Brain, Vol. 125, No. 3, 562-574,
March 2002
© 2002 Guarantors of Brain
Global attentional–executive sequelae following surgical lesions to globus pallidus interna
1 Russell Cairns Unit, 2 Oxford Movement Disorder Group, 3 Department of Neurological Surgery, Radcliffe Infirmary, 4 University Laboratory of Physiology, Oxford University, Oxford, 5 Cambridge Psychometric Consultants, Ely and 6 West London Neurosciences Centre, Charing Cross Hospital, London, UK
Correspondence to: Dr Richard B. Scott, Russell-Cairns Unit, Neurosciences Directorate, Radcliffe Infirmary, Oxford OX2 6HE, UK E-mail: rbs{at}neuropsyche.net
Received September 21, 2001. Revised June 19, 2001. Second revision August 29, 2001. Accepted October 18, 2001.
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Summary |
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It has been demonstrated that selective unilateral surgical ablation of posteroventral globus pallidus interna relieves the movement disorders associated with advanced Parkinson’s disease, without necessarily incurring the executive cognitive sequelae that have been observed following gross pathological lesions to this brain region. This finding is consistent with established theory that underlying neuronal circuitry is functionally segregated into parallel cortico-striatal-pallidal-thalamo-cortical ‘loops’. We have studied a series of 12 patients with advanced Parkinson’s disease at baseline, and then following bilateral pallidotomy, with a battery of neuropsychological tests including the Cambridge Neuro psychological Test Automated Battery. We identified a selective and universal loss of individual patients’ ability to shift attention to novel dimensions in a test of abstract rule-learning following surgery, which was not reliably associated with any other change in cognition, personality, mood or medication. This finding is rare in its specificity and has implications for theoretical models of the functional architecture and pathophysiology of the globus pallidus, and the clinical practice of pallidotomy.
Keywords: pallidotomy; set-shifting; executive function; Parkinson’s disease
Abbreviations: ADL = activities of daily living; AMIPB= Adult Memory and Information Processing Battery; BNT = Boston Naming Test; BPVP = bilateral posteroventral pallidotomy; CANTAB = Cambridge Neuropsychological Test Automated Battery; CVF = categorical verbal fluency; Ed-shift = extradimensional set-shifting; FLP = Functional Limitations Profile; GP = globus pallidus; GPi = globus pallidus interna; HADS = Hospital Anxiety and Depression Scale; H&Y = Hoehn and Yahr; IED = Intra-Extra Dimensional set-shifting task; NART = National Adult Reading Test; PDQ-39 = Parkinson’s Disease Questionnaire; PVF = phonemic verbal fluency; REMT = Repeatable Episodic Memory Test; RSPM = Raven’s Standard Progressive Matrices; RT = reaction time; SDMT = Symbol Digit Modalities Test; SOC = Stockings of Cambridge; SS = spatial span; STN = the subthalamic nucleus; SWM = spatial working memory; UPDRS = Unified Parkinson’s Disease Rating Scale; UPVP = unilateral posteroventral pallidotomy
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Introduction |
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Evidence has accumulated that the globus pallidus (GP) is one of the neural substrates of executive cognitive function (Laplane et al., 1989
; Strub, 1989; Haaxma et al., 1993; Bhatia and Marsden, 1994). These observations have been broadly consistent with the theory of parallel segregated neuronal circuitry in cortico-striatal-pallidal-thalamo-cortical ‘loops’ (Alexander et al., 1986), and evidence from animal studies (Middleton and Strick, 1994). Nevertheless, mapping the functional architecture of this system in humans has been constrained by three pervasive methodological problems in the neuropsychology of executive function. First, the gross and unpredictable quality of naturally occurring brain lesions, secondly the lack of behavioural specificity in any associated deficits and thirdly the characteristic unavailability of premorbid cognitive data. These difficulties make assertions about brain–behaviour relationships probabilistic rather than definitive. Pathological brain lesions invariably damage critical, adjacent structures to a region of particular interest in the investigation of brain–behaviour relationships. For example, in the case of GP, the putamen, amygdala and substantia nigra have all been implicated in observations, and globus pallidus interna (GPi) cannot necessarily be distinguished from the external segment (Strub, 1989). The reliably targeted, elective, surgical ablation of GPi as a therapeutic intervention in advanced Parkinson’s disease has serendipitously provided a remedy to such difficulties, and the opportunity for patients to act as their own, optimal, controls.
