Voon, Kubu Et Al 2006

Movement Disorders
Vol. 21, Suppl. 14, 2006, pp. S305–S326

© 2006 Movement Disorder Society
Deep Brain Stimulation: Neuropsychological and

Neuropsychiatric Issues
Valerie Voon, MD,1,2* Cynthia Kubu, PhD,3 Paul Krack, MD,4 Jean-Luc Houeto, MD,5
and Alexander I. Tröster, PhD6
1
Department of Psychiatry, Toronto Western Hospital, Toronto, Canada
2
Human Motor Control Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health,
Bethesda, Maryland, USA
3
Department of Psychiatry and Psychology, Cleveland Clinic Foundation, Cleveland, Ohio, USA
4
Department of Neurology and INSERM U 318, University of Grenoble, Grenoble, France
5
Department of Neurology, Poitiers University Hospital, Poitiers, France
6
Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA
Abstract: Parkinson’s disease (PD) is a neurodegenerative erature on the cognitive and neuropsychiatric aspects of DBS
disorder characterized by motor, cognitive, neuropsychiatric, for PD. The majority of the observed neuropsychiatric symp-
autonomic, and other nonmotor symptoms. The efficacy of toms are transient, treatable, and potentially preventable. Out-
deep brain stimulation (DBS) for the motor symptoms of ad- come studies, methodological issues, pathophysiology, and
vanced PD is well established. However, the effects of DBS on preoperative and postoperative management of the cognitive
the cognitive and neuropsychiatric symptoms are less clear. and neuropsychiatric aspects and complications of DBS for PD
The neuropsychiatric aspects of DBS for PD have recently been are discussed. © 2006 Movement Disorder Society
of considerable clinical and pathophysiological interest. As a Key words: Parkinson’s disease; deep brain stimulation;
companion to the preoperative and postoperative sections of the depression; cognition; subthalamic
DBS consensus articles, this article reviews the published lit-
A range of neuropsychiatric symptoms have been in- tion-induced hypersexuality and pathological gambling.
creasingly recognized in Parkinson’s disease (PD) and While the efficacy of bilateral deep brain stimulation
are presumed to be due to the underlying neurodegen- (DBS) for the motor symptoms of advanced PD has been
erative process, dopaminergic medications, underlying well established,4 the effects of DBS on these nonmotor
vulnerabilities, and/or psychosocial factors. These symp- cognitive and psychiatric symptoms are less clear.
toms range from disorders of cognition, mood (depres- Thisarticle expands on the cognitive and neurobehav-
sion, mania), anxiety, hallucinations, to apathy.1,2 More ioral aspects of DBS for PD and is intended as a com-
recently, a group of behaviors resulting from the chronic panion to the preoperative and postoperative sections of
and pulsatile administration of dopamine (the dopamine the consensus articles. The concept of neuropsychologi-
dysregulation syndrome) has been identified.3 These be- cal or cognitive issues and neuropsychiatric or neurobe-
haviors include “hedonistic homeostatic dysregulation” havioral issues will be separated for the sake of clarity,
or a form of excessive and pathological use of dopami- although overlaps will occur. It is recognized that on a
nergic medications for nonmotor purposes and medica- clinical level, the assessment, management, and patho-
physiology of these symptoms do not exist indepen-
*Correspondence to: Dr. Valerie Voon, Human Motor Control Sec- dently. It should be noted that in the vast majority of
tion, NINDS/NIH, Building 10, Room 5S213, 10 Center Drive MSC well-selected patients, DBS has demonstrated efficacy
1428, Bethesda, MD 20892. E-mail: voonv@ninds.nih.gov
Published online in Wiley InterScience (www.interscience.wiley.
and safety. Furthermore, despite the range of postopera-
com). DOI: 10.1002/mds.20963 tive psychiatric symptoms reported, the majority of
S305
S306 V. VOON ET AL.
symptoms are transient, treatable, and potentially studies examining outcome following GPi DBS focused
preventable. on motor symptoms with relatively little attention paid to
As very few data on stimulation of the ventrointerme- nonmotor symptoms. In contrast, the more recent STN
dial nucleus (Vim) of the thalamus exist, this article will DBS studies have made a more concerted attempt to
focus primarily on the published literature on stimulation evaluate nonmotor as well as motor outcome following
of the subthalamic nucleus (STN) and globus pallidus surgery. Similarly, while there have been no reports of
internus (GPi) for PD. Outcome studies, methodological psychiatric symptoms and very few cognitive studies
issues, pathophysiology, and the preoperative and post- following Vim DBS, this literature has the same meth-
operative management of the cognitive and psychiatric odological limitations and further selection bias issues as
aspects of DBS for PD are discussed. The outcomes are the GPi literature.
covered in more detail in the preoperative and postoper- As there is a more comprehensive literature including
ative sections of the consensus articles and will only be several reviews on neuropsychological outcomes follow-
briefly discussed here. The focus of the article is on ing DBS surgery for PD, we refer readers to recent
methodological and pathophysiological issues. Issues re- comprehensive reviews pertaining to the neuropsycho-
garding preoperative and postoperative management of logical literature.10,11 The outcome studies on cognition
psychiatric aspects of DBS are found primarily in the and stimulation for advanced PD are summarized in
tables. Table 1.
OUTCOME STUDIES Subthalamic Stimulation

A range of postoperative cognitive and neurobehav-
ioral symptoms have been reported following STN DBS Cognitive Outcomes
and GPi DBS. While cognitive and neurobehavioral The vast majority of the neuropsychological outcome
symptoms were found to be less frequent following GPi literature following DBS for PD has been published with
compared to STN DBS in several small studies,5–7 the patients who underwent DBS in the STN. The findings
literature is far from conclusive as detailed comparative from these studies must be viewed with significant cau-
data have not been published. The discrepancies in neu- tion as most studies suffer from small sample sizes and
robehavioral outcome have been postulated to be related only three of the published studies included a PD control
to changes in dopaminergic medications, anatomical dif- group.12–14
ferences between the STN and GPi, and methodological The majority of the outcome literature suggests that
issues. For instance, STN DBS is associated with a STN DBS results in relatively little cognitive morbidity
greater reduction in dopaminergic medications than GPi in well-selected patients.13,15–20 Isolated studies note
DBS and symptoms such as depression and apathy have mild improvements in mental flexibility,15,21,22 working
been have been linked to postoperative dopaminergic memory,22 visuomotor sequencing,16,20,22,23 conceptual
withdrawal states.8,9 Consequently, some of the post- reasoning,22,23 and overall cognitive function.23
STN stimulation neurobehavioral symptoms might re- The most robust finding across studies appears to be a
flect differences in management of dopaminergic medi- decline in word fluency,12–16,20,23–27 although other stud-
cation following surgery rather than surgical site per se. ies have also reported declines in verbal memo-
Alternatively, the STN is much smaller and more vari- ry,13,15,23,24,28,29 conditional associative learning,22 visuo-
able in orientation than the GPi. Thus, current spread to spatial memory,15,24,29 processing speed,24 and selected
adjacent nonmotor circuits and possible electrode mis- measures of executive function.29 Specific patient sub-
placement are more likely to occur with STN than GPi groups (e.g., older patients, patients with moderate cog-
DBS, thereby resulting in greater stimulation-related nitive impairment prior to surgery) may be at greater risk
neurobehavioral symptoms. Finally, it is likely that of sustaining cognitive and neurobehavioral defi-
methodological issues and biases in the literature con- cits.15,24,28 –30 However, this has not been unequivocally
tribute to the perception that STN DBS is associated with demonstrated. For example, the available data do not
greater neurobehavioral morbidity. For example, the lit- make it clear if older age per se or other medical comor-
erature on GPi DBS has small cohort sizes, limited bidities associated with older age are responsible for the
long-term follow-up data, and does not focus on neuro- increased neurobehavioral changes found in some older
psychiatric issues. The apparently greater rate of cogni- patients following surgery.
tive and psychiatric adverse events after STN compared Most studies include dementia as an exclusionary cri-
to GPi DBS may also reflect report bias. The early terion; thus, there are no large-scale prospective data
Movement Disorders, Vol. 21, Suppl. 14, 2006

