9). Individuals classified as high AD risk scored at or above age- and education-adjusted norms on the Montreal Cognitive Assessment (MoCA) and reported either a maternal, multiple, or early-onset family history of AD. While earlyonset AD is known to be associated with the rare familial form of the disease [98], individuals with late-onset AD in their immediate family have also been shown to be at increased risk [137–139], especially if multiple family members are affected [140]. Paternal family history alone was not included in the high AD risk classification based on recent evidence that paternal history may not carry the same increased risk as maternal history [118,141,142]. Individuals classified as low AD risk were agedmatched with high AD risk participants, reported no dementia of any type within their known family history, scored at or above age- and education-adjusted norms on the MoCA, and expressed no memory complaints beyond normal expectations for their age. Exclusion criteria included vision or upper-limb impairments, any medical condition that would hinder task performance (e.g., severe arthritis), any neurological or psychiatric illnesses (e.g., schizophrenia, depression, alcoholism, epilepsy, Parkinson’s disease), and any history of stroke or severe head injury. High and low AD risk participants also underwent ApoE genotyping, which supported the notion of increased genetic

Diffusion Tensor Imaging Correlates of Cognitive-Motor Decline in Normal Aging and … 195 risk in our family history group (i.e., 80% of this sample were ApoE4 carriers, compared to only 20% of the no family history group). Demographic characteristics for all study participants are summarized in Table I. Our decision to focus on female participants in the current study was based on a few factors: 1) the prevalence of AD is higher in women, emphasizing the importance of studies specifically tailored towards early detection in this population [150,151], 2) recent evidence suggesting that sex-differences in the efficacy of

ApoE in redistributing myelin cholesterol during nerve repair may increase vulnerability to the degradation of WM tracts specifically in women who carry the ApoE4 allele [152], and 3) to avoid sex-related confounds inherent in brain imaging studies. The study protocol was approved by the Human Participants Review Sub-Committee, York University’s Ethics Review Board, and conformed to the standards of the Canadian Tri-Council Research Ethics guidelines.

Table I. Demographic characteristics of subjects Young

Low AD Risk

High AD Risk

Number

10

10

10

Age (SD)

26.6 (2.7)

58.7 (5.6)

58.5 (6.9)

Years of education (SD)

-

17.9 (3.1)

16.8 (3.1)

MoCA score (SD)

-

27.9 (1.7)

28.3 (2.2)

ApoE genotype (% E4 carriers)

-

20%

80%

SD: standard deviation; MoCA: Montreal cognitive assessment; ApoE: apolipoprotein E.

Visuomotor Assessment A detailed description of our visuomotor assessment is provided in Hawkins and Sergio [127]. Briefly, in the current study, participants were tested on two visuomotor transformation tasks presented on an Acer Iconia 6120 dualtouchcreen tablet: One standard task in which the spatial location of the viewed target and the required movement were the same, and one cognitively demanding non-standard task (plane dissociated + feedback reversal) in which the location of the viewed target was dissociated from the required movement (Fig. 1A). Task conditions were presented in randomized blocks consisting of five pseudo-randomly presented trials to each of four peripheral targets (from a common central ‘home’ target), for a total of 20 trials per condition and 40 trials per participant (Fig. 1B). Specifically, in the standard condition participants slid their finger directly to targets on

the vertical tablet, while in the non-standard condition the same targets were presented on the vertical screen, however now participants had to direct a cursor to these targets by sliding their finger along the horizontal tablet (i.e., in a different spatial plane), as well as in the opposite direction of the targets (i.e., feedback reversal). To ensure task comprehension each participant was given two practice trials per target prior to each condition, they were then asked to perform the experimental task (i.e., five trials to each target) as quickly and accurately as possible. To ensure dissociation between eye and hand movements in the non-standard task, participants were instructed to always look towards the visual target and not at their hand. To reinforce compliance with these task instructions, the eyes were monitored throughout the experiment using a webcam and a reminder was provided in the event that incorrect eye movements were performed.

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Figure 1. (A) Schematic drawing of the two experimental conditions. Light grey circle, eye, and hand symbols denote the starting position for each trial (i.e., the home target). Dark grey eye and hand symbols denote the instructed eye and hand movements for each task. Dark grey circle denotes the peripheral target, presented randomly in one of four locations. White square denotes the cursor feedback provided during each condition. (B) Trial timing. Open circles denote nonilluminated target locations. Disappearance of the home target (which occurred at the same time as presentation of the peripheral target) served as the “go-signal” to initiate movement. CHT: center hold time, RT: reaction time, MT: movement time, THT: target hold time.

Imaging Data Acquisition MRI data were acquired using a 3 Tesla Siemens Trio scanner at York University. Sequences included a high-resolution T1weighted anatomical scan using magnetization prepared rapid gradient echo (MPRAGE) and a whole-brain diffusion-weighted scan with 64 encoding directions. The MPRAGE sequence consisted of 192 sagittal slices with a slice thickness of 1 mm with no gap, field of view (FOV) of 256 x 256 mm, and a matrix size of 240 x 256, resulting in a voxel resolution of 1 x 1 x 1 mm3 [repetition time (TR) = 2300 ms, echo time (TE) = 2.96 ms, flip angle = 9°]. For the DTI sequence, 56 axial slices were acquired using diffusion weighted spin-echo single-shot echo planar imaging with a b-value of 1000 s/mm2 (including one volume with no diffusion gradient, b = 0 s/mm2), FOV of

192 x 192 mm, matrix size of 128 x 128, and slice thickness of 2 mm with no gap, resulting in a voxel resolution of 1.5 x 1.5 x 2 mm3 (TR = 6900 ms, TE = 86 ms).

ApoE Genotyping All older adult participants provided saliva samples for ApoE genotyping conducted at Viaguard Accu-metrics (Toronto ON). DNA samples were extracted from the filter paper blots of saliva, and standard polymerase chain reaction (PCR) techniques were applied. The PCR products were then analyzed by electrophoresis and visualized under ultraviolet illumination to determine the presence of specific ApoE haplotypes (i.e., E2, E3, and/or E4).


Kinematic Data Analysis The touchscreen data processing and kinematic outcome measures for the visuomotor tasks used in the current study are described in detail in Hawkins and Sergio [127]. Briefly, movement accuracy was determined by calculating the absolute on-axis (distance) and off-axis (direction) constant errors (CE), which involved computing the average distance between the center of the target and the endpoints of each ballistic movement. Movement precision, or consistency (i.e., variable error; VE), was determined by calculating the standard deviation of the ballistic movement endpoints. The extent to which corrective movements were required in order to reach the target was quantified as the difference between the total path length and the ballistic path length, resulting in a measure of corrective path length (CPL). The time between disappearance of the home target (i.e., the movement ‘go signal’) and movement onset served as the measure of reaction time (RT), and the time between movement onset and the final movement endpoint upon positioning the cursor inside the peripheral target served as the measure of movement time (MT). In order to minimize the number of correlations between the imaging and behavioral data, kinematic measures from the non-standard task were summarized by calculating z-scores and averaging across the CE, VE, and CPL variables to generate a performance error score, and across the RT and MT variables to generate a performance timing score.

Imaging Data Analysis Imaging data were analyzed using the Oxford Center for Functional Magnetic Resonance Imaging of the Brain (FMRIB) Software Library (FSL - http://www.fmrib.ox.ac .uk/fsl). In order to test for any hippocampal atrophy across groups, subcortical segmentation was performed on the brain extracted TIweighted MPRAGE data using the FSL tool

FIRST [153] and the FSLUTILS program fslstats was used to determine hippocampal volumes. DTI data were pre-processed using FMRIB’s Diffusion Toolbox (FDT). Eddy current and head motion corrections were applied using the affine image registration tool (FLIRT;[154]) and removal of non-brain structures was applied using the brain extraction tool [155]. Maps for fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (DA), and radial diffusivity (DR) were then extracted using DTIFIT to fit a tensor model to the raw diffusion data and analyzed using whole-brain tract-based spatial statistics (TBSS; [156]). Specifically, FA data for all subjects used in a particular comparison were aligned to a common space using FMRIB’s nonlinear image registration tool (FNIRT), then a mean FA image was created and thinned to generate a mean FA skeleton representing the centers of all tracts common to the group. Each subject’s aligned FA data was then projected onto the mean skeleton. The nonlinear warps and projection vectors estimated from the FA images were also applied to MD, DR, and DA using the script provided in TBSS for non-FA images. The resulting data were then fed into voxelwise cross-subject statistics and significant voxels were identified using the Johns Hopkins University (JHU) white matter atlas. Non-FA diffusion measures were examined in the present study in attempt to understand the underlying alterations driving any observed differences in FA. Specifically, decreased FA with increased MD suggests microstructural declines associated with increased brain water content and macrostructural tissue loss. Whereas, decreased FA without increased MD suggests microstructural changes without gross tissue loss [157]. Reduction in FA accompanied by increased DR may signify loss of myelin integrity, based on experimentally induced myelin degradation in mouse models [158–160]. And lastly, decreased FA and DA, without increased DR, may reflect axonal damage (e.g., wallerian degeneration), which has been

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demonstrated in both experiments [160,161].

rodent

and

human

Statistical Analysis Using SPSS statistical software, a mixeddesign analysis of variance (ANOVA) was carried out to compare kinematic measures across the two task conditions (standard/nonstandard; repeated), and between the three experimental groups (young/low AD risk/high AD risk). One-way ANOVA tests were also used to compare non-standard error and timing scores, and hippocampal volumes between the three experimental groups. When there were significant effects, post hoc analyses were adjusted for multiple comparisons using Bonferroni correction. ANOVA results were considered statistically significant at p < .05. FSL’s Randomise tool was used to run voxelwise statistics on the TBSS data, with threshold-free cluster enhancement (TFCE) applied to correct for multiple comparisons. Between-group contrasts in both directions for each of the diffusivity measures were tested for young versus low AD risk, young versus high AD risk, and low AD risk versus high AD risk groups. Due to the widespread decline in FA between the young and older adult groups, significant FA differences between groups are reported and displayed at p < .01, while significant DR and DA differences are reported and displayed at p < .05 (no significant differences in MD were observed). FSL’s cluster tool was used on the significant Randomise results to form clusters and report their sizes, locations (using the JHU white matter atlas), and significance levels. Lastly, mean diffusivity measures were calculated within the clusters that showed significant age-related WM impairment in the high AD risk group. One-way ANOVA tests were used to compare these mean diffusivity measures (i.e., FA/DR/DA) between groups for each WM cluster and post hoc analyses were adjusted for multiple comparisons using Bonferroni correction (alpha-level:

p < .05). In order to examine the relationship between WM integrity and cognitive-motor performance, mean FA, DR, and DA in these WM clusters were also correlated with error and timing scores from the non-standard task using two-tailed Pearson’s r in SPSS. Correlations were considered statistically significant at p < .01.

Results Kinematic Data Consistent with our previous findings [127], significant condition by group interactions driven by greater performance declines between the standard and non-standard tasks in the high AD risk group were found for all kinematic measures (On-axis CE: F2,27 = 7.36, p = 0.003; Off-axis CE: F2,27 = 7.13, p = 0.003; VE: F2,27 = 11.35, p < 0.0001; CPL: F2,27 = 25.51, p < 0.0001; RT: F2,27 = 4.52, p = 0.02; MT: F2,27 = 4.97, p = 0.015). Specifically, all three groups performed similarly on the standard visuomotor task, however in the non-standard task on-axis CE, off-axis CE, VE, and CPL were significantly larger in the high AD risk group relative to both the low AD risk and young groups, while RT and MT in the non-standard task were significantly longer in the high AD risk group relative to the young group only (see Table II for group means and effect sizes; group means are also plotted in Appendix A, along with a discriminant analysis). Average z-scores calculated to summarize the above error (i.e., CE, VE, CPL) and timing (i.e., RT and MT) results are displayed in Figure 2. Accordingly, error scores were significantly larger in the high AD risk group relative to both the young and low AD risk groups (F2,27 = 21.39, p < 0.0001; post-hoc: high AD risk - young = 4.95, p < 0.00001, high AD risk - low AD risk = 4.04, p < 0.0001), and timing scores were significantly larger in the high AD risk group relative to the young group only (F2,27 = 5.31, p = 0.011; post-hoc: high AD risk - young = 1.87, p = 0.009).

Diffusion Tensor Imaging Correlates of Cognitive-Motor Decline in Normal Aging and … 199 Table II. Group means and effect sizes for kinematic measures in each condition Group Means (SE) Kinematic Measures

Condition

Young

Low AD Risk

High AD Risk

ηp2

On-axis constant error

Standard Non-standard

4.01 (.4) 8.50 (1.0)a

4.47 (.3) 9.76 (1.8)a

3.91 (.2) 18.67 (3.1)b

.059 .334

Off-axis constant error


1.64 (.2) 2.96 (.5)a

1.50 (.3) 2.96 (.5)a

1.82 (.2) 5.93 (.6)b

.039 .420

Variable error


3.47 (.2) 6.41 (.7)a

3.01 (.3) 9.56 (1.2)a

3.28 (.2) 14.44 (1.7)b

.067 .440

Corrective path length


3.40 (.4) 8.73 (1.3)a

3.33 (.2) 10.45 (1.9)a

3.11 (.2) 32.91 (4.0)b

.026 .655

Reaction time


444 (14)a 603 (23)a

508 (20)b 875 (62)

470 (17) 1013 (142)b

.212 .282

Movement time


556 (28) 1096 (73)a

661 (35) 1577 (169)

586 (35) 2443 (496)b

.168 .270

Superscripts denote significant differences between group means (p < .05). Partial eta-squared (ηp2) effect sizes reflect the effect of group within each condition and are based on the linearly independent pairwise comparisons among the estimated marginal means. SE: standard error.

Figure 2. Mean z-scores for error and timing kinematic measures in the non-standard task across groups (young: light grey bars, low AD risk: medium grey bars, high AD risk: dark grey bars). Note that higher error scores reflect less accuracy and precision and higher timing scores reflect longer reaction and movement times. Means +/- 1 SEM, ** = < .01.

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Table III. White matter regions with significantly lower FA values in low AD risk and high AD risk older adults relative to young adults Low AD Risk Region (cluster extension)

# of voxels

x

y

z

t-value

p-value

R FMi (L FMi, R/L CC body, R/L SLF, R/L CST)

14402

17

35

-5

8.23

0.002

High AD Risk Region (cluster extension)

# of voxels

x

y

z

t-value

p-value

R FMi (L FMi, R/L CC body, R IFOF, R ILF, R SLF, R FMa, R hCG)

13926

20

42

10

6.58

0.002

L FMa

748

-26

-72

1

5.07

0.004

L SLF

263

-34

-44

31

4.39

0.006

L ILF

57

-41

-40

-9

3.49

0.01

L CST

20

-41

-4

35

7.51

0.008

Regions of maximum significant difference between groups with cluster sizes of at least 20 voxels are reported in MNI coordinates. R, right; L, left; FMi, forceps minor; CC, corpus callosum; SLF, superior longitudinal fasciculus; CST, corticospinal tract; IFOF, inferior fronto-occipital fasciculus; ILF, inferior longitudinal fasciculus; FMa, forceps major; hCG, cingulum (hippocampal region).

Table IV. White matter regions with significantly higher DR values in low AD risk and high AD risk older adults relative to young adults Low AD Risk Region (cluster extension)

# of voxels

x

y

z

t-value

p-value

L FMi (R FMi, R/L CC body)

14128

-7

49

-21

6.28

0.004

R ILF

493

41

-41

-4

6.73

0.038

R IFOF

121

37

-20

-6

4.35

0.048


# of voxels

x

y

z

t-value

p-value

L FMi (L CC body, L IFOF, L ILF, L SLF, L FMa)

8287

-11

43

-17

6.63

0.002

R FMi (R CC body, R IFOF)

5697

13

37

-15

5.87

0.002

Regions of maximum significant difference between groups with cluster sizes of at least 20 voxels are reported in MNI coordinates. See Table III for abbreviation definitions.

Diffusion Tensor Imaging Correlates of Cognitive-Motor Decline in Normal Aging and … 201 Table V. White matter regions with significantly lower DA values in low AD risk and high AD risk older adults relative to young adults Low AD Risk Region (cluster extension)

# of voxels

x

y

z

t-value

p-value

L CST (L CC body)

3350

-19

-10

42

5.47

0.01

R FMi

200

22

46

13

4.73

0.034


# of voxels

x

y

z

t-value

p-value

R FMi

1291

22

46

10

5.76

0.014

R SLF

981

42

-3

25

5.5

0.022

R CC body

830

13

-6

32

5.09

0.022

R ILF

758

34

-55

19

5.07

0.022

R PMC

369

7

6

63

5.74

0.022

R M1/CST

362

11

-28

66

4.88

0.022

R IFOF

355

37

-17

-8

4.58

0.034

R CST

231

14

-23

-16

3.93

0.034

R IPL

216

52

-35

15

4.23

0.04

Regions of maximum significant difference between groups with cluster sizes of at least 20 voxels are reported in MNI coordinates. PMC, premotor cortex; M1, primary motor cortex; IPL, inferior parietal lobule. See Table III for other abbreviation definitions.

Imaging Data The whole-brain TBSS analysis revealed regions of significantly lower WM integrity in both low AD risk and high AD risk older adults relative to young adults. These results are displayed in Figures 3.3 using FSL’s tbss_fill to thicken the thresholded stats results for better visualization. No significant differences on any of the diffusivity measures were found in the opposite direction (i.e., there were no regions of lower WM integrity in young relative to older adults). Significantly lower FA (Figure 3A, left

panel; Table III), higher DR (Figure 3B, left panel; Table IV), and lower DA (Fig. 3C, left panel; Table IV) in the low AD risk group (bluelight blue) were found primarily in anterior regions including the forceps minor (FMi), body of the CC, and corticospinal tract (CST), while in the high AD risk group (red-yellow) these age-related declines in WM integrity were more widespread, extending into posterior regions including the forceps major (FMa), IFOF, ILF, SLF, and hippocampal CG. While the observed age-related declines in WM integrity were more extensive in the high AD risk group relative to

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the low AD risk group, this whole-brain analysis did not reveal any significant differences between low and high AD risk groups on any of the diffusivity measures. There were also no significant differences in MD and hippocampal volume between groups (group mean hippocampal volumes are plotted in Appendix B). In support of our hypothesis, a number of significant correlations were found between mean diffusivity measures in isolated WM clusters and cognitive-motor performance scores. Specifically, larger error and timing scores were significantly correlated with lower mean FA in the right FMi (extending into the IFOF, ILF, SLF, FMa, and hCG), left FMa, left SLF, and left CST (Figure 3A, right panel). Similarly, we also found significant correlations

between larger error and timing scores and higher mean DR in the left FMi (extending into the CC, IFOF, ILF, SLF, and FMa) and right FMi (extending into the CC and IFOF; Figure 3B, right panel). Finally, significant correlations were also observed between larger error scores and lower mean DA in the right FMi, SLF, ILF, primary motor cortex (M1), and IPL, and between larger timing scores and lower mean DA in the right FMi, SLF, CC, ILF, and IPL (Fig. 3C, right panel). The statistics for these correlations are listed in Tables VI. (Additional methodology and correlational results for diffusivity measure within JHU atlas generated WM tracts of interest are reported in Appendix C).

Table VI. Correlations between diffusivity measures and cognitive-motor kinematics Error Score

Timing Score

Mean FA TBSS clusters (cluster extension)

r

r2

p (2-tailed)

r

r2

p (2-tailed)

R FMi (L FMi, R/L CC body, R/L SLF, R/L CST) L FMa L SLF L CST

-0.51

0.26

0.004

-0.64

0.41

0.0002

-0.59 -0.56 -0.70

0.35 0.32 0.48

0.001 0.001 0.00002

-0.64 -0.47 -0.66

0.41 0.22 0.44

0.0002 0.01 0.0001

Mean DR TBSS clusters (cluster extension)

r

r2

p (2-tailed)

r

r2

p (2-tailed)

L FMi (L CC body, L IFOF, L ILF, L SLF, L FMa) R FMi (R CC body, R IFOF)

0.51

0.26

0.004

0.57

0.32

0.001

0.47

0.22

0.009

0.61

0.37

0.001

Mean DA TBSS clusters

r

r2

p (2-tailed)

r

r2

p (2-tailed)

R FMi R SLF R CC R ILF R IPL R M1

-0.55 -0.67 -0.47 -0.47 -0.57 -

0.30 0.45 0.22 0.22 0.32 -

0.002 0.00005 0.009 0.009 0.001 -

-0.60 -0.59 -0.50 -0.61 -0.49

0.37 0.34 0.25 0.37 0.24

0.001 0.001 0.006 0.0004 0.008

*R, right; L, left; FMi, forceps minor; CC, corpus callosum; SLF, superior longitudinal fasciculus; CST, corticospinal tract; IFOF, inferior fronto-occipital fasciculus; ILF, inferior longitudinal fasciculus; FMa, forceps major; hCG, cingulum (hippocampal region); IPL, inferior parietal lobule; M1, primary motor cortex.


Figure 3. Left panel: Significant voxelwise between group tract-based spatial statistics (TBSS) results demonstrating A. lower fractional anisotropy (FA), B. higher radial diffusivity (DR), and C. lower axial diffusivity (DA) in both low AD risk (blue-light blue) and high AD risk (redyellow) older adults relative to young adults. Thickened thresholded p-values (tbss_fill) are overlaid on the group mean FA skeleton and displayed on a standard MNI152 brain. Tracts are labeled using the JHU white matter atlas. Right panel: Scatterplots of significant correlations between diffusivity measures (A. FA, B. DR, C. DA) and cognitive-motor performance scores. Correlation statistics are listed in Table VI. R, right; L, left; FMi, forceps minor; CC, corpus callosum; IFOF, inferior fronto-occipital fasciculus; ILF, inferior longitudinal fasciculus; SLF, superior longitudinal fasciculus; FMa, forceps major; hCG, cingulum (hippocampal region); CST, corticospinal tract; M1, primary motor cortex; IPL, inferior parietal lobule.

Importantly, and in accordance with the whole-brain TBSS analysis, the one-way ANOVA tests comparing mean FA, DR, and DA in these isolated WM clusters revealed a stepwise decline in WM integrity across groups (Figure 4). Specifically, post-hoc analyses revealed significant age-related declines in WM integrity across all clusters and diffusivity measures, which were greater in the high AD risk group. In particular, decreased FA in the right and left ILF, and decreased DA in the right CC, M1, IFOF, CST, and IPL were only

significant between the young and high AD risk groups and not between the young and low AD risk groups (highlighted by light boxes in Figure 4). Furthermore, these post-hoc analyses revealed significant differences between the low and high AD risk groups that the whole-brain analysis was not sensitive enough to detect. Specifically, FA was significantly lower in the left SLF and CST clusters, and DA was significantly lower in the right SLF cluster, in high relative to low AD risk participants (highlighted by dark boxes in Figure 4).

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Figure 4. Mean fractional anisotropy, radial diffusivity, and axial diffusivity measures in isolated white matter (WM) clusters across groups (young: light grey bars, low AD risk: medium grey bars, high AD risk: dark grey bars). Asterisks denote Bonferroni corrected post-hoc analysis results. Means +/- 1 SEM, * = < .05, ** = < .01. Dark boxes indicate clusters showing significantly lower WM integrity in high relative to low AD risk participants, and light boxes indicate clusters showing significant age-related WM declines in the high AD risk group only. FMi, forceps minor; FMa, forceps major; SLF, superior longitudinal fasciculus; ILF, inferior longitudinal fasciculus; CST, corticospinal tract; CC, corpus callosum; PMC, premotor cortex; M1, primary motor cortex; IFOF, inferior fronto-occipital fasciculus; IPL, inferior parietal lobule.

Discussion The present study revealed declines in WM integrity associated with aging that were more pronounced in older adults at increased AD risk. Specifically, declines in WM integrity in the low AD risk group mainly involved the FMi, body of the CC, and CST, while declines in the high AD risk group extended into the FMa, IFOF, ILF, SLF, and hippocampal CG. These findings are consistent with the observation that WM changes in early AD and MCI typically occur in more posterior regions, whereas changes associated with normal aging tend to occur in anterior regions [162, 163]. Furthermore, the observation that hippocampal volumes did not differ between groups and MD was not increased in regions with decreased FA is consistent with previous evidence suggesting

that alterations in WM integrity in individuals at increase AD risk are not secondary to grey matter atrophy, but rather are the result of microstructural changes without macrostructural tissue loss [119, 120]. Our most notable finding, in support of our hypothesis, was the significant relationship between participant performance on a cognitively demanding visuomotor task and the underlying WM integrity of the brain. Consistent with our previous work [127], we found that measures of timing (reaction and movement time), consistency (variable error), and accuracy (constant error and corrective path length) were significantly impaired in older adults at increased AD risk. While, in accordance with changes in sensorimotor control typically observed in normal aging [59–61], older adults at low AD risk only showed slightly increased

Diffusion Tensor Imaging Correlates of Cognitive-Motor Decline in Normal Aging and … 205 reaction times, movement times, and variable errors relative to young adults. Correlations between visuomotor performance scores and measures of FA, DR, and DA in several WM clusters (see Table VI) revealed that lower WM integrity was associated with psychomotor slowing, as well as decreased movement accuracy. In combination with the more pronounced declines in WM integrity observed in high AD risk participants in both the wholebrain and isolated WM cluster analyses, these results provide novel evidence for an association between impaired cognitive-motor performance observed in high AD risk participants and underlying WM compromise. While no known previous studies have examined the relationship between WM integrity and cognitive-motor performance in AD, these results are consistent with the finding that lower FA values correspond with worse performance on neuropsychological assessments [164, 165]. In agreement with previous DTI studies [119,120,166], our observed WM alterations in participants at increased AD risk, without any clinical symptoms of dementia, suggest that disruption to the integrity of WM tracts takes place at an early stage of disease progression. Similar to our results, previous studies in preclinical populations have found declines in FA in the posterior CC, IFOF, and left hippocampus in ApoE4 carriers relative to noncarriers [166], as well as microstructural changes in WM tracts with direct and secondary connections to the medial temporal lobe (i.e., the fornix, CG, ILF and posterior portions of the IFOF) in cognitively normal women at increased AD risk due to family history and carrying one or more ApoE4 allele(s) [119, 120]. Earlier studies have also demonstrated reduced glucose metabolism in parietal and temporal areas of ApoE4 carriers over the age of 50 with AD affected relatives [114–116]. Furthermore, individuals with a maternal family history of AD have been shown to exhibit reduced cerebral metabolic rate of glucose in the posterior cingulate cortex/precuneus, parieto-temporal cortex, frontal cortex, and medial temporal lobe [118]. Taken together, the above results suggest

that disconnection between the medial temporal lobe and neocortex, as well as between parietal and frontal regions, may occur very early in the course of AD. Villain and colleagues [10] have provided direct evidence for this “disconnection hypothesis” using whole-brain voxel-based correlations to assess the relationships between hippocampal atrophy, WM integrity, and grey matter metabolism in early AD. Their results revealed that hippocampal atrophy is specifically related to cingulum bundle disruption, which is in turn highly correlated with hypometabolism of the posterior cingulate cortex, middle cingulate gyrus, parahippocampal gyrus, and right temporoparietal association cortex. Other studies using DTI in AD patients have also revealed reduced WM integrity in large-scale networks involving the cingulum bundle [167], as well as fibers connecting prefrontal, medial temporal and parietal cortices [168]. Based on results such as these, it has been suggested that later myelinating regions with lower oligodendrocyte-to-axon ratios and smaller diameter axons are more vulnerable to myelin degeneration and thus affected earlier in the course of the disease [112, 169, 170]. In accordance with this “retrogenesis model” of AD (i.e., degeneration occurring in a reverse pattern to myelogenesis), Stricker and colleagues [113] have demonstrated lower FA and higher DR values in late-myelinating (ILF, SLF) but not early-myelinating (internal capsule, cerebral peduncles) tracts in AD patients relative to healthy controls. While direct comparisons between late- and early-myelinating tracts were not made in the present study, the greater agerelated declines in WM integrity observed in posterior regions in high AD risk relative to low AD risk participants are consistent with this retrogenesis model. Furthermore, the observation that decreased FA and increased DR occur in similar WM clusters (including those forming the hippocampal-parietal and parietalfrontal connections required for visuomotor transformations), and the observation that these changes are correlated with poorer cognitivemotor performance, suggests that myelin

206


degradation may play a role in the visuomotor impairments reported in early AD. However, declines in DA, particularly in the right hemisphere, and significant correlations with performance were also observed, suggesting the additional involvement of axonal disruption. The present study represents the first attempt to investigate the neural basis of declines in cognitive-motor control observed in older adults at increased AD risk. In summary, our whole-brain and isolated WM cluster grouplevel analyses revealed that increased AD risk was associated with greater and more widespread age-related declines in WM integrity, while our correlational analysis demonstrated significant associations between WM compromise and cognitive-motor performance. It should be noted, however, that the findings presented here only apply to a relatively small sample of women at increased AD risk. Future work is needed to determine if these results can be generalized to a larger

sample and to include men at increased genetic risk for AD. Furthermore, considering the crosssectional nature of the present study, our findings are not predictive and will require longitudinal follow-up in order to demonstrate whether or not the brain-behavior alterations observed are associated with increased risk of future decline. That being said, not only do these findings in a preclinical population provide support for the view that disruption to WM tracts may be an early identifying feature of AD [112, 119, 120, 166, 169, 170], they also provide insight into the impact of AD-related brain alterations on the neural networks underlying complex visuomotor transformations. Importantly, the correlations observed in the present study between kinematic measures on an easily administered visuomotor assessment and microstructural brain alterations suggest that visuomotor performance testing may be applied as a novel behavioral approach to identify individuals at increased AD risk.

Appendix A Mean Kinematic Measures and Discriminant Analysis for Imaging Study Participants

Appendix A Figure 1. Results of group (young: light grey bars, low AD risk: medium grey bars, high AD risk: dark grey bars) by condition (standard, non-standard) mixed ANOVAs on task dependent measures. Means +/- 1 SEM, * = < .05, ** = < .01.


Discriminant Analysis A discriminant analysis between the high and low AD risk participants included in our imaging studies was conducted in order to examine whether or not we could reproduce the results from study #1. Corrective path length and off-axis constant error from the PD+FR task were entered as predictor variables (i.e., the two variables that discriminated best between family history negative and family history positive participants in study #1). The resulting discriminant function was significant (Wilks’ Lambda = .384, p < .001), with a canonical correlation of .79. The structure matrix indicated that corrective path length was the strongest predictor (r = .94) and off-axis constant error also added predictive power (r = .68). The resulting canonical discriminant function was D

= (.08 x corrective path length) + (.204 x offaxis constant error) - 2.643 and the grouping of cases resulted in an overall classification accuracy of 90%, with a sensitivity of 80% and specificity of 100%. These results are consistent with study #1 and support the use of error measures from our cognitively demanding PD+FR visuomotor task in discriminating between high and low AD risk participants. Furthermore, we also found that the two participants from the high AD risk group who were “misclassified” as low AD risk were the only two participants from this group who were not ApoE4 carriers, while the two participants from the low AD risk group who were ApoE4 carriers had the highest discriminant scores (i.e., the largest error scores) in this group (see Appendix Figure 2).

Appendix A Figure 2. Discriminant analysis classification results for imaging study participants.

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Appendix B Mean Hippocampal Volumes for Imaging Study Participants

Appendix B Figure 1. Right and left mean hippocampal volumes compared across groups (young: light grey bars, low AD risk: medium grey bars, high AD risk: dark grey bars). No significant differences were found between groups in a one-way ANOVA test. Means +/- 1 SEM.

Appendix C Methodology and Correlational Results for Diffusion Tensor Imaging AtlasGenerated Tracts of Interest Methods In order to calculate mean diffusivity measures within major white matter (WM) tracts, tracts of interest (TOIs) were also identified using the Johns Hopkins University’s (JHU) WM probabilistic atlas. Specifically, the diffusivity maps determined using DTIFIT were nonlinear registered to a standard space template (FMRIB58_FA) using tract-based spatial statistics (TBSS). These images were then smoothed to 2 mm Full Width Half Maximum (FWHM) using fslmaths, and TOI target masks for each subject were generated using the JHU WM probabilistic atlas in fslview. The tracts included in our analysis were the forceps major,

forceps minor, superior longitudinal fasciculus (SLF), inferior frontal occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), hippocampal cingulum bundle (hCG), and the corticospinal tract (CST). Average fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (DR), and axial diffusivity (DA) measures were calculated for each TOI using fslstats. In order to correlate WM integrity with cognitive-motor performance, mean diffusivity measures extracted from each TOI were correlated with kinematic measures from the non-standard task using Pearson’s r in SPSS. Statistically significant correlations are reported at p < .05.

Results The isolated TOIs from which mean diffusivity measures were extracted for correlational analyses are displayed in Appendix C Figure 1. MD and DA were not significantly correlated with any of the kinematic measures,

Diffusion Tensor Imaging Correlates of Cognitive-Motor Decline in Normal Aging and … 209 however significant correlations were found for measures of FA and DR. Specifically, significant negative correlations were found between FA and RT (Appendix C Figure 2A), MT (Appendix C Figure 2B), and VE (Appendix C Figure 2C) within several TOIs. Accordingly, significant positive correlations were also found between

DR and RT (Figure C.2A), MT (Appendix C Figure 2B), and VE (Appendix C Figure 2C), as well as on-axis CE (not shown in Appendix C Figure 2). The statistics for these TOI-based FA and DR correlations are listed in Appendix C Tables I and II, respectively.

Appendix C Figure 1. Example tract of interest (TOI) target masks generated using the Johns Hopkins University’s (JHU) white matter probabilistic atlas and color-coding for correlation scatterplots. CST: corticospinal tract; hCG: cingulum (hippocampal region); ILF: inferior longitudinal fasciculus; FMi: forceps minor; FMa: forceps major; IFOF: inferior fronto-occipital fasciculus; SLF: superior longitudinal fasciculus.

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Appendix C Figure 2. Scatterplots of significant correlations between diffusivity measures (FA/DR) and (A) reaction time, (B) movement time, and (C) variable error. Correlation statistics listed in Appendix B Tables I and II.

Appendix C Table I. Mean FA correlations with cognitive-motor kinematics Kinematic measures

TOI

R

r2

p (2-tailed)

Reaction time

Forceps minor Left SLF Left IFOF Forceps major Right SLF Right IFOF Right CST Left CST

-0.58 -0.54 -0.43 -0.41 -0.41 -0.39 -0.39 -0.38

0.34 0.29 0.19 0.17 0.17 0.15 0.15 0.15

0.001 0.003 0.019 0.026 0.027 0.038 0.039 0.041

Movement time

Forceps minor Right CST

-0.47 -0.40

0.22 0.16

0.011 0.034

Variable error

Forceps major Forceps minor

-0.46 -0.43

0.21 0.19

0.011 0.018

TOI, tract of interest; see Figure D.1 for other abbreviation definitions.

Adults at Increased Alzheimer’s Disease Risk Display Cognitive-Motor Integration …

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Appendix C Table II. Mean DR correlations with cognitive-motor kinematics Kinematic measures Reaction time

TOI R Left SLF 0.62 Right SLF 0.54 Right CST 0.45 Right IFOF 0.37 Movement time Right CST 0.40 Left SLF 0.38 Variable error Forceps minor 0.54 Right SLF 0.43 Left SLF 0.39 Forceps minor 0.40 On-axis constant error Rights CST 0.36 TOI, tract of interest; see Figure D.1 for other abbreviation definitions.

SECTION IV Adults at Increased Alzheimer’s Disease Risk Display CognitiveMotor Integration Impairment Associated with Changes in Resting-State Functional Connectivity Kara M. Hawkins1 and Lauren E. Sergio2 1

r2 0.39 0.29 0.20 0.14 0.16 0.15 0.29 0.19 0.15 0.16 0.13

p (2-tailed) 0.000 0.002 0.015 0.049 0.031 0.041 0.002 0.017 0.035 0.028 0.050

risk population. Methods: Three groups of ten adults (young: mean age = 26.6 +/- 2.7, low AD risk: mean age = 58.7 +/- 5.6, and high AD risk: mean age = 58.5 +/- 6.9) performed a simple cognitive-motor integration task using a dual-touchscreen laptop and also underwent functional magnetic resonance imaging at rest. Results: We found poorer cognitive-motor integration performance in high AD risk participants, as well as an association with lower resting-state functional connectivity in this group. Conclusion: These findings provide novel insight into underlying AD-related brain alterations associated with a behavioral assessment that can be easily administered clinically.

Toronto Rehabilitation Institute, UHN Toronto, ON, Canada 2 Graduate Program in Kinesiology and Health Science, York University, Toronto, Ontario, Canada

This work was supported by a Canadian Institutes of Health Research Banting and Best Canadian Graduate Scholarship, Institute of Aging Special Recognition Award, and Ontario Women’s Health Scholars Award. © Kara Hawkins, 2015

Abstract

Keywords: Alzheimer’s disease, Visual-spatial processing, Cognitive-motor interaction, Functional connectivity, Resting state functional connectivity

Background: Many neuroimaging parameters have demonstrated utility as biomarkers in preclinical AD, including resting-state functional connectivity in the default mode network. However, neuroimaging is not a practical, cost effective screening instrument. Objective: Here we investigate the relationship between performance on a cognitive-motor integration assessment and alterations in resting-state functional connectivity in an at-

Reprinted from the Journal of Alzheimer’s Disease, in press, Hawkins KM & Sergio LE, Adults at increased Alzheimer’s disease risk display cognitive-motor integration impairment associated with changes in restingstate functional connectivity, Copyright (2016), with permission from IOS Press [171].

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Introduction Current clinical criteria for the probable diagnosis of Alzheimer’s disease (AD), largely involving behavioral assessments of short-term and episodic memory, can only identify individuals after significant damage to the brain has already occurred [100]. In order to develop and evaluate treatments to prevent or delay neurodegeneration, research investigating early disease detection strategies is essential. In recent years, four approaches in particular have been widely used to identify individuals at increased risk for AD [100]: 1) apolipoprotein E epsilon 4 (ApoE4) genotyping, in which individuals who carry the ApoE4 allele are at greater risk of lateonset AD, amyloid deposits in the walls of cerebral blood vessels, and cognitive decline in normal aging [102], 2) family history, in which individuals who have a first-degree relative with AD are more likely to develop the disease then those who do not [137–139], 3) amyloid-beta (Aβ) imaging, whereby a high level Aβ deposition in the brains of cognitively healthy individuals is associated with increased AD risk and future declines in episodic and working memory [103], and 4) neuropsychological tests of subtle cognitive changes (i.e., mild cognitive impairment – MCI), whereby a clinical diagnosis of MCI (particularly amnestic MCI) is associated with increased risk of progressing to AD dementia [105]. Using these methods to identify at-risk groups and compare neuroimaging measures relative to cognitively healthy low-risk groups can provide important insight into early brain changes that may prove useful in developing biomarkers for the early detection of AD pathology and the prediction of dementia before the onset of clinical symptoms. The accumulation of recent evidence from functional connectivity and DTI studies provides support for the view that AD is a disconnection syndrome with cognitive impairment resulting from disruption to functional activity across interconnected brain regions [172, 173]. Furthermore, evidence in preclinical populations of functional and structural disconnection suggests this may be an early identifying feature

of the disease [112, 119, 120, 122–126, 169, 166, 170, 174, 175]. E.g., several studies using resting-state functional magnetic resonance imaging (rs-fMRI) in preclinical AD have demonstrated reduced functional connectivity across interconnected cortical regions including the precuneus, lateral parietal, lateral temporal, and medial prefrontal cortices, known as the default mode network (DMN), that are normally active in correlation with each other during rest [119, 120, 166, 169, 170]. One way to test the integrity of communication among different brain regions is to employ a task that requires the integration of different domains. To this end there have been recent behavioral demonstrations of impaired visuo-motor control under cognitively demanding conditions, which requires sound connections between disparate brain regions, in early and preclinical AD [1–6, 89, 127, 149]. Specifically, these populations demonstrate impaired reaching performance on visually-guided tasks that rely on the ability to inhibit the default tendency to move towards a visual stimulus, in order to move in the opposite direction and/or in a different spatial plane [1, 125, 126, 149, 175]. Initial evidence for the neural underpinnings of such impairment comes from our previous structural neuroimaging work in preclinical AD, which demonstrated an association between diffusion tensor imaging (DTI) measures of white matter (WM) integrity and cognitive-motor performance [148]. Here we test the utility of a simple behavioral cognitive-motor integration task to serve as a marker for disrupted reciprocal communication in resting-state functional neural networks. Specifically, we test the hypothesis that the cognitive-motor integration deficits observed in high AD risk participants may be associated with brain alterations disrupting reciprocal communication in the DMN. By investigating the relationship between measures of neural network efficiency and simple kinematic measures of cognitive-motor integration performance in preclinical AD, we provide novel insight into a pragmatic, clinically accessible behavioral assessment for early disease detection.