It has now been adequately demonstrated that unilateral posteroventral pallidotomy (UPVP) can improve contralateral parkinsonism and dyskinesias in advanced Parkinson’s disease without necessarily causing clinically significant motor or cognitive or psychiatric deficits (e.g. see Baron et al., 1996; Goetz and Diederich, 1996; Lang et al., 1997; Soukup et al., 1997). However, some commentators have noted that certain aspects of motor outcome (e.g. reduced dyskinesias) are ‘paradoxical’ (Brown and Marsden, 1998), and would not necessarily be predicted given Alexander et al.’s model of basal ganglia function. From the cognitive perspective, UPVP outcomes have been variable and of uncertain individual, clinical significance, although reductions in verbal fluency tasks represent the most consistently reported sequelae (for a review, see York et al., 1999). Some studies have suggested a pattern of post-operative cognitive deficits purportedly subserved by cortex ipsilateral to the pallidal lesion, following the analysis of group central tendencies (for a review, see Green and Barnhart, 2000). However, a number of difficulties constrain definitive conclusions in this respect. First, there are relatively small numbers of comprehensively (and similarly) studied patient series with sufficient numbers of left and, in particular, right UPVP patients. Secondly, there is potential for disagreement about which psychometric tests are truly lateralizing, particularly with respect to the non-dominant hemisphere. Thirdly, it has been suggested that hemiparkinsonism (with contralateral basal ganglia dysfunction—the pallidotomy target) may be associated with vulnerability in cognitive functions purportedly subserved by cortex ipsilateral to the motor symptoms (Green and Barnhart, 2000). Finally, careful perusal of individual cognitive outcomes (where reported) suggests that there is often a considerable degree of variability, with both gains and deficits in performance across tests, that is masked by analyses of group central tendency (Scott et al., 1998; Trepanier et al., 1998; York et al., 1999; Lacritz et al., 2000).
A range of neuropsychological tests that are thought to be sensitive to frontostriatal lesions (i.e. the Wisconsin Card Sort Test, the Stroop, the Trailmaking test, the California Verbal Learning Test, the Spatial Conditional Associative Learning Test and phonemic verbal fluency) have been variously employed to audit executive function following UPVP (Baron et al., 1996; Riordan et al., 1997; Uitti et al., 1997; Masterman et al., 1998; Rettig et al., 1998; Scott et al., 1998; Trepanier et al., 1998; Green and Barnhart, 2000). Both gains and deficits in group mean scores following left and/or right UPVP have been reported on various parameters of these tests. However, a meaningful or reliable constellation of executive cognitive sequelae has not been consistently identified, although it has, for example, been suggested that left UPVP selectively impairs ‘verbally mediated’ executive functions (Green and Barnhart, 2000).
Stebbins et al. (2000) have argued that a post-UPVP deterioration in group mean scores (relative to controls) on Raven’s Progressive Matrices, the Digit Ordering Test, the Symbol Digit Modalities Test (SDMT) and the Listening Span Test reflect impaired frontostriatal functioning with respect to processing speed, reasoning and working memory. These findings were interpreted within the context of a ‘working memory’ model of frontal functions (Baddeley, 1986) that posits a multicomponent system comprising a central executor and associated verbal and non-verbal ‘buffer systems’. Other studies have also explicitly or implicitly endorsed this model in their interpretation of post-UPVP changes on other tests of working memory (i.e. Backwards Digit Span and the Paced Auditory Serial Addition Test) (Jahanshahi et al., 1997; Lombardi et al., 2000). Where individual UPVP outcomes have been examined, ‘frontal’ changes in personality, as measured by the Frontal Lobe Personality Scale (and clinical interview), were identified in 25–30% of patients, and a constellation of poor scores on tests of Backwards Digit Span, California Verbal Learning Test (encoding of trials 1–5), verbal fluency and a complex figure planning score was also reported (Trepanier et al., 1998) in some cases. There were, however, no deficits on a more ‘direct’ test of executive function (the Spatial Conditional Associative Learning Test).
Bilateral posteroventral pallidotomy (BPVP) has also been found to benefit patients with advanced Parkinson’s disease (Iacono et al., 1995; Schuurman et al., 1997; Scott et al., 1998; Taha et al., 1998) and generalized dystonia (Lozano et al., 1997), but concerns about increased risk to speech-motor apparatus (Roberts and Heilbrun, 1997), personality (Ghika et al., 1996) and/or global cognition (Galvez-Jimenez et al., 1996; Trepanier et al., 2000) have limited its use, as a staged or simultaneous procedure. However, these audits of BPVP outcome have either tended to exclude sufficient neuropsychological measures or reported only a handful of (sometimes, untypical) cases. The only published multidimensional outcome audit on eight consecutive cases of BPVP found a selective reduction in group mean scores on a measure of phonemic verbal fluency (which is thought to make demands upon executive function) in the context of well-preserved general cognitive abilities and substantial neurological and functional gains (Scott et al., 1998). Essentially irreversible, severe (Dujardin et al., 2000) and much less severe (Jahanshahi et al., 2000; Trepanier et al., 2000) deterioration in executive functions has been reported following bilateral GPi stimulation in small numbers of cases. These data are, however, difficult to interpret, as occult or unspecified variations in stereotaxic trajectories and the level, chronicity and location of stimulation, raise uncertainties regarding the precise region of GP that was inactivated (Dujardin et al., 2000); difficulties in the placement of electrodes post-operatively (due to MRI artefact) further exacerbates these difficulties.
