Neuropsychological consequences of chronic ... - Semantic Scholar

Brain (2000), 123, 2091–2108

Neuropsychological consequences of chronic bilateral stimulation of the subthalamic nucleus in Parkinson’s disease Jean A. Saint-Cyr,1,2,3 Lisa L. Tre´panier,1,4 Rajeev Kumar,5 Andres M. Lozano2 and A. E. Lang1 Departments of 1Medicine, Division of Neurology and 2Surgery, Division of Neurosurgery, University Health Network, Toronto Western Hospital Research Institute, University of Toronto and The Toronto Western Hospital, 3Department of Psychology, University of Toronto, 4Department of Psychology, York University, Toronto, Canada and 5Colorado Neurological Institute, Englewood, Colorado, USA

Correspondence to: Dr Jean Saint-Cyr, University Health Network, Toronto Western Hospital, 399 Bathurst Street, Centre for Movement Disorders, Main Pavillion, 11-304, Toronto, Ontario, Canada M5T 2S8 E-mail: [email protected]

Summary The aim of this study was to examine possible neuropsychological changes in patients with advanced idiopathic Parkinson’s disease treated with bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN). Eleven patients (age ⍧ 67 ⍨ 8 years, years with Parkinson’s disease ⍧ 15 ⍨ 3, verbal IQ ⍧ 114 ⍨ 12) were evaluated (in their best ‘on state’) with tests assessing processes reliant on the functional integrity of frontal striatal circuitry, prior to the procedure (n ⍧ 11), at 3–6 months (n ⍧ 11) and at 9–12 months (n ⍧10) postoperatively. Six of these patients were older than 69 years. Despite clinical motor benefits at 3–6 months postoperative, significant declines were noted in working memory, speed of mental processing, bimanual motor speed and co-ordination, set switching, phonemic fluency, long-term consolidation of verbal material and the

encoding of visuospatial material. Declines were more consistently observed in patients who were older than 69 years, leading to a mental state comparable with progressive supranuclear palsy. ‘Frontal’ behavioural dyscontrol without the benefit of insight was also reported by half (three of six) of the caregivers of the elderly subgroup. At 9–12 months postoperative, only learning based on multiple trials had recovered. Tasks reliant on the integrity of frontal striatal circuitry either did not recover or gradually worsened over time. Bilateral STN DBS can have a negative impact on various aspects of frontal executive functioning, especially in patients older than 69 years. Future studies will evaluate a larger group of patients and examine the possible reversibility of these effects by turning the DBS off.

Keywords: neuropsychology; subthalamic nucleus; deep brain stimulation; Parkinson’s disease Abbreviations: ADL ⫽ activities of daily living; BEM ⫽ Batterie d’efficience mne´sique; CALT ⫽ Conditional Associative Learning Test; CVLT ⫽ California Verbal Learning Test; DBS ⫽ deep brain stimulation; FLOPS ⫽ Frontal Lobe Personality Scale; fMRI ⫽ functional MRI; GDI ⫽ Geriatric Depression Inventory; GPi ⫽ globus pallidus, internal segment; PASAT ⫽ Paced Auditory Serial Addition Test; PSP ⫽ Progressive Supranuclear Palsy; PVP ⫽ posteroventral pallidotomy; SMA ⫽ supplementary motor area; STN ⫽ subthalamic nucleus; TMT ⫽ Trail Making Test; UPDRS ⫽ United Parkinson’s disease Rating Scale

Introduction Current models of basal ganglia dysfunction in Parkinson’s disease have focused on the key role of the subthalamic nucleus (STN) (Wichmann and DeLong, 1996). Increased tonic activity in the STN has been demonstrated with single unit recording during neurosurgical interventions in Parkinson’s disease (Hutchison et al., 1998), as well as © Oxford University Press 2000

in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)induced parkinsonian monkey chemotoxic preparation (Wichmann and DeLong, 1996). As a treatment approach, the implantation of deep brain stimulating (DBS) electrodes is preferred over lesions because of the potential for fewer persistent complications (especially hemiballismus when

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dealing with the STN) and the capacity for individualized treatment by adjustment of electrode and stimulation parameters (Krack et al., 1997, 1998; Benabid et al., 1998; Limousin et al., 1998). In addition, DBS is believed to permit bilateral application more safely than lesions (Louw and Burchiel, 1998). Our experience with three cases (Galvez-Jimenez et al., 1996; Tre´ panier et al., 2000) and the outcome of cases reported by others (Roberts and Heilbrun, 1997; Bronstein et al., 1998; Scott et al., 1998; Tierney et al., 1998; Ghika et al., 1999) generally indicate that, despite clinical motor improvement, this procedure carries a high risk of unacceptable adverse effects in other aspects of motor, cognitive and behavioural functioning. Neuropsychological studies have generally concluded that the DBS procedure is benign (Ardouin et al., 1999b; Ghika et al., 1998). However, placement of the DBS electrode within the internal segment of the globus pallidus (GPi) has been shown to result in vastly different clinical outcomes (Bejjani et al., 1997) and there have been some reports of decreased cognitive function (Tro¨ ster et al., 1997; Limousin et al., 1998; Tre´ panier et al., 1999, 2000; Vingerhoets et al., 1999). Also, lesion location within the GPi has been shown to differentially affect both clinical outcome and cognitive profile (Gross et al., 1999; Lombardi et al., 2000). Although a recent multicentre study of DBS for both the GPi and STN targets failed to demonstrate significant neuropsychological impairment (Ardouin et al., 1999b), scrutiny of their data did indicate that some patients experienced cognitive problems. Factors such as the age of these patients and the scope of the assessment battery could have combined to mask potential problems, as we had previously described (cf. Tre´ panier et al., 1999, 2000). The current study was designed to evaluate patients in two age groups and to provide longitudinal data with regard to their neuropsychological functions subsequent to bilateral STN DBS treatment.

Subjects and methods Selection criteria Patients with idiopathic Parkinson’s disease (diagnosis confirmed by a neurologist with expertise in movement disorders) were considered for bilateral DBS in the STN if they met the following inclusion criteria: substantial disability due to frequent ‘off’ periods or drug-induced dyskinesias despite optimization of antiparkinson medications, and compliance with pre- and postoperative assessments. Exclusion criteria included: dementia, unstable medical status, prior neurosurgical procedure, MRI evidence of other CNS disease, current psychiatric complications compromising cooperation, failure to obtain informed consent, or incapacity to deal with management and adjustment of the DBS device post-operatively.

Patients Clinical and demographic data for the 11 patients are presented in Table 1A. Due to our preliminary clinical

observations, patients older than 69 years at time of surgery were separated into an older subgroup (see Table 1B) and analysed separately as well as part of the whole group. Only one patient could not contribute to several of the verbally based tests due to a language barrier. All participating patients gave informed consent. The study was approved by the Hospital Committee for Research on Human Subjects.

Surgical procedure The STN target was identified by MRI and was located by the stereotaxic guidance of microelectrode recordings and stimulation (Lozano et al., 1996; Hutchison et al., 1998). Once the final target coordinates were determined, a permanent quadripolar DBS macroelectrode (Medtronic, Columbia Heights, Minn., USA, model 3387) was implanted and then intraoperative test stimulation was carried out to optimize clinical effects and reduce adverse effects. After 1 week, the electrode cables were internalized and connected to an internal pulse generator (Medtronic, Itrel). Details of the procedures and equipment employed are described elsewhere (Kumar et al., 1998a, b). Beginning in the first month following surgery, systematic screening of the effects of DBS applied through the various electrode combinations was carried out and optimal parameters selected.