NEUROPSYCHOLOGICAL/NEUROPSYCHIATRIC ISSUES S307
TABLE 1. Cognitive outcome studies following deep brain stimulation for advanced Parkinson’s disease
Postoperative
Medications/stimulation test interval
Reference Sample size Exclusion criteria status (mo) Improvements Declines
Alegret and STN ⫽ 15 ⬎75 years, MMSE ⱕ Off medications, 3 Trails B Phonemic and Semantic
colleagues15 25, major ON stimulation Word fluency,
depression, visuospatial (JOLO),
marked atrophy verbal memory (Rey
AVLT), Stroop Color
and Word,
Ardouin and STN ⫽ 49, Significant cognitive ON stimulation, 3-6 Trails A and B Phonemic and Total
colleagues16 GPi ⫽ 13 or mood off medications Word fluency
impairment variable
Daniele and STN ⫽ 20 History neurosurgery, On medications, 3, 6, 12, 18 MMSE (ON and Phonemic Word fluency
colleagues23 dementia, severe ON/OFF OFF stimulation (ON and OFF
psychiatric stimulation at 3, 6, 12 stimulation, 3, 6, 12
diagnosis, MMSE months); WCST- months), verbal
⬍20 modified (ON learning (Rey AVLT;
stimulation at 3, OFF stimulation, 3
6, 12 months) months)
Dujardin and STN ⫽ 9 Not specified On medications, 3, 12 3 months: reaction 3 months: verbal
colleagues28 ON stimulation time test (trend) memory (Grober and
Bushke Word List
Test); 3 months: 30%
(n ⫽ 3) overall
cognitive decline
defined as a decline
more than 1 SD
below preoperative
scores on 20% or
more of tests; 12
months: Stroop
Interference
Funkiewiez and STN ⫽ 50 Not specified On/off 3-48 None noted None noted
colleagues96 medications,
ON/OFF
stimulation
Funkiewiez and STN ⫽ 70 Not specified ON stimulation, 12, 36 None noted Word fluency
colleagues26 mostly off
medications
Gironell and STN ⫽ 8, ⬎ 70 years, MMSE On medications, 6 None noted STN: Semantic Word
colleagues14 unilateral ⬍ 25, major ON stimulation fluency
GPi (L ⫽ 5, depression,
R ⫽ 3), PD marked atrophy
controls ⫽ 8
Hariz and n⫽1 Not specified On medications, 1, 12 None noted Overall cognitive
colleagues31 ON stimulation function (assessed
via Kokmen Short
Tests of Mental
Status)
Hershey and STN ⫽ 24 Dementia on clinical Off medications, 2 None noted Stimulation reduced
colleagues32 examination, ON/OFF working memory/
history of stimulation response inhibition
neurological under high-cognitive-
events, non-PD demand conditions
diagnosis (Spatial Delayed
Response Task, Go–
No Go Task)
Jahanshahi and STN ⫽ 7, Not specified Off medications, Not specified STN stimulation: GPi stimulation: random
colleagues22 bilateral OFF/ON/OFF trails B, WCST, number generation,
GPi ⫽ 6 stimulation random number WCST; GPi or STN
generation; STN stimulation:
or GPi conditional
stimulation: trails associative learning
A, Stroop (Visual–Visual
Control, PVSAT, Conditional Learning
Missing Digit Test)
Test, modified
Krack and STN ⫽ 49 Dementia, major On medications, 1, 3, 5 years None noted Three patients
colleagues18 ongoing ON stimulation developed dementia
psychiatric illness, (per DSM-IV
⬎ 70 years criteria) over 5-year
interval
Limousin and STN ⫽ 20 ⬎ 70 years, MMSE Off medications, 12 None noted None noted
colleagues126 ⬍ 24, MRI ON stimulation
abnormality
Lopiano and STN ⫽ 16 Dementia, depression Not specified 3 None noted None noted
colleagues127 psychosis, MRI
abnormality
Moretti and STN ⫽ 9, PD Not specified Not specified 1, 6, 12 None noted Stroop, Phonemic,
colleagues12 controls ⫽ 9 Semantic, Syllabic
Word fluency

S308 V. VOON ET AL.
TABLE 1. (Continued)
Morrison and STN ⫽ 17, PD Dementia ON/OFF ⬃3 None noted Surgery (without
colleagues13 controls ⫽ stimulation, stimulation): attention
11 medications and language
variable composite scores
comprised of several
measures (Digit Span
forward and
backward, Brief Test
of Attention, Boston
Naming Test,
Phonemic and
Semantic word
fluency); mild
declines in verbal
memory (Hopkins
VLT-R, Randt
Memory Test) as a
function of the
procedure (electrode
placement and
stimulation)
Moro and STN ⫽ 7 Dementia, ongoing Not specified 9 None noted None noted
colleagues27 psychiatric
problems, prior
brain surgery, poor
general condition,
mild parkinsonism
or unstable drug
regimen
Perozzo and STN ⫽ 20 “Important cognitive On/off 6 None noted None noted
colleagues19 decline,” severe medications,
depression, ON stimulation
psychotic
symptoms, MRI
abnormality
Pillon and STN ⫽ 48, Significant cognitive Most patients off 3, 12 STN stimulation: STN stimulation:
colleagues20 GPi ⫽ 8 or mood medications, Stroop Word and Semantic Word
impairment ON/OFF Color, Trails; fluency;
stimulation Graphic Series;
reaction time;
Spatial Working
Memory
Saint-Cyr and STN ⫽ 11 Dementia, prior On medications, 3-69-12 None noted Working memory
colleagues24 neurosurgery, ON stimulation (PASAT, Digit Span,
unstable medical Backward), Trails B,
status, MRI manual speed and
abnormality, coordination (Purdue
current psychiatric pegboard, coin
complications sorting while finger
tapping), Phonemic
and Semantic Word
fluency, verbal
memory (CVLT
Long Delay Free and
Cued Recall),
visuospatial memory
(Battery of Memory
Efficiency), declines
more apparent in
patients ⬎ 69 years
Trepanier and Unilateral Dementia, other On medications, 3, 6, ⫾ 12 None noted STN: Trails B, verbal
colleagues29 pallidotomy neurological or ON stimulation memory (CVLT
⫽ 42, unstable medical Long Delay Free and
bilateral disorders, prior Cued Recall),
STN ⫽ 9, neurosurgery, MRI Phonemic Word
bilateral GPi abnormality, fluency, visual
⫽4 current psychiatric learning and memory
complications (Battery of Memory
Efficiency); GPi:
Phonemic Word
fluency, verbal
memory (CVLT
Long Delay Free and
Cued Recall)
Volkman and STN ⫽ 16, Not specified On medications, 6, 12 None noted None noted
colleagues5 GPi ⫽ 11 ON stimulation
Witt and STN ⫽ 23 Dementia (⬍130 On medications, 6-12 ON stimulation: OFF stimulation: Stroop
colleagues21 DRS) ON/OFF Random Number Interference errors
stimulation Generation Test

TABLE 1. (Continued)
Fields and Staged bilateral Dementia, psychiatric On medications, 2 months Delayed verbal None noted
colleagues54 GPi ⫽ 6 disturbance (except ON stimulation after first recall (CVLT
for mild DBS; 3 Long Delay Free
depression) months Recall, Logical
after Memory II),
second WCST,
DBS Perseverative
Errors
Fukuda and L GPi ⫽ 2, Not specified ON stimulation Not noted DLPFC activation None noted
colleagues128 bilateral GPi during motor
⫽5 sequence learning
Miyawaki and Bilateral GPi Not specified On medications, One month Left GPi: Stroop Right GPi: CVLT
colleagues62 ⫽1 ON stimulation after left Color/Word; perseverations, Free
DBS; 3 WMS-R Figural and Cued Recall
weeks Memory Right intrusions
right DBS GPi: CVLT Total
Trials and Long
Delay Free Recall
Tröster and GPi ⫽ 9 On medications, 3 None noted DRS Construction
colleagues56 ON stimulation subtest, Semantic
Word fluency
Vingerhoets and L GPi ⫽ 13, R Dementia, MMSE ⬍ On medications, 3 None noted None noted on group
colleagues55 GPi ⫽ 7 24, nonidiopathic ON stimulation analyses, individual
PD, MRI patient analyses
abnormalities, any showed decline in ⬃
illness that would 30% of patients based
compromise on study defined
neuropsychological cognitive impairment
evaluation index
Hugdahl and Mixed Not specified Off medications? Not noted Verbal memory None noted
Wester65 thalamotomy ON stimulation
and Vim
DBS
Schuurman and Mixed MMSE ⬍ 24 On medications, 6 None noted Left stimulation:
colleagues68 thalamotomy ON stimulation Semantic Word
and Vim fluency
DBS with
PD
(thalamotomy
⫽ 21,DBS
⫽ 19), ET
⫽ 13, MS
⫽9
Tröster and Vim ⫽ 9, L ⫽ Non-PD diagnosis ON stimulation, 4 Verbal memory None noted
colleagues67 5, R ⫽ 4 on medications (CVLT, Delayed
Recognition,
Logical Memory
II)
Tröster and Vim ⫽ 1 Not specified 3, 6 months: on 3, 6, 18 3 months: DRS 3 months: Semantic
colleagues129 medications and Construction; 6 Word fluency, verbal
ON stimulation; months: semantic learning; 18 months
18 months: on/ word fluency, (ON vs. OFF
off medications verbal learning stimulation): episodic
and ON/OFF (CVLT); 18 memory
stimulation months (ON vs.
OFF stimulation):
semantic fluency
Woods and Unilateral No longer responsive On medications, 12 DRS None noted
colleagues66 Vim ⫽ 6 to DA medications ON stimulation Conceptualization;
or intolerable DA Verbal Memory
SE (CVLT Long
Delay Free Recall,
WMS-I, Logical
Memory I)
AVLT, Auditory Verbal Learning Test; CVLT, California Verbal Learning test; DA, dopamine; DLPFC, dorsolateral prefrontal cortex; DRS, Mattis
Dementia Rating Scale; DSM-IV, Diagnostic and Statistical Manual of Mental Disorder, 4th edition; GPi, globus pallidus interna; JOLO, Judgment
of Line Orientation Test; L, left; MMSE, Mini Mental Status Exam; PVSAT, Paced Visual Serial Addition Test; R, right; SD, standard deviation;
STN, subthalamic nucleus; Trails A and B, Trail Making Test, Part A and B; Vim, ventrointeromedial nucleus of the thalamus; VLT, Verbal Learning
Test; WCST, Wisconsin Card Sorting Test; WMS-R, Wechsler Memory Scale–Revised; SE, side effects.
available documenting the potential effect of STN DBS following placement of DBS electrodes in the STN. No
on cognitive function in patients who met diagnostic patient met diagnostic criteria for dementia prior to sur-
criteria for dementia prior to surgery. Krack and col- gery. The authors attributed the development of dementia
leagues18 reported the gradual development of dementia to ongoing Parkinson’s disease progression as no acute
in 3 of 49 patients who were followed for 5 years cognitive changes were evident immediately following

