Hindawi

Parkinson’s Disease
Volume 2018, Article ID 4328371, 13 pages
https://doi.org/10.1155/2018/4328371

Research Article
Standardised Neuropsychological Assessment for the Selection of
Patients Undergoing DBS for Parkinson’s Disease

Jennifer A. Foley ,1,2 Tom Foltynie,1,2 Patricia Limousin,1,2 and Lisa Cipolotti 1,3

1
National Hospital for Neurology and Neurosurgery, Queen Square, London, UK
2
UCL Institute of Neurology, Queen Square, London, UK
3
Dipartimento di Scienze Psicologiche, Pedagogiche e della Formazione, Università degli Studi di Palermo, Palermo, Italy

Correspondence should be addressed to Jennifer A. Foley; [email protected]

Received 17 November 2017; Revised 23 March 2018; Accepted 30 April 2018; Published 3 June 2018

Academic Editor: Jan Aasly

Copyright © 2018 Jennifer A. Foley et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.

DBS is an increasingly offered advanced treatment for Parkinson’s disease (PD). Neuropsychological assessment is considered to
be an important part of the screening for selection of candidates for this treatment. However, no standardised screening procedure
currently exists. In this study, we examined the use of our standardised neuropsychological assessment for the evaluation of
surgical candidates and to identify risk factors for subsequent decline in cognition and mood. A total of 40 patients were assessed
before and after DBS. Evaluation of mood and case notes review was also undertaken. Before DBS, patients with PD demonstrated
frequent impairments in intellectual functioning, memory, attention, and executive function, as well as high rates of mood
disorder. Post-DBS, there was a general decline in verbal fluency only, and in one patient, we documented an immediate and
irreversible global cognitive decline, which was associated with older age and more encompassing cognitive deficits at baseline.
Case note review revealed that a high proportion of patients developed mood disorder, which was associated with higher levels of
depression at baseline and greater reduction in levodopa medication. We conclude that our neuropsychological assessment is
suitable for the screening of candidates and can identify baseline risk factors, which requires careful consideration before and
after surgery.

1. Introduction successful surgery. In this study, we discuss the limitations of

existing presurgical protocols and evaluate the use of stand-
Drug therapies for advanced Parkinson’s disease (PD) can be ardised neuropsychological assessment in a sample of patients
unsatisfactory, with unwanted side effects, and/or insufficient undergoing DBS for PD. We describe patients’ performance
control of disabling motor symptoms. Thus, there has been on this neuropsychological assessment before and after DBS
resurgence in interest in surgical treatments, with deep brain and identify potential baseline predictors of after DBS decline,
stimulation (DBS) now increasingly offered as an option. DBS which warrant further investigation.
is the chronic, high-frequency electrical stimulation of most DBS has been shown to be relatively safe, with few
usually the subthalamic nucleus (STN) or internal segment of negative events occurring during or following surgery, when
the globus pallidus (GPi) [1], which is thought to alter the performed on appropriate candidates [5]. However, STN
pattern of neural activity, with resulting beneficial effects DBS is thought to result in better improvements in motor
upon motor function [2]. Its success relies heavily upon control; there is some evidence to suggest that it also poses
appropriate selection of candidates, which in turn relies in a greater risk of negatively affecting speech articulation,
part upon neuropsychological screening [3, 4]. However, no impulsive behaviours, and/or mood [6–10], and therefore,
standardised screening procedure currently exists, and it GPi DBS may be preferred for patients presenting with these
remains unclear what level of cognitive dysfunction precludes difficulties. However, marked global cognitive deterioration
2 Parkinson’s Disease