Clinical motor evaluation Clinical effectiveness of the various parameters of stimulus delivery was evaluated with the motor section of the Unified Parkinson’s Disease Rating Scale (UPDRS) (Fahn and Elton, 1987). Details concerning the neurological evaluation protocol and related results from the patients of the current study (in part or in full) are fully reported elsewhere (Kumar et al., 1998 a, b; Lang et al., 1997b). Table 2A indicates UPDRS ratings and the L-dopa equivalent doses of medication (calculated as outlined in Lang et al., 1997b) before surgery and at each follow-up visit for the younger and older subgroups of patients. At the time of the first postoperative neuropsychological evaluation, all patients had benefited from stable DBS settings for at least 2 months. Settings were either bipolar or monopolar and are reported in Table 2B. In addition, adaptation to altered L-dopa dosages had also been achieved. Separate statistical analyses of medication dosages (L-dopa or agonists) revealed no significant differences between the two groups of patients, either pre- or postoperatively, although the younger patients tended to tolerate higher doses (preoperatively older ⫽ 1284.2 mg/equivalent, younger ⫽ 1704 mg/equivalent; 12 months postoperatively older ⫽ 679.2 mg/equivalent, younger ⫽ 782.5 mg/equivalent). Stimulation parameters for each group were not statistically different postoperatively at any point (i.e. 3, 6 or 12 months).

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Table 1A Bilateral STN: patient characteristics Variable

Sum

n 11 Females 5 Males 6 Handedness Right 10 Left 1 Age (years) . Education (years) . Estimated premorbid IQ . Current WAIS-R VIQ . Duration of disease (years) . Severity of disease (H and Y) ‘Off’ medication . ‘On’ medication . Medication regime at baseline (L-dopa equivalents in mg/day) .

Mean (SD)

Range

. . .

. . .

. . 66.5 (7.9) 14.5 (4.5) 117.4 (11.2) 113.8 (12.1) 14.7 (3.3)

. . 54–75 3–20 87–128 94–130 11–22

4 (1.2) 2.6 (0.3) 1475 (630.5)

2.5–5 2–3 650–2375

Table 1B Bilateral STN: patient characteristics (older than 69 years of age) Variable

Sum

Mean (SD)

Range

n Females Males Handedness Right Age (years) Education (years) Estimated premorbid IQ Current WAIS-R VIQ Duration of disease (years) Severity of disease (H and Y) ‘Off’ medication ‘On’ medication Medication regime at baseline (dopa equivalents in mg/day)

6 2 4

. . .

. . .

6 . . . . .

. 72.5 (2.3) 16.3 (2.6) 123.3 (2.9) 117.5 (9.1) 16.2 (3.5)

. 70–75 12–20 119–128 107–130 12–22

. . .

4.3 (1.2) 2.8 (0.3) 1284.2 (609.8)

2.5–5 2.5–3 700–2300

H and Y ⫽ Hoehn and Yahr Rating Scale (Hoehn and Yahr, 1967). For other abbreviations see Appendix 1.

Neuropsychological evaluations Baseline or preoperative evaluation In order to assess suitability for trial inclusion, as well as to establish a baseline cognitive profile, a thorough clinical interview and neuropsychological evaluation were completed preoperatively. Patients were then re-assessed at 3–6 and 9–12⫹ months postoperatively. Not all patients were seen on all occasions, nor was it always possible to assess patients on all measures, but all patients had at least one follow-up assessment and all but one younger patient had at least two follow-up assessments. In order to maximize postoperative data for each measure, data were collapsed across time periods, such that patients’ first evaluation (3 or 6 months) was used for the short-term follow-up analyses (since no statistical differences were found between those time periods on initial analyses) and patients’ last assessment (9–12 months) was used for the longer-term follow-up analyses (see Table 2C). In the latter group, seven evaluations were completed at 12 months, and three at 9 months postoperatively. Patients were evaluated in their optimal

behavioural state on medication (i.e. in the ‘on’ state) and had their stimulators turned on during all assessments (current and total energy parameters are reported in Table 2B). There were significant reductions in the dosage of total dopaminergic medication postoperatively (Kumar et al., 1998a) (see also Table 2A). Components of the neuropsychological test battery were selected with three considerations in mind: the battery had to be relatively brief (3–4 h), evaluate a range of cognitive domains often affected by Parkinson’s disease, and include tests assessing aspects of cognitive, behavioural and emotional processes that have been shown to be affected by thalamotomy and/or pallidotomy (Riklan et al., 1960; Vilkki and Laitinen, 1976; Kocher et al., 1982; Tre´ panier et al., 1998; and which are commonly used in the neuropsychological evaluation of Parkinson’s disease (Taylor et al., 1986; Brown and Marsden, 1990; Taylor and Saint-Cyr, 1995; Dubois and Pillon, 1997). Neuropsychological tests administered are listed in Appendix 1, along with abbreviations as used in the text and

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J. A. Saint-Cyr et al. Table 2A L-DOPA equivalent doses (mg/day) preoperatively and postoperatively at 3, 6 and 12 months; total and motor UPDRS scores Evaluation

mg/day (⫾SD)

UPDRS total (⫾SD)

UPDRS motor (⫾SD)

Younger patient subgroup, younger than 69 years Pre-operatively 1704 (651.2) 3 months 941 (592.5) 6 months 835 (519.5) 12 months 782.5 (492.7)

62.5 (16.9) 49 (19.2) 45.2 (20.7) 43.4 (17.9)

29.3 15.3 13.9 14.3

(11.4) (12.2) (8.6) (6.4)

Older patient subgroup, older than 69 years Pre-operatively 1284.2 (609.8) 3 months 687.5 (384) 6 months 595.8 (334.8) 12 months 679.2 (394.5)

62.8 62.8 64.9 68.3

36.7 24.1 25.6 29.2

(13.7) (7.4) (7.8) (6.1)

(16.3) (23.2) (18.7) (15.3)

For younger patient subgroup, mean decline in medication ⫽ 54% (mg/day) (baseline versus 12 months). For older patient subgroup, mean decline in medication ⫽ 47% (mg/day) (baseline versus 12 months).

Table 2B Mean current (I ⫻ 10-3) and energy (in coulombs ⫻ 10-5) parameters at 3, 6 and 12 months Evaluation

Mono I (⫾SD)

Mono C (⫾SD)

Bipolar I (⫾SD)

Bipolar C (⫾SD)

3 months 6 months 12 months

2.69 (0.88) 3.21 (1.28) 2.89 (1.04)

2.54 (1.05) 3.20 (1.40) 3.01 (1.42)

2.46 (1.06) 2.75 (0.91) 2.89 (0.92)

2.53 (1.24) 2.67 (0.80) 3.02 (1.10)

Mono ⫽ monopolar stimulation; bipolar ⫽ bipolar stimulation; I ⫽ current in milliamperes (calculated from measured voltage and impedance); C ⫽ coulombs (⫻10–5) (amp-s) (s calculated from frequency and pulse width settings). For one case of tripolar stimulation (double negative), the voltage value was doubled for the calculation. For one case of tripolar (double positive), voltage value was not adjusted.

Table 2C Schedule of neuropsychological assessments Evaluation

All bilateral STN cases

STN cases older than 69 years

STN cases younger than 69 years

Preoperative Postoperative 3–6 months 9–12⫹ months

11

6

5

11 10

6 6

5 4

tables. Care was taken not to confound practice effects with improvement in cognitive processing by using alternate forms (order randomized across patients), where available, to examine verbal memory [California Verbal Learning Test (CVLT) forms 1 and 2] and verbal phonemic fluency (FAS and CFL versions of the Controlled Oral Word Association Test). Forms were alternated for each evaluation. While the battery of tests was designed to be as short as possible, evaluations were extended across as many as three separate sessions if fatigue was a factor. Therefore, no patient’s results were contaminated by undue stress, lack of sleep, poor clinical response to stimulation or medication, or other factors which could functionally reduce test performance. In addition to the formal neuropsychological evaluation, a clinical interview was conducted to assess the presence of

depressive or other psychiatric complications and their possible impact on either test performance or the patient’s ability to give informed consent.

Statistical analyses Paired comparisons (Student’s t-test) were made between pre-operative and short-term (3–6 months) postoperative scores. No correction was made for multiple comparisons since all tests had been selected a priori as being potentially sensitive for these patients and treatment. This may have inflated Type 1 error, which is in the direction of safety for a clinical trial. For patients with long-term follow-up data, scores were subjected to a RMANOVA (repeated measures analysis of variance). Previous experience has demonstrated

STN DBS and cognitive outcome that very little decline in cognitive abilities is observed over a 1-year period in typical Parkinson’s disease patients without surgery or on measures known to be insensitive to surgery (see Baron et al., 1996; Tre´ panier et al., 1998, 1999; Stebbins et al., 2000). Thus, significant decline at 9–12 months would indicate a further unexpected weakening of frontal striatal functions that would not normally occur in the course of disease progression.