S310 V. VOON ET AL.
surgery in the three patients and the bulk of the literature needed to evaluate the role of medication status in cog-
indicates that stimulation does not result in marked cognitive function ON and OFF STN DBS.
nitive declines.
Although most of the literature suggests that STN Neuropsychiatric Outcomes
DBS is relatively benign from a cognitive perspective,
Like cognitive outcomes, the outcome data on neuro-
there are reports of patients who sustained significant
psychiatric symptoms should be approached with caution
cognitive decline following surgery. Morrison and col-
due to similar methodological issues. The following fre-
leagues13 stated that 1 of their 20 subjects demonstrated
quencies of postoperative psychiatric symptoms have
significant cognitive decline following surgery with later
been reported following STN stimulation. Transient con-
improvement in function following STN stimulation. De-
fusion in the immediate postoperative period has been
spite the improvement noted with stimulation, his overall
reported in 1% to 36% of patients.4,8,18,33– 40 Postopera-
cognitive function was worse after surgery and he had to
tive hypomania has been reported in 4% to 15% of
move from an independent to an assisted living setting
patients, usually occurring within the first 3 postopera-
due to cognitive changes. He was an older man, but
tive months.18,38,41,42 Emotional reactivity, or excessive
another case report by Hariz and colleagues31 docu-
mood-congruent emotional responses to minor triggers,
mented a similar negative outcome in a 53-year-old
following placement of DBS electrodes in the STN. was identified in 75% of STN stimulation patients.30
Thus, it does not appear that age per se is the only Suicide attempts and/or suicides have been documented
predictor of a potentially deleterious cognitive outcome. in uncontrolled series ranging from 0.5% to
To date, little has been done to assess potential cognitive 2.9%.18,30,43,44 A multicenter study of 450 STN DBS
risk factors systematically. patients reported a postoperative suicide rate of 0.5%.45
Only a handful of studies have systematically exam- In contrast, a study of 120 patients who underwent DBS
ined the role of stimulation and/or medications on neu- (including PD, dystonia, and essential tremor patients)
ropsychological performance. Systematic assessment documented a postoperative suicide rate of 2.9% in PD
ON and OFF STN stimulation demonstrated either no patients who had undergone STN DBS.44
significant cognitive effects13 or improvements in pro- Individual episodes of postoperative depression have
cessing speed,20,22 working memory,20,22 random number been reported in 1.5% to 25% of patients.8,18,30,33,38,46 – 48
generation,21,22 and problem-solving22 with stimulation. Although overall group depression scores have been
One study demonstrated a decline in performance on a reported to improve at 3, 12, and 36 months,8,26,42,49,50
conditional associative learning task22 following stimu- the clinical relevance of these findings is not clear. Stud-
lation, and impairments in response inhibition measures ies designed to examine mood symptoms utilizing stan-
(self-detected errors on Stroop interference task) have dardized diagnostic criteria reported frequencies of 21%
also been documented.21 Performances on working and 25% with the onset of depression within the first 2
memory and response inhibition measures under high- postoperative months.25,30 Another study distinguishing
cognitive-demand conditions were shown to decline with between depression requiring antidepressants and de-
STN stimulation.32 Systematic assessment on and off pression secondary to dopaminergic withdrawal symp-
medications during STN stimulation was not associated toms reported rates of 18% and 38%, respectively.8 In a
with cognitive changes19 on a variety of neuropsycho- large 3-year study using patient-rated depression scale
logical measure, including tests sensitive to frontostriatal cutoff scores, moderate to severe depression was docu-
dysfunction [the Raven Color Matrices, Corsi Block mented at baseline in 33%, in 20% in the first postoper-
Tapping Test, Bisyllabic Words Repetition Test, Paired ative year and in 15% in the third postoperative year.26
Associates Learning Test, Spatial Learning Test, River- Without a control group, the implications of these re-
mead Behavioural Memory Test, Visual Search Test, ported frequencies are not clear. Potential misinterpreta-
Reaction Times Tests, Modified Wisconsin Card Sorting tions of findings in uncontrolled studies are illustrated in
Test, Trial Making B Test, and word fluency measures the literature on pallidotomy. Early uncontrolled studies
(category, phonemic)]. These findings are at odds with suggested an elevated risk of postoperative depression
previous reports in the literature that demonstrated cog- following bilateral posteroventral pallidotomy.51,52 How-
nitive changes associated with dopaminergic medica- ever, a subsequent prospective randomized wait list con-
tions in unoperated PD patients. The discrepant findings trol group study did not demonstrate any differences in
might reflect methodological issues such as limited depression outcomes in the surgical or wait list control
power or measurement factors and clearly, more data are group.53 Furthermore, the only risk associated with de-

pression was a past history of depression, irrespective of any significant cognitive decline following GPi
surgical procedure.53 DBS.29,54,55 Mild declines in semantic word fluency56,57
Within the first 3 postoperative months, transient apathy and visuoconstruction scores56 have been documented.
occurs as part of the dopaminergic withdrawal syndrome, Pallidal surgery (i.e., pallidotomy or GPi DBS) in PD
although the incidence is not known. The proportion of patients appears to disrupt frontosubcortical circuits un-
patients with apathy as measured on the UPDRS part I was derlying efficient shifting between semantic categories
documented at baseline to be 8.7% and at the third postop- and/or access to semantic categories rather than affecting
erative year to be 24.6%.26 Permanent apathy was reported semantic stores.58
in the long term in 12% of patients, among whom 80% had In one study, a subgroup of older patients demon-
an associated dementia.18 In this same longitudinal study, strated a higher postoperative rate of mild cognitive
no visual hallucinations were reported within the first 3 deficits, although the clinical and statistical significance
postoperative months but in the long term 10% developed of these findings is uncertain.55 In particular, this study
visual hallucinations. Sixty percent of the patients with defined cognitive change in a very liberal manner (any
hallucinations also had associated dementia.18 Overall, 6% magnitude of change in the percentage of tests falling 1
of patients in the study developed dementia in the long SD below normative means) and did not find any signif-
term.18 One study reported that 6% developed visual hal- icant changes in average scores.
lucinations or psychotic symptoms, although whether these These observations highlight that some patients might
occurred in the early or late postoperative period is not be at increased risk for neurobehavioral deficits follow-
clear.8 ing DBS. For example, significant executive dysfunction
The effects of DBS on patients’ social reintegration was described in a case report following chronic bilateral
and adjustment have received limited attention. In a GPi stimulation that was partially reversible with discon-
retrospective study, late age of onset of PD was associ- tinuation of stimulation.59
ated with poor global social adjustment. Persistent levo-
dopa-induced motor symptoms were associated with Neuropsychiatric Outcomes
poor adjustments in social outcome measures. Despite Postoperative psychiatric symptoms in GPi DBS are
motor improvements, 25% had a deterioration in marital believed to be less frequent than after STN DBS. In one
relations following surgery.30 unblinded comparative study, 3 of 16 STN versus 0 of 11
The frequency of reported psychiatric symptoms in the GPi patients developed depression requiring psychiatric
literature varies for a variety of reasons: selection bias (e.g., treatment.8 In a 1-year follow-up of a small blinded
differences in the inclusion of patients with preoperative parallel randomized study, whereas none of the 11 GPi
psychiatric and cognitive vulnerabilities), measurement bias patients developed neuropsychiatric complications, 2 of
(e.g., differences in methods of assessment and diagnostic 12 STN patients developed transient perioperative anxi-
ascertainment), or lack of systematic consideration of con- ety, 1 of 12 transient hallucinations responding to a
founding variables (e.g., differences in the rate or degree of decrease in levodopa dose, and 1 of 12 persistent apathy
change of dopaminergic medications). in the context of cognitive changes.6 In an extension of a
The most common psychiatric symptoms observed third unblinded randomized comparative study reporting
include apathy, emotional reactivity, depression, and hy- on the 3- to 4-year outcomes, persistent neuropsychiatric
pomania. The reasons for such a range of symptoms adverse events were more common in the STN compared
observed is due to the multifactorial etiology of the to GPi group, although few details were reported. For
psychiatric symptoms, including preoperative vulnerabil- instance, 11 of 49 STN patients developed unspecified
ity, changes in dopaminergic medications, surgical and mild–moderate memory or psychiatric difficulties com-
stimulation effects, underlying PD-related factors, and pared to 1 of 20 GPi patients. Of these psychiatric events,
psychosocial effects. The pathophysiology underlying 3 of 49 STN patients had a mild–moderate depression
these different psychiatric symptoms is discussed in compared with 1 of 20 GPi patients.7
more detail below. While these preliminary data are intriguing, based on
the reasons previously discussed, the literature is far
GPi Stimulation from conclusive; larger controlled studies using system-
atic validated assessment tools are required. Overall im-
Cognitive Outcomes provement in group depression and anxiety scores have
Neuropsychological changes following GPi DBS have been documented with bilateral GPi, although the clini-
been investigated. Several studies have not documented cal relevance is not known.8,60,61 One study that differ-

