Chronic deep brain stimulation of the subthalamic nucleus for Parkinson's disease: effects on cognition, mood, anxiety and personality traits.

Abstract

To evaluate modifications occurring in cognitive functions and behavioural aspects in a group of 72 consecutive patients with Parkinson's disease (PD) 15 months after bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN).
72 consecutive PD patients bilaterally implanted for DBS of the STN were evaluated before and after surgery with a mean follow-up of 15 months. A neuropsychological assessment was performed to evaluate reasoning (Raven Colour Matrices), memory (Bisyllabic Word Repetition Test, Corsi's Block-Tapping Test, Paired-Associate Learning) and frontal executive functions (Trail Making Test Part B, Nelson Modified Card Sorting Test, phonemic and category verbal fluency tasks). Mood and suicidal ideation were evaluated using the Beck Depression Inventory (BDI). Anxiety was measured by means of the State-Trait Anxiety Inventory and personality traits were evaluated with the Structured Clinical Interview for the DSM-III-R Axis II Disorders (SCID-II). Assessment of thought disorders and apathy was based on subitems of the Unified Parkinson's Disease Rating Scale.
The comparisons between pre- and postoperative neuropsychological test scores showed a significant worsening only in phonemic and semantic verbal fluency tasks, while fewer errors were found in the Nelson Modified Card Sorting Test. Globally, behavioural assessment evidenced a small improvement in mood, as assessed by the BDI, in obsessive-compulsive and paranoid personality traits (SCID-II). Thought disorders worsened while suicidal ideation, anxiety and apathy showed no postoperative modifications. The analysis of individual outcomes (+/-1 SD criterion) evidenced a relevant postoperative cognitive decline in 3 patients out of 65 (4.5%). Moreover, following implantation, 1 patients exhibited psychosis (1.5%), 2 patients experienced a clinically relevant worsening of depressive symptoms (3%), 7 patients showed an increase in anxiety (12%) and 3 patients a worsening in depression and anxiety symptoms (3%). On the contrary, 12 patients (20%) showed a relevant improvement in mood and 14 patients (23%) a relevant reduction of anxiety symptoms after the surgery.
The present study confirms that STN DBS is cognitively safe since the only relevant change observed was a mild decrease in verbal fluency tasks. Globally, a small postoperative improvement was found in the BDI, and in two SCID-II subscales concerning obsessive-compulsive and paranoid personality traits, even though postoperative behavioural disturbances can occur in individual patients.

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Original Paper
Eur Neurol 2006;55:136–144
DOI: 10.1159/000093213
Chronic Deep Brain Stimulation of the
Subthalamic Nucleus for Parkinson’s Disease:
Effects on Cognition, Mood, Anxiety and
Personality Traits
L. Castelli a P. Perozzo a M. Zibetti a B. Crivelli a U. Morabito a M. Lanotte a
F. Cossa b B. Bergamasco a,
b L. Lopiano a
a
Casa di Cura Major, S. Maugeri Foundation, Turin , Italy
Department of Neuroscience, University of Turin, and b
Department of Neuromotor Rehabilitation,
between pre- and postoperative neuropsychological test
scores showed a signifi cant worsening only in phonemic
and semantic verbal fl uency tasks, while fewer errors
were found in the Nelson Modifi ed Card Sorting Test.
Globally, behavioural assessment evidenced a small im-
provement in mood, as assessed by the BDI, in obses-
sive-compulsive and paranoid personality traits (SCID-
II). Thought disorders worsened while suicidal ideation,
anxiety and apathy showed no postoperative modifi ca-
tions. The analysis of individual outcomes ( 8 1 SD crite-
rion) evidenced a relevant postoperative cognitive de-
cline in 3 patients out of 65 (4.5%). Moreover, following
implantation, 1 patients exhibited psychosis (1.5%), 2 pa-
tients experienced a clinically relevant worsening of de-
pressive symptoms (3%), 7 patients showed an increase
in anxiety (12%) and 3 patients a worsening in depres-
sion and anxiety symptoms (3%). On the contrary, 12
patients (20%) showed a relevant improvement in mood
and 14 patients (23%) a relevant reduction of anxiety
symptoms after the surgery. Conclusions: The present
study confi rms that STN DBS is cognitively safe since the
only relevant change observed was a mild decrease in
verbal fl uency tasks. Globally, a small postoperative im-
provement was found in the BDI, and in two SCID-II sub-
scales concerning obsessive-compulsive and paranoid
personality traits, even though postoperative behav-
ioural disturbances can occur in individual patients.
Copyright © 2006 S. Karger AG, Basel
Key Words
Parkinson’s disease ? Deep brain stimulation of the
subthalamic nucleus ? Cognitive functions ? Mood ?
Anxiety ? Personality traits
Abstract
Objective: To evaluate modifi cations occurring in cogni-
tive functions and behavioural aspects in a group of 72
consecutive patients with Parkinson’s disease (PD) 15
months after bilateral deep brain stimulation (DBS) of
the subthalamic nucleus (STN). Methods: 72 consecutive
PD patients bilaterally implanted for DBS of the STN
were evaluated before and after surgery with a mean fol-
low-up of 15 months. A neuropsychological assessment
was performed to evaluate reasoning (Raven Colour Ma-
trices), memory (Bisyllabic Word Repetition Test, Corsi’s
Block-Tapping Test, Paired-Associate Learning) and
frontal executive functions (Trail Making Test Part B, Nel-
son Modifi ed Card Sorting Test, phonemic and category
verbal fl uency tasks). Mood and suicidal ideation were
evaluated using the Beck Depression Inventory (BDI).
Anxiety was measured by means of the State-Trait Anx-
iety Inventory and personality traits were evaluated with
the Structured Clinical Interview for the DSM-III-R Axis II
Disorders (SCID-II). Assessment of thought disorders
and apathy was based on subitems of the Unifi ed Par-
kinson’s Disease Rating Scale. Results: The comparisons
Received: December 1, 2005
Accepted: March 2, 2006
Published online: May 8, 2006
Lorys Castelli
Department of Neuroscience, University of Turin
via Cherasco 15
IT–10126 Turin (Italy)
Tel. +39 11 6638034, Fax +39 11 6335668, E-Mail castelli_lorys@hotmail.com
© 2006 S. Karger AG, Basel
0014–3022/06/0553–0136$23.50/0
Accessible online at:
www.karger.com/ene