Individual patterns of change To evaluate test score changes among individual patients at their first follow-up evaluation, each reported test score was transformed to a standard (Z) score using published normative data for all measures except the Paced Auditory Serial Addition Test (PASAT) 5⬘ and 3⬘, where a conservative 15% change in the number correct was considered to be clinically significant. This criterion was used for the PASAT due to high variability at baseline and the fact that it is an experimental but clinically valid measure for this population. The clinical criteria of more than ⫾1 SD and more than ⫾2 SD were employed to tally improvements and declines. Both levels of analyses were completed for the whole bilateral STN DBS group and for the older than 69 years subgroup.

Results Baseline neuropsychological profile As seen in Table 1, there were no statistically significant differences between premorbid and current IQ measures within the whole group or the elderly subgroup, mean scores being well above average preoperatively. Examination of other selected baseline psychometric tests indicated that the study group had evidence of mild to moderate executive dysfunction comparable with scores obtained by advanced Parkinson’s disease patients in other studies. These frontal executive difficulties affect processing across many cognitive domains, a neuropsychological profile comparable with that seen in other groups of Parkinson’s disease patients with on/ off fluctuations (e.g. within 1 SD of means and standard deviations presented in Taylor et al., 1986, 1987) on the Conditional Associative Learning Test (CALT), Trail Making Test (TMT) part B, FAS and CVLT.

Postoperative course As reported in detail elsewhere (Kumar et al., 1998a, b; Lang et al., 1997b) and in Table 2A, clinically significant improvements in motor function were observed. At the time of the first post-operative neuropsychological assessment, patients showed 60% improvement in off-period motor scores and 30–40% improvement in off-period activities of daily living (ADL) scores. On-period motor scores improved by about 40%. In general, older patients did not improve as much as the younger patients (on medication, on stimulation

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motor UPDRS scores: older ⫽ 34, 30 and 20%, relative to preoperative scores at 3, 6 and 12 months, respectively, versus 48, 53 and 51% for the younger patients at the same postoperative times). Postoperative doses of dopaminergic medication were significantly reduced in the post-operative period (46% for the elderly group and 45% for the younger group, in mg/day L-dopa equivalent dosage) (Kumar et al., 1998a, b). These clinical and drug changes were sustained for the 12 month follow-up period (47% and 54% at 12 months for the older and younger patient groups, respectively). Parameters of DBS also remained stable across assessments (Table 2B). MRI verification of DBS placement within the STN was available for nine of 11 patients, of which eight were reconstructed three-dimensionally (Saint-Cyr et al., 2000). For the other two patients, a CT scan was available for one and the other had electrode position verified at surgery with fluoroscopy using stereotaxic frame fiducials. In addition, all of the neurophysiological data from the surgeries were cross-correlated to the imaging. It was determined that, for all patients, stimulation via DBS electrodes was in the STN. For seven of 12 electrode contacts in the older patients and five of 10 electrode contacts for the younger patients, current invaded the dorsally adjacent lenticular fasciculus as well. One patient had a small haemorrhage in the supplementary motor area (SMA) at surgery. His postoperative course was comparable with other patients of his age group (young). There was a tendency towards intraoperative and postoperative confusion in the elderly (older than 69 years) STN DBS patients (Kumar et al., 1998a, b). Confusional states lasting 1–2 weeks postoperatively developed in four of the first 16 STN DBS patients (all older than 69 years) in the study by Kumar and colleagues (Kumar et al., 1998a, b), and two of these patients (in our group) were still experiencing confusional episodes at their 3 month followup assessment.

Pre- and postoperative group comparisons and individual analyses Pre- to 3–6 month (short-term) follow-up group comparisons indicated reduced finger tapping with and without divided attention, slower set alternation, decreased lexical fluency, and impaired verbal and non-verbal memory (Table 3A). Further analyses of the elderly subgroup (older than 69 years, n ⫽ 6) during the same follow-up period suggested that some of these results were possibly due to the elderly patients’ performance (Table 3B). Tallies of the number of patients demonstrating ⬎1 SD change (decline, improvement or no change) are presented by cognitive domain and specific test measure in Tables 3A and B. Results of the longitudinal analyses for the individuals who received specific tests at all follow-up evaluation times are presented in Table 3C. Tables 4A (whole group) and B (elderly subgroup) indicate the general patterns of change by testing domain at the first 3–6

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J. A. Saint-Cyr et al.

Table 3A Neuropsychological test scores pre- and 3–6 months post-bilateral STN stimulator implantation (n ⫽ 11) and number of patients demonstrating test score changes ⬎1 and ⬎2 SD Tests/subtests (n)

Mean score (SD) Preoperative

Digit Span-F (9) 7.6 (2.6) Digit Span-B (9) 6.1 (1.9) PASAT 5 s (9) 34.1 (12.5) PASAT 3 s (9) 27.7 (15.9) TMT-A, s (10) 56 (21.4) Fine motor functions Purdue Pegboard Total score (9) 34.1 (8.4) Both hands (9) 7.6 (1.9) Finger tapping PH (10) 36.6 (8.7) NPH (10) 32.7 (8.8) Coin sorting while finger tapping % savings PH (9) 78.3 (25.9) t% savings NPH (9) 73.8 (15.8) Executive functioning Petrides 4-disk CALT 56.5 (15.3) Trial score/68 (10)†,‡ 37.9 (29.7) No. of errors (10)‡ 101.2 (39.3) TMT-B, s (9)† 50.9 (30) TMT-B – A, s (9)† Language Verbal fluency (FAS/CFL) Total score (10) 36.5 (12.1) Switching (10) 25.2 (10.4) Clustering (10) 0.38 (0.2) Semantic fluency (3 categories) Total score (10) 38.8 (11.5) Switching, animals 6.4 (1.8) Clustering, animals 1.1 (0.4) Verbal learning and memory CVLT Total score (9) 42.2 (13.4) Trial 1 (9) 5.7 (2.6) Trial 5 (9) 10.3 (3) Trial B (9) 5.2 (2.4) SDFR (9) 8.3 (3.5) SDCR (9) 9.3 (3.8) LDFR (9) 9.1 (4.2) LDCR (9) 10.1 (3.4) Recognition (8) 15.4 (0.9) 3.6 (2.7) No. of perseverations‡ Free recall intrusions (9)‡ 1.3 (2.1) Proactive interference (trial B – trial 1) (9) –0.4 (2.6) 25.4 (11.5) % Clustering (9)† Visual learning and memory BEM (visual subtests) Total score (9) 48.6 (12.4) tAL (9) 7.4 (1.7) RL (9) 7.7 (2.5) RIE (9) 8.8 (2.3) RDE (9) 7.9 (2.7) AP (9) 9 (3.4) RC (9) 7.7 (2.9) Mood and frontal lobe behavioural questionnaires 11.6 (4.6) GDI (10)‡ FLOPS 94.7 (14.1) Self ratings (10)‡ 80.7 (18.1) Caregiver ratings (9)‡

Number of patients demonstrating changes Postoperative

⬍1 SD

Declined ⬎2 SD

⬍1 SD

7.4 (2.0) 5.3 (2.4) 30.9 (11.3) 23.8 (10.1) 92.1 (94.3)

0 0 2 2 1

0 3 0 2 2

30 (11.1) 6 (2.9)*

0 1

42.3 (9.4) 38.2 (7.4)*

Improved ⬎1 SD

⬎2 SD

9 5 5 3 6

0 1 2 1 1

0 0 0 1 0

3 4

6 4

0 0

0 0

0 0

1 0

5 6

1 3

3 1

56.6 (27.3)@ 48.7 (26.5)*

2 3

2 3

4 3

1 0

0 0

64.3 (17.7) 44.8 (30.2) 136 (35.1)** 76 (37.4)@

2 2 1 2

1 1 5 3

6 5 3 3

1 1 0 1

0 1 0 0

23.7 (11.7)** 16.1 (8.8)** 0.29 (0.2)

