Biomedical Applications Laboratory and the MS Technology Transfer Program of which this capstone is a small part. Thank you son. I would like to express my ...
Neural Energy Density Assessment of Cognitive Processing by Multiple Sclerosis Patients following Liquid Cooling Therapy: A research and development case study A Capstone Project presented to the College of Notre Dame in partial fulfillment of the requirement for the degree of Master of Science in Systems Management
by
Leslie D. Montgomery, Ph.D.
This Capstone Project has been accepted for the faculty of The College of Notre Dame by
____________________________________________ Program Director
________________ Date
____________________________________________ Faculty Reader
________________ Date
Table of Contents Acknowledgement Executive Summary Preface 1.0 Project Implementation Plan (PIP) 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8
Introduction Goals and Objectives Strategy Technology Needs Assessment The NASA Role Implementation Plan Products and Deliverables Resource Requirements and Schedules
2.0 Review of the Literature: Evolution of the Systemic View of the Brain 2.1 2.2 2.3 2.4 2.5 2.6 2.7
Introduction Historical View of the Brain Development View of the Brain Systemic View of the Brain Electrophysiologic View of the Brain Three Dimensional View of the Brain References
3.0 Analytical Methods: Derivation of Energy Density Analytical Procedures for Topographic Electroencephalography 3.1 3.2 3.3 3.4 3.5 3.6 3.7
Introduction Methods Results Discussion Conclusion Appendix Bibliography
4.0 Experimental Approach (Human Use Protocol): Evaluation of Lowering Body Temperature to Facilitate Neurocognitive Function in Multiple Sclerosis Patients 2
4.1 4.2 4.3 4.4
Title Submitted by Organization Code, Mail Stop and Ames Phone Number Statement of Problem and Its Importance and Impact of Research on Solving Problem 4.5 Objectives 4.6 Approach 4.7 Justification 4.8 Safety Precautions 4.9 Possible Inconveniences, Discomfort, Pain, and Risk tosubjects 4.10 Meassures Taken to Minimize Discomfort orRisks 4.11 Conditions on Withdrawal from Experiment 4.12 References 5.0 Preliminary Study Visual Discrimination Assessment using Cortical Energy Analysis: Verification of Multiple Sclerosis Test Paradigm 5.1 5.2 5.3 5.4 5.5 5.6 5.7
Abstract Background Objectives Methods Results Summary Suggested Reading
6.0 Pilot Study: Enhancement ofCognitive Processing by Multiple Sclerosis Patients using Liquid Cooling Technology 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8
Abstract Introduction Objectives Methods Results Discussion Acknowledgement References
7.0 Project Summary: Accomplishments to Date 7.1 Program Implementation 7.2 Outreach and Technology Transfer Activities 3
4
Acknowledgement I would like to take this opportunity to acknowledge and express my appreciation to the many people who encouraged me to undertake the College of Notre Dame, Master of Science in Systems Management degree program, to the many people who have collaborated in the development of the unique analytical procedures used in this project, and to the many people who have helped me in the various aspects of my capstone. This work could not have been completed without their assistance. My thanks to my wife; Patricia Ann Montgomery; and my three sons; Jerry, David, and Nathaniel; for convincing me that I could take on the MSSM degree program so ‘late in life’. They have stood by me during the many evenings ‘away from home’ and the many weekends that I spent at work completing various class assignments. I especially want to thank Pat for her unfaltering faith in me during this degree. The extra load that she took upon herself to compensate for my absence more than rivals my work in completing the degree. Thank you honey - I love you more than I can ever say. I also want to acknowledge the technical assistance given by my son, Nathaniel. He helped me through those parts of my degree program that required the use of HTML and other ununderstandable network languages. He has also developed a very attractive and extensive web site for the NASA Ames Research Center Biomedical Applications Laboratory and the MS Technology Transfer Program of which this capstone is a small part. Thank you son. I would like to express my gratitude to Dr. Raul Guisado, neurologist, and Dr. Richard W. Montgomery, my talented economics professor brother, for their work in the development of the electroencephalographic testing and analytical procedures used in this capstone. Their
5
association and collaboration over the years have provided a firm scientific basis for work described herein. Lastly, I would like to thank all of those people at NASA Ames Research Center who have contributed to this effort. Dr. Bruce W. Webbon, Chief of the Commercial Technology Office, provided the economic support for the recent MS cooling program. Dr. John Kaumeyer, my immediate supervisor at Lockheed Martin Engineering & Sciences Company, for his encouragement and for approving my tuition reimbursement program. I especially want to thank my colleagues Ms. Yu-Tsuan E. Ku, Senior Scientist, Mr. Hank Lee, Biomedical Applications Laboratory Manager, and Ms. Bernadette Luna, NASA Senior Engineer, who have all taken part in and heavily contributed to the project. Thank you one and all.
6
1.0 Executive Summary This capstone report outlines the development of neurophysiological procedures to monitor the enhanced cognitive processing by multiple sclerosis patients following short term body cooling therapy. The approach included use of topographic electroencephalographic (TEEG) measures of cerebral function, a visual discrimination task administered by computer, and the use of a NASA developed liquid cooling garment (LCG). TEEG was used to determine changes in cortical function associated with cognition. The visual discrimination task was used to produce stimulus gated event related potentials of each patient’s task performance neural activity. The LCG was used to provide cooling of the patient to lower their body temperature by the amount needed to improve cognition. During the study period testing, analytical and display procedures for TEEG monitoring were developed, that extend the state of the art and provide a valuable tool for the study of cerebral circulatory and neural activity during cognition. It is expected that the analysis of cognitive TEEG test sequences will facilitate studies of learning and memory disorders, dementias and other encephalopathies. The near real time capability of the recording equipment will facilitate monitoring of patients with a variety of neurological disorders and will allow researchers to obtain immediate feed-back of results to optimize experimental conditions during the recording session.
TEEG Methods Our TEEG methodology was influenced by the generally accepted view that certain regions of the cerebral cortex have specialized roles in cognition. For instance, the occipital cortex plays a major role in initial analysis of visually presented cognitive stimuli and may also
7
facilitate visualization during later stages of reasoning; linguistic analysis draws more strongly on left hemispheric resources and so on. This emphasis upon topographic sequences of cortical activation over the course of a cognitive task dictated two special objectives: 1) the development of computer graphical techniques for integrating separate electrode time traces into a 3-D picture of the evolving cortical electrical field and 2) development of data reduction procedures to enhance the spatial resolution of TEEG data. Both goals were attained by use of a least squares surface modeling technique that fitted a surface to the set of simultaneous electrode voltage readings at each instant. The resulting surface displays, on a computer screen, the evolving pattern of cortical activation during cognition. The least squares equation for the voltage surface at each instant permits direct mathematical transformation of the data to increase spatial resolution. This approach represents a departure from traditional TEEG analysis techniques that rely on measurements of cortically-generated currents flowing through the skull and onto the scalp. These procedures assume that the recorded EEG voltage fluctuations are primarily due to the effects of the radiated cortical electrical field upon scalp surface charges, instead of conduction effects through the skull. This approach seems plausible considering the high resistivity of the skull.
Experimental Approach The experimental approach included the following aspects: 1) development of distinct visual-motor cognitive tasks presented by means of a computer screen for use in cooling related cognitive tests; 2) generation of ensemble averaged event-related potentials (ERPs) for each cognitive task; 3) development of analytical procedures to evaluate the whole-scalp shape of the 8
cognitive ERP; 4) mathematical modeling of the scalp electrocortical field to increase the spatial resolution of the EEG signal; 5) correlation of electrocortical activity and indices of task performance; 6) preliminary testing of cognitive stimulus; and 7) pilot testing of cognitive stimulus with MS patients before and after body.
Results The following paragraphs summarize the outcome of each of these aspects: a) Cognitive tasks: A discrete visual-motor cognitive task was developed by modification of a standard cognitive protocol (Action and Crabtree, 1985; Shingledecker, 1984). During the early phase of this project (Guisado, et. al., 1988) it was found that apparent monotonic changes in the ERP voltages in the occipital region with increasing levels of task difficulty could be related to physical changes in the nature of the cognitive stimulus. During later phases of this project, the cognitive protocol was modified to correct these artifacts. Two cognitive tasks were used during this project. The first, a mental arithmetic task, was used during the development of the energy density analytical procedures. The second, a visual pattern dicrimination task consisting of red and blue triangles and squares, was used during the preliminary and pilot investigations in preparation for the multiple sclerosis cooling experiments. b) Data analysis: Time-gated EEG segments from each cognitive task were ensemble averaged to obtain cognitive ERPs. A least squares estimate of the spatial distribution of scalp voltage levels was obtained, at each digital sampling point in the ensemble-averaged ERP. The Laplacian of the voltage distribution was then obtained by using the leastsquares equation for the voltage surface. This produced a second surface that improved 9
the spatial resolution of the EEG data, by reducing spatial smearing of the signal induced by volume conduction. A further improvement in the spatial resolution of the EEG data was obtained by estimating the potential energy of the electrical field imposed upon the scalp by the cortical electropotential field. c) Correlation with performance: A procedure was developed for regressing task performance on EEG energy density. Task performance was represented by an "error rate" index which combines a subject's average reaction-time and percentage of mistakes in the responses included in the averaged cognitive ERP. Energy density was measured as an integral over a 40 msec period at a particular electrode site. A search procedure was carried out to find time windows and electrode locations for which the regression fit is optimal. It was then possible to relate performance differences (with very high statistical confidence) to differences in the energy density of the cortically- generated electrical field. At certain instants during the task and at certain cortical locations, more than 95% of the intersubject performance variation could be explained by a simple linear relationship to energy density. d) Topographic display of cognitive ERP: In the regression of performance on energy density, very good fitting results were obtained at specific cortical (scalp) and instants during the task. This suggests that these are locations where cortical activity is specifically related to task performance in the sense that effective performance is critically related to either a high or low level of cortical activity at that location at that instant during the task. The locus of this contingency relationship over the cortex during the task differs from one task to another and may provide valuable clues to the localization of cognitive function.
10
e) Preliminary testing of visual discrimination task: Twelve right-handed young men were presented a random series of equally likely red or blue triangles or squares and asked to respond upon detecting the designated target, i.e. red squares. Multichannel topographic EEG event-related potentials (ERPs) were used to estimate scalp distributions of surface energy densities of the cortically generated electrical fields. Cross-subject regression analyses were then used to map sites and post-stimulus latencies, for which there was a high correlation of energy densities with subjects’ performance. High R-square values for the regression (in excess of 0.5) were found at distinct sites and periods: 118-157 msec: left frontal lobe (planning activity), 196-235 msec: right temporal lobe (spatial analysis of stimuli).These peak correlations with performance correspond to evidence about cortical localization of neural processing derived from studies of cognitive capacities of patients suffering localized lisions which supports the general validity of the approach. This procedure revealed a strong cross subject group correlation between neural activity and target discrimination during visual monitoring. Thus it may offer an inexpensive, noninvasive tool for evaluating effects body cooling upon the cognitive processing by multiple sclerosis patients. f) Pilot testing: A case study explored the possibility that liquid cooling therapy could be used to enhance the cognitive processing of MS patients in the same way that it provides temporary relief of some physical impairment. Two MS patients were presented a series of pattern discrimination tasks before and after being cooled with a liquid cooling garment for a one hour period. The subject whose ear temperature was reduced during cooling showed greater electroencephalographic (EEG) activity and scored much better on the task after cooling. The patient whose ear temperature was unaffected by cooling 11
showed less EEG activity and degraded performance after the one hour cooling period. The results of this phase of the project demonstrated that body cooling of MS patients may enhance their cognitive processing.
In summary, changes in scalp TEEG energy density measures show cortical areas that specifically relate to performance. The TEEG energy density changes appear to reflect the degree of arousal or changes in subjects' neural state during performance of computer generated stimulus gated cognitive tasks. It is anticipated that these techniques can be used to shed light on the benefit of body cooling upon cognitive processing by individuals with multiple sclerosis. It is also anticipated that these analytical procedures can also be used to investigate other neurologic disorders. For example, we have studied a small group of subjects with dyslexia (and sex and age matched controls), using a semantic task. The major difference between normal and dyslexic subjects appear to be sequential activation of cortical areas and their relationship to cognitive performance.
12
Preface
13
1.0 Project Implementation Plan (PIP) This project implementation plan sets forth the goals, objectives, and strategy for a NASA program entitled the Multiple Sclerosis (MS) Technology Transfer Program. It defines the roles and responsibilities of various organizations and individuals who will participate in the program and the management structure and strategic approach to be used. This plan is the toplevel document for the program.
14
Table of Contents 1.1 Introduction .................................................................................................. 1.2 Goals and Objectives ................................................................................... 1.3 Strategy ........................................................................................................ 1.4 Technology Needs Assessment .................................................................... 1.5 The NASA Role ........................................................................................... 1.6 Implementation Plan .................................................................................... 1.6.1 Program and Project Management ..................................................... 1.6.2 Current MOU Tasks............................................................................... 1.6.3 Collaborative and Joint Enterprise Agreements .................... ............. 1.6.4 Reporting ............................................................................................ 1.7 Products and Deliverables ........................................................................... 1.8 Resource Requirements and Schedule..........................................................
15
1.1 Introduction It is commonly accepted that heat sensitive Multiple Sclerosis patients (HSMS) are impaired by warm environments and exercise. Typical acute physiologic, motor, and selfperceived hyperthermic stress among these HSMS include: 1) worsening of existing neurologic signs and symptoms, 2) the development of new signs and symptoms, and 3) lassitude and increased fatigue. These HSMS patients often improve after the ambient environmental temperature decreases or upon lowering of their body temperature. Anecdotal evidence suggests that artificially cooling HSMS can improve their physical strength, endurance, motor control (balance) and self-perceived energy and exertion. Several methods are currently employed in thermal conditioning and cooling of MS patients. These include hypothermic rooms, administration of ice baths, cold pool therapy, ingestion of cold fluids, and personal cooling systems. Many of the personal cooling systems currently being used by MS patients are based upon the liquid cooling garment technology developed by NASA for aerospace environments. Protective systems are required for astronauts during extravehicular activity (EVA) to shield the crewman from environmental hazards such as radiation, temperature, lack of an atmosphere, and meteorites. Usually, this personal protection is acquired by wearing a selfcontained space suit and associated life-support equipment. Because of the impermeability of these protective garments, normal body heat is retained within the space suit and as many as 500 watts of metabolic heat must be removed by an artificial cooling system. Although several means can be employed to remove excess body heat, the development of the liquid cooling garment (LCG) used in the Apollo and currently in the shuttle programs provides an adequate method of cooling astronauts enclosed in space suits. In its current configuration, many meters 16
of small diameter (2 to 3 mm.) polyethylene tubing traverse over each part of the body that is to be cooled. Chilled water is circulated through the tubing and the excess heat is thus transported by the circulating water to a sublimator or other heat exchanger. Ames Research Center has a proven history of developing advanced concepts of liquid cooling garments and human thermoregulatory systems for both industrial and biomedical applications for the past 25 years. The work has been performed within various organizations at Ames, and is now contained in the Biomedical Applications Lab of the Regenerative Life Support Branch, in collaboration with the Commercial Technology Office. Examples of this work include: - liquid cooled helmets for helicopter pilots and race car drivers, - vests for fire and mine rescue personnel, - lower body garments for young women with burning leg syndrome (erythromelalgia) and other types of peripheral neuritis, - cooling systems used by patients with Multiple Sclerosis. The benefits of the biomedical application of artificial thermoregulation received national attention through two events in recent years: 1) the liquid-cooled garment technology was inducted into United States Space Foundation’s Space Technology hall of Fame (1993), and 2) NASA signed a joint memorandum of understanding with the Multiple Sclerosis Association of America (1994) to share this technology for use with the MS community. On May 23, 1994 The National Aeronautics and Space Administration (NASA) signed a Memorandum of Understanding (MOU) with the Multiple Sclerosis Association of America (MSAA) whereby both groups would cooperate in the application and assessment of NASA’s “cool suit” technology for the benefit of multiple sclerosis patients. Since that time this program 17
has become a national focal point for many investigators involved in basic and clinical research of MS. The MOU was extended in June 1997, and Lockheed Martin became a contributing commercial partner. The work done to date, summarized in Appendix A, includes studies of the response among both healthy individuals and MS patients to head and neck cooling and a comparison of individuals’ response to different commercially available cooling systems. These data help to establish the scientific basis of cooling therapy and this understanding will in turn expand its use to more patients. This documented, scientific data is a great contribution to the MS community, and is a giant first step toward gaining an understanding of the relationship between the MS patient and their environment. The intent of the new June 1997 MOU was for the signing parties to co-fund and carry out two well-defined tasks which will be completed during FY98: one will investigate the effects of cooling therapy on cognitive function and the other will compare the effects of four commercially available cooling systems on the physical capabilities of MS patients.