This very mixed picture regarding the association of executive cognitive sequelae with pallidotomy is invariably explained by occult variation in lesion placement and/or contour (Miyawaki and Troster, 2000). Indeed, in the context of Alexander and colleagues’ theory (Alexander et al., 1986), the identification of any cognitive sequelae following pallidotomy implies variation around the intended posteroventral target (e.g. the motor circuit) or, alternatively, a degree of ‘convergence’ (Percheron and Filion, 1991) or integration (Joel and Weiner, 1994) rather than segregation, in parallel circuitry. In support of this explanation, variation in cognitive and neurological outcomes that is associated with differences in lesion placement along a posteroventral–anteromedial axis has been demonstrated (Gross et al., 1999; Lombardi et al., 2000). Furthermore, substantial individual variation in executive cognitive outcomes (which may have been masked in the majority of studies examining changes in group mean scores) implies either individual differences in pre-operative patient characteristics and/or the pallidal lesion.
It has also been suggested that the failure to identify a consistent pattern of executive cognitive changes following pallidotomy might be due to the lack of appropriate specificity in psychometric test paradigms (York et al., 1999). The range of tests of ‘executive function’ that have been applied, and the lack of any general consensus regarding how they might map onto alternative theoretical models in cognitive neuropsychology and/or various frontostriatal lesions, would tend to support this view. Established theory (Alexander et al., 1986; Middleton and Strick, 1994), lesion studies (Haaxma et al., 1993; Laplane et al., 1989; Strub, 1989; Bhatia and Marsden, 1994), animal models (Dias et al., 1997) and the literature on neuropsychological function in Parkinson’s disease (Downes et al., 1989; Owen et al., 1992) all point to tests of attentional set-shifting and abstract rule acquisition as being potentially sensitive indices. We hypothesized that the Intra-Extra Dimensional set-shifting task (IED), taken from the Cambridge Neuropsychological Test Automated Battery (CANTAB) (Robbins and Sahakian, 1994) would be sensitive to BPVP. This battery has been used to fractionate the executive cognitive deficits associated with a range of disorders involving the basal ganglia and frontostriatal circuitry, including mild and advanced Parkinson’s disease, frontotemporal dementia, Huntington’s disease, progressive supranuclear palsy, multiple system atrophy and following neurosurgical lesions to the prefrontal cortex (Owen et al., 1991, 1992; Robbins et al., 1994; Lawrence et al., 1998; Rahman et al., 1999).
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Methods |
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Subjects and design
We designed a longitudinal within-subjects clinical investigation of a consecutive series of six males and six females undergoing BPVP for alleviation of the disabling symptoms of advanced Parkinson’s disease. All patients in the series satisfied UK Parkinson’s Disease Society brain bank diagnostic criteria for idiopathic Parkinson’s disease (Gibb and Lees, 1988
), and none was dementing or satisfied the criteria for any diagnosis on Axis I of DSM-IV (Diagnostic and Statistical Manual of Mental Disorders; American Psychiatric Association, 1994). Patients were evaluated with a routine clinical assessment protocol (Scott et al., 1998) in the 4 weeks preceding surgery and then, on average, at 5 months follow-up (range 3–9 months). Further neuropsychological follow-up was completed on four patients, on average 30 months (range 27–33) after first follow-up.
Statistical analysis
With interval data, paired-sample statistics, and with ordinal data, non-parametric statistics, were employed to examine pre- to post-operative changes on the group mean scores of all measures. Given the number of analyses (>20) a more conservative 
of <0.01 was chosen.
To examine the significance of changes in individual test scores, we employed a technique where a 95% confidence interval is plotted around an individual’s calculated ‘true’ pre-operative scores (Brophy, 1986). This true score is calculated according to the following formula:
T = M + r(X – M)
where X is the obtained score, M is the mean of the scores on the test and r is the reliability coefficient of the test. This confidence interval around this true score is obtained by calculating the SEP (standard error of prediction) according to the following formula:
SEP = SD 1 – rii2
where SD is the standard deviation and rii is the reliability coefficient. Post-operative scores (for tests where the necessary reliability coefficient data were available) falling outside this interval were judged to have significantly changed.
Surgical technique
An image-guided neurosurgical technique (Papanastassiou et al., 1998; Bowen et al., 2000) involving intra-operative macro stimulation was employed to make asymmetrical lesions; measuring 
150 mm3 in the dominant hemisphere, and 100 mm3 in the non-dominant hemisphere, occupying the posterior one-third of the medial pallidum. Asymmetrical lesions were made to avoid sequelae that have been observed following large symmetrical bilateral thalamotomies. Some case reports of the neuropsychological sequelae of large bilateral pallidotomies have also appeared to confirm these fears. Two patients had staged procedures and six had simultaneous procedures.
Some commentators have suggested that intra-operative micro-electrode recording is not necessarily essential to the accurate placement of pallidal lesions, and does not lead to significantly better results; indeed it may well be associated with higher operative risks (Carroll et al., 1998). Stimulation at 2 Hz and maintaining a threshold of 2 V at a pulse width of 1 ms minimizes capsular encroachment, and injury to the optic tract is avoided by stopping exploration at the point where visual phosphenes are elicited (at the above parameters) and when impedance sharply rises from the usual 500–600 to 800–1000 
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The placement of lesions was confirmed by MRI within 1 week post-operatively in all cases. An axial slice through the lesion at the level of the anterior and posterior commissures was projected onto a transparency (taken from the Schaltenbrand–Wahren atlas of the same level). For each patient an outline was drawn around the lesion where the signal intensity returned to normal, i.e. around peri-lesional oedema (Fig. 1A). These were superimposed and the composite image digitized. Shading was applied to the image based on the number of overlapping lesions in that area. Thus we obtained an overall representation of the accuracy of lesion localization (Fig. B and C). Figure also illustrates that, overall, the left lesion is larger than the right with some capsular encroachment, though this was not significant functionally in any case.