S312 V. VOON ET AL.
entiated between primary and secondary anxiety sug- adequate power to detect large effect sizes and none had
gested that GPi stimulation improved primary anxiety the power to detect small or medium effects. Conse-
symptoms.61 Case reports of mania have been reported.62 quently, the neuropsychological safety of DBS may be
Case reports of hypersexuality have been reported, al- overestimated.
though it is unclear if this was part of a manic syndrome
or dopamine dysregulation.63,64 Control Groups and Inferences About Change
The absence of control groups makes it difficult to
Thalamic Stimulation determine whether a change occurring after DBS might
Very few studies have examined the neuropsycholog- also have occurred in a nonoperated control group, thus
ical consequences of Vim DBS for the treatment of PD. reflecting non-DBS factors (e.g., disease progression,
These studies have been hampered by small cohorts, medication, test–retest practice effects, or some other
mixed thalamotomy or Vim stimulation groups, or mixed extraneous variable). Several practical and ethical diffi-
patient groups with non-PD diagnoses, thus limiting gen- culties exist in selecting and obtaining a control group.10
eralization of the findings. On the whole, thalamotomy or Given the now widespread availability of DBS, it is
Vim DBS appears not to have a significant effect on increasingly difficult to recruit the most relevant control
cognitive abilities.65,66 Improvements in verbal memory for DBS research: a surgical wait list control group. A
have been documented.65– 67 Left-sided Vim stimulation PD control group not matched to the surgical group in
may be more likely to be associated with verbal fluency disease and demographic characteristics is a secondary
decline.68 Despite the limited evidence, Vim is consid- option and is preferable to using a normal control group.
ered a relatively safe target with fewer cognitive or However, even use of a wait list control group is not
neurobehavioral sequelae, particularly since postopera- without potential interpretative pitfalls. Since medication
tive changes in dopaminergic medications are less nec- dosage is often greatly reduced after STN DBS, neurobe-
essary and the stimulation site is less likely to overlap havioral changes, when they occur in the surgical but not
with regions with limbic activity (see Lang and col- the control group, cannot confidently be interpreted as
leagues in this issue for further details on patient effects of DBS. Medication effects, although expected to
selection). be mild, can both positively and negatively impact cog-
nitive functions and have a more profound effect on
METHODOLOGICAL ISSUES mood. The interactive effect of surgery or DBS and
Numerous methodological issues confront DBS re- medication is a further complexity. For example, it has
search on neurobehavioral outcomes.10,11 The greatest recently been shown that pallidotomy may alter the ef-
methodological issues in the current literature are the fect that levodopa has on certain cognitive functions.70
small sample sizes and the general absence of control
groups. Test–Retest Effects
The absence of a control group makes it difficult to
Sample Size and Power to Detect Effects determine the extent to which changes in test scores
Modest sample sizes limit the power of a study to reflect practice effects. When individuals undergo re-
detect the effects of DBS on cognition and behavior and peated evaluations using the same or similar test instru-
also limit the reliability and generalizability of findings. ments, scores may improve simply due to experience
For instance, a recent study investigated the issue of with the test rather than improvement of the function
sample size by calculating the effect sizes and statistical being evaluated. Strategies to minimize practice effects
power associated with verbal fluency changes reported in include employing multiple versions of the test that dif-
previously published studies.69 The parameter of verbal fer in specific content but not in difficulty, maximizing
fluency was selected given its relatively common and the test–retest interval, or utilizing statistical techniques
sizeable neuropsychological change after DBS. The au- such as Reliable Change Indexes or standardized regres-
thors found that the power to detect verbal fluency sion-based norms.71–73 Notably, a familiarity or “test
changes was typically very low, ranging in published wise” effect may occur even when alternate forms are
studies from 0.06 to 0.45 (power is expressed in a range used.
from 0 to 1, with 1 indicating perfect or 100% power, and The proper PD control group remains necessary even
adequate power is commonly accepted to be 0.80 or when one has knowledge of test–retest effects in test
above). Furthermore, in reviewing 30 neuropsychologi- normative samples because it is generally not known
cal studies of STN DBS, only 2 of 30 studies had whether similar test–retest effects occur in normative and

clinical populations. For instance, there is suggestion that To identify preoperative predictors of neurobehavioral
practice effects may not occur in PD on numerous morbidity, preexisting neurobehavioral conditions
tests.13,74 The absence of “assumed practice effects” should be accurately defined and systematically assessed
complicates interpretations of both the presence and the and diagnosed. The identification of neurobehavioral
absence of test score changes. For example, if a practice outcome predictors represents an urgent clinical need.
effect does not occur in PD, then postoperative score Most studies have excluded, not assessed, or not reported
gains likely represent improvements rather than practice on patients with preoperative neurobehavioral symp-
effects, while the lack of gain or decrements likely rep- toms. In order to determine the role of preoperative
resent a true lack of change or deterioration, respectively. neurobehavioral symptoms in postoperative outcomes,
Conversely, if practice effects occur in PD, then a lack of prospective studies with such groups of patients are
gain may represent a decline. Furthermore, if practice required.
effects do occur, then small declines in scores may
The screening of patients for behavioral conditions,
actually represent a sizeable deterioration in function,
the formation of diagnostic subgroups, and outcome
and a score gain would have to exceed the practice effect
evaluation should be achieved using different test in-
before it is considered an improvement. Interpreting in-
struments, otherwise circularity may occur. Since a
dividual patient test score changes is rendered even more
complex by possible interactions between surgery, med- score on a given instrument is usually the best predic-
ication, stimulation, and practice effects. tor of a score obtained by the same person on that
instrument at a later time point (given shared construct
Changes in Average Scores vs. Caseness and and method variance), separate measures would ide-
Frequency of Changes ally be used to define risk factors and outcomes.
Most studies focusing on neurobehavioral changes Consequently, an ideal evaluation would utilize mul-
associated with DBS report changes in group mean tiple measures of the same construct that rely on
scores on various tests, symptom self-report inventories, different administration methods to provide conver-
and rating scales. Studies should more consistently report gent evidence of change.
the frequency of individual changes of various magni- Several other knowledge gaps related to method-
tudes and also changes in caseness. That is, changes in ological and study design limitations remain to be
average scores and caseness (the number of persons addressed in future studies. Very few studies have
having a condition, such as depression, before and after compared STN DBS outcome with stimulators turned
surgery) do not always go hand in hand and may be ON or OFF.20,22 Fewer studies have examined the
misleading.75 The establishment of caseness and fre- relationship between stimulation parameters and cog-
quency of changes of given magnitude are important in nition,76 behavior,77 or subjective psychotropic ef-
determining the incidence of certain conditions before fects.26 No studies have systematically varied stimu-
and after surgery and thus more accurately define the lation parameters and assessed cognition in a within-
risks of morbidity. subject design. Future studies should clearly indicate
Other Methodological Issues stimulation parameters in their patients and how elec-
trode placement was verified. Behavioral studies, in
The current lack of accurate estimates of the incidence
addition, should control for standard markers associ-
of various conditions before and after DBS highlights
ated with neurobehavioral outcomes (e.g., family his-
several other methodological needs. Specifically, studies
tory of depression and depression outcome in PD, the
should be prospective and assess neurobehavioral func-
tions systematically. Unfortunately, many studies appear effects of mood on obsessive– compulsive rating
to have relied on the patient’s or caregivers’ spontaneous scores) and psychosocial factors. The literature is dif-
report of changes after surgery, subjective impressions of ficult to interpret given the significant heterogeneity in
patients and physicians, or on retrospective searches of participants, surgical and neurobehavioral evaluation
databases in documenting cognitive or psychiatric methods, time intervals between assessments, and
changes following DBS. Studies should also use stan- postoperative medication adjustments. Large multi-
dardized criteria and test instruments and several authors center collaborative studies are likely needed to ad-
have already commented thoughtfully and extensively on dress important questions about neurobehavioral out-
considerations in neuropsychological test selection for comes and their prediction, and in particular, about
movement disorders surgery.20,24,72 long-term outcomes.