1.2 Goals and Objectives The overall objective of the NASA - ARC MS Technology Transfer Program is to perform the research and development activities needed to improve and to thoroughly evaluate cooling technology and cooling therapy as a means of symptoms management for MS patients. All work performed will adhere to the intent of the Memorandum of Understanding that was signed between the National Aeronautics and Space Administration and the Multiple Sclerosis Association of America on May 23, 1994, and extended on June 17, 1997. The resources
18
necessary to implement this program will be provided as a result of a the renewal of the original MOU between NASA and MSAA. Specific project goals include: • Development of an improved, prototype personal cooling system for use by MS patients. • Scientific evaluation of this new cooling system for MS patients, including comparison with currently available systems in both acute and chronic modes of therapy • More detailed definition of the basal thermal state of MS patients. • Continued consultation and collaborative support to the MS research community. • Publication of scientific results in appropriate medical literature. • Facilitation of the transfer of the new cooling system technology to industry to better meet
the needs of MS patients.
1.3 Strategy Implementation of this program will require a collaborative effort involving several government agencies, commercial companies, private and government medical institutions, nonprofit foundations, and universities. All phases of the program will require support, both financial and technical. These relationships will be formalized as appropriate by further Memoranda of Understanding or other such documents which will outline the respective responsibilities and contributions of the participants. Joint Enterprise, Space Act or other type of agreements as appropriate, will also be negotiated with other commercial partners. These will similarly define the respective roles and contributions of the partners. These documents are also 19
necessary to enable the loan of equipment and transfer of resources required to implement the program and to allow transfer of technology while still protecting all parties’ interests. The Commercial Technology Office, in collaboration with the Regenerative Life Support Branch, has initiated a program that will: • seek out institutions/investigators who are potential collaborators in our efforts to achieve the goals defined above, and/or users of the identified technology • define specific applications based upon user needs • collaborate with outside institutions/investigators to develop and test applications • provide a basis of continued technical assistance in further developments • facilitate transfer of technology between developers, users, industry, and other researchers
1.4 Technology Needs Assessment Members of the Biomedical Applications Laboratory have placed particular emphasis upon assessing the technology needs of the MS patient, clinical, and research communities. Our approach has been to make all of the components of the NASA/MS Technology Transfer Program including our facilities, equipment, and expertise available to all relevant MS research and patient advocacy groups. These include, as appropriate, organizations such as the National Multiple Sclerosis Society, the Consortium of MS Centers, and other attendees at the initial program definition workshop in January 1995. Whenever possible Biomedical Applications staff members or support personnel have visited regional MS centers, private MS physicians, MS research investigators, and MS patients to introduce our program and solicit joint cooperation. In all cases we have emphasized the joint nature of the program between NASA and the potential 20
user. We have continually sought advice concerning the biomedical or clinical elements of the program from appropriate experts. The following steps were taken during the initiation of our current program to ensure adequate participation by medical, industrial, and government groups in the assessment of the technology needs of this program: • Introduction of the program to the NASA EVA community (government, academic, industry) at an EVA Working Group meeting at Massachusetts Institute of Technology and to the MS community at the Annual Meeting of the Consortium
of Multiple Sclerosis Research Centers. (September 1994)
• Initiated program through site visits, conference attendance, and regional group discussions at universities and MS clinics in MN, MA, CO, WA, OH, CA, IN
and Washington, D.C. These discussions led to the idea and
format of an MS
workshop. (Fall 1994)
• Sponsored invited workshop at NASA Ames Research Center (January 1995). This workshop was attended by approximately 30 physicians, rehabilitation therapists, and MS researchers and 15 members of the industrial community. Representatives from the Multiple Sclerosis Association of America, the National Multiple Sclerosis Society, and The Consortium of Multiple Sclerosis Centers all agreed to work together to scientifically establish the efficacy of “NASA cool suit” technology for use in therapeutic management of MS patients. Attendees at the workshop helped to define NASA’s role in the program. They also identified the technology needs of the MS researcher, MS clinic, MS patient, as well as the
21
desired technological improvements to the currently available commercial cooling systems. In the ensuing years, we continued our collaborative efforts. We have presented research at annual professional meetings and held working groups/symposiums during the meetings, including the Consortium of Multiple Sclerosis Centers Workshop. Extensive research was performed or is planned at MS Clinics in Colorado, Arkansas, and Arizona. Additionally, we facilitated the donation of four Neslab Cooling Units from Kaiser Electronics in San Jose to the MSAA. NASA Ames staff subsequently modified those units in order for each to accommodate simultaneous cooling of up to six patients. These systems were then placed by MSAA in cooling therapy clinics in Washington, D.C. (Wadsworth VA Hospital), Denver (ADEP), and Arkansas (INN Research). The fourth cooling therapy clinic (location TBD in conjunction with MSAA) will be established during FY98.
1.5 The NASA Role NASA has many years of experience in developing protective equipment and complete work systems to enable humans to live and work in the hostile environment of outer space. NASA also has highly relevant experience in developing the technology required to provide thermoregulation garments for biomedical applications. Part of this experience includes a systems engineering approach to problem solving. This includes mandatory steps such as requirements definition based on user needs, objective studies of alternative system designs that meet the requirements, development of the required subsystems and components necessary to assemble the complete system, and testing, evaluation, and documentation of the final product. This methodical approach will be a key element in the 22
development of improved personal thermoregulatory systems for multiple sclerosis patients and MS research investigations. As a result, NASA has developed unique capabilities to respond to the technical requirements of the medical and clinical communities. The Biomedical Applications Lab of the Regenerative Life Support Branch at NASA Ames Research Center has a long history of working with physicians, commercial firms, and medical researchers to develop unique thermoregulatory systems for industrial and biomedical applications. As a result of this experience, the Biomedical Applications Lab staff is uniquely qualified to lead the effort to develop and prove the technology required to provide the advanced cooling systems and to conduct the research required for this program. The most appropriate roles for NASA to play in collaboration with the MS community were originally defined at the MS Workshop held at NASA Ames Research Center, January 1995 which was attended by approximately 30 physicians, rehabilitation therapists, and MS researchers and 15 members of the industrial community. It was determined that NASA had unique expertise, facilities, and equipment as defined above. These could best be utilized if NASA functioned as an objective organization that collaborated with but remained separate from the permanent MS community and its internal political and personality issues. To the best of our ability, we have attempted to function as objective researchers, facilitators, and consultants to all interested parties regardless of their organizational affiliation. We agreed to perform specific tasks in the following areas: • Assist in the preparation of cooling therapy evaluation protocols and consultation on the r
esulting clinical trials.
23
• Conduct thermal physiological studies to quantify the performance of currently available personal cooling systems used by MS patients. • Collaborate with MS research organizations to apply NASA expertise to quantify the improvements in cognitive performance that result from cooling MS patients. • Work with commercial companies producing cooling system for MS patients to help transfer
applicable NASA technology
We also agreed that all of the physiological, technological, and other data that resulted from our efforts would be published in the open literature and made available to all interested parties.
1.6 Implementation Plan 1.6.1 Program and Project Management Overall program management of the Multiple Sclerosis Technology Transfer Program will be performed by NASA’s Commercial Technology Division (NASA HQ Code RW) in the Office of Aeronautics and Space Transportation Technology. The Code RW Division Director will be responsible for advocating and supporting the program at NASA HQ, and serving as the program interface and representative to other government agencies in Washington, D.C. Funding will be provided to Ames Research Center (ARC), which will be responsible for the actual project level implementation. The project will be administratively managed by the ARC Commercial Technology Office (ARC Code DK). The Chief of Code DK will be responsible for overall strategic guidance of the project as well as serving as principal investigator. He will work with both NASA HQ and the staff of the Regenerative Life Support Branch (ARC Code STR) to ensure the 24
successful delivery of the products. Day to day management and task implementation will be performed by the STR Branch Chief and the staff of the Biomedical Applications Laboratory. The Principal Investigator, currently serving as the Chief of Code DK, will have overall responsibility for the project implementation. This includes overall resource management, coordination with HQ, working with other ARC organizations and outside agencies to secure and manage the overall resources, and setting internal staff priorities as necessary to ensure that the project is completed successfully. The Principal Investigator in collaboration with the STR Branch Chief, will appoint a Project Manager from the STR staff who will have direct responsibility for accomplishing the technical tasks within the project. The MS Technology Transfer Project Manager’s responsibilities include: - Producing a detailed management plan for the implementation of the project - Defining and directing technical staff and tasks - Performing engineering and scientific tasks as required - Establishing resource requirements and working with the Principle Investigator to secure staff and other ARC resources - Preparing and presenting project reports and briefings as required - Coordinating external communications and commitments with ARC management - Working with outside agencies to secure and coordinate resources - Managing allocated R&D funds.
1.6.2 Current MOU Tasks 25
Two technical tasks and NASA/Program outreach activities will be conducted under the current MOU. Technical Tasks. Task 1 • We will conduct a joint collaborative study entitled, “ Physiologic Responses of Multiple Sclerosis (MS) Patients to Body Cooling Using Commercially Available Cooling Garments”. This study will compare four cooling vest systems using both healthy male and female subjects, and male and female subjects with MS. We will assess the cooling capability of each system as they may be used by MS patients. This work is Task 1 under the 1997 MOU between NASA Ames, Lockheed-Martin, and the MSAA. This study will be conducted between November 1997 and June 1998. Collaborating medical institutions include the Institute for Neuroscience and Neurological Research (INNR) of Hot Springs, Arkansas; the Rocky Mountain MS Clinic in Denver, Colorado; and the Mayo Clinic in Scottsdale, Arizona. We anticipate providing support to our collaborators as appropriate and necessary to complete the research. We plan to present the results of this study at the 1998 Annual Meeting of the MS Research Consortium. Task 2 • We will conduct a joint collaborative study entitled, “Evaluation of Lowering Body Temperature to Facilitate Neurocognitive Function in People with Multiple Sclerosis” to determine whether cooling of MS patients will improve their cognitive abilities in the same way that it has been used to improve their physical abilities. This work is Task 2 of the 1997 MOU. The data acquisition phase of this study will be conducted between January 1998 and June 1998. As with Task 1 above, we anticipate providing support to our collaborators as appropriate and necessary to complete the research. We also plan to present the results of this study at the 1998 Annual Meeting of the MS Research Consortium. 26
Outreach Activities. We will also continue to support the research activities, exhibits, and committee meetings of the MS community as appropriate during FY98. We will modify the fourth Neslab cooling unit and provide it to an MS Clinic to promote cooling therapy in another large, localized population of MS patients. We will leverage travel and products that are costed under the above-listed plan elements to accomplish this.
1.6.3 Collaborative and Joint Enterprise Agreements Successful implementation of this plan will require the support and participation of a number of medical institutions, MS foundations, industrial companies and government agencies. This support and participation must be formalized via one of the following mechanisms before actual collaboration or transfer of resources can begin: Memorandum of Understanding - These will be used to define and formalize the roles and responsibilities of participating government agencies. Joint Enterprise/Space Act Agreements - These will be used to formalize agreements between NASA and potential industrial partners where both parties agree to provide resources and share the results. Contracts - Standard R&D and purchase contracts will be used as appropriate The following list of agencies, organizations, and companies have assisted with formulating this program and have become formal partners in its implementation: - NASA/MSAA Memorandum of Understanding (MOU) - NASA/CMSC Memorandum of Understanding (MOU) - NASA/Wadsworth VA Hospital Memorandum of Understanding (MOU) - NASA research contract with Brigham Young University 27
- NASA purchase contracts for cooling systems (Life Enhancement Tech., LLC., Redwood City, CA; MicroClimate Systems, Inc., Sanford, MI; Oceaneering Space Systems, Houston, TX) and physiological monitoring equipment (UFI,
Morro Bay ,CA)
1.6.4 Reporting NASA - Ames Research Center will be responsible for organizing and implementing an annual project review process. This review process will include participation by the ARC project staff and line management, NASA HQ management, management and technical staff from other involved and interested government agencies, as well as the industrial, clinical, and other partners. The purpose of this review will be to report and demonstrate technical progress, refine upcoming resource requirements and identify problem areas and most importantly to provide assurance that the ultimate user needs are going to be met. Internal (NASA and Lockheed Martin) project reviews and other interim reports and briefings will be provided as required. Project personnel will participate in periodic meetings, conferences, site visits, or collaborative work sessions as appropriate and required to ensure full and successful implementation and completion of project goals. Regenerative Life Support Branch personnel will be responsible for preparing, submitting, and presenting MS Technology Transfer Program research results at scientific meetings and in the open, peer-reviewed literature.
1.7 Products and Deliverables
28
Products and deliverables of the Multiple Sclerosis Technology Transfer Program to be completed during this project will include: - Design and evaluation test data for an improved, more affordable liquid cooling system (new garment and heat sink) for MS patients - Database of both chronic as well as acute physiological MS patient responses to cooling therapy - Database of basal thermal state of MS patients in a sedentary state - Presentation of research results at appropriate scientific meetings. - Publication of research activities and results in peer reviewed medical literature. - Participation in professional activities of partner organizations, i.e. committee meetings, professional exhibits, conferences, and workshops. - Support of popular press and media as appropriate to implement program outreach goals.
1.8 Resource Requirements and Schedule The financial and staff resources required to perform this program and meet the delivery schedules presented in this plan are shown in the following tables and figures. Table 1 - Staff Resource Requirements MS Technology Transfer Program Labor Type
FY98
FY99
CS
1.0
1.5
SSC
0.25
2.5
29
Figure 1 - Project Task Phasing 1998 ID
MS Technology Program
1
1. MS Working Group
Duration
347d
2
1998 M eeting
86d
3
1999 M eeting
86d
4
2. MS Chronic S tudy
195d
5
3. Advanced Concept Feas. S tudy
107d
6
4. Enhanced Heat S ink
131d
7
5. New Garment Development
87d
8
6. New Garment Eval. (Acute)
86d
9
7. New Garment Eval. (Chronic)
195d
10
8. Alternate Therapies
456d
11
9. Basal Thermal S tudy
456d
12
10. Outreach Activities
456d
30
Qtr 1
1999 Qtr 2
Qtr 3
Qtr 4
Qtr 1
Qtr 2
Qtr 3
Qtr 4
2.0 Review of the Literature: Evolution of the Systemic View of the Brain
Preface to this section
31
Table of Contents 2.1 Introduction....................................................................................................... 2.2 Historical View of the Brain................................................................................ 2.3 Development View of the Brain.......................................................................... 2.4 Systemic View of the Brain................................................................................. 2.5 Electrophysiologic View of the Brain................................................................... 2.6 Three Dimensional View of the Brain.................................................................. 2.7 References.........................................................................................................
32
2.1 Introduction: For hundreds of years man has sought to characterize the structural and functional attributes of his brain. The evolution of this quest has, for the most part, paralleled the emergence of modern system’s engineering and the system’s perspective of thinking. Initial endeavors were largely observational and empirical in nature, striving for insight into the basic elements of thought and cognition. Ongoing efforts were dependent upon the level of sophistication of the technology available to the researcher. As new tools were developed investigations became more rigorous, using scientific procedures. Emphasis based upon cause and effect of specific areas of the brain gave way to definition of interactive and associative components of thought. Research objectives became more “macro”, viewing larger areas of the brain as being involved in parallel and series propagation of thought patterns. The recent advent of radioisotopes, large volume scanning instruments, and high speed computers has greatly accelerated brain research. Modern scientists are finding that no one specific area of the brain is solely responsible for a given task. Diffuse areas of the cerebral cortex act in concert to process each thought. Today’s view of the brain is truly global, the whole must be considered even when seeking understanding of its most fundamental building blocks. In this paper I hope to provide examples of the evolution of systems thinking as it was used in brain research. I will show how technological development brought about the more global view of the brain. I will also show how interdisciplinary team based investigations can facilitate current cognitive research.
33
2.2 Historical View of the Brain: The anonymous fifteenth-century drawing shown in Figure 1 illustrates pre-Cartesian brain theories, which followed the views of Aristotle. The senses of touch and taste are shown connected to the heart, while boxes on the head depict specific areas or “cerebral cells” where mental faculties such as memory and fantasy were thought to be located.
Figure 1. Pre-Cartesian View of the Brain
34
The seventeenth-century French philosopher Rene Descartes (Posner and Raichle, 1994) is considered by many to be the father of modern neuroscience. He was among the first investigators to picture the common reflex of withdrawing a limb from a hot fire as a physical neural circuit, a view that had been common since the ancient Greek physicians. Descartes’s model of reflexive behavior in the human being is given in Figure 2. The message from the sensory nerve receptors reaches the spinal cord at IV, where it is transmitted to the muscle nerve (V) leading back to the foot. The message from the sensory receptors continues along a nerve to the brain, which enables us to consciously perceive the heat.