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We would argue that all lesion localization techniques are confounded to some degree as lesions, initially surrounded by oedema, diminish on scans over time to be virtually invisible by 3 months post-operatively.
Assessment protocol
The assessment protocol is routinely employed in the Oxford Movement Disorder Group to clinically screen patients for functional neurosurgery. Its primary components have been described in detail elsewhere (Scott et al., 1998), although the test battery has evolved to shorten and refine the ‘pencil and paper’ component and include additional tests of executive function (CANTAB). Unified Parkinson’s Disease Rating Scale (UPDRS), Hoehn and Yahr (H&Y) and neurological examinations were completed (Fahn et al., 1987), and the remainder of the neuropsychological protocol then administered to patients on optimal medication and in the ‘ON’ state. It included a semi-structured clinical interview and patient-rated questionnaire measures of psychological symptomatology [Hospital Anxiety and Depression Scale (HADS)] and quality of life [Parkinson’s Disease Questionnaire – 39 (PDQ-39)]. Both patient- and carer-rated questionnaires of functional disability were also obtained on the Functional Limitations Profile (FLP; the UK version of the Sickness Impact Profile) (Gilson et al., 1979). The FLP is a well-validated generic measure of functional disability that has been employed in a wide variety of conditions and in both self- and carer-rated forms. The PDQ-39 is a disease-specific quality of life measure that has been shown to be sensitive to the impact of Parkinson’s disease (Peto et al., 1995). Detailed descriptions of these measures (including subscales not employed in this study) and a demonstration of their sensitivity to changes following both UPVP and BPVP are provided elsewhere (Scott et al., 1998).
The primary psychometric assessment measures were five subtests drawn from CANTAB designed to examine patients’ attention, spatial and executive cognitive functions; prior to their administration, all patients completed the motor screening subtest of CANTAB to confirm adequate motor function prior to performing the rest of the battery.
(1) Intra-Extra Dimensional set-shifting
This task is a decomposition of the Wisconsin Card Sort Test. Subjects learn a series of nine two-alternative, forced-choice discriminations using feedback provided automatically by the computer. Throughout the task, participants are required to discover rules, initially through trial and error. For example, the first stage of the test requires the participant to make a simple visual discrimination between two abstract stimuli. Touching the ‘correct’ stimulus is rewarded, whereas if the participant touches the ‘wrong’ stimulus they are informed that their selection was incorrect. Once the rule is achieved on six consecutive occasions the computer establishes a new rule. At each stage of the test two sets of visual stimuli are displayed. Two critical shifts occur during the test, one at the sixth rule change when subjects must shift to new exemplars of the most recent dimension and a second at the eighth rule change, where subjects must shift to a second dimension.
Owing to the graded nature of this task, the most obviously useful metric is the number of categories achieved by the subject. A second outcome metric that has proven popular with users of the CANTAB system is the total number of occasions upon which the subject fails to select the correct stimulus. However, because subjects who fail to complete the test do not have the opportunity to make as many errors as those that do, an adjustment is made to the total error score based on the total number of possible errors that can be made at levels not reached, less a correction for trials correct by chance.
(2) Five-choice reaction time
This a relatively brief (nine trials) traditional test of reaction time (RT) in which the subject must release a ‘home’ button and then touch whichever of five target stimuli has been indicated on the touchscreen. Metrics traditionally examined on RT tasks are (i) speed of response (latency) and (ii) errors, either of omission (e.g. failures to respond) or commission (anticipations and decision errors). Before beginning the experimental trial phase of this task, participants are provided with practice trials in which they first master simple release of the home button, progressing to full versions of the task in which the home button is released to record RT and then the screen is touched to record movement time. All trials for which a correct response was recorded were included in the calculation of individual mean performance.
(3) Spatial Working Memory
The Spatial Working Memory (SWM) task measures ability to retain information regarding memory for locations previously visited, and devise a ‘self-ordered’ search strategy. Participants are initially shown an array of three boxes and are told that within one of these boxes they will find a blue token reward. They are further informed that once they have found a blue token in a box, the token will not be found again at that location and that they will have to search other boxes in the array to find the remaining blue tokens. Once all three tokens have been located a new array is displayed and participants must again locate all three tokens. The task progresses in difficulty from three boxes, up to the most difficult stage of eight boxes. Within each trial, information regarding previously visited locations is measured by recording the number of occasions upon which the subject revisited a box in which a reward token had already been found on that particular trial (a ‘between error’). Strategy is measured by recording upon how may occasions the subject begins a trial at the same location as previous searches on the current trial.