Materials and Methods Participants The same thirty right-handed female participants as in Hawkins et al. [148] were included in this study: 10 healthy young controls (mean age = 26.6 +/- 2.7), 10 low AD risk older adults (mean age = 58.7 +/- 5.6), and 10 high AD risk older adults (mean age = 58.5 +/- 6.9). In this preliminary study, we focused on female participants due to the greater prevalence of AD in this population [150,151], evidence that women who carry the ApoE4 allele may be particularly vulnerable to AD pathology affecting brain connectivity [152], and in order to avoid sex-related confounds inherent in brain imaging studies when there is not enough data available to perform sex-difference analyses. Exclusion criteria were vision or upper-limb impairments, medical conditions that would hinder task performance (e.g., severe arthritis), neurological or psychiatric illnesses (e.g., schizophrenia, depression, alcoholism, epilepsy, Parkinson’s disease), and/or history of stroke or severe head injury. Participants were not specifically questioned about chronic conditions such as hypertension or diabetes, which could have an impact on white matter integrity and brain connectivity, however none reported these conditions during the screening interview and

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there is no reason to suspect any group differences. Classification as high AD risk was based on reporting either a maternal, multiple, or early-onset family history of AD [137–139], but with no cognitive impairment as indicated by the Montreal Cognitive Assessment (MoCA). Since paternal history alone may not carry the same increased risk as maternal history, this was not included as part of the high AD risk classification [118,141,142]. Low AD risk participants were age-matched with high AD risk participants and reported no dementia of any type within their known family history, expressed no memory complaints beyond normal expectations for their age and scored at or above age- and education-adjusted norms on the MoCA. Older adult participants also provided saliva samples for ApoE genotyping (Viaguard Accu-metrics, Toronto ON), which supported the increased genetic risk in our positive family history sample (i.e., 80% ApoE4 carriers). Demographic characteristics for all study participants are summarized in Table I. The study protocol was approved by the Human Participants Review Sub-Committee, York University’s Ethics Review Board, and conforms to the standards of the Canadian Tri-Council Research Ethics guidelines.

Table I. Demographic characteristics of subjects

Number Age (SD) Years of education (SD) MoCA score (SD) ApoE genotype (% E4 carriers)

Young 10 26.6 (2.7) -

Low AD Risk 10 58.7 (5.6) 17.9 (3.1) 27.9 (1.7) 20%

High AD Risk 10 58.5 (6.9) 16.8 (3.1) 28.3 (2.2) 80%

SD: standard deviation; MoCA: Montreal cognitive assessment; ApoE: apolipoprotein E.

Rule-Based Visuomotor Assessment Our visuomotor assessment is described in detail in Hawkins and Sergio [127]. Briefly, participants were tested on two visuomotor

transformation tasks presented on an Acer Iconia 6120 dual-touchcreen tablet. In one task the spatial location of the viewed target and the required movement were the same (standard task), and in the other, more cognitively

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demanding non-standard task, the location of the viewed target was dissociated from the required movement (i.e., in both a different spatial plane and in the opposite direction; Figure 1A). These two tasks were presented in a random order across participants and consisted of five pseudorandomly presented trials to each of four peripheral targets (from a common central ‘home’ target), for a total of 20 trials per

condition and 40 trials per participant (Figure 1B). Participants were instructed to move as quickly and accurately as possible. Each participant was also given two practice trials per target prior to each condition and their eyes were monitored throughout the experiment using a webcam to ensure compliance with the task instructions (i.e., always look towards the visual target).

Figure 1. (A) Schematic drawing of the two experimental conditions. Light grey circle, eye, and hand symbols denote the starting position for each trial (i.e., the home target). Dark grey eye and hand symbols denote the instructed eye and hand movements for each task. Dark grey circle denotes the peripheral target, presented randomly in one of four locations. White square denotes the cursor feedback provided during each condition. (B) Trial timing. Open circles denote nonilluminated target locations. Disappearance of the home target (which occurred at the same time as presentation of the peripheral target) served as the “go-signal” to initiate movement. CHT: center hold time, RT: reaction time, MT: movement time, THT: target hold time. Reprinted with permission from Hawkins et al. [148].

Imaging Data Acquisition A 3 Tesla Siemens Trio scanner was used to acquire anatomical and functional magnetic resonance imaging (MRI) data. Sequences included a high-resolution T1-weighted anatomical scan using magnetization prepared rapid gradient echo (MPRAGE), and an echo planar imaging (EPI) sequence sensitive to blood-oxygenation-level dependent (BOLD) contrast. The MPRAGE sequence consisted of 192 sagittal slices with a slice thickness of 1 mm with no gap, field of view (FOV) of 256 mm x

256 mm, and a matrix size of 240 x 256, resulting in a voxel resolution of 1 x 1 x 1 mm3 [repetition time (TR) = 2300 ms, echo time (TE) = 2.96 ms, flip angle = 9°]. For the functional sequence, participants were asked to lie still in the scanner with their eyes closed for six minutes and to let their mind wander. 35 axial slices were acquired with a TR of 2000 ms, TE of 30 ms, flip angle of 90°, slice thickness of 4 mm with no gap, FOV of 210 mm x 210 mm, and matrix size of 56 x 70, resulting in a voxel resolution of 3 x 3 x 4 mm3.


Kinematic Data Analysis A custom written C++ application was used to record and convert the touchscreen data to MATLAB format in order to calculate kinematic outcome measures [127]. On- and off-axis constant errors (CE), measuring accuracy, were computed as the average distance between the target and the ballistic (initial) movement endpoints. Variable error (VE), measuring precision, was computed as the standard deviation of the ballistic movement endpoints. Corrective movements (CPL: corrective path length) were quantified as the difference between the total path length and the ballistic path length. Reaction time (RT) and movement time (MT) were calculated as the time between disappearance of the home target (‘go signal’) and movement onset, and the time between movement onset and the final movement endpoint, respectively. All kinematic measures were averaged across the four peripheral targets. For the non-standard condition, these kinematic measures were summarized into error and timing scores by calculating z-scores and averaging across the CE, VE, and CPL variables, and the RT and MT variables, respectively. These performance error and timing scores from the non-standard condition were then used to assess the relationship between cognitive-motor performance and resting-state functional connectivity in our seed-based correlational analyses.

Imaging Data Analysis Imaging data were analyzed using the Oxford Center for Functional Magnetic Resonance Imaging of the Brain (FMRIB) Software Library (FSL - http://www.fmrib.ox .ac.uk/fsl; [176]). First, in order to identify regions with coherent spontaneous fluctuations in the BOLD signal, a temporally concatenated independent component analysis (ICA) was applied to the resting state data using FSL’s MELODIC. For each experimental group, the 2D matrices of each subject’s preprocessed (i.e.,

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high-pass filtered at 0.01 Hz, MCFLIRT motion corrected, slice timing corrected, spatially smoothed by an 8 mm FWHM Gaussian kernel, and registered to standard MNI space) functional data set were stacked on top of each other, and then a single ICA was run on this concatenated data matrix. This approach allowed us to look for common spatial patterns in the resting state data without assuming that the associated temporal response was consistent between subjects. In order to minimize false-positives, a threshold level of 0.66 was used. The spatial maps generated by the MELODIC ICA allowed us to identify the component representing the default mode network (DMN), which was then isolated using the ‘fslsplit’ command. In order to estimate a “version” of the healthy young grouplevel DMN functional connectivity for each subject, the FSL ‘dual_regression’ command was used to regress the young DMN spatial map into each subject’s 4D dataset, resulting in a set of time courses. These time courses were then regressed into the same 4D dataset to get subject-specific spatial maps of the DMN [177]. The FSL ‘cluster’ and ‘fslmaths’ commands were also used on the subject-specific spatial maps in order to determine the peak activations (local maxima) and cluster sizes within each subject’s DMN. In order to conduct seed-based analyses, the DMN cluster coordinates generated in standard MNI space by FSL MELODIC for each subject were converted to functional space using the FSL command ‘std2imgcoord’. Eight seed regions were isolated, including the precuneus (PCUN), medial frontal cortex, right/left parietal cortex, right/left middle temporal gyrus (MTG), and right/left middle frontal gyrus (MFG). Seed masks (6 mm radius) for each subject were then generated around these coordinates in functional space. Next, the raw functional data were preprocessed, which included applying a high pass filter (0.01 Hz), motion correction (MCFLIRT; [154]), slice timing correction (interleaved), removal of non-brain structures, spatial smoothing (6 mm FWHM), and registration to both brain-extracted anatomical (BET; [155]) and standard (MNI152) images. A

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5th order bandpass Butterworth filter was then applied in MATLAB in order to include only low-frequency fluctuations in the BOLD signal between 0.01 and 0.1 Hz [178]. These preprocessed and filtered resting state data were then used to calculate the average time series of all voxels in each seed mask for each volume in every subject. In order to calculate mean white matter, cerebral spinal fluid, and global signals for use, along with the translational and rotational motion correction parameters, as nuisance regressors, the brain-extracted anatomical images were also segmented using FMRIB’s Automated Segmentation Tool (FAST; [179]). Prior to running group-level statistical analyses, within subject first-level analyses were run for each seed region using FSL’s FMRI Expert Analysis Tool (FEAT), with the above nuisance regressors entered as additional confound variables and the seed time course entered as the predictor variable.

Statistical Analysis Statistical analyses of the behavioral data were carried out in SPSS and included a mixeddesign analysis of variance (ANOVA) to compare all six kinematic measures across the two task conditions and between the three experimental groups, as well as one-way ANOVAs to compare the summarized nonstandard error and timing z-scores between the three experimental groups. Post hoc analyses were adjusted for multiple comparisons using Bonferroni correction and were considered statistically significant a p < .05. In order to statistically compare the DMN spatial maps between groups, permutation testing (thresholded at p < 0.05 and corrected for multiple comparisons using threshold-free cluster enhancement - TFCE) was applied using the FSL ‘randomise’ command. Peak activations and cluster sizes for the six classic DMN clusters (precuneus, medial frontal, right/left parietal, and right/left temporal; [172,180]) were also compared between the high and low AD risk

older adult groups using independent samples ttests in SPSS (alpha-level = 0.05). Since no significant age-related declines in DMN functional connectivity were observed (based on the DMN spatial maps permutation testing between young and older adult low AD risk groups), we restricted our seed-based correlational analyses examining the relationship between resting-state functional connectivity and cognitive-motor performance to older adult participants. Specifically, group-level analyses comparing low and high AD risk older adults, with error and timing scores entered as covariates of interest, were run separately in FEAT for each DMN seed region using FMRIB’s Local Analysis of Mixed Effects modeling (FLAME 1; cluster-thresholding for multiple comparisons: z = 2.7, p = 0.05). The purpose of this analysis was to examine the effects of error and timing scores on functional connectivity between the eight isolated DMN seed regions and the rest of the brain. Specifically, a significant positive effect of error or timing score would suggest an association between greater functional connectivity and poorer performance, whereas a significant negative effect would suggest the expected association between impaired functional connectivity and poorer performance (i.e., larger error and timing scores). For seed regions where significant effects of error and/or timing score(s) on functional connectivity were found, mean z-transformed r-values across all voxels were calculated for each participant and scatterplots were generated by correlating these values with error or timing scores in SPSS (twotailed Pearson’s r; alpha-level = 0.05).

Results Kinematic Data The ANOVA analyses demonstrated that all three groups performed similarly across all outcome measures in the standard visuomotor task, whereas performance in the non-standard task was significantly slower, less accurate and

Adults at Increased Alzheimer’s Disease Risk Display Cognitive-Motor Integration … less consistent in the high AD risk group. These cognitive-motor deficits observed in high AD risk participants are summarized in Fig. 2, illustrating that error scores were significantly larger in high AD risk relative to both young and low AD risk participants (F2,27 = 21.39, p menthone > pyridine, consistent with the hypothesis that pleasant odors are more appreciated in left hemisphere and unpleasant odors more in right hemisphere. Anterior frontal and temporal cortex regions previously found activated by imagination and smell of odors accounted for most hemispheric differences. Henkin and Levy, [134] later employed fMRI to define brain activation in response to odors and imagination (“memory”) of odors and tastes in patients who never recognized odors (congenital hyposmia). These authors studied nine patients with congenital hyposmia as they responded to odors of amyl acetate, menthone, and pyridine, to imagination (“memory”) of banana and peppermint odors, and to salt and sweet tastes. Functional MR brain scans were compared with those in normal subjects and patients with acquired hyposmia. The authors found that brain activation in response to odors was present in patients with congenital hyposmia, but activation was significantly lower than in normal subjects and in patients with acquired hyposmia Regional activation localization was in anterior frontal and temporal cortex similar to that in normal subjects and patients with acquired hyposmia. Activation in response to presented odors was diverse, with a larger group exhibiting little or no activation with localization only in anterior frontal and temporal cortex and a smaller group exhibiting greater activation with localization extending to more complex olfactory integration sites. “Memory” of odors and tastes elicited activation in the same central nervous system regions in which activation in response to presented odors occurred, but responses were significantly lower than in normal subjects and patients with acquired hyposmia and did not lateralize. Odors induced CNS activation in patients with congenital hyposmia, which distinguishes

olfaction from vision and audition since neither light nor acoustic stimuli induce CNS activation. Henkin and Levy concluded that odor activation localized to anterior frontal and temporal cortex is consistent with the hypothesis that olfactory pathways are hard-wired into the CNS and that further pathways are undeveloped with primary olfactory system CNS connections but lack of secondary connections. However, some patients exhibited greater odor activation with response localization extending to cingulate and opercular cortex, indicating some olfactory signals impinge on and maintain secondary connections consistent with similar functions in vision and audition. Activation localization of taste “memory” to anterior frontal and temporal cortex is consistent with CNS plasticity and cross-modal CNS reorganization as described for vision and audition. Thus, there are differences and similarities between olfaction, vision, and audition; the differences are dependent on the unique qualities of olfaction, perhaps due to its diffuse, primitive, fundamental role in survival. These studies add further support in employing odor intervention strategies in neurobehaviorally-involved children in programs of differential hemispheric activation. The effect of the olfactory system on the limbic system is profound especially when we consider the evolutionary development of the brain. The limbic system is intimately connected to the rhinencephalon or primitive “nose brain.” Therefore, we would expect that odors or pheremonal activity would have direct affect on emotions, autonomic regulations, and through effects on the parahippocampal complex, on memory acquisition. Although it has been generally accepted that the sense of smell is the only sense that is not related to the thalamus, there has been recent evidence of a hypothalamic -thalamo-cortical circuit mediates pheremonal influences on eye and head movement [135]. Through this mechanism, pheremonal activity is thought to regulate attentional mechanisms. Risold and Swanson used a method for simultaneous iontophoretic (movement of ions as a result of an applied

What Functional Neurology Can Offer the Treatment of Developmental Disabilities electric filed) injections of anterograde tracer phaseolus vulgaris leukoagglutinin and the retrograde trace of flora gold was used to characterize in the rat a hypothalamic-thalamocortical pathway ending in a region thought to regulate attentional mechanisms by way of eye and head movement. The investigators thought that the relevant medial hypothalamic nuclei receive pheremonal information from the amygdala and project to specific parts of the thalamic nucleus reuniens and antero-medial nucleus, which then projects to a specific lateral part of the retrosplenial area (or medial visual cortex). They note that this area receives convergent input from the lateral posterior thalamic nucleus and projects to the superior colliculus. In addition, bi-directional connections with the hippocampal formation suggest that activity in this circuit is modified by previous experience. Risold and Swanson [135] note that there are striking parallels with basal ganglia circuitry. In discussion of their results, they note that their evidence suggests that the rostral medial zone nuclei of the hypothalamus participate in a thalamo-limbic projection similar to the classic mammillo-thalamic limbic projections from the caudal medial zone and that the former receives olfactory information and modulates well established attention mechanisms involving eye and head movement. In regard to intra-cortical projections of the retro-splenial area, these are divided into three streams. One major stream extends rostrally to end in the anterior cingulate caudal pre-limbic and ventral lateral orbital areas. They note that their double injection results suggest that the first two areas project back to the retro-splenial area. This is of interest because in the rat, anterior and to a lesser extent caudal pre-limbic areas are thought to be associated with the frontal eye fields along with the adjacent secondary motor areas mainly because they project to several brainstem regions involved in ocular motor control including the superior colliculus [136]. It is also noted that the anterior cingulate and the secondary motor areas receive inputs from the lateral posterior thalamic nuclei and the medial dorsal nucleus No. 17 [135]. The

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anterior cingulate area receives input from the lateral dorsal nucleus No. 20 [137] and the rostral nucleus reuniens. Risold and Swanson [135] suggest that information arriving at the rostral medial hypothalamus from pheremonal cortex (in the cortical medial amygdala ) projects to the midbrain motor regions by descending pathways, as well as to parts of the cerebral cortex involved in regulating eye and head movements by ascending pathways to the rostral nucleus reuniens and ventral intermedial nucleus. They note that the hippocampal formation participates in conceptually similar circuitry involving the caudal medial hypothalamus (mammillary body), which is thought to give rise to the mammillo-thalamic and mammillo-tegmental tracks. Iso-cortical regions project to the basal ganglia, which in turn generate descending projections to mid-brain motor regions and ascending projections to secondary motor cortical regions by way of the ventral anterior thalamic nucleus. In summary Risold and Swanson [135] state that their model predicts that the rostral nucleus reunions and ventral anterior medial nucleus projecting to the retrosplenial area pathway, conducts pheremonal information to a polymodal cortical mid-brain pathway eliciting attentional motor responses involved in the procurement phase of appropriate motivated or goal directed behavior. We know that goal directed behavior is a function of the prefrontal cortex and approach and avoidance behavior. Olfactory stimulation therefore would be expected to increase frontal cortex activation through its affect on orbital-frontal and frontal eye fields, as well as secondary motor cortex. Olfactory stimulation affects limbic structures like the amygdala and hypothalamus, which regulate emotional and autonomic responses and which are inhibited by frontal cortical activity. It can also influence learning and memory through its affect on the hippocampal formation and intra-hippocampal circuit. The intrahippocampal circuit plays a critical role in shortterm episodic or declarative memory [135].

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Gerry Leisman and Robert Melillo

Olfactory stimulation also affects the anterior and posterior cingulate areas, which have been implicated in several aspects of spatial memory [138]. By affecting attentional mechanisms of eye and head movements, it would also be expected that there may be influence on cerebellar activity either through affects on ocular-motor or brainstem motor nuclei. Therefore, the use of olfactory therapy or pheremonal activity has a neurophysiological basis for affecting both learning abilities and behavioral and emotional disorders.

Integrated Sensory-Motor Intervention Strategies According to practitioners, Occupational Therapy is a health profession concerned with improving a person’s occupational performance. In a pediatric setting, the Occupational Therapist deals with children whose occupations are usually players, preschoolers, or students. The Occupational Therapist evaluates a child’s performance in relation to what is developmentally expected for that age group. If there is a discrepancy between developmental expectations and functional ability, the OT looks a variety of perceptual and neuromuscular factors, which influence function. A. Jean Ayres [139] is credited with having first identified sensory integrative dysfunction, which is defined as an irregularity or disorder in brain function that makes it difficult to integrate sensory input effectively. It is thought that sensory integrated dysfunction may be present in motor, learning, social, emotional, speech, language, or attention disorders. Ayres thought that proprioceptive input is extremely important to the function of the sensory system and the brain as a whole. She identified gravity as an important input to the central nervous system because of its constancy of input. She thought that the primary source of this proprioceptive and gravitational input was from the vestibular apparatus of the inner ear and the vestibular system. She called this the cerebellar vestibular system. She thought that this system was a

primary force in brain development. This was insightful considering the paucity of research to then support her theories of the development and function of the brain. Her observations and results were impressive enough that now Occupational Therapy with its developmental early intervention focus is universally adopted. The vestibular apparatus and its receptors do not vary their sensitivity or influence the brain directly. The balance and sensitivity of the apparatus is set by the function of the cerebellum and the function of the cerebellum is a product of the service of four major pathways: (1) the visual system, (2) the proprioceptive system from muscles and joints, especially the cervical spine, (3) the vestibular system, and (4) the cerebral cortex. Since the cerebral cortex is just forming in a developing child and the vestibular and visual systems are relatively constant, the proprioceptive system is by far the most important to the cerebellum and its effects on the thalamus and the neocortex. Ayres observed that children with learning and neurobehavioral problems exhibit what she termed sensory defensiveness. It was thought that this sensory defensiveness was the result of an over-activation of our protective senses. It was noticed that some children had decreased responses to sensory stimuli and some appeared to have increased sensitivity to sensory input. We now have a better way of understanding and explaining these observations and realize that both are the product of decreased sensory input to the cerebellum, thalamus, and neocortex. The cerebellum has two halves as does the cerebrum. These two halves must be balanced in their activation. If they are not, the hemisphere with decreased activity may initially be less sensitive to incoming sensory stimuli with an increased threshold of activation because the neurons are less active. However, over time, this decreased activation causes the cells to shift closer to threshold as a compensatory mechanism. This makes the child more sensitive to stimuli that affect the dysfunctional half of the cerebellum. Tactile, proprioceptive, extra-ocular, and vestibular input indeed results in over-firing of the cerebellum. The child will experience lower

What Functional Neurology Can Offer the Treatment of Developmental Disabilities threshold to touch, movement of the head, neck, or body expressed as motion sickness, disordered eye movements, or visual perceptual disturbances. Cerebral activity associated with cognition or emotion also can make the cerebellum fire aberrantly and the cells, which have less endurance or fatigability to this input, may cause these cells to produce free radicals and result in oxidative stress injury to these same cells [140]. In the basal ganglia this may produce hyperkinetic and/or hypokinetic behavior through the same process. In the cerebrum, we recognize this as epilepsy, epileptiform activity, or spontaneous firing of neurons [5, 11]. Ayres [139] observed the symptoms of this process and described several types of sensory defensiveness. 1

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Tactile defensiveness: Children with tactile defensiveness avoid letting others touch them and would rather touch others. They frequently fuss or resist hair washing or cutting. They may act as if their life is being threatened when being bathed or having clothes changed. Some types of clothes, clothing labels, or new clothes often irritate these children. They may dislike being close to others or avoid crowds. People accidentally bumping into them can agitate them. They often do not like to get their hands or feet dirty. They may seem unnecessarily rough to people. Some may bump or crash into things on purpose as a way of seeking sensation or seen under responsiveness to certain sensations or pain. Oral defensiveness: Some children dislike or avoid certain textures or types of foods. They may be over or under sensitive to spicy or hot foods, avoid putting objects in their mouth and/or intensely dislike teeth brushing or face washing. Sometimes have a variety of feeding problems since infancy. Gravitational insecurity: This appears to be an irrational fear of change in

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position or movement. These children are often fearful of having their feet leave the ground or having their head tip backwards. Postural insecurity: This is a fear and avoidance of certain movement activities due to poor postural mechanisms. Visual defensiveness: This may involve an over sensitivity to light and visual distractibility. With this problem, children may avoid going outside in certain light and/or need to wear hats or sunglasses to block out light. They may startle more easily and/or overt their eyes or seem to avoid eye contact. Auditory defensiveness: This reflects an over sensitivity to certain sounds and may involve irritable or fearful responses to noises like vacuum cleaners, motors, fire alarms, etc. Children sometimes make excessive amounts of noise to block out sounds [cf. 139]. Other symptoms can include unusual sensitivity to taste and/or smell (cf. preceding section).

When we understand how the cerebellum functions and how it affects the thalamus and cerebral cortex, we will then be able to explain more fully all of the symptoms of autistic spectrum disorders as a primary deficit or imbalance of cerebellar -cortical activation. We remember that the primary output of the cerebellar cortical cells or Purkinje cells is inhibitory to the cerebellar output nuclei. The cerebellum also controls motor coordination, balance, postural stability, and extra-ocular eye movements. It also activates the thalamus, which relays all sensory input to the cerebrum. Decreased activation of the cerebellum results in its dysfunction even though it may be more sensitive to input and may cause decreased stability of thalamus and cerebrum, even though the overall level of stimulation is decreased. This decreased threshold or increased signal-to-noise ratio may cause the cells to fire prematurely, they may reach oxidative stress earlier. This

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increased sensitivity is a product of decreased activation and is perceived as unpleasant by the child. This explains why a child with the same problem can present differently with one being over-reactive to certain stimuli and another being under-reactive. The underlying problem is the same, a lack of the central nervous system being properly activated. The same lack of stimulation can produce hyperkinetic behavior, while another may present with hypokinetic behavior. Ayres devised a number of ways of treating these problems of sensory defensiveness. In Occupational Therapy, the approach to treatment primarily involves vestibular, proprioceptive, and tactile stimulation along with behavior modification techniques. Examples of some of these treatments for particular problems are: 1

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Tactile defensiveness: OT treatment approaches include applying rapid and firm pressure touch to arms, hands, back, legs, and feet with a nonscratching brush with many bristles. The brushes recommended are specific plastic surgical scrub brushes. This is followed by gentle joint compression to the shoulders, elbows, wrists, hips, knees, ankles and sometimes fingers and feet. This treatment is recommended because the results are effective for short periods. Occupational Therapists note that if these procedures are applied consistently over time, the defensiveness is permanently reduced or even eliminated. Deep pressure touch, compression, or traction to the joints and heavy muscle action together is a special combination to reduce or eliminate sensory defensiveness. (Summation of sensation that is neurologically experienced in a short period over a large body space). Oral defensiveness: OT treatment of applying heavy pressure across the roof of the mouth and giving input to the temporo-mandibular joint. Oral motor activities are also used that involve

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biting or resistive sucking use with a knot on the end, fruit roll-ups, beef jerky, etc. to bite and pull on. Occupational Therapists use small straws, sports bottles, plastic tubes, etc. for sucking as well as mouth toys that involve sucking and blowing. Gravitational and postural insecurity: in which treatment includes jumping on bouncing surfaces, trampolines, bed mattresses, or on the floor with jarring action, jumping and crashing into piles of pillows or beanbag chairs, bouncing while sitting on an inflated ball, play wrestling, swinging on suspended tire inner tubes, “frog” sling swings, wet hammocks, platform swings, and “bungy” cords. Climbing and crawling over an under large pillows, beanbag chairs, jungle gyms, rocks, trees, upstairs, on hands and knees through obstacle courses made of furniture, balance activities, walking on a balance beam, rocker and wobble boards, fine motor coordination, handwriting, and peg board drawing.

A significant number of outcome studies have indicated the effectiveness of this approach to treatment along with support of Ayers’ [139] concept of sensory defensiveness. [e.g., 141,142] In general though, OT techniques do not utilize a specific approach based on asymmetric hemispheric function or deficits.

Theories of Physical-Mechanical Interventions The Effects of Physical Exercise on Cognitive Performance If there is one activity that seems to be the “magic bullet” against almost every disease or disorders, it is exercise, especially aerobic exercise. It seems almost every day a new study shows exercise to reduce the risk and severity of a new disease from cancer to the common cold to depression, exercise seems to be the one thing

What Functional Neurology Can Offer the Treatment of Developmental Disabilities that prevents or cures them all. There have been many theories proposed as to why exercise has such dramatic health benefits. Some think it is because of its affect on heart and cardiovascular system. Some think because of its affect on the endocrine system, while others think it affects the immune system. The fact is that it affects all of these systems but aerobic exercise most impact the efficient functioning of the central nervous system. When one modality affects all of the systems of the body, it must be because of a primary affect on the brain. As we have seen, autonomic, immune, endocrine, cognitive, emotional, and sensory systems are all asymmetrically distributed in the brain. Exercise therefore must have a generalized affect on all brain functions. As we know, the primary source of activation of the brain is through the motor system, therefore, high frequency low intensity activity of the motor system will have powerful affects on the global activation, arousal, and attention of the cerebellum, thalamus, basal ganglia and cerebrum. Aerobic exercise affects all muscles of the body including the involuntary postural antigravity muscles, as well as the voluntary muscles of the extremities and trunk. It also increases the efficiency of the cardiovascular system to deliver blood and oxygen to the brain, and increases the capacity of the lungs to take in oxygen. We would expect, therefore, that exercise would be helpful in improving a child’s ability to learn and control behavior and to focus attention. Lack of physical activity would be expected to cause the opposite affect. It has been demonstrated that mice who regularly exercise on running wheels had twice the number of new brain cells compared to sedentary mice. One of the study’s authors, Fred Gage, has said that, “More people in my lab have started running since we found this result.” The studies published in the Proceedings of the National Academy of Sciences and in Nature, Neuroscience by Henriette van Praag and colleagues [143, 144] are remarkable in several ways. Gauge’s laboratory demonstrated that humans along with mice and non-human primates do grow new brain cells after birth. In a

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previous study, the Salk researchers had found that those mice who had “enriched environment” with a tunnel, toys and an exercise wheel grew more cells than those in regular lab cages [145]. What’s more, in the area of new brain cell growth, the hippocampus is associated with learning and memory. Researchers thought that it might not just be running per se, but exercise in general that causes the growth of new brain cells. Does growing more brain cells mean the running mice are necessarily smarter? Henriette Van Praag and Gauge have said it is reasonable to think so because previous studies on “enriched environment” mice showed that they perform better on learning tasks. Exercise has been shown to enhance cognitive function and to help stroke victims recover from brain injury [146, 147]. The type of exercise is important and the combination of physical activity and mental focus or “purposeful” activity at the same time or close together, appear to yield the greatest changes. Nudo and associates [148] documented plastic changes in the functional topography of primary motor cortex (M1) that are generated in motor skill learning in the normal, intact primate. The investigators employed intracortical micro-stimulation mapping techniques to derive detailed maps of the representation of movements in the distal forelimb zone of M1 of squirrel monkeys, before and after behavioral training on two different tasks that differentially encouraged specific sets of forelimb movements. After training on a small-object retrieval task, which required skilled use of the digits, their evoked-movement digit representations expanded, whereas their evoked-movement wrist/forearm representational zones contracted. These changes were progressive and reversible. In a second motor skill exercise, a monkey pronated and supinated the forearm in a key (eyebolt)-turning task. In this case, the representation of the forearm expanded, whereas the digit representational zones contracted. Their results show that M1 is alterable by use throughout the life of an organism. These studies also reveal that after digit training there was a real expansion of dual-

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response representations, that is, cortical sectors over which stimulation produced movements about two or more joints. Movement combinations that were used more frequently after training were selectively magnified in their cortical representations. This close correspondence between changes in behavioral performance and electrophysiologically defined motor representations indicates that a neurophysiological correlate of a motor skill resides in M1 for at least several days after acquisition. The finding that co-contracting muscles in the behavior come to be represented together in the cortex argues that, as in sensory cortices, temporal correlations drive emergent changes in distributed motor cortex representations. Tantillo and associates [149] had performed a study examining the effects of exercise on children with ADHD evaluated by studying the rate of spontaneous eye blinks, the acoustic startle eye blink response (ASER), and motor impersistence. The children evaluated, both male and female, were between 8 and 12 years old all meeting the DSM-III-R criteria for ADHD. All children in their study ceased methylphenidate medication 24 hours before and during each of three daily conditions. After a maximal treadmill walking test to determine cardio-respiratory fitness (VO(2peak)), each child was randomly assigned to counterbalanced conditions of treadmill walking at an intensity of 65-75 percent VO(2peak) or quiet rest. Responses were compared with a matched group of control participants. Boys with ADHD had increased spontaneous blink rate, decreased ASER latency, and decreased motor impersistence after maximal exercise. Girls with ADHD had increased ASER amplitude and decreased ASER latency after sub-maximal exercise. The authors’ findings suggest an interaction between sex and exercise intensity that is not explained by physical fitness, activity history, or selected personality attributes. Their findings support the employment of vigorous exercise programs as adjuvant in the management of the behavioral features of ADHD.

Elliot and associates [150] examined the effects of antecedent exercise conditions on maladaptive and stereotypic behaviors in 6 adults with both autism and moderate to profound mental retardation. The behaviors were observed in a controlled environment before and after exercise and non-exercise conditions. From the original group of participants, two were selected subsequently to participate in aerobic exercise immediately before performing a community-integrated vocational task. Only antecedent aerobic exercise significantly reduced maladaptive and stereotypic behaviors in the controlled setting. Neither of the less vigorous antecedent conditions did. When aerobic exercise preceded the vocational task, similar reductions were observed. There were individual differences in response to antecedent exercise. These authors note that the use of antecedent aerobic exercise to reduce maladaptive and stereotypic behaviors of adults with both autism and mental retardation is supported. Rosenthal-Malek and Mitchell [151] reported similar results. They investigated the reduction self-stimulatory behaviors in adolescents with autism after vigorous exercise. Celiberti and colleagues [152] in a detailed case study of an autistic boy also examined the differential and temporal effects of two levels of antecedent exercise (walking versus jogging) on his self-stimulatory behavior. The exercise conditions were applied immediately before periods of academic programming. Maladaptive self-stimulatory behaviors were separately tracked, enabling identification of behaviors that were more susceptible to change (e.g., physical self-stimulation and “out of seat” behavior) versus those that were more resistant (e.g., visual self-stimulation). Examination of temporal effects indicated a decrease in physical selfstimulation and “out of seat” behavior, but only for the jogging condition. In addition, sharp reductions in these behaviors were observed immediately following the jogging intervention and gradually increased but did not return to baseline levels over a 40-minute period. We now know that exercise has benefits for overall health as well as for cognitive function.

What Functional Neurology Can Offer the Treatment of Developmental Disabilities Recent studies using organism models have been directed towards understanding the neurobiological bases of these benefits. It is now clear that voluntary exercise can increase levels of brain-derived neurotrophic factor (BDNF) and other growth factors stimulate neurogenesis, increase resistance to brain insult, and improve learning and mental performance. Recently, high-density oligonucleotide microarray analysis has demonstrated that, in addition to increasing levels of BDNF, exercise mobilizes gene expression profiles that would be predicted to benefit brain plasticity processes. Thus, exercise can provide a simple means to maintain brain function and promote brain plasticity [153]. Lieberman and colleagues [154] noted that the brain requires a continuous supply of glucose to function adequately. During aerobic exercise, peripheral glucose requirements increase and carbohydrate supplementation improves physical performance. The brain's utilization of glucose also increases during aerobic exercise. However, the effects of energy supplementation on cognitive function during sustained aerobic exercise are not well characterized. The investigators examined the effects of energy supplementation, as liquid carbohydrate, on cognitive function during sustained aerobic activity. Young, healthy men were randomly assigned to 1 of 3 treatment groups. The groups received a 6 percent (by vol.) carbohydrate (35.1 kJ/kg), 12 percent (by vol.) carbohydrate (70.2 kJ/kg), or placebo beverage in 6 isovolumic doses, and all groups consumed two meals (3200 kJ). Over the 10-hour study, the subjects performed physically demanding tasks, including a 19.3-km road march and two 4.8-km runs, interspersed with rest and other activities. Wrist-worn vigilance monitors, which emitted auditory stimuli (20/h) to which the subjects responded as rapidly as possible, and a standardized self-report mood questionnaire were used to assess cognitive function. These investigators found that vigilance consistently improved with supplemental carbohydrates in a dose-related manner; the 12 percent carbohydrate group performed the best and the placebo group, the worst. Mood-questionnaire

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results corroborated the results from the monitors; the subjects who received carbohydrates reported less confusion, and greater vigor than did those who received the placebo. Supplemental carbohydrate beverages enhance vigilance and mood during sustained physical activity and interspersed rest. In addition, ambulatory monitoring devices can continuously assess the effects of nutritional factors on cognition as individuals conduct their daily activities or participate in experiments. These approaches have not been employed in studying neurobiological involved children. In an interesting study reported by Thornton and associates [155], Positron Emission Tomography (PET) was used to identify the neuroanatomical correlates underlying 'central command' during imagination of exercise under hypnosis, in order to uncouple central command from peripheral feedback. Three cognitive conditions were used: imagination of freewheeling downhill on a bicycle (no change in heart rate, HR, or ventilation, V(I)), imagination of exercise, cycling uphill (increased HR by 12 percent and V(I) by 30 percent of the actual exercise response), or volitionally driven hyperventilation to match that achieved in the second condition (no change in HR). The researchers found significant activations in the right dorso-lateral prefrontal cortex, supplementary motor areas (SMA), the right premotor area (PMA), supero-lateral sensorimotor areas, thalamus, and bilaterally in the cerebellum. In the second condition, significant activations were present in the SMA and in lateral sensorimotor cortical areas. The SMA/PMA, dorso-lateral prefrontal cortex, and the cerebellum are concerned with volitional motor control, including that of the respiratory muscles. The neuroanatomical areas activated suggest that a significant component of the respiratory response to 'exercise', in the absence of both movement feedback and an increase in CO2 production, can be generated by what appears to be a behavioral response. Lardon and Polich [156] examined the electrophysiologic effects of physical exercise by comparing groups of individuals who engage

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in regular intensive physical exercise (12 + h/week) to control subjects (2 + h/week). Electroencephalographic (EEG) activity was recorded under eyes open/closed conditions to assess baseline differences between these groups. Spectral power was less for the exercise compared to the control group in the delta band, but greater in all other bands. Mean band frequency was higher for the exercise compared to controls in the delta, theta, and beta bands. Some differences in scalp distribution for power and frequency between the exercise and control groups were found. The findings suggest that physical exercise substantially affects resting EEG and again supports the effects of exercise on brain function. Traditionally the view has been that there is a separation between motor skills and cognitive ability. However, the same pathways and same global increase activation of the areas involved with motor skill also underlie the areas that form the foundation of cognitive ability. However, the brain is activity dependent, therefore even though the potential to learn is enhanced through motor training, if a specific cognitive skill is not trained, it will not adequately develop. Humans speak, they type, they sign, they write each and intricate motor skill. In the domain of music people play the fiddle, may dance to it and they may sing or hum along. People build cabinets, knit, and blow fine glassware. These diverse motor activities are beyond the realm of other organisms and suggest that motor capabilities are related to other intellectual capabilities. Indeed some psychologists such as Jerome Bruner have suggested that even human language capability is an outgrowth of capabilities involved to create new motor sequences.” “Extensive evidence suggests that knowledge is acquired as a result of extensive practice, thousands of hours of highly dedicated practice is key in separating the most successful people in various motor and non-motor skill domains from the rest of us. This perspective grew initially out of analysis of chess expertise, but also has been found to apply to muscle performance and basketball.” Keele concluded,

“…The surprising idea that stands out in the expertise literature is that the extraordinary motor capabilities of humans are best understood as an extension of their extraordinary cognitive abilities.” When we examine “geniuses” through out history, we can see that artists and sculptors like da Vinci and Michelangelo, musicians like Bach and Mozart, were geniuses not only in their cognitive ability but also in their motor skill as well, to paint or play music.” The question is, does the constant practice of developing a motor skill like painting, or playing an instrument creates the cognitive genius or visa-versa? Motor skills develop first. We know motor skills develop first in a child but if they focus on the motor skill to the exclusion of all else, then they will not perform well in other areas of life. However, if motor skill is used as a tool to develop brain areas, and then academic and social pursuits are diligently taught, the child will learn those activities better and faster. The key is balance and in an otherwise normal child who is behind, and in a child who is developmentally delayed, the fastest and most effective way to increase the rate of development of their brain function may be through motor activity and motor development. If there is a delay in motor skill development, then there will be a subsequent delay in their cognitive and emotional development as well. Occupational Therapists think that hyperactive children often have persistent tonic neck reflexes. This is a normal reflex present in young children and they think that if this reflex persists in older children, it is not only a sign of poor neurological organization, but makes it difficult and uncomfortable for the child to sit normally. OT’s note that many children who are hyperactive are also fidgety, sit in unusual postures, especially a slumped posture or hook their feet under the chair for support. They may tend to stand when eating or doing homework and they may experience fatigue of their neck and postural muscles, which becomes painful and affects the child’s ability to concentrate. Occupational Therapists have designed a series of crawling exercises and claim that these

What Functional Neurology Can Offer the Treatment of Developmental Disabilities intervention techniques are effective in alleviating the ADD symptoms and improve academic performance and behavior. These techniques emphasize the importance of the motor system to effect the neurological development of a child’s brain and a subsequent improvement in learning and behavior. While the theory does not take into the cerebellum, differential hemispheric activation, and their effects on developing brain function into consideration, the theory does emphasize the role of postural muscles in the manifestation of the observed symptoms. Most children with learning disability and ADD do have poor postural tone, indicative of cerebellar, thalamic and frontal lobe dysfunction. Therefore, any activity emphasizing proximal and postural coordination will increase feedback to these brain regions. These activities may be more significant to right brain development and therefore would be expected to improve symptoms of right brain deficit, including hyperactivity, ADD, and behavioral problems.