S314 V. VOON ET AL.
TABLE 2. Regions implicated in psychiatric symptoms associated with subthalamic stimulation for Parkinson’s disease
Neuroanatomical regions Comments
Medial limbic subthalamic nucleus Connection via indirect CSTC pathway to limbic cortical regions88,130; embroyologically and structurally
related to LH with efferents to VTA88,131; implicated in psychiatric symptoms of STN stimulation81
Anterodorsolateral sensorimotor Most effective site of stimulation for motor symptoms132,133; potential regions affected: current diffusion
subthalamic nucleus to ZI or H2 fields of Forel132,134; retrograde stimulation of afferent dopaminergic or serotonergic
neurons from SN or DRN; anterograde stimulation of ascending dopaminergic neurons projecting to
basal ganglia135,136
Anterior cingulate (AC), Connection to medial limbic STN via indirect CSTC pathway and connections of basal ganglia
orbitofrontal cortex, amygdala circuitry88,130; impaired performance on response conflict task associated with decreased activation of
right AC in STN DBS patients137
Lateral hypothalamus and ventral Medial limbic STN embryologically and structurally related to LH; efferent projection from LH to
tegmental area VTA88,131; VTA implicated in reinforcing effects of drugs of abuse138; implicated in psychiatric
symptoms of STN stimulation81
Subgenual cingulate (Cg25) Cg25 postulated to play a modulatory role in major depression and normal sadness139; Cg25 efferents to
LH in nonhuman primates140; LH and medial limbic STN embryologically and structurally
related88,131; Cg25 efferents to brainstem, ventral striatal, and thalamic regions140 with indirect
connections to STN
Zona incerta Structural and functional relationship between hypothalamus and rostral ZI implicated in autonomic
symptoms141; cingulate cortical efferents to rostral and dorsal ZI in rodents142; reciprocal projection
of SN pars reticulata and pars compacta to ZI143; reciprocal projection of amygdala to rostral ZI in
rodents144; fiber bundles within or adjacent to ZI: ascending dopaminergic neurons from SN135,136;
ascending serotonergic fibers; fields of Forel and pallidosubthalamic fibers119; stimulation of ZI
associated with depressive symptoms89
Substantia nigra Reciprocal projections of STN to SN88; ascending projections from SN to striatum via MFB run through
ZI and appositioned to anterodorsal border of STN135,136; stimulation of SN pars reticulata (⫾ pars
compacta) associated with acute depressive symptoms78
Medial forebrain bundle SN and VTA project to striatum and cortex via MFB which ascends near ZI135,136
Pedunculopontine nucleus Reciprocal projections of PPN to STN88,145; implicated in STN hyperactivity in PD animal model145;
observed motivational effects in excitotoxic lesioned PPN in rodent models may be mediated by
executive deficits146,147
Dorsal raphe nucleus Serotonergic fiber efferents from DRN to STN88; ascending serotonergic fibers to widespread cortical
regions run through ZI
Area TE of inferotemporal cortex CSTC pathway originating in area TE117; hypothesized to be involved in visual hallucinations in PD117
Fiber bundles Stimulation more likely to affect large myelinated axons than cell bodies148; most effective site of
stimulation at anterodorsal border of sensorimotor STN with current diffusion to fiber bundles located
at or near ZI132,133
Thalamic nuclei Afferents from parafascicular (PF) thalamic nuclei to STN implicated in STN hyperactivity in PD
animal models145; PF nuclei project primarily to limbic and cognitive STN regions88
Adapted from Voon and colleagues.45

CSTC, cortico–striato–thalamo– cortical; DRN, dorsal raphe nucleus; LH, lateral hypothalamus; MFB, medial forebrain bundle; PD, Parkinson’s
disease; PPN, pedunculopontine nucleus; SN, substantia nigra; STN, subthalamic nucleus; VTA, ventral tegmental area; ZI, zona incerta.
PATHOPHYSIOLOGY OF PSYCHIATRIC AND neurodegenerative process and involvement of nondo-

COGNITIVE SYMPTOMS ASSOCIATED WITH paminergic symptoms).80 The following section on
SUBTHALAMIC STIMULATION pathophysiology focuses primarily on STN stimulation
The postoperative cognitive and psychiatric symptoms rather than GPi or Vim. Given the paucity of data in the
evident following DBS, similar to those observed in PD literature, the following discussion is by nature specula-
itself, most likely reflect a multifactorial etiology. For tive. Some aspects of the pathophysiology on neurobe-
instance, six etiological factors, which are not necessar- havioral symptoms and its relationship to stimulation for
ily mutually exclusive, can be postulated to account for PD have been reviewed in the literature.45,81
the psychiatric symptoms following STN stimulation: Table 2 outlines neuroanatomic regions and down-
preoperative factors (including premorbid psychiatric stream connections of potential psychiatric relevance,
vulnerabilities),30 surgical factors (e.g., the duration of which may be affected by STN stimulation either di-
the surgical procedure, electrode trajectories, the number rectly, by current spread, or by misplaced electrodes.
of electrode passes, complications),24 STN stimulation Table 3 summarizes some of the neurobehavioral
factors (e.g, placement, parameters),78 postoperative fac- changes associated with the treatment of PD with spe-
tors (e.g., antiparkinsonian drug changes),9 psychosocial cific reference to STN activity. The range of behavioral
adjustment,79 and underlying PD-related factors (e.g, the symptoms associated with presumed increases or de-

TABLE 3. Neurobehavioral symptoms proposed to be associated with stimulation of the subthalamic motor, cognitive, and
limbic regions in Parkinson’s disease
Increased STN activity88,149-152 Decreased STN activity152,153
Behavior of Interest (off drug or OFF STN stimulation) (on drug or ON STN stimulation)
Motor (motor circuit) Bradykinesia,149-151 rigidity,149-151 tremor,153 off Dyskinesias152,154
dystonia154
Cognition (DLPFC) Bradyphrenia,155,156 executive function deficits,157,158 Enhanced cognitive flexibility,21,22 improved
impaired working memory,157,158 reduced executive function,22 improved working
conditional associative learning22 memory,20 increased psychomotor speed,22
Response inhibition (ventromedial Disinhibition/impaired response
orbitofrontal cortex) inhibition21,22,24
Mood (anterior cingulate and Off period depression8,9,159-161 Mania/hypomania, impaired emotional
orbitofrontal cortex) control9,30,41,43,84,92,96
Motivation/ goal directed behavior Apathy22,23,111,112 Aspects of dopamine dysregulation syndrome3
(anterior cingulate)
Adapted from Funkiewiez and colleagues.96