Figure 2. Descartes’s Model of the Brain
35
Descartes’s clear separation of the world into the mental and the physical became known as Cartesian dualism, a view that has dominated brain research ever since. With the advent of serious brain research about 150 years ago, scientists began to develop new theories of how the brain and cognitive processing are related. These theories broke away from Cartesian dualism by suggesting how conscious thought and feelings might be produced by basic biological mechanisms. At the turn of the century students of phrenology attempted to correlate prominent landmarks of the skull and even the face with psychological processes. Phrenologists proposed specific areas of the brain for complex tasks such as processing language, forming mental images, or reasoning and for individual traits such as authority and wisdom. This pseudoscience was originated in the late 18th century by a German anatomist and physician, Franz Joseph Gall (1758 - 1828). Gall (Posner and Raichle, 1994) made the astute assumption that particular brain regions are associated with particular parts of the body. However, he incorrectly assumed that abstract qualities such as integrity or depravity were similarly localized and that they were associated with the bumps and ridges of the skull. Although this notion was rejected by many scientists of that time, phrenology did not, in fact, die out until the early part of the 20th century. Phrenology was based not only on an idea about cognition, but also on one of the brain: that similar types of computation are performed in the brain in contiguous locations. This basic notion did find confirmation in 1863 when I. M. Sechenov introduced the nature of electrical activity in the brain by publishing his book, “Reflexes of the Brain.” This work founded the Russian school of reflex brain conduction that eventually led to Pavlov’s famous work on the modification of reflex activity by learning.
36
By 1906, understanding of the reflex arc had progressed so that the British physiologist Charles Sherrington (Posner and Raichle, 1994) could use the concept in a more sophisticated way. Whereas Sechenov thought of the reflex as a simple physical circuit, Sherrington did not think such simple circuits could be isolated from the brain’s complex mesh of interconnected neurons. Instead, reflexes were far more elaborate in design. Sherrington viewed the reflex as a convenient tool for the analysis of both physical and mental processes. The ability to record the activity of individual cells in the brain of awake animals has led to an enormous expansion of our knowledge of the structure of sensory and motor systems. Sensory receptors from each part of the body project to a specific area of the cortex (the somatic sensory cortex), and, similarly, a specific area of the cortex (the motor cortex) controls the movement of each body part. Thus the cortex forms a map (Thompson, 1967) of the body surface, represented by the misshapen body parts in Figure 3. They are distorted because the area of the cortex devoted to a body part is proportional not to the size of the part but to the precision with which it is sensed or controlled. These cortical maps of functional projection areas are further organized in a hierarchical manner. Each map corresponds to a distinct area of the brain responsible for carrying out a particular type of analysis of the sensory information sent to the brain. For example, our recognition of a particular visual pattern appears to involve a set of areas that go from the primary visual area in the back of the
37
Figure 3. Early Map of the Somatic Sensory Cortex brain out into the temporal lobes in the lower middle of the brain. This set of areas has been called the “what” pathway. Within the “what” pathway there exists regions that are specialized to recognize such attributes as shape, color, and speed of movement. On the other hand, information about where an object resides in our visual environment seems to concern areas that, again, go from the primary visual area, but then ascend into the parietal lobes in the upper middle of the brain. This set of areas is referred to as the “where” pathway because it is concerned with the location of an object in the visual world.
38
As shown in Figure 4, the “what” and “where” pathways in the visual system include areas specialized for processing depth perception (symbolized by a pair of spectacles), form (an angle), color, and direction (the curve ahead sign). The result is object recognition (the “what” pathway) or object location (the “where” pathway).
Figure 4. Neural Pathways of the Brain Which Process Visual Images
2.3 Developmental View of the Brain The development of specific cognitive pathways as one matures has been the focus of intense study. This relationship was best explained in terms the stages of cognitive growth by the Swiss psychologist Jean Piaget (1971). Piaget demonstrated that mental development of young children proceeds through distinct stages. Children from widely different cultures pass through each of these stages at about the same mental age. The first stage is that of sensory-motor learning. While still in the crib, at 39
first through such simple acts as tugging on a blanket or pull-toy, infants begin to discover which aspects of their environment are preserved in spite of transformations they impose upon that environment. For instance, at a certain age, a child comes to realize that a doll is ‘still there’ (has not ceased to exist) even though the doll may be placed out of sight behind a pillow. Early discovery of such seemingly obvious ‘invariance’ (relationships that do not change in spite of transformations) is vital to adaptation, for this is the way we learn what aspects of our environment can and cannot be manipulated. Thus, even as infants, we begin to focus our attention upon the regularities from which we construct our ‘objective’ (manipulable) world. Young children are apparently incapable of perceiving many invariant features of the environment that adults take for granted, however. Until the age of approximately seven, children almost universally fail to appreciate, for example, the conservation of fluid volume. When their orange juice or soft drink is poured, in full view, from a tall, slender glass to one with a much wider diameter, most young children will insist that part of the fluid has mysteriously disappeared. By use of conservation experiments such as this, Piaget found that a mental age of approximately seven marks a distinct transition to a new stage of mental development. At about this age, children acquire an ability to anticipate the outcome. Evidently they can manipulate mental images of invariant relationships. Piaget called this the stage of ‘concrete operations’, since children are still not able, at this stage, to mentally manipulate relationships that are not clothed in some concrete representation. They still have great difficulty with problems involving formal logic. For example, they cannot offer consistently correct answers to problems involving transitivity relationships of the sort, "If A is larger than B, and B is larger than C, which is larger, A or C?" 40
By a mental age of approximately eleven, most children reach the stage of ‘formal operations.’ At this age they are able to abstract invariant relationships from a concrete setting. They can anticipate, through formal reasoning, the results of performing transformations on transformations. They can anticipate the answers to such problems as, “If A operates on relationships in one particular way, and if B represents a different operation, what is the result of the combination of both operations?" This is the phase of cognitive development that is further stimulated, of course, through study of geometry and laboratory science in secondary school. Study of the development of the brain mechanisms in children seems to reveal a complex picture where asymmetries between different zones of the two hemispheres may occur at different age periods. These differences seem to be closely connected to speech functions of the child: the familiarity - unfamiliarity of a certain stimulus word is found to be an essential variable in these asymmetries. The general conceptual framework of our understanding of the development of neural function with age and the role of hemispheric interaction may be over simplistic. What can be said is that most cognitive processing is highly dependent upon interconnectivity between the right and left sides of the brain.
2.4 Systemic View of the Brain: During the 1950s Russian neuropsychologists and neurophysiologists began to look at the functioning brain as a complex system of interdependent subsystems. This general, holistic systems-theory approach or perspective has greatly influenced their investigation of cortical location of cognitive function. According to this systems-theory view, the brain is organized as a complex functional system uniting different levels and different areas within a level of the brain to processes information. 41
The identification of different parts of the brain in the global system which carry out certain functions can be characterized using two different approaches: observation of cognitive deficits exhibited by people with brain injuries or by measuring the spatial synchronization of brain biopotentials in these different centers during cognitive processing. Both approaches stress that the functional objective of the brain is to act as a global system which integrates incoming information and develops operational options which increases the adaptability of the organism to its environment. The first approach, studying the brain via lesion studies, was originated by a Russian psychologist, Aleksandr Luria and his associates (Luria, 1966), who attempted to correlate the location of brain damage suffered by soldiers during the First World War with deficits in their cognitive performance. Lauria was able to identify smaller areas of cortical neural activity that were responsible for conducting subtasks of mental arithmetic. These areas included cortical locations in both the right and left hemispheres (Witelson, 1983) as well as anterior and posterior lobes of the cerebral cortex. He was also able to define the short term temporal sequence (300 500 msec.) of activation of these locations that, when integrated, were used for arithmatic processing. This sequence is graphically portrayed in Figure 5, where circles have been superimposed over a stylized outline of the brain to show the sites of highest neural activation during mental arithmetic. Figure 5 reveals four regions of sustained activity: Site A: An early period of activity in the left temporal-parietal region which Lauria identified as a preparatory response for arithmetic, Site B: The second period of high neural activity that takes place within approximately 120 - 150 msec. following problem presentation 42
occurs in the frontal lobes and are involved in “planning” activity, whenever individuals are presented “complex” mental arithmetic problems, i.e. those involving carrying or borrowing, Site C: The third peak activity occurs in the right temporal-parietal region from 180-250 msec. after presentation of the problem. Lauria thought that this is a manifestation of spatial analysis of the equations and grouping of terms. His theory was based on the plausibility that this period follows that of primary visual processing, and the general view that the right hemisphere resources have a major role in spatial analysis, Site D: Finally, the area of high cortical activity during mental arithmetic performance returns to the left temporal-parietal region that Lauria considered to be a “calculation center.” This occurs approximately 250 400 msec. after problem presentation.
It is important to emphasize that Lauria’s objective was to identify only those areas of the brain that were directly responsible for cognitive processing of the presented arithmetic problems. This would inherently omit those cortical sites where all individuals (regardless of performance) would experience a light level of activation. This is why Figure 5 does not show, for example, the high levels of cortical
Figure 5. Lauria’s Activation Centers for Processing Mental Arithmetic
43
activation known to be mandated in the occipital cortex during primary processing of a visual stimulus. Though such events are clearly critical to performance, they may not necessarily determine a person’s ultimate success is solving a problem correctly.
2.5 Electrophysiologic View of the Brain: The second approach, measuring the spatial synchronization of brain biopotentials, was made possible by the development of electroencepalography (EEG). EEG enabled researchers to study of higher cognitive processing and the cortical location and interconnecting pathways of specific neural activities related to specific tasks. In its early stages, EEG research had to rely upon electrophysiologic recordings made from only a few electrodes at a time. Oscillations observed in those recordings naturally attracted attention and thus influenced the generation of hypotheses about underlying cortical processes. Richard Caton, in 1876, was the first to discover that a fluctuating current could be 44
observed flowing between two electrodes placed on the skull of an animal. In 1929 Hans Berger showed that a similar fluctuating current could, with sufficient amplification, be detected by means of electrodes placed on the human scalp. Ever since that time, one of the chief goals of EEG research has been to explain the oscillatory patterns in terms of underlying cortical activity. The rapidity of the oscillation is often regarded as synonymous with “cortical activity.” At first it was assumed that EEG oscillations reflect axonal discharges, although it was difficult to reconcile the relatively slow waves of the EEG with the practically instantaneous nature of the axonal spike discharge. One proposal was that the slow (EEG) wave was an envelope produced by a large volley of slightly unsynchronized spikes (Gevins, 1983). Later, when it was discovered that a nerve cell dendrites may accumulate post-synaptic potential in a graded manner, this became the preferred basis for interpreting the EEG record, especially when combined with empirical evidence of ionic currents induced in extracellular fluids by dendritic graded potentials. Afferent stimulation of cortical pyramidal cells offered another plausible explanation. These cells have their extensive dendritic mass close to, and in the plane of, the cortical surface, yet their major axes are oriented normal to the cortical surface. Therefore, extracellular ionic gradients between soma and dendrites of cortical pyramidal cells might, if massively synchronized, create localized sheets of dipoles oriented normal to the scalp. Whatever the source of the electrical forces sensed by EEG, the attention of EEG researchers was strongly attracted to the rythmicity of the fluctuations: the fact that these fluctuations often remain within a narrow frequency range for several seconds or even minutes. Neurologists found correlations of EEG frequency with clinical symptoms. For example, hepatic coma was often found to be associated with high voltage slow “delta” waves (0.5 to 1 Hz).
45
Psychologist widely studied the “alpha” waves (8 - 13 Hz), which dominate the EEG pattern during a restful awake state but which are quickly disrupted by attention. By the late 1940’s, interest in EEG frequency led to the use of Fourier frequency analysis to quantify “bandpower” spectra of EEG records. This development was made possible by the growth of communications theory during World War II. It was pioneered by Grey Walter at Bandon Laboratories in England during the same period that Radar was being developed, using the same techniques. Today, spectral analysis is routinely implemented in many fields of engineering, using the Fast Fourier Transform (FFT) on small digital computers. So it was inevitable that the FFT and other digital signal processing (DSP) techniques, such as recursive filtering of digitized data, would be imported into EEG. Software packages are available now which, for example, produce a computer display of a diagram of the head, color coded to indicate which frequencies dominate various areas of the scalp during a selected EEG recording period. Another EEG procedure that is used to define regions of the brain that are involved in specific mental processing is the study of cognitive event related potentials (Kramer, 1983), ERPs. This is the analysis of the average of a large number of response EEG recordings, each of which contain a timing spike showing the instant of presentation of an experimental stimulus. The spike allows the whole “ensemble” to be precisely overlaid and averaged. The object of doing this is to average-out chance variations, “noise”, and thereby reveal underlying stable patterns which may characterize an individual’s neurophysiological or neuropsychological response to a particular stimulus. Although typically there is considerable inter-trial variance among an individual’s EEG responses, their ensemble average does often reveal a stable response pattern. 46
This technique is used clinically with simple stimuli, such as clicks, tones, and light flashes, to evaluate the integrity of neural pathways for sensory input. In this mode it is usually called “evoked potential analysis”. But increasingly the technique is being expanded to analysis of human responses to cognitive tasks, where it is more often called analysis of “Event Related Potentials”. Recording ERPs from the scalp of humans is one method for obtaining detailed information about the duration and sequence of activity. However, recordings taken from the surface of the scalp are unable to isolate the precise location of the electrical generators - the multiple cell assemblies located in different parts of the brain, and in particular deep within the cortical tissue. In addition, the details of ERP recordings are very specific to each individual’s thought pattern. ERPs recorded from several different subjects using the same cognitive stimulus will show generally the same pattern. However, the latency and amplitude characteristics of the recorded peaks and valleys will vary from one subject to another. This makes cross subject comparisons and combination of ERPs from multiple subjects difficult. Still, event related potentials have been quite helpful in linking mental operations to various cortical subsystems.
2.6 Three Dimensional View of the Brain: Three dimensional functional maps can be obtained using radioisotope based scanning techniques such as positron emission tomography (PET) and nuclear magnetic resonance imaging (MRI). Both of these procedures are based upon the x-ray computed tomography technology that was first introduced in the early 1970s. 47
PET scans employ the injection of a positron emitting radioisotope into the body. The positrons then emit gamma radiation, which can be sensed by detectors outside the body segment under study. MRI exploits the fact that many atoms in the presence of a magnetic field behave like little bar magnets or compass needles. By manipulating the atoms in a magnetic field, scientists, can line up the atoms just as the needle of a compass lines up in the earth’s magnetic field. When radio-wave pulses are applied to a segment of the body whose atoms have been so aligned, the tissue will emit detectable radio signals that are characteristic of the physiologic processes taking place in the segment. What was really unique in the development of both PET and MRI was the employment of clever computing and mathematical techniques to process the vast amount of information to create actual images from the recorded data. Without powerful computers the task would have been impossible. PET and MRI both can be used to produce colored functional maps of cerebral activity. The use of different isotopes with PET or different magnetic fields with MRI allows the researcher to investigate different functional aspects and locations that the brain uses to process information. By subtracting PET or MRI images obtained before and after completion of a cognitive task it is possible to determine how the brain mobilizes its resources to accomplish the task. Figure 6 gives one example of how differential PET images are used to show how a group of individual subjects respond to a visual stimulus. In the upper row of these PET scans, the control condition (in this case resting while looking at a static fixation point) is subtracted from the experimental condition of looking at a flickering checkerboard positioned 5.5 degrees 48
from the fixation point. The subtraction produces a somewhat different image for each of the five subjects, as shown in the middle row. The individual images can then be averaged to eliminate noise, producing the grouped mean response image at the bottom. Images such as the one shown in Figure 6 can be obtained at different levels (slices) through the brain. They are providing new insight into the functional subsystems deep within the brain, knowledge that previously could only be inferred from postmortem autopsy of brain injured patients.
Figure 6. Differential PET Images of Visual Image Processing
2.7 Summary - Future Views of the Brain:
49
Recent technological developments have made it possible to combine the temporal resolution of EEG and ERP procedures with the spatial resolution available from PET and MRI images. The combination of the anatomical data from PET and the time course data from ERPs has greatly enhanced our knowledge of how the mental processing of arithmatic, verbal and other cognitive processing is organized. Understanding both the anatomy and the time course of activation amounts to knowing the general circuitry of a cognitive process. Although the study of the cortical location and temporal sequence relationships in humans will clearly depend upon the joint application of both brain-imaging techniques like MRI and PET in conjunction with electrical techniques, our ultimate understanding of the relationship will require the integration of information from all levels of inquiry. Scientists will have to join together, to form interdisciplinary teams, to undertake the cognitive research of the future. As our perspective of the functional brain has become more systemic we have realized that all systems of the body; i.e. neural, circulatory, and chemical; all act in concert to process or interpret our sensory information. It is becoming ever more difficult for a single individual or discipline to effectively study the workings of our brains. Cognitive research teams are also starting to include chemists, mathematicians, engineers, and other areas of science that have previously been considered far removed from this field of investigation. Examples of this “shared interest” include Talbot’s (1991) view of the brain as a holographic processor, the use of chaos theory (Gleick, 1987) to explain the complex electromagnetic phenomenology and seemingly continuous instability of the brain, or the use of econometric regression theory to model the electrical activity of the brain (Montgomery, Montgomery, and Guisado, 1992, 1995).