(4) Spatial span
The spatial span (SS) test is analogous to the Corsi block-tapping test in that it requires subjects to monitor and recall a sequence of blocks; it is a test of non-verbal ‘working memory’. The test begins by requiring the subject to recall correctly a sequence of two spatial locations. Success at this level of the test qualifies the subject to progress to a sequence of three boxes, which, if correctly negotiated, allows progression to later levels of the test to a maximum of a sequence of nine spatial locations. Subjects are permitted a maximum of three attempts at each level of the test. The sole outcome metric recorded for this test is the maximum sequence length correctly recalled, the subject’s maximum ‘span’.
(5) Stockings of Cambridge (SOC)
This is a modified version of the Tower of London spatial planning task that allows the measurement of both speed and accuracy. Participants are shown a split screen with a set of three ‘stockings’ displayed at the top of the screen and again in the bottom half of the screen. The top half of the screen shows the location of coloured balls within the stocking array in a ‘goal’ state. The bottom half of the screen contains the same number of coloured balls in a ‘start’ state. Participants are instructed to make the bottom half of the screen ‘look like’ the top half of the screen, in as few moves as possible, by moving coloured balls from one stocking to another.
A variety of outcome measures from this test have been evaluated by different authors, including time taken to make the first move of the sequence (‘initial thinking time’), time taken to make remaining moves in the sequence (‘subsequent thinking time’) and the number of occasions upon which the subject completes the problem in the minimum number of moves (‘minimum move solutions’). We selected the third of these measures for our evaluation as we wished to measure the efficiency with which our subjects completed trials on this test.
In addition to CANTAB, a number of other psychometric tests were administered in order to obtain measures of premorbid and non-verbal IQ and screen other cognitive domains (i.e. language and spatial functions, auditory attention, praxis, speed of information processing and memory). These tests included the National Adult Reading Test (NART), Raven’s Standard Progressive Matrices (RSPM), the SDMT, tests of categorical (CVF) and phonemic (PVF) verbal fluency, the Boston Naming Test (BNT), the Judgement of Line Orientation Test, the story recall subtest from The Adult Memory and Information Processing Battery (AMIPB), the Repeatable Episodic Memory Test (REMT), bells test of spatial neglect, the Digit Span subtest taken from the Wechsler scales, and both copy and recall administrations of the Medical College of Georgia Complex Figures (Thompson and Heaton, 1989; Lezak, 1995; Parker et al., 1995; Woodard et al., 1996; Scott et al., 1998).
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Results |
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Pre-operative presentation
Demographic and core clinical information on the patient series is detailed in Table 1. The mean age of the patient series was 59.9 years (range 44–68 years), with a mean time since first diagnosis of 16 years (range 9–35 years). The patient series included a broad range of intellectual abilities, presenting with an average premorbid (NART) verbal and current non-verbal (RSPM) IQs of 101 (range 70–120) and 97 (range 75–121), respectively. Group mean age-scaled scores (relative to normal controls) on other tests of auditory–verbal (digit span 50%tile) and spatial (CANTAB SS 27%tile) working memory, verbal ‘long-term’ memory (see Table 3), categorical (38%tile) and phonemic (31%tile) verbal fluency and some executive skills (CANTAB SOC 21%tile; SWM 27–31%tile) were similarly in the average range, though
1 or 2 standard deviations below control mean scores. Speed of information processing (mean ‘oral’ SDMT score 8%tile; RT response latency 1%tile) was more significantly impaired. Overall, these findings were consistent with the well-documented cognitive characteristics of Parkinson’s disease patients with advanced disease.
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Three patients had been treated for depression in the past, and all but four had, in the past, experienced episodes of confusion and/or hallucination related to medication. There were five instances of ‘caseness’ (i.e. score >8–10) on the anxiety subscale of the HADS and five of depression; however, none satisfied the criteria for current diagnoses on Axis I of DSM-IV.
Group neurological and quality of life outcomes
Presenting mean total UPDRS scores of 106 and H&Y ‘OFF’ scores of 4.23 improved significantly (P < 0.01) post-operatively to 67 and 3.0, respectively (see Table 1). Table 2 reveals that all carer- and patient-rated FLP dimension scores (except patient-rated ‘psychosocial’ and ‘alertness’ disability) and selected PDQ-39 scores (except ‘emotional well-being’) reflected significant improvements post-operatively. Specifically, mean patient and carer-rated ‘Total’ percentage functional disability scores on the FLP declined significantly (P < 0.01) from 35 to 23% and 33 to 21%, respectively. On the ‘alertness’ sub-category of the FLP, carer ratings suggested significant (P < 0.01) improvements in cognition with functional disability ratings falling from 45 to 32%. On the PDQ-39, patients also rated significant improvements in cognition, with scores falling from 38 to 23. Only two patients achieved ‘caseness’ on the anxiety subscale following surgery, and there were no new psychiatric diagnoses. Other than Case 2, where there was, in error, significant under-medication post-operatively, there were no spontaneous complaints of changes in personality or cognition. Those post-operative changes reported in Table 1 were carefully elicited at interview with patient and carer; the four reports of low mood were either transient or secondary to unrealistic surgical expectations. Post-operative MRI confirmed satisfactory placement of lesions in posteroventral GPi, and there were no surgical complications.