has also been reported [11, 12], and mild decline in verbal Examination (MMSE) [41]. This may be criticised for
fluency has frequently been documented [13–30]. a number of reasons. Firstly, the MMSE comprises very few
Decline in cognitive functioning following DBS has been subtests that are sensitive to the typical cognitive dysfunc-
found to be more common in patients who are older, es- tion displayed in PD, namely, executive dysfunction [42–48]
pecially above 70 years [29, 31], particularly affecting frontal and cognitive slowing [49–52] and thus is insufficient for
executive functions [28]. Yet others have cautioned against detecting cognitive impairment [53, 54]. Secondly, the
a strict age criterion, as many people older than 70 can MMSE suffers from significant ceiling and floor effects [55],
demonstrate good outcomes [32, 33]. Indeed, it has been so cannot capture very mild nor very severe cognitive
reported that other factors, particularly cognitive perfor- dysfunction. Thirdly, MMSE scores are affected by age and
mance, may be more useful as predictors of postoperative education [56, 57], so that a low score in an older person
decline [3, 29, 34, 35]. Several studies have suggested that with minimal formal schooling may present a false positive
lower cognitive functioning at baseline is predictive of for dementia. Fourthly, an individual may attain a low
poorer cognitive outcome following surgery [36], perhaps MMSE score for a number of noncognitive reasons, in-
because of lower “cognitive reserve” [35]. It has even been cluding poor speech intelligibility, high levels of anxiety,
suggested that the presence of any cognitive deficits at fatigue, and distracting dyskinesia. Therefore, a low score on
baseline, particularly in executive function and memory, this test should not necessarily be used to preclude surgery.
should serve as exclusion [36, 37]. However, PD is usually Moreover, such brief screening tools do not permit
accompanied by at least mild cognitive deficits, particularly scrutiny of the wider cognitive profile, important for con-
in executive function, and the evolution of a dementia is firming diagnosis. Many cases of “failed” DBS have been
rather insidious, without any clear boundary features. Thus, later found to have atypical Parkinsonian syndromes, known
it remains unclear what level of impairment should con- not to benefit from DBS [58]. Thus, there is a need to identify
stitute a contraindication to surgery. a suitable presurgical neuropsychological protocol, which is
Despite the widespread agreement on the importance of sufficiently sensitive to both the typical cognitive dysfunc-
appropriate screening and careful selection of surgery tion displayed in PD and atypical cognitive decline, as seen
candidates, to the best of our knowledge no standardised in other Parkinsonian disorders and has clear guidelines for
neuropsychological assessment procedure currently exists. its interpretation.
The Consensus on DBS for PD [38] published guidance on In addition to changes in cognition, there are also a few
presurgical screening and selection of patients but did not reports of dramatic deterioration in mood and greatly in-
provide a presurgical neuropsychological protocol. Rather, creased apathy following DBS [22, 59–61], with an associated
they listed an extensive range of neuropsychological do- elevated risk of suicide despite successful reduction of motor
mains to be assessed and tests commonly used. The tests symptoms [62, 63]. As such deterioration can clearly negate
listed ranged from very brief screens (including the MMSE) any potential benefits [64], it is essential that candidates at
to very long and extensive batteries (such as the Wechsler high risk of such postoperative decline are identified at
Memory Scales and Delis–Kaplan Executive Functioning baseline. Specifically, postoperative risk of suicide has been
System). They stated that tests chosen should be reliable and associated with higher levels of mood disorder, apathy,
valid, with adequate normative data for referencing per- and/or family or social stress at baseline [65, 66]. This may
formance. However, without any guidance on how to choose not only reflect the additional stressor of surgery [67, 68] but
between the vast range of tests, nor how to interpret scores also the direct effects of the stimulation itself [69] and any
when deciding on suitability for surgery, it remains unclear reductions in dopaminergic medication [70, 71]. As mood
how to use neuropsychological assessments to identify disorder is so prevalent in PD and may reduce with im-
candidates suitable for DBS. Indeed, defining what consti- provements in motor symptoms following surgery [35], it
tutes unacceptable cognitive dysfunction remains the most remains unclear what level of mood disorder should act as an
controversial aspect of patient selection [2]. absolute contraindication for DBS.
Moreover, there is scant official guidance. The British Thus, the aims of this study were to evaluate the use of
Psychological Society [39] recommends that candidates our standardised neuropsychological protocol in the eval-
undergo presurgery neuropsychological evaluation but does uation of patients undergoing DBS for PD in order to
not describe what this should consist of. The Australian identify any contraindication for surgery and to be sensitive
guidelines [40] simply recommend that patients should be to changes following DBS.
able to give a good account of themselves and capable of
giving informed consent. Of course, even marked cognitive 2. Methods
impairment may be masked by higher levels of cognitive
reserve and/or fluctuating levels of attention and vice versa; 2.1. Participants. A total of 40 patients (29 male, 11 female)
gross physical and speech disability may mask intact cog- who underwent DBS took part in this study. All patients had
nition. Thus, the absence of any firm guidelines for the had a diagnosis of idiopathic PD for at least five years
assessment and interpretation of cognitive performance (according to Queen Square Brain Bank criteria), were
clearly poses a significant hurdle for the appropriate se- younger than 70 years, and suffered from disabling motor
lection of candidates for DBS. complications despite optimal treatment. Each patient un-
In lieu of such guidance, several studies have relied upon derwent multidisciplinary evaluation to decide on suitability
brief cognitive screens only, such as the Mini-Mental State for DBS. Formal levodopa challenge confirmed dopaminergic
Parkinson’s Disease 3