1 0 2

6 6 0

3 4 7

0 0 1

0 0 0

31.6 (14.6)* 5.2 (2.2)* 1.4 (0.7)

0 0 0

3 3 1

7 7 5

0 0 2

0 0 2

37.6 (16.1) 5.4 (2.7) 9.1 (4) 4 (2.4) 6.6 (4.9) 8.4 (4.4) 6.4 (5.3)* 7.8 (4.7)** 14.5 (1.4) 4.3 (4.2) 2 (3.3)

0 0 2 1 2 1 1 1 0 1 1

4 4 2 4 1 3 3 5 3 3 3

4 3 3 3 4 5 2 3 5 4 3

1 1 1 1 2 0 2 0 0 1 1

0 1 1 0 0 0 1 0 0 0 1

–1.4 (1.3) 19.1 (15.7)

1 1

1 3

6 4

1 0

0 1

42.7 (12.8)* 5.7 (2.7)* 6.7 (3.2) 7.4 (2.3)* 6.4 (2.1)@ 7.7 (3.6) 8.9 (2.3)@

0 2 1 1 0 4 0

7 3 4 4 5 1 2

1 4 3 4 3 1 2

1 0 0 0 1 2 3

0 0 1 0 0 1 2

10 (5.6)

1

0

7

2

0

95 (12) 91.9 (26.7)

1 2

2 2

6 5

0 0

1 0

Paired t-tests ** ⫽ 0.001 艌 P 艋 0.009, * ⫽ 0.01 艌 P 艋 0.05, @ ⫽ 0.06 艌 P 艋 0.10. †Floor effects forced the elimination of one patient’s TMT-B data and caused underestimates for the tallies of individual decline, but deterioration in performance was evident. Floor effects were also seen on CALT-trial score and % clustering a CULT. ‡A lower score means better performance. For abbreviations see Appendix I.

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Table 3B Neuropsychological test scores pre- and 3–6 months post bilateral STN stimulator implantation and number of patients older than 69 years of age (n ⫽ 6) demonstrating test score changes ⬎1 and ⬎2 SD Tests/subtests (n)

Mean score (SD) Preoperative

Attention Digit Span-F (4) 9 (2.9) Digit Span-B (4) 6.5 (1.7) PASAT 5 s (6) 31.7 (14.9) PASAT 3 s (6) 21.8 (16.2) TMT-A, s (6) 62.2 (26.0) Fine motor functions Purdue Pegboard Total score (6) 30.5 (6.7) Both hands (6) 6.8 (1.6) Finger tapping PH (6) 33 (6.5) NPH (6) 27.2 (3.8) Coin sorting while finger tapping % savings PH (6) 82.8 (22.7) % savings NPH (6) 76.7 (11.9) Executive functioning Petrides 4-disk CALT 49.7 (16.7) Trial score/68 (6)‡† 31.5 (34.8) No. of errors (6)‡ 102.2 (38.6) TMT-B, s (5)† 49 (24.3) TMT-B – A, s (5)† Language Verbal fluency (FAS/CFL) Total score (6) 39.5 (11.9) Switching (6) 27.2 (9.4) Clustering (6) 0.4 (0.2) Semantic fluency (3 categories) 39.7 (14.2) Total score (6)† Switching, animals 6.3 (2.4) Clustering, animals 1.1 (0.4) Verbal learning and memory CVLT Total score (6) 43.8 (14.7) Trial 1 (6) 6 (3.1) Trial 5 (6) 11 (3.5) Trial B (6) 5.5 (2.8) SDFR (6) 8.2 (4.4) SDCR (6) 9 (4.4) LDFR (6) 8.7 (4.6) LDCR (6) 10 (3.7) Recognition (6) 15.2 (1) 2.5 (2.3) No. of perseverations‡ ‡ 1.2 (1.8) Free recall intrusions (6) Proactive interference (trial B – trial 1) (6) –0.5 (3.2) % Clustering (6) 27.2 (13) Visual learning and memory BEM (visual subtests) Total score (6) 48.8 (15.4) AL (6) 7.4 (2.2) RL (6) 7.5 (3.1) RIE (6) 9 (2.5) RDE (6) 7.9 (3.3) tAP (6) 9.3 (4.2) RC (6) 7.6 (3.3) Mood and frontal lobe behavioural questionnaires 11.8 (4) GDI (6)‡ FLOPS ‡ 95.2 (15.3) Self ratings (6) 79.5 (21.3) Caregiver ratings (6)‡

Number of patients demonstrating changes Postoperative

⬍1 SD

Declined ⬎2 SD

⬎1 SD

8 (2.6) 5.3 (2.2) 29.2 (11.9) 21.3 (11.0) 115.3 (119)

0 0 0 0 1

0 1 1 0 2

26 (11.6) 4.8 (2.8)@

0 1

39 (10.3) 35.3 (7.7)@

Improved ⬎1 SD

⬎2 SD

4 3 5 5 2

0 0 0 1 1

0 0 0 0 0

2 3

4 2

0 0

0 0

1 0

0 0

3 2

0 3

2 1

51.3 (30.6) 38 (18.6)*

2 4

2 2

1 0

1 0

0 0

61.8 (15.1) 46.3 (37.2) 139.8 (34)* 71.6 (33.4)

1 1 1 1

0 1 3 2

4 4 1 1

1 0 0 1

0 0 0 0

24.5 (12.8)** 17.2 (9.2)** 0.3 (0.2)

1 0 0

3 4 0

2 2 6

0 0 0

0 0 0

33.3 (16.1)* 5.2 (2.6)* 1.4 (0.7)

0 0 0

1 2 0

5 4 4

0 0 1

0 0 1

36.5 (18.2)@ 5.7 (2.8) 8.7 (4.6)@ 3.7 (2.3)@ 6 (5.4)@ 8.3 (4.9) 6.2 (6)* 7.3 (5.3)* 14.2 (1.5) 3.5 (4.7) 0.8 (1.3)

0 0 2 1 1 0 0 1 0 0 0

4 3 2 3 1 3 2 3 2 2 2

1 2 2 2 3 3 2 2 4 2 2

1 0 0 0 1 0 2 0 0 2 1

0 1 0 0 0 0 0 0 0 0 1

–2.0 (0.9) 21.7 (18)

1 1

1 2

3 2

1 0

0 1

41.8 (15.3)* 5.6 (3.2)@ 6.3 (3.4)@ 7 (2.8)* 6.8 (2.5) 7.5 (4) 8.6 (2.6)

0 2 0 2 0 3 0

5 2 3 2 3 1 2

1 2 3 2 2 1 1

0 0 0 0 1 0 1

0 0 0 0 0 1 2

9 (4.6)*

0

0

4

1

1

88.7 (8.8) 94 (31.2)

0 1

1 2

4 3

0 0

1 0

Paired t-tests ** ⫽ 0.001 艌 P 艋 0.009, * ⫽ 0.01 艌 P 艋 0.05, @ ⫽ 0.06 艌 P 艋 0.10. †Floor effects forced the elimination of one patient’s TMT-B data and caused underestimates for the tallies of individual decline, but deterioration in performance was evident. Floor effects were also seen on CALT-trial score and semantic fluency total score. ‡A lower score means better performance. For abbreviations see Appendix I.