Therapeutic Relations between Musculoskeletal and Cognitive Function The majority of all sensory input arises from somatosensory receptors of the musculoskeletal system and the largest percentage of that amount comes from the receptors of the spinal muscles and joints located in the upper cervical spine receptors [72]. Through the ability of these spinal receptors and based on their upright orientation and transduction of gravitational forces into electrochemical impulses that constantly bombard the brain by way of the dorsal column and spino-cerebellar and nonspecific thalamic pathways, they provide the baseline activation or arousal on which, in part, other brain activity is based. Through specific pathways, the same somatosensory receptors can affect specific cortical areas that are involved with higher functions of perception, cognition, and emotional behavior, especially in the frontal lobe.

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However, with manifestation of symptoms, especially musculoskeletal symptoms, which make up the vast majority of health complaints of humans, they are primarily symptoms of neurological dysfunction and are best treated by effecting the nervous system directly. This can be achieved by use of spinal manipulation, joint mobilization, exercise and by stimulating the brain through a variety of environmental stimuli, such as sound, light, heat, cold, odors, tactile sensation, and cognitive activities. Virtually all those with neurobehavioral disorders of childhood also demonstrate dysfunction of their motor-sensory system. Either this dysfunction of the motor-sensory system may in fact be a primary cause of the brain dysfunction or the brain dysfunction may be the primary cause of the motor-sensory dysfunction. Either way, the motor-sensory systems, which include the postural muscles and joints of the spine and neck are dysfunctional. Therefore, no matter what the primary source, an intervention strategy for the motorsensory dysfunction ought to result in an improvement of brain function and vice versa. This is especially true in the frontal lobe where we have seen that both motor and non-motor functions can be measured and a dysfunction of one is reflective of an equal dysfunction of the other. Therefore, an improvement of frontal lobe motor function associated with an improvement in a child’s motor function capacities, such as muscle tone, coordination, mobility, strength, and endurance, should also be reflective of an improvement in non-motor functions of the frontal lobe such as cognitive, emotional, and behavioral. By directing and including diagnosis and treatment of musculoskeletal system function, we develop tools of measuring and affecting central nervous system status. Luoto et al. [157] examined the relationship between musculoskeletal complaints relating to higher brain function. The authors examined the mechanisms explaining the association between lower back pain and deficits in information processing. Low back trouble, chronic pain in general and depression has been associated with impaired cognitive functions and slow reaction

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times. It is known that the preferred hand performs significantly better than the nonpreferred hand in motor tasks. The authors hypothesize that chronic low back pain hampers the functioning of short-term memory in a way that leads the preferred hand to loose its advantage over the non-preferred hand, but that the advantage would be restored during rehabilitation. Reaction times for the preferred and non-preferred upper limbs were tested in 61 healthy control and 68 low back pain patients. A multi way analysis of covariance was used to examine the group, handedness, and rehabilitation effects on reaction time. A significant interaction among group, handedness, and rehabilitation was found. At the beginning, the reaction times for the preferred hand were faster among the control subjects, but not among the patients with low back pain. After the rehabilitation, the preferred hand was faster among both the control subjects and the patients with low back trouble. During the rehabilitation, back pain, psychological distress, and general disability decreased significantly among the patients with chronic low back trouble. The results support the hypothesis that chronic low back pain and disability impedes the functioning of short-term memory, resulting in decreased speed of information processing among patients with chronic low back symptoms. Numerous studies [158] report on a theory that suggests that a dysfunction in the way of the brain receives and processes information from the body, may trigger so called writer’s and musician’s cramps. Researchers have found that the debilitating disorder also called focal dystonia of the hands stems from pushing the brain past its ability to learn quick repetitive movements. When the brain signals become “jumbled” these researchers think the muscles spasm and stiffen. Byl and Merzenich [159] based their studies on previous research that explains the mechanism of how messages are wired to the brain. Studies explain how tactile receptors or nerves on the skin speed signals to sensory maps, which undergo rewiring or plasticity with each learning experience. We can read these maps and identify zones

corresponding to individual fingers and parts of the fingertips. According to ongoing studies conducted by Byl, Merzenich, and colleagues [160] on monkeys, rapid repetitive movements result in degeneration of the brain’s sensory map that leads to muscle spasm and impaired muscle tone. They suggested that during successive movements, the brain is forced to process too numerous sensations and muscle commands. This gives rise to faulty movements they say that causes fingers and hands to spasm. Standard therapy is used to treat focal dystonia including anti-Parkinson’s drugs, muscle relaxants, and injections of botulinuium toxin (Botox) to weaken problematic muscles. The authors feel that this treatment approach may be inappropriate. Instead, they suggest retraining therapy that consists of exercises to help patients fine-tune their tactile senses. This should, they think, help diffuse overloaded sensory maps so they can discriminate sensations better. Byl noted that after 12 weeks of retraining therapy, 14 of 16 patients with severe focal dystonia of the hand who were not helped by standard therapies reported improvement in function and were able to return to work. A brain scan taken on one of the patients showed that the sensory maps appeared more neatly arranged. Although many think that there are primary biomechanical factors that produce repetitive strain type injuries, Byl thinks that focal dystonia of the hand is more likely to occur if a person is exposed to biomechanical risk factors like a high level of repetitive movements and small fingers spread. She maintains that a significant factor focal dystonia is a disorganization of the sensory maps adding that Botox and other treatments simply “quiet symptoms.” She further states, “The nervous system is responsive to repetitive behaviors but we have always assumed that those modifications of the nervous system from repetitive movements would have a positive outcome, that it would make one smarter and be able to test more accurately. But what we are saying is we have identified a dysfunctional reorganization of the sensory brain that seems to

What Functional Neurology Can Offer the Treatment of Developmental Disabilities be associated with the disability disorder negative outcome.” Focal dystonia, as described by Byl and associates, can be considered a primary dysfunction in the motor system, including the basal ganglia, thalamus, cerebellum, and frontal lobe. Focal dystonia or hypokinetic behaviors may be isolated to the sensory-motor cortices. Lower back and neck pain are also oftentimes considered repetitive strain injuries and the same mechanism may apply. Hypermobility of the spinal joints may also produce improper repetitive sensory input that may rewire sensory maps to produce fatigability or oxidative stress to brain cells. This may result in a focal dystonia of the spinal muscles with effects on the sensory- motor cortices. These painful muscle spasms either may be a product of the central nervous system irregular activation or may also result in abnormal repetitive feedback to the cortex.

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Cortical Asymmetry and the Optimization of Learning Gerry Leisman1,2,3,* and Robert Melillo1,3

Abstract

1

In numerous reviews that have appeared in the literature of learning disabilities over the past 100 years, we can conclude that overall, the literature suports the following: (1) reading disability (congenital word blindness) can manifest in children with normal ability, (2) males seem to be more often affected than females, (3) children present with varied symptoms, but all suffer a core deficit in reading acquisition, (4) normal or even extended classroom instruction does not significantly improve reading ability, (5) some reading problems seem to be transmitted genetically, and (6) the core symptoms seem similar to those seen in adults with left temporo-parietal lesions.

The National Institute for Brain and Rehabilitation Sciences, Nazareth, Israel 2 Department of Clinical Neurophysiology, Institute for Neurology and Neurosurgery, Universidad de Ciencias Médicas de la Habana Facultad 'Manuel Fajardo' Havana, Cuba 3 The National Institute for Brain and Rehabilitation Sciences-USA, Gilbert, AZ USA

Keywords: cortical asymmetry, learning, learning disabilities, cerebellum, dyslexia

Introduction

*

Correspondence: Dr. Gerry Leisman, The National Institute for Brain and Rehabilitation SciencesIsrael, Pisgat Schneller, POB 6785, 5058 Street, Nazareth, Israel 16470. Email: [email protected]

While no one would contest the idea that learning disabilities may differentially manifest in many areas of learning, including arithmetic, writing spelling, and so on, there is little doubt that it is with reading disabilities, or dyslexia, where most researchers have concentrated their efforts. For this reason and because so many researchers from Neuropsychology, neurology, and neurolinguistics have focused their efforts on reading disabilities, we will examine this literature in an attempt to draw some meaning from the volumes of research that have investigated brain-behavior relationships in this most common of learning disabilities. In fact, an understanding of this literature and the theoretical ideas concerning the meaning of lateralized function and potentially associated

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deviations in brain morphology may well assist future scholars in their investigation of the neurobiological basis of other forms of learning disabilities. As the early case studies suggested, learning disabilities have always been thought to have a neurological origin and present definitions of learning disability reflect this perspective (Wyngaarden, 1987). However, the literature supporting this perspective has generated a great deal of controversy. As Golden (1982) and Taylor and Fletcher (1983) have pointed out, much if not most of the literature through the early part of the 1980s was correlational in nature. For example, some research indicates that reading-disabled children have an increased incidence of electrophysiological abnormalities (Duffy et al. 1980) and perhaps differentially so in subtypes of reading disabilities (e.g., Fried et al. 1981). Soft signs are also more frequently found in reading-disabled children (Peters et al. 1975) and few would argue that reading disabled children have a higher incidence of left- or mixed handedness (Bryden & Steenhuis, 1991). Further, reading-disabled children are often inferred to have weak or incomplete laterality, as evidenced on perceptual measures such as dichotic listening (Obrzut, 1991). In fact, volumes summarizing the research in this area have been written (Bakker & van der Vlugt, 1989; Gaddes, 1985; Kershner & Chyczij, 1992; Obrzut & Hynd, 1991), but we are stiff to a significant degree left with inferential or correlative evidence supporting the presumption of a neurological etiology for learning disabilities. Typical of such inferential evidence were studies that found that children with learning disabilities performed more poorly than normal children on any given task (cognitive or perceptual) but did better than children with documented brain damage (e.g., Reitan & Boll, 1973). Needless to say, the inference was often made that the learning-disabled children suffered “minimal brain dysfunction” because their level of performance was somewhere between normality and known brain damage. This was clearly an inference and while not without merit theoretically, it did not directly correlate a

known neurological deviation of any kind (e.g., developmental, traumatic) with observed behavioral or cognitive deficits, as we might find in learning-disabled children. This absence of confirming evidence is certainly not due to a shortage of theories or research, however. Historically relevant is the theory of Orton (1928) who proposed that as children become more linguistically competent, the left cerebral hemisphere becomes progressively more dominant for speech and language. He believed that motor dominance and its evolution in the developing child reflected this process of progressive lateralization. Consequently, according to Orton, children who had mixed cerebral dominance, as might be reflected in poor language skills, reading words or letters backward and inconsistent handedness, were most likely delayed in cerebral lateralization and therefore neither cerebral hemisphere, particularly the left, was dominant for linguistic processes. While decades of research documented that learning-disabled children were indeed deficient in language processes, especially phonological coding, the model of progressive lateralization has not been supported by the research (Benton, 1975; Kinsboume & Hiscock, 1981; Satz 1991). Most of the development and normal function of the cerebrum is dependent on subcortical structures especially the cerebellumand basal ganglia. A failure to develop and or a dysfunction in these areas can affect both the nonspecific arousal system as well as specific transfer of information in the brain. Dysfunction in these areas will usually result in specific motor and sensory symptoms that are commonly seen in children with cognitive or behavioral disorders. These brain regions are often seen to be underactive or atrophied as well in these children. These cortical loci have been shown to be connected with the prefrontal cortex, which have also often been noted to be underactive or atrophied in children with the neurobehavioral developmental disorders. The underactivity and or atrophy is usually either restricted to the right or left side of

Cortical Asymmetry and the Optimization of Learning the sub-cortex and cortex (Melillo & Leisman, 2004). An imbalance of activity or arousal of one side of the cortex or the other can result in a functional disconnection syndrome similar to what is seen in split-brain patients, this could be an underlying source of many if not all of the symptoms that we see with children with behavioral and cognitive disorders. For example, post-mortem examinations have indicated structural differences between the brains of good and impaired readers. High concentrations of micro-dysgenesis are noted in the left temporoparietal regions of dyslexic brains. The concentration is most evidenced in the planum temporale region (Galaburda et al. 1985; Kaufman & Galaburda, 1989; Duane 1989). These micro-dysgeneses seriously impair the normal pattern of architecture of dyslexics and remove the asymmetry normally observed between the enlarged language areas of the left temporoparietal region and the smaller homologous areas of the right hemisphere (Galaburda et al. 1985; Leisman & Ashkenazi, 1980). The capacity for language is generally correlated with a significant development in the magnitude of the left temporoparietal region and an attrition of neurons in the right hemisphere. These neuronal casualties may produce the observed asymmetry between corresponding areas in the left and right hemispheres (Geschwind & Levitsky, 1968; Leisman & Ashkenazi, 1980). The relative symmetry in the dyslexics’ brains might reflect their impaired linguistic development. In one study, (Leisman, 2002; Leisman, and Melillo, 2004)) left parieto-occipital EEG leads recorded a frequency spectrum in dyslexics that was consistently different from the spectrum obtained from normals. It is suggested that these effects represent significant differences in the functional organization of these areas. EEG coherence values indicate that normals have significantly greater sharing between hemispheres at symmetrical locations. Dyslexics demonstrate significantly greater sharing within hemisphere than do normals as evidenced in Table 1. The data supports the notion that

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developmental dyslexia is a functional hemispheric disconnection syndrome. Other conditions in the spectrum of disorders that we are discussing yield similar results. This spectrum of childhood disorders that we are discussing generally relates to an increase or decrease in activation of the brain and the balance of activation between brain regions. These conditions result from two primary system effects: 1) primary arousal deficit or imbalance, and 2) a specific activation deficit, imbalance, or asynchrony. The brain is driven by sensory input. We know that the brain receives more simultaneous sensory input than it can possibly consciously process (Heilman, 1995; Leisman, 1976; Broadbent, 1958; 1965) In general the more stimulation a brain cells receive the better their function allowing it to process more information faster, for longer periods of time (Venables, 1989; Pascual & Figueroa, 1996; Szeligo & Leblond, 1977; van Praag et al. 2000). Therefore all sensory input is important although not all of it can be consciously processed and perceived. In fact, without subconscious baseline stimulation higher conscious processing of sensory stimuli would be difficult if not impossible. Before higher brain centers can develop, the lesser supportive brain structures must develop. In the cortex, Luria (1973) thought that lateralized cortical functions progress from primary cortical areas to secondary and tertiary areas as the child matures (Luria, 1973). Going back even further we see that development of cortical areas and the cortex itself are dependent on the anatomic and functional development of subcortical areas especially the cerebellum and the thalamus. Studies suggest that intact cerebellar functioning is required for normal cerebral functional and anatomical development (Rae et al. 1998; Llinas, 1995). The same has been seen for the thalamus - that intact thalamic function is necessary to cortical development and function (Castro-Alamancos, 2002; Scannell et al. 1999; 2000; Gil et al. 1999; Albe-Fessard et al. 1983; Kalivas et al. 1999). Developmental dysfunction of the same brain areas as seen in acquired disorders such as post-traumatic

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aphasia may be the basis of developmental learning disabilities and neurobehavioral disorders (Dawson, 1996; 1988; Obrzut, 1991). As Orton (1928) had indicated, it is generally assumed that persons with learning disabilities have abnormal cerebral organization including atypical or weak patterns of hemisphere specialization (Bryden, 1988; Corballis, 1983; Obrzut, 1991). The developmental lag hypothesis proposed by Lenneberg (1967) suggested that learning-

disabled persons are slower to develop basic language skills and demonstrate weak hemispheric specialization for language tasks. In a reformulation of the progressive lateralization hypothesis (Satz, 1991), it may be that subcortical and antero-posterior progressions have a differential developmental course with learning disabled children and adults compared to control subjects or those with acquired syndromes.

Table I. Average frequency (in Hz), power (in dB), left-right asymmetry of power (in dB) between hemisphere and within hemisphere coherence values at P3-O1/P4-O2 locations for dyslexics and normals

S 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Freq (Hz) 09.2 10.4 11.7 09.8 10.8 10.6 10.6 11.2 12.0 09.8 10.8 11.7 08.7 09.0 10.7 10.3 09.5 12.2 11.9 08.4

Dyslexic Power (dB) 12 21 22 18 17 24 28 12 19 14 25 22 13 27 13 08 22 20 09 15

L-R (dB) -03 -04 10 04 03 -01 -05 -07 -04 --02 --01 08 -04 -06 -07 -07 -01 -04

Bilat. Coher. ---------0.7 -1.0 ---------

W/in Coher. 1.1 1.8 2.4 1.6 1.4 0.8 1.5 2.1 1.9 0.6 1.0 -0.9 2.1 2.4 1.8 2.0 1.9 0.9 1.6

Since learning disabled children exhibit deficient performance on a variety of tests thought to be a measure of perceptual laterality, evidence of weak laterality or failure to develop laterality has been found across various modalities (audio, visual, tactile) (Boliek & Obrzut, 1995). It is thought these children have abnormal cerebral organization as suggested by Corballis (1983) and Obrzut (1991). The basic assumption is that dysfunction in the the central nervous system either prenatally or during early postnatal development, results in abnormal cerebral organization and associated

Freq (Hz) 09.2 10.8 12.7 10.9 08.6 08.9 11.2 11.7 10.0 10.7 10.6 12.0 11.7 08.9 09.5 08.8 08.6 09.3 12.4 11.6

Power (dB) 28 24 18 20 16 08 11 13 12 15 11 09 07 11 10 11 14 09 12 10

Normal L-R (dB) ----4 ----2 --1 ------2 -----

Bilat. Coher. -2.4 1.9 1.3 1.9 1.8 2.4 1.5 1.3 1.3 1.2 0.8 1.0 1.9 1.7 2.1 1.4 1.8 1.9 0.9

W/in Coher. 0.8 ------1.8 -0.9 1.4 1.1 --0.6 ------

dysfunctional specialization needed for lateralized processing of language function and non-language skills. It is thought that cortical and subcortical dysfunction which results from aberrant patterns of activation or arousal (Obrzut, 1991), inter- and intrahemispheric transmission deficits, inadequate resource allocation (Keshner & Peterson, 1988), or any combination of these may compromise hemispheric specialization in those with cognitive and behavioral deficits (Bolick & Obrzut, 1995).

Cortical Asymmetry and the Optimization of Learning Development of higher processing areas in the cerebellar cortex would develop after other more primary areas. For example, the lateral cerebellum would be dependent on proper development of the more midline areas in the inter-medial and medial zones first. Similarly, any region to which lateral cerebellum projected would be dependent on the effective development of the lateral cerebellum and it in turn would be dependent on the more medial cerebellar development. Therefore, if the medial aspects of the cerebellum do not develop adequately, then the lateral areas would still grow however, they may be smaller or atrophic, and dysfunction would be expected. The cerebellumis thought to be part of a neuronal system that includes the thalamus basal gangliaand prefrontal cortex (Thatch, 1980). Anatomic and functional development of the nervous system is dependent on sensory input, which is associated with growth of a given brain area and its associated connectivities with other brain regions. Brain area growth and the capacity to make functional connectivities is highly dependent on: continued regional stimulation and by global stimulation through connected and coordinated function. If specific regions are inadequately stimulated, then we may see failure of anatomic or functional development in that region with a preservation of basic lower level functionality. Higher functions that depend on greater areas of integrated stimulation may be lost or dysfunctional. If the sensory loss develops after a critical period, these areas may still be smaller due to atrophy or reverse plasticity, with either global or specific effects depending on the modality of dysfunction. In children with learning disabilities or affective disorders, there are specific areas of the nervous system that have been noted in imaging studies to be smaller than normal (von Plessen et al. 2002; Frank & Pavlakis, 2001; Larsen et al. 1990). Most often, these areas involve the prefrontal cortex, basal ganglia, thalamus, and cerebellum. Some neurophysiologists regard the central nervous system as partly a closed and part open system (Llinas, 1995). An open system is one

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that accepts input from the environment, processes it, and returns it to the external environment. A closed system suggests that the basic organization of the central nervous system is geared toward the generation of intrinsic images and is primarily self-activating and capable of generating a cognitive representation of the outside environment even without incoming sensory stimuli. Although it is possible that a certain level of activation or stimulation will be intrinsic to single neuronal cells and the nervous system as a whole, this stimulation does not seem adequate to sustain a conscious, awake, individual. Behaviorally, arousal is a term used to describe an organism that is prepared to process incoming stimuli. From a physiologic standpoint, arousal also refers to the excitatory state or the propensity of neurons to discharge when appropriately activated (neuronal preparation). A non-aroused organism is comatose (Heilman, 1995). Therefore, an aroused alert individual that is prepared to process information is in a state dependent on sensory input with an attendant intrinsic excitability. Remove stimulation and the individual will eventually lose conscious awareness and become comatose or at least inattentive. The majority of brain activity associated with arousal comes from the ascending reticular activating system. The majority of this activity is relayed by the nonspecific thalamic nuclei or intralaminar nuclei. All sensory perception is based on the effectiveness of the arousal level of nonspecific, mostly subconscious, activity of the brain. There can be no specific sensory modality perception like vision or hearing without a baseline arousal level. The more stimulation or greater frequency of stimulation the more aroused an individual will be. Low frequency stimulation of midline thalamic non-specific nuclei produces inattention, drowsiness, and sleep accompanied by slow wave synchronous activity and so called spindle bursts. High frequency stimulation on the other hand has been shown to arouse a sleeping subject or alert a waking organism (Tanaka et al. 1975; Arnulf et al. 2000; Halboni, 2000). Specific sensory perception and

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processing is dependent on specific thalamic relays, if one of the specific thalamic nuclei are damaged such as the lateral geniculate body, that specific sensory modality is lost (e.g., blindness) but it does not result in loss of other specific nuclei input like hearing. However, if lesions of the non-specific intralaminar nuclei exist, patients cannot perceive or respond to any input by the specific intact nuclei even though those pathways are intact. In essence, the person does not exist from a cognitive standpoint (Llinas, 1995). Luria postulated that the brain was divided into three functional units: 1) the arousal unit, 2) the sensory receptive and integrative unit, and 3) the planning and organizational unit. He subdivided the last two into three hierarchic zones. The primary zone is responsible for sorting and recording incoming sensory information. The secondary zone organizes and codes information from the primary zone. The tertiary zone is where data are merged from multiple sources of input and collated as the basis for organizing complex behavioral responses (Luria, 1973). Luria's dynamic progression of lateralized function is similar to Hughlings Jackson's Cartesian coordinates with respect to progressive function from brainstem to cortical regions (Kinsbourne & Hiscock, 1983). Satz (1991) suggested that developmental invariance describes the lateral (x-axis) dimension of asymmetry, whereas current formulation of equipotentiality and the progressive lateralization hypothesis better describes vertical (subcortical-cortical) and horizontal (antero-posterior) progression during infancy and early childhood. Interestingly it has been noted that most research designed to address laterality issues in developmental disabilities (i.e., learning disabilities) has not dealt systematically with subcortical-cortical development or antero-posterior progression, all based on the concept of arousal unit. The arousal unit is really the non-specific thalamic nuclei. We know that arousal is dependent on external and internal environmental sensory input. The largest

proportion of subconscious sensory input passes between the thalamus, cerebellum, and dorsal column from slowly adapting receptors found in muscles with a preponderance of slow-twitch fibers - or slowly adapting muscle spindle receptors. The highest percentage of these is found in antigravity postural muscles especially muscles of the spine and neck (Guyton, 1986). The receptors, which provide the major source of input to the brain, only receive sensory information. These receptors only work when muscles are stretched or contracted with gravity being the most frequent and constant sensory stimulus. In summary, brain development and the adequacy of it continued functioning is dependent on sensory input. Specific sensory perceptual processes like vision and hearing are dependent on non-specific sensory input. This, in turn, creates a baseline arousal and synchronization of brain activity (consciousness). This is a form of constant arousal and is dependent on a constant flow of sensory input from receptors that are found in muscles of the spine and neck. These receptors receive the majority of their stimulation from gravity, creating a feedback loop that forms the basis of most if not all of brain function. Sensory input drives the brain, and motor activity drives the sensory system. Without sensory input the brain cannot perceive or process input. Without motor activity provided by constant action of postural muscles a large proportion of sensory stimuli are lost to further processing. This loop is the somatosensory system. Higher processing is also dependent on the baseline sensory functions. For example, it has been shown that when performing a complex task, it is likely that transfer of motor commands to produce a final output is preceded to some degree, by transfer of information between association areas, which in turn may precede transfer between sensory regions (Banich, 1995). Actually, there is a growing body of evidence that indicates that very young children, including infants, are lateralized for language processing (Molfese & Molfese, 1986). Thus, none would refute the notion that in the majority

Cortical Asymmetry and the Optimization of Learning of cases language is lateralized to the left cerebral hemisphere. However, while language abilities clearly develop over the course of human ontogeny, language remains lateralized, as it was early in infant development. What may devolve is the capacity for plasticity of function; i.e., the capacity for the other cerebral hemisphere to assume language functions when the dominant hemisphere is severely damaged may decrease significantly with the course of development (Piacentini & Hynd, 1988). What neurological structures or deficient neuropsychological systems underlie the behavioral and cognitive symptoms we associate with learning disabilities, particularly reading disabilities? While there are likely many different ways in which one could begin to address this question, we will approach this question from a neurolinguistic-neuroanatomic perspective. We first present a discussion of the lateralized system of language and associated reading processes and then examine its impact and relation to research that employs brainimaging procedures to investigate morphologic differences in the brains of reading-disabled children and adolescents. In this fashion we hope to directly tie deviations in lateralized brain processes (e.g., language, reading) to potentially associated deviations in brain structure.

Neurolingulstic-Neuroanatomic Model For over a century, those concerned with reading and language disorders have attempted to correlate observed functional deficits with the location of known brain lesions (Bastian, 1898; Dejerine, 1892; Dejerine & Vialet, 1893; Dejerme & Dejerine-Klumpke, 1901; Geschwind, 1974; Head, 1926; Kussmaul, 1877; Wemicke, 1910). These scholars and others interested in the lateralization and localization of language and reading processes contributed to a literature that resulted in a neurolinguistic model of language and reading referred to by some as the Wernicke-Geschwind model (Mayeux & Kandel, 1985). While Wernicke and Dejerine

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deserve the most credit for the development of this model, it is clear that Geschwind (1974) did much to revive interest in the perspective first proposed in part by Bastian (1898), Liepmann (1915), Marie (1906), and others, whose ideas were controversial even when they were first proposed. As Head (1926) suggested over 60 years ago, “localization of speech became a political question; the older conservative school, haunted by the bogey of phrenology, clung to the conception that the ‘brain acted as a whole,’ whilst the younger liberals and Republicans passionately favored the view that different functions were exercised by the various portions of the cerebral hemispheres” (p. 25). Even among the “diagram makers” (Head, 1926) controversy existed. For example, Bastian (1898) argued strongly against the popular perspective advocated by Dejerine whose views so influenced Geschwind in his thinking. Bastian proposed that bilateral visual word centers existed in the brain, each of which was involved in visual perception, low-level feature analysis, and cross-modal integration with the central language centers. Dejerine’s views prevailed, however, as the accumulation of case studies supported the notion that there was indeed a leftlateralized “word center,” most notably, it seemed, in the region of the angular gyrus. Figure 1 graphically contrasts Dejerine and Bastian’s views on the posterior cortex involved in reading. Based on the contributions of Broca, Wernicke, and the others noted above, a more complete neurolinguistic model of language and reading evolved. This model presupposes that visual stimuli such as words are registered in the bilateral primary occipital cortex, meaningful low-level perceptual associations occur in the secondary visual cortex, and this input is shared with further input from other sensory modalities in the region of the angular gyms in the left cerebral hemisphere. This sequential neurocognitive process presumably then associates linguistic-semantic comprehension with input from the region of the angular gyms; a process which involves the cortical region of the left posterior superior temporal region, including the region of the planum temporale.

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The process is completed when interhemispheric fibers connect these regions with Broca’s area in the left inferior frontal region. Figure 2 presents this model, and the Dejerine’s theory of the left lateralized “word center” seen in the posterior aspect of the figure. It was Geschwind (1974), of course, who revived interest in this neurolinguistic-neuroanatomic model. He contributed significantly, however, by focusing attention on the natural left-sided asymmetry of the region of the planum temporale. Reports by early investigators (Flechsig, 1908; von Economo & Horn, 1930) encouraged Geschwind and Levitsky (1968) to investigate asymmetries associated with the region of the planum temporale. They examined 100 normal adult brains and found that the region of the planum temporale (the most posterior aspect of the superior temporal lobe) is larger on the left in 65% of brains, whereas it is larger on the right in only 11 percent of brains. These findings were taken as evidence of a specialized and asymmetric neuroanatomical region in support of language functions. Studies by other investigators documented the finding of plana asymmetry in both adult and infant brains

(Kopp et al. 1977; Rubens, Mahuwald, & Hutton, 1976; Wada, Clarke, and Hamm, 1975; Witelson & Pallie, 1973). Figure 3 shows the left-sided asymmetry typically found in normal brains that is thought to subserve the evolution of higher-order neurolinguistic processes. The research that was encouraged by the findings of Geschwind and Levitsky (1968) was significant in that other morphologic asymmetries in the human brain were soon reported. For example, Weinberger and colleagues (1982) found evidence that in approximately 75% of normal brains the right frontal volume (R) exceeds that of the left frontal cortex (L). Also this pattern of L < R asymmetry seems evident in fetal development as early as 20 weeks. Other documented asymmetries include the left anterior speech region (pars opercularis and pars triangularis of the third frontal convolution) favoring the left side (Falzi et al. 1982) and cytoamhitectonic asymmetries favoring the left inferior parietal lobe (Eidelberg & Galaburda, 1984), the left auditory cortex (Galaburda & Sanides, 1980), and the posterior thalamus (Pidelberg & Galaburda, 1982).

Figure 1. A comparison o Dejerine’s and Bastain’s views on the neuroanatomical basis of “pure word blindness” as presented by Bastian (1898). (Above) A simplified diagram representing Dejerine’s views of the mode of production of pure word blindness. The dark line indicates the site of a lesion that cuts off the left visual word center (L.V.W.C.) from the Half vision center (H.V.C.) of each side. (Below) A diagram representing Bastian’s views of the mode of production of pure word blindness. C.C., corpus callosum.

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Figure 2. The brain as viewed in horizontal section. The major pathways and cortical regions thought to be involved in reading are depicted neurolinguistic processes important in reading are also noted.

Figure 3. A graphic representation (top) of a slice up the sylvian (lateral) fissure exposing the posterior portion of the superior temporal region. The planum temporale is shaded bilaterally (bottom) and it can be seen that it is generally larger on the left.

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Based on these as well as other research findings, Geschwind (1974, 1984) and especially Geschwind and Galaburda (1985a-c) argued that these natural asymmetries may be associated in a meaningful manner with language processes and, in cases of reversed asymmetry or symmetry, they ‘may underlie the deficits we observe in severe reading disabilities. While the theory outlined by Geschwind and Galaburda (1985a-c) addresses the possible relations between male gender differentiation, the effects of testosterone on neuronal assemblies, and correlated asymmetries in brain morphology, immune function, and left-handedness, may indicate that deviations in natural brain asymmetries may be related to the deficient linguistic and reading processes observed in reading disabled children. Thus, in this context, the remainder of this chapter will address the brain-imaging literature and examine the findings in relation to whether or not evidence exists in support of the notion that deviations in natural asymmetries in the language-reading system in the brain are indeed related in some fashion to the cognitive or behavioral deficits observe in these children.

Brain Imaging Many methodologies have been employed to investigate laterality and asymmetries in human performance. Certainly, visual half-field and dichotic listening experiments have assisted us greatly in better understanding perceptual asymmetries that underlie linguistic and visuospatial perception. Dual-task paradigms have helped develop a better understanding of the lateralization of hemispheric attentional mechanisms and handedness-manual preference inventories have likewise helped in documenting variability in human laterality. All of these methodologies rely on the recording of a behavioral response that in turn leads to a measure of laterality. The documentation of morphologic asymmetries in the human brain that seemed to favor the left hemisphere central

language zones encouraged speculation that variability in these patterns of asymmetry might be related to the behavioral deficits we see in such conditions as severe reading disability. Geschwind and his colleagues deserve much of the credit for encouraging this perspective. In this context then, measures of manual preference or perceptual asymmetries might still be of interest but they could not provide a window from which to actually view the brain and its associated morphology. Computed tomography (CT) and magnetic resonance imaging (MRI) were obviously technologic advances that could help researchers examine directly structure-function relations in living humans. CT, of course, is considered an invasive procedure, as there is some limited exposure to radiation, whereas with MRI scans there are no known risk factors. Until MRl became more readily available, CT was the method employed to examine deviations in normal patters of asymmetry in the brains of reading-disabled children and adults. CT studies typically employed a scan between 0 and 25 degrees above the acanthomedial line to examine for posterior asymmetries. With the increased sophistication of MRI scanning procedures it became possible to obtain thinner slices and extreme lateral sagittal scans were used to examine sulcul topography as well. Most s canning facilities now have the capability to obtain three-dimensional volumetric scan data so that later reconstructions can be made on any plane desired. These technological advances have been accompanied by very significant methodological challenges with regard to head positioning, using a standardized grid system to normalize data acquisition across scans, and other difficulties in defining morphologic boundaries that may have functional significance. Nonetheless, these studies have been revealing and have encouraged increasing interest in using brain-imaging procedures to investigate many issues important to the study of lateralized functioning.

Cortical Asymmetry and the Optimization of Learning Table II. Brain imaging studies of subjects with developmental dyslexia

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As can be seen in Table II, at least eleven studies using either CT or MRI have been conducted to examine whether or not deviations in normal patterns of asymmetry in brain morphology are associated with the manifestation of reading disabilities. The first such study was reported by Hier and colleagues (1978) who employed CT to investigate posterior asymmetries in 24 dyslexic subjects. They found that only 33 percent of the dyslexic group had a wider left posterior region while 67 percent had either symmetry or reversed asymmetry of the posterior region. Since fully 66 percent of the normal population is expected to show the expected L > R asymmetry, this lower incidence among the dyslexic group was taken as support for Geschwind’s (1974) idea that patterns of asymmetry were meaningfully associated with linguistic functioning. In a further study, Rosenberger and Hier (1980) found that a brain asymmetry index correlated with verbal performance intelligence quotient (IQ) discrepancies, whereas lower verbal IQ was correlated with symmetry or reversed asymmetry in the posterior region in the dyslexic subjects. This study actually was the first to examine whether there was any psychometric or behavioral relationship between asymmetry patterns and performance. In this respect this study was unique and an entire decade elapsed before several new studies also examined behavioral relationships to brain morphology data Thus, most of the early literature was characterized by examining the rather straightforward issue as to whether there was any deviation from normal patterns of brain asymmetry in subjects with severe reading disability. In 1981, Haslam and associates found in their sample of dyslexic subjects that 46 percent had L > R asymmetry similar to the normals, but in contrast to Rosenberger and Hier (1980), no relationship was found with regard to verbal ability. As Hynd and Semrud-Clikeman (1989) have pointed out, however, the-criteria employed by Haslam and colleagues for defining language delay were less strict than in the Rosenberger and Hier study. Nonetheless, Haslam’s group (1981) did note that fewer

dyslexic subjects had the normal L > R posterior asymmetry. The mid-1980s marked a time of transition in that fewer CT studies were reported with increasingly more studies employing MRI procedures as MRI scanners became more available to the research community. In fact, the last CT study reported was by Parkins et al. (1987) who found that there existed some relationship of handedness to deviations from normal patterns of asymmetry by dyslexic subjects. They found in their older adult sample (mean age, 57 years) that symmetry of the posterior region was characteristic only in the left-handed dyslexic subjects. The results of this study are unusual because previously and in the studies to follow, handedness may have differentiated the normal from the severely reading-disabled sample, but no relationship was ever reported with handedness. The mean age of this sample is also unusual as these were reading-disabled adults who may represent an unusual part of the reading disability spectrum in that their reading disability persisted to such a severe degree well into advanced adulthood. Most other studies typically employed subjects in early adolescence through young adulthood. The first reported MRI study was in 1986 by Rumsey and associates who found in their brief report that 90 percent of the dyslexic subjects showed evidence of posterior asymmetry. In a sense, this study was typical of the rather unsophisticated methodology that characterized the studies at that tie in that determination of asymmetry, symmetry, and reversed asymmetry of the posterior region most often relied on the clinical judgment of a radiologist or other expert in reading scans. Rarely were data presented as to the morphometric measurements that were obtained, if any, and for this reason it was difficult to compare results across studies. About the only conclusion that could reasonably be advanced was that deviations in normal patterns of posterior asymmetry may be found more frequently in the brains of severe reading disabled persons. Based entirely on the Rosenberger and Hier (1980) study, there was limited but tantalizing evidence that symmetry

Cortical Asymmetry and the Optimization of Learning or reversed asymmetry may somehow be associated with poor verbal-linguistic ability as is often found in dyslexic children. To this point most studies had focused on posterior asymmetries, but theory had continued to emphasize the region of the planum temporale as being vitally important in verbal- their four consecutive autopsy cases and reported that the focal dysplasias clustered preferentially in the left superior posterior temporal region by a ratio of 2:I. Thus, there was good reason to shift the attention of researchers away from simple posterior asymmetries toward linguistic processes, particularly phonological coding. In fact, Galaburda et al. (1985) summarized attempts at measuring asymmetry of the region of the planum temporale. The focal dysplasias, Galaburda and colleagues reported, certainly could not be visualized on MRI scans, but different method could be employed in attempting to measure either the area or length of this region bilaterally in the brains of persons with dyslexia. Leisman & Ashkenazi (1980) present sample CT and Leisman & Melillo (2004) present sample MRI scans showing the anomalous cortex in the dyslexic subjects exemplifying measurement of asymmetry issues in dyslexia. Two studies employed different methodologies aimed at investigating asymmetries in the region of the planum temporale in dyslexic persons. Using MRI to examine the size and patterns of asymmetry in this region in adolescents with dyslexia, Larsen, and colleagues (1990) found that 70 percent of their dyslexic group had symmetry in the region of the plana in contrast to 30 percent of the normals. In addition to the importance of this finding, Larsen et al. also found that when symmetry of the plana was present in dyslexia, the subjects demonstrated phonological deficits. They concluded that some relationship may exist between brain morphology patterns and neurolinguistic process, consistent with Rosenberger and Hier’s (1980) conclusions. That same year, Hynd et al. (1990) also reported a study employing MRI in which the relative specificity of patterns of plana

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morphology were investigated in relation to a population of normal controls and clinic control children. In this case the clinic control group comprised children with attention-deficit hyperactivity disorder (ADHD). For this reason, the study was unique in that of all studies reported previously, none had included a clinic contrast group but rather compared dyslexic subjects only with normal controls. While such an approach has value in determining whether a line of investigation might be productive, the results only suggested differences from normals. There was no way to address the specificity of deviations in brain morphology in relation to the behavioral deficits seen in any one clinical syndrome such as reading. Based on the previous literature, it was hypothesized that if differences existed in the brains of the dyslexic children in the region of the plana, similar differences would not be evident in the brains of the ADHD children who were carefully diagnosed so that this group did not include children with reading or learning disabilities. Similar to Larsen et al. (1990), Hynd et al. (1990) found that the dyslexic group was characterized by either symmetry or reversed asymmetry (L < R) of the plana. Underscoring the importance of this region scientifically, they found that in 70% of the normals and ADDH children, L > R plana asymmetry existed. This is what would be expected according to the normative data provided originally by Geschwind and Levitsky (1968). Fully 90% of the dyslexic children demonstrated symmetry or reversed asymmetry of the plana. In a follow-up study, Semrud-Clikeman and colleagues (1991) reported that symmetry and reversed asymmetry of the planum temporale was associated with significant deficits in confrontational naming, rapid naming, and neurolinguistic processes in general. If one compares the Larsen et al. (1990) and Hynd et al. (1990) studies, differences seem evident in the way in which the plana were measured. Hynd et al. (1990) measured the length of the plana on extreme lateral sagittal MRI scans. Larsen et al. (1990), however, took measurements from sequential scans so that a

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measurement of area could be derived. Both studies found that significant indices of symmetry or reversed asymmetry characterized the brains of dyslexic children even though different methodologies were employed. A point to derive from this discussion is that there are no agreed-upon standardized methodologies, although the method employed by Larsen et al. (1990) most likely provides more reliable data. Further, in examining the literature regarding the neuroanatomical morphology of the ilana, one quickly realizes that there may be different sulcul patterns associated with whether or not a parietal bank of the planum temporale exists. In a study reported by Leonard et al. (1993), the morphology of the posterior superior temporal region was examined bilaterally including the relative contribution of the temporal and parietal banks to an asymmetry index. The results of this study are particularly revealing in several ways. First, it turns out that nearly all dyslexic subjects and normals demonstrated a natural leftward asymmetry in the temporal bank and a rightward asymmetry in the parietal bank. When they examined intrahemispheric asymmetry, some dyslexic subjects had an anomalous intrahemispheric asymmetry between the temporal and planar banks in the right hemisphere because of an increased proportion of the plana being in the parietal bank What this suggests is that consideration must be given to measuring both the temporal and parietal banks of the planum temporale and the relative contribution of both banks bilaterally in deriving asymmetry indexes. To quickly illustrate this issue the reader may wish to refer to Figure 3, which illustrates the typical fashion in which the plana were described in the literature. By looking at the figure at the top where the slice location is noted, one can see at the end of the sylvian fissure where the slice line cuts horizontally that there is a small ascending ramus that is actually part of the planum. By not including this parietal aspect in lateral measures of asymmetry, the Larsen et al. (1990) and Hynd et al. (1990) studies were incomplete, although at the time they were published they were excellent studies.