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Group neuropsychological outcomes
Pre- to post-operative changes in group mean scores are presented in Tables 3 and 4. On ‘pencil and paper’ psychometric tests there was a significant deterioration (P > 0.01) in scores on the PVF, CVF (category ‘tools’) and BNT (errors), but on no other measure. Although changes were not approaching significance, there was some reduction in scores on the Complex Figures (copy, immediate and delayed recall), the time taken to complete the Bells test of visual neglect (i.e. visual search), and the ‘% retained’ and ‘subjective organization’ indices of the REMT.
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On all CANTAB tests except the IED task, there were no significant changes, although number of errors on the motor screen, not unexpectedly, decreased; furthermore, there were non-significant trends toward an increase in response latency on RT and a decrease on the IED task. Of the 12 patients tested, seven successfully completed the extradimensional set-shifting phase (Ed-shift) of the IED test prior to BPVP, but all 12 failed to do so post-operatively. An effect of this magnitude is clearly statistically significant (P < 0.01) when analysed using within-subjects inferential statistics. Of the two cases who underwent staged procedures, one failed at all three administrations of the IED task; the other failed pre-operatively, then passed following the initial left PVP, before finally failing after his subsequent right PVP. Long-term follow-up was obtained on four of the seven post-BPVP Ed-shift failure cases, and none were able to achieve Ed-shift subsequently.
Individual neuropsychological outcomes
In order to characterize the individual neuropsychological context and specificity of the Ed-shift deficit, patient medical records and subjective reports were examined for any evidence of collateral changes; dimensions of interest included changes in mood, personality, behaviour and medication. A 95% confidence interval was plotted around individuals’ ‘true’ pre-operative scores, to determine whether post-operative scores were significantly changed. Table 5 summarizes the results of this analysis and illustrates the characteristic heterogeneity of outcomes following pallidotomy. Inspection of individual neuropsychological profiles suggests that the loss of Ed-shift ability is not reliably associated with, and cannot be wholly accounted for by, any collateral changes in medication, personality, mood or other executive or general cognitive functions, although these also occurred in various, apparently unpredictable, combinations.
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Discussion |
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These findings provide compelling evidence that bilateral ablation of GPi entirely removes the capacity to negotiate successfully the IED task at a conceptually critical stage. There have been no reports previously of surgical or pathological frontostriatal lesions with such selective and reliable cognitive consequences, although in pre-clinical Huntington’s disease and mild Parkinson’s disease there is a general deterioration in the ability to perform the IED task (relative to controls), but no impairment on other CANTAB subtests of executive function (Owen et al., 1991
, 1992; Robbins et al., 1994; Lawrence et al., 1998; Rahman et al., 1999). Recently, published data confirmed that at first exposure, 16% of normal subjects fail at the Ed-shift stage of the task. In the same study 88% of those initially failing Ed-shift manage to pass at retest, and only 3% of those who initially pass Ed-shift subsequently fail (Harrison et al., 1998). Long-term follow-up, where available, also suggests that the Ed-shift deficit following BPVP is permanent, although the influence of disease progression in Parkinson’s disease cannot be ruled out in this respect.
With one of the two cases in this series where a staged procedure was performed, left UPVP was associated with the attainment of Ed-shift, but an additional right UPVP with its loss. A preliminary perusal of CANTAB data obtained on 37 other patients with advanced Parkinson’s disease who have been treated within the Oxford Movement Disorder Group and had lesions or stimulators placed, suggests that BPVP is required to reliably produce Ed-shift failure. In 16 left UPVP cases, there were two of a pre-operative Ed-shift pass (P) followed by failure (F) (P
F), and one of a failure followed by a pass (FP). Of the seven cases of right UPVP, there was one case of PF and three of FP. In 17 cases of left subthalamic nucleus (STN) ablation (four left, six right, one bilateral) and stimulation (two left, two right, two bilateral), there was only one case of FP (left STN lesion) and none of PF. These and other data will be reported in detail elsewhere, but their distribution suggests that patients selected for right UPVP (i.e. by implication those with left hemiparkinsonism and right GPi disequilibrium) have a higher pre-operative Ed-shift failure rate (six out of seven; 86%) than those selected for left UPVP (nine out of 16; 56%), but that following surgery there is a greater likelihood of FP (three out of six; 50%) than following left UPVP surgery (one out of nine; 11%). These data suggest that disturbances in right GPi output may compromise Ed-shift attainment more than disturbed output from left GPi, but that surgical release of excess inhibition to right thalamus may enhance Ed-shift performance. Interestingly, Parkinson’s disease patients’ impaired performance relative to controls on the SOC CANTAB task has been found to be associated with hypometabolism in right GPi (Owen et al., 1998).
Alexander et al.’s theory argues that the (functionally unspecified) lateral dorsomedial GPi projects to dorsolateral prefrontal cortex, the lesioning of which in the non-human primate causes Ed-shift deficits (Dias et al., 1997). A worsening in Parkinson’s disease patients’ performance on tests including the CVF and a test of verbal ‘working memory’ (Paced Auditory Serial Addition Test) has also been correlated with more anteromedial GPi lesions on an anteromedial–posteroventral axis (Lombardi et al., 2000). In contrast, we have found a reliable and complete loss of the ability to Ed-shift associated with posteroventral lesions to the motor circuit. The excellent motor outcomes in this series offer persuasive evidence that the posteroventral motor circuit in GPi was successfully ablated, but do not exclude the possibility that left and/or right lesions also encroached functionally upon more anterior regions of GPi. There was, for example, evidence to suggest that individual Ed-shift failure was associated with a significant group trend toward deterioration in scores on one test (the CVF for ‘tools’) similar to those associated by Lombardi et al. (2000) with more anteriomedial lesions. This raises the possibility that a post-BPVP reduction in working memory capacity below a certain threshold might somehow trigger Ed-shift failure.