50
2.8 References: Gevins AS. “Brain potential (BP) evidence for lateralization of higher cognitive functions.” In: Cerebral hemisphere asymmetry: Method, theory, and application. JB Hellige (Ed.), Praeger Publishers, 1983. Gleick J. Chaos: Making a new science. Viking Penguin Inc., New York, 1987. Kramer AF. “Event related potentials.” In: Psychophysiology and the electronic workplace. A Gale, B Christie (Eds.), John Wiley and Sons, New York, 1983. Luria AR. Higher cortical functions in man. Basic Books, Inc., New York, 1966. Montgomery LD, Gleason CR. Simultaneous use of rheoencephaolograpy and electroencephalography for the monitoring of cerebral function. Aviation, Space, and Environmental Medicine, 63:314-321, 1992. Montgomery LD, Montgomery RW, Guisado R. Rheoencephalographic and electroencephalographic measures of cognitive workload: Analytical procedures. Biological Psychology, 40:143-159, 1995. Piaget J. Biology and knowledge: An essay on the relations between organic regulations and cognitive processes. University of Chicago Press, Chicago, 1971. Posner MI, Raichle ME. Images of the mind. Scientific American Library, New York, 1994. Talbot M. The holographic universe. Harper Collins Publishers, New York, 1991. Thompson RF. Foundations of physiological psychology. Harper & Row, Publishers, Yew York, 1967.
51
Witelson SF. “Bumps of the brain: Right-left anatomic asymmetry as a key to functional lateralization.” In: Language functions and brain organization. SJ Segalowitz (Ed.), Academic Press, New York, 1983.
52
3.0 Methods: Derivation of Energy Density Analytical Procedures for Topographic Electroencephalography
Preface to this section
53
Table of Contents 3.1 Introduction 3.2 Methods 3.2.1 Mental Arithmetic Task 3.2.2 Data Recording 3.2.3 Locus of Performanc-Related Activation 3.2.4 Locus of Peak Activation 3.3 Results 3.3.1 Performance-Related Activation 3.3.2 Peaks of Activation 3.4 Discussion 3.4.1 Expectational Priming 3.4.2 Need for Methodological Clarification 3.4.3 EEG Recording Limitations 3.5 Conclusion 3.6 Appendix 3.7 Bibliography
54
3.1 Introduction This chapter demonstrates a method of mapping cortical localization of cognitive function, using topographic electroencephalographic (EEG) data. It emphasizes two methodological innovations: The first is the use of cross-subject regression analyses to identify cortical sites and post-stimulus latencies for which there is a high correlation between subjects' peformance and their cognitive event-related potential (ERP) amplitude. The second (described in the appendix) is a mathematical treatment of the ERPs which enhances their spatial resolution. The procedure was tested using a mental arithmetic task and was found to identify essentially the same cortical regions that have been associated with such tasks on the basis of research with patients suffering localized cortical lesions. Thus, it appears to offer an inexpensive, non-invasive tool for exploring the dynamics of localization in neurologically normal subjects. Cognitive event-related potentials (ERPs) are recurring patterns of cortical electrical activity elicited by discrete problem-solving tasks. They are detected in scalp-recorded EEG waveforms by averaging a large number of stimulus-gated records. Galambus and Hillyard (1981) review recent efforts to interpret cognitive ERPs. The use of averaging to raise the signal-to-noise ratio was introduced by G.D.Dawson, (1947); its least-squares statistical properties are described in Thompson & Patterson, (1947); and a valuable discussion of underlying stationarity assumptions is found in Turetsky, et al.(1989). Though usually shown as an average of traces recorded at a particular electrode site, the ERP actually involves the whole scalp electrical field. A picture of the whole field at each instant (voltage as a function of scalp location) can be reconstructed from multielectrode data by least- squares or interpolation techniques. The result can be displayed as a contour map or as a 55
wire-frame figure, and a series of such surfaces will show the evolution of the shape of the field over the period of the ERP. These spatial-ERPs may be used to discern the path of localized cortical activity related to a cognitive stimulus. However, localization research currently employs two different definitions of localized cortical activity. PET and rCBF approaches regard cortical regions as specialized for certain cognitive tasks if evidence of elevated metabolism (compared to control) is detected in those regions after subjects have performed a given task (such as listening to a story). These approaches typically emphasize the effects, for individual subjects, of experimental variation of the task rather than differences in cortical activation that are correlated with performance for a fixed task. In contrast, inferences drawn from cognitive deficit syndromes of patients suffering localized cortical lesions obviously depend upon clinical correlations of lesion sites with performance. To the extent that EEG has in the past been used to infer sites of cortical localization of cognitive function, the approach has been similar to that of PET and rCBF. Whether involving frequency analysis of continuous EEG or peak-and- latency analysis of ERPs, the experimental paradigm typically emphasizes inter-task comparisons rather than differences correlated with performance. (Gevins, 1983, is a critique of several of the best of these studies.) Magnetoencephalographic (MEG) approaches are similar in that they infer sites of localized cortical activity on the basis of changes in the magnetic field elicited by changes in the task -- rather than on the basis of covariation with performance. Our EEG methodology takes the opposite approach. It compares several subjects' spatial ERPs for a given task with differences in their performance. This approach is analogous to that of lesion studies, except that it permits us to use healthy subjects and hence observe the "positive 56
compentence" of cortical regions rather than the easily confounded consequences of brain damage (cf. Hellige, 1983). Using a mental arithmetic task as an example, this paper demonstrates that there are cortical locations where inter- subject differences in activation are highly correlated with performance -- even though the absolute activation level at some of these sites is quite low in all of the subjects' ERPs. These sites of high correlation correspond to those which other researchers have identified, on the basis of lesion studies, as having special roles in the performance of arithmetic. Conversely, the sites where the most "familiar" ERP peaks are observed (eg. P300) often have a low correlation with intersubject differences performance.
3.2 Methods 3.2.1 Mental Arithmetic Task This study employed five healthy, right-handed, college-age male subjects. During an experimental session, a subject was seated comfortably before a computer screen in a quiet, dimly lit room. The subject held a two-button key pad in his right hand. As the computer screen presented arithmetic expressions, such as 6-3+8-2, the subject pressed either the right or left button, depending on whether he thought the algebraic value of the expression was above or below zero (none were exactly equal to zero). Digits (from 1 to 9) and operators (+ or -) were randomly generated, but a large number of checks were performed to avoid expression with obvious answers. For example, no expressions were employed where two like digits appeared with opposite signs (eg. 1+9-2-9) and no expressions were used where the same operator occurred in each position (eg. 1-3-6- 2). Zeros were permitted, but the number of zeros in each expression was controlled: An equal 57
number of problems were presented with two zeros, one zero, and no zeros, in order to produce a spectrum of levels of difficulty. The arithmetic expressions were presented within a large circle to avoid corner-fixation and to provide a constant background. Each response triggered presentation of another problem after a five second delay. Reaction time and score (correct vs incorrect) was recorded for each response.
3.2.2 Data Recording Data were recorded via a "Brain Atlas III" system (Biologic, Inc., Mundelin, ILL), which digitized 21-channel voltage time traces at a sample rate of 128 Hz. Recording impedance was kept below 2,000 ohms, with 20,000 gain, 30 Hz high filter, and 1 Hz cosine cut-off low filter. Silver-chloride cup electrodes were applied according to a modified version of the International "10-20" (Figure 1) convention (Chatrien, et.al., 1988; Homan, 1987), using linked earlobes as reference. The electrode cream employed was the "EEG-Sol" brand manufactured by Medi-Trace Products Division of Graphic Controls, Inc. Buffalo, NY (part number 16-004).
58
Figure 1 International 10 - 20 EEG scalp Electrode Assignment
The computer program controlling stimulus presentation emitted a timing spike upon presentation of each problem. The first 96 stimulus-gated epochs free of eye-blink or other artifacts within the first second were smoothed with a moving average filter equivalent to a non-recursive FIR low-pass LTI filter with a high frequency cut-off at approximately 11.52 Hz (Lynn & Fuerst, 1989) as recommended by Ruchkin (1987, pg 28). These 96 stimulus-gated response epochs were then averaged to produce a single 21-channel ERP.
59
3.2.3 Locus of Performance-Related Activation Each subject's performance scores were converted into an "error rate" for the responses included in the ERP: Error rate = RT x [1+ (100 x Wrong/Trials)]
At each electrode site and for each data sampling period (every 7.8125 milliseconds) simple linear regression analysis was employed to regress the subjects' error rates upon the values of their respective ERPs, integrated over that site for approximately 39 milliseconds. The purpose of using this brief forward time integral instead of the instantaneous value of each subject's ERP was to allow for slight temporal variation among the subjects' ERPs. Experimentally, it was found that this slight reduction in temporal resolution enhances cross-subject comparisons. On the other hand, we found it necessary to improve the spatial resolution of ERPs, by a method discussed below. (See Wood, 1983, for a discussion of the optimum spatial- temporal resolution for examining neurological complexity.) One example of the regression is shown in Figure 2. A similar regression is conducted at each electrode site and sampling period. In order to reveal the path of locations of high correlation with performance, circles are drawn on a schematic outline of the electrode grid at each location where the adjusted R-square value for the regression exceeds a given threshold value. This is shown in Figure 3, where the threshold was set at 0.8 and the circles are drawn proportional to R-square.
60
Figure 2 Example Correlation of Performance with TEEG Energy Density
Figure 3 Locus of Peak R-square Correlations of Task Performance on TEEG Energy Density
61
3.2.4 Locus of Peak Activation For comparison, the same schematic outline of the brain and electrode grid was overlaid with circles scaled proportionate to the pooled- subject average ERP voltage -- at each site and period where this average exceeded a positive threshold value. This procedure led to Figure 4.
Figure 4 Locus of EEG - ERP Voltage Amplitude Peaks
3.3 Results 3.3.1 Peformance-Related Activation Figure 2 shows a path of performance-related activation consisting of five stages which are labeled by the letters A through D in the figure. Although necessarily speculative, our interpretation of these stages is as follows: 62
A. (89-94 msec): Preparatory response in the left parietal-occipital region. Lesion studies have established that this region has a specialized role in calculation tasks. (Luria, 1966) Since the subjects knew that each task would require calculation, their performance was partially automated by pre-selection of appropriate algorithms (cf. Jaynes, 1976).
B. (118-157 msec): Frontal lobe planning activity. Frontal lobe involvement is known to be critically important for planning the execution of even slightly complex calculational tasks, such as those requiring "carrying" and "borrowing" (Luria, 1966; Filippycheva, 1952; Andreeva, 1950; Rudenko, 1953; Maizel', 1949).
C. (180-243 msec): Spatial analysis in the right pareital- occipital region. Efficient calculation of the values of the arithmetic expressions usually required more that one scan of the terms and was often enhanced by grouping terms with like signs. Thus the task inadvertently entailed spatial analysis. The right parietal region (in right handed males) is well known to be specialized for analysis of spatial as well as metaphorical and contextual relationships (cf Cook, 1986; Hellige, 1983)
D. (344-391 msec): Arithmetic calculation in the left parietal-occipital region. The final stage of the task depended upon the cortical region which, when damaged, is known to produce acalcula syndromes (Luria, 1966).
3.3.2. Peaks of Activation 63
Figure 3 illustrates that a quite different picture of the locus of activation emerges when one plots merely the (pooled) ERP peaks, rather than the occasions of high correlation between subjects' performance and their ERP values. In the early period, 0-300 msec., the peaks reveal predictable occipital activity associated with primary visual processing, following a brief burst of central activity which may reflect eye-coordination motor responses. A subsequent period of central activity lasts from 300-400 milliseconds and corresponds to the familiar P300 peak.
3.4 Discussion 3.4.1 Expectational Priming One thing of particular interest in Figure 2 is the cognitive preparatory response (location A in the figure). Although it is known that "priming" facilitates improved performance in cognitive tests, Figure 2 suggests the nature of the mechanism. Expectation that a task will be of a certain character permits frontal-lobe planning activity to be "informed" that the plan will need to conform to certain requirements. Specifically, it must prepare incoming information to fit the algorithms that are "pre-wired" in the cortical analyzers that will ultimately be required to complete the task. This is mere speculation, of course, but the important point is that the spatial ERP allows exploration of hypotheses such as this, which involve the detailed dynamics of localization.
3.4.2 Need for Methodological Clarification In general, the results of this research point to a conflict in the empirical definition of "cortically localized cognitive function". Conventional EEG methods (as well as those of MEG, rCBF and PET) locate peaks of activation rather than peaks of correlation with performance. 64
The conventional approach may reveal important differences in cortical localization linked to differences in types of cognitive tasks, but it may obscure subtle differences in degrees of localization that account for intersubject differences in capacities for performing a given task (which, for dyslexia and dementia reseach, for example, is the more important question.) This distinction is not the same as that often made between the short latency evoked components of ERPs, which are attributed to exogenous causation -- and later endogenous components whose amplitude seems to reflect subjects' judgments about task-relevance and probability the stimulus. Based on many experiments (usually involving the odd-ball paradigm) the dividing line is drawn at approximately 300 milliseconds. Although it may indeed be true that the short- latency ERP peaks are mandated by the physical nature of the stimuli, Figure 2 reveals that certain early phases of activation are critical nonetheless for cognitive success. The figure serves to remind us that some individuals may accomplish the mandated stages of processing more effectively than others and hence establish a better foundation for the subsequent stages of reasoning. (This point, too, would seem to be crucial for such investigations as those related to dyslexia.) In effect, correlation with performance "filters out" those peaks of cortical activity which, though they may be large, are related to processes that are either equally well accomplished by all subjects or not germane to the cognitive content of the task. It is impossible to draw a line between signals of "cognition" on the one hand, and electrical signatures of the brain's passive reactivity to physical stimuli, on the other. This is, after all, the perennial Mind-Body Problem. Yet, as a working definition, it would seem useful to define cortical localization of cognitive function in terms of the degree to which the outcome of problem solving is contingent upon the level of the putative localized activity. 65
The fact that this approach is based upon cross-subject rather than within-subject differences might seem to be a weakness. So far, we have found that individuals have remakably stable ERPs in spite of variation in their own performance. Hence regression of individual's performance upon a collection of their own ERPs was not successful. However, this may point to a strength of the approach. Its success with cross-subject data implies that it localizes cortical regions contingently related to a comparative capacity for performing the task -- and hence to a property of brains in general.
3.4.3. EEG Recording Limitations The definitional issue raised in this paper is especially relevant for localization research based on EEG data. Scalp EEG can record cortical electrical activity only under a narrow set of conditions, which may systematically lead to low voltage levels being recorded in those regions most involved in higher level reasoning. It is generally assumed that EEG senses cortical electrical fields produced by brief ionic gradients in extracellular fluids surrounding cortical neurons, especially pyramidal cells. (cf. Speckman and Elger, 1987; Gevins, 1983). But these electrical dipoles last only an instant and their fields cancel out to the extent that they are randomly aligned. An electrical field powerful enough to be sensed at the scalp would occur only if two conditions are met: First, a large mass of adjacent cortical neurons must be affected at nearly the same instant. Second, the resulting dipoles must be parallel to each other (with the same polarization) and aligned normal to the scalp surface. The most likely place for this to occur is in the primary projection areas, and these may not necessarily be the sites of cortical processes most critical to the subtle difference between a correct and an incorrect answer to, say, a mental arithmetic task. 66
Presumably, "higher" cortical functions depend upon secondary and tertiary cortical fields, especially in association areas. But as information radiates out through cortico- cortical connections from primary projection areas, less and less temporal synchronization should be expected. And regions where time-synchronized dipoles do occur may be expected to be smaller and smaller -- and hence have a declining impact on the net electrical field. (This conclusion would hold even if one assumes that the radiation of activation to association areas is mediated by subcortical connections with the basal ganglia, as suggested, for example, by Pribram, 1971, pg 320). Scalp EEG thus confronts a dilemma: the cortical electrical surges which are easiest to detect and localize will be those associated with events that have more to do with the physical nature of the stimulus than with the subtleties of higher level reasoning. Events associated with the latter are likely to be diffused both temporally and spatially. To some extent, this trade-off may be mitigated by the fact that, in the posterior half of the cortex at least, the pyramidal cells of secondary and tertiary fields occupy layers of the cortex close to the surface, in various sublayers of layer III (Luria, 1966; White, 1989). But the whole problem is side-stepped by mapping correlations of activation with performance rather than mere peaks of activation. This approach also side-steps a problem of experimental control. In exploring the effects of changes in task content (eg. semantic matching of wordpairs versus calculation of arithmetic expressions) small changes in the physical characteristics of task stimuli (visual angle subtended by the length of character strings, for example) may produce changes in cortical activation which may be misinterpreted as due to changes in the cognitive requirements of the task. But this problem should not as strongly affect correlations between activation and task performance;
67
individuals are surely able to adapt to slight changes in the physical parameters of stimuli within which cognitive tasks are embedded, without resorting to entirely different cognitive strategies.