Finally, the Leonard et al. (1993) study documented that the dyslexic persons were more likely to evidence anomalies such as missing or duplicated gyri bilaterally in the region of the posterior end of the lateral fissure. These cerebral anomalies most likely evolve somewhere between the 24 and 30th week of fetal gestation when gyration occurs and represent a neurodevelopmental anomaly possibly related to a genetic etiology. What does this literature suggest about cerebral morphology and lateralized function in reading-disabled or dyslexic children? First, it suggests that asymmetry may indeed be characteristic of most normal brains. Second, in the region of the planum temporale there may be an increased incidence of symmetry or reversed asymmetry if one only measures the temporal bank. If one measures the bilateral temporal and parietal banks in the dyslexic group one may actually end up with these persons having more leftward asymmetry because of intrahemispheric variation in the right hemisphere, at least according to Leonard et al. (1993). As the Leonard et al. (1993) study clearly indicates, measuring highly variable brain regions in different subject groups is fraught with complications, and decisions that must be made in terms of what to measure can dramatically influence outcomes. Finally, as Rosenberger and Hier (1980) first suggested, there may indeed be relationships between deviations in brain morphology and neurolinguistic processes. The Larsen et al. (1990) and Semrud-Clikeman et al. (1991) studies provide further support for this important aspect of the theory advanced by Geschwind (1974,1984).

Recent Advances and the Future Agenda in Understanding the Relation between Coritcal Asymmetry and Learning Disability There should be little doubt that brainimaging procedures offer much promise in investigating issues related to possible

Cortical Asymmetry and the Optimization of Learning relationships between brain structure morphology and behavioral observations, whether these observations be clinical or experimental. What needs to be kept in mind however is that across all of these studies in which over 200 subjects have been scanned, not one brain of a reading-disabled subject was judged to be abnormal in structure (other than asymmetry patterns). In other words, no evidence of brain damage was found. This should underscore the important findings of Galaburda and colleagues (1985) who find developmental anomalies in the brains of dyslexic persons. The anomalous cortex identified by Leonard et al. (1993) provides further data implicating neurodevelopmental processes as underlying the behavioral symptoms exhibited in dyslexia. It appears that reasonable evidence exists implicating unusual developmental processes sometime during the fifth to seventh month of fetal gestation in dyslexia. Clearly, the exact cause of these neurodevelopmental anomalies is one of the most important unanswered questions. In autopsy research, Galaburda and his colleagues have been the main contributors to this area of investigation (Galaburda, 1988, 1989, 1993, 1994, 1997; Galaburda & Livingstone, 1993; Galaburda, Menard, & Rosen, 1994). These researchers have found areas of symmetry and asymmetry in normal brains that differ in individuals with reading disabilities. The autopsied brains of individuals with dyslexia show alterations in the pattern of cerebral asymmetry of the language area with size differences, and minor developmental malformations, which affect the cerebral cortex. The work of Galaburda and colleagues has shown that about two-thirds of normal control brains show an asymmetry; the planum temporale of the left hemisphere is larger that that of the right hemisphere. Between 20% and 25% of normal control brains show no asymmetry, with the remaining having asymmetry in favor of the right side (Best & Demb, 1999). This asymmetry is thought to be established by 31 weeks of gestation (Chi, Dooling, & Gilles, as cited in Best & Demb,

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1999), and Witelson and Pallie (1973) have shown hemispheric asymmetry of the planum temporale to be present in fetal brains. In contrast, the brains of reliably diagnosed cases of developmental dyslexia have shown the absence of ordinary asymmetry; symmetry is the rule in the planum temporale of brains of dyslexic subjects studied at autopsy, and increased symmetry is also found in imaging studies (Best & Demb, 1999; Galaburda, 1993). These findings are relevant since individuals with dyslexia have language-processing difficulties, and reading is a language-related task. Therefore, anatomical differences in one of the language centers of the brain are consistent with the functional deficits of dyslexia. Because abnormal auditory processing has been demonstrated in individuals with dyslexia, accompanying anatomical abnormalities in the auditory system have also been the focus of autopsy studies, specifically in the medial geniculate nuclei (MGN), which are part of the metathalamus and lie underneath the pulvinar. From the MGN, fibers of the acoustic radiation pass to the auditory areas in the temporal lobes. Normal controls showed no asymmetry of this area, but the brains of individuals with dyslexia showed that the left side MGN neurons were significantly smaller than those on the right side. Also, there were more small neurons and fewer large neurons in the left MGN in individuals with dyslexia versus controls (Galaburda & Livingstone, 1993; Galaburda et al. 1994). These findings are of particular relevance in view of the left hemisphere-based phonological defect in individuals with dyslexia (Tallal, Miller, & Fitch, 1993). Neuroanantomical abnormalities in the magnocellular visual pathway have been reported (Galaburda & Livingstone, 1993), and these have been postulated to underlie functioning of the transient visual system in individuals with reading disabilities (Iovino, Fletcher, Breitmeyer, & Foorman, 1998). Jenner, Rosen, and Galaburda (1999) concluded that there is a neuronal size difference in the primary visual cortex in dyslexic brains, which is another anomalous expression of cerebral asymmetry

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(similar to that of the planum temporale) which, in their view, represents abnormal circuits involved in reading. According to Galaburda, symmetry may represent the absence of necessary developmental “pruning” of neural networks, which is required for specific functions such as language. In other words, the pruning, which takes place in normal controls, does not take place in individuals with dyslexia (Galaburda, 1989, 1994, 1997), thereby resulting in atypical brain structures, which are associated with language-related functions. MRI (magnetic resonance imaging) studies have substantiated the findings of autopsy studies; namely, individuals with dyslexia do not have the asymmetry or the same patterns of asymmetry of brain structures that is evident in individuals without dyslexia. A number of investigators have demonstrated a high incidence of symmetry in the temporal lobe in individuals with dyslexia. (Best & Demb, 1999; Hugdahl et al. 1998; Kushch et al. 1993; Leonard et al. 1993; Logan, 1996; Rumsey et al. 1996;). Duara et al. (1991) and Larsen, Høien, Lundberg, and Ødegaard (1990) showed a reversal of the normal leftward asymmetry in the region of the brain involving the angular gyrus in the parietal lobe. Dalby, Elbro, and Stodkilde-Jorgensen (1998) demonstrated symmetry or rightward asymmetry in the temporal lobes (lateral to insula) of the dyslexics in their study. Further, the absence of normal left asymmetry was found to correlate with degraded reading skills and phonemic analysis skills. Logan (1996) reported that individuals with dyslexia had significantly shorter insula regions bilaterally than controls. Hynd et al. (1995) identified asymmetries in the genu of the corpus callosum of individuals with dyslexia and positively correlated both the genu and splenium with reading performance. This supports the hypothesis that, for some individuals with dyslexia, difficulty in reading may be associated with deficient interhemispheric transfer (Leisman & Melillo, 2004). Hynd and his colleagues (Hynd, Marshall, & Semrud-

Clikeman, 1991) also reported shorter insula length bilaterally and asymmetrical frontal regions in individuals with dyslexia. The latter was related to poorer passage comprehension. Best and Demb (1999) examined the relationship between a deficit in the magnocellular visual pathway and planum temporale symmetry. They concluded that these two neurological markers for dyslexia were independent. There has been substantial replication of findings, particularly with respect to the planum temporale. On the other hand, there have been conflicting reports regarding other areas, especially the corpus callosum (Hynd et al. 1995 versus Larsen, Höien, & Ødegaard, 1992). Methodological and sampling differences, such as slice thickness, orientation and position, and partial volume effects may account for this variability. In a review of the literature on the planum temporale, Shapleske et al. (1999) summarized the methodological concerns in operationalizing consistent criteria for anatomical boundaries when measuring the planum temporale and the need to use standardized measures of assessment and operationalized diagnostic criteria. They concluded that dyslexics may show reduced asymmetry of the planum temporale, but studies have been confounded by comorbidity. Njiokiktjien, de Sonneville, and Vaal (1994) concluded that, despite a multitude of developmental factors influencing the final size, total corpus callosal size is implicated in reading disabilities. In a study by Robichon and Habib (1998), in which more rigid methods were applied, MRI and neuropsychological findings of dyslexic adults were correlated and compared with normal controls. Different morphometric characteristics were positively correlated with the degree of impairment of phonological abilities. The corpus callosum of the dyslexic group was more circular in shape and thicker, and the midsaggital surface was larger, particularly in the isthmus. Neuroanatomical investigations have substantiated what had been surmised from the early traditional studies of acquired brain lesions and associated changes in functions and have

Cortical Asymmetry and the Optimization of Learning brought forward new evidence to support the neurobiological basis of learning disabilities. Advances in neuroimaging have permitted brain dissection “in vivo,” a transparent window of brain functions, concurrent with neurological and neuropsychological evaluations. This methodology has supported previous findings and hypotheses while providing new evidence of brain structure/function relationships. Although the neuroanatomical correlates of dyslexia do not answer the question about whether dyslexia is a condition at one extreme in the normal distribution of reading skill (Dalby et al. 1998), the neuroanatomical and neuroimaging studies have provided evidence linking learning disabilities to neurobiological etiology. In a PET scan study, Horwitz, Rumsey, and Donohue (1998) demonstrated that in normal adult readers there was a correlation of regional cerebral blood flow in the left angular gyrus and flow in the extrastriatal, occipital, and temporal lobe regions during single word reading. In men with dyslexia, the left angular gyrus was functionally disconnected from these areas. Gross-Glenn et al. (1991) found regional metabolic activity measured with PET scan to be similar in individuals with dyslexia and those without dyslexia, reflecting that reading depends on neural activity in a widely distributed set of specific brain regions. There were also some differences concentrated in the occipital and frontal lobe regions. In contrast to controls, individuals with dyslexia showed little asymmetry. These findings correspond well with the reduced structural posterior asymmetry observed in the CT scan and postmortem studies. Prefrontal cortex activity was also symmetrical in individuals with dyslexia versus asymmetrical in normal controls. Higher metabolic activity (local utilization rate for glucose) in the lingual area (inferior occipital regions bilaterally) was reported by Lou (1992) with PET studies, and a SPECT (single photon emission computed tomography) scan showed striatal regions as hypoperfused and, by inference, underfunctioning. Numerous studies have attempted to identify the neurological basis of learning disabilities in

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terms of left–versus right–hemisphere dysfunction. Adult strokes were found to affect cognitive abilities such as reasoning, perceptual speed and memory clusters, scholastic aptitude, written language (Aram & Ekelman, 1988), reading, language or verbal learning (Aram, Gillespie, & Yamashita, 1990; Eden et al. 1993; Leavell & Lewandowski, 1990), and arithmetic processing (Ashcraft, Yamashita, & Aram, 1992). It is hypothesized that, as a result of genetic or epigenetic hormonal and/or immunological factors, the cortical language areas are disturbed in their development through migration disorders and abnormal asymmetry, such that normal left hemisphere dominance does not develop, resulting in dyslexia in some children (Njiokiktjien, 1994). Right hemisphere dysfunction has also been associated with specific learning disabilities. Damage to the right hemisphere in adults is associated with deficits in social skills, prosody, spatial orientation, problem-solving, recognition of nonverbal cues (Semrud-Clikeman & Hynd, 1991), impaired comprehension and production of affective signals, and higher-order cognition about social behaviors (Voeller, 1995). The right hemisphere is therefore implicated in the processing of social-emotional information in the same way that the left hemisphere is specialized for language (Voeller, 1995). The association of chronic social difficulties coupled with deficits in producing and comprehending emotional expressions, in combination with left-hemibody signs, has been reported as the right hemisphere deficit syndrome (Voeller, 1995). Lower reading performance has also been associated with the right hemisphere (Aram & Ekelman, 1988; Aram et al. 1990; Branch, Cohen, & Hynd, 1995), as have mathematical problems (Ashcraft et al. 1992; Branch et al. 1995; Rourke & Conway, 1997; Shalev, Manor, Amir, WertmanElad, & Gross-Tsur, 1995), and visuospatial deficits (Tranel et al. 1987). With regard to arithmetic disabilities, both the right and left hemispheres have been implicated (Ashcraft et al. 1992; Branch, Cohen, & Hynd, 1995; Rourke & Conway, 1997; Shalev

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et al. 1995). In the child, early damage or dysfunction in the right or left hemispheres has been reported to disrupt arithmetic learning, with very profound effects resulting from early right hemisphere insults, whereas in the adult, left hemisphere lesions predominate in the clinicopathological analysis of acalculia or computation difficulty (Rourke & Conway, 1997). The effective treatment of any condition or disease must be based on an adequate understanding of the etiology and genesis of that condition. Appreciating the neurobiological basis can facilitate the development of effective educational programs, with instructional goals, content, and pace of delivery designed to maximize success for individuals with learning disabilities. However, public policy makers have been slow to recognize the implications of this fact for the field of learning disabilities. Recognition of the neurobiological basis of learning disabilities does not necessarily lead to a bleak outlook, because the individual’s environment has the potential to reduce or amplify the impact of the learning disabilities. Supportive care giving (Kopp, 1990), quality of the home environment (Kalmar, 1996), and socioeconomic factors (Drillien, Thomson, & Burgoyne, 1980; Werner, 1990), as well as educational programs designed specifically to meet the needs of individuals with learning disabilities (Fiedorowicz & Trites, 1991; Lerner, 1989), have the power to mitigate the academic and cognitive deficits associated with the condition.

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Clinical Papers



A Retrospective Risk Prediction of Other-Directed Aggression and Violence in a Patient with Mixed Dementia Samuel T. Gontkovsky Mercy Health – St. Elizabeth Hospital, Youngstown, Ohio, USA

Abstract This report describes a retrospective risk analysis conducted based primarily on information and data obtained from the evaluation of a patient with mixed dementia completed approximately two months prior to an aggressive and violent episode in which he physically attacked his spouse resulting in his commitment to a locked residential facility. The objective of this retrospective assessment was to identify anything that may have served to predict his future behavior. Findings disclosed several variables that collectively may have been useful to some extent in predicting risk for the aforementioned aggression and violence, including premorbid factors and performances on objective measures of neuropsychological status. The most salient features identified in the analysis, however, were his spouse’s ratings of his behavior and function in conjunction with a marked discrepancy between his self-ratings and his spouse’s ratings concerning his level of disinhibition post-dementia. Results also revealed an apparent pattern of behavioral escalation in this case, beginning with anxiety and progressing to violence, which may be useful in guiding future research and clinical intervention in patients with dementia exhibiting aggression and violence. Keywords: Aggression, Agitation, Dementia, Risk, Violence

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Correspondence: Dr. Samuel T. Gontkovsky, St. Elizabeth Family Health Center, 1053 Belmont Avenue, Youngstown, OH 44504 USA Email: [email protected]

Introduction Dementia is a major public health concern with worldwide prevalence expected to reach more than 115 million individuals by the year

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2050 [1, 2]. Dementia, referred to in the Fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders [3] as Major Neurocognitive Disorder, is characterized by a progressive decline in cognitive functioning that interferes significantly with activities of daily living and frequently involves disturbances of behavior [4]. Behavioral issues consistently are reported to be present in the majority of patients with dementia [5] and usually are the most challenging manifestations of the disease, often resulting in increased caregiver burden, diminished quality of life for patients and their families, greater financial costs, and premature institutionalization [6, 7]. Apathy has been identified as the most common behavioral issue across various dementia syndromes [8]. Although not exhibited as frequently as apathy, disturbances of behavior involving agitation, anger, aggression, and violence also are not uncommon among persons diagnosed with dementia and are of particular concern to family members and caregivers not only because patients with such behaviors are more difficult to manage but also because they present a substantial risk for harm to self and others. Agitation, anger, aggression, and violence in patients with dementia is a complex issue, involving the interaction of multiple variables including but not limited to premorbid personality characteristics, the particular dementia syndrome with which an individual has been diagnosed (e.g., vascular disease, Lewy

body disease, etc.), the specific brain regions in which neuropathology has manifested, the degree of neurocognitive impairment, and the presence of other comorbid emotional and behavioral disturbances. For example, disinhibited behavior is most commonly seen among individuals diagnosed with frontotemporal dementia [8]. Further, autopsy studies of patients with Alzheimer’s disease who had exhibited agitation and aggression found increased neurofibrillary tangle deposition in the orbitofrontal and anterior cingulate cortices [8, 9]. Classifying behavioral manifestations specifically as agitated, angry, aggressive, or violent may be difficult. Indeed, conceptualizations of the terms vary by school of thought, and their definitions are not consistent within the literature. Further, some authors have described multiple subtypes of aggression, which may or may not be distinguished from violence. Frameworks for defining aggression, for example, may include whether or not the behavior exhibited was verbal or physical, adaptive or maladaptive, or reactive or planned. Anger may or may not influence aggression, and the contributions of anxiety/fear also must be taken into account. For the purposes of this report, the terms will be conceptualized according to the simple definitions provided in Table I and will be viewed as distinct behavioral manifestations that may occur independently of or in combination with and/or relation to one another.

Table I. Definitions of Behavioral Terms Agitation increased motor behavior or restlessness, such as pacing, wandering, or fidgeting Anger emotion, or feeling, of hostility and extreme frustration that may or may not be overtly apparent Aggression overt behavioral expression, verbal and/or physical, that neither results in injury to the self or others nor in the destruction of property Violence an extreme form of aggression that results in injury to the self and/or others and/or the destruction of property

The conduction of psychological autopsies has become increasingly more common following the completion of suicide. It is rare, however, for similar procedures to be done retrospectively absent such an extreme outcome. Prospective clinical risk assessments for

potential aggression and violence are not uncommon for certain populations and settings, such as adolescent psychiatric inpatient facilities [10] but are not routine for individuals with dementia likely due to a number of confounding factors, in particular the presence of

A Retrospective Risk Prediction of Other-Directed Aggression and Violence … neurocognitive deficits. This case report describes an independent, third party, retrospective analysis of information and data obtained primarily from the administration of a formal clinical neuropsychological evaluation completed with a patient diagnosed with mixed dementia of a mild degree of severity approximately two months prior to an aggressive and violent episode in which he verbally and physically attacked his spouse, resulting in the involvement of law enforcement and his formal civil commitment to a locked residential facility. This independent analysis was requested by the medical center at which the patient was being treated solely to determine whether any information existed that may have been used to predict his behavior so that a protocol might be developed for identifying prospectively potential aggression and violence in future patients with a diagnosis of dementia. Findings would be used for no other reason (e.g., forensic matters, clinical care of the patient, review of treatment provider standards of practice, etc.), whatsoever.

Case Report The following information was obtained from a retrospective, comprehensive review of available medical records for the patient as well as a post-incident interview with his spouse regarding the circumstances resulting in his civil commitment. The subject of this report is a 75year-old, right-handed, White male with 18 years of formal education. He had been employed in white collar, management / leadership positions throughout his career, primarily at the executive level for the 10 years preceding his retirement. Although no longer employed, he remained involved in financial analysis and investment, more so as a hobby. According to available records, he had experienced the onset of symptoms, initially involving gait instability and forgetfulness, approximately five years prior (i.e., at the age of approximately 70 years). Medical evaluation completed by the patient’s family physician shortly following symptom onset yielded a

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diagnosis of probable Lewy body disease, and the patient was referred for neurological workup for more extensive evaluation as well as treatment recommendations. He elected to forgo further evaluation and treatment at that time and reportedly exhibited an ongoing but gradual decline in physical and cognitive functioning over the following three to four years. It was not until he began experiencing marked difficulties with instrumental activities of daily living that presented a risk for harm, such as becoming lost while driving and forgetting to turn off the stovetop after preparing meals, that he reluctantly was willing to agree to complete the recommended neurological evaluation. Formal neurological workup by a board certified neurologist yielded a diagnosis of mixed dementia. The Alzheimer’s Association [11] describes mixed dementia as being characterized by the hallmark abnormalities of more than one form or cause of dementia, the most common combination being Alzheimer’s disease and vascular dementia followed by the combination of Alzheimer’s disease and dementia with Lewy bodies. In this case, the patient exhibited signs and symptoms of both Alzheimer’s disease and Lewy body disease. He subsequently was prescribed Aricept and was referred for neuropsychological evaluation to assess more comprehensively his cognitive and emotional status. Aside from these neurological issues and the use of corrective lenses, the patient had no remarkable medical history. He had been physically active throughout his life up to the time of this neurological evaluation that yielded a diagnosis of mixed dementia. Following diagnosis, however, he reportedly began to withdraw socially and spend greater periods of time lying in bed, and his wife suspected that he had become depressed. Although reluctant to undergo neuropsychological evaluation seemingly due to concerns of losing his independence as well as embarrassment about his deficits, the patient eventually agreed to participate with testing. The neuropsychological assessment battery included the following measures in addition to a clinical

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interview of the patient and a collateral interview of his spouse: 1) Test of Memory Malingering (TOMM) to evaluate the patient’s level of effort and assist in ruling out potential cognitive dissimulation [12], 2) Mini-Mental State Examination (MMSE) to provide an indication of the patient’s degree of orientation and basic global cognitive status [13], 3) Wechsler Abbreviated Scale of Intelligence – Second Edition (WASIII) to assess verbal comprehension and perceptual reasoning and to measure overall IQ [14], 4) Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) to provide a general screening of the patient’s attention / concentration, immediate and delayed memory, language, and visuospatial construction [15], 5) Texas Functional Living Scale (TFLS) to evaluate his practical skills in the execution of everyday instrumental activities of daily living, such as time management, calculation and use of money, communication, and memory [16], 6) Quality of Life Inventory (QOLI) to evaluate the patient’s overall level of well-being and satisfaction with life [17], 7) Satisfaction with Life Scale to evaluate global cognitive judgment of personal life satisfaction [18], 8) Fatigue Severity Scale to measure the patient’s current level of fatigue [19], 9) Brief Symptom Inventory 18 (BSI 18) to assess his emotional symptomatology in the dimensions of somatization, depression, and anxiety [20], and 10) Frontal Systems Behavior Scale, Self and Family Rating Form (FrSBe) completed by the patient and his spouse, respectively to provide information concerning their individual perceptions

regarding changes in his levels of apathy, disinhibition, and executive dysfunction pre-dementia to postdementia [21]. A more extensive battery of formal measures, including tests to evaluate sensory and motor capabilities, complex attention, more detailed aspects of memory, and specific domains of executive functioning (nonverbal concept formation, planning skills, cognitive flexibility, etc.), reportedly was planned but necessitated elimination of these additional measures secondary to the patient’s increasing levels of frustration and overt sadness (e.g., tearfulness) during the course of the testing session. Upon inquiry, he reportedly recognized that certain aspects of the testing were difficult for him to complete. The patient obtained raw scores of 48 and 50 on trial 1 and trial 2 of the TOMM, respectively, suggesting a sufficient level of effort to perform well. A total raw score of 26 on the MMSE suggested a mild degree of impairment in basic cognition, with deficits being noted on items assessing orientation and those involving the calculation of serial 7s. He obtained a raw score of 19 on the Satisfaction with Life Scale, suggesting slight dissatisfaction in this regard. An obtained raw score of 35 on the Fatigue Severity Scale also indicated elevations and associated concerns in this domain of functioning. Summary scores for the remaining administered measures are presented in Table 2. As can be seen, his Full Scale IQ was within the Superior range of performance as assessed by the WASI-II but with a marked strength in skills involving verbal comprehension in comparison to those involving perceptual reasoning. He demonstrated somewhat variable performances on the RBANS, with primary score reductions being noted in the larger domains of language and delayed memory. His score reduction on the Language index primarily reflected substantial impairment on the Semantic Fluency subtest, as indicated by an obtained z-score of -2.46. The remaining domain-specific RBANS index scores

A Retrospective Risk Prediction of Other-Directed Aggression and Violence … fell within the Average range of functioning but might be interpreted as being below expectation in light of his educational level, work history, and IQ. It also should be noted that although his obtained score on the Attention index was within the low end of the Average range, a marked discrepancy was present between his scores on the Digit Span subtest (z-score = 0.64) and Coding subtest (z-score = -2.03), the latter involving more complex attention/concentration demands and rapid processing of information. Although the patient obtained scores within the Average range of functioning on the Time subscale as well as the Money and Calculation subscale of the TFLS, impaired performances were demonstrated on the Communication and Memory subscales. No significant concerns were noted with respect to quality of life or emotional status, as assessed by the QOLI and BSI 18, respectively. Responses on the FrSBe revealed notable discrepancies between the patient’s and his spouse’s ratings of his behavior and function both prior and subsequent to the onset of dementia. As can be seen in Table 2, the patient’s self-ratings remain almost unchanged pre-dementia to post-dementia, although it should be noted that even prior to disease onset, his endorsements reflect the presence of mild apathy. Interestingly, his self-rating of disinhibition decreased by one standard deviation pre-dementia as compared to postdementia. His spouse’s ratings of his behavior revealed substantial changes pre-dementia to post-dementia, with concerns being identified in all assessed domains and reflective of behavioral issues involving apathy, reduced inhibitory control, inflexibility, impulsivity, executive dysfunction, and reduced self-awareness. A discussion with the patient’s spouse following the episode of aggression and violence conducted for the purposes of this assessment revealed that it occurred at the home of a family member during a casual gathering of the patient’s friends and relatives at his request. According to his spouse, approximately two weeks following his diagnosis of dementia the patient asked for her to organize an informal gettogether so that he could spend time with those

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individuals for whom he cares deeply before he progressed to the point cognitively that he no longer felt comfortable doing so. On the day of the gathering, the patient spent an unusually longer period of time grooming and dressing so that he looked his best. They arrived for the event early and prior to any guests other than the family members hosting the event. Although reportedly calm when departing for the gathering, he became slightly anxious, both by observation and his spontaneous verbal expression, during the drive to their family’s home. Within 15 minutes of arriving, his anxiety increased and progressed to include overt motor agitation. As guests began arriving, his agitation increased, and his spouse stated that she noticed his facial expression had changed to one of apparent frustration. Upon noticing his overt discomfort, she inquired as to whether he was feeling okay. He verbalized concern about the number of guests and of feeling overwhelmed at the number of conversations taking place simultaneously. In light of his behavior, she indicated making every effort to remain at his side in order to monitor his status and provide him with a sense of security and comfort. By her best recollection, after approximately one hour following their arrival and 30 minutes past the scheduled start time of the gathering and all guests having arrived, she told him she needed to use the restroom and would return to his side shortly. While in the restroom, she heard a disturbance followed by his shouting. Apparently, his young nephew had dropped a plate of food on the floor. The patient had become upset by this and raised his voice in the direction of his nephew in a critical manner. Another family member attempted to calm him, and he subsequently began cursing and shouting. Upon his spouse’s return, his verbal aggression was redirected towards her. She convinced him to exit the room to a quieter place, hoping the decreased sensory stimulation would be beneficial. His verbal aggression continued and while shouting he began to poke her in the chest with his finger. As she further tried verbally to calm him, even offering to take him home and

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reschedule the event to a later date, he grabbed her by the arm and threw her to the ground, resulting in a strain/sprain to her shoulder and elbow. He then exited the front door of the house and continued shouting outside. Family members were fearful of his behavior and called

law enforcement to handle the situation, which ultimately resulted in his formal civil commitment to a locked residential facility. The patient’s behavior was described by his spouse as surprising and entirely unexpected, given that he had no known history of such behavior.

Table II. Neuropsychological Assessment Summary Scores T Score Test Wechsler Abbreviated Scale of Intelligence – Second Edition Full Scale-4 Full Scale-2 Perceptual Reasoning Block Design Matrix Reasoning Verbal Comprehension Vocabulary Similarities Repeatable Battery for the Assessment of Neuropsychological Status Immediate Memory Visuospatial/Constructional Language Attention Delayed Memory Total Scale Texas Functional Living Scale Quality of Life Inventory Brief Symptom Inventory Somatization Depression Anxiety Total Frontal System Behavior Scale Family Rating Form Before Illness/Pre-Dementia Apathy Disinhibition Executive Dysfunction Total Another Illness/Post-Dementia Apathy Disinhibition Executive Dysfunction Total Frontal System Behavior Self-Rating Form Before Illness/Pre-Dementia Apathy Disinhibition Executive Dysfunction Total After Illness/Post-Dementia Apathy Disinhibition Executive Dysfunction Total

Composite/Index Score 122 123 96

49 46 144 80 73 103 100 78 91 79 86 35 53 18 56 45 47 50 45 63 41 48 89 93 87 101 74 61 65 72 74 51 64 67

A Retrospective Risk Prediction of Other-Directed Aggression and Violence …

Discussion This case analysis illustrates the challenges involved in attempting to identify factors that may result in aggressive and violent behavior among individuals with dementia. Comprehensive review of all material including neuropsychological testing data in conjunction with an interview of the patient’s spouse disclosed several variables that may have been used to assist in predicting risk for behavior similar to the aforementioned incident in this case. Premorbid factors identified during the clinical interview conducted at the time of his neuropsychological evaluation included physical abuse during childhood and a domineering personality throughout adulthood. Performances on objective measures of neuropsychological status generally revealed mild score reductions, overall, with the most notable deficits observed on certain tests of language, complex attention/information processing speed, and delayed memory. Obtained scores on formal measures completed by the patient’s spouse indicated behavioral issues on his part, such as emotional dyscontrol, inflexibility and resistance to change, and reduced self-awareness. The most salient factor was the marked discrepancy of 42 T score points between the patient’s and his spouse’s subjective ratings of his level of disinhibition post-dementia, which may, at least in part, reflect denial and/or anosognosia on the part of the patient. Some research suggests that anosognosia in individuals with dementia is greater in cases of low cognitive reserve [22]; while other research indicates that it seems unrelated to severity of dementia [23]. In any event, anosognosia in dementia remains poorly understood, and additional research is needed in this area. Patterns of behavioral escalation and deescalation among patients with dementia has been discussed by some researchers [24, 25] and may be critical at a given point in time in predicting progression in behavior that may lead to harm. In this case, it seems the patient exhibited a relatively clear and perhaps not entirely unexpected progression beginning with

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anxiety and eventually resulting in violence (see Fig. 1). Additional research concerning such behavioral escalations in individuals with dementia is necessary not only for identifying various circumstances that may lead to escalation as well as patterns of escalation but also in determining specific interventions that may be helpful in behavioral de-escalation and specifically when in the progression those interventions should be implemented. Anxiety

Agitation

Anger

Aggression

Violence

Figure 1. Stages of Progression to Violence in this Case.

Prospective identification of aggressive behavior, or the assessment of potential risk for aggression and violence, has important clinical implications for patients with dementia as well as for their families, caregivers, and treatment providers. Indeed, behavioral disturbances of this nature often lead to institutionalization [26], increased costs and caregiver burden, and poorer prognosis [4, 27]. Retrospective analyses of cases in which individuals exhibit aggression and violence may facilitate appropriate methods for better predicting those patients with increased risk for future episodes. Prospective empirical investigations designed to identify systematically the multitude of variables involved in these behaviors clearly are

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necessary. At this point in time, there does not appear to exist a single variable or group of variables that may reliably predict whether an individual with dementia will exhibit future aggression and violence. Clinicians probably are left to rely on the old adage that the best predictor of future behavior is past behavior, although that did not seem to hold true in this case, as the patient had no known history of aggression and violence. In any event, family member and caregiver education about behavioral issues is essential in cases of dementia.

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Chouraki V, Beiser A, Younkin L, Rosner Preis S, Weinstein G. Hannson O, Skoog I, Lambert JC, Au R, Launer L, Wolf PA, Younkin S, Seshadri S. Plasma amyloid-β and risk of Alzheimer’s disease in the Framingham Heart Study. Alzheimers Dement 2015;11:249-257. World Health Organization. Dementia: a public health priority. 2012. Geneva. World Health Organization. American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Washington, DC. Rachal F, Kunik ME. Treating aggression in patients with dementia. Psychiatric Times, 2006 (http://www.psychiatrictimes.com/articles/treatin g-aggression-patients-dementia) Whitehead RL, Golden CJ, McCormisk K. Psychological stress and behavioral issues in dementia. In S. T. Gontkovsky (Ed.), The cognitive therapeutics method: Nonpharmacological approaches to slowing the cognitive and functional decline associated with dementia Palo Alto, CA: Home Care Press. 2014, pp. 183-204. Desai AK, Schwartz L, Grossberg, GT. Behavioral disturbance in dementia. Curr Psychiatry Rep 2012;14:298-309. Jones RW, Romeo R, Trigg R, Knapp M, Sato A, King D, Niecko T, Lacey L. Dependence in Alzheimer’s disease and service use costs, quality of life, and caregiver burden: The DADE study. Alzheimers Dement 2015;11:280-290. Teng E, Marshall GA, Cummings JL. Neuropsychiatric features of dementia. In: BL Miller, BF Boeve (Eds.), The behavioral

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neurology of dementia. New York, NY: Cambridge University Press,2009, pp. 85-100. Tekin S, Mega MS, Masterman DM, Chow T, Garakian J, Vinters HV, Cummings JL. Orbitofrontal and anterior cingulate cortex neurofibrillary tangle burden is associated with agitation in Alzheimer disease. Ann Neurol 2001;49:355-361. Phillips NL, Stargatt R, Brown A. Risk assessment of self- and other-directed aggression in adolescent psychiatric inpatient units. Aust N Z J Psychiatry 2012;46:40-46. Alzheimer’s A. 2015 Alzheimer's disease facts and figures. Alzheimers Dement 2015;11:332384. Tombaugh TN. Test of Memory Malingering. North Tonawanda, NY: Multi-Health Systems, 1996. Folstein MF, Folstein SE, McHugh PR. ‘Mini Mental State’: A practical method of grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189-198. Wechsler D. Wechsler Abbreviated Scale of Intelligence – Second Edition. Bloomington, MN: Pearson, 2011. Randolph C. Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). San Antonio, TX: The Psychological Corporation, 1998. Cullum CM, Weiner MF, Saine KC. Texas Functional Living Scale. San Antonio, TX: Pearson, 2009. Frisch MB. Quality of Life Inventory Manual and Treatment Guide. Minneapolis, MN: NCS Pearson and Pearson Assessments, 1994. Diener E, Emmons RA, Larsen RJ, Griffin S. The Satisfaction with Life Scale. J Pers Assess 1985;49:71-75. Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The Fatigue Severity Scale: Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol 1989;46:11211123. Derogatis LR. BSI 18 Brief Symptom Inventory 18: Administration, scoring, and procedures manual. Bloomington, MN: Pearson, 2000. Grace J, Malloy PF. Frontal Systems Behavior Scale professional manual. Lutz, FL: Psychological Assessment Resources, 2001. Spitznagel MB, Tremont G. Cognitive reserve and anosognosia in questionable and mild dementia. Arch Clin Neuropsychol 2005;20:505515. Volpi L, Pagni C, Carlesi C, Frittelli C, Falorni I, Ghicopulos I, Tognoni T, Murri L. Understanding

A Retrospective Risk Prediction of Other-Directed Aggression and Violence …

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anosognosia in Alzheimer’s patients. Alzheimers Dement 2011;7:S268. Woods DL, Rapp CG, Beck C. Escalation/deescalation patterns of behavioral symptoms of persons with dementia. Aging Ment Health 2004;8:126-132. Milz A, Gontkovsky ST, Manning EL. Aggression and violence in rehabilitation populations. In: ST Gontkovsky, CJ Golden (Eds.), Neuropsychology within the inpatient rehabilitation environment Hauppauge, NY:Nova Science, 2008, pp. 133-158.

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Received: March 10 2016 Revised: June 5 2016 Accepted: June 29 2016



Cognitive Gains after Vestibular and Balance Therapy in a Patient with Progressive Balance Dysfunction Subsequent to Ependymoma Radiation Therapy Michael S. Trayford* APEX Brain Centers, Asheville, NC 28803 USA

Abstract External irradiation of different head and neck cancers has been associated with disorders of balance and hearing. In turn, disruption in either (or both) vestibular or auditory sensory input to the central nervous system has been associated with various aspects of cognitive decline. Characteristic measurements on both computerized dynamic posturography (CDP) and standardized cognitive testing demonstrate the associated deficits seen in individuals with balance impairment and cognitive decline; and concurrent gains in both areas of function with specific balance and vestibular therapies delivered Keywords: memory, cognition, balance, vestibular rehabilitation, balance therapy, memory improvement, cognitive decline, ependymoma

Introduction

*

Correspondence: Dr. Michael S. Trayford, APEX Brain Centers, 2 Walden Ridge Dr. (STE 80), Asheville, NC 28803 USA, Email: [email protected]

External irradiation of different head and neck cancers has been associated with disorders of balance [1] and hearing [2]. In turn, disruption in either (or both] vestibular or auditory sensory input to the central nervous system has been associated with various aspects of cognitive decline. Characteristic measurements on both computerized dynamic posturography (CDP) and standardized cognitive testing demonstrate the associated deficits seen in individuals with balance impairment and cognitive decline; and concurrent gains in both areas of function with specific balance and vestibular therapies delivered.

320

Michael S. Trayford

Background Cognitive decline, more specifically mild cognitive impairment (MCI), the intermediate stage of cognitive decline between that expected with normal aging and more serious types of dementia, can be observed by looking at specific biomarkers of cognitive function, including verbal memory (VBM), visual memory (VSM), composite memory (CM), cognitive flexibility (CF), complex attention (CA) and the neurocognition index (NCI) [3]. The associated balance impairments of an individual can be accurately measured via CDP [4] with an emphasis on measurements of overall stability, center of pressure (CoP) and fatigue ratios on a perturbed surface. This case report describes the relationship between cognitive decline and balance impairment in an elderly male subsequent to radiation therapy to the head; and the concurrent improvements in both with targeted vestibular and balance therapy.

Case Presentation A 70-year-old male was referred for evaluation of balance and incoordination that primarily affected his left side and began after radiation therapy for an ependymoma in 2008. He had undergone numerous aspects of intervention subsequent to the decline in balance, including physical therapy, vestibular rehabilitation, hyperbaric treatment, and acupuncture; all with very limited results. While he was used to being a very active and successful man, he has maintained sub-optimal function through golf, calisthenics and eating a healthy diet; although he was unable to pursue golf activities for several months prior to evaluation. According to his wife, he had been struggling with continued difficulties in memory and thinking, which quickly became an area of focus at the time of examination. Aspirin and prevachol (40mg) were the only medications being used at the time of evaluation. He had history of bilateral eye surgeries in 2009 with muscle shortening, although surgical records were not able to be retained. Physical

examination revealed a right handed male with bilateral blood pressure of 128/74 mm Hg, pulse rate of 96 bpm, height of 70”, weight of 175 lbs, fingertip oximetry of 96% bilaterally and a windmill spirometry measurement of 1800cc. Gait analysis revealed a broad-based presentation with absent left arm swing unchanged with dual tasking, and shuffling / labored gait upon pivoting/turning. Neurological assessment revealed weakness in left hip flexion (4/5), hyperreflexia in left patellar tendon (3+), dysdiadochokinesia left hand, left sided dysmetria, and left anterior sway with eyes closed and feet together in standing position. Multiple impairments in oculomotor gaze holding, visual pursuit, visual saccades and optokinetic activity were recorded with videonystagmography (VNG).

Investigations CDP, used to measure the central nervous system’s adaptive mechanisms involved in the control of balance and posture [4], revealed moderate-severe reductions in ability to maintain balance on a perturbed surface in eyes open (EO) (Figure 1A) and eyes closed (EC) scenarios (Figure 1B). A stability score of 73.9% (moderate reduction), relative to an age and gender matched population with no known balance disorders, was rendered in the EO condition; and 38.5% (severe reduction) with EC. EC condition also revealed a posterior CoP of -1.63” and high fatigueability of balance with a fatigue ratio of 105.5%. Standardized cognitive assessments [3] (Table I) revealed the following: VBM, VSM and CM scores placed the patient in the 19th, 47th and 27th percentiles respectively as compared to same-age peers in the general population. Validity indicators (VI) were present for these memory-specific tests. The remaining key performance indicators of CF, CA and NCI were reported as being not valid relative to VI standards largely due to the patient’s inability to adapt to shifting sets in a standardized shifting attention test (SAT). These scores placed the patient in 1st, 5th and 10th percentiles, respectively, compared to same-age peers.

Cognitive Gains after Vestibular and Balance Therapy in a Patient …

321

A

B Figure 1. Pre-intervention CDP testing results for perturbed stability during (A) eyes open and (B) eyes closed condition.