However, analysis of changes in individual and group scores on more specific tests of verbal (digit span) and non-verbal (SS) ‘working memory’ showed no reliable pattern of significant decline associated with Ed-shift failure. Furthermore, careful examination of post-operative MRI scans did not suggest that lesions collectively or grossly encroached into more anteriomedial portions of GPi. Given the reliability and specificity of our observation of Ed-shift failure, lesioning more anterior GPi would probably need to be a routine (rather than an occult and occasional) feature of the surgical technique, that might reasonably be expected to be associated with more widespread cognitive deficits. A previous report of neuropsychological outcomes on eight patients who had BPVP by exactly the same surgical technique found no evidence of either widespread or more selective (i.e. executive) deficits other than a significant reduction in PVF (Scott et al., 1998). This series of 12 patients also demonstrated a significant reduction in group mean scores on PVF, and in addition two tests not previously administered (one measure of CVF and the BNT); however, the CVF and the BNT are tests of word retrieval, rather than global or executive cognitive function. In addition, among the seven post-BPVP Ed-shift failure patients, there were only three separate cases of a significant post-operative planning deficit (SOC), a deficit in ‘strategic search’ ability (SWM) and a PVF deficit. There were only two subjective reports of a change in personality resembling a dysexecutive syndrome.
One interesting feature of our findings is the identification of a global loss in Ed-shift capacity in the absence of a similarly widespread loss of functional integrity on tasks such as SWM and SOC. It is generally believed that normal performance on these three tasks requires the integrity of several shared cognitive capacities. However, dissociations between these three tasks are common in the CANTAB literature and there seems to us no particular expectation that deficits on one of these tasks should necessarily mean impairment on the other two. Our findings clearly demonstrate a dissociation between IED performance and both SWM and SOC, suggesting that successful IED performance is reliant on a cognitive skill that is not common to performance on SOC or SWM. An alternative possibility is that a common cognitive module is shared by these three tasks, but that the levels of modular degradation caused by BPVP leads to deficits specific to the IED task.
The variability in individual outcomes on tests other than the IED task may indeed be associated with a degree of occult targeting or ablation error. But despite the theoretical zeitgeist in the literature of cognitive outcome from pallidotomy, that motor and cognitive basal ganglia circuits are entirely segregated, it has also been argued that from a neuroanatomical point of view, segregated circuitry and discrete function ‘need not be interchangeable notions’ (Miyawaki and Troster, 2000). Consideration of the possibility of either a degree of convergence or integration in parallel motor and cognitive circuitry to explain Ed-shift failure may also be necessary, and it may be overly simplistic to constrain explanation to anatomy, without reference to the pathophysiology of Parkinson’s disease. Ed-shift failure may therefore also result from the defocusing effect of a lack of dopamine or surgical intervention on circuits that overlap or actually converge to some extent (Percheron and Filion, 1991). Each of these pathways is thought to consist of direct and indirect components. Gene regulation studies have shown that dopamine depletion affects the direct and indirect pathways differentially so that D1 receptors become supersensitive and the direct component becomes overactive, causing dyskinesias (Gerfen, 2000). Just as dyskinesias are involuntary movements, associated with akinesia (i.e. not being able to make wanted movements), so cognitive ‘dyskinesia’ (i.e. involuntary thoughts) may be associated with not being able to make desired mental shifts.
Ed-shift failure may also reflect ‘disconnection’ of a more fundamental process that impacts upon both motor and cognitive functions, indeed links them, and this may reflect the alterations in receptor sensitivity. Brown and Marsden (1998) have proposed that the basal ganglia subserve an automatic process of ‘focused attention’ that binds sensory input and the voluntary execution of thought or action sequences. The neurophysiological substrate of this attentional mechanism is local 
-band (30–50 Hz) synchronization (against a background of desynchronization in lower frequencies) necessary for the coherence of a gestalt or action. They argue that in patients with Parkinson’s disease, L-dopa medication initially supports this system by decreasing the firing rate (at low frequencies) of GPi and its excessive inhibitory output, thereby releasing excitatory glutaminergic thalamo-cortical projections to relieve akinesia. However, chronic L-dopa use may lead to excessive -band synchronization, increasing the likelihood of entraining random unrelated elements of movement, in other words dyskinesias, into action. The anatomically ‘paradoxical’ outcome of pallidotomy is therefore explained physiologically, by its therapeutic inactivation of both an excessive low frequency firing-rate and excessive -band synchronization, to relieve parkinsonism and dyskinesia without any gross motor deficits. This neurophysiological explanation may be relevant to our finding of selective and reliable attentional deficits associated with BPVP.