STN, subthalamic nucleus; DLPFC, dorsolateral prefrontal cortex.
creases in STN activity was used to organize the data and preoperative survey documented that 60% of patients
the presumed relationships to various frontosubcortical presenting for STN surgery had a past history of depres-
circuits are highlighted. Increased STN activity is gen- sion requiring antidepressants.84 Whether effective treat-
erally associated with restricted behavior and decreased ment and antidepressant prophylaxis of the preoperative
STN activity typically results in excessive behavior. It is depression change this risk is not known.
recognized that the symptoms likely have a significantly Dopaminergic medication withdrawal has been asso-
more complex pathophysiology. ciated with transient depressive symptoms.8,9 The affec-
tive and behavioral effects of levodopa abuse have been
Depression
compared to those due to psychostimulants (drugs that
Individual episodes of postoperative depression have increase catecholaminergic activity), suggesting similar
been reported in 1.5% to 25% of patients.8,18,30,33,38,46 – 48 underlying neural substrates to the withdrawal states.85
The literature on the prevalence of postoperative depres- In addition, dopaminergic agonists have also been dem-
sion is discussed in the outcomes section.
onstrated to improve depression rating scores in major
The prevalence of depression in PD is between 40% to
depression associated with PD, suggesting a potential
50%,82 with the incidence rate reported to be 1.86% per
dopaminergic role.86
year.83 The natural course of PD likely plays a greater
Reports of stimulation-locked depressive states are
role in the depression occurring long after surgery as
infrequent but help delineate an association with stimu-
opposed to that observed soon after surgery.
lation. However, the significance of these acute changes
Based on the literature, it is not clear if a history of
preoperative depression is a risk factor for early postop- is not clear; for instance, it is not known if the symptoms
erative depression. For instance, in one retrospective persist in the long term or if neuroplastic changes occur.
review, 33% of patients with a preoperative history of Clinical observations must also carefully differentiate
depression developed postoperative depression, suggest- between acute stimulation-induced mood symptoms and
ing that a history of preoperative depression acts as a risk autonomic or anxiety effects.77 The STN is a small
factor but is not necessarily predictive of this outcome.30 nucleus (180 mm3)87 surrounded by dense fiber bun-
In contrast, a prospective study found that a personal dles.88 STN stimulation may be associated with mood
history of depression, family psychiatric history, and changes due to current spread to the small medial limbic
preoperative depression scores did not differentiate be- tip of the STN, the surrounding fiber bundles, or stimu-
tween the postoperatively depressed (25%) and nonde- lation may affect afferent or efferent connections to
pressed groups.25 The factors associated with postoper- cortical, brainstem, and thalamic regions by anterograde
ative depression included postoperative confusion and or retrograde stimulation. In addition, current may spread
female gender.25 Severe depression at baseline appears to into adjacent structures, such as the posterior hypothal-
be a risk factor for depression in the long term. Ten amus or midbrain tegmentum and their connections.
percent of 77 patients had severe depression at 3 years, of A depressive state fulfilling DSM-IV criteria was re-
which half had been severely depressed at baseline.26 A ported with stimulation of the left central substantia nigra

S316 V. VOON ET AL.
primarily within the pars reticulata.78 The symptoms psychosocial factors such as marital status, past and
were suggested to be due to stimulation of nigral or current stressors, support, and underlying personality
nigrothalamic fibers. An increase in cerebral blood flow traits can also be associated with depression in the gen-
was demonstrated in the left orbitofrontal cortex, globus eral population.
pallidus, amygdala, anterior thalamus, and the right pa- Based on the literature8,9 and on clinical experience,
rietal lobe. A similar state was reported with stimulation we speculate that the dysphoric or depressive symptoms
of the right zona incerta/fields of Forel,89 suggested to be that occur within the first three postoperative months
due to stimulation of fiber bundles within the zona in- are most commonly secondary to dopaminergic with-
certa/fields of Forel, or connections of the STN to the drawal symptoms potentially interacting with premorbid
substantia nigra or pedunculopontine nucleus. Right- vulnerabilities. That acute mood changes may not be
sided BOLD signal increases were demonstrated in the reproducible using the same parameters suggests a role
superior prefrontal cortex, anterior cingulate, anterior for neuroplastic adaptation. Stimulation-induced acute
thalamus, caudate, and brainstem and decreases in me- psychiatric symptoms, while intriguing, are infrequent
dial prefrontal cortex. The symptoms reported in the and likely transient. As yet, there has not been any
latter paper could not be reproduced despite a trial of convincing evidence for long-term effects of STN stim-
identical stimulation parameters suggesting a role for ulation resulting in depressive symptoms. Stimulation
neuroplastic adaptation. within the STN may occasionally be associated with
In contrast, two patients were described with stimula- dysphoria. However, the limited frequency of occurrence
tion-linked easy tearfulness, which was qualitatively dif- of acute stimulation-induced dysphoric symptoms sug-
ferent from the patients’ premorbid experience of major gests either a placement effect within the STN (e.g., that
depression.43 Similar symptoms of acute sadness second- the stimulated electrode was located closer to the medial
ary to an increase in stimulation parameters has also been limbic STN or that current had spread to peri-STN re-
described.90 Three of these five cases of acute depressive gions) or a potential interaction with underlying vulner-
states had a premorbid history of depression suggesting a abilities such as a mood diathesis, emotional reactivity,
potential interaction between an underlying vulnerability or personality traits consistent with an affective release
and the site of stimulation.43,89 phenomenon.
These reports suggest that while dysphoric states may Depressive symptoms occurring late in the postoper-
occur with stimulation of electrodes located within the ative period may be more likely related to premorbid
STN, depressive symptoms that are associated with the vulnerabilities, the natural course of depression in PD,
range of vegetative, cognitive, and motivational symp- and psychosocial factors. Dopaminergic withdrawal may
toms of a major depression may be more likely to be still continue to play a more muted role and the symp-
associated with electrodes misplaced outside the STN. toms should be distinguished from apathy.
Stimulation of optimally placed contacts in either uni-
lateral STN or GPi was found to be associated with
Hypomanic/Manic Symptoms
greater improvement of mood in comparison to being
OFF stimulation in a study of acute mood changes fol- Postoperative hypomania has been reported in 4% to
lowing blinded randomized changes in stimulation.77 15% of patients following STN stimulation surgery, usu-
Stimulation dorsal or ventral to the optimal contact was ally occurring within the first 3 postoperative
associated with greater worsening of mood for the STN months.18,38,41,42
group than for the GPi group. Changes in mood were The observation of stimulation-linked mirthful laugh-
suggested to be more likely to be associated with STN ter and more chronic euphoria and hypomania occurring
stimulation as compared to GPi given differences in the within the same patient who had undergone STN stim-
sizes of the nuclei and thus greater current spread to the ulation has led some authors to hypothesize a continuum
nonmotor STN, adjacent fibers, and nearby structures. of symptoms characterized by mood elevation with po-
Psychosocial factors including psychological re- tentially similar underlying pathophysiology.92 Mirthful
sponses to motor and functional changes, unrealistic laughter is characterized by excessive and inappropriate
expectations, poor supports, or changes in identity or laughter in response to trivial stimuli. In contrast to
relationships are also likely to play a role in postopera- pathological laughter in which the affective state of
tive depression. Psychosocial changes have been re- laughter is dissociated from the mood state, in mirthful
ported following other major life-altering surgeries91 and laughter, the affective state of laughter is congruent with
have been noted after STN stimulation.30 Furthermore, the mood state of mirth.