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Chronic DBS of STN for Parkinson’s
Disease
Eur Neurol 2006;55:136–144
137
Introduction
Deep brain stimulation (DBS) of the subthalamic nu-
cleus (STN) has been shown to represent a valid thera-
peutic option for patients with advanced Parkinson’s dis-
ease (PD). Several studies have shown a signifi cant ame-
lioration of motor symptoms in STN-stimulated PD
patients [1–3] , with a reduction in dopaminergic treat-
ment dose and in the duration and severity of dyskinesias;
moreover, the improvement in motor function is still ev-
ident after a 5-year period [3] .
Overall neuropsychological evidence is consistent with
a global safety of the surgical procedure [4–8] . The cogni-
tive side-effect most frequently observed after surgery was
a decline in the verbal fl uency tasks, in both the phonemic
and/or semantic domains [5, 7–12] ; on rare occasions, a
mild cognitive decline was also reported in cognitive tasks
such as free recall of words (episodic verbal memory) [5,
9, 13] , judgement of line orientation (spatial functions) [9]
and attention [7] , while postsurgical dementia seems to be
relatively rare [3, 8] . On the contrary, an improvement fol-
lowing surgery was noted in other tasks related to frontal
executive functions, such as in the Trail Making Test Part
B (attention shifting) and the Wisconsin Card Sorting Test
(categorisation and set shifting) [5, 9, 14] .
Concerning psychiatric complications of STN DBS, a
wide range of symptoms are reported, even though most-
ly transient [5, 8, 15] ; these include mild to severe depres-
sive episodes, apathy, hypomania, aggressive and psy-
chotic episodes [3, 5, 8, 13, 15, 16] .
A postoperative mood improvement was observed af-
ter STN DBS [4, 8] ; in a recent review of 23 studies, the
positive effect of DBS on depression is highlighted, with
the majority of PD patients reporting improved or un-
changed mood after surgery [17] . Nevertheless, some PD
patients, despite a clear motor improvement, experienced
mood worsening after the procedure [13, 18, 19] and
some cases of suicide or suicide attempt were also de-
scribed [8, 20, 21] . It was suggested that suicide is more
frequent in PD patients who suffered severe depression
or behavioural disturbances before surgery and had un-
dergone multiple DBS surgery, but this issue is still de-
bated and it requires high attention [20] .
Anxiety, like depression, seems to decrease after sur-
gery, even though it has rarely been investigated [5, 22] ;
in addition, STN DBS seems to be effective in reducing
obsessive-compulsive symptoms whether associated with
PD or not [9, 23] . Nevertheless, so far, no exhaustive as-
sessment of personality traits of STN-operated PD pa-
tients has been performed.
The study of Funkiewiez et al. [8] , evaluating 70 STN-
operated PD patients at 1 and 3 years from surgery,
showed an increase in apathy and thought disorders, par-
ticularly at 3 years, whereas a recent study showed a re-
duction in apathy in STN-operated PD patients with
acute stimulation [24] .
Although the effectiveness of STN DBS on motor
symptoms is largely demonstrated, cognitive and behav-
ioural aspects need to be further clarifi ed. Behavioural
complications negatively affect postoperative manage-
ment and can prevent PD patients from benefi ting from
the motor improvement achieved with DBS [15, 19, 21] .
Moreover, most studies assessing cognitive and behav-
ioural effects of STN DBS have a short-term follow-up
(up to 6 months).
The aim of this study was to assess the postoperative
modifi cations occurring in cognitive functions, mood,
anxiety and personality traits in 72 consecutive PD pa-
tients after bilateral STN DBS, with a mean follow-up of
15 months.
Methods
Patients and Procedure
A consecutive series of 72 PD patients bilaterally implanted for
STN DBS were involved in the study and gave their written in-
formed consent. The principal inclusion criteria for the surgical
treatment were the diagnosis of idiopathic PD, the presence of se-
vere motor fl uctuations and drug-related dyskinesias, the absence
of marked atrophy or focal abnormalities on brain MRI, the ab-
sence of dementia or severe cognitive decline, the absence of a
clinically relevant depression, and age less than 70 years [25] . All
patients were submitted to STN DBS following the surgical proce-
dure previously described [26] . A postoperative three-dimensional
MRI was performed to exclude surgical complications and then it
was fused with the pre-operative CT scan to check the corrected
position of the electrodes.
Seven patients were lost to follow-up because of reasons unre-
lated to cognitive or behavioural side-effects and were excluded
from the study.
The remaining 65 PD patients (38 male, 27 female) underwent
motor, neuropsychological and behavioural assessment 2 weeks
before and at a mean of 15 months after surgery (range: 12–20
months).
The motor evaluation was performed according to the Core As-
sessment Program for Surgical Interventional Therapies in Parkin-
son’s Disease [27] . In order to assess the rate of motor improvement
induced by STN high-frequency stimulation, data relative to sec-
tion 3 of the Unifi ed Parkinson’s Disease Rating Scale (UPDRS)
are reported [27] in two conditions: ‘pre-operative medication off’
(med-off) and ‘postoperative stimulation on/medication off’ (stim-
on/med-off). Antiparkinsonian medications are expressed as le-
vodopa equivalent daily dosage (LEDD) [28] .