3.5 Conclusion The results of this study suggests that the approach may be a potentially valuable tool for brain research. It combines the virtues of EEG (low cost, non-invasive, amenable to close experimental control) with the performance capacity-related conception of cortical localization implicit in the insights and hypotheses derived from clinical evaluation of effects of cortical lesions. As described in the following appendix, one element of the procedure also has standalone value as a technique for improving the spatial resolution of EEG data.
68
3.6 Appendix This appendix describes a treatment which helps overcome the problem of spatial resolution of EEG data. It is well known that electrical currents along the scalp (volume conduction) make it difficult to use EEG voltage data for localization of regions of interest (cf. Miyamato, 1991; Hjorth, 1975; Nunez, 1981). The problem is that voltage (or "electropotential") is defined as potential energy per unit of electrical charge, therefore voltage is an ambiguous measurement unless the charge density at the recording site is known. This problem is separate from the dependence of EEG data on the location of the reference electrode. There is no way to escape the fact that potential energy -- the numerator in the definition of voltage -- is inherently a relative measure. That is why voltage values can be stated only relative to "ground" or, in EEG, relative to the voltage level of a reference electrode. The problem at hand is the necessity of knowing the scalp distribution of charge concentration -the denominator in voltage -- in order to reveal even relative levels of potential energy over the scalp, and hence the locations of the cortical electrical energy surges which produce the voltage fluctuations recorded by EEG. Methods to circumvent this problem exploit the fact that there is information in the spatial juxtaposition of multielectrode voltage readings which is not available in the same set of readings viewed as a random array. Although such voltage values cannot be trusted to directly show even the relative distribution of potential energy, their spatial juxtaposition can be used to infer the distribution of charge concentration, and that information can be used to normalize the voltage values at each location so that they will show the relative distribution of potential energy.
69
It demonstrated in most textbooks (eg. Schiey, 1973) that by application of the divergence theorem to Gauss's law one can show that the surface charge density (s) at each point in an electrostatic field is proportionate to the divergence of the electrical field intensity (E) at that point. (The bold type for E is a reminder that it is a vector quantity: force as a function of direction.) Using x and y subscripts to indicate components in a rectangular coordinate system, and Dx and Dy to represent partial derivatives, this result can be expressed as:
s = Dx(Ex) + Dy(Ey)
or,
s = DIV(E),
where "DIV" (for "divergence") is merely shorthand notation for the indicated vector derivative operation. By Stokes theorem it can also be shown that the intensity vector E at any point is simply the negative of the gradient of the voltage profile of the field at that point. (The negative sign arises from the definition of electrical force as positive when it is repulsive.) With all constants of proportionality set equal to unity, this can be expressed as:
E = -{Dx(V) + Dy(V)}
or,
E = - GRAD(V)
70
Substitution of this result into the previous equation for charge density, produces "Poisson's equation":
s = - DIV GRAD(V)
The importance of this result is that the divergence of the gradient is simply the sum of second partial derivatives (of the voltage profile) in the x and y directions. Representing these derivatives as Dxx and Dyy,
s = -{Dxx(V) + Dyy(V)}
or,
s = -L(V),
where "L" represents "Laplacian" the name commonly given to the combined operation DIV GRAD. (This is not the same as the Laplace transform, an equation similar to the Fourier transform used in the analysis of transfer functions of systems. Nor should it be confused with "Laplace's equation" which is the special case of Poisson's equation when it is everywhere zero.) The Laplacian, by itself, is often recommended as a means of "source localization" in EEG (cf. Hjorth, 1980; Murry & Cobb, 1989; Nunez, 1989). It is assumed that points of maximum divergence represent points where currents flow up through the skull and onto the scalp. But the Laplacian can also be used to normalize voltage values at each scalp location, by multiplication. This "cancels out" charge- density in the denominator of the defining equation for voltage. 71
If, at a limiting point on a surface, voltage is defined as energy density (U) per unit of charge density (s),
V = U/s,
then, - V L(V) = Vs = U.
This method of calculating the energy density distribution of an electrostatic field from a spatial set of voltage readings was developed years ago by William Thompson (later Lord Kelvin) while he was still a young student at Cambridge (Thompson, 1848). It is now described in standard textbooks (cf. Lorrain & Corson, 1962, pg 76). But it could not be implemented for EEG work until the recent advent of dense electrode grids and inexpensive computers. The key empirical step is obtaining the necessary partial derivatives for the Laplacian. This is often done by interpolation, but a simpler approach is to employ least- squares to estimate parameters of a single equation for the voltage surface (voltage as a function of x and y) and then take the derivatives of the equation. We have found that the voltage surface can be estimated with remarkable accuracy by fitting the equation: 3 V(x,y) = (a + bx + cy + dxy) When expanded, this is a linear equation in 16 terms, each of which is a combination of various powers of x and y, the coordinates of the electrodes:
2
23 72
33
V = b + b x + b x + ... + b x y + b x y . 1 2 3 15 16
In order to observe the time-evolution of this voltage surface (and the density distribution derived from it), it is necessary to repeat the least squares routine on each successive sample of voltages. This is expedited by the fact that the values of x and y in the above equation are fixed; the inverse matrix for the multiple regression procedure needs to be calculated only once. The following figures illustrate the energy-density conversion. Figures A1 and A2 show how a voltage surface is fitted to a single set of multielectrode voltage values. In all figures the flattened electrode grid is oriented with the subject facing the right.
73
Figure A1 Typical TEEG Voltage Values at Given Point in Time
Figure A2 Regression Surface Fit to TEEG Voltage Values Shown in Figure A1
74
Figure A3 compares least-squares estimated voltage values with the raw data. Only 18 of the 21 electrode traces are shown in order to avoid crowding. On average, 92% of the variation in the raw data is matched. (We have found that a more dense grid is counterproductive since it leads to multicollinearity.) Figure A3 Comparison of Raw EEG Data (solid line) and Estimated (dotted line) Values using Fitted Surface Regression Model
Figure A4 compares an estimated voltage surface with the charge density surface derived from it, and with the energy density surface obtained as the product of the two. The insert shows the point in time for which the surfaces were calculated, relative to selected voltage traces (from the 21 employed).
75
Figure A4 Voltage, Charge-Density, and Energy-Density Surfaces for One Instant in an Arbitrary Segment of TEEG Data
Figure A5 illustrates the effect of using energy density rather than voltage for the regression of five subjects' mental arithmetic performance on their ERPs (at a right parietal electrode site.) Note the poor correlation achieved when the actual voltages are used. Figure A6 shows that the energy density conversion may also be valuable for improving frequency resolution in analysis of continuous EEG traces.
76
Figure A5 Correlation of TEEG Voltages with Task Performance
Figure A6 Ongoing Raw TEEG Voltage Values
77
To a certain extent the oscillations appearing in EEG voltage traces are due to complicated patterns of "slushing" of currents, rather than to variations in the potential energy of the scalp electrical field near the recording electrode. By estimating the spatial charge-density distribution at each instant, and by using it to normalize the voltage values, one obtains a much sharper picture of the dominate frequencies of oscillations of potential energy. Figure A6 illustrates the effect. (The subject was a healthy adult male who was resting with his eyes open; the trace is from the left occipital electrode.)
Figure A7 Same Segment of TEEG Signal Shown in Figure A6 After Application of Energy Density Analysis
78
3.7 Bibliography Andreeva, E.K. (1950) Disturbance of the System of Logical Associations in Frontal Lobe Lesions. Moscow: Instutute for Psychology. Ardila, A. (1987) "Neuroelectric Correlates of a Neuropsycho- logical Model of Word Decoding and Semantic Processing in Normal Children," Journal of Neuroscience 34: 97-113. Barber, Paul J. (1988) Applied Cognitive Psychology: An Information Processing Framework. London: Methuen & Co. Bogen, Joseph E. (1969) "The other side of the brain, II: An appositional mind," Bulletin of the Los Angeles Neurological Society 34 (3):135-162. Brazier, Mary A. B. (1977) Electrical Activity of the Nervous System. Baltimore: Williams & Wilkins Co. Broca, P. (1861) "Remarques sur le siege de la faculte du langage articule," Bulletin of Social Anthropology: 6. Chatrian, G. E., Lettich, E., and Nelson, P. E. (1988) "10% Electrode System," Journal of Clinical Neurolophysiology 5:183-6. Churchland, Patricia Smith (1986) Neurophilosophy. MIT Press: Cambridge, Mass. Cook, Norman D. (1986) The Brain Code: Mechanisms of Information Transfer and the Role of the Corpus Callosum. London: Methuen & Co. Dawson, G.D. (1974) "Cerebral Responses to Electrical Stimulation of Peripheral Nerve in Man," Journal of Neurology, Neurosurgery, and Psychiatry 10:134-140. Doyle, J. C., Ornstein, R., and Galin, D. (1974) "Lateral Specialization of Cognitive Mode: II. EEG Frequency Analysis," Psychophysiology, Vol. 11: 567-578.
79
Farah, Martha J. and Peronnet, F. (1989) "Event-related Potentials in the Study of Mental Imagery," Journal of Psychophysiology 3: 99-109. Filippycheva, N.A. (1952) Inertia of the Higher Cortical Processes n Local Lesions of the Cerebral Hemispheres Moscow: USSR Academy of Medical Sciences. Galambos, R. and Hillyard, S. (eds.) (1981) "Electrophysiological Approaches to Human Cognitive Processing," Neurosciences Research Progress Bulletin 20:1- 270. Gazzania, M.S., Bogen, J.E. and Sperry, R.W. (1965) "Observations on visual perception after disconnection of the cerebral hemispheres in man," Brain 8:221-236. Gevins, Alen S. (1983) "Brain Potential (BP) Evidence for Lateralization of Higher Cognitive Functions," in Hellige, Joseph B. (ed) Cerebral Hemisphere Asymmetry: Method, Theory, and Applications. Praeger Publishers. Guisado, R., Montgomery, L. D., and Montgomery, R. W. (1988) Electroencephalographic Monitoring of Complex Mental Tasks, Final Report NASA Contract NAS1-18625. Gioradano, Arthur A. and Hsu, Frank M. (1985) Least Squares Estimation with Applications to Digital Signal Processing Wiley & Sons. Hellige, Joseph B. (1983) Cerebral Hemisphere Asymmetry: Method, Theory, and Applications. Praeger Publishers. Hjorth, Bo. (1980) "Source Derivation Simplifies EEG Interpretation," American Journal of EEG Technology 20: 121- 32. Homan, Richard W. (1987) "The 10-20 Electrode System and Cerebral Location," American Journal of EEG Technology, 28:269-279.
80
Jaynes, Julian (1976) The Origin of Consciousness in the Breakdown of the Bicameral Mind. Princeton University & Houton Mifflin Co. Kramer, A. F. (1983) "Event Related Potentials" in Gale, A. and Christie, B. (eds.) Psychophysiology and the Electronic Workplace. John Wiley and Sons. Lathi, B. P. (1965) Signals, Systems and Communication. John Wiley & Sons. Lorrain, Paul and Corson, Dale (1970) Electromagnetic Fields and Waves. Freeman and Co. Luria, Aleksandr Romanovich (1966) Higher Cortical Functions in Man. Basic Books, Inc. Lynn, Paul A. and Fruest, Wolfgang. (1989) Digital Signal Processing with Computer Applications. Wiley & Sons. Marbe, K. (1901) Experimentell-Psycholgische Untersuchungen uber das Urteil, eine Einleitung in die Logik. Leipzig: Englemann. Muyamoto, Akira and Wilson, Glen (1991) "Mapping of Evoked Magnetic Field with Visual Stimulation: A Secondary Projection Area," Aviation, Space, and Environmental Medicine 62: 638-47. Montgomery, D. and Johnson, L (1976) Forcasting and Time Series Analysis. McGraw-Hill Book Co. Maizel' I. I. (1959) Disturbance of intellectual activity following disntegration of active, goal-directed activity. Moscow: State University.
Nunez, Paul L. (1981) Electric Fields of the Brain: Neuro- Physics of EEG. Oxford Univesity Press. 81
Nunez, Paul L. (1989) "Estimation of Large Scale Neocortical Source Activity with EEG Surface Laplacians," Brain Topography, 2:141-154. Penfield, Wilder and Phanor Perot (1963) "The brain's record of auditory and visual experience: a final summary and discussion," Brain, 86: 595-702. Pfurtscheller, G. and Klimesch, W. (1990) "Topographical Display and Interpretation of Event-related Desynchronization During a Visual-verbal Task," Brain Topography 3:85-93. Piaget, Jean (1971) Biology and Knowledge: An Essay on the Relations between Organic Regulations and Cognitive Processes University of Chicago Press. Pirozzolo, Francis J.; Rayner, Keith; and Hynd, George (1983) "The Measurement of Hemispheric Asymetries in Children with Developmental Reading Disabilities," in Hellige, Joseph B. (1983) Cerebral Hemisphere Asymmetry: Method, Theory, and Applications. Praeger Publishers. Plonsey, R. and Fleming, D. (1969) Bioelectric Phenomena. McGraw-Hill: New York. Pribram, Karl H. (1971) Languages of the Brain: Experimental Paradoxes and Principles in Neuropsychology. Prentice-Hall. Regan, David (1981) Human Brain Electrophysiology: Evoked Potentials and Evoked Magnetic Fields in Science and Medicine Elsever Science Publications. Rockstroh, B., et.al. (1982) Slow Brain Potentials and Behavior. Urban and Schwarzenberg, Baltimore. Rotman, Brian (1977) Jean Piaget: Psychologist of the Real Cornell University Press. Rudenko, Z.Y. (1953) Disturbance of Arithmetical Skill in Brain Lesions. Moscow: USSR Academy of Medical Science.
82
Ruchkin, D.S. (1987) "Measurement of Event-Related Potentials: Signal Extraction,:" in Pitcon, T.W. (ed): Handbook of Electroencephalography: Human Event Related Potentials. Elsever Science Publishing Co. Shadowitz, Albert. (1975) The Electromagnetic Field. Dover: New York Speckmann, E. J. and Elger, C. E. (1987) "Introduction to the Neurophysiological Basis of the EEG and DC Potentials," in: Niedermeyer, E. and da Silva, F. L. (eds.), Electroencephalography: Basic Principles, Clinical Applications, and Related Fields, 2nd Edition. Urban and Schwarzenberg, Baltimore, pp. 1-13. Spehr, W. (1976) "Source Derivation after Hjorth: An Improved EEG Derivation Technique. Electromedica 4:148-155. Thompson, R. F. and Patterson, M. M. (1974) Biolectric Recording Techniques. Academic Press: New York. Thompson, William. Lord Kelvin (1848) "Note on the integration of the equations of equilibrium of an elastic solid," Cambridge and Dublin Mathematical Journal 3: 87-9. Vasilescu, V and Margineanu, D. G. (1982) Introduction to Neuro-Biophysics. Abacus Press: Tunbridge Wells, Kent. Vaughan, H. G. and Arezzo, J. (1988) "The Neural Basis of Event Related Potentials," Chapter 3 in Pitcon, T. W. (ed.) Human Event Related Potentials: EEG Handbook (revised series, Vol 3). Elsevier Science Publishers. Wada, J and Rasmussen, T. (1960) "Intracarotid Injection of Sodium Amytal for the Lateralization of Cerebral Speech Dominance," Journal of Neurosurgery 17:266-282. Watt, H.J. (1905) "Experimentelle Beitrage zur einer Theorie des Denkiens," Archiv fur geschite der Psycholgie 4:289-436. 83
White, Edward L. (1989) Cortical Circuits: Synaptic Organization of the Cerebral Cortex; Structure, Function and Theory. Boston: Birkhauser. Wernicke, C. (1874) Der aphasische Symptomenkomplex. Brelau: Cohn & Weigart. Wonnacott, Ronald J. and Wonnacott, Thomas H. (1970) Econometrics. Wiley & Sons. Wood, Frank (1983) "Laterality of Cerebral Function: Its Investigation by Measurement of Localized Brain Activity," in Hellige, Joseph B. (1983) Cerebral Hemisphere Asymmetry: Method, Theory, and Applications. Praeger Publishers.