However, euphoria is common following transplant suggesting the potential role of premorbid vulnerabil-
surgery,93 suggesting a commonality in the observed ity.41,92,94 A preoperative survey documented 10% of
psychological reactive improvements following life-al- patients presenting for STN stimulation had a history of
tering surgery. As such, the euphoria observed after STN medication-induced mania.84 Of four patients described
DBS may also be related to psychological reactive in the literature with a preoperative history of medica-
improvements. tion-induced hypomania/mania, two have had transient
In contrast, the hypomania or mania observed after postoperative mania, suggesting an interaction between
STN DBS may be more likely to have alternate expla- underlying vulnerabilities, stimulation, and medication
nations related to underlying biological factors. For in- changes.34,84
stance, hypomania has been observed prior to initiation Based on the literature and on clinical experience,
of STN stimulation, suggesting an etiological effect of postoperative hypomania is likely predominantly due to
localized edema or a microlesion effect.41 Furthermore, the synergistic interaction between stimulation and do-
two patients in whom high STN stimulation parameters paminergic stimulation affecting similar dopaminergic-
temporally linked to acute mirthful laughter have been mediated regions. That mania has mood (euphoria), mo-
described.92 The authors proposed that chronic stimula- tivational (increased goal directed activity), cognitive
tion of the STN–limbic system, particularly involving the (increased rate of thought processes or rapid speech), and
lateral hypothalamus and ventral tegmental area projec- motoric (increased motor activity) symptoms could be
tions, could play a role in the observed euphoria, hypo- hypothesized to be related to stimulation affecting the
mania, and improvements in depression rating scores. A limbic, cognitive, and motoric STN regions and their
dissociation between the motor and limbic circuits has downstream striatal and frontal processes.96 This behav-
further been reported in a patient in whom stimulation- ior could be mediated by initial surgical, stimulation,
linked manic symptoms did not improve with termina- and/or dopaminergic effects.
tion of stimulation, whereas immediate changes in par-
kinsonian symptoms were apparent OFF stimulation.94
Emotional Processing
Stimulation of the limbic system outside of the STN,
such as within the midbrain caudal to the substantia Emotional reactivity, or excessive mood-congruent
nigra, has also been implicated with manic symptoms.95 emotional responses to minor triggers, is common fol-
Proposed etiologies have included stimulation of ventral lowing STN DBS surgery and was identified in 75% of
tegmental area projections or midbrain projections to the STN stimulation patients.30
frontal cortex. Observations of emotional reactivity, euphoria, and
STN stimulation and dopaminergic medications have changes in social adjustment have led to investigations
been observed to be synergistic. Postoperative mania on the effect of STN stimulation on emotional process-
improves with either a decrease in stimulation or with a ing. For instance, emotional processing during STN
decrease in dopaminergic medications, thus emphasizing stimulation was studied utilizing a mood-induction par-
the role of appropriate postoperative management of adigm of exposure to differing facial emotional expres-
stimulation and medications.9,41 Mania, hypomania, and sions.97 Consistent with the observation of increased
euphoria have all been associated with dopaminergic emotional reactivity, the ON stimulation/off medication
medications. Parallels between the mood-enhancing ef- state was associated with enhanced emotional experience
fects of levodopa and STN stimulation were investigated and recall of emotionally valenced immediate memory in
using systematic questionnaires96 measuring the percep- comparison to the OFF stimulation/off medication state.
tion of euphoria, motivation, fatigue, anxiety, and ten- Nonverbal information processing was investigated in
sion. Patients in the ON stimulation state and those on two studies using an emotional facial expression recog-
levodopa both perceived a greater improvement of these nition paradigm.98 Stimulation was associated with a
features as compared to the groups of patients in the OFF decline in anger recognition and a decline in sadness and
stimulation state and those off levodopa. Given their anger recognition was found ON stimulation compared
similarities, mood-elevating properties of both STN to preoperative baseline.99 Subjects were unable to rec-
stimulation and levodopa were suggested to be mediated ognize this impairment. Interactions between the medial–
by the STN–limbic system. limbic STN and the anterior cingulate and nondopamin-
Some of the reported patients with postoperative ergic mechanisms were implicated. In both studies, the
manic symptoms have a history of premorbid depression, recognition of positive emotional facial expression was
emotional lability, or a family history of bipolar disorder, not impaired.

S318 V. VOON ET AL.
These studies suggest that the experience, recall, and Hedonistic Homeostatic Dysregulation
expression of emotion may be increased following STN or Levodopa Abuse
stimulation; however, the recognition of negative emo- Excessive (or inappropriate) levodopa use in the post-
tional facial expressions and, as a corollary, the appro- operative period for its subjective euphorigenic effect
priateness of response to these expressions may be im- rather than its motor effect has been reported as case
paired. These observations were suggested to have a reports. Three patients have been described with a pre-
potential impact in social relationships that require the
operative history of levodopa abuse who required limi-
ability to process such nonverbal cues. The relationship
tations on the postoperative dose of levodopa.18,30 How-
between this impairment and the states of euphoria or
ever, recently the postoperative outcomes of two patients
emotional reactivity is not known. Regions commonly
with preoperative histories of severe levodopa abuse or
implicated in emotional processing include the amyg-
dopamine dysregulation syndrome were reported follow-
dala, medial prefrontal cortex, and orbitofrontal cortex,
ing STN stimulation.103 One patient had postoperative
which have indirect connections to the medial limbic
STN. transient alcohol abuse symptoms but the outcomes of
Affective dysregulation or disorders of emotional ex- the two patients were otherwise unremarkable. The pa-
pression such as pathological crying or mood-incongru- tients were characterized by a younger age of PD onset,
ent crying associated with pseudobulbar palsy has been shorter duration of PD, and high motivation to cease
described following STN stimulation.100 Similar to self-medication. The dose of levodopa was dramatically
pathological affect observed in multiple neurological dis- reduced immediately after surgery. The replacement of
orders, the symptoms responded rapidly to agents with the pulsatile administration of high doses of levodopa
serotonin reuptake inhibitor properties.101 Okun and col- with continuous stimulation was hypothesized to play a
leagues100 speculated on several mechanisms of action stabilizing role in decreasing the addictive behaviors.
including inhibition of STN output resulting in an affec- Decreasing the pulsatile administration of levodopa may
tive release phenomenon, activation of the medial limbic decrease the experience of negative emotional states and
STN or the connections within the zona incerta and decrease the abnormal sensitization of motivational
medial forebrain bundle to limbic circuits, and activation symptoms associated with the meso–striato–limbic sys-
involving centers regulating facial expression in the tem.102 A study investigating cognitive measures in post-
brainstem, hypothalamus, or thalamus. The resolution operative PD patients off medications did not demon-
with a serotonin reuptake inhibitor was suggested by the strate any group differences in a gambling task or
authors to affect the serotonergic dorsal raphe projec- reward-learning paradigm either ON or OFF STN stim-
tions potentially involved in the integration of bucco– ulation. This outcome suggests that STN stimulation per
oral–facial activity. That these symptoms are infrequent se does not worsen these cognitive measures, which may
suggests that electrode placement may be playing a role. be implicated in substance use disorders; however, as
preoperative measures were not obtained, changes with
Response Inhibition
respect to the preoperative state were not reported. Given
Impairments in response inhibition following STN the differences in postoperative outcomes between the
stimulation have been recently demonstrated by abnor- case reports,18,30 caution should be exercised with these
malities in the interference arm of the Stroop task.21,22 patients pending further studies of predictive outcome
This observation could explain the behavioral symptoms factors.
of disinhibition,24 emotional reactivity,30 and potentially
of the emotional and cognitive domains of hypomanic
Obsessive–Compulsive Symptoms
symptoms, which may reflect impaired inhibitory pro-
cesses in the early postoperative period. For instance, Obsessive– compulsive disorder symptoms were doc-
hypomania may be due to excessive dopamine stimula- umented to improve in case reports of PD patients with
tion or STN stimulation, resulting in downstream impair- STN stimulation localized in the anteromedial STN and
ments of medial frontal and inhibitory functioning in zona incerta.104,105 Obsessive– compulsive symptom
vulnerable individuals.102 The disinhibition of underly- scores were reported to improve in patients following
ing vulnerabilities including that of premorbid mood STN DBS.15 However, the potentially confounding vari-
disorders or personality traits may also help explain the able of depression was not examined. Furthermore,
observation of the range of psychiatric symptoms (such whether the prevalence of comorbid obsessive– compul-
as dysphoria and hypomania) following STN DBS. sive symptoms is elevated in PD is not clear.106 –109

Apathy Visual Hallucinations

Apathy is a common postoperative symptoms in the New-onset visual hallucinations (VHs) were described
long term and has been reported to occur between 12% following STN DBS responding to decreases in levo-
and 25% in 3 to 5 years after STN stimulation dopa; recurrence of hallucinations 3 years later was time-
surgery.18,26 locked with stimulation of an electrode within the zona
Apathy is defined as decreased responses to internal incerta.116 The recurrent VH responded to decreases in
and external stimulation. In the general PD population, stimulation and to clozapine. Proposed etiologies in-
apathy has been reported between 16.5% and 42%.1,110 cluded stimulation affecting the medial limbic STN, the
Apathy, understood as a distinct clinical syndrome, also ventral tegmental area (VTA) projections, or serotoner-
has overlaps with depression, hedonic tone, personality gic fibers projecting to the frontal cortex. The cortico–
traits, and cognitive function. In the general PD popula- striato–thalamo– cortical loop involving area TE of the
tion, apathy has been associated with cognitive dysfunc- inferotemporal cortex has also been implicated in VH.117
tion, particularly executive dysfunction, rather than de- However, connections to the STN have not yet been
pression.110 Apathy in neuropsychiatric disorders and in demonstrated. Indeed, late-onset hallucinations appear to
PD has been reported to respond to dopaminergic med- be more likely to be associated with the underlying PD
ications implicating an underlying dopaminergic process potentially interacting with increases in dopami-
etiology.111,112 nergic medications given its association in patients with
The limbic cortico–striato–thalamo– cortical cognitive deficits18 and may reflect underlying progres-
(CSTC) loop projecting to the anterior cingulate has sion of nondopaminergic pathology.
been implicated and bilateral lesions to the anterior The role of preoperative symptoms remains to be
cingulate or globus pallidus are reported to be associ- clarified. A survey of patients presenting for STN stim-
ated with symptoms of apathy.112 However, a study ulation revealed a preoperative history of hallucinations
comparing apathy states both ON and OFF stimulation or delusions in 35% of patients.84 The decrease in med-
found an improvement in group scores of self-reported ications following STN stimulation presumably de-
apathy with ON stimulation.113 The patients with im- creases the stimulation of dopaminergic receptors out-
provements in apathy had a shorter disease duration side of motor pathways and in theory should decrease
and less severe parkinsonism compared to those with- postoperative psychotic symptoms. However, hallucina-
out improvements. However, conclusions from the tions may have nondopaminergic etiologies including
study are limited by the lack of preoperative assess- serotonin and acetylcholine and furthermore may be as-
ment of apathy, limitations due to the self-report na- sociated with cognitive decline, aspects of which are not
ture of the Apathy Scale, and limitations of the use of modifiable with stimulation. As such, whether patients
such a scale to assess transient acute states induced by with a history of preoperative psychotic symptoms,
changes in stimulation. which may be a marker for cognitive decline, are at
Similarly, transient apathy early in the postoperative greater risk of postoperative neurobehavioral symptoms
period is commonly part of the dopaminergic or psycho- is not known.
stimulant withdrawal syndrome114,115 and responds to
increasing levodopa. Levodopa administration and acute
STN stimulation have similar subjective effects.96 Apa- Anxiety
thy can also occur in the context of postoperative Generalized anxiety disorder (GAD) was diagnosed
depression. retrospectively in 18 of 24 patients with PD (75%) fol-
In contrast, more permanent symptoms of apathy late lowing STN DBS in one study, 17 of whom had a
in the postoperative period may be more likely related to preoperative history of GAD. Ten patients (42%) had a
underlying frontal dysexecutive symptoms18,26 related to specific fear that the stimulator would suddenly fail.34
the neurodegenerative process of PD. STN stimulation The extent to which these symptoms overlap with those
appears to act on motor regions mediated by dopaminer- of other comorbid psychiatric disorders is not known.
gic systems but has a more variable effect on the limbic However, overall group anxiety rating scores have been
regions mediated by dopamine.26 Apathy associated with reported in some studies to improve significantly on
cognitive deficits may also be mediated by nondopam- anxiety measurements,23,28 although specificity of the
inergic or neurodegenerative etiologies. symptoms was not reported.