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Eur Neurol 2006;55:136–144
138
The neuropsychological and behavioural assessments were per-
formed in the optimal clinical condition for the patients: pre-opera-
tive med-on and postoperative stim-on/med-on condition (daily dos-
age of dopaminergic drugs), except for the 6 patients who complete-
ly stopped the dopaminergic treatment after STN DBS. Some tests
were not administered to the fi rst patients of our series and few oth-
ers were lost during the follow-up period (see tables). Table 1 shows
the main demographic and clinical characteristics of the patients.
Neuropsychological Assessment
All PD patients underwent a standardised cognitive test battery
assessing reasoning, memory and frontal executive functions. The
neuropsychological tests were described in a previous study [29] .
Visuospatial reasoning was evaluated by means of the Raven Col our
Matrices (PM 47) [30] ; verbal and spatial short-term memory were
assessed by means of the Bisyllabic Word Repetition Test (BWR)
[31] and Corsi’s Block-Tapping Test (CBT) [31] , respectively. The
assessment of verbal learning was achieved by means of the Paired-
Associate Learning (PAL) [32] , a Wechsler Memory Scale subtest.
Frontal lobe executive functions, including the development of ab-
stract concepts and the shift of attentional and motor sets, were as-
sessed by means of the Trail Making Test Part B [33] and the Nelson
Modifi ed Card Sorting Test (MCST) [34] , a modifi ed version of the
Wisconsin Card Sorting Test. In addition, patients were adminis-
tered the phonemic and category verbal fl uency tasks [31, 35] .
Two parallel forms were used for all the memory tests (BWR,
CBT, PAL) in order to avoid the test-retest effect.
Mood, Anxiety and Personality Trait Assessment
Mood was evaluated by means of the Beck Depression Inven-
tory (BDI), a 21-item self-rated scale [36, 37] . The total score was
obtained considering all items, rated from 0 to 3. Total scores of
0–9 indicate absence of depression, of 10–17 mild depression, of
18–24 moderate depression, and, fi nally, scores higher than 25 are
indicative of severe depression [35] . Suicidal ideation was assessed
by item No. 9 of the BDI, rating from 0 (absence of suicidal ide-
ation) to 3 (indicating the purpose to commit suicide). The State-
Trait Anxiety Inventory (STAI) was used to assess anxiety as a re-
action to episodic stress conditions (STAI-X1) and as a predisposi-
tion to experience persistent anxious behaviour (STAI-X2) [38] .
The semi-structured Clinical Interview for the DSM-III-R Axis
II Disorders (SCID-II) was used to evaluate personality traits. The
SCID-II is composed of a 12-subscore questionnaire (113 items),
each related to a different diagnostic category (avoidant, dependent,
obsessive-compulsive, passive-aggressive, self-defeating, paranoid,
schizotypal, schizoid, histrionic, narcissistic, borderline and anti-
social) [39] . Thought disorders and apathy were assessed by means
of item 2 and item 4 of the UPDRS section 1, respectively.
Statistical Analyses
To compare pre- and postoperative test scores, t tests for paired
samples were run. Correlations between variables were assessed by
means of the Pearson correlation analysis. In order to assess changes
among individual patients after surgery, each raw score was trans-
formed to a standard z-score using means and standard deviation
(SD) values of the total sample at baseline. The clinical criterion of
8 1 SD was used to register a patient as improved or worsened, re-
spectively. Given the explorative nature of the study, a p value
! 0.05 was considered statistically signifi cant. Nevertheless, values
of p between 0.05 and 0.01 should be accepted with caution.
Results
Motor Effectiveness
A signifi cant reduction in motor disability, equal to
50%, was found 15 months after surgery (pre-operative
med-off vs. postoperative stim-on/med-off conditions,
p ! 0.001); moreover, STN stimulation allowed PD pa-
tients to reduce the daily dose of antiparkinsonian drugs
by 56% (p ! 0.001). Six patients completely stopped all
dopaminergic treatments after surgery. Nine patients
(14%) developed dysarthria/hypophonia after STN DBS
(UPDRS part 3, item 18, score 6 2). These data are sum-
marised in table 1 . Stimulation parameters are detailed
in table 2 . A stable pattern of stimulation was usually
reached within the fi rst month after surgery; afterwards,
minimal modifi cations were made in individual patients.
At the moment of the postoperative assessment, the pa-
rameters of the 65 PD patients were stable for a mean
period of 7 months (range 3–17 months).
Neuropsychological Data
Scores from neuropsychological tests are shown in ta-
ble 3 . Tests investigating reasoning (PM 47) and memory
evidenced no changes after STN DBS. Both verbal and
Table 1. Clinical characteristics of the 65 PD patients
Male/female
Age, years
Education, years
Duration of disease, years
LEDD, mg/day
Before surgery
After surgery
UPDRS part 3
Before surgery, med-off
After surgery, stim-on/med-off
38/27
60.5 (6.5)
8.7 (4.2)
15.1 (5.1)
1,010.5 (419.9)
447.1 (284.8)
54.4 (13.4)
27.2 (11.7)
Results are means with SD in parentheses.
Table 2. Stimulation parameters at the time of the postoperative
assessment
Right STNLeft STN
Voltage, V
Pulse width, ?s
Rate, Hz
3.3 (0.4)
67.5 (13.1)
143.1 (19.9)
3.3 (0.3)
68.5 (19.3)
142.7 (22.2)
Results are means with SD in parentheses.