322

Michael S. Trayford Table I. Pre-intervention cognitive testing results

Differential Diagnosis The important differential diagnosis to be considered in a senior male patient with concurrent balance and cognitive decline, particularly with a history of cancer, would be recurrence or metastasis of cancer. Primary benign brain tumors such as ependymoma have been shown to recur. Other space occupying lesions would need to be ruled out as well via MRI/CT analysis. Cerebrovascular events and both acute and chronic traumatic brain or spinal cord injuries may cause concurrent conditions as outlined. Other diagnoses to consider are cerebellar ataxia and other cerebellar disorders, dementia/Alzheimer’s, Parkinson’s, multiple sclerosis, myasthenia gravis, chronic fatigue syndrome, sleep disorders, depression, and various toxicity causes.

Treatment The patient was treated for a period of 10 days subsequent to initial testing and examination, with two days off between two 5day protocols. A combination of balance and vestibular therapies was complemented by oculomotor stabilization, complex motor skills, cognitive tasking, sensory-based modalities (i.e. vibration and electrical stimulation), breathing

exercises, and home exercises to reinforce daily gains made with the aforementioned therapies. In-office therapies were delivered at a high frequency of 3 times per day (approximately one hour each session) for the duration of his therapeutic regimen.

Outcome and Follow Up The patient was able to realize substantial gains in both balance and cognitive function as evidenced by the following: CDP measurements after his 10-day program revealed percentage increases in EO (see Figure 2A) and EC (see Figure 2B) conditions on a perturbed surface of 5.2% and 20.5%, respectively (both now classified as mild reduction in stability scores). His posterior CoP was reduced by 1.29” in EC condition on a perturbed surface, and the fatigue ratio in both circumstances was eliminated. Cognitive testing scores (Table II) showed positive VI on all re-tests and his scores of VBM, VSM, CM, CF, CA and NCI were in the 40th, 55th, 45th, 70th, 81st and 58th percentiles, respectively. Now able to attend to shifting sets, his scores for CF, CA and NCI were notably improved. These improvements translated into a return to the active and social lifestyle of which he was accustomed to.

Cognitive Gains after Vestibular and Balance Therapy in a Patient …

323

A

B Figure 2. CDP testing results for perturbed stability during (A) eyes open and during (B) eyes closed conditions.

324

Michael S. Trayford Table II. Post intervention cognitive testing results

Discussion

References

Balance and cognition are inextricably linked [5]. Valid measurements and key performance indicators as outlined [3,4], along with associated improvements observed after therapeutic regimens have been delivered, will continue to bridge the gap in understanding how our physical and mental processes are related and impact one another reciprocally. This continued and elevated understanding will allow for improvements in early detection of neurodegenerative diseases such as dementia, and therapeutic protocols to best address the ever-increasing numbers of those afflicted with balance and cognitive decline as our senior population continues to grow with limited resources available to them to combat these often debilitating conditions.

[1]

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[5]

Gabriele P, Orecchia R, Magnano M, Albera R, Sannazzari GL. Vestibular apparatus disorders after external radiation therapy for head and neck cancers. Radiother Oncol 1992;25:25-30. Schultz C, Schmidt Goffi-Gomez MV, Pecora Liberman PH, Cássio de Assis Pellizzon A, Lopes otherapy. Carvalho A. Hearing Loss and Complaint in Patients With Head and Neck Cancer Treated With Radi Arch Otolaryngol Head Neck Surg 2010;136:1065-1069. Gualtieri CT, Johnson LG. Reliability and validity of a computerized neurocognitive test battery, CNS Vital Signs. Arch Clin Neuropsychol 2006;21:623-643. Baloh RW, Jacobson KM, Enrietto JA, Corona S, Honrubia V. Balance disorders in older persons: Quantification with posturography. Otolaryngol Head Neck Surg 1998;119:89-92. Hitier M, Besnard S, Smith PF. Vestibular pathways involved in cognition. Front Integ Neurosci 2014 Jul 23;8:59.

Received: 2 August 2016 Revised: 15 August 2016 Accepted: 20 August 2016



The Clinical Relevance of CNS Injury-Induced Immune Deficiency Syndrome (CIDS) in Functional Neurology Practice Samuel Yanuck1, 2, 3

Abstract

1

Department of Physical Medicine and Rehabilitation, University of North Carolina, School of Medicine, Chapel Hill, NC, USA 2 The Yanuck Center for Life & Health, Chapel Hill, NC, USA 3 Cogence LLC, Chapel Hill, NC, USA

One of the most important determinants of recovery outcome in traumatic brain injury (TBI), stroke, and spinal cord injury (SCI) is the extent of brain inflammation in the postevent brain and cord environments. As a clinical matter, it therefore becomes crucial for clinicians to identify sources of persistent inflammation in the patient’s brain and body. Infection is one such source of persistent inflammation. Therefore, it is crucial to a successful patient outcome that the clinician be alert to the possibility of post-event infection. CNS injury-induced immune deficiency syndrome (CIDS) is a mechanism by which the patient can become substantially more vulnerable to infection, in the post-event state. Appreciation of CIDS is therefore crucial to the clinician’s understanding of the post-event neuroimmunological status of the patient in clinical practice.

Infection in the Post-Event Setting




Persistence of brain inflammation yields poorer clinical outcomes in the post-stroke and post-TBI clinical setting [1]. Body inflammation is a known driver of brain inflammation and infection is a known driver of inflammation and therefore a worsening of outcomes in brain [2, 3]. In addition, Hazeldine, et al. [4] have shown that, among patients who develop hospital acquired infection (HAI), those for whom HAI is a comorbidity with stroke or TBI have longer hospital stays, a greater degree of organ dysfunction, and worse neurological outcomes at follow up. Therefore, the clinician attending

326

Samuel Yanuck

patients with stroke, TBI, or SCI must be attuned to the possible presence of infection, must be versed in the clinical relevance of infection to their patients’ outcomes, and must possess the skills to choose appropriate clinical support for normalization of immune surveillance in the context of stroke, TBI, or SCI. In the PANTHERIS STUDY, a human trial of short term antibiotics immediately post-stroke in human patients, Klehmet, et al. [5] have shown that, in the post-stroke setting, plasma levels of interferon-gamma (IFNɣ) are markedly lower. They reported, “Rapid T-lymphopenia and long-lasting suppression of lymphocytic IFNɣ production were observed in all stroke patients.” As a cytokine that promotes maturation of naïve T cells into a T helper cell

type 1 (Th1) polarization morphology, IFNɣ promotes the autocrine loop activation of Th1 cells. Th1 cells are both activated by IFNɣ and also produce IFNɣ, yielding a Th1 autocrine loop activation pattern. The IFNɣ made by Th1 cells also activates the efficiency with which macrophages kill phagocytosed pathogens, and promotes macrophage production of interleukin12 (IL-12). The IL-12 in turn further promotes naïve T cells to mature as Th1 cells, yielding another loop mechanism. Further, the IL-12 produced by macrophages promotes natural killer (NK) cell activation. NK cells kill virally infected cells. NK cells also make IFNɣ, yielding another loop activation, through the stimulation of both Th1 cells and macrophages (Figure 1).

Figure 1. The Th1 macrophage and NK cell macrophage loops.

These loop activation mechanisms form an important arm of the total immune response against bacterial and viral pathogens. Diminishing the efficiency of this immune surveillance mechanism gives bacteria and viruses an opportunity to expand their populations in a way that can lead to frank infection.

Emergence of Infection vs. Normal Body Burden There is a baseline body burden of bacteria and viruses in the normal human host. The normal host immune response keeps these

bacterial and viral populations from expanding into what would be considered an active infection. Thus, the difference between normal body burden and expansion of a particular pathogen into an infection is typically a function of the extent to which host immunological defenses are intact. The extent of diminution in host defenses after a stroke, TBI, or SCI is therefore a crucial determinant of vulnerability to infection. Loss of IFNɣ-mediated activation of Th1 cell, macrophage, and NK cell efficiency of loop co-activation, and resulting loss of the immune surveillance and anti-pathogenic functions of these cells, yields diminished suppression of the host’s bacterial and viral pathogen burdens. This increases the likelihood of infection.

The Clinical Relevance of CNS Injury-Induced Immune Deficiency Syndrome (CIDS) in … 327 Suppression of Th1 polarization occurs via increased production of catecholamines and cortisol in the post-injury phase. Borger, et al. [6] and Sanders, et al. [7] have shown that prolonged catecholamine exposure drives a shift in T helper cell morphology away from Th1 polarization. Borger, et al. showed that beta adrenergic stimulation inhibits IFNɣ, while the work of Sanders, et al. showed that Th1 cells expressed beta2 adrenergic receptors, stimulation of which yielded inhibition of IFNɣ by those cells, whereas Th2 cells did not possess beta2 adrenergic receptors and accordingly did not experience downregulation of their production of Th2 cytokines as a consequence of adrenergic stimulation. The Th1 inhibition effects of stresspromoted catecholamine and cortisol elevation have been discussed in relation to asthma by Anderson [8] and discussed in the context of CNS injury by Meisel, et al. [9]. In asthma, which is for the most part a Th2-dominance based disorder, the use of steroid and catecholamine inhalers has been described as “hardwiring the Th2 response” by promoting the shift in the tissue cytokine environment away from Th1 and toward Th2. Meisel, et al. [9] discuss the shifts toward persistent catecholamine and cortisol production that occur with autonomic dys-regulation in the post-stroke and post-TBI patient, driving inhibition of Th1 cells. The effect, again, is an increase in the likelihood of infection. Hazeldine, Meisel, and others [4, 9] cite research describing additional mechanisms by which immune suppression may be occurring, including inhibition of populations of Th1 cells and NK cells, phenotypic shifts in neutrophil populations, and other mechanisms related to both innate and adaptive immunity. From a clinical perspective, the key theme of these mechanisms is that they are components of an overall loss of integrity of Th1 capacity, and the capacity of a robust Th1 response to provide T cell help to drive a robust innate immune response.

Chronicity of Infection as a Driver of Inflammation While suppression of efficient immune surveillance in the post-event setting can yield infection, the infection itself can drive further inflammatory activation that creates further risk to the patient’s outcome. LPS, aka endotoxin, is a B cell mitogen found in the outer cell membrane of gram negative bacteria. Rivest [10] describes simulating the infection state by injecting LPS into the peritoneum, to evoke a systemic immune response that mirrors that of body infection. He states that, “A single systemic injection of LPS (1 mg/kg intraperitoneally) results in the robust induction of expression in microglial cells of genes that encode proinflammatory cytokines and chemokines, as well as proteins of the complement system.” The ability of systemic LPS injection to promote microglial inflammatory cytokine production demonstrates the relationship between bacterial infection in the body and neuroinflammation. The recent review by Hinson, et al. emphasizes the importance of limiting secondary brain trauma that results from excessive neuroinflammation. From a clinical perspective, this adds to the necessity of identifying infectious sources of chronic inflammation. Further, the level of systemic inflammation may be sufficient to promote further autonomic dysregulation and an increase in sympathetic barrage, further driving catecholamine and cortisol levels, yielding a further suppression of adequate surveillance against bacteria and viruses by Th1 cells, NK cells, and other immune cells. This constitutes a positive feedback loop that includes both infection and inflammation. As Brown and Neher [11] and Biber, et al. [12] emphasize, neuroinflammation can drive excessive neuronal loss, through excessively exuberant microglial phagocytosis of neurons.

328

Samuel Yanuck TBI  autonomic dysregulation  catecholamine & cortisol upregulation  loss of Th1 surveillance  expansion of pathogen pools  infection  systemic inflammation  neuroinflammation  neuronal loss & further autonomic dysregulation (loop)

The Clinical Picture

References

Given the above considerations, the clinician attending a patient with stroke, TBI, or SCI must take steps to identify acute infections and to evaluate the patient’s overall burden of bacterial and viral pathogens. It’s also necessary to use laboratory testing to evaluate the state of the patient’s immune system, focusing particularly on the question of immune suppression. In this regard, a cbc is not adequate to identify changes in immune surveillance status, since changes in T cell polarization patterns can occur without changing the total number of T and B lymphocytes. Communication among the cells of the immune system is accomplished by a complex orchestration carried on primarily through chemical signaling mechanisms and their receptor-mediated impacts. Clinically, influencing this complex system requires influencing the body chemistry. This can arguably be done indirectly in several ways, including through exercise, stress reduction, or other means. However, the only primary mechanism for influencing body chemistry is through changes to the chemicals ingested by the patient. These are the foods, nutritional substances, and medications that the patient ingests. Accordingly, the clinician’s ability to properly identify and manage the immunological factors that impact the outcome in stroke, TBI, or SCI cases depends upon the clinician’s understanding of the immune system and knowledge of the specific immunological impacts of foods, nutritional supplements, and medications on specific immunological targets. As with the functional neurological components of complex stroke, TBI and SCI cases, the depth and detail of the clinician’s knowledge of functional immunology will determine the clinician’s effectiveness in attending the immunological components of these cases.

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

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Corps KN, Roth TL, McGavern DB. Inflammation and neuroprotection in traumatic brain injury. JAMA Neurol. 2015 Mar;72(3):35562. Rivest S. Regulation of innate immune responses in the brain. Nat Rev Immunol. 2009 Jun;9 (6):429-39. Perry VH, Nicoll JA, Holmes C. Microglia in neurodegenerative disease. Nat Rev Neurol. 2010 Apr;6(4):193-201. Hazeldine J, Lord JM, Belli A. Traumatic Brain Injury and Peripheral Immune Suppression: Primer and Prospectus. Front Neurol. 2015 Nov 5;6:235. Klehmet J, Harms H, et al. Stroke-induced immunodepression and post-stroke infections: lessons from the preventive antibacterial therapy in stroke trial. Neuroscience 2009 Feb 6; 158(3):1184-93. Borger P, Hoekstra Y. Beta-adrenoceptormediated inhibition of IFN-gamma, IL-3, and GM-CSF mRNA accumulation in activated human T lymphocytes is solely mediated by the beta2-adrenoceptor subtype. Am J Respir Cell Mol Biol. 1998 Sep;19(3):400-7. Sanders VM, Baker RA, et al. Differential expression of the beta2-adrenergic receptor by Th1 and Th2 clones: implications for cytokine production and B cell help. J Immunol. 1997 May 1;158(9):4200-10. Anderson GP. Interactions between corticosteroids and beta-adrenergic agonists in asthma disease induction, progression, and exacerbation. Am J Respir Crit Care Med. 2000 Mar;161(3 Pt 2):S188-96. Meisel C, Schwab JM, et al. Central nervous system injury-induced immune deficiency syndrome. Nat Rev Neurosci. 2005 Oct;6(10): 775-86. Rivest S. Regulation of innate immune responses in the brain. Nat Rev Immunol. 2009 Jun;9(6): 429-39. Brown GC, Neher JJ. Microglial phagocytosis of live neurons. Nat Rev Neurosci. 2014 Apr;15(4): 209-16. Biber K, Neumann H, Inoue K, Boddeke HW. Neuronal ‘On’ and ‘Off'’ signals control microglia. Trends Neurosci. 2007 Nov. 30 (11): 596-60

Abstracts from the 2016 IAFNR Conference

November 4 - 6, 2016 Green Valley Ranch Resort Henderson, Nevada .



A Multimodal Approach to Care of an Adolescent Male with Absence Seizures Joseph Coppus, Michael Longyear*, and Michael Hall NeuroLife Institute, Marietta, GA, USA

Abstract Background; An 11-year-old male presents with a chief complaint of absence seizures, occurring 15-to-30 times per day. Methods: Physical examination findings included a left anisocoria with sluggish direct light reflex, absence of the vestibular ocular reflex (VOR), and pincer test ratings of two bilaterally. Videonystagmography (VNG) testing revealed saccadic latency of 184 ms leftward and 190 ms rightward. A weeklong treatment was implemented to engage the frontal lobe, basal ganglia, cerebellum, and parietal-insular-vestibular cortex consisting of whole body rotation with gaze fixation, interactive metronome, and neurosensory integration. Coupled motion cervical and standing rib manipulations were implemented to prime the nervous system upon each visit. The patient was also placed on a ketogenic diet complimenting his neurologic rehabilitation. Results: The patient showed significant improvement concluding treatment. He now experiences 0-to-5 absence seizures per day, versus the initial 15-to-30 times per day. Additional physical findings that improved included the correction of the left anisocoria with brisk direct and indirect light reflexes bilaterally, as well as regaining full VOR. Upon follow-up VNG testing, the patient improved his saccadic latency to 179ms leftward, and 180ms rightward. Conclusion: Results highlighted by this case provide evidence into the need for further research into the benefits of a ketogenic diet in conjunction with brain-based therapies for the treatment of absence seizures.

*

E-mail: [email protected]



Cognitive Improvements in a Teenage Male with Post-Concussive Syndrome Following Functional Neurology Intervention Dominic Fetterly1,*, Rachel Abbott2, and Michael Hall2 1

Life University, Marietta, GA USA 2 NeuroLife, Marietta, GA USA

Abstract Background: A 16-year-old male presented to a university-based functional neurology clinic with persistent cognitive difficulties following a concussive injury sustained one-year prior. Specifically, he reports difficulty reading, poor memory and inattention. Methods: Initial evaluation included a physical examination, Computerized Dynamic Posturography (CDP), Videonystagmography (VNG), and C3 Logix evaluation. Significant findings are demonstrated within Table I. Overall deficiencies were correlated with the neurological delineates of hypofunction within the left frontal lobe, left mesencephalon and right cerebellum. He began a course of care over 5 days’ time, receiving daily chiropractic spinal adjustments, off vertical axial rotation (OVARD) treatments, and specific balance and optomotor exercises. Results: The patient demonstrated improvements upon re-examination with his balance, coordination, oculomotor function, and cognitive testing. Significant findings are demonstrated within table 1. Conclusions: Post-concussive syndrome may cause long-term impairment with few conventional treatment options. Positive outcomes of this case suggest further investigation into the reproducibility of a chiropractic functional neurologic approach is warranted. Table I. Results Pre- and Post-treatment Initial Examination

Re-Examination

% Improvement

Simple Reaction Time (C3 Logix)

385ms

357ms

7.3%

Choice Reaction Time (C3 Logix)

519ms

367ms

29.3%

CDP Stable Surface, Eyes Closed (stability score) CDP Perturbed Surface, Eyes Closed (stability score) VNG Leftward Saccadic Latency (avg)

78.7%

87.8%

9.1%

42.6%

72.7%

30.1%

214ms

207ms

3.3%

VNG Rightward Saccadic Latency (avg)

219ms

208ms

5.0%

*

Full Disclosure: Correspondence: Dominic Fetterly, Life University, 1415 Barclay Cir, Marietta, GA USA Email: [email protected]



Adolescent Learning Disability, Functional Neurological Management in a 13-Year-Old Female Brittany Forrester1,*, Michael Longyear2, and Michael Hall2 1

2

Life University, Marietta, GA USA NeuroLife institute, Marietta, GA, USA

Abstract Background: A 13-year-old female presented with a learning disability, difficulty reading, memorization task failure, low marks in school, and a previous diagnosis of dyslexia. Methods: Functional neurologic examination revealed convergence insufficiency, impaired responsiveness with both saccades and pursuits movements as well as balance deficiency (Table 1). An individual treatment plan targeted at optimizing frontal lobe connectivity and oculomotor function was utilized 2 times per week for 5 weeks. Treatments included: utilization of the Off Vertical Axis Rotational Device (OVARD), N Back, Trails B, and word creation while standing on a Vibeplate. Observed aberrancies in normal cervical-coupled motion patterns were reduced with specific spinal manipulative procedures on a daily basis while monitoring neurologic responsiveness. Results: Re-examination after 5 weeks revealed restoration of near convergence. Follow-up VNG and balance testing showed marked improvement (Table 1). Following treatment, she received her first high A mark in school and passed standardized testing for admittance into 6th grade. Conclusions: Observed outcomes were significant for improvement in eye movements, postural stability limits, and classroom performance. Questions regarding accurate diagnosis of dyslexia and frontal lobe disorder should be carefully considered. Quantitative outcome research with larger samples is warranted, as there is a growing trend in the prevalence of dyslexia in the North American population. Table I. Pre-Treatment

Post-Treatment

Videonystagmography latency leftward

221

212

Videonystagmography latency Rightward

236

231

% of Saccade greater than 415 degrees per second Computerized Assessment of Postural Systems Pertubated Surface Eyes Open Computerized Assessment of Postural Systems Pertubated Surface Eyes Closed

50% 74.1% Stability Rating 73.7% Stability Rating

100% 83.6% Stability Rating 75.5% Stability Rating

*




Cervical-Ocular-Vestibular Therapy and Functional Neurology in a Concussed Collegiate Male Wrestler Katherine E. Leonardis1,*, Jonathan Vestal2, nd Michael Hall3 1

Life University, Marietta, GA, USA 2 NeuroLife, Marietta, GA, USA

Abstract Background: A 19-year-old male wrestler presents with headaches, insomnia, and photophobia following an injury during practice 5 days earlier. He collided with a concrete wall and lost consciousness for approximately 10 seconds. Methods: Upon presentation, the patient was administered the headache disability index (HDI) and C3 Logix evaluation. The physical examination revealed occipital pain during active and passive range-of-motion of the neck, bilateral hypofunction of active vestibuloocular reflex during head thrust test, and blurry vision during near accommodation. The results from the C3 Logix, HDI and physical exam indicated cervicogenic and vestibuloocular dysfunctions. A treatment plan involving cervical manipulation, optomotor neurotherapeutics and vestibular training was utilized with goals of improving cervicalocular-vestibular function over 13 days. Results: Patient experienced gradual improvements in all symptoms as well as significant improvements in visual acuity, Balance Error Scoring System (BESS) testing, and symptom severity index. Conclusions: Traumatic insult to the head and cervical spine can cause marked dysfunction in the cervical-ocular-vestibular system causing a multiplex of clinical symptomology. Utilization of specific neurologic rehabilitative therapies may be an important consideration in the management of the athlete with sports related concussion. This case demonstrates the importance in identifying areas of functional neurologic deficits on both a horizontal and longitudinal level. Functional neurology and chiropractic should be considered in similar cases.

HDI

Pre-Treatment

Post-Treatment

34%

0%

Symptom Severity Index (C3 Logix)

61

6

BESS (C3 Logix)

16 errors

13 errors

Visual Acuity (C3 Logix)

2.0 line diff.

.8 line diff.

Horizontal Head Thrust Test

+ bilaterally

Normal

*




Improved Sensory Perception, Fine Motor Coordination and Balance in Patient with Brain Injury Following Lifting Event Paula Rhodes* and Jon Eberle Life University’s Center for Health and Optimum Performance

Abstract Background: A 26-year-old male complained of numbness and tingling of his entire left body, poor balance and difficulty handling trays as a server. He was left-handed and also noticed deficits with handwriting. The symptoms began the morning after a particularly vigorous workout performing hack squats with a heavily-weighted machine and holding his breath versus free weights. He had received 3 MRI’s, 2 spinal taps, 2 CT scans, anti-seizure medication, which he discontinued, and corticosteroids. The initial MRI and CT scan showed a lesion at the basal ganglia that was nearly absent in imaging performed 15 days later. No diagnosis was rendered. Objectives were to improve feeling to the left soma, and restore balance and fine motor coordination. Methods: A detailed chiropractic functional neurological examination was performed which revealed hypertonicity and decreased ROM of the cervical spine. Gait demonstrated decreased arm swing and instability; tandem gait was unable to be performed. Neurological motor testing and optokinetics revealed marked deficits in fine motor performance on the left. A treatment plan involving active movements, specific ocular exercises, somatosensory stimulation and spinal manipulative therapy (SMT) was applied. Results: Initial exam: Decreased ROM in C-spine Tandem gait: unable to perform OPK: L hypermetric, R hypometric Gait: decreased L arm swing Heel-to-Shin: poor on L Finger-to-nose: poor on L with slight terminal tremor

End of treatment: C-spine ROM normal Tandem gait – normal OPK: WNL Normal amplitude, equal bilaterally WNL WNL

Conclusion: Rapid progressive improvement in sensory perception, fine motor coordination, gait and balance was achieved with functional neurological rehabilitation and SMT, suggesting the importance and efficacy of early functional neurological intervention in cases of brain injury. Further studies are indicated.

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Learning Disability and Reading Difficulty in a 12-Year-Old Male Rachel Smith1,*, Michael Longyear2, and Michael Hall2 1

2

Life Univesity, Marietta, GA, USA NeuroLife Institute, Marietta, GA, USA

Abstract Background: The patient is a 12-year-old male who presented with a chief complaint of difficulty reading. Methods: Functional neurologic examination revealed a breakdown of near convergence and an inability to perform smooth, uninterrupted rightward pursuits. Videonystagmography (VNG) revealed saccadic eye movement latency of 212 milliseconds, rightward and 187 milliseconds, leftward. The Comprehensive Assessment of Postural Systems (CAPS) was performed and revealed: Normal Stability Eyes Open (NSEO) 93% stability score, Normal Stability Eyes Closed (NSEC) 90.4% stability score, Perturbed Surface Eyes Open (PSEO) 79.1% stability score, and Perturbed Surface Eyes Closed (PSEC) 72.1% stability score. The treatment plan consisted of twice a week for eleven weeks and was aimed at improving function of the left frontal lobe, cerebellum, mesencephalon and mid-line inferior frontal lobe. Specific chiropractic spinal adjustments were performed on the upper three ribs, occiput and upper cervical where indicated. Neurologic rehabilitative therapies included the utilization of a Marsden ball, interactive metronome, Brock string, vestibular stimulation with an off vertical axial rotational device (OVARD) with targets, and a vibration plate. Results: Following eleven weeks of care, the patient was re-evaluated and his CAPS scores were as follows: NSEO 86.6%, NSEC 92.7%, PSEO 85.5%, PSEC 83.3%. His post VNG scores revealed 170ms latency leftward and 169ms rightward. Near convergence was restored and pursuit eye movements were without interruptions in all planes. Conclusion: Based on the results presented in this case, further research needs to be conducted to fully understand the application of convergence and stability exercises for individuals suffering with learning disabilities and reading difficulties.

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Letter to the Editor The Effects of Stress and Chiropractic Adjustments on Neural Regulation Richard G. Barwell and Jonathan Vestal Private Practice, Melbourne Florida, USA




Dear Editor, The Chiropractic profession has always involved neurological function, albeit, as a secondary involvement through the theory of vertebral subluxation and nerve root pressure. This theory, while intended to be foundational for the profession, remains a theory after more than 120 years. Little, if any, explanation has been offered as to the etiology of the vertebral subluxation, and the lack of supporting science for either its cause or the effectiveness of the Chiropractic adjustment has placed the profession in a position for critical challenges. The field of neuroscience offers an opportunity for answers to both of these challenges. The profession continues to teach that emotional, physical and chemical stressors are the cause of vertebral misalignment, but fails to explain the mechanism as to how they are involved. While the traditional approach to stress tends to regulate stress to a psychological foundation, we now understand that the stress response is much more complex and diverse. The human response to stressors is under the control of the Central Nervous System and its ability to maintain a regulatory balance with all other bodily systems. New terms such as neuro-regulation, allostasis, processing resources, neuroplasticity, selfregulation and neurologically based chiropractic are all part of the influence of the new knowledge being provided by neuroscience. This paper and my presentation will address how this new field of neuroscience is changing concepts in health care including the role of Chiropractics.

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Richard G. Barwell and Jonathan Vestal

Neural Regulation It has long been accepted that the Central Nervous System (CNS) is the major controlling authority to other body systems. There is more to this concept than the brain simply responding to it environment through motor pathways. First there must be accurate sensory input to the brain, then proper information processing followed by an appropriate motor response. This loop completes the cycle of neural regulation. Any level of breakdown in this loop has a consequence. The challenge the chiropractic profession continues to face lies in the differentiation between the functional and structural models of the Chiropractor’s approach to patient management. The traditional approach is the structural model of the dysrelationship of spinal vertebra as the primary insult; while the modern understanding is that the vertebral misalignment is a tertiary response to a neuroregulation imbalance. This imbalance is often found in evaluating brain function as a result of the effect of stressors overloading the ability of the CNS to maintain ideal balance. These patterns can be observed in both cortical patterns of activity and limbic system responses [1]. While all humans have neurological predispositions in place that are preprogramed (genetic), we also have programs that have been learned through experience and training. Throughout life we continue to wire and rewire our brains through the learning process and repetition. This process is called neuroplasticity. An excellent example of a learned neurological response is the scenario where a child inquisitively touches a hot surface for the first time and develops a neural association that prevents future injuries. This is an example of experience creating a neural response (function) thus being the driving factor in the need for the brain to rewire itself. The neural response builds a neuronal memory connection (structural change) for survival value. These systems of the body were designed to preserve life by optimizing the human’s ability to fight, freeze, or avoid a stressor. They were also designed to respond in an opposite manner

when no stressor is present. If the stressors continue, the system stays in arousal. If the stress continues from many sources, the system may become unbalanced. We have known that we can measure many of these signs or symptoms such as: blood pressure, heart rate, respiratory rate, muscle tension, extremity temperature and recently heart rate variability. These are all affected by the limbic system’s response to stress. Today we have another method where we can measure the effects of stress. Cortical function patterns and the responses of brain wave generation can indicate if the brain is in an over-aroused, under-aroused, instable or exhausted state [2]. If the CNS is locked into one of these patterns, the consequences are that the body will develop physical signs and symptoms, which align with the state of the neurological pattern. The body loses its ability for an appropriate homeostatic response.

Allostatic Response The role of homeostasis has been included in all life forms when discussing survival. It was commonly taught as a static balance with all systems of the body. Homeostasis is the ideal state of being. When Hans Selye published new information in his research called “Stress and Disease” [3] researchers began to recognize that there was much more going on within the body than simply keeping a static physiologic balance. There was a moving balance that was expressed in a variety of physiological responses. There are physical limitations to the amount of a system’s capability of stressor response, but it is understood that a person can have much more adaptability than previously presented. The ability to shift is called “Allostasis” or adaptive balance. The clinical challenge begins when the stressors create an allostatic load [4], which the system can no longer accommodate. There are several conditions or combinations of stressors, which can create allostatic load. Examples are: extreme levels of stressors; regular high level stress demands; lack of recovery from a stressor and/or an inappropriate system response to a

Letter to the Editor stressor. When we consider a disruption to neuroregulation as part of the contributing factors of allostatic load and the role of the brain as the central controlling authority of all body functions, we now have a serious challenge to an ability to maintain ideal health.

Sensory Input All Systems ideally receive accurate afferent information in order to produce ideal output. The computer adage of “garbage in – garbage out” holds true to neurological function. The human body is equipped with a wide range of sensory receptors designed to supply information to the CNS on both the internal and external environment so that it can maintain a homeostatic balance. If the sensory input contributes to a person exceeding their allostatic load level, the system loses its ability to maintain optimum performance and the system’s interaction starts to break down. The next step is integration of the sensory information by the brain before any motor action will take place. This of course excludes any spinal reflex action, which is what I call “a stage 1 response.” This quote from Settiet [5] offers some relevant insight: “We are continuously exposed to stimulation across our senses; some of which is relevant to the task at hand but most of which is not. The ability to isolate and process appropriate sensory stimulation whilst inhibiting irrelevant stimulation is essential in order to achieve our goals in a timely and efficient manner. However, as we age, it is thought that this inhibition of irrelevant information becomes more difficult such that available sensory information is processed more extensively.”

Integration – Processing Resources The central organising authority is a good title for the brain. The processing resources [6] of the brain are extremely complicated and are a living computer of fantastic capabilities. That

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said, every Physiological system has its functional limitations and the CNS is no exception. When the allostatic load is reached, the allocation of processing resources becomes the disruption in the integration process. The main issues are timing of the processing and accuracy of the response. A secondary consideration lies in the bottleneck created by the allostatic load on the brain structure itself. The ideal integration of sensory information is challenged and the efficiency of the CNS system is compromised. The motor response to the sensory information is also compromised. This is the “garbage in - garbage out” challenge to neuro self-regulation. The internal/external issues that the body faces daily are stressors to the homeostatic balance required to maintain good health.

Self-Regulation The eternal question of all regulators of systems is “who regulates the regulators?” When we consider the question regarding the brain, we begin to see a major problem in brain function. Neural patterns begin to develop through repetition. This is how we learn; however, if that pattern is a response pattern designed for shortterm application, but becomes a fixed response pattern, the ideal homeostatic balance is disrupted. The real problem lies in the brain’s lack of ability to regulate itself [7]. As we are looking at a top down control system, any functional challenge at the brain level will have serious effects on all other systems under its control. Once the nervous system builds toward an inappropriate pattern, the effects of any further challenge to the processing resources will elevate the allostatic load. The effects of prolonged stress directly affect the cognitive function of the individual via impaired prefrontal cortical activity [8] (PFC). Disruption of the PFC has a wide ranging effect on total brain function including: memory, amygdala function, cortical structure [9] and the hypothalamic pituitary adrenal tract (HPA) responses [10].

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The Neurological Subluxation The term “subluxation” has a historical application to the Chiropractic profession. The original theory of vertebral misalignment, which put pressure on the spinal nerve root, tied the profession to structural involvement and to a peripheral neurological foundation. The reason for this lies in the general approach to health challenges being focused on down-stream effects, signs and symptoms treatment, rather than up-steam regulation, being irregularities in regulation control as cause. The “Art” of Chiropractic technique at first was focused on physically affecting (adjustment) the joint function. This was thought to reduce the pressure on the nerve root and therefore allow improved neurological function. The term “subluxation” became repurposed amongst chiropractors to vertebral misalignment and became synonymous with Chiropractic. In later years the art of the profession began to develop other non- physical approaches, which achieved results similar to the physical model of adjustment. However, while the profession saw many claims being made as to the success of Chiropractic care, the original theory of pressure on the nerve root and neurological interference remains unproven. The field of neuroscience offers a better understanding of not only the effectiveness of Chiropractic care in improved health but also provides the opportunity to put to rest the “bone on nerve” theory that has restricted the mainstream acceptance of the chiropractic profession. There has been research into how neurological patterns develop. We know there are the spinal reflex arcs, sensory input for CNS processing and efferent output (motor response). I suggest we look at this from a different point of view. First - the spinal reflex arc is a “quick action” protection, based on genetic design and learned experience. Secondly, I propose for the purposes of this paper that we make the aforementioned “sensory input for CNS processing” synonymous with the phrase

“increased afferentation”. I am not using the term afferentation as defined by Seaman and Winterstein [11] but simply as a condition of increased sensory input. Increased sensory input also increases demand on the processing resources of the brain. As the stress or threat to the system increases, through physical, chemical and/or mental stressors, the amount of sensory input will also increase. The majority of the input is below the conscious awareness state. In fact, there is a built in system to block some of the sensory input [12]. Seaman and Winterstein [13] also limited the blockage of input by the nociceptors in the spinal joints and called this dysafferentation. There is a much bigger picture than simply at the spinal level involved in the response. Much more information is now available that suggests pain sensations are more of a perception than a receptor response. In 1965, Melzack and Wall [12] proposed a new theory regarding pain and neurological function. They included a concept of “blocking gates” on the sensory system, which reduced the amount of pain input. “Although this gate theory was disproven a year later, the actual mechanism of intrinsic nociceptive adaptability is related to the function of neuroplasticity within the spinal cord.” These signals are transmitted to a specialized part of the spinal cord called the dorsal horn where they can be dampened or amplified before being relayed to the brain. The existence of endogenous mechanisms that diminish pain through net “inhibition” is now generally accepted [14]. Pain modulation likely exists in the form of a descending pain modulatory circuit with inputs that arise in multiple areas, including the hypothalamus, the amygdala, and the rostral anterior cingulate cortex. The nervous system appears to have a built in “failsafe” program, where, although the problem still exists, the sensory warning system is blocked or significantly reduced so that the pain is not debilitating. The conscious mind is relieved, but the subconscious still has to manage the challenge. This will keep the CNS in stress or defense mode.

Letter to the Editor This “failsafe” program is an example of how the brain responds to stressors and results in building neuronal patterns that, while they modulate the sensory stressor warning, subconsciously the system continues to acknowledge its existence and the allostatic load builds. The protection patterns represent the best the system can do when the allostatic load is in play1. The brain eventually fails to self-regulate and these patterns become hard wired cortical patterns. In order to alter these patterns the brain will need some form of outside influence to create the opportunity for the system to correct itself. The lack of the brain’s self-regulation becomes the primary factor. This is the foundation for the neurological subluxation. The CNS disruption has downstream consequences such as inappropriate muscle response patterns and structural alterations which, in turn, feed back into the sensory system.

Stress and Neurophysiological response to Fight/Flight As the nervous system continues to deal with the heightened allostatic load, the fight/flight response continues to control the system’s defense mechanisms. The following are some of the physiological reactions which push the body into deeper health challenges: An environmental stressor reaction stimulates the amygdala, which triggers neurons in the hypothalamus to secrete corticotrophinreleasing hormone (CRH) and argininevasopressin (AVP). CRH stimulates the secretion of Adrenocorticotropic Hormone (ACTH). ACTH stimulates increased production of corticosteroids including cortisol and aldosterone, which increases blood pressure, blood sugar, and suppresses the immune system. Vasopressin increases reabsorption of water by the kidneys and induces vasoconstriction. The adrenal glands are activated almost simultaneously and releases catecholamine neurotransmitter hormones, such as adrenaline (epinephrine) or noradrenaline (norepinephrine), which facilitate immediate physical reactions

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associated with a preparation for violent muscular action. This initial response and subsequent reactions are triggered in an effort to create a boost of energy. This boost of energy is activated by epinephrine binding to liver cells and the subsequent production of glucose. Additionally, the circulation of cortisol functions to turn fatty acids into available energy, which prepares muscles throughout the body for response. CRH and AVP activate the hypothalamic-pituitary-adrenal (HPA) axis [15]. The flight/fight response can render individuals suffering from chronic stress highly vulnerable to infection. The hippocampus, the region of the brain where memories are processed and stored, can become overwhelmed by cortisol which actually causes atrophy [1618] - usually reversible.[18,19] Circadian rhythms are disrupted. Acute sleep loss confuses the HPA axis and disrupts negative glucocorticoid feedback regulation. The excitatory/inhibitory balance of the autonomic nervous system is disrupted and the neuroregulation of the CNS moves to an allostatic load. The immune system breaks down and the most common way a person learns of their health challenge is through the development of signs or symptoms.

The Effects of Chiropractic Adjustments As a clinician in practice for 32 years, I was challenged with the bone on nerve theory and was constantly questioning why the adjustment, especially in approaches that were outside the manual work, seemed to get the same level of improvement in the patient’s response. I also was deeply challenged in finding any explanation as to how the vertebral fixation developed in the first place. Others were quick to offer chemical, mental or physical stress as the cause but failed to explain the mechanism. The intent of the research I did along with Long, Byers and Schisler was to determine if the chiropractic adjustment altered cortical brain

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patterns [1]. The first step was the null hypothesis to try to prove it did not alter cortical function. Within the first 10 EEG pre and post studies, it was obvious that the adjustments were dramatically changing brain wave patterns. The next step was to see if chiropractic adjustments altered just one set of frequencies or more. We did well over 100 pre and post scans over the next three years and saw changes across all frequencies. We noted that most adjustments moved the pattern toward a better balance of brain wave engagement and disengagement. Some adjustments however, did not improve the balance and in fact made matters worse. The patient also subjectively reported the effects of these poor responses to chiropractic adjustment. What was gained from this work was insightful and of great promise. These results indicate that outside of duration and frequency as the basis of a care plan, the intensity of the care (heavy force, multiple areas, high frequency or a combination of these verses lower force, less frequency and/or less areas involved) needed to be a consideration. An example: someone in an overaroused state was a contraindication for an intensive care program or someone in an underaroused state needed a more intensive care plan. These findings also demonstrate the critical need for an objective method of analysis of the CNS function to be able to design the ideal care program. The Research being done by Dr. Heidi Haavik has furthered the understanding if the effects of Chiropractic care to alter neurological function. Dr. Haavik is a PhD in neuroscience and is extremely well published. She continues to produce quality work that far surpasses my efforts. Her first paper demonstrated that cervical spine manipulation altered cortical somatosensory processing and sensorimotor integration [20]. This supported what I found in my research. Dr. Haavik’s work continues to produce a better understanding of the Chiropractic adjustment and its relationship to CNS function. A review of her work shows that Chiropractic adjustments (termed manipulation)

have an effect on: lower limb muscle strength, [21] altered motor control, [22] altered reflex excitability, [23] improved brain reaction time – changes in cortical processing, [24] improved prefrontal activity, [25] and improvement in muscle strength following the adjustment [26]. There are many other research papers available regarding Chiropractic adjustments and their influence on CNS function but Dr. Haavik’s work continues to set the standard for quality research in this field. The amount of high quality research, which establishes that the Chiropractic adjustment acts as neurological pattern interrupt, is of great value to the profession. It represents the missing information for the shift from the “bone on nerve” theory to a strong neurological foundation for Chiropractic. The chiropractic profession has always been focused on the role of the nervous system and its relationship to health. The profession claims that stressors such as chemical, physical and mental stressors play a role in the challenges to health; however, it has failed to explain the relationship between stress, the nervous system and chiropractic. The 102-year-old theory of vertebral misalignment and nerve root pressure is not valid as a foundation for Chiropractic. It is the responsibility of the profession to provide a sound, research supported, neurological foundation that will move the profession forward. The uniqueness of the Chiropractic profession lies in its philosophy, which separates it from the practice of medicine. That said, without quality supporting scientific research, the profession will always remain outside of mainstream acceptance [27]. Today, neuroscience is changing health concepts across all professions. The profession needs to better conceptualize the effects of stress on neurological function and health. We now know the effects of brain malfunction, beyond the obvious severe traumatic brain injury, and are realizing that low-grade stressors have an accumulative effect on brain health. The evidence of the effectiveness of the chiropractic

Letter to the Editor adjustment to alter Central Nervous System function is growing. Today we have instruments that can measure a wide range of brain function. The goal of Chiropractic is to help the brain maintain a high level of functional efficiency and thereby reduce the allostatic load, which will reduce the effect of stress on health. It is time for the profession to recognize our responsibility of furthering Chiropractic by removing an unproven theory from chiropractic curriculum and marketing. The Profession must invest in quality research regarding the relationship between Chiropractic and neurologic function. The future of the profession depends on understanding the effects of stress, chiropractic adjustments and neural regulation.