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Table 3C Results of longitudinal RMANOVA and post hoc t-tests following bilateral STN DBS Psychometric tests/domain

Attention PASAT 3⬘ (raw score/48) Digit Span-B (raw score) Fine motor functions Purdue Pegboard, both hands (no. of pegs, 45 s) Finger tapping, non-preferred hand Grip strength, non-preferred hand Coin sorting while finger tapping (% savings, preferred hand) Coin sorting while finger tapping (% savings, non-preferred hand) Executive functions TMT-B (s) CALT (total score/68) Language: fluency Phonemic fluency (FAS/CFL) (no. of words in 1 min) Category fluency (A, F, V) (no. of words in 1 min) Verbal learning (CVLT) LDFR (no. of words/16) LDCR (no. of words/16) Visuospatial encoding/learning BEM-RIE BEM-AL BEM-RC FLOPS Total score, caregivers Executive dysfunction index, caregivers Apathy index, caregivers Disinhibition index, caregivers

Pre-operative mean scores

3–6 month follow-up mean scores

9–12 month follow-up mean scores

Subgroup sample size

F

P

31 5.7

24.3 4.3

21* 4.6@

8 7

4.887 9.000

0.025* 0.004**

7.6 32.2 29.3

6.0* 38.1* 26.2

6.3@ 39.0* 25.6*

9 9 9

3.824 3.478 3.012

0.044* 0.056@ 0.078@

78.3

56.6@

53.8@

9

2.589

0.106@

73.8

48.7*

49.7*

9

3.573

0.05*

152 55.2

190** 63.9

237* 64.4*

9 9

5.917 1.93

0.012* 0.178

35.2

22.4**

22.8**

9

21.662

0.000**

38.6

29.7*

29.8*

9

7.026

0.006*

9.5 10.3

6.3* 7.8*

8.1 8.1

8 8

4.253 3.136

0.036* 0.075@

8.8 7.4 7.7

7.4* 5.7* 8.9@

6.7* 7.3*,† 9.3*

9 9 9

7.333 5.259 4.713

0.005** 0.018* 0.025*

73.2 28.0 25.2 20.0

92.4 40.6 28.2 23.6@

98.0* 41.4@ 34.4* 22.2

5 5 5 5

6.611 4.671 4.277 3.491

0.020* 0.045* 0.055@ 0.081@

The subgroup of patients who received all assessments contributed to these analyses (hence the smaller sample sizes). RMANOVA results reported in right columns as F and P values. All other statistics are post hoc t-tests comparing baseline and post-surgical results. ** ⫽ 0.001 艌 P 艋 0.009, * ⫽ 0.01 艌 P 艋 0.05, @ ⫽ 0.06 艌 P 艋 0.10. †3–6 to 12⫹ months comparison. For abbreviations see Appendix I.

month follow-up. Table 5 tallies the prevalence of behavioural complaints made by patients and caregivers. These complaints are presented in three general categories: environmental dependency, psychosocial/emotional control and executive/ cognitive. Results will be presented by cognitive domain.

majority of patients performed consistently more slowly on a task requiring the ability to alternate sets (TMT-B). Patients also had increased problems in forming spatial conditional associations (CALT) at the 9–12 month follow-up.

Language Attention and working memory Although attention did not change significantly over the short term (3–6 months), a decline in working memory was seen across both groups of patients at the 9–12 month period.

Fine motor functions The STN DBS patients became quicker but weaker with their non-preferred hand and had more difficulties with bimanual co-ordination post-operatively. Patients in the elderly subgroup were more vulnerable to these effects.

The majority of patients declined significantly on phonemic fluency and category/semantic fluency and did not recover to baseline levels during the following year. Individuals who were followed for longer than 1 year also did not show recovery. Process analysis indicated that the cognitive process of ‘switching’, a measure known to decline in patients with frontal lobe but not temporal lobe lesions (Troyer et al., 1998a), declined for both measures of fluency. Further post hoc analyses of category fluency scores indicated that the category of ‘Fruits’ was the most sensitive contributor to this effect, with production being significantly impaired at both follow-up periods.

Executive functioning

Verbal learning

On direct tests of executive functioning, which were both visual in nature and had large attentional components, the

In the 3–6 month comparisons, significant declines were noted for the long delay free recall (LDFR) and long delay

STN DBS and cognitive outcome

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Table 4A Pattern of change by testing domain at first follow-up evaluation (3–6 months) for bilateral STN DBS patients (n ⫽ 11) Testing domain

Number of data points

Worsened ⬎1 SD (%)

No change ⬍1 SD (%)

Improved ⬎1 SD (%)

Attention Bimanual motor tasks Unilateral finger tapping Executive functioning Language: fluencies Verbal learning (CVLT) Visual learning (BEM) Mood (GDI) FLOPS

46 27 20 28* 20** 116 63 10 19

26 56 5 50 50 44 54 10 37

61 40 55 39 50 42 29 60 58

13 4 40 11 0 14 17 30 5

Clinically significant %/domain are highlighted in bold to indicate general trends. *Trial score for CALT from Table 3A was not included for the tallies due to floor effects for several patients. **Only total score measures were used for tallies. For abbreviations see Appendix I.

Table 4B Pattern of change by testing domain at first follow-up evaluation (3–6 months) for bilateral STN DBS patients older than 69 years (n ⫽ 6) Testing domain

Number of data points

Worsened ⬎1 SD (%)

No change ⬍1 SD (%)

Improved ⬎1 SD (%)

Attention Bimanual motor tasks Unilateral finger tapping Executive functioning Language: fluencies Verbal learning (CVLT) Visual learning (BEM) Mood (GDI) FLOPS

26 18 12 16* 12** 78 42 6 12

27 78 8 56 42 47 60 0 33.3

58 17 42 38 58 39 29 67 58.3

15 5 50 6 0 14 12 33 8.3

Clinically significant %/domain are highlighted in bold to indicate general trends. *Trial score for CALT from Table 3B was not included for the tallies due to floor effects for several patients. **Only total score measures were used for tallies. For abbreviations see Appendix I.

cued recall (LDCR) trials. Both measures recovered slightly over time but did not return to baseline levels (see Tables 3A–C). Individual analyses indicated that some patients made more intrusive and perseverative errors or had more difficulties with the strategic categorical organization of the 16-item shopping list. In the elderly subgroup, more early post-operative difficulty with verbal learning was found, with impairment of the initial encoding and switching between shopping lists [Trial to list B, short delay free recall score (SDFR)].

Visual learning and memory Total scores for seven visual subtests on the Batterie d’efficience mne´ sique (BEM) significantly declined at the 3– 6 month follow-up but resolved by the 9–12 month evaluation. Individual subtest analyses indicated that recognition of supraspan amounts of material (i.e. 24 designs, multiple choice format) significantly improved at 3–6 months postoperatively and continued to improve at the 9–12 month

follow-up (should be intact in non-demented Parkinson’s disease patients), but the encoding phases of new learning were more problematic 3–6 months postoperatively. Delayed recall of 12 designs and a complex figure were impaired at the 3–6 month follow-up, but both recovered. Although the latter did not recover completely when multiple trials of exposure were initially given, the immediate and delayed recall of 12 designs significantly improved from an initial impairment. In contrast, the initial encoding of the complex figure continued to decline mildly over time.

Mood and frontal lobe personality/behavioural changes No significant changes were noted on the Geriatric Depression Inventory (GDI) (patient rated) for the whole group, but significant improvements in depressive symptomatology (i.e. declines in score) were noted for the elderly subgroup. However, this benefit was not sustained over the first year

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Table 5 Prevalence of behavioural complaints postbilateral STN DBS Behavioural description

Prevalence of complaint (individual tallies) Patient (n ⫽ 11)

Environmental dependency (i) Perseveration (actions/ideas)

organizational abilities, word-finding and memory at patients’ first follow-up.