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spatial short-term memory (BWR, CBT) and verbal learn-
ing (PAL) remained globally stable at follow-up. Concern-
ing frontal executive functions, a signifi cantly lower num-
ber of total errors (p ! 0.02) and perseverative errors
(p ! 0.04) were found in the Nelson MCST, while perfor-
mance in verbal fl uency tasks showed a signifi cant decline
after surgery; this was observed both for phonemic (p !
0.001) and category fl uency tasks (p ! 0.005). The pa-
tients with dysarthric/hypophonic disturbances did not
show a signifi cant difference in the performance in verbal
fl uency tasks when compared to the other PD patients of
the present series. Finally, no signifi cant change was ob-
served in the ability to shift attention between different
sets of stimuli (Trail Making Test Part B).
Analysing changes among individual patients on neu-
ropsychological tests ( table 4 ), the percentage of PD pa-
tients whose performance deteriorated after surgery var-
ied from a minimum of 2% (errors, Nelson MCST) to a
maximum of 26% (phonemic fl uency test), while im-
provements were observed in a minimum of 5% (verbal
fl uency tasks) to a maximum of 32% of the patients (short-
term memory tests). Most of the patients did not show
clinically relevant negative changes at the 15-month fol-
low-up. One patient (1.5%), who developed a progressive
onset dementia according to DSM-IV criteria [40] , also
showed, after some months from surgery, a progressive
motor deterioration unresponsive to levodopa therapy,
urinary incontinence and symptomatic orthostatic hypo-
tension, with a clinical picture suggestive of multisystem
atrophy. This patient evidenced a clinically relevant de-
cline in all the neuropsychological test scores (10/10).
Two other PD patients (3%) evidenced a cognitive wors-
ening with a relevant decline in 6 out of 10 neuropsycho-
logical variables.
n Before surgery After surgeryt test d.f.p
Raven Colour Matrices
Bisyllabic Word Repetition Test
Corsi’s Block-Tapping Test
Paired-Associate Learning
Trail Making Test Part B
65
65
65
65
55 276.2 (172.8)
26.7 (4.6)
4.4 (0.7)
4.4 (0.7)
10.9 (3.1)
27.0 (4.4)
4.2 (0.8)
4.2 (0.8)
10.8 (3.2)
276.2 (166.6)
–0.54 64
1.94 64
1.30 64
0.25 64
0.01 54
0.593
0.056
0.199
0.805
0.999
Nelson Modifi ed Card Sorting Test
Categories
Errors
Perseverations
Phonemic fl uency
Semantic fl uency
55
55
55
65
65
5.2 (1.5)
8.9 (10.3)
3.5 (5.5)
41.6 (15.7)
17.6 (4.7)
5.6 (1.0)
5.4 (6.2)
1.6 (3.7)
34.3 (14.8)
16.1 (4.3)
–1.72 54
2.66 54
2.21 54
4.42 64 <0.001
3.46 64
0.092
0.010
0.031
0.001
Results are means with SD in parentheses. Bold = p value ! 0.05.
Table 3. Neuropsychological test scores
before and 15 months after DBS of STN
n Declined, %Unchanged, %Improved, %
Raven Colour Matrices
Bisyllabic Word Repetition Test
Corsi’s Block-Tapping Test
Paired-Associate Learning
Trail Making Test Part B
65
65
65
65
55
977
56
47
74
75
14
32
32
11
9
12
21
15
16
Nelson Modifi ed Card Sorting Test
Categories
Errors
Perseverations
Phonemic fl uency
Semantic fl uency
55
55
55
65
65
11
2
2
26
18
65
82
82
69
77
24
16
16
5
5
A performance was considered as declined or improved when it was >81 SD.
Table 4. Individual score changes on
neuropsychological tests 15 months after
DBS of STN