84
4.0 Experimental Approach (Human Use Protocol): Evaluation of Lowering Body Temperature to Facilitate Neurocognitive Function in Multiple Sclerosis Patients
Preface for this Section
85
Table of Contents 4.1 Title 4.2 Submitted by 4.3 Organization Code, Mail Stop and Ames Phone Number 4.4 Statement of Problem and Its Importance and Impact of Research on Solving Problem 4.5 Objectives 4.6 Approach 4.7 Justification 4.8 Safety Precautions 4.9 Possible Inconveniences, Discomfort, Pain, and Risk to Subjects 4.10 Meassures Taken to Minimize Discomfort or Risks 4.11 Conditions on Withdrawal from Experiment 4.12 References
86
4.0 Experimental Approach (Human Use Protocol) National Aeronautics and Space Administration AMES RESEARCH CENTER Moffett Field, California 94035 Human Research Proposal
4.1 Title
Evaluation of Lowering Body Temperature to Facilitate Neurocognitive Function in Multiple Sclerosis Patients
4.2 Submitted by Bruce W. Webbon, Ph.D. Chief, Extravehicular and Protective Systems Branch
Collaborators: Leslie D. Montgomery, Ph.D. (Lockheed Martin Engineer & Science Corp.) Yu-Tsuan E. Ku, M.S. (Lockheed Martin Engineer & Science Corp.) Karl Syndulko, Ph.D. (V.A. Medical Center, Los Angeles, CA) Wallace W. Tourtellotte, M.D., Ph.D. (V.A. Medical Center, Los Angeles, CA) Richard W. Montgomery, Ph.D. (Management Analytics, Inc., Corvallis, OR)
87
4.3 Organization Code, Mail Stop and Ames Phone Extension Extravehicular and Protective Systems Branch Code: STE Mail Stop 239-15 Phone: 415-604-6646
4.4 Date Submission Date: January 17,1996
4.5 Statement of Problem and Its Importance and Impact of Proposed Research on Solving Problem On May 23, 1994 The National Aeronautics and Space Administration (NASA) signed a Memorandum of Understanding (MOU) with the Multiple Sclerosis Society of America (MSAA) whereby both groups would cooperate in the application and assessment of NASA’s “cool suit” technology for the benefit of multiple sclerosis (MS) patients. Since that time this program has become a national focal point for many investigators involved in basic and clinical research of MS. NASA staff and support personnel have visited many of the leading MS research centers. We have sponsored a national MS workshop at Ames Research Center to define the types of personal thermoregulatory systems that might be applied for symptom management of MS patients. The workshop attendees stressed the need for quantification of the thermoregulatory responses of MS patients to segmental body cooling. It was felt that much of this work could not be done using the limited facilities and personnel available within the MS clinical community
88
and that this is one area in which NASA can be of assistance to present and planned research investigations. The National Multiple Sclerosis Society, The Consortium of MS Research Centers, and all of the attendees at the NASA/MSAA MS Workshop have agreed to cooperate in this effort. However, all of the present attention is directed toward the use of NASA’s thermoregulatory systems for lessening the physical disabilities and fatigue that are manifest with MS. Through the proposed work we would like to assess the extent of improved cognitive function that might be possible by application of our liquid cooling garment technology. Recent neuropsychological studies demonstrate that cognitive dysfunction is a common symptom in patients with multiple sclerosis (Rao, 1990; Beatty, 1993). Prevalence estimates of cognitive impairment among MS patients range from 43% for a large community-based sample (Rao et. al., 1991) to 59% for a large clinic-based sample (Heaton et. al., 1985). In many cases the presence of cognitive impairment affects the patients’ daily activities to a greater extent than would be found due to their physical disability alone (Rao et. al.,1991). Cognitive dysfunction can have a significant impact on the quality of life of both the patient and that of their primary care giver. MS-related cognitive dysfunction most often affects short term memory recall and processing of verbal information (Fischer et. al. 1994). Electroencephalographic multimodality evoked potential research was used (Phillips et. al., 1983; Beatty, 1993) to investigate the cognitive impairment associated with MS. These studies show that the degree of right-left asymmetry in the brain’s neural activity is one measure of MS cognitive impairment. They also demonstrate that an MS patient’s cognitive processing is very sensitive to hyperthermia. However, these studies were limited by the lack of indices of cortical localization and EEG activity to quantify a patient’s short term neural response to 89
evoked potential based investigations. Fischer et. al. (1994) have also stressed that more accurate methods for assessing the cognitive disturbance in MS must be developed before the effectiveness of various treatments can be validly evaluated.
4.6 Objectives This proposed research will exploit areas of NASA STE expertise to pursue the following objectives which will directly benefit MS patients and address the above needs: a) to determine whether cooling of MS patients will enhance their cognitive function in much the same way as it has been shown to improve their physical abilities, and b) to demonstrate that new EEG/energy density analytical procedures, developed under NASA sponsorship, can be used to quantify the cognitive short term “cooling”
improvement of MS patients that may be produced by therapy.
4.7. Approach Our investigation will employ advanced EEG measures to assess the processing of verbal and reading related information of MS patients before and after administration of short term “cooling” therapy. We will use such data to show how patient differences in reading performance relate to a conventional theoretical model of cortical processing of reading-related information and how they may be improved by localized cooling of the MS patient. This work will be done in collaboration with members of the Neurology Service of the Department of Veteran Affairs Medical Center - West Los Angeles, CA. 90
After a training period to familiarize the patient with the test conditions, each patient will be instrumented for EEG, using the International 10-20 system (Homan, 1988), and seated comfortably before a computer screen. A series of word pairs will be presented on the screen using a standardized format (Guisado, Montgomery, and Montgomery, 1992). The patient will then decide whether each pair are synonyms or antonyms and will indicate the choice by either a verbal or physical response that is compatible with their extent of disability. An equal number of word pairs will selected at random (without repetition) from three lists representing what the researchers believe to be easy, moderate, and difficult judgments. The patient's response will automatically trigger presentation of the next word pair after a five second delay. This particular task, antonym-synonym discrimination, may not necessarily represent all reading-related processing. But it is particularly suited to our measure inter-hemisphere interaction, which is affected by multiple sclerosis. The task requires recognition of the connotations of words (which is often assumed to call upon right-hemisphere resources) as well as their denotations (for which the left hemisphere is assumed to be more specialized). The patient's average performance (errors and reaction time) will be automatically recorded and subsequently converted into an "Error Index" which combines both aspects of performance:
Error Index = RT (1 + percent wrong)
Each patient will be given two series of cognitive tests; one prior to being cooled and one following a period of body cooling using a liquid cooling garment. The extent of cooling and the
91
body segments to be cooled will be determined through preliminary pilot studies during the first year of this investigation. A novel feature of our research will be the conversion of the voltage ERPs into "energy density ERPs" so that scalp recorded surges in electrical energy rather than the resulting voltage fluctuations can be used as a measure of localized cortical activity (Montgomery and Gleason, 1992; Montgomery, Montgomery, and Guisado, 1992,1993). In addition to improving the spatial resolution of scalp EEG data, the estimate of electrical energy has another important advantage: It permits time-integration. No meaning can be attached to the time-integral of voltage (and if DC variation has been filtered out during recording, the time integral will be zero). However, electrical energy is an inherently positive quantity and its time-integral is meaningful (it is electrical power.) Time integration of cortical energy over specified periods following stimulus presentation is useful because it facilitates quantitative cross-subject comparisons and statistical analyses. The more conventional approach to ERP analysis, which emphasizes the amplitude of selected ERP peaks, may obscure cross-subject comparisons because of slight differences in ERP latency and waveform among subjects.
4.8 Justification This proposed research will establish the efficacy of “cooling therapy” as a means to improve the cognitive processing of MS patients. As such, it will aid in the management of one of the more severe disabilities produced by multiple sclerosis. This research could also lead to a commercially vendable PC interface which will allow cognitive ERP testing to be performed conveniently in any human factors or neurophysiologic laboratory, clinical environment, or classroom. This inexpensive PC based system for cognitive ERP analysis will be valuable for 92
human factors research applications: i.e. the design of control panels, instrument surveillance procedures, and safety regulations - or in the selection and training of operators. We believe it will also be a valuable asset for diagnosis of dyslexia and other learning disabilities and clinical assessment of other neurologic disorders.
4.9 Safety Precautions a. A systems analysis has been conducted of all monitoring components. All primary instrumentation is battery powered and electrically isolated to ensure subject safety. All system components that are powered by laboratory electrical supply are grounded together at a common point at the computer/instrument interface. All system components have been tested for electrical safety by their respective manufactures. b. All individual system components and biomedical instrumentation have been calibrated against known simulator values and full functional testing has been conducted using simulators supplied for that purpose by the manufacture. c. The subjects will remain seated in an upright chair with back and arm supports during the various test sequences. d. Subjects will be requested to remain in the laboratory vicinity for a short recovery period after the experiment. e. Laboratory personnel will remain with the subjects during all test sequences.
4.10 Possible Inconveniences, Discomfort, Pain and Risk to Subjects a. Skin chafing at the point of torso contact with the cooling garment and physiologic transducers and electrodes attached to the skin. 93
b. Discomfort of using ear, oral, skin and rectal temperature sensors. c. Discomfort from continuous participation.
4.11 Measurements Taken to Minimize Discomfort or Risks a. Careful design consideration has been given to ensure that the subject feels as comfortable as possible during the tests. b. Subjects will be given several practice sessions to acquaint themselves with the test procedures, cooling device and the physiological testing sensors. c. Subjects will be given at least five days of rest between cooling test sessions. d. A test will be stopped if heart rate exceeds 140 BPM, and/or rectal temperature decreases more than 2F or at the subjects request..
4.12 Conditions on Withdrawal from Experiment Subjects will be informed that they are free to withdraw from the experiment at any time for any reason without any personal consequences. They will be asked to give their written informed consent prior to taking part in the study.
4.12 References W. W. Beatty. Cognitive and emotional disturbances in multiple sclerosis. Neurol. Clin. 11: 189-204; (1993) J. S. Fischer, F. W. Foley, J. E. Aikens, G. D. Ericson, S. M. Rao, S. Shindell. What do we really know about cognitive dysfunction, affective disorders, and stress in multiple sclerosis? A practitioner’s guide. J. Neuro. Rehab. 8(3): 151-164 (1994).
94
R. Guisado, L. D. Montgomery, R. W. Montgomery. Electroencephalographic monitoring of complex mental tasks. Final Report NASA Contract NAS1-18847. NASA Langley Research Center, Hampton, VA. (1992). R. K. Heaton, L. M. Nelson, D. S. Thompson, J. S. Burks, G. M. Franklin. Neuropsychological findings in relapsing-remitting and chronic-progressive multiple sclerosis. J. Consult. Clin. Psychol. 53: 103-110; (1985). R. Homan. The 10-20 system and cerebral location. Am. J. EEG Tech. 28: 269-279; (1988). L.D. Montgomery, C.R. Gleason. Simultaneous use of rheoencephalography and electroencephalography for the monitoring of cerebral function. Aviat. Space Environ. Med., 63; 314-321 (1992). R. W. Montgomery, L.D. Montgomery, R. Guisado. Cortical localization of cognitive function by regression of performance on event related potentials. Aviat. Space Environ. Med. 63; 919-924 (1992). R.W. Montgomery, L.D. Montgomery, R. Guisado. Electroencephalographic scalp energy analysis as a tool for investigation of cognitive performance. Journal of Biomedical Instrumentation and Technology. 27(2): 137-142 (1993). K. R. Phillips, A. R. Potvin, K. Syndulko, S. N. Cohen, W. W. Tourtellotte, J. H. Potvin. Multimodality evoked potentials and neurophysiological tests in multiple sclerosis: Effects of hyperthermia on test results. Arch. Neurology. 40: 159-164 (1983). S. M. Rao. Neurobehavioral aspects of multiple sclerosis. New York: Oxford University Press; (1990)
95
S. M. Rao. The cognitive effects of multiple sclerosis. Multiple Sclerosis. 2(1): 2-5; 1994. S. M. Rao, G. J. Leo, L. Bernardin, F. Unverzagt. Cognitive dysfunction in multiple sclerosis, I: Frequency, patterns, and prediction. Neurology. 41: 685-691; (1991). S. M. Rao, G. J. Leo, L. Ellington, T. Nauertz, L. Bernardin, F. Unverzagt. Cognitive dysfunction in multiple sclerosis, II: Impact on social functioning. Neurology. 41: 692-696; (1991)
96
5.0 Preliminary Study Visual Discrimination Assessment using Cortical Energy Analysis: Verification of Multiple Sclerosis Test Paradigm
Preface for this Section
97
Table of Contents 5.1 Abstract 5.2 Background 5.3 Objectives 5.4 Methods 5.5 Results 5.6 Summary 5.7 Suggested Reading
98
5.1 Abstract VISUAL DISCRIMINATION ASSESSMENT USING CORTICAL ENERGY ANALYSIS. L.D. Montgomery*, Y.E. Ku, R.W. Montgomery, B.W. Webbon*, NASA Ames Research Center, Moffett Field, California, 94035-1000 INTRODUCTION: Cognitive stimuli, such as color and shape discrimination tasks, induce localized activity in the cerebral cortex. Definition of the electroencephalographic (EEG) changes during these tasks would provide a more complete understanding of the physiologic responses of the human operator during visual monitoring. METHODS: Twelve right-handed young men were presented a random series of equally likely red or blue triangles or squares and asked to respond upon detecting the designated target, i.e. red squares. Multichannel topographic EEG event-related potentials (ERPs) were used to estimate scalp distributions of surface energy densities of the cortically generated electrical fields. Cross-subject regression analyses were then used to map sites and post-stimulus latencies, for which there was a high correlation of energy densities with subjects’ performance. RESULTS: High R-square values for the regression (in excess of 0.5) were found at distinct sites and periods: 118157 msec: left frontal lobe (planning activity), 196-235 msec: right temporal lobe (spatial analysis of stimuli).These peak correlations with performance correspond to evidence about cortical localization of neural processing derived from studies of cognitive capacities of patients suffering localized lisions which supports the general validity of the approach. DISCUSSION: This procedure revealed a strong cross subject group correlation between neural activity and target discrimination during visual monitoring. Thus it may offer an inexpensive, non-invasive tool for evaluating effects of state changes in human operators and for evaluating alternative designs of operator tasks and workstations. Acknowledgements: This work was completed under NASA MS Cool Suit Technology RTOP No. 199-61-99-02, in support of the recent Memorandum Of Understanding between The National Aeronautics and Space Administration and the Multiple Sclerosis Association of America for the application of Liquid Cooling Garment Technology to Multiple Sclerosis Patients.
99
5.2 Background Cognitive stimuli, such as color and shape discrimination tasks, induce localized activity in the cerebral cortex. Definition of the electro-encephalographic (EEG) changes during these tasks would provide a more complete understanding of the physiologic responses of the human operator during visual monitoring. Means to correlate these changes with task performance would provide a valuable human factors tool for assessing new display formats and the neural activity required to complete given tasks.
5.3 Objectives The objectives of this study were: 1. To demonstrate the use of TEEG Energy Density Analysis as a cognitive research tool for multiple sclerosis patients, 2. To correlate neural activity during a visual discrimination task with subject performance.
5.4 Methods Twelve right-handed young men were presented a random series of equally likely red or blue triangles or squares and asked to respond upon detecting the designated target, i.e. red squares. Multichannel topographic EEG event-related potentials (ERPs) were used to estimate scalp distributions of surface energy densities of the cortically generated electrical fields. Cross-subject regression analyses were then used to map sites and post-stimulus latencies, for which there was a high correlation of energy densities with subjects’ performance.
100
Figure 1 SCALP ELECTROENCEPHALOGRAPHIC ELECTRODE ASSIGNMENT
Data were recorded via a Biolog, Inc. Brain Atlas III system, 2000 ohms, 20000 gain, 1 - 30 Hz., 21 ear-referenced electrodes (silver-chloride cup) were used in the standard grid locations shown above (using ‘EEG-Sol’ brand cream).
101
Figure 2 TASK FORMAT
Each subject was presented a psuedorandom series of visual stimuli (red square/triangle or blue square/triangle) for a period of five minutes. Subjects were instructed to press a left hand choice response button to discriminate a specified target ( i.e. red triangles probability = 0.25) from nontargets (i.e. red squares, blue triangles, and blue squares probability = 0.75). Response times and the number of correct responses were recorded and used as an index of subject performance.
102
Figure 3 TYPICAL TWO SECOND ELECTROENCEPHALOGRAPHIC RECORD
The electroencephalographic records were recorded beginning 100 ms prior to stimulus delivery for a period of two seconds as a montage of time traces showing voltages between several scalp electrodes and a common reference (i.e., linked earlobes). The vertical lines in this example mark 100 ms intervals: labels refer to the standard location scheme shown in Figure 1.
103
Figure 4 TYPICAL EVENT-RELATED POTENTIALS
Event-related potentials (ERPs) were obtained for each EEG electrode position and each target and non-target stimulus by averaging 50 individual stimulus-responses recorded from each position. The example shown here is for the center occipital electrode (Oz), gated by presentation of each stimulus.
104
Figure 5 SPATIAL DISTRIBUTION OF EVENT-RELATED POTENTIALS OVER THE SURFACE OF THE HEAD
This figure shows one ERP for a single subject stimulus response to illustrate the spatial distribution and variance of the averaged response over the surface of the head.