Closer inspection of the performance of patients with Parkinson’s disease on the IED task has led to the proposition that Ed-shift failure may not represent an inability to shift from the stimulus dimension previously relevant (i.e. ‘perseveration’), but rather an enhanced tendency to ignore a previously irrelevant dimension (i.e. ‘learned irrelevance’) (Downes et al., 1989). The latter failure is, in turn, thought to explain patients’ observed tendency to entertain an excessive number of new diverse possibilities at the Ed-shift phase of the task, rather than perseverate on a previously relevant stimulus dimension. This quality of ‘attentional divergence’ in Parkinson’s disease patients’ performance on the IED task again raises the intriguing possibility that it might in some sense represent a ‘cognitive’ equivalent of motor dyskinesias, and that both are markers for overly robust -band synchronization (and random disturbances in ‘focused attention’). If this were the case, then patients with robust -band synchronization (and marked dyskinesia) might be expected to demonstrate differences in the quality of their performance on the IED task relative to patients with advanced Parkinson’s disease, but no dyskinesias. Interestingly, this patient series (with, by definition, marked bilateral dyskinesias) did indeed present with an unexpectedly conservative pre-operative Ed-shift failure rate.
In other studies, Parkinson’s disease patients’ performance on the IED task has been found to be a function of medication and disease severity. Variation in Ed-shift failure rates between medicated (37–46%) and unmedicated (54–68%) Parkinson’s disease groups (Downes et al., 1989; Owen et al., 1992) may be explained by contaminated sampling (Hughes et al., 1992). However, sampling error is perhaps less likely to explain the marked disparity between the pre-operative 42% Ed-shift failure rate in our carefully selected, heavily medicated sample with advanced Parkinson’s disease, when compared with a 79% failure rate found in a general clinical sample with advanced Parkinson’s disease (Owen et al., 1992). This difference may be associated with a much higher prevalence of dyskinesias (and possibly excessive -band synchronization), although it is not possible retrospectively to confirm the absence of dyskinesias in Owen et al.’s sample.
Increased -band synchronization in dyskinetic Parkinson’s disease patients may therefore be associated with a decrease in the incidence of Ed-shift failure relative to patients with advanced Parkinson’s disease without dyskinesias and underactive GPi, due to an increase in the ‘random’ diversity of patients’ consideration of alternative possibilities at the Ed-shift stage; this is a testable hypothesis. Surgical ablation of all frequencies of disturbed GPi output causes a more fundamental disconnection in the process of ‘focused attention’ (Brown and Marsden, 1998), perhaps constraining random diversity of attention to alternative dimensional sets. Just as the quality and distribution of movement disorders varies according to differences in the pathophysiology of GPi output, so too their cognitive component or equivalent (i.e. disorders in the ability to shift attention) may vary in their expression, from perseveration on one input stimulus to abnormalities in the distribution of attention to reinforced alternatives—two faces of the same attentional process.
Finally, although it is not a focus of our research, it is tempting to speculate about the consequences of BPVP for clinical outcome and with regard to lesion location. The significance of Ed-shift failure for activities of daily living (ADL) is not apparent from the established literature. However, no studies, including our own, have yet been conducted to determine whether Ed-shift failure gives rise to significant difficulties in everyday life. Given the absence of any commentary in the literature, it seems probable to us that the loss of Ed-shift capacity is unlikely to have any consequences for either basic ADL or instrumental ADLs. However, it might well be that the loss of this cognitive skill may give rise to difficulties with advanced ADLs. Advanced ADLs typically feature complex planning or organizational tasks, and it might be that these skills are compromised in patients who fail the Ed-shift stage of the IED task. We plan to address this issue in future research.
Conclusions
In patients with advanced Parkinson’s disease, bilateral ablation of GPi entirely and selectively removes the capacity to negotiate successfully the IED task at a conceptually critical stage, without any reliable pattern of collateral changes in general or executive cognitive function, mood, personality or medication. There is no evidence to suggest that this deficit resolves in time, or that it occurs following UPVP, or STN lesioning or neuromodulation unilaterally or bilaterally. This finding has implications for current models of the functional architecture of the GP, both from a neuroanatomical and neurophysiological point of view. Although patients and relatives/carers are clearly subjectively satisfied with overall functional and quality of life outcomes following BPVP, our finding raises further questions about whether this procedure should be employed without extremely careful patient selection and both explicit and detailed consenting. The clinical significance of the loss of Ed-shift ability in patients with advanced Parkinson’s disease (who are likely to eventually acquire this deficit as a function of disease progression), remains uncertain. However, even greater caution may need to be exercised with respect to BPVP in paediatric cases of generalized dystonia (Lozano et al., 1997), as there may be delayed functional sequelae (i.e. general cognitive or personality development) if the lesions are acquired at or before the emergence of Ed-shift attainment in the middle years of childhood (Luciana and Nelson, 1998).
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We wish to thank A. Mehmet of Maracis Solutions Ltd for assistance with data management and analysis, Cambridge Cognition for technical support and M. N. Scott sine qua non. CANTAB is available from Cambridge Cognition, Vision Park, Histon, Cambridge, UK.
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