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Behavioural Data
Data of the behavioural scales are shown in table 5 . A
signifi cant improvement was found in mood (p ! 0.01),
investigated by means of the BDI; the PD patients expe-
rienced less depressive symptoms after the surgical treat-
ment. Suicidal ideation (item 9, BDI) was absent in the
pre-operative period ( table 5 ) and remained unchanged
after STN DBS. State and trait anxiety did not vary sig-
nifi cantly.
As for personality traits (SCID-II), we found lower
scores indicative of obsessive-compulsive traits (p !
0.005) and paranoid traits (p ! 0.005) after surgery, while
scores concerning other personality traits did not show
modifi cations. Apathy (item 4, UPDRS part 1) was sub-
stantially stable after surgery, whereas the patients showed
a signifi cantly higher score of thought disorders (item 2,
UPDRS part 1, hallucinations and delusions) at postop-
erative follow-up (p ! 0.001).
As far as individual score changes were concerned ( ta-
ble 6 ), 10% of the patients revealed a clinically relevant
worsening of depressive symptoms (BDI), most of the
patients (70%) remained stable and 20% evidenced an
improvement on mood after surgery. According to BDI
categories, the proportion of patients with severe depres-
sive symptoms decreased from 12% pre-operatively to 8%
15 months after surgery; the absence of depression varied
from 28% before to 48% after surgery, mild depression
from 43 to 32% and moderate depression from 17 to
12%.
The score relative to suicidal ideation (item 9, BDI)
increased in 6 patients (10%); however, no patients
reached a score of 3 indicating a clear purpose to commit
suicide, and only 1 patient had a score of 2. State and trait
anxiety were unchanged in the majority of the patients
with less than 20% experiencing higher levels of anxiety
after surgery.
In addition, STN DBS seems to have a positive effect
on obsessive-compulsive and paranoid traits (SCID-II):
only 7% of the patients showed a worsening of these per-
sonality traits on the postoperative assessment, while
more than 20% of patients showed a clinically relevant
improvement.
A signifi cant increase in scores related to thought dis-
orders was found in 32% of patients. The percentage of
patients with a score 6 2 after surgery was 13% compared
to 5% prior to surgery. Nevertheless, only 1 patient showed
a postoperative score of 4 indicating true psychosis.
Most patients (64%) did not show a signifi cant increase
in apathy scores, 18% improved and an equal percentage
worsened. Both before and after surgery, the proportion
of PD patients with an apathy score 6 2 (clinically rele-
vant) was 8%.
Table 5. Behavioural data before and 15 months after DBS of STN
n Before surgeryAfter surgeryt test d.f.p
BDI
Suicidal ideation (item 9, BDI)
STAI-X1
STAI-X2
60
60
60
60
14.9 (8.6)
0.16 (0.45)
45.6 (9.5)
46.3 (9.5)
11.6 (7.0)
0.14 (0.39)
44.0 (9.2)
45.3 (9.0)
2.76
0.22
1.19
0.73
59
59
59
59
0.008
0.829
0.237
0.466
SCID II
Avoidant
Depending
Obsessive-compulsive
Passive-aggressive
Self-frustrating
Paranoid
Schizotypical
Schizoid
Histrionic
Narcissistic
Borderline
Antisocial
Thought disorders (item 2, UPDRS part 1)
Apathy (item 4, UPDRS part 1)
60
60
60
60
60
60
60
60
60
60
60
60
62
62
2.9 (1.9)
2.9 (1.6)
4.4 (2.1)
2.6 (1.8)
3.6 (2.0)
2.5 (1.5)
1.7 (1.5)
2.4 (1.0)
1.9 (1.4)
3.2 (2.1)
3.0 (2.3)
0.6 (0.9)
0.18 (0.51)
0.35 (0.68)
2.9 (1.9)
3.0 (2.1)
3.8 (2.0)
2.9 (2.0)
3.2 (2.0)
1.8 (1.5)
1.7 (1.4)
2.2 (1.2)
2.0 (1.5)
3.4 (2.4)
3.0 (2.3)
0.8 (1.2)
0.52 (0.76)
0.35 (0.72)
0.17
0.37
2.33
–1.09
1.34
3.32
–0.16
1.39
–0.34
–0.57
0.05
–0.98
–3.81
0.07
59
59
59
59
59
59
59
59
59
59
59
59
61
61
0.869
0.710
0.002
0.281
0.184
0.002
0.871
0.171
0.733
0.568
0.957
0.333
<0.0001
0.942
Results are means with SD in parentheses. Bold = p value ! 0.05.

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As for postoperative modifi cations of psychopharma-
cological agents, the percentage of PD patients assuming
anxiolytics decreased from 43 to 32%, whereas the use of
antidepressants increased from 23 to 37% of patients.
The patients assuming antipsychotics drugs were 20%
pre-operatively and 22% after surgery.
Taken together, the analysis of individual outcomes
evidenced that 9 patients of the present series (14%) ex-
perienced a clinically relevant deterioration 15 months
after the surgical procedure. In particular, 3 cases showed
a relevant cognitive decline (4.5%), 1 of whom associated
with increased anxiety and 1 with increased anxiety and
mood worsening, 1 patient developed psychosis (1.5%),
5 patients experienced a clinically signifi cant worsening
of depressive symptoms (8%), 3 of whom (3% of the total)
associated with an increase in anxiety symptoms. Seven
other patients experienced an increase in anxiety symp-
toms alone (12%). Nevertheless, it is worth noting that 12
patients (20%) showed a relevant improvement in mood
and 14 patients (23%) a relevant improvement in anxiety
symptoms after surgery.
Correlations
A statistically signifi cant correlation between postop-
erative test modifi cations (pre-operative minus postop-
erative values) was found for mood state improvement
(BDI) and motor improvement (UPDRS part 3) (r 60 =
0.3; p ! 0.03), while no correlation was found between
mood changes and LEDD reduction. Also, obsessive-
compulsive and paranoid subscale scores of the SCID-II
showed a correlation between each other (r 60 = 0.6; p !
0.001), whereas no signifi cant correlation was found be-
tween age, duration of illness, and postoperative test
modifi cations. Apathy and verbal fl uency score modifi ca-
tions (phonemic and semantic separately) did not corre-
late with each other.
Discussion
The present study confi rms that STN DBS can be con-
sidered a relatively safe procedure in terms of cognitive
and behavioural effects. In agreement with most studies
investigating cognitive effects of STN DBS, we found a
signifi cantly lower number of words produced during the
phonemic and semantic verbal fl uency tasks after the sur-
gical procedure [5, 7–12] . Recently, some investigators
have suggested that the decline on these tasks could de-
pend on the postoperative increase in apathy, since verbal
fl uencies are internally guided tasks [8] . Our fi ndings do
not seem to support this hypothesis because no worsening
in apathy scores was detected concomitant with verbal
nIncreased
%
Unchanged
%
Lowered
%
BDI
Suicidal ideation (item 9, BDI)
STAI-X1
STAI-X2
SCID II
Avoidant
Depending
Obsessive-compulsive
Passive-aggressive
Self-frustrating
Paranoid
Schizotypical
Schizoid
Histrionic
Narcissistic
Borderline
Antisocial
Thought disorders (item 2, UPDRS part 1)
Apathy (item 4, UPDRS part 1)
60
60
60
60
10
10
17
18
70
80
60
59
20
10
23
23
60
60
60
60
60
60
60
60
60
60
60
60
62
62
23
23
7
28
20
7
17
30
20
13
13
15
32
18
49
52
73
55
52
66
68
27
67
70
74
60
66
64
28
25
20
17
28
27
15
43
13
17
13
15
2
18
A score was considered as increased or lowered when it was >81 SD.
Table 6. Individual score changes on
behavioural tests 15 months after DBS of
STN