105
Figure 6 DERIVATION OF ELECTROENCEPHALOGRAPHIC ENERGY DENSITY SURFACE
Fitted voltage surfaces (upper left), using the equation V = (a + bX + cY + dXY)^3, which is linear with 16 coefficients are calculated for each set of EEG voltages at each sample period. Charge densities (upper right) are then calculated for each electrode position which are proportional to the (negative of) sum of the second partial spatial derivative of this fitted surface equation. These two surfaces are then multiplied(voltage x charge) to obtain an energy density surface (lower right) at each sampling period. TEEG energy density ERPs can be used to provide further definition between experimental conditions than is possible using conventional voltage based ERPs.
106
5.5 Results Figure 7 ERP VOLTAGE TRACES OF TARGET AND NON-TARGET STIMULI
This figure illustrates the conventional voltage ERPs for the target (red triangles) and nontarget (red squares and blue triangles/squares) stimuli. As can be seen, the two traces are quite similar for all of the fp, f, t, and c electrodes. The voltages of the target ERPs are higher than those of the non-target ERPs at the parietal and occiptal electrode sites after approximately 250- 300 msec. The maximum difference between the target and non-target ERPs occurs at the pz electrode.
107
Figure 8 ERP ENERGY DENSITY TRACES OF TARGET AND NON-TARGET STIMULI
Larger differences are found between the target and non-target ERPs when the energy density analysis is used to transform the TEEG data. The energy density values of the target ERPs also show a more marked peak in time at approximately 350 msec. In this way, the energy density approach not only shows larger differences in target/non-target ERP amplitudes but also provides better definition of the time of peak activation.
108
Figure 9 DIFFERENTIAL VOLTAGE ERPs ABS( TARGET - NONTARGET)
This figure shows the differential voltage target - non-target ERPs for each electrode position. It indicates that the maximum difference between the two ERPs occur at the Cz and Pz electrodes at approximately 350 msec. This position and time may be interpreted as that of the customary P300 phenomenon. In addition, due to the similarity of the C3/C4 and the P3/P4 electrode ERPs, it may be assumed that the right and left hemishperes contribute equally to the ERP observed at Cz or Pz.
109
Figure 10 DIFFERENTIAL ENERGY DENSITY ERPs ABS(TARGET - NONTARGET)
This figure shows the same target - non-target ERPs obtained using the energy density analysis. The peak energy density difference between target and non-target ERPs is now located at the P3 electrode. If the scalp energy distribution is regarded as the fundamental signature of cortical electrical activity, then this asymmetrical, left parietal peak may suggest that the cortical resources most involved in visual discrimination are slimilarly localized.
110
Figure 11 INTEGRATED ENERGY DENSITY VALUES (LEFT) AND RELATIVE Z SCORES (RIGHT) AT EACH ELECTRODE LOCATION FOR TARGET-NONTARGET STIMULI
Unlike EEG voltages, the energy density procedure provides numeric values for localized
cortical neural activity that can be integrated over specified electrode sites and between any desired time periods. The upper left diagram illustrates this point. The individual value positioned at each electrode site is the integrated energy density for that site between 0 and 459 msec. The diagram in the lower right gives the relative Z scores (No. of standard deviations from the mean) for each electrode. This diagram also shows that the peak visual discrimination neural activity takes place at the P3 electrode site.
111
Figure 12 CORRELATION OF ENERGY DENSITY TO PERFORMANCE 600 550
500
450
400
Least squares estimate: Error index = -4462.0 + 1.63 Energy (t =3.7) Unadj. R-sq=0.58
350 300 2900
2950 3000 3050 Cortical Energy at f3 (126-165 mesc.)
3100
The individual integrated energy densities at each electrode site for a number of subjects can be cross correlated with their task performance scores to identify cortical sites that are directly responsible for successful completion of the given task. This procedure can be repeated for each electrode site and for advancing time periods to determine the sequence of cortical sites that are involved in the visual discrimination task. Similarly, this procedure can be used to compare the task performance of different groups of subjects or of the same subjects performing different tasks.
112
5.6 Summary The use of TEEG energy density analysis reveals differences between the neural activity responses of test subjects during visual discrimination tasks with more fidelity than conventional EEG techniques.In addition, energy density values can be correlated with subject performance and used to define cortical locations of cognitive activity. Thus it may offer an inexpensive, non-invasive tool for evaluating potential beneficial effects cooling therapy upon the cognitive pr4ocessing of multiple sclerosis patients. In addition it may be useful in monitoring the neural state changes in human operators and for evaluating alternative designs of operator tasks and workstations.
5.7 Suggested Reading L.D. Montgomery and C.R. Gleason, "Simultaneous use of rheoencephalography and electroencephalography for the monitoring of cerebral function," Aviat. Space Environ. Med., 63; 314-321 (1992). R. W. Montgomery, L.D. Montgomery, and R. Guisado, "Cortical localization of cognitive function by regression of performance on event related potentials," Aviat. Space Environ. Med. 63; 919-924 (1992). R.W. Montgomery, L.D. Montgomery, and R. Guisado, "Electroencephalographic scalp energy analysis as a tool for investigation of cognitive performance," Journal of Biomedical Instrumentation and Technology. 27(2): 137-142 (1993). L.D. Montgomery, R.W. Montgomery, and R. Guisado, "Continuous monitoring of cerebral blood flow: Correlation of rheoencephalographic activity during cognition," Journal of Clinical Engineering, 18(3): 235-244 (1993). L. D. Montgomery and R. Guisado, “Rheoencephalographic and electro-encephalographic measures of cognitive workload: Analytical procedures,” Biological Psychology, 40: 143159 (1995).
113
6.0 Pilot Study: Enhancement ofCognitive Processing by Multiple Sclerosis Patients using Liquid Cooling Technology
Preface for this Section
114
Table of Contents 6.1 Abstract 6.2 Introduction 6.3 Objectives 6.4 Methods 6.5 Results 6.6 Discussion 6.7 Acknowledgement 6.8 References
115
6.1 Abstract Cognitive dysfunction is a common symptom in patients with multiple sclerosis (MS). This can have a significant impact on the quality of life of both the patient and that of their primary care giver. This case study explores the possibility that liquid cooling therapy may be used to enhance the cognitive processing of MS patients in the same way that it provides temporary relief of some physical impairment. Two MS patients were presented a series of pattern discrimination tasks before and after being cooled with a liquid cooling garment for a one hour period. The subject whose ear temperature was reduced during cooling showed greater electroencephalographic (EEG) activity and scored much better on the task after cooling. The patient whose ear temperature was unaffected by cooling showed less EEG activity and degraded performance after the one hour cooling period.
Key Words: Multiple Sclerosis, Cooling Therapy, Cognitive Processing, Electroencephalography
116
6.2 Introduction Recent neuropsychological studies demonstrate that cognitive dysfunction is a common symptom in patients with multiple sclerosis (Rao, 1990; Beatty, 1993). Prevalence estimates of cognitive impairment among MS patients range from 43% for a large community-based sample (Rao et. al., 1991) to 59% for a large clinic-based sample (Heaton, Nelson, Thompson, Burks, & Franklin, 1985). In many cases the presence of cognitive impairment affects the patients’ daily activities to a greater extent than would be found due to their physical disability alone (Rao, Leo, Bernardin, & Unverzagt,1991). Cognitive dysfunction can have a significant impact on the quality of life of both the patient and that of their primary care giver. MS-related cognitive dysfunction most often affects short term memory recall and processing of verbal information (Fischer et. al. 1994). Electroencephalographic multimodality evoked potential research was used (Phillips et. al., 1983; Beatty, 1993) to investigate the cognitive impairment associated with MS. These studies show that the degree of right-left asymmetry in the brain’s neural activity is one measure of MS cognitive impairment. They also demonstrate that an MS patient’s cognitive processing is very sensitive to hyperthermia. However, these studies were limited by the lack of indices of cortical localization and EEG activity to quantify a patient’s short term neural response to evoked potential based investigations. Fischer et. al. (1994) have also stressed that more accurate methods for assessing the cognitive disturbance in MS must be developed before the effectiveness of various treatments can be validly evaluated.
6.3 Objectives 117
The objectives of this research were: a) to determine whether cooling of MS patients will enhance their cognitive function in much the same way as it has been shown to improve their physical abilities, and b) to demonstrate that new EEG/energy density analytical procedures, developed under NASA sponsorship, can be used to quantify the cognitive improvement of MS patients that may be produced by short term “cooling” therapy.
6.4 Methods Two cognitively impared male MS patients were given a visual discrimination task before and after a one hour cooling period. The subjects were presented a series of either red or blue circles or triangles. One of these combinations, or one fourth of the stimuli, was designated as the “target” presentation. The subjects were asked to respond to each presented stimuli by pressing a yes or no button on a hand keypad. Patient “cooling” was accomplished using a Life Enhancement Technologies, Inc. (LET) Mark VII head and torso cooling garment. EEG was recorded from 20 scalp electrodes using a Tracor Northern 7500 EEG/ERP system at the Wadsworth VA Hospital. Subject skin and rectal temperatures were recorded using a UFI, Inc. Biolog ambulatory monitoring system. Oral and ear temperatures were obtained and recorded manually every five minutes during the one hour cooling period. The EEG ERP signatures from each series of stimuli were analyzed using energy density procedures ( Montgomery, Montgomery, & Guisado, 1992; Montgomery, Montgomery, & Guisado, 1993) to determine the locus of neural activity at each EEG sampling time. 118
After a training period to familiarize the patient with the test conditions, each patient was instrumented for EEG, using the International 10-20 system (Homan, 1988), and seated comfortably before a computer screen. A series of visual stimuli in the form of red squares, red triangles, blue squares and blue triangles were presented on the screen using a standardized format. The patient then decided whether a given individual stimulus belonged to the designated target series and indicated his choice by pressing an appropriate key pad. The patient's response automatically triggered presentation of the next stimulus after a five second delay. This particular pattern discrimination task, may not necessarily represent all cognitiverelated processing. However, it is particularly suited to measure inter-hemisphere interaction, which is affected by multiple sclerosis. The task requires recognition of shape and color as well as the subsequent motor performance in making a response. The patient's average performance (errors and reaction time [RT - sec]) was automatically recorded and subsequently converted into an "Error Index" which combines both aspects of performance: Error Index = RT (1 + [stimuli misidentified/total stimuli presented]) Each patient was given two series of cognitive tests; one prior to being cooled and one following a period of body cooling using the liquid cooling garment. A novel feature of our research will be the conversion of the voltage ERPs into "energy density ERPs" so that scalp recorded surges in electrical energy rather than the resulting voltage fluctuations can be used as a measure of localized cortical activity (Montgomery & Gleason, 1992; Montgomery, Montgomery, & Guisado, 1992; Montgomery, Montgomery, & Guisado, 1993). In addition to improving the spatial resolution of scalp EEG data, the estimate of electrical energy has another important advantage: It permits time-integration. No meaning can 119
be attached to the time-integral of voltage (and if DC variation has been filtered out during recording, the time integral will be zero). However, electrical energy is an inherently positive quantity and its time-integral is meaningful (it is electrical power.) Time integration of cortical energy over specified periods following stimulus presentation is useful because it facilitates quantitative cross-subject comparisons and statistical analyses. The more conventional approach to ERP analysis, which emphasizes the amplitude of selected ERP peaks, may obscure crosssubject comparisons because of slight differences in ERP latency and waveform among subjects.
6.5 Results Figure 1 shows the mean precooling (PRE) and postcooling (PST) ear temperature (TEMP), errors (ERROR), and cortical energy density (ENERGY) for the two subjects. The first subject’s ear temperature did not decrease during the cooling period. It was actually elevated approximately 0.05 C by the end of the cooling period compared to his mean ear temperature during the control period. In turn, Subject One’s discrimination performance and cortical energy remained essentially the same after body cooling. In contrast, Subject Two’s ear temperature decreased ~ 0.8 C during his cooling period. Subject Two’s ERROR score decreased from 12 during the precooling control period to 2 after cooling. His ENERGY value increased approximately 300%, from a precooling value of approximately 200 to a postcooling value of nearly 600. Figure 1 Patient Performance Before and After Cooling 120
36.6
15
600 500
36.2 36.0
10
ENERGY
ERROR
EAR TEMP
36.4
5
35.8
400 300 200 100
35.6
0 PRE 1PST 1PRE 2PST 2
0 PRE 1PST 1PRE 2PST 2
PRE 1PST 1PRE 2PST 2
Figure 2 illustrates the individual pre (dotted traces) and postcooling (solid traces) energy density ERPs at each EEG electrode site for Subject Two. The vertical lines in Figure 2 denote every 100 msec. during the ERP. As can be seen from these traces, his post cooling ERP amplitudes are markedly increased compared to his precooling traces, especially between 100 and 200 msec. and again at approximately 300 - 350 msec. No differences were found in the similar recordings for Subject One.
121
Figure 2 Energy Density Evoked Responses for Patient Two Before (blue) and After (red) Cooling
Figures 3 and 4 show the locus of peak energy activity throughout the duration of the 600 msec. ERP at the various electrode sites divided into 100 msec. intervals. The level of activity at each site is proportionatal to the diameter of the circle plotted in these figures. Subject Two showed a large increase in occipital activity between 100 and 200 msec. and a large increase in the left angular gyrus between 200 and 300 msec. after cooling.
122
Figure 3 Locus of Peak Energy for Patient Two Before Cooling
Figure 4 Locus of Peak Energy for Patient Two After Cooling
123
6.6 Discussion This case study indicates that “cooling therapy” may be used to temporarily improve the cognitive processing of MS patients. It also shows that the energy density analysis of topographic EEG can be used to assess the performance of cognitively impaired MS patients. These findings might be interpreted by the following three-part hypothesis: 1) the general cognitive impairment of MS patients may be a result of low or unfocused metabolic energy conversion in the cortex; 2) such differences show up most strongly in reduced energy in the occipital region during the initial processing of the precooling period visual stimulus, which may indicate impaired early visual processing; 3) increased post cooling activation in the left angular gyrus, as evidenced by the higher P3/C3 energy peaks at 300 ms in Figures 2 and 4 may result in enhanced higher-level processing of information. By this hypothesis the superior performance of Subject Two following body cooling may be a result of increased neural activation in his early visual recognition and processing centers. The application of NASA “cool suit” technology to cognitive enhancement of neurologic patients needs to be studied further. An enlarged study, such as the one described herein, is needed to conclusively establish the efficacy of cognitive enhancement due to cooling therapy.
124
6.7 Acknowledgement This work was performed in support of the Memorandum of Understanding that was signed May 23, 1994 between The National Aeronautics and Space Administration and the Multiple Sclerosis Association of America whereby both groups would cooperate in the development of NASA’s liquid cooling garment technology for the benefit of multiple sclerosis patients. The author thanks Drs. Karl Syndulko and Steven M. Breman for their technical assistance during this effort.
6.8 References Beatty, W. W. (1993). Cognitive and emotional disturbances in multiple sclerosis. Neurol. Clin. 11, 189-204. Fischer, J. S., Foley, F. W., Aikens, J. E., Ericson, G. W., Rao, S. M., & Shindell, S. (1994). What do we really know about cognitive dysfunction, affective disorders, and stress in multiple sclerosis? A practitioner’s guide. J. Neuro. Rehab. 8(3), 151-164. Guisado, R., Montgomery, L. D., & Montgomery, R. W. (1992). Electroencephalographic monitoring of complex mental tasks. Final Report NASA Contract NAS1-18847. NASA Langley Research Center, Hampton, VA. Heaton, R. K., Nelson, L. M., Thompson, D. S., Burks, J. S., & Franklin, G. M. (1985). Neuropsychological findings in relapsing-remitting and chronic-progressive multiple sclerosis. J. Consult. Clin. Psychol. 53, 103-110. Homan, R. (1988). The 10-20 system and cerebral location. Am. J. EEG Tech. 28: 269279.
125
Montgomery, L. D., & Gleason, C. R. (1992). Simultaneous use of rheoencephalography and electroencephalography for the monitoring of cerebral function. Aviat. Space Environ. Med., 63, 314-321. Montgomery, R. W., Montgomery, L. D., & Guisado, R. (1992). Cortical localization of cognitive function by regression of performance on event related potentials. Aviat. Space Environ. Med. 63, 919-924. Montgomery, R. W., Montgomery, L. D., & Guisado, R. (1993). Electroencephalographic scalp energy analysis as a tool for investigation of cognitive performance. Journal of Biomedical Instrumentation and Technology. 27(2), 137-142. Phillips, K. R., Potvin, A. R., Syndulko, K., Cohen, S. N., Tourtellotte, W. W., & Potvin, J. H. (1983). Multimodality evoked potentials and neurophysiological tests in multiple sclerosis: Effects of hyperthermia on test results. Arch. Neurology. 40, 159-164. Rao, S. M. (1990). Neurobehavioral aspects of multiple sclerosis. New York: Oxford University Press. Rao, S. M. (1994). The cognitive effects of multiple sclerosis. Multiple Sclerosis. 2(1), 25. Rao, S. M., Leo, G. J., Bernardin, L., & Unverzagt, F. (1991). Cognitive dysfunction in multiple sclerosis, I: Frequency, patterns, and prediction. Neurology. 41, 685-691. Rao, S. M., Leo, G. J., Ellington, L., Nauertz, T., Bernardin, L., & Unverzagt, F. (1991). Cognitive dysfunction in multiple sclerosis, II: Impact on social functioning. Neurology. 41, 692-696.