drug responsiveness. A structural MRI was obtained to exclude but as the “gold standard” screening instrument, it
surgical contraindications, such as advanced brain atrophy, permits easy comparison between studies.
white matter changes, or any other abnormality contra- (2) Vocabulary, similarities, arithmetic, and digit span
indicating surgery. Detailed neuropsychological and neuro- subtest scores from the Wechsler Adult Intelligence
psychiatric assessments excluded patients with significant Scale-Third Edition (WAIS-III) [72] were prorated
cognitive impairment and/or psychiatric comorbidities. Con- to generate verbal IQ (VIQ). Picture Completion
traindications for STN DBS included the presence of clinically and Matrix Reasoning subtest scores were prorated
relevant speech difficulties and cognitive impairment. The final to generate scores for nonverbal IQ (PIQ). The
decision regarding suitability for DBS and appropriate target WAIS-III has been found to have good sensitivity
for each patient was taken during a joint meeting of patient, and specificity for cognitive disorders [73] and good
immediate family, neurologist(s), and neurosurgeon(s). reliability for Parkinson’s disease [74].
Motor status was evaluated using part III of the Unified
(3) The National Adult Reading Test-Revised (NART-R)
Parkinson’s Disease Rating Scale (UPDRS-III). Prior to
[75] was used to estimate the premorbid level of
surgery, patients were assessed in the practically defined “off
intellectual functioning, by generating each patient’s
state” after overnight withdrawal of anti-Parkinsonian drugs
Predicted Full-Scale IQ (PFSIQ). The NART-R has
and the “on state,” following a levodopa challenge using
very good interrater and test-retest reliability, and
a suprathreshold dose of oral levodopa. After DBS, motor
good validity, although suffers from a ceiling effect
assessments were sequentially performed under the fol-
limiting prediction of IQ scores beyond 125.
lowing conditions, in open fashion: off medication/on
stimulation (with stimulation switched on after 12 h med- (4) Memory was assessed using the following:
ication withdrawal) and on medication/on stimulation (1 h (a) The Warrington Words and Faces Recognition
after the administration of a routine dose of levodopa while Memory Tests (RMTs) [76] were used to assess
stimulation was reintroduced). All medications before and recognition memory. The RMT correlates well
after surgery were recorded, noting any dopamine agonist with other measures of memory and has ade-
treatment, and levodopa-equivalent dosage was calculated quate reliability for patients with neurological
(www.parkinsonsmeasurement.org). History of impulse disorders [77, 78].
control disorder was recorded by reviewing the medical (b) The People and Shapes subtests from the Doors
notes and noting any mention of compulsive gambling, and People Test were used to assess verbal and
eating, shopping, or sexual behaviour before or after DBS. visual recall memory (D&P) [79]. These tests
All patients underwent assessment of neuropsycho- have sufficient validity and reliability [80] and
logical and mood functioning before and after surgery, are recommended for assessing recall in PD [81].
under optimal conditions. Thus, preoperatively, this was in
the on medication and postoperatively on stimulation/on (5) The Graded Naming Test (GNT) [82] was used to assess
medication. The postoperative assessment was performed language. The GNT has good test-retest reliability and
a mean of 19.60 months after surgery (range � 1–54; is well suited for detecting any gradual changes in
SD � 11.56). This broad range reflected the early recall of one performance over time [83]. Moreover, it is sensitive to
patient following concern about cognition immediately cognitive impairment in Parkinson’s disease [84].
following DBS, as well as later routine follow-up of cogni- (6) The Silhouettes subtest from the Visual Object and
tively intact patients after surgery. Space Perception Battery (VOSP) [85] was used to
The most appropriate DBS target was chosen on clinical assess visuoperceptual functioning. This test has
grounds based on patient motor phenotype, imaging, and been validated as a test of object perception [86] and
preoperative cognitive assessment. Twenty-eight patients is sensitive to visuospatial impairment seen in PD
underwent bilateral STN DBS and twelve bilateral GPi DBS. dementia [87] and atypical PD [88].
2.2. Neuropsychological Assessment. The tests included (7) Elevator Counting and Elevator Counting with
general screening and IQ measures, as well as tests of specific Distraction subtests from the Test of Everyday At-
cognitive functions. This was to enable both the quantifi- tention (TEA) [89] were used to assess sustained and
cation of any intellectual deficit and the elucidation of selective attention. These tests have high test-retest
specific cognitive profiles. Thus, the measures included tests reliability and correlate with other measures of at-
of general cognitive functioning, memory, language, tention. Furthermore, these tests have been shown to
visuoperceptual ability, attention, executive functions, and be sensitive to Parkinsonian disorders, including
speed of processing. The tests chosen were considered to Lewy body dementia [90].
have acceptable test validity and reliability, as described (8) Executive functioning was assessed using the following:
below. The assessments took around two hours to complete
(a) FAS and Category subtests from the Delis–
and were as follows:
Kaplan Executive Function System (DKEFS) [91]
(1) The MMSE was used as a screening test of global were used to assess verbal fluency. The tests have
cognitive functioning [41]. It is not sufficient as been standardised and found to be sufficiently
a measure of cognition in Parkinson’s disease [53], reliable [92].
4 Parkinson’s Disease