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Barwell R, Long A, Byers A, Schisler C. The effect of the chiropractic adjustment on the brain wave patterns as measured by EEG. 2004 International Research and Philosophy Symposium October 9 -10 2004, Sherman College of Straight Chiropractic. Selye, H. Stress and disease Science 1955;122(3171);625-631. Othmer S, Othmer SF, Kaiser DA. EEG biofeedback: An emerging model for its global efficacy. Introduction to quantitative EEG and neurofeedback. 1999;243-310. McEwen BS. Stress, adaptation, and disease: Allostasis and allostatic load. Ann NY Acad Sci 1998;840(1):33-44. Setti A, Burke KE, Kenny RA, Newell FN. Is inefficient multisensory processing associated with falls in older people?. Exp Brain Res 2011;209(3):375-84. Zwarts F, Toffanin P, te Sandrigo I. Brain Economics: Housekeeping Routines in the Brain. Heatherton TF, Wagner DD. Cognitive neuroscience of self-regulation failure. Trends Cognit Sci 2011;15(3):132-139. Mika A, Mazur GJ, Hoffman AN, Talboom JS, Bimonte-Nelson HA, Sanabria F, Conrad CD. Chronic stress impairs prefrontal cortexdependent response inhibition and spatial working memory. Behav Neurosci 2012;126(5):605. Arnsten AF. Stress signalling pathways that impair prefrontal cortex structure and function. Nature Rev Neurosci 2009;10(6):410-422.

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Diorio D, Viau V, Meaney MJ. The role of the medial prefrontal cortex (cingulate gyrus) in the regulation of hypothalamic-pituitary-adrenal responses to stress. J Neurosci 1993;13(9):38393847. Seaman DR, Winterstein JF. Dysafferentation: a novel term to describe the neuropathophysiological effects of joint complex dysfunction. A look at likely mechanisms of symptom generation. J Manip Physiol Therapeut 1998;21(4):267-280. Melzack R, Wall PD. Pain mechanisms: a new theory. Survey Anesthesiol 1967;11(2):89-90. Ossipov MH, Dussor GO, Porreca F. Central modulation of pain. J Clin Invest 2010; 120(11):3779-3787. Giordano R, Pellegrino M, Picu A, Bonelli L, Balbo M, Berardelli R, Lanfranco F, Ghigo E. Neuroregulation of the hypothalamus-pituitaryadrenal (HPA) axis in humans: effects of GABA-, mineralocorticoid-, and GH-Secretagoguereceptor modulation. Scientific World J 2006;6: 1-1. Lupien SJ, de Leon M, De Santi S, Convit A, Tarshish C, Nair NP, Thakur M, McEwen BS, Hauger RL, Meaney MJ. Cortisol levels during human aging predict hippocampal atrophy and memory deficits. Nature Neurosci 1998; 1(1):6973. Frodl T, O'Keane V. How does the brain deal with cumulative stress? A review with focus on developmental stress, HPA axis function and hippocampal structure in humans. Neurobiol Disease 2013;52:24-37. Sudheimer KD, O'Hara R, Spiegel D, Powers B, Kraemer HC, Neri E, Weiner M, Hardan A, Hallmayer J, Dhabhar FS. Cortisol, cytokines, and hippocampal volume interactions in the elderly. Front Aging Neurosci 2014;6. McEwen BS. Brain on stress: how the social environment gets under the skin. Proc Nat Acad Sci USA. 2012;109(Suppl. 2):17180-17185. Ortiz JB, Mathewson CM, Hoffman AN, Hanavan PD, Terwilliger EF, Conrad CD. Hippocampal brain-derived neurotrophic factor mediates recovery from chronic stress-induced spatial reference memory deficits. Euro J Neurosci 2014;40(9):3351-3362. Haavik-Taylor H, Murphy B. Cervical spine manipulation alters sensorimotor integration: a somatosensory evoked potential study. Clin Neurophysiol 2007;118(2):391-402. Taylor HH, Murphy B. Altered sensorimotor integration with cervical spine manipulation. J Manip Physiol Therapeut 2008;31(2):115-1126.

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Richard G. Barwell and Jonathan Vestal Suter E, McMorland G, Herzog W, Bray R. Conservative lower back treatment reduces inhibition in knee-extensor muscles: a randomized controlled trial. J Manip Physiol Therapeut 2000;23(2):76-80. Haavik H, Murphy B. The role of spinal manipulation in addressing disordered sensorimotor integration and altered motor control. J Electromyograph Kinesiol 2012; 22(5):768-776. Kellya DD, Murphy BA, Backhouse DP. Use of a mental rotation reaction-time paradigm to measure the effects of upper cervical adjustments on cortical processing: a pilot study. J Manip Physiol Therapeut 2000;23(4):246-251.

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Lelic D, Niazi IK, Holt K, Jochumsen M, Dremstrup K, Yielder P, Murphy B, Drewes AM, Haavik H. Manipulation of Dysfunctional Spinal Joints Affects Sensorimotor Integration in the Prefrontal Cortex: A Brain Source Localization Study. Neural Plasticity 2016;2016. [26] Niazi IK, Türker KS, Flavel S, Kinget M, Duehr J, Haavik H. Changes in H-reflex and V-waves following spinal manipulation. Exp Brain Res 2015;233(4):1165-1173. [27] Meeker WC, Haldeman S. Chiropractic: a profession at the crossroads of mainstream and alternative medicine. Ann Intern Med 2002; 136(3):216-227.



IAFNR News and Events 2016 Conferences Related to Functional Neurology National Institute for Brain & Rehabilitation Sciences Sponsored Events

November 4 - 6, 2016 Green Valley Ranch Resort Henderson, Nevada https://www.iafnr.org/content/2016-conference

Society for Neuroscience 2016 Annual Meeting Date: November 12 - 16, 2016 Location: San Diego, USA Website: http://www.sfn.org/annual-meeting/past-and-future-annual-meetings

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Neuroscience 2016 is the premier venue for neuroscientists to present emerging science, learn from experts, forge collaborations with peers, explore new tools and technologies, and advance careers. Join more than 30,000 colleagues from more than 80 countries at the world’s largest marketplace of ideas and tools for global neuroscience.

The 4th International Congress on Sports Sciences Research and Technology Support – icSPORTS 2016 icSPORTS 2016 will be held in conjunction with NEUROTECHNIX 2016. Date: November 7 – 9, 2016 Organization: INSTICC Type: Congress Location: Porto, Portugal Website: http://www.icsports.org/ In the XXI century most human activities, including sports, are becoming more and more technological. Engineering in general and Information Technology in particular are becoming an important support for many activities directly or indirectly related to sport sciences, including improvement of physical activities, sports medicine, biotechnology and nutrition, sports management, and all imaginable application areas in sports. This congress intends to be a meeting point of both academics and practitioners, in order to exchange ideas and developed synergies. CONGRESS AREAS Each of these topic areas is expanded below but the sub-topics list is not exhaustive. Papers may address one or more of the listed sub-topics, although authors should not feel limited by them. Unlisted but related sub-topics are also acceptable, provided they fit in one of the following main topic areas. TOPIC AREAS 1. SIGNAL PROCESSING AND MOTOR BEHAVIOR 2. SPORTS MEDICINE AND SUPPORT TECHNOLOGY 3. HEALTH, SPORTS PERFORMANCE AND SUPPORTTECHNOLOGY 4. COMPUTER SYSTEMS IN SPORTS

32nd Annual Meeting, International Society for Traumatic Stress Studies Date: November 10, 2016 Location: Dallas, Texas, United States Website: http://www.istss.org/meetings-events/events-calendar/istss-32nd-annual-meeting.aspx


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International Neuroscience and Biological Psychiatry ISBS Symposium TRANSLATIONAL NEUROSCIENCE OF STRESS Date: November 10 (10:00) – 11, 2016 Organization: International Stress and Behavior Society (ISBS) Location: San Diego, United States Website: https://www.scribd.com/document/274040475/International-Neuroscience-and-BiologicalPsychiatry-ISBS-Symposium-TRANSLATIONAL-NEUROSCIENCE-OF-STRESS-Nov-10-112016-San-Diego-CA-USA The 2-day symposium will exchange and share the developing translational knowledgebase of the molecular and genetic link between biological psychiatry and behavior/neurobiology, with the particular focus on stress and stress-evoked neuropsychiatric disorders. Anyone interested in stressrelated human or animal behaviors, neurobehavioral disorders and their mechanisms are welcome to join the symposium.

Memory Mechanisms in Health and Disease Date: December 5 – 8, 2016 Location: Tampa, Florida, United States Website: http://www.zingconferences.com/conferences/memory-mechanisms-in-health-and-disease/ Contact: Evie Hartley; Email: [email protected] We are proud to announce the 1st Zing Memory Mechanisms in Health and Disease Conference which shall be taking place in December 2016. This conference will present cutting-edge, multidisciplinary research on mechanisms of learning and memory in health and disease. Particular emphasis will be given to address the questions of how memory is stored at the molecular and neuronal circuit level. How is memory storage affected in dementia and autism? What are the molecular and neuronal circuits of retrieval-induced memory modulation? How of retrieval-induced memory modulation impaired in post-traumatic stress disorder?

10th International Neuroscience and Biological Psychiatry ISBS Regional (S. America) Conference NEUROSCIENCE OF STRESS Date: December 1 (10:00) – 3, 2016 Organization: International Stress and Behavior Society Location: Rio de Janeiro, Brazil Website: http://www.scribd.com/doc/274041339/10th-International-Neuroscience-and-Biological-Psy chiatry-ISBS-Regional-S-America-Conference-NEUROSCIENCE-OF-STRESS-Dec-1-3-2016-Riode-Janeir The 3-day International Regional ISBS Conference will exchange and share the developing translational knowledgebase of the molecular and genetic link between biological psychiatry and behavior/neurobiology, with the particular focus on stress and stress-related neuropsychiatric disorders. Anyone interested in stress-related human or animal behaviors, neurobehavioral disorders and their mechanisms are welcome to join the Conference.

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Transcranial Direct Current Stimulation (tDCS): 1-Day Course Date: December 2, 2016 Organization: neuroCademy Venue: neuroCademy Location: Rindermarkt 7, Munich, Germany Website: http://www.neurocaregroup.com/event-details/transcranial-direct-current-stimulation-tdcs-1day-course-english-kopie.htmlSpecialty The course is for academics and clinicians who want to use the technique of transcranial direct current stimulation (tDCS). The technical and neurophysiological background will be covered as well as an overview of the current research situation. An external speaker well-known in tDCS research will be invited to present his/her research (details will be announced closer to the workshop). Furthermore tDCS application will be practiced during this workshop.

6th World Congress on ADHD Date: April 20 – 23, 2016 Location: Vancouver, Canada Contact: Christian Reim Phone: +49406708820 Email: [email protected] Event website: http://www.adhd-congress.org Dear colleagues, I am very happy to invite you to be again with us, taking part of the most global meeting on ADHD where you can share and exchange experiences and knowledge on the best strategies of diagnosing and caring individuals affected by ADHD. Our 6th World Congress on ADHD will take place from 20-23 April 2017 in Vancouver, Canada. As in keeping with tradition of the World Federation on ADHD, the scientific committee and the local organizing committee will work hard to develop a wide range of topics that will appeal to clinicians, researchers and academics stimulating the exchange of information. TOPICS Aetiology Autism spectrum disorder Co-morbidity Diagnosis Epidemiology Electrophysiology Etiopathogenesis Genetics Imaging studies Life quality Models, experimental Neurophysiology Non pharmacology treatment Pathophysiology Pharmacology treatment Pharmacogenetics Substance abuse Treatment Other

International Neuromodulation Society 13th World Congress Date: May 27 – June 1, 2017 Location: Edinburgh, United Kingdom Website: http://www.neuromodulation.com/inscongress We have chosen the title “Neuromodulation: Medicine Evolving through Technology,” to emphasize our field’s transformative force on the treatment of disease states – how it is approached now and will be approached in the not too distant future. We see almost daily reports in the mainstream media of innovation in the area of neuromodulation treating not only pain, but many conditions of the cardiovascular, neurological, gastrointestinal, urological and other systems. This meeting will mark an important time for our field.


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MOVEMENT – 2017 Functional Neurology Brain, Body, Cognition Date: July 9 – 11, 2017 Location: Oxford University, Oxford, UK Website: www.movementis.com In conjunction with Spaulding Hospital of Harvard University School of Medicine, the M.I.N.D. Institute M.I.T., the Hebrew University of Jerusalem School of Medicine, and The National Institute for Brain and Rehabilitation Sciences, Nazareth, Israel

Dear colleagues, We have the pleasure of inviting you to attend the world conference on Movement, sponsored, in part, by the Harvard University School of Medicine’s Spaulding Rehabilitation Hospital, the M.I.N.D. Institute at M.I.T., the Hebrew University of Jerusalem, the Wingate Institute for Sports and Exercise Science, the National Institute for Brain and Rehabilitation Sciences, Nazareth, Israel, the Institute for Neurology and Neurosurgery, Havana, the University of the Medical Sciences facultad ‘Manuel Fajardo’ Havana, the School of Public Health of the University of Havana, and Bielefeld University in Germany. The purpose of the conference is to share knowledge of all those whose interests lie in the nature of human movement. The conference will address issues related to gait, motion, kinesiology, disorders of movement, movement rehabilitation, motion, and balance, movement and cognition, human factors and ergonomics, as well as optimized movement in elite athletes, developmental issues of movement and coordination. Workshops on dance, dance therapy, and physiotherapy of movement impairment will also be provided.

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ABSTRACT TOPIC AREAS • Kinesiology Bipedalism as a signature of humanity Factors influencing the kinds and amounts of motor performance Identification of critical components of physical activity Heredity and motor performance Motor behavior • Sport and Exercise Psychology and Physiology • Physical Education of Movement • Coaching of Movement Effectiveness • Anatomical and Physiological Fundamentals of Human Motion Neurophysiology Cardiac and autonomic effects of movement • Therapeutic Exercise • The Musculoskeletal System The skeletal framework and its movements The neuromuscular basis of movement Upper extremity movement – Reach and Grasp (elbow, forearm, wrist, and hand) Brain and biomechanical control Lower extremity movement (knee, ankle, and foot) Brain and biomechanical control • Biomechanics of Movement Biomechanical measurement of movement Conditions of linear motion Conditions of rotary motion Center of gravity and stability • Motor Skills: Principles and Applications Kinesiology of fitness and exercise Moving objects: pushing and pulling Moving objects: throwing, striking, and kicking Locomotion: solid surface Locomotion: The aquatic environment Locomotion: When suspended and free of support Impact Instrumentation for motion analysis • Developmental Aspects of Movement Primitive reflexes and normal and abnormal motor development Motion and developmental disabilities Functional movement development across the life span • Movement Disorders Age related Posture and balance Locomotion Prehension Functional aspects of the basal ganglia Electrophysiology of movement disorders Movement disorders: structural and functional imaging Genetic techniques, impact, and diagnostic issues in movement disorders

IAFNR News and Events Parkinsonism: differential diagnosis Parkinsonism: management Multiple system atrophy (MSA) Progressive supranuclear palsy and cortico-basal degeneration Primary dementia syndromes and Parkinsonism Essential tremor and other tremors Dystonias Huntington's disease and look-alikes Non-Degenerative choreas Wilson's disease Tic disorders and stereotypies Myoclonus Paroxysmal movement disorders Hereditary and acquired cerebellar ataxias Drug-induced movement disorders Systemic disease and movement disorders Psychogenic movement disorders • Motor Control Sensory contributions to motor control Closed-loop control systems Vision-motor Audition-motor Proprioception and motor control Feed-forward influences on motor control Vestibular-motor Central Contributions to Motor Control Open-loop processes Central control mechanisms Central control of rapid movements Motor program issues Generalized motor programs • Speed and Accuracy in Movement Fitts’ Law: the Logarithmic speed–Accuracy trade-off Linear speed–accuracy trade-off The temporal speed–accuracy trade-off Central contributions to the speed–accuracy trade-off Correction models of the speed–accuracy trade-off • Coordination • Individual Differences and Capabilities in Movement • Motor Learning • Augmented Feedback • Gait • Rehabilitation of Motor Dysfunction • Movement and Cognition • Physics of Movement • Physics of Dance • Physics of Sports • Technology and Movement Sciences • Optimizing Human Motor Performance

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WORKSHOPS Physiotherapy Restorative and Functional Neurology Kinesiology and Physical Education Dance Therapy Dancer’s Workshop Technology Workshops for Rehabilitationists Cognitive Movement Therapy ABSTRACT SUBMISSION INSTRUCTIONS You can participate in the conference as a delegate, although we encourage you to submit an abstract. Please, read carefully the following instructions before submitting your abstract. Only abstracts submitted in English will be accepted. Full papers of accepted abstracts will, pending additional review, be published in a special issue of the journal Functional Neurology, Rehabilitation and Ergonomics. Details will follow after acceptance of the submitted conference abstracts. ● Submit your abstract in Microsoft Word format. ● Authors names should be provided in the format Alvarez, RS. Do not add Dr. Prof. Mr., Mrs., etc. ● The title should have a maximum of 150 characters, typed in capitals. ● Affiliation should be included in line a. If authors’ affiliations are different, you should indicate them filling b, c, and d lines. ● The presenting author’s email address must be included. ● The abstract should have a maximum of 350 words. Any longer and the abstracts will not be accepted. ● Indicate whether the abstract is intended for oral or poster presentation or either. ● The abstract should be structured using the following headings: Objective, Methods, Results, Conclusions, and Keywords (no more than four keywords). ● The abstract should be as informative as possible, including statistical evaluation. ● Statements such as "results will be discussed" or "data will be presented" are not acceptable. ● Standard abbreviations such as: PVS, MCS, EEG, MEEG, MRI, etc., may be used. Others should be described in full when first mentioned, followed by the abbreviation in parenthesis. ● Tables may be included, but not photographs, figures, or references. ● You will be notified via e-mail to confirm that your abstract has been received. ● If you do not receive a confirmation within two weeks, please contact the Symposium Secretariat. ● The Scientific Committee will review all abstracts. ● Some very high quality abstracts offered for oral presentation might be included in satellite symposium or courses. ● Deadline for submission of abstracts: Apr. 15, 2016 ● Notification of Accepted Abstracts: Jul. 15, 2016 ● Full papers submitted for review: Oct. 15, 2016 ● Abstracts and full papers are to be submitted directly to the head of the conference’s scientific committee: [email protected]

Society for Neuroscience 2017 Annual Meeting Date: November 11 – 17, 2017 Location: Washington D.C., United States Website: http://www.sfn.org/annual-meeting/past-and-future-annual-meetings


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Neuroscience 2017 is the premier venue for neuroscientists to present emerging science, learn from experts, forge collaborations with peers, explore new tools and technologies, and advance careers. Join more than 30,000 colleagues from more than 80 countries at the world’s largest marketplace of ideas and tools for global neuroscience.

Society for Neuroscience 2018 Annual Meeting Date: November 3 – 7, 2018 Location: San Diego, United States Website: http://www.sfn.org/annual-meeting/past-and-future-annual-meetings Neuroscience 2018 is the premier venue for neuroscientists to present emerging science, learn from experts, forge collaborations with peers, explore new tools and technologies, and advance careers. Join more than 30,000 colleagues from more than 80 countries at the world’s largest marketplace of ideas and tools for global neuroscience.

Recent Conference Presentations 1. Leisman, G. Optimization Methodology and Functional Connectivities Inform the Cognitive Modifiability in the Rehabilitation of Developmental Language Difficulties [Invited Plenary Paper presented at the Conference on Cognitive Modifiability, Jerusalem, Israel 3-5 June 2013]. (http://www.brainconvention.org/en/index.php?page_id=48) 2. Leisman, G. If It Is Localization then There Is No Development, Education, & Rehabilitation: It’s the Networks Silly. [Invited Plenary Paper presented at the 4th Conference of the International Association for Functional Neurology, and Rehabilitation, 10-13 October, 2013 Phoenix, AZ]. 3. Leisman, G., Machado, C., Melillo, R. The Development of Fetal And Neonatal Consciousness [Invited Plenary Address, VI International Conference on Brain Death and Disorders of Consciousness, 3-6 December, 2013](http://www.komascience-cuba.com/) 4. Leisman, G. & Mualem, R. Brains, Bilinguals, and Functional Connectivities: Neural Networks Play Out in the Classroom. [Invited Speaker Oxford Education Research Symposium at St. Edmund Hall, Oxford University. 25-26 March 2014] (http://www.oxford-education-researchsymposium.com/) 5. Leisman, G. Functional Connectivities and Re-connectivities Reflect Cognitive Modifiability in Neurorehabilitation. [Invited paper presented at the Second Annual Conference in Rehabilitation Medicine, Balitmore, MD USA 1-16 July 2014]. (http://dx.doi.org/10.4172/2329-9096.S1.006) 6. Leisman, G. Optimization Models for Quantifying Visual Search Scanpath Efficiency: Measuring Treatment Recovery in Traumatic Brain Injury. [Invited paper presented at the Second Annual Conference in Rehabilitation Medicine, Baltimore MD, USA 1-16 July 2014]. (http://dx.doi.org /10.4172/2329-9096.S1.006) 7. Leisman, G., Gilchriest. J., Rodriguez-Rojas, R., Estevez, M., Machado, C., Kaspi, M., Melillo, R. A Method for Quantifying Visual Search Scanpath Efficiency in Elucidating Cognitive Status Post Traumatic Brain Injury. [Paper presented IEEE-Israel, Eilat, Israel 2-5 December, 2014]. 8. Leisman, G., Rodríguez Rojas, R., Batista, K., Carballo, M., Morales, J.M., Iturria, Y., Machado, C. Measurement of Axonal Fiber Connectivity in Consciousness Evaluation. [Paper presented IEEE-Israel, Eilat, Israel 2-5 December, 2014]. 9. Leisman, G. The Coincident Decline of Movement and Cognitive Ability: Movement Sciences in the Aid of Public Health Policy Intervention. [Paper presented at the 4th International Conference on Pediatric Disease, Disability and Human Development, 20-23 January, 2015, Jerusalem Israel]

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10. Mualem, R., Leisman, G., Mograbie, S.K., Boshnak S. Brain-Based Learning during Preschool: An Underused Window of Opportunity. [Paper presented at the 4th International Conference on Pediatric Disease, Disability and Human Development, 20-23 January, 2015, Jerusalem Israel] 11. Leisman, G. Machado, C. Thinking, Walking, Talking: The Development of Integratory Brain Function [Paper presented as part of a Symposium on Movement and Thought at the International Convention of Psychological Sciences, Amsterdam, The Netherlands, 12-14 March, 2015] 12. Leisman, G. and Braun-Benjamin, O. Symposium on Movement and Thought at the International Convention of Psychological Sciences, Amsterdam, The Netherlands, 12- 14 March, 2015] 13. Koch, P. Leisman, G. Cortical Activity Waves are the Physical Carriers of Memory and Thought. [Paper presented at the 7th Annual IEEE Engineering in Medicine and Biology Society Meeting on Neuroengineering. Montpellier, France, 22-24 April 2015]. 14. Leisman, G. Government Policy Implications of a Cognitive Neuroscience on the Effects of Movement on Functional Connectivity [Plenary presentation, 7th International Symposium on Brain Death and Disorders of Consciousness, 8-11 December 2015, Havana, Cuba] 15. Leisman, G. Leisman, G. Public Health Policy Implications of a Cognitive Neuropsychology of Language and Movement in Neurorehabilitation of Integrative Brain Function. [Paper presented 11th World Congress of Brain Injury, 2-5 March, 2016 The Hague, The Netherlands] 16. Leisman, G. Functional Connectivities in the Understanding of the Restoration of Integrative Brain Function [Paper presented 9th World Congress for Neurorehabilitation, Philadelphia, PA, USA, 10-13 May, 2016] 17. Leisman, G. Lifespan Developmental Issues in Functional Connectivities [Paper presented 10th FENS Forum for Neuroscience, 2-6 July Copenhagen, Denmark]. 18. Leisman, G. Motor-Cognitive Interactions in the Nervous System: Obesity and Sedentary Behavior Dumbs Down Cognitive Function in Childhood [Invited Address, International Conference on Childhood Obesity, 29-30 March, 2016, Atlanta, Georgia].

Recent Books and Chapters 1. Leisman, G. Optimization Methodology and Functional Connectivities Inform the Cognitive Modifiability in the Rehabilitation of Developmental Language Difficulties. Cognitive Modifiability. Bologna, Italia: Medimond s.r.l. 2013 (http://www.medimond.com/ebook/Q602 .pdf) 2. Estevez, M., Machado, C., Leisman, G., Melillo, R., Machado, A., Hernandez-Cruz, A., Arias, A., Rodriguez-Rojas, R., Carballo, M. EEGConn: A Software Tool for Offline qEEG Analysis, Including Spectral Univariate and Bivariate Processes and Linear and Non-Linear Indices of Brian Connectivity in Autistic Spectrum Disorder. Chronic Disease and Disability in Childhood. Haupague, NY: Nova Science Publishers, 2013, p. 65. 3. Jammalieh, J., Mualem, R., Leisman, G. Clinical Effects of Physiological Rhythms in Premature Infants. Chronic Disease and Disability in Childhood. Haupague, NY: Nova Science Publishers, 2013, p. 109. 4. Leisman, G. Advances in Cognitive Neuroscience and Optimization Can Inform The Rehabilitation Process in Developmental Language Difficulties. Chronic Disease and Disability in Childhood. Haupague, NY: Nova Science Publishers, 2013, p. 123. 5. Leisman, G. Functional Connectivities in the Postnatal Development of Consciousness. Chronic Disease and Disability in Childhood. Haupague, NY: Nova Science Publishers, 2013, p. 124. 6. Machado, C., Estevez, M., Leisman, G., Melillo, R., Machado, A., Hernanandez-Cruz, A., Arias, A., Rodriguez-Rojas, R., Carballo, M. Exploration of Resting Brain Connectivity Using Linear Coherence Measures in the Autistic Spectrum Disorder. Chronic Disease and Disability in Childhood. Haupague, NY: Nova Science Publishers, 2013, p. 149. 7. Machado, C. Estevez., M., Melillo, R., Leisman, G., Carrick, R., Machado, A., Hernandez-Cruz, A., Arias, A., Rodriguez-Rojas, R., Carballo, M., Quantitative Resting EEG in the Autistic


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Spectrum Disorder. Chronic Disease and Disability in Childhood. Haupague, NY: Nova Science Publishers, 2013, p. 150. Melillo, R. and Leisman, G. Functional Brain Imbalance and Autistic Spectrum Disorder. Olfman, S (Ed.) The Science and Pseudoscience of Children's Mental Illness: Cutting Edge Research and Practice. Childhood in America Book Series. Santa Barbara, CA: Praeger, 2015, pp. 65-91. (http://www.abc-clio.com/Praeger/product.aspx?pc=A4219C) Leisman, G., Rodriguez-Rojas, R. Batista, K, Carballo, M Morales, J. M., Iturria, Y., Machado, C. Measurement of Axonal Fiber Connectivity in Consciousness Evaluation. Proceedings of the 2014 IEEE 28th Convention of Electrical and Electronics Engineers in Israel, IEEE: Minneapolis, MN, 2014. IEEE Cat. No: CFP14417-CDR; ISBN: 978-1-4799-5987-7; DOI: 10.13140 /2.1.4845.7289 (https://www.researchgate.net/publication/269404631_Measurement_of_Axonal_ Fiber_Connectivity_in_Consciousness_Evaluation) Koch, P and Leisman, G. Cortical Activity Waves are the Physical Carriers of Memory and Thought. Neural Computation. IEEE/EMBS, Minneapolis MN, 2015. (http://emb.Citengine.com /event/ner-2015/author?authorID=12426) (https://www.researchgate.net/profile/Gerry_Leisman/ publications) Leisman, G., Melillo, R., Machado, C. Intentionality and “Free-Will” from a Neurodevelopmental Perspective. In: Santrock, J. (Ed.) To be used in connection with: A Topical Approach to Lifespan Development Plymouth, MA; McGraw-Hill Education, 2015 (ISBN-13: 978-0078035500). Rodríguez-Rojas, R., Machado, C., Batista, K., Carballo M., Leisman, G. (2015). Neuroimages in Autism. In: Robinson-Agramonte, M. Translational Approaches to Autism Spectrum Disorder. New York, NY: Springer, pp. 95-117. (ISBN: 978-3-319-16320-8) (http://www.springer.com/gp/ book /9783319163208#aboutBook) (http://link.springer.com/chapter/10.1007/978-3-319-163215_6) Leisman, G. Cognitive Rehabilitation in Developmental Disabilities. In: S. Misciagna (Ed.). Handbook of Cognitive Rehabilitation. Secaucus, NJ: Austin Press, 2015 [In Press]. (http://austinpublishinggroup.org/ebooks/handbook-cognitive-rehabilitation-volume-1/index.php) Leisman, G. and Moustafa, A. (Eds.) Thinking about Action: Integration of Functional Connections in Movement and Cognition. Frontiers in Public Health; Child Health and Human Development. Zurich. Switzerland, Frontiers, 2015. [In Press] (http://www.frontiersin.Org /Child_Health_and_Human_Development/researchtopics/Thinking_about_Action_Integrat_1/336 9) Leisman, G. and Moustafa, A. (Eds.) Thinking about Action: Integration of Functional Connections in Movement and Cognition. Frontiers in Public Health; Child Health and Human Development. Zurich. Switzerland, Frontiers, 2016. [In Press] (http://www.frontiersin.org /Child_Health_and_Human_Development/researchtopics/Thinking_about_Action_Integrat_1/336 9) Vojdani, A. Nova Series in Functional Neurology. Vol. 1. Neuroimmunity and the Brain-Gut Connection. Leisman, G. and Merrick, J. (Series Eds.). Hauppauge, NY: Nova Science Publishers. 2016 [In Press]. (https://www.novapublishers.com/catalog/product_info.php?products _id=56306&osCsid=42666102c643021c47b41e653e7fb66f) Leisman, G. Neuroimmunity. In: A. Vojdani. Neuroimmunity and the Brain-Gut Connection. Leisman, G. and Merrick, J. (Eds.). Hauppauge, NY: Nova Science Publishers. 2016 [In Press]. (https://www.novapublishers.com/catalog/product_info.php?products _id=56306&osCsid=42666102c643021c47b41e653e7fb66f) Leisman, G. The coincident decline of movement and cognitive ability. Movement sciences in the aid of public policy intervention. In: J. Merrick (Ed.). Disability, Chronic Disease and Human Development. Hauppauge, NY: Nova Science Publishers. 2015, pp. 97-98. (https://www. novapublishers.com/catalog/product_info.php?products_id=55227&osCsid=6de28dbcde62a15b8 12faba057064716) Mualem, R., Leisman, G., Mograbie, S.K., and Boshnak, S. Brain-based learning during preschool: An underused window of opportunity. In: J. Merrick (Ed.). Disability, Chronic Disease and Human Development. Hauppauge, NY: Nova Science Publishers. 2015, pp. 56-57.

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IAFNR News and Events (https://www.novapublishers.com/catalog/product_info.php?products_id=55227&osCsid=6de28d bcde62a15b812faba057064716) Leisman, G., and Merrick J. (Ed.) Considering Consciousness Clinically. Nova Series in Functional Neurology. Vol. 3. Leisman, G. and Merrick, J. (Series Eds.) Hauppauge, NY: Nova Science Publishers. 2016 [In Press]. (https://www.novapublishers.com/catalog/product_info.php ?products_id=56691) Leisman, G., Machado, C., and Merrick, J. Considering Consciousness Clinically. In: Leisman, G., and Merrick J. (Eds.) Considering Consciousness Clinically. Nova Series in Functional Neurology. Vol. 3. Hauppauge, NY: Nova Science Publishers. 2016 [In Press]. (https:// www.novapublishers.com/catalog/product_info.php?products_id=56691) Leisman, G., and Koch, P. Networks of conscious experience: Computational neuroscience in understanding life, death and consciousness. In: Leisman, G., and Merrick J. (Eds.) Considering Consciousness Clinically. Nova Series in Functional Neurology. Vol. 3. Hauppauge, NY: Nova Science Publishers. 2016 [In Press]. (https://www. novapublishers.com/catalog/product_info. php?products_id=56691) Rodriguez-Rojas, R. Batista, K., Iturria, Y., Machado, C., Leisman, G., Chinchilla, M., DeFina, P., Carballo, M., and Morales, J.M. Disrupted axonal fiber connectivity as a marker of impaired consciousness states. In: Leisman, G., and Merrick J. (Eds.) Considering Consciousness Clinically. Nova Series in Functional Neurology. Vol. 3. Hauppauge, NY: Nova Science Publishers. 2016 [In Press]. (https://www.novapublishers.com/catalog /product_info.php?products _id=56691) Machado, C., Estévez, M., Rodríguez-Rojas R., Carballo, M., Pérez-Nellar, J., Gutiérrez, J., Fleitas, M., and Leisman, G., Vegetative state and the outer world. In: Leisman, G., and Merrick J. (Eds.) Considering Consciousness Clinically. Nova Series in Functional Neurology. Vol. 3. Hauppauge, NY: Nova Science Publishers. 2016 [In Press]. (https://www.novapublishers.com/ catalog/product_info.php?products_id=56691) Perez-Nellar, J., Machado, C., Scherle C., Rodríguez, R., Carballo, M., Leisman, G., and Melillo, R. Persistant vegetative state: Ventricular CSF pulsation artifact. In: Leisman, G., and Merrick J. (Eds.) Considering Consciousness Clinically. Nova Series in Functional Neurology. Vol. 3. Hauppauge, NY: Nova Science Publishers. 2016 [In Press]. (https://www.novapublishers.com/ catalog/product_info.php?products_id=56691) Perez-Nellar, J., Machado, C., Scherle C., Rodríguez, R., Carballo, M., Leisman, G., and Melillo, R. Persistent vegetative state: Ventricular CSF pulsation artifact. In: Leisman, G., and Merrick J. (Eds.) Considering Consciousness Clinically. Nova Series in Functional Neurology. Vol. 3. Hauppauge, NY: Nova Science Publishers. 2016 [In Press]. (https://www.novapublishers.com/ catalog/product_info.php?products_id=56691) Leisman, G. Neuroplasticity in Learning and Rehabilitation. Nova Series in Functional Neurology. Vol. 2. Leisman, G. and Merrick, J. (Series Eds.) Hauppauge, NY: Nova Science Publishers. 2016 [In Press]. (https://www.novapublishers.com/catalog/product_ info.php?products _id=56789) Leisman, G. Plasticity and Functional Connectivities in Rehabilitation. In: Leisman, G. and Merrick, J. (Series Eds.) Neuroplasticity in Learning and Rehabilitation. Nova Series in Functional Neurology. Vol. 2. Hauppauge, NY: Nova Science Publishers. 2016 [In Press]. (https://www.novapublishers.com/catalog/product_info.php?products_id=56789) Leisman, G. and Merrick, J. Neuroplasticity in Learning and Rehabilitation In: Leisman, G. and Merrick, J. (Eds.) Neuroplasticity in Learning and Rehabilitation. Nova Series in Functional Neurology. Vol. 2. Hauppauge, NY: Nova Science Publishers. 2016 [In Press]. (https://www. novapublishers.com/catalog/product_info.php?products_id=56789) Leisman, G. Neuroeducational networks. In: Leisman, G. and Merrick, J. (Eds.) Neuroplasticity in Learning and Rehabilitation. Nova Series in Functional Neurology. Vol. 2. Hauppauge, NY: Nova Science Publishers. 2016 [In Press]. (https://www. novapublishers.com/catalog/product_ info.php?products_id=56789)


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31. Leisman, G. Auditory, visual, spatial aesthetic and artistic training facilitates brain plasticity. In: Leisman, G. and Merrick, J. (Eds.) Neuroplasticity in Learning and Rehabilitation. Nova Series in Functional Neurology. Vol. 2. Hauppauge, NY: Nova Science Publishers. 2016 [In Press]. (https://www.novapublishers.com/catalog/product_info .php?products_ id=56789)

Published Papers in Indexed Peer-Reviewed Journals 1. Oggero, E., Carrick, F.R., Pagnacco, G. Frequency content of standard posturographic measures biomed 2013. Biomedical Science Instrumentation. 2013;49, 48-53. (http://www.ncbi.nlm.nih.gov /pubmed/23686180) 2. Koch, P. and Leisman G. Computational Model of Attention Brain Function Functional Neurology, Rehabilitation and Ergonomics. 2012;2(4):353-363. (https://www.novapublishers .com/catalog/product_info.php?products_id=41117&osCsid=1578167af1850a70f1ac579581504a 7e1) 3. Leisman, G. and Melillo, R. The Basal Ganglia: Motor and Cognitive Relationships in a Clinical Neurobehavioral Context Reviews in the Neurosciences. 2013;24(1):9-25. doi: 10.1515/ revneuro-2012-0067. (http://www.ncbi.nlm.nih.gov/pubmed/23241666) 4. Leisman, G., Machado, C., Mualem, R. The merging the neurosciences principles with educational practice in the treatment of ADHD: Function specific treatment for rehabilitation. Frontiers of Public Health: Frontiers of Child Health and Human Development. 2013, 1:22. doi: 10.3389/fpubh.2013.00022 (http://www.frontiersin.org/Journal/Abstract.aspx?ART_DOI=10.338 9/fpubh.2013.00022&name=Child_Health_and_Human_Development) (http://www.ncbi.nlm.nih. gov/pubmed/24350191) 5. Machado C, Estévez M, Rodríguez R, Pérez-Nellar J, Chinchilla M, Defina P, Leisman G, Carrick FR, Melillo R, Schiavi A, Gutiérrez J, Carballo M, Machado A, Olivares A, Pérez-Cruz N. Zolpidem Arousing Effect in Persistent Vegetative State Patients: Autonomic, EEG and Behavioral Assessment. Current Pharmaceutical Design. 2013 Sep 10. [Epub ahead of print] (http://www.ncbi.nlm.nih.gov/pubmed/24025063) 6. Machado, C., Estevez, M., Leisman, G., Melillo, R., Rodriguez, R., Hermandez, A. Perez-Nellar, J., Naranjo, R., and Chinchilla, M. EEG Coherence Assessment of Autistic Children in Three Different Experimental Conditions. Journal of Autism and Developmental Disorders. DOI 10.1007/s10803-013-1909-5. (http://link.springer.com/article/10.1007/ s10803-013-1909-5#page1) (http://www.ncbi.nlm.nih.gov/pubmed/24048514) 7. Howard N. and Leisman G. DIME (Diplomatic, information, military and economic power) effects modeling system: Dual use in brain small-world connectography and rehabilitation. Functional Neurology, Rehabilitation, and Ergonomics, 2013; 3(2-3): 257-274. (https://www. novapublishers.com/catalog/product_info.php?products_id=45010) 8. Rodriguez-Rojas, R., Batista K., Iturria, Y. Machado, C. Chinchilla, M. Carballo, M. Morales JM., De Fina P., and Leisman G. Disrupted axonal fiber connectivity as a marker of impaired consciousness states. Functional Neurology, Rehabilitation and Ergonomics, 2013; 3(2-3):319328. (https://www.novapublishers.com/catalog/product_info.php?products _id=45010) 9. Leisman, G. If It Is Localization Then There is No Development, Education, and Rehabilitation: Neuroeducation Needs to be about Building Networks. Functional Neurology, Rehabilitation, and Ergonomics. 2013:3(2-3):329-340. (https://www.novapublishers.com/catalog/product_info.php? products _id=45010) 10. Estevez, M., Machado, C., Leisman, G., Melillo, R., Machado, A., Hernandez-Cruz, A., Arias, A., Rodriguez-Rojas, R., Carballo, M. EEGConn: A Software Tool for Offline qEEG Analysis, Including Spectral Univariate and Bivariate Processes and Linear and Non-Linear Indices of Brian Connectivity in Autistic Spectrum Disorder. International Journal of Child Health and Human Development. 2013; 6(4): 427. (https://www.novapublishers. com/catalog/product_info .php?products_id=43824)