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Castelli et al.

Eur Neurol 2006;55:136–144
142
fl uency decline. An alternative explanation of this neuro-
psychological side-effect might imply a negative effect of
STN stimulation on the frontotemporal network during
execution of a verbal fl uency task, as demonstrated by a
recent PET study [41] . So, STN stimulation could have a
positive effect on routine and automatic activities, but a
negative effect on some tasks that require a higher rate of
cognitive fl exibility [41, 42] .
On the other hand, the PD patient of our series com-
mitted a lower number of perseverative and total errors
on the Nelson MCST; this fi nding is in agreement with
previous studies that reported an improvement on some
aspects of executive functions after STN DBS [5, 14] .
Nevertheless, the same version of this test was used in
both assessments, possibly making the practice effect re-
sponsible for this improvement.
Three patients out of 65 in our series (4.5%) developed
a relevant cognitive decline. This percentage was in line
with the 6.5% of patients with a cognitive decline ob-
served in another study over 3 years [8] . In agreement
with previous studies, a small improvement in mood state
was found after surgery [4, 8, 16] . In addition, a signifi -
cant correlation was observed between postoperative re-
duction of depressive symptoms and motor benefi t in-
duced by the STN stimulation; probably, the improve-
ment in mood could partially arise as a consequence of
the reduction in motor disability. A clinically relevant
mood worsening was experienced by 6 patients (10%); a
similar proportion of mood worsening was reported by
other studies [13, 18, 19] . To date, no univocal explana-
tion for the post-DBS increase in depressive symptoms
has been provided. On the basis of the correlation be-
tween motor improvement and mood state modifi ca-
tions, one might speculate that a lesser degree of motor
improvement after surgery can have a negative effect on
mood. The correlation we found was statistically weak,
so no certain explanation can be derived from it. Indeed
many factors, such as pre-existing illness, drug therapy or
psychological expectations towards the surgical proce-
dure, may be involved in mood modifi cations [43, 44] .
Recently, it has been suggested that following DBS sur-
gery PD patients could be at higher risk of suicide com-
pared to non-operated PD patients [20, 45] . Burkhard et
al. [20] pointed out that patients at higher risk were those
with a previous history of severe depression, even if de-
pression alone could not predict the decision to commit
suicide. In our series, as in the one of Albanese et al. [45] ,
none of the PD patients attempted or committed suicide;
moreover, we provided an index of suicidal ideation, and
we did not fi nd a signifi cant modifi cation after surgery.
However, further studies are necessary to clarify this im-
portant issue, and a careful selection of PD patients suit-
able for surgery, excluding individuals suffering severe
depressive symptoms, should be considered [20] .
Globally, we evidenced no change in anxiety symp-
toms after surgery, at variance with the few other studies
that reported a postoperative reduction in anxiety [5, 22] .
In a single study, a great number of PD patients with some
kind of anxiety disorder after STN DBS were observed;
however, all except one of these PD patients had already
experienced anxiety disorder before surgery [44] . In our
series, 18% of the patients experienced a clinically rele-
vant worsening in anxiety symptoms, concomitant or not
with a worsening of mood, while 23% of the patients
showed a relevant improvement in anxiety.
An interesting fi nding of the present study is the signi-
fi cant reduction of obsessive-compulsive traits after STN
DBS. This is in agreement with other studies [9, 23] and
provides further support for the recent application of DBS
surgery in the treatment of severe obsessive-compulsive
disorder associated or not with PD [15, 23, 46, 47] . It was
suggested that the amelioration of obsessive-compulsive
traits could result from activation of serotonergic fi bers in
the subcortical-limbic circuitry or, alternatively, from cur-
rent diffusion to the limbic part of the STN [15, 23] .
Paranoid personality traits were also ameliorated after
the surgical procedure: STN-stimulated patients become
less distrustful of other people, and the motor benefi t may
allow them to be more autonomous in life and less wor-
ried about negative judgements of others in social situa-
tions. In accordance with another study [8] , thought dis-
order scores evidenced an overall increase after surgery,
but only 1 patient of our series developed permanent psy-
chosis after STN DBS.
Taken together, our results pointed out a total of 9 pa-
tients (14%) that experienced relevant postoperative cog-
nitive or behavioural disturbances following the DBS
procedure.
As for depression, these behavioural side-effects could
depend on many factors, such as stimulation per se, the
procedure as a whole, the progression of the disease, the
reduction of dopaminergic drug treatment as well as post-
operative psychological adjustments [44] . The present
study does not allow us to discriminate between these
variables. That being said, in our experience it is impor-
tant to moderate the patients’ expectations towards the
benefi t of the intervention. Many patients, especially the
ones with pre-operative depression, frequently developed
wild and unrealistic expectations of becoming complete-
ly healthy [20] .