(b) The Stroop [93] was used to assess verbal in- Table 1: Patient demographic characteristics.
hibition. It has high reliability [94] and is sen- STN (n � 28) GPi (n � 12) p
sitive to cognitive deficits in PD [95].
Gender (male) 17 8 0.72
(c) The Hayling and Brixton tests [96] were used to Age (at first assessment,
assess verbal suppression/strategy formation 57.50 ± 7.32 61.33 ± 6.30 0.12
years)
[97] and nonverbal set-shifting, respectively. NART Predicted Full-Scale
They have moderate sensitivity and specificity for 111.57 ± 11.08 103.42 ± 15.43 0.07
IQ
detecting executive dysfunction [98] and are Age at PD diagnosis (years) 45.55 ± 7.80 48.60 ± 6.35 0.29
sensitive to PD [99, 100]. PD disease duration (years) 18.77 ± 6.12 19.00 ± 4.55 0.92
History of impulse control
(9) The Symbol Search and Digit Symbol Coding sub- 9, 28.1% 1, 3.1% 0.08
disorder (n, %)
tests from the WAIS-III [72] were used to assess
processing speed. These tests have been shown to be
sensitive to PD [101]. terms of age, gender split, or premorbid level of intellectual
functioning, as estimated by the NART. They also did not
2.3. Mood Assessment. All patients were screened for mood significantly differ in age at diagnosis, duration of disease, or
disorder using the Hospital Anxiety and Depression Scale history of impulse control disorder.
(HADS) [102] and the Apathy Evaluation Scale (AES) [103].
These tests have been validated for use in PD [104, 105]. 3.2. Clinical Characteristics before and after DBS. At baseline,
there were no significant differences between the STN and
2.4. Case Note Review. The case notes were reviewed by one GPi DBS patient groups in UPDRS-III scores off or on
clinical neuropsychologist (JAF) to identify any change in medication, nor in baseline levodopa-equivalent dosage (as
cognition, mood, or behaviour since DBS, as highlighted by shown in Tables 2 and 3). STN DBS was successful in im-
the surgery team, neurologists, or nursing staff. Any mention proving UPDRS-III scores off medication (t(23) � 6.50,
of decline in memory, attention, perception, language, p < 0.001), with a corresponding reduction in levodopa-
reasoning, mood, anxiety, depression, or motivation was equivalent dosage (t(21) � 4.50, p < 0.001). There was no
recorded, along with number of months elapsed since significant difference in UPDRS-III scores on medication. In
surgery. As discussed before, any mention of a de novo the GPi DBS group, there was no significant change in
impulse control disorder was recorded. levodopa-equivalent dosage and change in motor perfor-
mance was not examined because of insufficient collection of
postsurgery motor performance data.
2.5. Statistical Analysis. Scores for each of the neuro- There were also no significant differences between the
psychological assessments were compared with published STN and GPi DBS patients groups in proportion of patients
normative data. For each measure, patients were judged to receiving dopamine agonist treatment before or after DBS.
be impaired if scores were ≤2 SD. When multiple measures
were used, performance was classified as impaired when ≤2
SD on at least one of the measures used. 3.3. Cognitive Performance before and after DBS. When
Normality of distribution was assessed using the baseline neuropsychological assessment scores were com-
Kolmogorov–Smirnov test and, if significant, by examining pared with published normative data, impairment was
the z-scores for skewness and kurtosis. Homogeneity of documented on at least one domain of cognitive function in
variance was assessed using Levene’s test. Unless otherwise 85% of all patients (STN: n � 22, 64.7%; GPi: n � 12, 100%).
stated, all data met the assumptions of normality and ho- In both groups, impairments were frequently in intellectual
mogeneity of variance. Baseline scores of the STN and GPi functioning, memory, attention, and executive function
DBS groups were compared using t-tests or Mann–Whitney (Table 4). The GPi DBS group also demonstrated frequent
tests, as appropriate. Pre- and after DBS scores were com- impairments in the additional domains of cognitive screen
pared using t-tests for related samples or Wilcoxon signed- and speed. There was a significant association between DBS
ranks, as appropriate. Pearson’s correlations, chi-squared location and frequency of impairment, with the GPi group
analyses, and logistic regression techniques were used to having more frequent impairments on the cognitive screen
detect any significant associations. All analyses were con- (χ 2(1) � 9.20, p < 0.05), measures of memory (χ2(1) � 5.80,
ducted using IBM SPSS Statistics Data Editor, version 19. p < 0.05), executive function (χ2(1) � 9.20, p < 0.05), and
The research was done in accordance with the Helsinki speed (χ2(1) � 9.20, p < 0.05).
Declaration and the Institute of Neurology Joint Research When investigated further, we found that the GPi DBS
Ethics Committee UCLH, NHS Trust Research and De- patients obtained lower baseline scores on tests of general
velopment Directorate. intellectual functioning (VIQ: t(38) � 4.24, p < 0.001; PIQ:
t(38) � 2.33, p < 0.05), recognition memory (RMT words:
3. Results U � 65.5, p < 0.05; RMT faces: t(37) � 3.74, p < 0.01), atten-
tion (TEA EC with distraction: t(37) � 2.76, p < 0.05), and
3.1. Patient Demographics. As shown in Table 1, the STN executive functioning (category fluency: t(37) � 2.75,
and GPi DBS patient groups did not significantly differ in p < 0.05; Stroop: t(35) � 3.49, p < 0.01; Brixton: t(33) � 4.12,
Parkinson’s Disease 5

Table 2: Patient motor characteristics before and after DBS.

STN GPi
Before DBS (n � 28) After DBS (n � 24) p Before DBS (n � 11) After DBS (n � 4) p
UPDRS-III off medication 48.68 ± 14.10 28.67 ± 9.99 0.00 50.73 ± 11.09 35.20 ± 15.32 —
UPDRS-III on medication 17.29 ± 7.967 15.83 ± 7.20 0.49 24.64 ± 10.97 20.75 ± 11.56 —

Table 3: Patient medication characteristics before and after DBS.

STN (n � 28) GPi (n � 12)
Before DBS After DBS p Before DBS After DBS p
Levodopa-equivalent
1321.82 ± 638.68 863.73 ± 583.92 0.00 1263.40 ± 971.08 1205.10 ± 626.68 0.81
dosage (mg/d)
Dopamine agonist
15, 46.9% 6, 18.8% 0.01 7, 21.9% 5, 15.6% 0.16
treatment (n, %)