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11. Jammalieh, J., Mualem, R., Leisman, G. Clinical Effects of Physiological Rhythms in Premature Infants. International Journal of Child Health and Human Development. 2013; 6(4): 470. (https://www.novapublishers.com/catalog/product_info.php?products_ id=43824) 12. Leisman, G. Advances in Cognitive Neuroscience and Optimization Can Inform The Rehabilitation Process in Developmental Language Difficulties. International Journal of Child Health and Human Development. 2013; 6(4): 484. (https://www.novapublishers.com/catalog/ product_info.php?products_id=43824) 13. Leisman, G. Functional Connectivities in the Postnatal Development of Consciousness. International Journal of Child Health and Human Development. 2013; 6(4): 485. (https://www.novapublishers.com/catalog/product_info.php?products_id=43824) 14. Leisman, G., Melillo, R., Machado, C. Rodriguez-Rojas, R., Batista, K., Carballa, M., Mualem, R. Functional Disconnectivities in Individuals with Autistic Spectrum Disorders. International Journal of Child Health and Human Development. 2013; 6(4): 486. (https://www.novapublishers .com/catalog/product_info.php?products_id=43824) 15. Machado, C., Estevez, M., Leisman, G., Melillo, R., Machado, A., Hernanandez-Cruz, A., Arias, A., Rodriguez-Rojas, R., Carballo, M. Exploration of Resting Brain Connectivity Using Linear Coherence Measures in the Autistic Spectrum Disorder. International Journal of Child Health and Human Development. 2013; 6(4):510. (https://www. novapublishers.com/catalog/product_info .php?products_id=43824) 16. Rodriguez-Rojas, R., Machado, C., Alvarez, L., Carballo, M., Estevez, M., Perez-Nellar, J., Pavon, N., Chinchilla, M., Carrick, F.R., DeFina, P. Zolpidem induces paradoxical metabolic and vascular changes in a patient with PVS. Brain Injury. 2013;27(11),1320-1329. (http://www. ncbi.nlm.nih.gov/pubmed/23924270) 17. Machado, C. Estevez, M., Melillo, R., Leisman, G., Carrick, R., Machado, A., Hernandez-Cruz, A., Arias, A., Rodriguez-Rojas, R., Carballo, M., Quantitative Resting EEG in the Autistic Spectrum Disorder. International Journal of Child Health and Human Development. 2013; 6(4):511. (https://www.novapublishers.com/catalog/product_info.php? products_id=43824) 18. Rodriguez-Rojas, R., Batista, K., Carballo, M., Iturria, Y., Sanabria, G., Machado, C., Leisman, G., Estevez, M., Melillo, R. Anatomical and Topological Connectivity Reveal Different Attributes of Disrupted Small-World Networks in Autistic Children. International Journal of Child Health and Human Development. 2013; 6(4):551. (https://www. novapublishers.com /catalog/product_info.php?products_id=43824) 19. Leisman, G., Braun-Benjamin, O., Melillo, R. Cognitive-Motor Interactions of the Basal Ganglia in Development. Frontiers in Systems Neuroscience. 2014, 8:16. doi: 10.3389/ fnsys.2014.00016. [Cross-referenced in Frontiers in Computational Neuroscience]. (http://www.frontiersin.org /Journal/10.3389/fnsys.2014.00016/abstract) (http://www.frontiersin.org/computational_neurosci ence/researchtopics/Basal_Ganglia_XI_-_Proceedings /1118) 20. Pagnacco, G., Wright, C.H., Oggero, E., Bundle, M.W., Carrick, F.R. On "Comparison of a laboratory grade force platform with a Nintendo Wii Balance Board on measurement of postural control in single-leg stance balance tasks" by Huurnink, A., et al. [J. Biomech 46(7) (2013) 1392]: Are the conclusions stated by the authors justified? J Biomech. 2014 7;47(3):759-670. Epub 2013 Dec 4. (http://www.ncbi.nlm.nih.gov/pubmed/24359674) 21. Leisman, G. Functional Connectivities and Re-connectivities Reflect Cognitive Modifiability in Neurorehabilitation. International Journal of Rehabilitation. 2014, 2:4, 54-55. (http://dx.doi. org/ 10.4172/2329-9096.S1.006) 22. Leisman, G. Optimization Models for Quantifying Visual Search Scanpath Efficiency: Measuring Treatment Recovery in Traumatic Brain Injury. International Journal of Rehabilitation. 2014, 2:4, 43-45. (http://dx.doi.org/10.4172/2329-9096.S1.006) 23. Machado, C., Estevez, M., Leisman, G., Melillo, R., Rodriguez, R., Hernandez, A. Perez-Nellar, J., Naranjo, R., and Chinchilla, M. EEG Coherence Assessment of Autistic Children in Three Different Experimental Conditions. Journal of Autism and Developmental Disorders. 2015, 45:406-424 DOI 10.1007/s10803-013-1909-5. (http://link.springer.com/ article/10.1007/s10803013-1909-5#page-1) (http://www.ncbi.nlm.nih.gov/pubmed/24048 514)


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24. Leisman, G. and Melillo, R. (2015) The Plasticity of Brain Networks as a Basis for a Science of Nervous System Rehabilitation. International Journal of Neurorehabilitation. 2:2, 155. doi:10.4172/2376-0281.1000155 25. Mualem, R., Leisman, G., Mograbie, K.K., and Boshnak, S. Brain-Based Learning During Preschool: An Underused Window Of Opportunity. International Journal of Child Health and Disability. 2015 [In press] 26. Leisman, G. The Coincident Decline of Movement and Cognitive Ability: Movement Sciences In the Aid of Public Health Policy Intervention. International Journal of Child Health and Disability. 2015 [In press] 27. Estévez, M., Machado C., Leisman, G., Hernández-Cruz, A., Estévez-Hernández, T., AriasMorales, A. Machado, A., Montes-Brown, J. Spectral Analysis of Heart Rate Variability. International Journal of Disability and Human Development. 2015 [In Press]. 28. Leisman, G. Thinking, Walking, Talking: The Development of Integratory Brain Function. Frontiers in Public Health: Child Health and Human Development, 2015 [In Press]. 29. Estévez-Báez, M., Machado, C., Leisman, G. Brown-Martínez, M., Jas-García, J.D., MachadoGarcía, A., Montes- Brown, J., Carricarte-Naranjo, C. A Procedure to Correct the Effect of Heart Rate on Heart Rate Variability Indices: Description and Assessment. International Journal of Disability and Human Development. 2015 [In Press] 30. Machado C., Rodríguez, R., Estévez, M., Leisman, G., Chinchilla, M., Melillo, R. Electrophysiologic and fMRI Anatomic and Functional Connectivity Relationships in Autistic Children During Three Different Experimental Conditions. Brain Connectivity. 2015. doi:10.1089/brain.2014.0335 (http://www.ncbi.nlm.nih.gov/pubmed/26050707) (http://online. liebertpub.com/doi/abs/10.1089/brain.2014.0335?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3 Acrossref.org&rfr_dat=cr_pub%3Dpubmed) 31. Leisman, G., Moustafa, A. Thinking about action: Integration of Functional Connections in Movement and Cognition. Frontiers in Pediatrics. 2015. (http://journal.frontiersin.org/ researchtopic/3369/thinking-about-action-integration-of-functional-connections-in-movementand-cognition) 32. Estévez, M., Machado C., Leisman, G., Hernández-Cruz, A., Estévez-Hernández, T., AriasMorales, A. Machado, A., Montes-Brown, J. Spectral Analysis of Heart Rate Variability. International Journal of Disability and Human Development. DOI: 10.1515/ijdhd-2014-0025, April 2015 (http://www.degruyter.com/view/j/ijdhd.ahead-of-print/ijdhd-2014-0025/ijdhd-20140025.xml?format=INT) 33. Leisman, G., Mualem, R., Mougrabi, S.K. The Neurological Development of the Child with Educational Enrichment in Mind. Psicología Educativa. 2015. doi: 10.1016 / j.pse.2015.08.006 (http://www.sciencedirect.com/science/article/pii/S1135755X15000226) 34. Leisman, G., Dorta-Contreras, A.J., Machado, C. International Cooperation with Cuban Science: Research on Connectivities Brings Advances in Functional Brain Science at the Highest Levels. Functional Neurology, Rehabilitation and Ergonomics, 2015, 5(3), [In Press] 35. Mualem, R., Leisman, G., Mograbie, K.K., and Boshnak, S. Brain-Based Learning During Preschool: An Underused Window Of Opportunity. International Journal of Child Health and Disability. 2015 [In press] 36. Leisman, G. The Coincident Decline of Movement and Cognitive Ability: Movement Sciences In the Aid of Public Health Policy Intervention. International Journal of Child Health and Disability. 2015 [In press] 37. Leisman, G. Thinking, Walking, Talking: The Development of Integratory Brain Function. Frontiers in Public Health: Child Health and Human Development, 2015 [In Press]. 38. Estévez-Báez, M., Machado, C., Leisman, G. Brown-Martínez, M., Jas-García, J.D., MachadoGarcía, A., Montes- Brown, J., Carricarte-Naranjo, C. A Procedure to Correct the Effect of Heart Rate on Heart Rate Variability Indices: Description and Assessment. International Journal of Disability and Human Development. 2015 [In Press]

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39. Rosner, A.L., Leisman, G. Gilchriest, J. Charles E., Keschner, M.G. Minond, M. Reliability and Validity of Therapy Localization as Determined from Multiple Examiners and Instrumentation. Functional Neurology, Rehabilitation and Ergonomics, 2015, 5(3) [In Press] 40. Leisman, G., Dorta-Contreras, A.J., Machado, C. International Cooperation with Cuban Science: Research on Connectivities Brings Advances in Functional Brain Science at the Highest Levels. Funct. Neurol. Rehab. Ergon. 2015, 5:3 [In Press]. 41. Leisman, G., Melillo, R. Hirsh, O., Mualem, R. (Autistic Spectrum Disorder as a Functional Disconnection Syndrome) Harefuah, (Hebrew) [submitted] 42. Jammalieh, J. Mualem, R, Leisman, G. Clinical Effects of the Development of Physiological Rhythms. Journal of Pediatrics and Neonatology, 2014 [submitted] 1. Leisman, G., Moustafa, A. Shafir, T. Thinking, Walking, Talking: The Development of Integratory Brain Function. Frontiers in Pediatrics, 2015 [Submitted].



Literature Calling A Survey of Recent Publications of Interest to Functional Neurology

Key Interoperability Initiatives Are Set to Change the Healthcare Landscape Cynthia Weber IEEE Life Sciences May 2016 Major announcements by government agencies support emerging healthcare interoperability standards and open the playing field to increased innovation. This year’s conference of the Healthcare Information and Management Systems Society (HIMSS16), held in Las Vegas, NV, provided an important venue for announcements regarding key initiatives for health IT and interoperability at the federal level. On Monday evening, February 29, Sylvia Mathews Burwell, Secretary of Health and Human Services, announced during her opening address that those companies currently providing 90 percent of electronic health records in the United States, along with the five largest healthcare systems and more than one dozen professional organizations, agreed to three specific commitments regarding healthcare interoperability. Burwell stated that these include agreement on standardizing APIs, agreeing not to block information flow, and efforts to “speak the same language.” Sylvia Mathews Burwell, Secretary of Health and Human Services, speaking at HIMSS16. According to HealthIT.gov, the core commitments are: Consumer Access To help consumers easily and securely access their electronic health information, direct it to any desired location, learn how their information can be shared and used, and be assured that this information will be effectively and safely used to benefit their health and that of their community. No Information Blocking To help providers share individuals’ health information for care with other providers and their patients whenever permitted by law, and not block electronic health information (defined as knowingly and unreasonably interfering with information sharing). Standards Implement federally recognized, national interoperability standards, policies, guidance, and practices for electronic health information, and adopt best practices including those related to privacy and security. Burwell also noted that the Center for Medical Interoperability will be leading efforts to beta test interoperability among data and devices.

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In other announcements, Steve Posnack, director of the Office of the National Coordinator for Health IT (ONC) standards and technology, shared details on the Interoperability Proving Ground (IPG). The goal of the proving ground is to highlight interoperability successes and bring the community together to address challenges. According to Posnack, the site is “like Match.com for FHIR” (Fast Healthcare Interoperability Resources). Participants can sign up, share information about what they are working on, and choose to receive updates on topics of interest. Karen DeSalvo, MD, national coordinator for Health IT, echoed this emphasis by announcing three new developer challenges that aim to advance interoperability via the FHIR standard. These grants will total $US 625,000 and consist of three streams: a consumer-facing, vendor neutral app; a provider-facing app; and a discovery place where people can download these products. The intent is “to create a world that is more Internet-like” for health care, much like other consumer industries, DeSalvo commented. “It’s time for us to see some digital dividend,” she added. Interoperability will continue to be a priority for U.S. government agencies in the foreseeable future, which will in turn drive national interoperability standards. In a session at HIMSS16, Elliot Sloane, IEEE senior member and president of the nonprofit Center for Healthcare Information Research and Policy, noted that the interoperability problem is bigger than any one entity, “but there’s light at the end of the tunnel.” The IEEE Standards Association (IEEE–SA), in conjunction with the IEEE Engineering in Medicine and Biology Committee and the Personal Health Devices (PHD) Working Group has been working to develop standards that help enable personal health devices to plug and play with mobile phones and home hubs, using Bluetooth and USB specifications. The IEEE 11073 standards are coordinated across the entire healthcare continuum, supporting communications for monitors, pointof-care communication foundations, and transport files. In addition, an IEEE Working Group for Location Services in Healthcare was recently formed. For more information on healthcare IT standards, see the IEEE-SA website. These efforts, combined with growing support of open APIs that further level the playing field for consumer health technology, are posed to stimulate the market and spur health care innovation into the future.

Questions and Answers on the New Study Linking Cellphones and Cancer in Rats Andrew Pollack The New York Times May 27, 2016 Recent research has been interpreted as suggesting that cellphones cause cancer. But Gina Kolata explains that the overwhelming evidence suggests that there is no link between the devices and the disease. Do cellphones cause cancer? Most health authorities do not think so, but a new federal study could reignite the controversy over this issue. The preliminary study, found that radiation from cellphones appears to have increased the risks that male rats developed tumors in their brains and hearts. But there are many caveats and some experts are debunking the study. The study is from the National Toxicology Program, an interagency group in the Department of Health and Human Services whose job it is to assess the possible risks of chemicals.

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Rats lived in special chambers where they were exposed to different levels of radiation of the type emitted by cellphones for nine hours a day, every day. The exposure started before they were born and continued until they were about 2 years old. About 2 to 3 percent of the male rats exposed to the radiation developed malignant gliomas, a brain cancer, compared with none in a control group that was not exposed to radiation. About 5 to 7 percent of the male rats exposed to the highest level of radiation developed schwannomas in their hearts, compared with none in the control group. Schwannomas are tumors that occur in cells that line the nerves. The authors concluded the brain and heart tumors were “likely caused’’ by the radiation. Oddly enough, the incidence of tumors in females was minimal, barely different from the control group. It is not clear why the results would vary between the sexes, which is one reason some experts are questioning the findings. Even for males, the differences between particular groups of rats and the control group were not statistically significant. Another anomaly was that the rats exposed to the radiation lived longer on the whole than animals in the control group. And schwannomas can occur all over the body, not just the heart, but the study did not find increased rates in other organs. Also it was unusual that the control group had zero tumors. In previous studies at the National Toxicology Program, an average of 2 percent of rats in control groups developed gliomas. Had that happened in this study, there would have been virtually no difference between the exposed rats and the controls. “I am unable to accept the authors’ conclusions,” said one reviewer of the study, Dr. Michael S. Lauer, deputy director for extramural research at the National Institutes of Health. Dr. Lauer, whose comments were in an appendix to the report, said it was likely that the findings represented false positives. The amounts of radiation that rats were exposed to might be higher than what cellphone users typically experience, though toxicology studies often use higher doses to make sure to detect any effect that might exist. The authors of the report write: “Given the extremely large number of people who use wireless communication devices, even a very small increase in the incidence of disease resulting from exposure to the RFR generated by those devices would have broad implications for public health.” RFR refers to radio-frequency radiation. Dr. Otis Brawley, chief medical officer of the American Cancer Society, issued a statement that called this study “good science,” and called for further research because the animal research used very high signal strengths. But he said, “The NTP report linking radiofrequency radiation (RFR) to two types of cancer marks a paradigm shift in our understanding of radiation and cancer risk.” Dr. David O. Carpenter, director of the Institute for Health and Environment at the University at Albany, said he thought the study provided backing for the human epidemiological studies that suggested cellphone use was associated with an increased risk of gliomas and acoustic neuromas, a type of schwannoma. “I think this is real,’’ he said, suggesting people used wired earpieces to talk on cellphones. Dr. Carpenter’s view is not the prevailing one. Many studies have been conducted, including some very large ones like the Million Women Study in Britain, and a Danish study of more than 350,000 cellphone users. There also were studies examining the effects of these radio waves in animals and cells growing in petri dishes. The results are reassuring. There is no convincing evidence of any link between cellphone use and cancer or any other disease. Also, the incidence of brain cancer in the United States has remained steady since 1992, despite the stark increase in cellphone use. The International Agency for Research on Cancer, part of the World Health Organization, rates cellphone radiation a “possible’’ human carcinogen, based on limited evidence in both people and animals. It gives the same rating to coffee and pickled vegetables.

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Ionizing radiation, the powerful type from nuclear weapons, nuclear power plants and X-ray machines, is strong enough to knock electrons off atoms and damage DNA. That can cause cancer. But the radiation from cellphones, called radio-frequency radiation, is nonionizing and not known to damage DNA. The findings are preliminary and part of a larger study, so more data will be coming out, probably next year. The existing report will also be reviewed further by more experts.

More Than Meets the Eye Variability in Visual Cortex Neurons Reflects Input Diversity Elizabeth Cooney Harvard Medical School News July 14, 2016 We can thank neurons in the brain’s cerebral cortex for the rich representation of the world we “see.” In response to sensory stimuli—sights, sounds, tastes, smells, touch—neurons fire electrical spikes that collectively make up our brain’s model of the world. To help construct that world, individual neurons are so specialized that they fire in response to specific external inputs. With vision, that could mean a neuron would respond to an upward motion but not a downward one; another neuron to a right shift but not a left one. Yet despite their consistency in stimulus preference, cortical neurons are surprisingly messy in how they respond to repetitions of a sensory stimulus, seemingly firing or not firing randomly. Why, then, are the spikes so variable in the first place? The general view in the field holds that, on the spectrum of signal to noise, neurons are just noisy by nature. The brain could deal with this noise by averaging responses from many cells to produce a clear signal, engendering the reliable behavior needed for survival.Harvard Medical School scientists now have a different interpretation. In a paper published online July 14 in Neuron, a team led by Richard Born, HMS professor of neurobiology, and Gabriel Kreiman, HMS associate professor of ophthalmology at Boston Children’s Hospital, reports that inactivating neurons in one part of the primate visual cortex caused this wellknown variability to disappear in nearby cortical areas. The neurons in the neighboring areas remained active but now produced unusually regular spike patterns to repeated visual stimulation. When the researchers reactivated the silenced area, spiking became irregular again. “This suggests that neurons are likely not intrinsically noisy,” said Camille Gómez-Laberge, HMS research fellow in neurobiology and co-first author of the paper. Instead, said the researchers, neuronal variability seems to reflect input diversity. “Neurons, especially those in the cortex, are both highly variable and highly interconnected with neurons from all over the brain,” Gómez-Laberge said. “We found that these ‘noisy’ neurons become unusually consistent when their connectivity is reduced during our intervention.” The study’s results may help us understand how the connectivity of the cortex’s neurons make it such a powerful computational device, said Born, who is co-senior author of the paper. “By manipulating some of the inputs, we’ve shown that these many inputs are a big part of the variability,” he said. “But we still need to understand how much of that variability is irreducible noise, and how much of it is due to different sources of input. What we’re thinking now is it’s the connectivity and not the firing variability of the neurons.” To illustrate the difference, Born said, think of a blind person who hears one voice advising on how to navigate a room. That would be one source. Then imagine 100 voices yelling go right, turn left, it’s

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raining. The blind person’s path might become erratic in response to so many sources. Variability would decrease if those multiple voices were silenced. Something similar may be happening in the brain when multiple inputs cause neurons to fire. The firings may appear to be noise, but they could also be providing context for the brain to make judgments, Born said. “What the brain is trying to do is extract meaning out of those patterns of spikes that allow it to form a model of the world,” Born said. “How much is noise and how much is signal we don’t yet understand?” “Perhaps neurons don't play dice after all,” Kreiman said. “Neurons are actually quite reliable once we rigorously control for changes in the external variables and internal milieu.” Source Material: Gómez-Laberge, C., Smolyanskaya, A., Nassi, J.J., Kreiman, G. and Born, R.T., 2016. Bottom-Up and Top-Down Input Augment the Variability of Cortical Neurons. Neuron.

In a Scientific First, Mice Regain Eyesight Alice Park Time Magazine July 11, 2016 In an astonishing study, scientists restored the sight nerves in blind mice, helping them to see again. Once the optic nerve that’s responsible for sight is damaged, it’s impossible to see again. At least that’s been the dogma. But a group of U.S. scientists has upended that thinking and helped mice with destroyed optic nerves to see again. It does not have immediate implications for humans yet, but it points researchers in promising new directions. Andrew Huberman, an associate professor of neurobiology at Stanford University, and his team describe their advance in a study published in Nature Neuroscience. To learn about the way vision nerves grow, they crushed the optic nerve in one eye of mice. Once destroyed, the long finger-like extensions sent out by nerve cells from the eye to the brain start to shrivel, eventually severing any connection to the brain and resulting in blindness. Huberman and his colleagues, however, found that a combination of visual stimulation of the nerve, along with nerve-growing chemicals, can rescue these extensions, called axons, and coax them to stretch out again. Not only that, but the axons are able to find their appropriate connections to the correct sight-dedicated parts of the brain to restore vision. Mice with similar damage to the nerve that didn’t receive the treatment did not show much regrowth of the axons. About three weeks after the optic nerves in the mice were damaged, the researchers saw evidence of axons extending back into the brain from the eye, something that previous efforts to regenerate eye nerves haven’t done with much reliability. The combination of keeping the damaged but remaining axons stimulated, by exposing the mice to bars on a screen that are moving in different directions, and the nerve growth factors lead to a 500-fold increase in axon regrowth. Granted, not all of the axons managed to sprout again, but those that did were able to do so with impressive speed and distance to reach the brain. When the researchers conducted four different tests to verify how much of the regrowth contributed to actual restoration of vision in the animals, the animals passed two of the tests that detected large objects and movement.

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“For the longest time people in the field wondered if neurons could regenerate and form the correct patterns to connect to the brain, and we found that they did,” says Huberman. The most compelling finding is that the study suggests that once nerves are coaxed to grow again, they retain the instructions to find their proper connections in the brain’s visual center. If nerves growing toward the brain are like visitors to New York’s Grand Central Station, these nerves are like well-equipped travelers with maps and specific instructions for finding their destination. “It means that neurons remember the way home; they never forget,” says Huberman. That’s encouraging him and his team to start considering how to translate the results to treat blindness in people. Keeping the axons stimulated by exposing them to stimuli is an easy first step; if these axons are kept alive, then they have a chance of regrowing again, as the mouse study showed. And now that it’s possible to push those axons to grow long enough to reach the brain, there is hope that some people with diseases like glaucoma, for example, might be able to retain their vision if they keep their compromised axons stimulated enough, and then eventually treat them with nerve growth factors. That may be a few years away yet for people, but, Huberman is hopeful. “I want to see something positive in humans within five years,” he says. Source: Lim, J.H.A., Stafford, B.K., Nguyen, P.L., Lien, B.V., Wang, C., Zukor, K., He, Z. and Huberman, A.D., Neural activity promotes long-distance, target-specific regeneration of adult retinal axons. Nature Neuroscience, May 2016.

Stand to Work if You Like, but Don't Brag about the Benefits Angus Chen NPR March 17, 2016 I've been itching to get a standing desk. After all, America's sitting itself into an early grave. Sitting is the new smoking. Clearly, a standing desk would stop me from sitting, and standing is just so much better for you than sitting, right? Contrary to popular belief, science does not say so. Too much sitting increases heart failure risk and disability risk, and shortens life expectancy, studies have found. But according to an analysis published Wednesday of 20 of the best studies done so far, there's little evidence that workplace interventions like the sit-stand desk or even the flashier pedaling or treadmill desks will help you burn lots more calories, or prevent or reverse the harm of sitting for hours on end. “What we actually found is that most of it is, very much, just fashionable and not proven good for your health,” says Dr. Jos Verbeek a health researcher at the Finnish Institute of Occupational Health. Verbeek says that the studies he and his co-authors analyzed came to conflicting conclusions about whether sit-stand desks reduce sitting time. Even the best research available wasn't great, the researchers write in the Cochrane Database of Systematic Reviews. The studies were either too small to be significant, the scientists say, or were poorly designed. For example, most were not randomized controlled trials, and the longest study followed participants for only six months. In fact, there isn't really any evidence that standing is better than sitting, Verbeek adds. The extra calories you burn from standing over sitting for a day are barely enough to cover a couple of banana chips.

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“The idea you should be standing four hours a day? There's no real evidence for that,” he says. “I would say that there's evidence that standing can be bad for your health.” A 2005 study in Denmark showed prolonged standing at work led to a higher hospitalization risk for enlarged veins. But standing doesn't have to be harmful, says Lucas Carr, a behavioral medicine professor at the University of Iowa who was not involved in the meta-analysis. He thinks as long as you stand in moderation, you can still reap some benefits. “The health benefits of standing are not well-known,” Carr agrees. “But you're going to burn more calories standing than sitting. I know it's not a tremendous amount.” Still, he says, “those calories every day over many years will add up.” Carr says the finding of the Cochrane review doesn't mean that standing desks and variations are useless. It just means there hasn't been enough study of the desks to say either way. “The state of the science is definitely early,” he says. “There needs to be longer studies with more people to get a good sense these desks actually cause people to stand.” Carr thinks there is the the potential for sit-stand desks to prove useful in preventing healthy office workers from becoming unhealthy. Verbeek is less optimistic. Just because the standing desk or the pedaling desk is in the cubicle doesn't mean people will get out of the chair and use it. “Changing behavior is very difficult,” Verbeek says. He thinks redesigning work environments might be a better way to go. “For example, organize a printer in the corridor that's further away from your desk,” he says. Or — and architects can have this one for free — make the one bathroom five flights of stairs up, and restrict use of elevators to people with accessibility needs. Source: Shrestha N, Kukkonen-Harjula KT, Verbeek JH, Ijaz S, Hermans V, Bhaumik S. Workplace interventions for reducing sitting at work. The Cochrane Library. 2016 Jan 1.

Creating a Prosthetic Hand That Can Feel DARPA’s HAPTIX Program Aims to Develop a Prosthetic Hand That’s Just As Capable As the Original Dustin J. Tyler IEEE Spectrum April 28, 2016 Wearing a blindfold and noise-canceling headphones, Igor Spetic gropes for the bowl in front of him, reaches into it, and picks up a cherry by its stem. He uses his left hand, which is his own flesh and blood. His right hand, though, is a plastic and metal prosthetic, the consequence of an industrial accident. Spetic is a volunteer in our research at the Louis Stokes Cleveland Veterans Affairs Medical Center, and he has been using this “myoelectric” device for years, controlling it by flexing the muscles in his right arm. The prosthetic, typical of those used by amputees, provides only crude control. As we watch, Spetic grabs the cherry between his prosthetic thumb and forefinger so that he can pull off the stem. Instead, the fruit bursts between his fingers. Next, my colleagues and I turn on the haptic system that we and our partners have been developing at the Functional Neural Interface Lab at Case Western Reserve University, also in Cleveland. Previously, surgeons J. Robert Anderson and Michael Keith had implanted electrodes in Spetic’s right forearm, which now make contact with three nerves at 20 locations. Stimulating different nerve fibers produces realistic sensations that Spetic perceives as coming from his missing

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hand: When we stimulate one spot, he feels a touch on his right palm; another spot produces sensation in his thumb, and so on. To test whether such sensations would give Spetic better control over his prosthetic hand, we put thin-film force sensors in the device’s index and middle fingers and thumb, and we use the signals from those sensors to trigger the corresponding nerve stimulation. Again we watch as Spetic grasps another cherry. This time, his touch is delicate as he pulls off the stem without damaging the fruit in the slightest. In our trials, he’s able to perform this task 93 percent of the time when the haptic system is turned on, versus just 43 percent with the haptics turned off. What’s more, Spetic reports feeling as though he is grabbing the cherry, not just using a tool to grab it. As soon as we turn the stimulation on, he says, “It is my hand.” Eventually, we hope to engineer a prosthesis that is just as capable as the hand that was lost. Our more immediate goal is to get so close that Spetic might forget, even momentarily, that he has lost a hand. Right now, our haptic system is rudimentary and can be used only in the lab: Spetic still has wires sticking out of his arm that connect to our computer during the trials, allowing us to control the stimulation patterns. Nevertheless, this is the first time a person without a hand has been able to feel a variety of realistic sensations for more than a few weeks in the missing limb. We’re now working toward a fully implantable system, which we hope to have ready for clinical trials within five years. What would adding a sense of touch to prosthetics do? Right now, people with prostheses typically can use their fake limbs only for tasks that don’t require precision, such as bracing and holding. The sensory feedback from our haptic system would improve control and confidence, allowing greater use of the prosthesis for all the many small tasks of daily life. Beyond that, we hope to restore one of the most basic forms of human contact. Imagine what it must be like to lose your sense of touch—touch gives us such a profound sense of connection to others. When we ask Spetic and other prosthetic wearers how to improve their mechanical limbs, universally they say they want to hold a loved one’s hand and really feel it. Our technology should one day enable them to achieve this very human goal. Implanted electrodes in this amputee’s arm make this haptic hand feel like the real deal I’ve spent my entire career studying the marriage between human and machine. My work at the intersection of biomedical engineering and neural engineering has driven me to seek the answers to some basic questions: How can electronic circuits speak to the nervous system in a way that the nervous system will understand? How can we use that capability to restore a sweeping range of sensations to someone who has lost a hand? And how can that technology be used to enhance and augment other people’s lives? The past few decades have seen remarkable advances in the field, including better hardware that can be implanted in the brain or body and better software that can understand and mimic the natural neural code. In that code, electrical impulses in the nervous system convey information between brain cells or along the neurons in the peripheral nerves that stretch throughout the body. These signals drive the actuators of the body, such as the muscles, and they provide feedback in the form of sensation, limb position, muscle force, and so on. By inserting electrodes directly into muscles or wrapping them around the nerves that control the contraction of the muscles, we can send commands to those electrodes that roughly replicate the signals associated with moving a hand, standing up, or lifting a foot, for example. More recent efforts are aimed at understanding and restoring the sensory system, through funding from the U.S. Department of Veterans Affairs and the Defense Advanced Research Projects Agency’s Hand Proprioception and Touch Interfaces (HAPTIX) program. Our work on haptic interfaces falls under both of these new programs, but the focus is instead on restoring the sensory signals from the missing limb to the brain. Engineering such an interface is

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difficult because it has to allow precise patterns of stimulation to the person’s peripheral nerves, without damaging or otherwise altering the nerves. It also must function reliably for years within the harsh environment of the body. There are several approaches to designing an implanted interface. The least invasive is to embed electrodes in a muscle, near the point where the target nerve enters that muscle. Such systems have been used to restore function following spinal-cord injury, stroke, and other forms of neurological damage. The body tolerates the electrodes well, and surgically replacing them is relatively easy. When the electrodes need to activate a muscle, however, it often requires a current of up to 20 milliamperes, about the same amount you get when you shuffle across a carpet and get “shocked”; even then, the muscle isn’t always completely activated. The most invasive approach involves inserting electrodes deep into the nerve. Placing the stimulating contacts so close to the target axons—the parts of nerve cells that conduct electrical impulses—means that less current is required and that very small groups of axons can be selectively activated. But the body tends to reject foreign materials placed within the protective layers of its nerves. In animal experiments, the normal inflammatory process often pushes these electrodes out of the nerve.

Figure 1. 2-D Hand Illustration: James Provost; 3-D Illustration: Bryan Christie The Sense of Touch: To allow a person with a prosthetic hand to perceive sensations, researchers at Case Western Reserve University surgically implanted electrode cuffs around the median, radial, and ulnar nerves in the affected arm. The flattened cuff [above right] is more effective than the traditional circular cuff [above left] because electrical signals can access the nerve fibers more easily. When precise patterns of electrical pulses are sent to each electrode, the subject feels sensations at specific sites on the front and back of his hand, as well as different textures. Although this experimental system uses an external computer, the eventual goal is to implant a controller, which will wirelessly communicate with the prosthetic hand.

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Somewhere between these two approaches are systems that encircle the nerve and place electrical contacts on the surface of the nerve. Simple systems that stimulate just one site on one nerve are commercially available to treat epilepsy and to help stroke patients speak and swallow. More complicated, multiple-channel versions have been used reliably for nearly a decade in clinical trials to restore upper- and lower-extremity function following a spinal-cord injury. Since the late 1990s, my group has been working on such encircling electrodes, also known as nerve cuffs. One early problem we tackled was how to increase access to the nerve without actually penetrating it. The small surface area and cylindrical shape of a traditional electrode cuff weren’t well suited to the task. We therefore flattened out the nerve cuff so that it fit around an oblong cross section of the nerve.

Figure 2. Tyler Lab/The Cleveland VA Medical Center. Cuff Links: These flattened electrode cuffs, developed by the author’s group, encircle a nerve and allow signals to be sent on 8 channels. In 2014, we unveiled the latest version of the flattened cuff, which has eight contact points, each connected to a different channel for stimulation. To date, we’ve implanted our eight-channel cuff in a handful of subjects. Spetic, the cherry-plucking volunteer, has the flat electrode cuffs placed around the median and ulnar nerves, two of the three main nerves in his arm. He has a traditional circular electrode placed around the radial nerve. This provides a total of 20 stimulation channels in his forearm: eight each on the median and ulnar nerves and four on the radial nerve. The first time Spetic tested our system, we didn’t know whether any of the channels would actually translate to different sensations or different locations. Anxiously, we turned it on and activated a contact on Spetic’s median nerve. “Wow!” he said. “That’s the tip of my thumb. That’s the first time I’ve felt my hand since the injury.” It was one of those moments a researcher lives for. Further testing revealed that our 20 stimulation points created sensations at 19 places on Spetic’s missing hand, including spots on the left and right sides of his palm, the back of his hand, his wrist, his thumb, and his fingertips. The next generation of our cuff will have four times as many contacts. The more channels, the more selectively we’ll be able to access small groups of axons and provide a more useful range of sensations. In addition to the tactile, we’d like to produce sensations like temperature, joint position (known as proprioception), and even pain. Despite its negative connotation, pain is an important protective mechanism. During our tests, one stimulation channel did cause a painful sensation. Eventually, we would like to include such protective mechanisms. For now, we are exploring the other channels and continuing to work with Spetic, who has had the implanted system since May 2012. It’s still working well. When the system is turned off, he says, he doesn’t even realize he has anything implanted in his body.

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Of course, triggering a basic sensation is one thing; controlling how that sensation feels is another. It’s analogous to talking: You need to generate sound, but to be understood, that sound has to come out in distinct patterns that can be interpreted as language. In our first experiments, we excited the nerves with regular pulses at a constant strength. This regular stimulation resulted in a tingling sensation called paresthesia—the pins-and-needles feeling of a foot that’s fallen asleep. So we were generating sound but not speech. Such electrical impulses aren’t part of the nervous system’s repertoire when it’s operating properly: The only time we see them in the brain is during abnormal activity, such as an epileptic seizure. We think this kind of stimulation causes a group of several hundred neurons to fire together, creating an unusual signal that the brain interprets as a generic sensation of tingling. In our next experiments we varied the pattern of electric pulses that we sent up the nerves to the brain. We tried changing the timing of pulses and interspersing the sequence with pairs of pulses. Neither of these tests made a significant difference. And because there were so many variables, it proved difficult and time-consuming to understand how changing the pattern of pulses affected what Spetic felt. To move the experiment forward, I ended up testing many of the patterns on myself. Using a clinically available, noninvasive nerve-stimulation system, a team member placed electrodes on my finger where they could activate a superficial nerve, and then I got my students to “buzz” me with varying patterns. We found that changing the pulse strength in a wavelike pattern, increasing and then decreasing in about a one-second cycle, changed the sensation from tingling to a more natural feeling of pressure—it felt as though something was squeezing my finger. We were then ready to try the pattern on Spetic. As the stimulation started, he looked confused for a moment, and then he placed the fingers of his remaining hand on his neck. “It doesn’t feel like tingling anymore,” he said. “It’s a pulsing pressure, like I put my fingers on my neck and felt my pulse.” With a little adjustment, we were able to remove the pulsing, and he reported a natural touch, “like someone just laid a finger on my hand.” We think that the weaker pulses activate fewer of the neurons in the nerve, whereas stronger pulses cause more of them to fire. The variation in the firing rates of the different neurons is part of the neural code that the brain understands. If the pattern we apply resembles a pattern that the brain already knows, it interprets the sensation according to its experience: In effect, the brain says, Okay, that’s touch. We are now working to understand how more complex patterns can produce more nuanced perceptions of sensation. So far, Spetic has reported feeling textures that he described as Velcro and sandpaper and also feeling objects moving, fluttering, and tapping on his skin. What’s more, Spetic can manipulate fine and delicate objects in a manner that he was unable to do before. He no longer has to rely on vision alone to know how his prosthesis is performing. And he’s far more confident using the prosthesis when he has sensation than when he does not. So how will all this knowledge help others? Working with our partners at Medtronic and Lawrence Livermore National Laboratory, we are creating a fully implantable stimulation system paired with an advanced anthropomorphic haptic prosthetic. The project aims to have a working device within three years so that it will be ready for clinical trials by the last year of our five-year contract. Building a sophisticated neural stimulation device that actually works outside the laboratory won’t be easy. The prosthesis will need to continuously monitor hundreds of tactile and position sensors on the prosthesis and feed that information back to the implanted stimulator, which then must translate that data into a neural code to be applied to the nerves in the arm. At the same time, our system will determine the user’s intent to move the prosthesis by recording the activity of up to 16 muscles in the residual limb. This information will be decoded, wirelessly transmitted out of the body,

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and converted to motor-drive commands, which will move the prosthesis. In total, the system will have 96 stimulation channels and 16 recording channels that will need to be coordinated to create motion and feeling. And all of this activity must be carried out with minimal time delays. As we refine our system, we’re trying to find the optimal number of contacts. If we use three flattened electrode cuffs that each have 32 contacts, for example, we could hypothetically provide sensation at 96 points across the hand. So how many channels does a user need to have excellent function and sensation? And how is information across these channels coordinated and interpreted? To make a self-contained device that doesn’t rely on an external computer, we’ll need miniature processors that can be inserted into the prosthesis to communicate with the implant and send stimulation to the electrode cuffs. The implanted electronics must be robust enough to last years inside the human body and must be powered internally, with no wires sticking out of the skin. We’ll also need to work out the communication protocol between the prosthesis and the implanted processor. It’s a daunting engineering challenge, but when we succeed, this haptic technology could benefit more than just prosthetic users. Such an interface would allow people to touch things in a way that was never before possible. Imagine an obstetrician feeling a fetus’s heartbeat, rather than just relying on Doppler imaging. Imagine a bomb disposal specialist feeling the wires inside a bomb that is actually being handled by a remotely operated robot. Imagine a geologist feeling the weight and texture of a rock that’s thousands of kilometers away or a salesperson tweeting a handshake to a new customer. Such scenarios could become reality within the next decade. Sensation tells us what is and isn’t part of us. By extending sensation to our machines, we will expand humanity’s reach—even if that reach is as simple as holding a loved one’s hand. Source: This article appears in the May 2016 print issue as “Restoring the Human Touch.” IEEE Spectrum

Taking on Essential Tremor New Tools and Approaches Offer Patients Increased Treatment Options Leslie Mertz IEEE Pulse May 23, 2016 Every year, Doris’s primary care physician sends her to see a neurologist to check on her hand tremor, which has increasingly worsened over the past 20 years. Year in and year out, the neurologist asks her to draw a circle on a piece of paper. “The doctor looks at it, says ‘Hmm,’ and sends me home,” Doris explains, adding that she gets no treatment, no recommendations, nothing except a request to schedule next year’s appointment. Doris’s experience is all too typical. “Still today, it remains very common for primary care practitioners to say to patients, ‘Oh, you have essential tremor, but it’s not going to kill you, so you just have to learn to live with it,’” notes Kelly Lyons, Ph.D., president of the International Essential Tremor Foundation and director of research and education at the Parkinson’s Disease and Movement Disorder Center at the University of Kansas Medical Center. “We’re trying really hard to break through the barriers to make physicians aware that there are treatment options, and there are things we can do to help people with essential tremor.”