Page 8

Chronic DBS of STN for Parkinson’s
Disease
Eur Neurol 2006;55:136–144
143
The present study has some limitations that are usu-
ally present in longitudinal studies. First, we did not in-
clude a control group of unoperated PD patients. So, even
if little cognitive decline is usually observed over a period
of 12 months [5, 11] , it is still possible that some of the
cognitive and behavioural modifi cations observed derive
from the progression of the illness independently of the
DBS procedure. Second, since only memory tests were
administered in parallel versions, the improvement ob-
served in other tasks could partially result from practice
effect. However, we can suppose that the test-retest effect
has been partially limited by the suffi ciently long interval
elapsed between the two evaluations.
In conclusion, our fi ndings confi rm that STN DBS did
not lead to cognitive decline or behavioural disturbances
in most of the cases. Nevertheless, since 14% of the STN-
stimulated PD patients experienced neuropsychological
or relevant behavioural disturbances, further studies are
still needed to clarify which pre-operative clinical fea-
tures or postoperative modifi cations can be responsible
for this.
References
1 Lopiano L, Rizzone M, Bergamasco B, et al:
Deep brain stimulation of the subthalamic nu-
cleus: clinical effectiveness and safety. Neurol-
ogy 2001; 56: 552–554.
2 Vingerhoets FJG, Villemure JG, Temperli P,
et al: Subthalamic DBS replaces levodopa in
Parkinson’s disease: two years follow-up. Neu-
rology 2002; 58: 396–401.
3 Krack P, Batir A, Van Blercom N, et al: Five-
year follow-up of bilateral stimulation of the
subthalamic nucleus in advanced Parkinson’s
disease. N Engl J Med 2003; 349: 1925–1934.
4 Woods SP, Fields JA, Tröster AI: Neuropsy-
chological sequelae of subthalamic nucleus
deep brain stimulation in Parkinson’s disease:
a critical review. Neuropsychol Rev 2002; 12:
111–126.
5 Daniele A, Albanese A, Contarino MF, et al:
Cognitive and behavioural effects of chronic
stimulation of the subthalamic nucleus in pa-
tients with Parkinson’s disease. J Neurol Neu-
rosurg Psychiatry 2003; 74: 175–182.
6 Gironell A, Kulisevsky J, Rami L, et al: Effects
of pallidotomy and bilateral subthalamic stim-
ulation on cognitive function in Parkinson’s
disease. A controlled comparative study. J
Neurol 2003; 250: 917–923.
7 Morrison CE, Borod JC, Perrine K, et al: Neu-
ropsychological functioning following bilateral
subthalamic nucleus stimulation in Parkin-
son’s disease. Arch Clin Neuropsychol 2004;
19: 165–181.
8 Funkiewiez A, Ardouin C, Caputo E, et al:
Long-term effects of bilateral subthalamic nu-
cleus stimulation on cognitive function, mood,
and behaviour in Parkinson’s disease. J Neurol
Neurosurg Psychiatry 2004; 75: 834–839.
9 Alegret M, Junqué C, Valldeoriola F, et al: Ef-
fect of bilateral subthalamic stimulation on
cognitive function in Parkinson disease. Arch
Neurol 2001; 58: 1223–1227.
10 Ardouin C, Pillon B, Peiffer E, et al: Bilateral
subthalamic or pallidal stimulation for Parkin-
son’s disease affect neither memory nor execu-
tive functions: a consecutive series of 62 pa-
tients. Ann Neurol 1999; 46: 217–223.
11 Saint-Cyr JA, Trépanier LL, Kumar R, Lozano
AM, Lang AE: Neuropsychological conse-
quences of chronic bilateral stimulation of the
subthalamic nucleus in Parkinson’s disease.
Brain 2000; 123: 2091–2108.
12 Trépanier LL, Kumar R, Lozano AM, Lang
AE, Saint-Cyr A: Neuropsychological outcome
of GPi pallidotomy and GPi or STN deep brain
stimulation in Parkinson’s disease. Brain Cogn
2000; 42: 324–347.
13 Dujardin K, Defebvre L, Krystkowiac P, et al:
Infl uence of chronic bilateral stimulation of the
subthalamic nucleus on cognitive function in
Parkinson’s disease. J Neurol 2001; 248: 603–
611.
14 Jahanshahi M, Arduin C, Brown RG: The im-
pact of deep brain stimulation on executive
function in Parkinson’s disease. Brain 2000;
123: 1142–1154.
15 Piacesky SD, Jefferson JW: Psychiatric com-
plications of deep brain stimulation for Parkin-
son’s disease. J Clin Psychiatry 2004; 65: 845–
849.
16 Anderson KE, Jake Mullins BA: Behavioural
changes associated with deep brain stimulation
surgery for Parkinson’s disease. Curr Neurol
Neurosci Rep 2003; 3: 306–313.
17 Takeshita S, Kurisu K, Trop L, et al: Effect of
subthalamic stimulation on mood state in Par-
kinson’s disease: evaluation of previous facts
and problems. Neurosurg Rev 2005; 28: 179–
186.
18 Berney A, Vingerhoets F, Perrin A, et al: Effect
on mood of subthalamic DBS for Parkinson’s
disease. Neurology 2002; 59: 1427–1429.
19 Thobois S, Mertens P, Guenot M, et al: Sub-
thalamic nucleus stimulation in Parkinson’s
disease: clinical evaluation of 18 patients. J
Neurol 2002; 249: 529–534.
20 Burkhard PR, Vingerhoets FJC, Berney A, et
al: Suicide after successful deep brain stimula-
tion for movement disorder. Neurology 2004;
63: 2170–2172.
21 Doshi PK, Chhaya N, Bhatt MH: Depression
leading to attempted suicide after bilateral sub-
thalamic nucleus stimulation. Mov Disord
2002; 17: 1084–1085.
22 Higginson CI, Fields JA, Troster AI: Which
symptoms of anxiety diminish after surgical
intervention for Parkinson’s disease? Neuro-
psych Neuropsychol Behav Neurol 2001; 14:
117–121.
23 Mallet L, Mesnage V, Houeto JL: Compul-
sions, Parkinson’s disease, and stimulation.
Lancet 2002; 360: 1302–1304.
24 Czernecki V, Pillon B, Houeto JL, et al: Does
bilateral stimulation of the subthalamic nucle-
us aggravate apathy in Parkinson’s disease? J
Neurol Neurosurg Psychiatry 2005; 76: 775–
779.
25 Lopiano L, Rizzone M, Bergamasco B, et al:
Deep brain stimulation of subthalamic nucleus
in PD: an analysis of the exclusion causes. J
Neurol Sci 2002; 195: 167–170.
26 Lanotte M, Rizzone M, Bergamasco B, et al:
Deep brain stimulation of the subthalamic nu-
cleus: anatomical, neurophysiological, and
outcome correlations with the effects of stimu-
lation. J Neurol Neurosurg Psychiatry 2002;
72: 53–58.
27 Defer GL, Widner H, Marié RM, et al: Core
assessment program for surgical interventional
therapies in Parkinson’s disease (CAPSIT-
PD). Mov Disord 1999; 14: 572–584.
28 Lozano AM, Lang AE, Galvez-Jimenez N, et
al: Effect of GPi pallidotomy on motor func-
tion in Parkinson’s disease. Lancet 1995; 346:
1383–1387.
29 Perozzo P, Rizzone M, Bergamasco B, et al:
Deep brain stimulation of the subthalamic nu-
cleus in Parkinson’s disease: comparison of
pre- and post-operative neuropsychological
evaluation. J Neurol Sci 2001; 192: 9–15.
30 Raven JC: Coloured Progressive Matrices (Sets
A, AB, B). London, Lewin HK, 1962.
31 Spinnler H, Tognoni G: Standardizzazione e
taratura italiana di test neuropsicologici. Ital J
Neurol Sci 1987; 6(suppl 8):1–120.
32 Wechsler D: A standardized memory scale for
clinical use. J Psychol 1945; 19: 87–95.
33 Reitan RM: Validity of the Trail Making Test
as an indication of organic brain damage. Per-
cept Mot Skill 1958; 8: 271–276.