Table 4: Cognitive performance before DBS: proportion impaired 3.4. Predictors of Cognitive Decline following DBS.
in each domain. Pearson correlational analysis revealed no significant
Cognitive domain STN (n � 28) GPi (n � 12) p baseline cognitive, mood, or motor correlates of decline in
phonemic fluency after either STN or GPi DBS. Greater
Screen 1, 3.7% 5, 41.7% 0.01
IQ 12, 42.9% 8, 66.7% 0.30
decline in category verbal fluency following STN DBS was
Memory 9, 33.3% 9, 75.0% 0.04 associated with higher levels of apathy (r � 0.47, p < 0.05)
Language 1, 3.7% 3, 27.3% 0.07 and levodopa-equivalent dosages at baseline (r � −0.43,
Perception 2, 7.4% 1, 8.3% 1.00 p < 0.05) and greater change in cognitive speed, as indexed
Attention 5, 18.5% 4, 33.3% 0.42 by change in performance on both Digit Symbol Coding
Executive function 4, 14.8% 8, 66.7% 0.01 (r � 0.49, p < 0.05) and Symbol Search (r � −0.53, p < 0.01).
Speed 2, 7.4% 4, 36.4% 0.05 However, only the correlation between decline in category
Results are given as number and percentage. Chi-squared significant group fluency and Symbol Search survived the Bonferroni ad-
comparisons are indicated in bold. justment for multiple comparisons. Greater decline in cat-
egory fluency following GPi DBS was associated with worse
p < 0.01). Thus, all subsequent analyses of cognitive per- UPDRS-III scores off medication at baseline (r � 0.70,
formance were split according to site of DBS. p < 0.05), but this did not survive the Bonferroni adjustment.
As shown in Table 5, there was a significant drop in There were also no significant baseline correlates of
phonemic and category fluency following both STN and GPi decline in Symbol Search after STN DBS. However, greater
DBS. In the STN patients, there was also a significant decline decline in PIQ following GPi DBS was associated with slower
in performance on Symbol Search, and in the GPi patients, baseline performance on the Digit Symbol Coding subtest.
there was also a decline in PIQ. There were also near-significant There were no other significant predictors of decline fol-
declines in Stroop performance and VIQ following STN DBS. lowing DBS.
There were no other significant or near-significant differ- In order to identify baseline predictors of the subsequent
ences in cognitive performance following either STN or GPi global and irreversible cognitive decline following STN DBS
DBS. noted in the one patient, Crawford and Howell [106] single-
Case note review revealed mention of decline in cog- case methodology was used. This revealed that this patient
nitive function in 15% (n � 6) of patients after DBS (4 STN was significantly older (68 years) than the mean age (59.15
DBS, 14.3%; 2 GPi DBS, 16.7%). There was no significant years) of the STN DBS patients who remained stable
association between DBS location and subsequent cognitive (t � 1.86, p < 0.05). Indeed, although the baseline neurology
decline (χ 2(5) � 4.73, p � 48). Number of months elapsed assessment revealed no atypical symptoms, it did raise
since surgery had a bimodal distribution, with two patients concerns about the older age. MMSE performance was
demonstrating marked decline immediately (STN and GPi flawless, but the patient demonstrated mild baseline im-
DBS, resp.), but others demonstrating decline at least a year pairments in all domains, including language and visuo-
after surgery (n � 4, range � 13–72 months). When con- perceptual functioning. Indeed, this patient was the only
sidering those who declined immediately, one demonstrated patient to demonstrate baseline impairment in language and
confusion and hallucinations immediately after GPi DBS subsequently undergo STN DBS. Another patient also
surgery, thought to be associated with a urinary tract in- demonstrated baseline impairment in visuoperceptual and
fection and which improved with appropriate treatment subsequently underwent STN DBS, which proved successful,
consistent with a diagnosis of delirium rather than dementia. but it is noted that this patient was younger (55 years) than
However, the other deteriorated physically and cognitively the mean age of the STN DBS group.
after STN DBS (as confirmed by repeat cognitive assess- When considering the remaining patients who demon-
ment), without any subsequent improvement. strated cognitive decline at least a year after surgery (as identified
6 Parkinson’s Disease

Table 5: Cognitive performance before and after DBS: mean scores on each test.
STN (n � 28) GPi (n � 12)
Assessment
Before DBS After DBS p Before DBS After DBS p
MMSE (30) 28.64 ± 1.41 28.64 ± 1.68 1.00a 26.75 ± 3.14 25.75 ± 2.87 0.31a
WAIS-VIQ 111.21 ± 12.40 107.54 ± 15.93 0.05a 92.75 ± 13.10 92.67 ± 10.71 0.97a
Vocabulary (66) 51.57 ± 9.61 49.96 ± 10.00 0.13a 40.64 ± 15.02 37.27 ± 14.14 0.16a
Similarities (33) 24.71 ± 4.51 22.75 ± 5.64 0.02a 19.36 ± 5.43 18.36 ± 5.12 0.43a
Arithmetic (22) 15.61 ± 2.94 14.04 ± 4.64 0.01a 10.36 ± 2.94 9.64 ± 3.04 0.90a
Digit span (30) 17.57 ± 4.15 16.43 ± 4.26 0.04a 14.08 ± 3.09 14.00 ± 3.16 0.41a
WAIS-PIQ 106.37 ± 15.17 104.04 ± 19.57 0.50a 93.64 ± 15.11 84.45 ± 12.91 0.01a
Picture Completion (25) 17.96 ± 4.25 17.19 ± 4.86 0.33a 12.92 ± 3.66 11.33 ± 3.53 0.07a
Matrix Reasoning (26) 16.35 ± 5.61 15.31 ± 5.90 0.24a 11.10 ± 4.33 9.20 ± 4.21 0.09a
RMT-W (50) 46.81 ± 3.50 45.12 ± 5.35 0.10b 39.20 ± 9.45 40.30 ± 8.68 0.16a
RMT-F (50) 41.88 ± 4.13 41.08 ± 5.68 0.54a 33.60 ± 6.85 34.00 ± 7.92 0.80a
D&P People delayed (12) 7.21 ± 3.68 7.50 ± 4.30 0.59b 6.40 ± 4.65 5.60 ± 3.95 0.57a
D&P Shapes delayed (12) 10.50 ± 3.28 10.25 ± 2.82 0.22b 8.86 ± 3.63 7.43 ± 3.78 0.30a
GNT (30) 23.69 ± 3.42 23.69 ± 3.28 1.00a 17.91 ± 8.11 19.45 ± 6.65 0.34a
VOSP Silhouettes (30) 22.81 ± 3.25 21.92 ± 3.91 0.13a 20.82 ± 3.52 19.00 ± 5.88 0.41a
DKEFS FAS (SS) 13.42 ± 4.89 11.54 ± 4.61 0.01a 10.92 ± 5.18 8.00 ± 4.88 0.01a
DKEFS Category (SS) 12.31 ± 4.21 10.00 ± 4.99 0.01a 8.50 ± 3.00 5.00 ± 3.30 0.01a
Stroop (112) 91.81 ± 21.36 83.77 ± 22.94 0.06a 63.00 ± 20.44 58.50 ± 23.45 0.12a
Hayling (SS) 5.68 ± 1.07 5.32 ± 1.52 0.28b 4.60 ± 1.84 4.70 ± 1.83 0.89a
Brixton (SS) 4.91 ± 1.53 5.00 ± 2.28 0.83a 2.33 ± 1.66 2.56 ± 2.07 0.72a
TEA EC (7) 6.67 ± 0.96 6.75 ± 0.44 0.85b 6.50 ± 1.41 5.88 ± 1.55 0.26b
TEA EC-Distraction (SS) 9.91 ± 2.66 8.96 ± 2.92 0.15a 7.13 ± 3.14 5.75 ± 1.91 0.17a
WAIS-SS (SS) 9.62 ± 2.25 8.46 ± 2.82 0.02a 7.89 ± 3.33 6.11 ± 2.42 0.86a
WAIS-DSC (SS) 8.20 ± 2.52 7.48 ± 2.65 0.22 4.89 ± 2.67 4.67 ± 1.87 0.86a
Results are given as mean ± SD (apaired t-test; bWilcoxon signed-rank). Significant differences are indicated in bold. MMSE: Mini-Mental Status Examination;
WAIS-VIQ, PIQ: Wechsler Adult Intelligence Scale-Third Edition-Verbal IQ, Performance IQ; RMT-W, F: Warrington Recognition Memory Test for Words,
Faces; D&P: Doors and People Test; GNT: Graded Naming Test; VOSP: Visual Object and Space Perception Battery; DKEFS: Delis–Kaplan Executive
Function System; SS: scaled score; TEA EC, ECD: Test of Everyday Attention Elevator Counting, Elevator Counting with Distraction; WAIS-III SC, DSC:
Wechsler Adult Intelligence Scale-Third Edition Symbol Search, Digit Symbol Coding.