126
7.0 Project Summary: Accomplishments to Date
Preface for this Section Accomplishments to Date - 12 December 1997 Accomplished by :
Bruce W. Webbon, Ph.D. (NASA) Bernadette Luna, M.S.M.E. (NASA) Leslie D. Montgomery, Ph.D. (LME&SC) Yu-Tsuan Ku, M.S. (LME&SC) Hank C. Lee, B.A. (LME&SC)
BACKGROUND On May 23, 1994 The National Aeronautics and Space Administration (NASA) signed a Memorandum of Understanding (MOU) with the Multiple Sclerosis Association of America (MSAA) whereby both groups would cooperate in the application and assessment of NASA’s “cool suit” technology for the benefit of multiple sclerosis patients. Since that time this program has become a national focal point for many investigators involved in basic and clinical research of MS. As much as possible, NASA is reaching out to regional MS centers, private MS physicians, MS research investigators, and MS patients to solicit cooperation. PROGRAM OBJECTIVES • define the basal thermal state of MS patients • scientific evaluation of the efficacy of cooling therapy for MS patients • development of prototype personal cooling systems required by MS patients • transfer of new cooling system technology to industry • publish results in the scientific and medical literature
127
Table of Contents
7.1 Program Implementation 7.2 Outreach and Technology Transfer Activities
128
7.1 Program Implementation 1) Initial Program Activities • Sept. 1994 - Introduced program to the NASA EVA community (government, academic, industry) at EVA Working Group meeting at MIT. • Sept. - Dec. 1994 - Initiated program through site visits, conference attendance, and regional group discussions at universities and MS clinics in MN, MA, CO, WA, OH, CA, IN and Washington, D.C. These discussions led to the idea and format of an MS workshop. • 29 - 31 January 1995 - Sponsored workshop at NASA Ames Research Center . Workshop was attended by approximately 30 physicians, rehabilitation therapists, and MS researchers and 15 members of the industrial community. One of the purposes of this workshop was to serve as a peer review for the NASA MS technology transfer program. Representatives from the Multiple Sclerosis Association of America, the National Multiple Sclerosis Society, and The Consortium of Multiple Sclerosis Centers all agreed to work together to scientifically establish the efficacy of “NASA cool suit” technology for use in therapeutic management of MS patients. NASA's role in the overall program was defined and areas of technology and scientific need were determined. 2) Research and Development Activities NASA AMES / COLLABORATIVE RESEARCH
129
• Investigated thermal physiological responses of 12 healthy male and female subjects to head and neck cooling using a cooling system widely used by MS patients (NASA Ames IRB#51, results published in Am. J. Phys. Med. Rehabil., 75:443-450; 1996). • Investigated MS patients thermal response to body cooling during winter and summer conditions at Rocky Mountain MS Clinic, Adult Day Enrichment Program. The objective of this study was to determine the effect seasonal temperature have upon the MS patient's thermal and physical performance responses to liquid cooling (manuscript in final preparation). • Served as technical advisors and consultants on a multicenter MS cooling efficacy study that was proposed at the NASA MS workshop and is being coordinated by the research committee of the MS Consortium. Dr. Kraft from the U. of WA. reported on the results of the study at the Annual Scientific Meeting of the MS Research Consortium on September 27 - 29, 1996 in Atlanta, GA. A journal research paper is currently being prepared by the investigators for submission to the New England Journal of Medicine. • Compared the performance of four commercially available cooling vest systems using 12 healthy male and female subjects. We assessed the cooling capability of each system as they may be used by MS patients (manuscript in preparation). • Investigated MS patients cognitive enhancement produced by body cooling at Wadsworth VA Medical Center (manuscript submitted for publication). • We have completed two student design research projects with the Bioengineering Department of Brigham Young University to construct prototypes of two cooling system hardware components that were identified as being needed by the industrial community attendees of the NASA Ames MS Workshop. 130
These components are: -1) a liquid temperature automatic control valve for use in cooling systems -2) an inexpensive small quick disconnect system for MS cooling system coolant tubes. • On June 17, 1997 The National Aeronautics and Space Administration (NASA) signed a Memorandum of Understanding (MOU) with the Multiple Sclerosis Association of America (MSAA) and Lockheed Martin Technology Services Group whereby these groups would cooperate in the application and assessment of NASA’s “cool suit” technology for the benefit of multiple sclerosis patients and others who are physically challenged. As a result, we have prepared and begun the following: -1) IRB#178 entitled "Physiologic Response of Multiple Sclerosis (MS) Patients to Hypothermic Therapy using Commercially Available Cooling Garments" being conducted with INNR at Hot Springs, AK; ADEP at Denver, CO; and Mayo Clinic at Scottsdale, AR. -2) IRB#182 entitled "Evaluation of Lowering Body Temperature to Facilitate Neurocognitive Function in People with Multiple Sclerosis" being conducted at ARC. CONFERENCES PRESENTATIONS • Poster session at the 66th Annual Scientific Meeting of the Aerospace Medical Association, May 7-11, 1995, in Anaheim, CA, entitled “Hemodynamic and thermal responses to head and neck cooling in women.” This paper was also submitted as a full manuscript by Ms. Yu-Tsuan Ku for the “Young Investigators Award.” It was selected as one of the finalists in the competition, being in the top 10% of the 170 papers submitted. 131
• Poster session entitled, “Hemodynamic and thermal responses to head and neck cooling in men and women” which described the results of the combined male/female head and neck cooling study at the Annual Scientific Meeting of the MS Research Consortium held September 15 - 17, 1995 in Portland, OR. • Poster session entitled, “A unique facility for metabolic and thermoregulatory studies,” at the Annual Scientific Meeting of the MS Research Consortium held September 15 - 17, 1995 in Portland, OR which described the thermophysiology test facility of NASA Ames Research Center that could be used for basic MS research. • Presented a paper at the 9th International Conference on Electrical Bio-Impedance, September 26-30, 1995 in Heidelberg, Germany entitled, “Rheoencephalographic (REG) assessment of head and neck cooling for use with multiple sclerosis patients” • Poster session entitled, “Physiological and thermal responses of male and female MS patients to head and neck cooling” which described the results of the combined MS male/female head and neck cooling study at the Annual Scientific Meeting of the MS Research Consortium held September 27-29, 1995 in 1996, Atlanta, GA. • Poster session entitled, “An ambulatory physiologic and thermal monitor for study of multiple sclerosis patients” which described how to record and analyze the body temperatures, heart rate, respiration, and activity on the monitor for MS study at the Annual Scientific Meeting of the MS Research Consortium held September 27-29, 1995 in 1996, Atlanta, GA. • Poster session entitled, “The effects of cooling on performance and perceived fatigue” which described the results of the functional improvements after 30 min. head and neck
132
cooling on MS male/female study at the Annual Scientific Meeting of the MS Research Consortium held September 27-29, 1995 in 1996, Atlanta, GA. • Poster session at the 68th Annual Scientific Meeting of the Aerospace Medical Association, May 11-15, 1997, Chicago, IL, entitled, "Operational characteristics of two commercially available personal cooling vests," which described the results of body temperatures, heart rate, respiration, and blood flows on the monitor of 10 healthy male. • Poster session entitled, "Visual discrimination assessment using cortical energy analysis," presented at the 68th Annual Scientific Meeting of the Aerospace Medical Association, May 11-15, 1997, Chicago, IL. • Poster session entitled, "Physiological and thermal responses of MS patients to head and vest cooling: A case study," presented at the 1997 annual meeting of The Consortium of Multiple Sclerosis (MS) Centers, Sept. 5 - 7,1997, Calgary, Alberta, Canada. CONFERENCES PANEL SESSIONS/WORKSHOPS • Chaired a panel session at the 66th Annual Scientific Meeting of the Aerospace Medical Association, Meeting, May 7-11, 1995, in Anaheim, CA, entitled, “Biomedical use of aerospace personal cooling garments.” • Chaired a panel session at the Second Annual INN Research Multiple Sclerosis Seminar “New Horizons in MS” held September 30, 1995 in Hot Springs, Arkansas, entitled, “An Introduction to Neuro-Hypothermia In Multiple Sclerosis."
133
• Facilitated a study session and a workshop at "Models of Care in Multiple Sclerosis", the eleventh annual meeting of the Consortium of Multiple Sclerosis Centers on Sept. 27-29, 1996, Atlanta, GA. Provided briefings on: - B.W. Webbon, Y.E. Ku, L.D. Montgomery, “Definition of basal thermoregulatory state of MS patients”. - B.W. Webbon, Y.E. Ku, L.D. Montgomery, “Benefit of personal cooling systems for therapeutic management of MS patients”. • Chaired a panel session at the Advanced Technology Applications to Combat Critical Care (ATACCC) Symposium and Conference sponsored by the Army Medical Research Lab on May 19-22 in Fort Walton Beach, Fl, entitled, “Cool Suit Technology”. • Participated in the MS thermoregulatory workshop at the Consortium meeting, Sept. 6, 1997, Calgary, Canada.
JOURNAL PUBLICATIONS • Y.E. Ku, L.D. Montgomery, B.W. Webbon, “Hemodynamic and thermal responses to head and neck cooling in men and women,” Am. J. Phys. Med. Rehabil., 75:443-450; 1996. • L.D. Montgomery, R.W. Montgomery, Y.E. Ku, "Enhancement of cognitive processing by multiple sclerosis patients using liquid cooling technology: A case study," submitted for publication to American J. Physical Medicine & Rehabilitation, (submitted for publication, March, 1997)
134
• Y.E. Ku, L.D. Montgomery, B.W. Webbon, “Physiological and thermal responses of male and female MS patients to head and neck cooling,” Am. J. Phys. Med. Rehabil. (in preparation) • K.C. Wenzel, Y.E. Ku, L.D. Montgomery, “The effects of cooling on performance and perceived fatigue,” Am. J. Phys. Med. Rehabil. (in preparation) • L.D. Montgomery, Y.E. Ku, H.M. Hanish, B.W. Webbon, “An ambulatory physiologic and thermal monitor for study of multiple sclerosis patients,” Aviation Space & Environmental Medicine. (in preparation)
7.2 Outreach and Technology Transfer Activities DISPLAY S/ EXHIBITS • Prepared exhibit material used by the Multiple Sclerosis Association of America in their booth at the American Neuroscience Society meeting May 6, 1995. • Prepared exhibit material on NASA MS program activities and EVA for, Annual Scientific Meeting, MS Research Consortium, Sept 15-17, 1995, Portland, OR and 2nd Annual INN Research, “New Horizons in MS”, Sept 30, 1995, Hot Springs, AK. • NASA Ames MS program included in American Medical Association "Leadership Conference", in Washington D.C. on Mar. 10-12, 1996. • NASA Ames MS program presented in a Press Conference to facilitate the transfer of NesLab commercial cooling systems from Kaiser Electronic to MSAA at Moffett Field on Mar. 28, 1996. • NASA Ames MS program displayed at "Art and Wine Festival", on Sept. 7-8, 1996, Mountain View, CA.
135
• NASA Ames MS program displayed at "AstroBiology Workshop", on Sept. 9-10, 1996, Moffett Field, CA. • NASA Ames MS program displayed at "New Horizons in MS", the third annual INN Research Multiple Sclerosis Seminar on Sept. 20-21, 1996, Hot Springs, AR. • Displayed a NASA Ames MS program at the "High School High Tech" conference and attended the conference to support of the national disability month on Oct. 28, 1996, Moffett Field, CA. • Displayed a NASA Ames MS program at the "1996 Ames Disabilities Awareness day" on Nov. 21, 1996, Moffett Field, CA. • Prepared "MS Technology Transfer Program" literature distributed from NASA Space Station Exhibit at American College of Physicians convention at Philadelphia on Mar 2223, 1997 . • Displayed the cooling vest to Rancol School at the "STELLAR night - open house", space related science touchy-freely on March 26, 1997, San Jose, CA. • NASA Ames MS program displayed at "Art and Wine Festival", on June. 7-8, 1997, Sunnyvale, CA. • Prepared and presented exhibit material for the NASA Ames Research Center Community day which describes the Biomedical Application Laboratory MS Technology Transfer Program, on Sept. 20, 1997. • Prepared exhibit material for the Lockheed Martin Sunnyvale Disability Awareness Day to be held Oct. 7, 1997 at the Headquarters of Lockheed Sunnyvale. • Prepared exhibit material for the INN Research, Hot Springs, AK community outreach seminar entitled, “New Horizons - 97” to be held at their facilities October 18 - 19, 1997. 136
SPEAKING ENGAGEMENTS • Briefing at UCSF/Mt. Zion MS Clinic to present NASA research plan on Nov. 16, 1994. • Gave a briefing at Kaiser Research Foundation at Santa Clara to present NASA research plan on Liquid Cooling Garment for Multiple Sclerosis Patients on Dec. 14, 1994. • Discussed future MS research plans with members of the MS community, Dr. Kraft, Dr. Burk and MS. Halper at the National Academy of Neurology meeting, San Francisco, CA, March 25-28, 1996. • Gave a briefing at INN Research, Hot Springs, Arkansas about NASA's on going MS research and MSAA's chronic progressive study involving the use of Neslab cooling systems on May 6, 1996. • Met with a personnel from Berlex Laboratories, Inc., to discuss a joint comparative study of Betaseron both with and without cooling on May 6, 1996. • Attended dedication ceremony in Washington D.C. the Veterans' Administration Hospital and briefed the staff on NASA/Neslab cooling systems and MS research on June 4-6, 1996. • Gave a briefing at the Veterans Administration Medical Center in Washington, D.C. about the modification of 6-patient Neslab cooling unit and NASA's on going MS research on May 23, 1997. INVENTION DISCLOSURES • A liquid temperature control valve for use in MS patient cooling systems - ARC /BYU (in preparation) • An inexpensive small quick disconnect system for MS cooling system coolant tubes - ARC / BYU, (in preparation) 137
• Wheelchair neck and spinal column liquid cooling system - ARC, (in preparation) TELEVISION / CD • Prepared an outreach program for a local cable television show in Beverley Hills, CA sponsored by the Multiple Sclerosis Association of America and hosted by Dr. Linda Blakely entitled, “Support America Style” August 17, 1995 which described the current MS research being conducted at NASA Ames Research Center. • Prepared an additional program for presentation in the “Support America Style” television series hosted by Dr. Linda Blakely August 29-30, 1995 which described NASA Ames Research Center’s biomedical application of liquid cooling garments program. • NASA Ames "Neslab" dedication press conference - March 1996 which included national television coverage (8 local TV stations located in San Jose, San Francisco, Chicago, Miami; NASA Television; and the Cable News Network - CNN ) and numerous newspaper articles and radio broadcasts. • Interviewed "Live at NASA Ames Research Center: Space Suits and Cooling Technology" by Tracy Gallagher, BayTV morning show, on March 12, 1997 • Interviewed April 7, 1997, by Q Media (Virginia Casada) for Evan-Gilruth Foundation, contracted by Code UL at HQ to produce a NASA Space Life Sciences "medical benefits" video for use during NASA/Congressional public relation activities. • Prepared educational CD at Digital Clubhouse Network describing "NASA MS Technology Transfer Program" - Feb. 1997. NEWS MEDIA / AWARDS • Aviation Week & Space Technology - June 1994 • NASA Ames Research Center "Astrogram" articles - 2/10/1995, 4/5/1996 138
• MSAA newsletter "Motivator" articles - 1994/1995 • Adult Day Enrichment Program - "Enriched News" - July and Dec. 1995; Feb. and Aug. 1996 • The "News INN Research" newsletter - July and Dec. 1995; May 1996 • Kaiser Electronics Newsletter "IMAGES"- April 1996 • Hot Springs Sentinel Record coverage of INN Research briefing - May 1996 • Participated the VA and MSAA "Partnership Awareness Technology" program at VA Medical Center, Washington DC on June 6, 1996. • Lockheed Martin Engineering & Science Services Newsletter "STAR TRACKER"- July 1996 • NASA Ames Contractor Council "Contractor Council Excellence Award" - Oct. 1995 • Lockheed martin Engineering & Science "Lighting Award" - May 1996 • Lockheed Martin Technology Services "SPOTLIGHT" Magazine "Very Cool – Technology Service, NASA, MSAA sign “cool” technology agreement” - August 1997 • Lockheed Martin "TODAY" Newsletter which described our MS Cooling Program.- Sept. 1997 • Lockheed Martin "THE STAR" Newsletter which described cool suit technology program.- Sept. 1997
139
140