2

Psychosocial/emotional control (i) Unawareness of deficits 0 (ii) Social judgement 1 (iii) Lability (unipolar or bipolar) 2 (iv) Depression (not reactive to DBS) 1 (v) Impulsivity 2 (vii) Sexually inappropriate behaviours 0 (viii) Personality change 1 Executive/cognitive (i) Word-finding (fluency/quantity) 2 (ii) Overall memory 10 (iii) Concentration/distractibility 6 (iv) Organizational abilities 1 (v) Increased confusion 2 (vi) ‘General cognitive decline’ 2* (vii) Increased mental slowing 5

Caregiver(s) (n ⫽ 11) 1 1 1 2 1 1 0 1 1 5 3 2 2 2* 3

Data jointly collected from clinical interview and FLOPS. *One patient became functionally demented at the 6 month follow-up evaluation following re-insertion of the left electrode postinfection. The infection occurred after the 3 month assessment. Significant cognitive declines were observed at the 3 month follow-up prior to any infection, but further deterioration in all cognitive domains except verbal learning were observed by the next evaluation despite motor improvements.

of follow-up. The GDI depression ratings improved by 20% for the whole group and 33% for the elderly subgroup. On the Frontal Lobe Personality Scale (FLOPS), mild score elevations (indicating increased endorsement of frontal symptomatology) were noted from the caregivers, but not the patients, at the first 3–6 month follow-up. However, caregiver total scores were significantly elevated by the 9–12 month follow-up. Post hoc analyses of the three indices on the FLOPS indicated score elevations by caregivers on Executive Dysfunction (9–12 months, significant at P ⬍ 0.05), Apathy (9–12 months, significant at P ⬍ 0.05) and Disinhibition (3–6 months, significant for the elderly subgroup at P ⬍ 0.05 and a trend towards significance for the whole group). ‘Frontal’ behavioural dyscontrol was also reported by half (three of six) of the caregivers of the elderly subgroup, with lack of insight noted in two of these three patients. There were no group changes for any FLOPS measure collected from the patients. Although most serious problems were rare, complaints of changes in behaviour such as perseveration, impulsivity, social judgement, overall personality, emotional lability, depression and lack of awareness of deficits were reported. More common complaints related to increased confusion, concentration/ distractibility and mental slowing, as well as reductions in

Exceptions to overall patterns of change With regard to one patient, it should be noted that the resulting post-operative neuropsychological profile was somewhat atypical compared with the other patients. This patient experienced frontal lobe related personality changes (i.e. poor social judgement, disinhibition) as endorsed by the patient and spouse consistently over time postoperatively (how much insight the patient initially had was questionable). These changes were sufficiently noticeable to cause disturbance of family or social interactions. Furthermore, this patient did not show the typical declines in verbal fluency and conditional associative learning, nor did he display the faster finger tapping, weaker grip strength and increased difficulties with bimanual co-ordination more often seen in the other patients in this study. General cognitive decline (many domains affected) was observed in two of the six elderly patients (both very well educated). One of these patients became functionally demented following re-insertion of the left electrode postinfection. The infection occurred after the 3 month evaluation and subsequent data were not retained for inclusion in the statistical analysis or tables. Significant decline in frontal executive functioning was noted in this patient prior to this infection, but further deterioration in all cognitive domains except verbal learning was noted by the next 6 month evaluation (post-re-insertion) despite motor improvements over this same period when the stimulators were on.

Discussion Summary of neuropsychological findings Based upon the results from the current study, various aspects of frontal striatal functioning can be further compromised with bilateral STN DBS. In the elderly subgroup (older than 69 years), despite significantly improved mood, these cognitive and motor declines were more consistently observed, leading to a mental state reminiscent of that associated with progressive supranuclear palsy (PSP), especially with regard to the slowness of mental processing (Dubois et al., 1988). Cognitive processes involving executive functioning, such as working memory, phonemic fluency, encoding efficiency, susceptibility to interference, associative learning, the speed of processing and switching of mental sets, as well as bimanual co-ordination under conditions of divided attention, were impaired following electrode implantation and chronic stimulation. Tasks reliant on the integrity of frontal striatal circuitry either did not recover or gradually worsened over time. Only learning based on multiple trials recovered by the end of the first year of follow-up. Simple motor speed and visual recognition of novel designs improved over time. Certain aspects of

STN DBS and cognitive outcome frontal behavioural control were also affected in some patients, with a couple of elderly patients becoming unaware of their deficits. These neuropsychological results are in direct contrast to and dissociable from the excellent motor benefits (especially for the younger patients) brought about by the procedure (Kumar et al., 1998a, b). More detailed discussion by cognitive domain will follow.

Attention and working memory Despite trends in some measures (i.e. Digit Span— Backwards, TMT-A), only the rapid PASAT (3⬘) was significantly impaired after STN DBS. This is the most effortful working memory task in our battery. Thus, these results echo the observations of Stebbins and colleagues, who documented impairments in the executive components of working memory tasks 1 year after posteroventral pallidotomy (PVP) in comparison with Parkinson’s disease control patients (Stebbins et al., 2000). They found impaired performance in Digit Ordering and Listening Span in the domain of working memory. Rapid visual scanning and transposition were also found to be impaired. Press and colleagues have recently indicated that working memory can be either facilitated or inhibited by levodopa repletion (Press et al., 1999). One hypothesis is that both inadequate and excessive dopaminergic stimulation of frontal lobes can impair functioning and our significant postoperative reductions in dopaminergic medication along with chronic stimulation may be contributing to these changes in working memory. Another possibility is that the stimulation blocked pallidal outflow via the lenticular fasciculus in addition to direct effects on the STN.

Fine motor functions Improvement in motor control, especially in the time required to initiate and execute movements, has been documented after PVP (Jankovic et al., 1999; Kimber et al., 1999; Limousin et al., 1999), but surgical interventions have also resulted in deterioration of handwriting (Lang et al., 1997a; Tre´ panier et al., 1998, 2000), grip strength in the hand contralateral to surgery (Riordan et al., 1997a; Cahn et al., 1998) and difficulties in co-ordinating visually guided motor performance when reaching and grasping for small or large objects (Bennett et al., 1998). Bimanual co-ordination may decline following bilateral STN DBS, especially under conditions involving divided attention. This is true despite improvement in simple motor speed, but may be affected by reduction in grip strength in the non-preferred hand. Some patients complained of feeling ‘more clumsy’ yet ‘quicker’, probably indicating their reduction in bradykinesia, but had increased difficulties when motor tasks required more complex mental processes for successful execution. The nonpreferred hand (mostly the left hand in this study) appears to become more affected following this bilateral procedure. In light of the positive changes in simple motor hand

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speed and negative changes in grip strength and bimanual co-ordination (especially with the left hand), it is also interesting to note that the PET data for some of these patients indicated a right activation in primary motor cortex (near area 4, lateral surface which could be near the hand area), as well as activation in the cingulate and SMA (Davis et al., 1998). Activation of the cingulate and ventral SMA has also been noted in healthy subjects during bimanual coordination tasks and this function can be impaired in patients who have lesions in these areas (Stephan et al., 1999). It may be the case that STN DBS can have beneficial effects on certain aspects of motor functioning (i.e. bradykinesia) and negative effects on other aspects (i.e. strength and bimanual co-ordination) already known to be affected in patients with Parkinson’s disease (Johnson et al., 1998). Also, given the older age of this sample (mean age 67 years) compared with other studies of the neuropsychological sequelae of neurosurgery for Parkinson’s disease (for reviews of PVP and DBS data, see York et al., 1999; Fields and Tro¨ ster, 2000; Green and Barnhart, 2000), right hemisphere dysfunction may be more apparent in the current study, due to age-related vulnerability (Lezak, 1995; Spreen and Strauss, 1998).

Executive functioning While it is generally agreed that executive functions are the most vulnerable in Parkinson’s disease, a negative impact of surgical therapies has been demonstrated by some (Riordan et al., 1997b; Lucas et al., 1998; Stebbins et al., 2000), but not others (Baron et al., 1996; Jahanshahi et al., 1997; Perrine et al., 1998; Tre´ panier et al., 1998; Yokoyama et al., 1999). It has been suggested that this might be due to floor effects, with the implication that any such residual functions are likely to be carried out by circuits which are relatively independent of the striatum (Marsden and Obeso, 1994; see Samuel et al., 1997, regarding this same issue applied to movement). Alternatively, the lesions in the relatively larger and functionally segregated GPi could have missed the cognitively relevant circuits. In the more compact STN, it may prove impossible for the current to avoid impinging on sectors that are associated with cognitive functions. Performance for both TMT-B and CALT measures declined over time despite practice and familiarity with the tests. Like other executive measures of working memory in this study (e.g. PASAT 3⬘, Digit Span—Backwards), they began to decline at the 3–6 month follow-up and continued to decline at the 9–12 month follow-up. This rate of decline is unlike that found in unoperated Parkinson’s disease patients seen clinically, or in patients followed longitudinally subsequent to PVP (Baron et al., 1996; Tre´ panier et al., 1998; Stebbins et al., 2000) and is in contrast to the clinical motor benefits seen in these patients over the same follow-up period (Kumar et al., 1998a, b).