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Such advances take on special significance when the prevalence of essential tremor is factored in. A recent estimate placed the number of Americans who have essential tremor at about 7 million, or more than 2% of the U.S. population [1]. High-tech care today includes deep-brain stimulation (see “Beyond Deep-Brain Stimulation”), which received approval from the U.S. Food and Drug Administration in 1997 to treat essential tremor, as well as many more recent technologies that reduce the tremor itself or help negate the symptoms of tremor. Beyond Deep-Brain Stimulation Technologies for hand tremor are particularly needed because, although essential tremor sometimes includes shaking of the head and the voice (symptoms that many people recall as afflicting actress Katharine Hepburn), the most common complaint by far is hand tremor, Lyons explains. In fact, about 90% of patients with essential tremor have uncontrolled shaking that affects the upper extremities, usually both hands, and the tremor often becomes pronounced as soon as the person tries to do something, whether it is moving a computer mouse, raising a spoonful of food, or buttoning a shirt. “In more severe cases, it can keep people from being able to perform their own activities of daily living or to care for themselves, because it is so disabling,” adds Lyons. Even patients with less-severe tremor find it very disruptive. According to Lyons, “There’s an embarrassment factor, whether it’s going to a movie and shaking while you’re trying to eat your popcorn so you end up throwing it, or eating your soup at a restaurant and it’s flying off the spoon.” This loss of dignity causes many people to stop going out in public, which leads to social isolation and often depression, she notes. Fortunately, however, more and more researchers are turning their attention to essential tremor. This extends beyond deep-brain stimulation, which—although very successful— is not for everyone. “It is brain surgery, so there is always the inherent risk of hemorrhage or stroke or even death, and even though that’s a very small percentage, it can be a risk not all patients are willing to take,” Lyons says. “The International Essential Tremor Foundation has done surveys and gotten patient opinion on deep-brain stimulation, and we’ve found that while it may be very successful for them, there’s a proportion of people who are just not willing to do it.” With new technologies now available or coming to market, this group of patients now has a growing number of choices. Tremor-Fighting Flatware

Figure 1. Liftware is a set of eating utensils that snap into a computerized handle designed to steady the utensil for people who have essential tremor. (Photo courtesy of Liftware).

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One product that has been getting a good deal of notice since its release in 2014 is a computerized eating utensil that compensates for hand tremor and steadies the utensil sufficiently so that many patients can regain the ability to feed themselves (Fig. 1). Called Liftware [2], the utensils look much like regular spoons or forks. “We designed it that way on purpose. We wanted to hide all the technology away from the user so it was just as simple as can be to use, even though there’s a pretty complicated system inside,” notes company founder Anupam Pathak. Any of the utensil attachments—a spoon, a soup spoon, and a fork—can snap into the handle, which is where the technology lies. Sensors detect the user’s hand movements, whether they are intended movements (lifting the utensil to the mouth, for instance) or unintended movements associated with tremor. The company, based in Mountain View, California, developed a variety of different algorithms that distinguish between the two different types of motion by taking into account certain features, such as the frequency of unintended versus intended movements, Pathak explains. A feedback controller sends commands to two actuators in the handle that move the utensil up and down or left and right. For this device, both function and form were critical. “It wasn’t enough just to cancel the unintended motion. We also wanted to make it feel to the user like they were still using a spoon, and that required additional design and algorithms,” he says, adding that patient insight was indispensable. “We met with patients over a couple of years, coming back to the lab, changing things, going back to get their input again, and finally shaping something that has turned out to be very useful.” Liftware functions through a combination of sensors that detect the user’s hand movements, algorithms that distinguish unintended movements associated with tremor, and a feedback controller that sends commands to two actuators designed to compensate for tremor and steady the utensil. Although Pathak can’t go into detail for proprietary reasons, he mentions that Liftware is working on additional attachments, including “some for personal hygiene and grooming,” and is also developing devices for other disorders that cause uncoordinated movements. “Once we started in this area, a lot of patients and other people have approached us looking for help, and we are very much focused on being able to do what we can in that broader sense.” Steadying Gloves Across the Atlantic, a team of students also tackling essential tremor is well on its way to a generating a new product. The project started when Faii Ong, a medical student at Imperial College London, met a 103-year-old patient with essential tremor. “She looked at me and said, ‘Will you take care of me?’ I simply didn’t know how to respond, as her memory was limited to several minutes, and I didn’t know if I could truly do anything for her. It was a poignant moment that got me thinking about tremor.” He jotted down the thought in a notebook that already had a long list of other things he noticed in the hospital that could use some innovation: “When I had a little bit of time, I ranked all of them, and the tremor issue came out on top.” That’s when he called on a few friends who were studying engineering to help with his idea of developing a tremor-canceling glove, ultimately named the GyroGlove [3]. They looked at everything from “rubber bands and weights to exotic robotic systems and magnetic fluid dampeners,” but decided that a gyroscope was the most elegant solution, Ong says. “Gyroscopes counteract tremor proportionally and exceedingly smoothly, and that’s the reason why we went with spinning gyroscopes.” Preliminary testing with patients has had promising results, he notes. “We have a video of a 71year-old lady with severe essential tremor, and on a good day she can barely use both hands to hold a bottle of water. We strapped on our weakest prototype—that was from July 2015—and even with that, she was able to simulate drinking from a bottle with one hand. The glove reduced the displacement of her palm quite significantly.”

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Since then, the glove has taken on a more stylish look, and the gyroscope is much smaller—but twice as powerful (Fig. 2). In miniaturizing the gyroscope, which spins at 20,000 rpm, the team had to ensure that it was perfectly balanced. “With the assembly, the motors, and everything else, an unbalanced disk is very noisy, so we will require costly precision equipment to balance the system,” Ong says. Today, they are hard at work refining the system, with a focus on better controlling the orientation of the gyroscope in response to the patient’s movements. At the same time, the team is planning formal clinical trials so the GyroGlove can make it to market by the end of the year.

Figure 2: This rendering provides a suggestion of the current GyroGlove prototype. The eventual product will be more stylish, Ong says. The researchers are keeping the current prototype under wraps for now but hope to have a commercial product available later this year. (Image courtesy of GyroGlove.). Tactile-Film Exoskeleton Researchers in Taiwan and Japan are also collaborating on technology for essential tremor. A group at Taiwan’s Industrial Technology Research Institute (ITRI) has joined with teams at Japan’s Waseda University (led by Prof. Masakatsu G. Fujie) and Kikuchi Seisakusho Company, Ltd., on a tactile-controlled upper-limb exoskeleton (Fig. 3). Called the Higher Sensitivity Tactile-Film System for Wearable Orthosis (HSTS), the externally worn device incorporates sensor cells in a novel “tactile film” that lies on the inner side of the orthosis near the wrist [4]. “The sensor cells are basically resistors that vary when mechanical strain is applied,” explains Jui-Yiao Su, research manager at ITRI’s mechanical and systems research laboratories. Combined with a data-acquisition circuit box and monitoring/image-process software, the HSTS interprets the user’s movements by reading pressure variations between the arm and the orthosis—even through clothing—and mechanically suppresses tremor while allowing for voluntary movement.

Figure 6: Researchers from Taiwan’s Industrial Technology Research Institute and Japan’s Waseda University and Kikuchi Seisakusho Company are collaborating on a tactile-controlled exoskeleton, called the Higher Sensitivity Tactile-Film System for Wearable Orthosis, which is designed to dampen tremor while allowing for voluntary movement. (Photo courtesy of ITRI.)

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The researchers are now developing the next-version device for preclinical studies and evaluations in Taiwan and Japan. Su remarks, “It is very likely that in the next two years we will produce an orthosis that is built to understand the wearer’s intentions and then to perform adequately.” Making a Difference All of these devices and technologies share the same goal: to improve the lives of people who have essential tremor. “The beautiful thing about the whole story of Liftware is that when we first started working on essential tremor, patients were very receptive to the fact that someone was recognizing the condition and dedicated to working on ways to help,” says Pathak. As they moved forward with the project, he says it became clear just how common and how devastating essential tremor is, which reinforced their desire to help. With the technologies that are already available and new technologies being investigated, patients have an increasing number of options to treat the condition or to dampen the symptoms of essential tremor. Dr. Lyons believes that the biggest obstacle now is getting the word out: “That awareness piece is so important in the professional and the lay community so that people can 1) get the right diagnosis, 2) get treated, and 3) hopefully become part of new research studies to advance the medications, devices, and surgical therapies that may be successful treatments for essential tremor.” She adds, “There’s definitely a new interest in the field, and several companies are becoming involved in developing new technologies and treatments for essential tremor. That’s very exciting.” References [1] E. D. Louis and R. Ottman, “How many people in the USA have essential tremor? Deriving a population estimate based on epidemiological data,” Tremor Other Hyperkinetic Movements, vol. 4, p. 259, Aug. 2014. [2] https://www.liftware.com/ (Downloaded 8 August 2016) [3] http://gyrogear.co/gyroglove (Downloaded 8 August 2016) [4] Industrial Technology Research Institute. (2015, Fall). https://www.itri.org.tw/eng/DM/Publicat ionsPeriods/654743136734356214/content/focus1_2.html (Dwloaded 8 August 2016).

Could Alzheimer’s Stem from Infections? It Makes Sense, Experts Say Gina Kolatamay NY Times May 25, 2016 Could it be that Alzheimer’s disease stems from the toxic remnants of the brain’s attempt to fight off infection? Provocative new research by a team of investigators at Harvard leads to this startling hypothesis, which could explain the origins of plaque, the mysterious hard little balls that pockmark the brains of people with Alzheimer’s. It is still early days, but Alzheimer’s experts not associated with the work are captivated by the idea that infections, including ones that are too mild to elicit symptoms, may produce a fierce reaction that leaves debris in the brain, causing Alzheimer’s. The idea is surprising, but it makes sense, and the Harvard group’s data, published in the journal Science, Translational Medicine, supports it. If it holds up, the hypothesis has major implications for preventing and treating this degenerative brain disease. The Harvard researchers report a scenario seemingly out of science fiction. A virus, fungus or bacterium gets into the brain, passing through a membrane — the blood-brain barrier — that becomes leaky as people age. The brain’s defense system rushes in to stop the invader by making a sticky cage

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out of proteins, called beta amyloid. The microbe, like a fly in a spider web, becomes trapped in the cage and dies. What is left behind is the cage — a plaque that is the hallmark of Alzheimer’s. So far, the group has confirmed this hypothesis in neurons growing in petri dishes as well as in yeast, roundworms, fruit flies and mice. There is much more work to be done to determine if a similar sequence happens in humans, but plans — and funding — are in place to start those studies, involving a multicenter project that will examine human brains. “It’s interesting and provocative,” said Dr. Michael W. Weiner, a radiology professor at the University of California, San Francisco, and a principal investigator of the Alzheimer’s Disease Neuroimaging Initiative, a large national effort to track the progression of the disease and look for biomarkers like blood proteins and brain imaging to signal the disease’s presence. Dr. David Holtzman, a professor and the chairman of neurology at the Washington University School of Medicine in St. Louis, was also intrigued. “It is obviously outside the box,” he said. “It really is an innovative and novel study.” The work began when Robert D. Moir, of Harvard Medical School and Massachusetts General Hospital, had an idea about the function of amyloid proteins, normal brain proteins whose role had long been a mystery. The proteins were traditionally thought to be garbage that accumulates in the brain with age. But Dr. Moir noticed that they looked a lot like proteins of the innate immune system, a primitive system that is the body’s first line of defense against infections. Elsewhere in the body, such proteins trap microbes — viruses, fungi, yeast and bacteria. Then white blood cells come by and clear up the mess. Perhaps amyloid was part of this system, Dr. Moir thought. He began collaborating with Rudolph E. Tanzi, also at Harvard Medical School and Massachusetts General Hospital, in a study funded by the National Institutes of Health and the Cure Alzheimer’s Fund. The idea was to see if amyloid trapped microbes in living animals and if mice without amyloid proteins were quickly ravaged by infections that amyloid could have stopped. The answers, they reported, were yes and yes. In one study, the group injected Salmonella bacteria into the brains of young mice that did not have plaques. “Overnight, the bacteria seeded plaques,” Dr. Tanzi said. “The hippocampus was full of plaques, and each plaque had a single bacterium at its center.” In contrast, mice that did not make beta amyloid succumbed more quickly to the bacterial infection, and did not make plaques. For years, researchers had been fixated on the idea of plaques as a sort of trash that gathered in the brain. Few had asked if there might be some other explanation. As Dr. Samuel E. Gandy, a professor of neurology and psychiatry at the Icahn School of Medicine at Mount Sinai Hospital in New York, explained, there was a long and persuasive body of research laying out the Alzheimer’s pathway: Plaques form and set off the formation of tangled threadlike tau proteins. Then, as tangles of tau kill nerve cells, the brain becomes inflamed, resulting in the killing of many more nerve cells. There were a few puzzling clues that something else might be going on, but they did not make much sense. For example, Dr. Weiner said, some investigators reported that people who had developed Alzheimer’s had higher levels of antibodies to herpes, an indicator of a previous infection, than people who did not have the disease. “The suggestion that herpes was causative seemed a bit far-fetched,” he said. The new paper, Dr. Gandy and Dr. Weiner said, provides a plausible explanation. Dr. Berislav Zlokovic, the director of the Zilkha Neurogenetic Institute at the University of Southern California, said his studies of the blood-brain barrier also fit well with the new hypothesis. When he discovered that the barrier started to break down with aging, he noticed that the leakiest part was the membrane that protects the hippocampus, the site of learning and memory. That is also where Alzheimer’s plaques form.

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Dr. Tanzi and Dr. Moir’s hypothesis, he said, “is very hypothetical at this point, but it does make sense.” Of course, there must be more to Alzheimer’s than the brain’s innate immune system. What about people who have a mutated gene that guarantees they will develop the disease at an early age? For them, Dr. Tanzi says, the problem is that they vastly overproduce beta amyloid. There is so much that it clumps on its own, without the presence of microbes. Not everyone who has had a brain infection develops Alzheimer’s, though. Why would some be more vulnerable than others? According to the new theory, it probably has to do with the brain’s ability to clear out the balls of beta amyloid after they have killed microbes, Dr. Tanzi said. For example, it is known that people with a gene called ApoE2 have brains that are good at sweeping out plaque, and have a low risk of Alzheimer’s in old age. Those with a different version, ApoE4, are inefficient in removing plaque and have a high risk of Alzheimer’s. Recent data suggests that the incidence of dementia is decreasing. It could be because of better control of blood pressure and cholesterol levels, staving off ministrokes that can cause dementia. But could a decline in infections also be part of the picture? “That’s a possibility,” Dr. Weiner said. At this point, the Harvard researchers have what many say is an intriguing hypothesis, but they readily acknowledge that much work lies ahead. The Cure Alzheimer’s Fund is starting a large collaborative project that will use gene-sequencing technology to carefully look for microbes in brains from people who had Alzheimer’s and those who did not. Researchers will also look for microbes in plaques found in human brains. That, though, “is a big, big second step,” Dr. Tanzi said. “First, we need to ask whether there are microbes that may sneak into the brain as we age and trigger amyloid deposition.” “Then,” he said, “we can aim at stopping them.” Source: Kumar DK, Choi SH, Washicosky KJ, Eimer WA, Tucker S, Ghofrani J, Lefkowitz A, McColl G, Goldstein LE, Tanzi RE, Moir RD. Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease. Science translational medicine. 2016 May 25;8(340):340ra72-. Editor’s Note: Given the incrediculous results of this paper and the New York Time’s writer’s description of the study and comments of others. Included below is a sample reaction to the above described paper

Remarkable Results, Questionable Report Claudiu Bandea Centers for Disease Control and Prevention Atlanta, Georgia, USA May 28, 2016 “Our findings raise the intriguing possibility that β-amyloid may play a protective role in innate immunity and infectious or sterile inflammatory stimuli may drive amyloidosis” [1]. Indeed, fascinating findings. What Kumar did not articulate, though, is that their result is one of many findings, observations, and arguments supporting the theory [2,3] that: (i) β-amyloid, tau, αsynuclein, huntingtin, TDP-43, prion protein and other primary proteins implicated in neurodegenerative diseases are members of the innate immune system; (ii) The isomeric

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conformational changes of these proteins and their assembly into various oligomers, plaques, and tangles are not protein misfolding events as defined for decades, nor are they prion-replication activities, but part of their normal, evolutionarily selected innate immune repertoire; (iii) The immune reactions and activities associated with the function of these proteins in innate immunity lead to Alzheimer’s, Parkinson’s, Huntington’s, ALS and Creutzfeldt-Jakob Disease, which are innate immunity disorders. Generating data and observations, although essential, represents only half of the scientific process; the other is their interpretation and integration into the existing knowledge and paradigms. That’s where the article by Kumar falls short. Perhaps the authors were not fully familiar with the literature and paradigms in the field of neurodegenerative diseases. Or, perhaps, Kumar did not consider it relevant to discuss their results in the context of previous findings, ideas and hypotheses. For example, the authors did not address or explain their results in context of the ‘prion’ paradigm, which has dominated the thinking in the field of Alzheimer’s and other neurodegenerative diseases in the last few years [e.g. 4-7]. Nor did they refer to a related study entitled “Alpha-synuclein expression restricts RNA viral infections in the brain” [8], which is highly relevant considering the fact that alpha-synuclein, a putative member of the innate immune system and the primary protein implicated in Parkinson’s, is a significant player in Alzheimer’s disease. Also, some might consider highly questionable leaving out the study by Kobayashi entitled “Binding sites on tau proteins as components for antimicrobial peptides” [9]. Given these omissions, it's no wonder in her The New York Times article on Kumar study, Gina Kolata wrote: “The Harvard researchers report a scenario seemingly out of science fiction.”

References [1] Kumar et al. 2016. Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer's disease. Sci Transl Med. 25;8(340); Kumar DK, 2016 [2] Bandea CI. 2013. Aβ, tau, α-synuclein, huntingtin, TDP-43, PrP and AA are members of the innate immune system: a unifying hypothesis on the etiology of AD, PD, HD, ALS, CJD and RSA as innate immunity disorders. bioRxiv. doi: 10.1101/000604; http://biorxiv.org/content/ biorxiv/early/2013/11/18/000604.full.pdf [3] Bandea CI. 2009. Endogenous viral etiology of prion diseases. Nature Precedings; http://precedings.nature.com/documents/3887/version/1/files/npre20093887-1.pdf [4] Frost B, Diamond MI. 2010. Prion-like mechanisms in neurodegenerative diseases. Prion. 1(3):155-9; Frost B, 2010 [5] Nussbaum JM, Seward ME, Bloom GS. 2013. Alzheimer disease: a tale of two prions. Prion. 7(1):14-9; Nussbaum JM, 2013 [6] Watts JC et al. 2014. Serial propagation of distinct strains of Aβ prions from Alzheimer's disease patients. Proc Natl Acad Sci U S A. 11(28):10323-8; Watts JC, 2014 [7] Jaunmuktane et al. 2015. Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy. Nature. 525:247-50; Jaunmuktane Z, 2015 [8] Beatman et al. 2015. Alpha-Synuclein Expression Restricts RNA Viral Infections in the Brain. J Virol. 90(6):2767-82; Beatman EL, 2015 [9] Kobayashi et al. 2008. Binding sites on tau proteins as components for antimicrobial peptides. Biocontrol Sci. 13(2):49-56. Kobayashi N, 2008 [10] Kolata G. 2016. Could Alzheimer’s Stem from Infections? It Makes Sense, Experts Say. The New York Times; May 25, 2016.http://www.nytimes.com/2016/05/26/health/alzheimers-disease -infection.html?_r=0

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Flipping a Genetic Switch Erases Mouse Memories Michael Franco Gizmag June 30, 2016 Associative memories can be extremely helpful. Touch the metal handle of a pot boiling water on the stove, for example, and chances are you won't do it again. But in other cases, associative memories can dramatically affect our development, such as in the case of a war veteran who associates all loud noises with the battlefield. A new technique tested in mice shows promise in turning off associative memories by preventing a gene from expressing itself. Researchers at KU Leuven in Belgium and the Leibniz Institute for Neurobiology in Germany found that by turning of the gene known as neuroplastin, they could make mice forget an associative behavior they had learned. In this case, that behavior consisted of knowing to move to the other side of maze when a light went on in order to avoid a shock to the foot. When the researchers turned off the neuroplastin gene, which is a gene that produces a protein, the mice couldn't complete the task properly. In other words, their associatively learned behaviors were erased. When the mouse brains were examined using a gamma-ray technique called single-photon emission computed tomography imaging, it was found that they contained “substantial electrophysiologic deficits” according to the abstract for a research paper published in the journal Biological Psychitry. These defects interfered with cellular communication. “We were amazed to find that deactivating one single gene is enough to erase associative memories formed before or during the learning trials,” said Professor Detlef Balschun from the KU Leuven Laboratory for Biological Psychology, who was involved in the study. “Switching off the neuroplastin gene has an impact on the behavior of the mice, because it interferes with the communication between their brain cells.” Previous research shows that neuroplastin is an important component in maintaining the brain's plasticity, or its ability to modify its own structure in response to stimuli. Alterations to the gene have also been linked to schizophrenia. While the work sheds even more light on neuroplastin's role in the brain, the researchers caution that the time when we can head into the doctor's office to have unpleasant memories erased is still quite a time away. “This is still basic research,” Balschun says. “We still need further research to show whether neuroplastin also plays a role in other forms of learning.” Source: Bhattacharya S, Herrera-Molina R, Sabanov V, Ahmed T, Iscru E, Stöber F, Richter K, Fischer KD, Angenstein F, Goldschmidt J, Beesley PW. Genetically Induced Retrograde Amnesia of Associative Memories After Neuroplastin Ablation. Biological Psychiatry. 2016 Apr 11.

In-Ear EEG Makes Unobtrusive Brain-Hacking Gadgets a Real Possibility Eliza Strickland IEEE Spectrum July 7, 2016 Brain hacking gadgets could soon be an unobtrusive part of daily life, thanks to EEG sensors that fit snugly inside the ear. Two research groups are making progress on discreet devices that offer

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reliable brain data—and that reliability is a key point. A few neuro gadgets for consumers have already hit the market, but it’s not at all clear that they deliver the promised brain data.

Why might you want a brain hacking gadget? Well, maybe you want to control objects in the physical world with your mind, and long to use a mere thought to unlock your front door or raise your X-wing spaceship from a swamp. Or perhaps you want to keep tabs on your brainwaves throughout the day, and seek a data-collecting gadget that acts as a Fitbit for your brain. Companies and DIYers can make such things today (okay, probably not the X-wing lifter) with sensors that use electroencephalography, or EEG, to pick up a rough recording of brain activity. Typically, these devices use EEG electrodes that are affixed to the scalp, where they detect the patterns of electrical activity generated when millions of brain cells act in concert. The different types of “brainwaves” have been associated with different mental states, such as focus and relaxation, and different actions. But such scalp-based electrode systems can look a little conspicuous and clunky. While startups are certainly racing to make sleeker and better EEG headsets, several research groups think that in-ear EEG sensors offer an elegant alternative. EEG-reading device by routing the electrode to the ear At John Chuang’s lab at UC Berkeley, engineers modified a commercial EEG headset from the Silicon Valley company NeuroSky, taking the electrode out of the plastic forehead piece and bringing it to the ear canal. The team decided to work with “the cheapest available consumer-grade EEG headset,” Chuang says in an email, to see what they could achieve with that “challenging” setup. The team’s ultimate goal is to use an in-ear EEG sensor to send mental commands that could control a computer, a drone, or any other electronic thing. But EEG isn’t a very clear signal. It can distinguish broad patterns such as alpha waves (with frequencies between 8 and 13 Hertz) generated when a user is resting with eyes closed, and beta waves (13 to 30 Hz), which are generated when the user is more alert. But it can’t decipher verbalized thoughts like “Go left, car!” To use EEG in a brain-machine interface, then, researchers calibrate their systems by having the user perform “mental gestures” and identifying the EEG signatures of those efforts. Chuang’s team tried out a five different mental gestures: Test subjects sang a song inside their head, imagined a face, pictured a rotating cube, listened to a sound, and simply breathed deeply with their eyes closed. For each person, the researchers chose the two gestures with the clearest EEG signatures. These two mental gestures could theoretically be used to create a binary control system for any hooked-up

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electronic device. For example, a user could imagine the rotating cube in order to make a remotecontrolled car move forward, and picture a face to make it stop. Of course, steering the car left or right would require a more sophisticated system. Chuang’s team presented their research at the IEEE Body Sensor Network conference last month. Chuang says this research points toward brainwave-sensing earbuds that quietly convey our commands to the machines in our lives. “Personally, I feel awkward speaking to my devices, or making gestures by waving my hands in the air,” he tells Spectrum. In-ear EEG could provide “a very natural and discreet way for us to ‘talk’ to our computers,” he says. Meanwhile, Danilo Mandic’s lab at Imperial College London has been through several iterations of an earbud-like EEG device. Their latest version uses a simple noise-blocking earplug made of a spongy material called memory foam. Such earplugs conform naturally to the shape of a user’s ear, enabling excellent contact with the skin inside the ear canal. By attaching two electrodes made of a soft silver-coated fabric to the sides of an earplug, the researchers obtained high-quality EEG signals. By inventing a device that’s cheap, unobtrusive, and comfortable, Mandic says his group is clearing the way for a “truly wearable” EEG system. “The ear-EEG also opens up completely new avenues in 24/7 monitoring of the state of body and mind,” Mandic says in an email. He imagines possibilities such as using EEG to monitor the progress of chronic diseases, to track sleep patterns, or to keep tabs on military personnel’s mental state and fitness for duty. Outside of the lab, a Kickstarter campaign for an in-ear gadget with a built-in EEG sensor raised more than $150,000 this spring. That gadget, called Aware, requires a 3-D scan of the user’s ear canal to produce a customized ear piece. It will be interesting to see who else jumps into this brand new commercial sector (iBrain, anyone?).

Childhood Developmental Learning Disabilities and Behavioral Disorders Certification Course Co-Sponsored through IAFNR and AIC

Italy Program – 7 modules Early Registration is now open Instructor: Robert J. Melillo, MS, DC, PhD(C) DABCN, FACFN, FABCDD Module 1: Physical Exam for the Newborn & Infant: Introduction to childhood neurobehavioral disorders examining the newborn, child and adolescent Module 2: ADHD, OCD, Tourette’s I Module 3: ADHD, OCS, Tourette´s II Module 4: Autism Module 5: Dyslexia and Learning Disabilities Module 6: Nutrition and Immune for Children: Nutritional, Dietary, Immune and Endocrine Considerations in Neurobehavioral Disorders of Childhood Module 7: Behavioral and Attachment Considerations in Neurobehavioral disorders in childhood Registration Information Registration is available at https://www.iafnr.org/content/courses IAFNR Members receive discount and 7 Module Package discount available. For Module Description visit the website listed above Location: http://www.hotelmanin.it/ Hotel Mannin, Milano, Italy The class hours for all modules will be Friday and Saturday 09.00 – 17.00 and Sunday 09.00 – 15.00. In total, 25 class hours per weekend.

AIM AND SCOPE OF THE JOURNAL The aim and scope of this interdisciplinary journal is to provide a forum for the fields of biomedical and rehabilitation engineering, neuropsychology, clinical neurology, human factors and ergonomics, and vocational assessment and training to present critical ideas, theories, proof-of-concept for technology solutions, and data-based evaluative research to facilitate return to work or more effective functional development in children and adults. FNRE accepts review papers, articles of original research, data-based and controlled case studies pertaining to functional neurology, man-machine interactions, rehabilitation sciences, brain-behavior relationships, and in applied cognitive neuroscience that relate to translational research. Engineering proof-of-concept applied to functional neurology as ergonomics are also welcome. FNRE also welcomes commentary on either the review papers or on original research as the journal intends to be an archival source of discussion of new advances in rehabilitation.

Description of the Fields Covered Assessment & Rehabilitation in Neurological Disorders

• Diseases and trauma of the brain • Cognitive, language, motor, sensory (e.g. visual, auditory, pain, vestibular, etc.) and behavioral disorders

• Developmental disabilities • Autism in childhood and adults • Diseases and trauma of the spinal cord • Neuropathy, myopathy, and peripheral nerve lesions • Diseases and trauma impacting on vestibular function Assessment & Rehabilitation in Orthopedic and Musculoskeletal Disorders

• Limb disease, trauma, and amputation • Rheumatic diseases; osteoporosis • Back and neck pain Assessment & Rehabilitation in Other Specific Populations

• Geriatric rehabilitation • Pediatric rehabilitation • Special medical conditions (e.g., heart disease; respiratory disorders; cancer; burns; vegetative state)

Topics of General Interest in P&RM Organization and management of rehabilitation services: rehabilitation in the framework of hospitalization and in the community; quality control in rehabilitation; vocational rehabilitation. Scope of the specialty: educational needs; ethical and medico-legal aspects; role for alternative/complementary medicine practices in P&RM. Functional assessment & outcome measurement at various levels: impairment; disability (activity); handicap (participation); quality-of-life (QOL); WHO-ICF system. Management of commonly encountered disabling conditions: pain; sexual disability; spasticity; postural instability & recurrent falls; wounds; sleep disorders; disability related emotional disorders. Other topics of general interest in P&RM: secondary and tertiary prevention in medical rehabilitation; nursing of disabled persons; sports medicine and sports for the disabled; rehabilitation of terror victims; electrodiagnosis; kinesiology; walking analysis; movement analysis; posturography; orthotic devices; advanced technologies in P&RM; augmentative devices; neuromuscular electrical stimulation; biofeedback; ergonomic considerations in the home and workplace of disabled persons.

Rationale for Why the Journal Is Needed The field of Rehabilitation does not presently exist as a cohesive discipline. Rehabilitation specialists define themselves as neurologists, practitioners of physical medicine and rehabilitation, vocational experts, engineers, psychologists, educators, social workers, physical therapists, occupational therapists and the like. The intrinsic cross-disciplinary nature of the rehabilitation process and the requirement for clinical-driven applied and basic science is not represented in any presently published journal, or for that matter, professional organization. The International Association of Functional Neurology and Rehabilitation and the F. R. Carrick Institute for Clinical Ergonomics, Rehabilitation, and Applied Neuroscience, the host organization and research institution for the journal FNRE, is addressing the foregoing by training interdisciplinary rehabilitation professionals whose dissertations also require patent and product development, the establishment of cross-disciplinary research laboratories and projects, the transfer of technology into community based services such as free medical equipment and services for those in need of getting to or back to work, regional clinical program integration systems, and international academic and research cooperative agreements. It is expected that the proposed journal will strongly reflect the structure and philosophy of science and practice.

Description of the Peer Review Process Papers will be solicited through the organs of fields impacting on rehabilitation science. Peer review will be performed on each paper but will be blind. Periodically, papers linking a particular cogent theme applied to rehabilitation will be compiled within a single issue and published in book form. Papers will be ranked as accepted without revision, accepted but with minor revision, requiring major rework and an additional review, or rejected. We do desire to create dialogue within the rehabilitation community, and reviewer’s comments, when appropriate, will be included with the published paper.

INSTRUCTIONS FOR AUTHORS All manuscripts for the Journal of Functional Neurology, Rehabilitation, and Ergonomics (FNRE) must be submitted to the Editor-in-Chief by e-mail only: [email protected] Type of Manuscripts Accepted FNRE accepts review papers, articles of original research, data-based and controlled case studies pertaining to Functional Neurology, Man-Machine Interaction, Rehabilitation Sciences, brainbehavior relationships, and in applied cognitive neuroscience that relate to translational research. Engineering proof-of-concept applied to functional neurology as ergonomics are also welcome. FNRE also welcomes commentary on either the review papers or on original research as the journal intends to be an archival source of discussion of new advances in rehabilitation. Manuscript Requirements [1] Manuscripts must be written in English and be typewritten with double spacing throughout the entire text and with margins of at least 2.5 cm. An original on 8½"  11" heavy duty white bond paper and two duplicate copies should be provided. An email copy as a file attachment in MS WORD for WINDOWS or a text file must also be submitted by email to the above indicated email address. [2] Each manuscript must have a title (first) page that includes the title, the authors’ full names, the laboratory or origin of the data, a running head, a list of 6-8 key words and the name, address and FAX number of the person to whom correspondence and proofs should be mailed. [3] Full length review articles should be divided into sections in the following order: Synopsis, Body (with relevant sub-headings), Acknowledgements, and References. Short notes should contain no sections. Number pages consecutively. [4] Abbreviations should be defined when first used by placing in parentheses after the full term; e.g., acetylcholin-esterase (AChE). [5] References will follow the "Uniform requirements for manuscripts submitted to biomedical journals" format (also called the Vancouver style, see http://www.icmje.org/index.html) determined by the International Committee of Medical Journal Editors and used for PubMed/Medline journals. Abbreviations of journal names should conform to the Index Medicus.

References (maximum of 25 for articles, 40 for review articles and 5 for case reports) should be cited consecutively (enclosing the number in parenthesis) in the text and listed in the same numerical order at the end of the paper. The Vancouver Style is required (http://www.icmje.org/).The first reference in the text should be (1) and the next (2) and so forth and then listed accordingly at the end of the paper after discussion or after acknowledgements.

Examples: Journal article Damianopoulos EN, Carey RJ. Pavlovian conditioning of CNS drug effects: a critical review and new experimental design. Rev Neurosci 1992; 3: 65-77. Note: no comma in between name an initials, no italics or bold, no capitol letters in title except at the begining of sentence, no period between jorunal name and year, year;vol:page-page without space betwwen and last page number shortened. All authors must be cited. Journal name abbreviated according to the international standard found at PubMed Journal Database. (http://www. ncbi.nlm.nih.gov/sites/entrez ?db=journals) Book Melillo R, Leisman G Neurobehavioral disorders of childhood: An evolutionary approach. New York: Kluwer, 2004. Book chapter Leisman G, Melillo R. Cortical asymmetry and learning efficiency: A direction for the rehabilitation process. In: Randall SV Learning disabilities: New research. Hauppauge, NY: Nova. 2006: 1-24. Research report Shek DTL. A positive youth development program in Hong Kong. Hong Kong: Soc Welfare Pract Res Centre, Univ Hong Kong, 2004. (Chinese) Unpublished thesis Kaplan SJ. Post-hospital home health care: The elderly’s access and utilization. Dissertation. St Louis: MO: Washington Univ, 1995. Internet materials / publication Internet journal: Morse SS. Factors in the emergence of infectious diseases. Emer Infect Dis 2006;5:1. Internet material Morse SS. Factors in the emergence of infectious diseases. Emer Infect Dis 2006. Accessed 2007 Jun 05. URL: http://www.cdc.gov/ncidod/EID/eid.htm [6] Case studies. FNRE will publish limited case-study material as long as the appropriate format is followed including the format for references, figures and tables. The conclusions must be supportable by laboratory-based evidence presented within the case study. The authors of case study material are strongly encouraged to study the following websites that may be useful in increasing the likelihood of the material being published (e.g. http://www.bgfl.org/bgfl/18.cfm?s=18&m=473&p =261.index or http://www.bmhlinguistics. org /joomla2/guidelines-for-writing-case-studies). [7] Copyright responsibility. This is the author’s own responsibility. If any figure(s), illustration(s), table(s) or extended quotation(s) etc. are to be taken from material(s) previously published, the author(s) must secure reproduction permission from the copyright owner. Only original papers will be accepted, and copyright of published papers will be retained by the publisher. [8] Transfer of author copyright. Please include a signed release of copyright to Nova Publishers with your manuscript. Include the title of the article being sub-mitted, as well as the date. Include the signatures of co-authors. [9] Manuscript editing. All accepted manuscripts are subject to manuscript editing. [10] The original manuscript and diagrams will be discarded one month after publication unless there is a written request for the material to be returned to the author.

Functional Neurology, Rehabilitation, and Ergonomics requires all authors and reviewers to declare any conflict of interest that may be inherent in their submissions. Conflict-of-Interest Statement Public trust in the peer review process and the credibility of published articles depend in part on how well conflict of interest is handled during writing, peer review, and editorial decision making. Conflict of interest exists when an author (or the author's institution), reviewer, or editor has financial or personal relationships that inappropriately influence (bias) his or her actions (such relationships are also known as dual commitments, competing interests, or competing loyalties). These relationships vary from those with negligible potential to those with great potential to influence judgment, and not all relationships represent true conflict of interest. The potential for conflict of interest can exist whether or not an individual believes that the relationship affects his or her scientific judgment. Financial relationships (such as employment, consultancies, stock ownership, honoraria, paid expert testimony) are the most easily identifiable conflicts of interest and the most likely to undermine the credibility of the journal, the authors, and of science itself. However, conflicts can occur for other reasons, such as personal relationships, academic competition, and intellectual passion. - International Committee of Medical Journal Editors ("Uniform Requirements for Manuscripts Submitted to Biomedical Journals") - February 2006 Statement of Informed Consent Patients have a right to privacy that should not be infringed without informed consent. Identifying information, including patients' names, initials, or hospital numbers, should not be published in written descriptions, photographs, and pedigrees unless the information is essential for scientific purposes and the patient (or parent or guardian) gives written informed consent for publication. Informed consent for this purpose requires that a patient who is identifiable be shown the manuscript to be published. Authors should identify Individuals who provide writing assistance and disclose the funding source for this assistance. Identifying details should be omitted if they are not essential. Complete anonymity is difficult to achieve, however, and informed consent should be obtained if there is any doubt. For example, masking the eye region in photographs of patients is inadequate protection of anonymity. If identifying characteristics are altered to protect anonymity, such as in genetic pedigrees, authors should provide assurance that alterations do not distort scientific meaning and editors should so note. - International Committee of Medical Journal Editors ("Uniform Requirements for Manuscripts Submitted to Biomedical Journals"_ - February 2006 Statement of Human and Animal Rights When reporting experiments on human subjects, authors should indicate whether the procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). If doubt exists whether the research was conducted in accordance with the Helsinki Declaration, the authors must explain the rationale for their approach, and demonstrate that the institutional review body explicitly approved the doubtful aspects of the study. When reporting experiments on animals, authors should be asked to indicate whether the institutional and national guide for the care and use of laboratory animals was followed. - International Committee of Medical Journal Editors ("Uniform Requirements for Manuscripts Submitted to Biomedical Journals") - February 2006

NSI is designed for, and available only to, Functional Neurologists. Using a 50 inch HD TV and touch screen, the NSI is designed to offer a host of therapy procedures to a wide range of patients requiring visual or neuro therapy following: decelerated closed head injury; accelerated closed head injury; strokes and CVA; concussion and diffuse axonal injury; whiplash injuries; MVA; neurological disorders; vestibular and balance disorders; and upper extremity or spinal cord injuries. The programmable instrument offers procedures to improve: pursuits; saccades; eye-hand coordination; visual reaction time; speed and span of recognition; visual-vestibular integration; occularmotor skills; visual motor skills; and neuro-cognitive skills.

Seven categories include:

• EYE HAND • SACCADES • CUSTOM TRACKING

Seven Therapy Categories Each category offers several customizable procedures.

Customizable Tracking Procedure The Customizable Tracking Procedure allows the creation of custom Pursuits, Saccades, and Saccadic Gap Pursuits procedures.

• METRONOME • TACHISTOSCOPE

Tachistoscope Visual abilities remediated/enhanced in the Tachistoscope Program

• OPTOKINETICS • VISUAL MOTOR

Selectable Parameters Allows you to quickly modify the visual demand of the VT procedure.

Visual Motor

OptoKinetics

Visual abilities remediated/enhanced

Eye-Hand Visual abilities remediated/enhanced in the Eye-Hand Program

Programmable Metronome Visual abilities remediated/enhance in the Metronome Program

Storage and Graphing of Results Data The results of each patient’s therapy sessions are stored for review. The data may be displayed both numerically and graphically.

Numbers / Letters / Word / Verbal Saccades Builds skill in saccadic accuracy and develops automaticity.

Adjustable Stand The adjustable stand accommodates patients of different heights and also allows wheelchair access for disabled/non-ambulatory patients.

Balance Board The NSI incorporates a Wii Balance Board allowing a Vestibular component to be added to all therapy procedures.