Table 6: Mood scores before and after DBS.

STN (n � 28) GPi (n � 12)
Assessment
Before DBS After DBS p Before DBS After DBS p
HADS anxiety (21) 7.50 ± 3.23 6.27 ± 4.85 0.19b 8.55 ± 3.30 9.00 ± 4.12 0.69a
HADS depression (21) 6.15 ± 4.42 6.00 ± 4.04 0.86a 7.00 ± 3.85 7.73 ± 4.63 0.67a
Apathy (54) 10.75 ± 6.02 13.96 ± 11.16 0.15b 14.57 ± 6.71 20.86 ± 11.11 0.67a
Results are given as mean ± SD (apaired t-test; bWilcoxon signed-rank).

in the case note review), no significant difference in de- Incidence of case note indication of cognitive impair-
mographics or cognitive performance at baseline was identified. ment or mood disorder, as a function of time, is depicted in
Figure 1.
One patient also developed de novo impulse control
3.5. Mood before and after DBS. Baseline mood assessment
disorder, namely, hypersexuality, after GPi DBS.
revealed high rates of anxiety disorder (n � 22, 56.4%),
depression (n � 14, 35.9%), and apathy (n � 14, 38.9%) but
no significant association between frequency of mood dis- 3.6. Predictors of Mood Disorder following DBS. Patients
order and subsequent DBS location. There were also no who had subsequent mood disorder were found to have
significant differences in anxiety, depression, or apathy significantly higher baseline levels of depression (t(36.65) �
mean scores between the two surgery groups after DBS −0 3.56, p < 0.01) and underwent a greater reduction in
(Table 6). Case note review indicated mention of mood levodopa medication than those who did not (t(30) � −3.43,
and/or motivation disorder in a high proportion of patients p < 0.01; Figure 2). There were no other significant baseline
following DBS (STN: n � 17, 60.7%; GPi: n � 8, 66.7%), predictors of subsequent mood disorder, including DBS
documented a mean of 23.16 months (SD � 18.09) after target.
surgery. There was no significant association between DBS Logistic regression confirmed these as significant
location and likelihood of mood disorder and no significant predictors of subsequent mood disorder (χ2(2) � 24.13,
difference in time since surgery between the two DBS patient p < 0.001), explaining 72.2% of the variance (Nagelkerke
groups. R2). Significant and independent associations were found
Parkinson’s Disease 7

30 4. Discussion
Neuropsychological assessment is considered to be an im-
25
portant part of the screening for selection of candidates for
DBS. However, to the best of our knowledge, no stand-
20 ardised assessment procedure currently exists, with many
Cumulative total

studies relying upon brief screening tools only. Neuro-

15 psychological screening should comprise tests with sufficient
reliability and validity, which are sensitive to cognitive
impairment and dementia in PD, able to disambiguate
10
between PD and other disorders, including atypical Par-
kinsonian syndromes, and be sensitive to the changes in
5 cognitive and mood functioning associated with DBS.
In this study, we examined the use of our standardised
0
neuropsychological assessment in a sample of patients un-
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 dergoing DBS for PD. Our assessment tested a wide range of
Months since DBS neuropsychological domains, including general intellectual
Cognitive impairment functioning, verbal and visual recognition and recall
Mood disorder memory, language, visuoperceptual functioning, attention,
verbal fluency, executive functioning, and speed of pro-
Figure 1: Cumulative cases of cognitive impairment and mood cessing. The tests were all standardised, with adequate
disorder as a function of time following DBS.
psychometric properties, easy to administer, and suitable for
routine clinical services.
Our neuropsychological assessment was sensitive to the
cognitive impairment found in PD. At baseline, we docu-
mented frequent impairments in intellectual functioning,
1400 memory, attention, and executive function, with more
Mean levodopa-equivalent dosage (mg/d)