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Language The majority of patients declined significantly on phonemic fluency and category/semantic fluency and did not recover over the first follow-up year. This was the most significant finding in the present study and is consistent with observations following unilateral and bilateral pallidotomy as well as GPi DBS procedures (Tro¨ ster et al., 1997; Uitti et al., 1997; Cahn et al., 1998; Ghika et al., 1998; Masterman et al., 1998; Scott et al., 1998; Tre´ panier et al., 1998, 2000; Green and Barnhart, 2000). Process analysis indicated that the cognitive process of ‘switching’, a measure known to decline in patients with frontal lobe but not temporal lobe lesions (Troyer et al., 1998a), declined for both measures of fluency, indicating a further weakening of frontostriatal functioning. Typically, ‘switching’ is only impaired in Parkinson’s disease patients who are demented (Tro¨ ster et al., 1998; Troyer et al., 1998b), although the patients in the present study were not demented either pre- or post-operatively. It is interesting to note that the brain areas that were activated with STN stimulation (without cognitive challenge) in a PET study of a subgroup of these patients at this centre (Davis et al., 1998; K. D. Davis, personal communication), included the peri Broca’s region, near area 44/46 border, and the anterior cingulate, area 24. These areas are also activated in normal subjects performing verbal fluency tasks as measured with PET or functional MRI (fMRI) (Parks et al., 1988; Frith et al., 1991; Cuenod et al., 1995; Klein et al., 1995; Yetkin et al., 1995; Pujol et al., 1996). With regard to localization of cognitive functions within the frontal lobes, most of the imaging studies of STN DBS have shown a unilateral activation in the left inferior frontal gyrus, especially in left dorsolateral prefrontal cortex (Brodmann area 46), but have also reported variable activation in sensorimotor cortex and SMA. It is also intriguing that in one of our subsequent patients with a previous right-sided PVP lesion and now bilateral STN DBS, fMRI indicated that the left dorsolateral area was activated while performing an alternating fluency task when the stimulators were ‘off’, but the activation disappeared and the left caudate became activated (along with reduced fluency) with the stimulators ‘on’ (J. A. Saint-Cyr, M.-P. McAndrews and D. M. Mikulis, 1999, unpublished observations).

Verbal learning With repeated exposure to word lists, typical Parkinson’s disease patients display poor free recall but near normal recognition (Taylor et al., 1986b; Massman et al., 1990; Knoke et al., 1998). Thus, encoding and/or retrieval strategies are believed to be weakened by the disease. In the present study, performance on half-hour delayed free and cued recalls of a 16-item shopping list declined at the short-term follow-up period but partially resolved by the 9–12 month follow-up. Thus, the problem in verbal learning and memory appears to be in the consolidation phase, although most

aspects of the process were initially affected in the elderly subgroup.

Visual learning and memory The initial encoding of visual material is transiently affected, especially when the material is complex and when multiple exposures to the material during the learning phases are not provided. Problems with the delayed recall of material appear to be secondary to the initial encoding problems. These findings are of significance since alternate test forms were not available (as with verbal phonemic fluency and verbal learning, CVLT), so patients also had the opportunity to benefit from practice on the same tests over time, but could not improve their performance on certain aspects of visual learning. These findings are also in agreement with the righthemisphere activation seen on PET with a subgroup of these patients (Davis et al., 1998) since visual processing is thought to be predominantly carried out there (Lezak, 1995; Spreen and Strauss, 1998).

Mood and frontal lobe personality/behavioural changes Changes in mood and personality are expected in cases of vascular lesions of the basal ganglia (see reviews by Mendez et al., 1989; Bhatia and Marsden, 1994; Dubois et al., 1995; Saint-Cyr et al., 1995). It can be proposed that circuits associated with the ventral portions of the frontal lobes are most involved and that these are dissociable anatomically from motor control pathways. However, after PVP there may be cases of altered personality or behavioural control (Tre´ panier et al., 1998, 2000). In the present study, such changes were also seen. These changes could be attributed either to a global action of the DBS on all portions of the STN or to the possibility of current spread to adjacent dopamine cell groups (i.e. substantia nigra, pars compacta) projecting to the frontal and anterior cingulate regions, as well as to the ventral striatum (Lynd-Balta and Haber, 1994a, b; Williams and Goldman-Rakic, 1998). There could also be remote orthodromic and antidromic activation of fibre pathways (i.e. ascending dopamine fibres, nigrothalamic fibres and the Fields of Forel, including the lenticular fasciculus). This assumes that all observed effects were due to DBS. Since we know that the STN has much broader influences than the GPi physiologically due to its extensive projections, a more significant impact of STN DBS versus GPi DBS could be anticipated. One must also consider the impact of surgery, which involves multiple microelectrode penetrations, as contributing to these changes. The postoperative confusional state observed in many patients is thought to be due to surgical factors and the presence of oedema. While this state was usually transient, it persisted for a longer time in certain patients. In this study, caregiver scores on the FLOPS were

STN DBS and cognitive outcome elevated by the 9–12 month follow-up, which may reflect long-term maladaptive strategies or an iatrogenic organic brain syndrome. The one patient who experienced clinically significant frontal lobe-related personality changes (i.e. poor social judgement, disinhibition) did not show the typical declines in verbal fluency and conditional associative learning, nor did he display the faster finger tapping, weaker grip strength and increased difficulties with bimanual co-ordination more often seen in the other patients of this study. That patient was not premorbidly demented, but did appear to have fewer cognitive resources at the time of surgery. General cognitive decline (many domains affected) was observed in two of the six elderly patients. One deteriorated further following electrode re-insertion after an infection. Even once the infection resolved, the patient only improved to his 3 month level of frontal executive functioning (which was significantly impaired compared with preoperative levels) at 9 and 12 months postoperatively. The other patient had significant frontal executive dysfunction prior to surgery. Both patients were intellectually intact, were very well educated (17–18 years formal education) and had no preoperative indications of cortical dementia. From the results of the present study, a recent study on the cognitive impact of bilateral GPi DBS (Vingerhoets et al., 1999) and a recent study indicating increased vulnerability of frontal executive functioning with age in healthy adults (Parkin and Java, 1999), advancing age can make individuals more vulnerable to cognitive decline postoperatively. Infection around the electrodes, albeit rare, may also worsen existing vulnerabilities.

Conclusions The major finding in the present study is that STN DBS puts elderly patients at risk for cognitive impairment, even in the absence of any signs of early or incipient dementia. In addition, the clinical motor improvement may be quite modest in patients older than 69 years. This suggests that advanced age per se may be associated with reduced neurological functional reserve, probably at the cortical level, and this may in turn lower the elderly patients’ capacity to reprogramme cognitive operations once the basal ganglia circuitry has been partially blocked by the DBS. The STN has widespread influences within the basal ganglia and these extend to cortical levels (Parent and Hazrati, 1995). At present, the mechanism of action of high frequency STN DBS is not understood (e.g. blocking of neuronal activity, release of inhibitory transmitters in the striatum and pallidonigral complex), but it is assumed that it causes disruption to basal ganglia circuitry, possibly allowing a resetting of function or re-programming of motor control. However, there are many reasons to believe that these hypothesized mechanisms may be too simplistic or may not uniformly be applied to all structures treated with DBS. One aspect currently under study is the actions of DBS on fibre