Page 9

Castelli et al.

Eur Neurol 2006;55:136–144
144
34 Nelson HE: A modifi ed Card Sorting Test sen-
sitive to frontal lobe defect. Cortex 1976; 12:
313–324.
35 Benton AL: Differential behavioural effects in
frontal lobe disease. Neuropsychology 1968; 6:
53–60.
36 Beck AT: Beck Depression Inventory. San An-
tonio, Psychological Corporation, 1987.
37 Beck AT: Depression. Philadelphia, Universi-
ty of Pennsylvania Press, 1970.
38 Spielberger CD, Gorsuch RL, Lushene RE:
STAI. Questionario di autovalutazione per
l’ansia di stato e di tratto. Firenze, Organizza-
zioni Speciali, 1980.
39 Spitzer RL, Williams JBW, Gibbon M, First
MB: Questionario SCID II (Italian transla-
tion). Firenze, Organizzazioni Speciali, 1993.
40 American Psychiatric Association: Diagnostic
and Statistical Manual of Mental Disorders, ed
4. Washington, American Psychiatric Associa-
tion, 1994.
41 Schroeder U, Kuehler A, Lange KW, et al: Sub-
thalamic nucleus stimulation affects a fronto-
temporal network: a PET study. Ann Neurol
2003; 54: 445–450.
42 Marsen CD, Obeso JA: The function of the
basal ganglia and the paradox of stereotaxic
surgery in Parkinson’s disease. Brain 1994;
117: 877–897.
43 Burn DJ, Tröster AI: Neuropsychiatric compli-
cations of medical and surgical therapies for
Parkinson’s disease. J Geriatr Psychiatry Neu-
rol 2004; 17: 172–180.
44 Houeto JL, Mesnage V, Mallet L, et al: Behav-
ioral disorders, Parkinson’s disease and sub-
thalamic stimulation. J Neurol Neurosurg Psy-
chiatry 2002; 72: 701–707.
45 Albanese A, Piacentini S, Romito LMA, et al:
Suicide after successful deep brain stimulation
for movement disorder. Neurology 2005; 65:
499–500.
46 Medina J: Neural implants and obsessive-com-
pulsive disorder. Psychiatr Times 2003; 20:
43–46.
47 George M: New methods of brain stimulation
are improving research and therapy in obses-
sive-compulsive disorder. CNS Spectr 2000; 5:
12–17.