frequent impairments, as expected, in the GPi group. Indeed,

only six of all DBS patients (15%) did not demonstrate
impairment in at least one cognitive domain. Despite this
only one patient demonstrated immediate and irreversible
1200 cognitive decline following DBS. This highlights the limi-
tation of using the presence of any baseline cognitive im-
pairment as an exclusionary criterion for DBS. As low test
scores may reflect a number of cognitive and noncognitive
variables, such as high levels of fatigue, low scores on any one
1000
test should not be used to preclude surgery.
Our neuropsychological assessment was also sensitive to
the cognitive impairments that warrant caution before
proceeding with DBS. In the patient who demonstrated
800 immediate and irreversible global cognitive decline, single-
case statistics revealed that this patient was significantly
Before DBS After DBS older than the mean age of those who remained stable and
No mood disorder had greater deficits in language and visuoperceptual pro-
Mood disorder cessing at baseline. Of course, this is a single case, and
therefore, these results may not be generalizable, but this
Figure 2: Mean levodopa-equivalent dosage of patients before and
finding supports earlier reports that decline in cognitive
after DBS in patients split according to subsequent onset of mood
disorder.
functioning following DBS is more common in patients who
are older [12, 28, 29, 34] and who have greater or more
encompassing cognitive deficits at baseline [36, 68].
for both baseline depression (p < 0.05; odds ratio: 2.23; Although previous guidance on patient selection has
95% confidence intervals: 1.17–4.25) and levodopa re- tended to focus on memory impairment as a core contra-
duction (p < 0.05; odds ratio: 1.00; 95% confidence in- indication for surgery [45, 124], PD patients often dem-
tervals: 1.00–1.00). Classification analysis revealed only onstrate patchy performance on tests of memory, likely
one false negative. reflecting the role of frontosubcortical-mediated cognition
The patient who developed impulse control disorder on memory functioning [107]. In our study, we observed
following GPi DBS did not experience a reduction in common impairments in memory at baseline, but frank
levodopa-equivalent dosage but rather an increase, with deficits in language and visuoperceptual processing were
ongoing dopamine agonist treatment. considerably less common and likely betrayed a greater level
8 Parkinson’s Disease

of general cognitive impairment. Previous guidance has been suggested that the surgery itself may contribute to
warned that lower cognitive functioning at baseline is increases in apathy [60, 113], possibly caused by micro-
predictive of poorer cognitive outcome, but hitherto, there lesions to the subthalamic area during implantation of the
have been no recommendations on what level of impairment electrode [114].
should constitute a contraindication to surgery. Our data Irrespective of the underlying mechanism, deterioration
suggest that, when using the present neuropsychological in verbal fluency can deleteriously affect activities of daily
assessments, caution must be advised if any deficits are living and quality of life [115] and is correlated with reduced
revealed in language and/or visuoperceptual processing independence in everyday functional tasks [116]. Therefore,
(scores <5th percentiles), particularly in patients who are it is recommended that patients and their families are
older and under consideration for STN DBS. counselled about this significant risk before deciding to
Previous studies describing negative cognitive outcomes proceed with surgery, particularly those who present with
following DBS may have failed to identify such risk factors higher levels of apathy at baseline.
because of insufficient scrutiny of baseline cognitive per- In addition to this finding of reduced verbal fluency, our
formance. Previous reports of immediate and global decline assessment detected declines in other aspects of cognitive
following DBS have often stated that such deterioration has functioning. Specifically, STN patients demonstrated sig-
occurred despite satisfactory performance on neuro- nificant slowing on the Symbol Search test and near-
psychological testing at baseline [11, 12]). Closer exami- significant slowing on the Stroop and reduction in VIQ.
nation reveals that such testing has often been limited to GPi patients demonstrated significant reductions in PIQ.
a few screening measures of cognitive function (e.g., the These findings confirm a slowing in the STN patients at least.
MMSE) or focused on executive function, rather than ex- In the absence of any other focal deficits, the heterogeneous
plicitly assessing the presence of impairment in others, more reductions in performance on the WAIS (in both DBS
atypical domains, such as language and visual processing. groups) may also reflect the composite nature of this
For example, York and colleagues [12] report the immediate measure and the effortful, sustained, and speeded aspects of
and global cognitive decline in one gentleman aged 73 years attentional functioning that it requires. Such reductions in
but limit discussion of baseline cognitive performance to speed of processing after DBS have rarely been discussed as
MMSE only, which was notably intact with a score of 28/30. most studies investigating cognitive changes have failed to
In keeping with this, our patient who demonstrated include any measure of processing speed [115]. In previous
immediate and permanent cognitive decline performed studies, there have been conflicting reports of faster
flawlessly on the MMSE and performed poorly on only two responding following STN DBS. However, further in-
out of four tests of executive function but demonstrated spection suggests this may be due to a speed-accuracy trade-
unexpected impairments, most clearly in language and vi- off [1, 117]. In our study, we have shown that deleterious
sual perception. This underlines the importance of a broad changes in speed of processing are present, with likely
neuropsychological assessment, interrogating a wide range important consequences for general intellectual functioning.
of cognitive domains, to reveal the full cognitive profile. When considering the patients who went on to report
Our neuropsychological assessment was also sensitive to cognitive decline at least a year after surgery (as identified by
the changes in cognitive functioning associated with DBS. case note review), there were no significant predictors at
Pre- and after DBS assessments revealed that alongside baseline. This may suggest that the observed decline reflects
improvements in the motor status and medication load are the normal progression of the disease, rather than any
noted in the STN group at least, and our assessment detected preexisting vulnerability in the cognitive profile. It is im-
significant declines in verbal fluency in both groups fol- portant to recognise that the case note review was limited to
lowing DBS. This confirms the mild changes frequently qualitative and subjective comments only, precluding
noted in this cognitive function following DBS [18, 35]. comment on the severity of any cognitive decline. However,
Although the exact cause of verbal fluency decline re- the current findings do support previous studies which
mains unclear, it has been linked with reductions in self- suggest that the risk of developing dementia following DBS
generation [18, 22]. Accordingly, the present study found is equivalent to that in medically treated patients
that greater decline in verbal fluency was associated with [34, 118, 119]. This should be validated through future re-
higher levels of apathy at baseline. Although this did not search that involves a medically treated control group.
persist after the Bonferroni adjustment for multiple com- Our study indicated no significant changes in mood or
parisons, several studies have described increases in apathy apathy, as measured by questionnaires, following DBS.
following DBS [16, 18, 22, 60, 108–110]. Such behavioural However, case note review revealed a very high incidence of
adynamia, as witnessed by the reduced fluency and increased depression, anxiety, and/or apathy after surgery. These
apathy, may in part relate to changes in cognitive speed [29]. contrasting findings may be explained by the fact that as-
We found that reduction in fluency was significantly as- sessment of mood relied upon self-reported symptoms of
sociated with greater changes on at least one measure of depression, anxiety, or depression, whereas case note review
speed of processing. These changes did not seem to simply simply indicated clinicians’ observations. Discrepancy be-
reflect withdrawal of dopaminergic medication [111, 112], as tween self- and proxy-ratings of mood in Parkinson’s disease
although reductions in verbal fluency were related to higher has been reported previously [45, 120, 125] and may be
levels of baseline levodopa dosage and there was no cor- explained by patients’ lack of insight and cognitive dys-
relation with change in dosage following DBS. It has also function [121].
Parkinson’s Disease 9