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systems at a lower threshold than those needed to act on neurons (Ashby et al., 1999). It should be recalled that not all aspects of basal ganglia functions, especially in the cognitive domain, are impaired in Parkinson’s disease. This has been amply demonstrated in numerous neuropsychological studies (for reviews, see Dubois et al., 1991; Saint-Cyr et al., 1995; Brown et al., 1997). If STN DBS causes the target nucleus to malfunction, this could mimic a lesion and induce a condition analogous to PSP since the stimulation would essentially produce an induced pathology in the STN, although pathology in PSP extends far beyond the STN (Gearing et al., 1994; Lantos, 1994). The PSP-like cognitive changes (especially mental slowness) observed following STN DBS may be specifically due to chronic stimulation of the STN, as well as to current spread to adjacent structures and remote antidromic and orthodromic actions. In these cases, involvement of the lenticular fasciculus was common and this would interfere with pallidofugal projections to the thalamus. Finally, nonspecific effects of surgery may also explain some of the cognitive changes. Specifically, bilateral frontal lobe or thalamic trajectories, rather than specific stimulation of the STN, may be contributing factors. The largest collaborative study to date of cognitive changes following STN and GPi DBS failed to demonstrate many significant changes in cognitive or behavioural functions (but see below) (Ardouin et al., 1999b). However, there are significant differences in patient characteristics and examination protocols between this study and ours. The most significant difference may be in the average age of patients enrolled, namely 51.5–55.2 years for the European study compared with 66.5 years in the present report. In our elderly group, age ranged from 70 to 75 years. Thus, the older patient may be less resilient to the stress of the procedure and basal ganglia–frontal cortical circuits may be less able to re-programme functions altered by the combination of disease and stimulation. In addition, we assessed all patients in their optimal ‘on’ drug state, whereas only 13 patients (Paris groups) (in Ardouin et al., 1999b) were similarly medicated and all were assessed at 6 months postoperatively. The Grenoble patients, in the same study (n ⫽ 49), were assessed ‘off’ drug at 3 months postoperatively. Although our patients were also able to reduce medication dosage postoperatively, the magnitude of this reduction was less than for the Grenoble–Paris STN patients (i.e. 46% for the older and 45% for the younger patient groups, see Table 2C, versus up to 100% for the French group). We must also consider the possibility that, in this small sample, the elderly patients were at risk for other dementing illnesses, such as Alzheimer’s disease, cortical Lewy body disease, vascular dementias, frontally-based dementias, etc., although there was no clear neuropsychological indication of this at baseline. The true test of the contribution of the STN DBS to their mental status would be to wean patients off the stimulation, rebalance their medications (and manage the potentially ensuing

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depression) and re-assess them. This would, however, be both logistically and ethically problematic. Examination of test performance, common to the assessment batteries of our study and that of the study from France (Ardouin et al., 1999a), indicates that lexical fluency scores were quite similar, but there was significant variability in the time taken to complete the TMT across all groups. It is notable that, in the French study (Ardouin et al., 1999a), some measures did decline post-operatively (Mattis score, 14%; delayed verbal free recall, 22%; lexical semantic fluency, 18%; motor series, 16%). This suggests that at least some individuals, despite their younger age, were nevertheless vulnerable to cognitive decline (which was true of our youngest patients as well). The relatively older group of patients we examined appeared to have been even more sensitive, while our oldest patients showed additional impairment. We showed a similar percentage improvement in mood (20 versus 21%) to that found by Ardouin and colleagues, but a 30–50% incidence of behavioural change or complaint (not assessed by Ardouin et al., 1999a). With regard to these declines in various aspects of frontal striatal functioning (i.e. working memory, problem solving, memory retrieval, speeded processing), it is interesting to note that, in healthy adults, PET or fMRI activations within this circuit have been observed in area 46 (dorsolateral prefrontal cortex) during working memory (Petrides et al., 1993; Owen et al., 1996; Smith and Jonides, 1999) and problem solving tasks (Berman et al., 1995; Fallgatter and Strik, 1998), and within the basal ganglia during memory retrieval (Dupont et al., 1998). Data from these studies provide support for the role of these structures and their associated circuits in these types of frontal striatal cognitive processes. Changes in neuropsychological functioning observed over the first year of follow-up could be attributed to one or more of the following factors: surgical trauma of microelectrode passes, macroelectrode implantation, chronic stimulation of the STN and/or current spread to adjacent structures, microlesion effects, significant postoperative declines in L-dopa equivalent dosages, and advanced age. Systematic measurement of stimulation parameters, including impedance, showed little significant change in total energy (measured in coulombs) delivered through the electrodes and no change in choice of electrode contact over time. Post-mortem studies of chronically implanted electrodes in the thalamus have shown little or no glial scarring or chromatolysis, and this is also the case for one of our patients who died 19 months after her last (12 month) neuropsychological assessment (J. A. Saint-Cyr and W. Halliday, unpublished observations). We can therefore infer that long-term frontal behavioural changes (i.e. 9–12 months postoperatively) are most likely due to plasticity within basal ganglia and/or cortical circuitry. Remaining questions include the possibility of reversal of cognitive impairment with cessation of DBS; interactions between lowered L-dopa dosage, DBS and cognition; and

neural reorganization of processing subsequent to surgery and DBS. We also now have histological, MRI and physiological evidence that some effective DBS placements must involve fibre tracts. Further studies will be needed to determine what role, if any, such actions have in the therapeutic and cognitive effects of STN DBS.

Summary of conclusions (i) Elderly patients are at greater risk for cognitive and behavioural impairment following STN DBS than younger patients. (ii) Factors to be considered include iatrogenic damage caused by microelectrode recordings and concomitant but undiagnosed dementia (degenerative or vascular most likely). (iii) Individual younger patients may also be at risk for cognitive and behavioural changes for the same reasons as those above. (iv) STN DBS may also affect adjacent fibre systems, interfering with pallidofugal projections to the thalamus, and this combined effect may underlie cognitive and behavioural changes. (v) Older patients do not benefit clinically as much as younger patients from STN DBS.

Acknowledgements This work was supported by the Parkinson’s Disease Foundation of Canada. Thanks are also due to Stephen Taylor and Philip Groff (statistical consultation), Taisha Chang, (contributing psychometrist), Eileen Halkett and Eppie Syme (clinical nurse co-ordinators), and Loraine May (research assistant) for their contributions to this work.

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Appendix I Neuropsychological tests and questionnaires Intelligence These measures were only used to establish premorbid and current verbal intellectual level (IQ) and to estimate cognitive weaknesses at baseline relative to the expected Parkinson’s disease cognitive profile (see Table 1). (i) American New Adult Reading Test (AMNART). (ii) Wechsler Adult Intelligence Test—Revised: Verbal (WAIS-R VIQ) includes Digit Span forwards (F) and backwards (B).

Fine motor functions Preferred hand (PH) and non-preferred hand (NPH) were measured separately.

Frontal executive tasks including attention, concentration and problem solving (i) PASAT 3⬘. (ii) Digit Span—Backwards (Digit Span-B) (verbal subtest from the WAIS-R). (iii) Conditional Associative Learning Test (CALT) (4-disk version).

Language (i) Controlled Oral Word Association Test (FAS and CFL versions, with ‘switching’ and ‘clustering’ scored on all three letters, according to the methodology of Troyer et al., 1998a). (ii) Semantic Category Fluency [‘Animals (A), Fruits (F) and

Vegetables (V)’ with only the ‘Animals’ trial used to score ‘switching’ and ‘clustering’].

Verbal memory and learning California Verbal Learning Test (CVLT): forms 1 and 2 [SDFR; LDFR; short delay cued recall (SDCR); LDCR; recognition].

Visual memory and learning This domain of function proved to be difficult to assess due to the dyskinesias exhibited in many patients’ drawing hand, as well as test sensitivity. In an attempt to circumvent these limitations, only the subtests requiring pointing or a verbal response were used for a couple of patients. Batterie d’efficience mne´ sique (BEM) (‘Battery of Memory Efficiency’): seven visual spatial subtests make up the total score, including: the immediate recall of a complex figure (RIE) and serial learning of 12 designs in three trials (AL) (both examining initial encoding), recognition of four paired associations (AP) and 24 designs (RC), along with delayed recall of the complex figure (RDE) and the 12 designs (RL) (Signoret, 1991).

Questionnaires (i) Frontal Lobe Personality Scale (FLOPS) (Grace et al., 1999). (ii) Clinical follow-up questionnaire regarding subjective experience of surgery by patient and caregiver. Description of and further references for these tests can be found in the following publications: Taylor et al., 1986a, 1990; Spreen and Strauss, 1998; Tre´ panier et al., 1998. (iii) Geriatric Depression Inventory (GDI) (Brink et al., 1982).