Mood disorder emerging after DBS has been largely at- to detect the identified red flags for DBS; verbal fluency
tributed to reduction in dopaminergic medications [111, 112]. (DKEFS FAS and Category) and another measure of ex-
Accordingly, we found that deterioration in mood was sig- ecutive function (Stroop) to determine severity of executive
nificantly correlated with reductions in levodopa medication, dysfunction; speed of processing (Digit Symbol Coding and
irrespective of DBS location. There was no association with Symbol Search); and measures of mood and behavioural
discontinuation of dopamine agonists, suggesting that overall functioning, targeting depression, apathy (HADS and AES),
levodopa load was more important than the type of medi- and impulse control disorder (using a measure such as the
cation. These findings are in keeping with previous reports of QUIP). Of course, analysis of neuropsychological perfor-
mood disorder occurring as a nonmotor dopamine with- mance should consider any relevant cultural or linguistic
drawal syndrome after DBS [70, 112]. factors, and it may be appropriate to replace some of the
Furthermore, the chance of developing mood disorder, present neuropsychological assessments with suitable sub-
as identified in the case notes, was even higher in those who stitutions for specific populations.
endorsed clinically significant levels of depression at base-
line. This may suggest that those who have a preexisting 5. Conclusion
vulnerability in mood are at high risk of developing pro-
found mood disorder following DBS. Of course, the high This study has presented a standardised neuropsychological
incidence of mood disorder as noted in the case notes may assessment procedure suitable for the selection of appro-
simply reflect clinicians’ recognition of (stable) low mood. priate candidates with PD for DBS and identified clear
However, its timing of onset and high incidence is consistent baseline risk factors for subsequent decline in cognitive
with several other studies [22, 59, 60, 122]. Therefore, we functioning and mood.
recommend careful and systematic longitudinal psycho-
logical follow-up for all PD DBS patients. Conflicts of Interest
High levels of postoperative apathy or mood disorder can
The authors declare that there are no conflicts of interest
negate any improvement in quality of life [63, 126], but few
regarding the publication of this article.
studies have researched the presence of any baseline correlates
of such decline. This study has found that a higher rating of
depression at baseline is a predictor of poorer psychosocial Acknowledgments
outcome following DBS. We found high rates of depression, This work was undertaken at UCLH/UCL, which received
apathy, and anxiety in our patients at baseline, which may a proportion of funding from the Department of Health’s
reflect elements of both reactive mood disorder and dysre- National Institute for Health Research Biomedical Research
gulation of reward and motivation processing [123]. Indeed, Centre’s funding scheme. The Unit of Functional Neuro-
previous research has suggested that mood disorder following surgery, UCL Institute of Neurology, is supported by the
DBS may reflect the effects of impaired extrastriatal dopa- Sainsbury Monument Trust and Parkinson’s Appeal for
minergic pathways not sufficiently compensated for by STN Deep Brain Stimulation.
stimulation [70]. Therefore, we would suggest that rather than
excluding such patients from DBS, any dopamine withdrawal References
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