S320 V. VOON ET AL.
Dementia and Cognition DLPFC function might reflect greater involvement of the
Dementia meeting DSM criteria was observed in only direct CSTC motor circuit.
3 patients (7%) in an uncontrolled 5-year outcome study A few studies have provided additional insight into the
of 42 of 49 original patients prospectively studied fol- pathophysiology of verbal fluency changes, though the
lowing STN DBS.18 That this figure is lower than de- studies’ results appear to be vexingly contradictory. On
mentia in the general PD population may reflect selection the one hand, a functional neuroimaging study found that
stimulation reduced verbal fluency, and that stimulation-
bias since patients with severe cognitive deficits are
related metabolic changes (inferior frontal and temporal)
excluded from DBS. Although the evolution of dementia
were correlated with verbal fluency performance differ-
has not been compared in DBS and unoperated PD
ences during and without stimulation.125 On the other
groups, other cognitive changes have been studied more
hand, clinical studies comparing verbal fluency with and
extensively (see prior section on cognitive outcomes).
without stimulation after surgery have generally failed to
The pathophysiology of cognitive changes after DBS find differences,13,49 even though declines are common
remains largely a matter of speculation. One might argue between presurgical baseline and postoperative assess-
that an anatomical basis for cognitive changes with STN ment. In addition, a 3-year follow-up study observed a
stimulation is plausible given that the STN has been decline in fluency between preoperative baseline and 1
observed to have more widespread connections with year, but no further decline between the first and third
basal ganglia and cortical areas than once thought, and years,26 suggesting that the change is unlikely to be due
that the segregated cortico– basal ganglionic limbic, as- to disease progression. How stimulation, changes in
sociative, and motor circuits may communicate via open medication, and microlesion effects might interact to
elements within these circuits.88,118 –120 Furthermore, it is produce verbal fluency changes remains to be deter-
a simple matter to argue that current spread from segre- mined. More detailed theoretically driven studies are
gated motor circuits to adjacent limbic and associate needed to tease out the underlying neurophysiological
circuits entrain cortical changes downstream that would processes involved in cognitive changes following DBS.
be expected to cause cognitive changes. Indeed, func-
tional imaging studies suggest that STN DBS is associ- PREOPERATIVE AND POSTOPERATIVE
ated with metabolic alterations in cortical areas extend- MANAGEMENT OF NEUROBEHAVIORAL
ing beyond motor and supplementary motor regions, and SYMPTOMS
specifically those areas that are part of the associative Treatment algorithms for the preoperative assessment
and limbic circuits.121,122 For example, PET activation and postoperative management of neurobehavioral
studies have demonstrated that STN and GPi stimulation symptoms associated with stimulation for PD are pre-
results in increased activation in the supplementary mo- sented in Tables 4 and 5, respectively. The algorithms
tor area (SMA), dorsolateral prefrontal cortex (DLPFC), are most relevant for STN stimulation given the potential
and anterior cingulate during random joystick move- interactions between medication changes and stimula-
ments.123 Inferences regarding the potential pathophysi- tion. The algorithms are based on expert opinion given
ology of cognitive changes observed following DBS can the limited published literature on this topic.
be drawn by combining findings from the functional
imaging and stimulation literatures. Jahanshahi and col- CONCLUSIONS
leagues22 demonstrated that acute stimulation of the STN A common evolution of cognitive or psychiatric
resulted in improvements in several executive function symptoms appears to emerge following STN stimulation.
tasks. These data, in combination with the PET findings, In the short term following surgery, symptoms may be
suggest that DBS might “release the brake” in PD and more frequent due to significant changes in dopaminer-
result in improvements in aspects of executive function gic medications, the effects of a life-changing event, and
presumably related to increased activation of DLPFC potentially stimulation-related effects. However, over the
and other frontal regions. Conversely, Jahanshahi and long term, with chronic stimulation replacing the pulsa-
colleagues22 found that DBS in the STN can also result tile effects of dopaminergic medications, fewer but qual-
in increased difficulty on cognitive tasks that require itatively different symptoms emerge. As patients are
behavioral changes in response to novel contexts.124 followed beyond a decade, dealing with the effects of
These latter findings might be driven via the indirect natural disease progression, increasing dopaminergic
CSTC motor circuit, whereas the facilitatory effect on medications, progressive cognitive decline, and a differ-

TABLE 4. Potential areas for preoperative psychiatric assessment for deep brain stimulation for Parkinson’s disease
Depression: current (see also Moderate
preoperative supplement) 1. Decision based on individual patient factors
2. Consider antidepressant prophylaxis
Severe
1. Refer to psychiatry
2. Surgery when depression treated
3. Antidepressant prophylaxis
4. Ensure antidepressants and benzodiazepines continued postoperatively
5. Psychoeducation for potential relapse
6. Close postoperative follow-up with adequate postoperative psychiatric management
and support
7. Gradual postoperative medication reduction
8. Patients with nonmodifiable high suicide risk should be contraindicated from surgery
Treatment-refractory severe depression: contraindicated from surgery
Depression: past history Mild: single episode, rapid improvement with antidepressants or psychotherapy
1. Proceed to surgery
Moderate–severe: hospitalization, suicidal ideation, electroconvulsive therapy
1. Refer to psychiatry for optimization of treatment
2. Psychoeducation for potential relapse
3. Ensure adequate postoperative psychiatric management and support
4. Ensure antidepressants and benzodiazepines continued postoperatively
5. Close postoperative follow-up
6. Gradual postoperative medication reduction
Hypomania/mania Primary bipolar disorder
1. Adequately controlled: decision based on individual patient factors and adequacy of
postoperative psychiatric management and support
2. Severe treatment refractory: contraindicated from surgery
Medication-induced hypomania/mania Past history
1. Psychoeducation of patient and family for potential relapse
2. Close postoperative follow-up (e.g., contact with patient or family at least once
every 2 weeks for the first 3 postoperative months)
Current
1. Decrease or discontinue associated medication or decrease overall dopaminergic
medication dose
2. Psychoeducation of patient and family for potential relapse
3. Proceed to surgery
4. Close postoperative follow-up
Suicidal ideation Referral to psychiatry for assessment of severity of ideation, need for management, and
appropriateness for surgery
Hallucinations/psychosis 1. Assessment for cognitive deficits
2. Mild (good insight, infrequent, does not affect behavior): consider atypical
antipsychotic (clozapine/quetiapine) prophylaxis; decision based on individual
patient factors
3. Moderate to severe (limited insight, frequent, or affects behavior): decision
dependent on factors such as cognitive status, degree of association with
dopaminergic medications (or expected improvement with decreasing dopaminergic
medications), response to atypical antipsychotics (clozapine/quetiapine), patient
supports, and access to postoperative neurobehavioral management
4. Primary severe psychotic disorder: contraindicated from surgery
Medication-related pathological 1. Assess potential relationship with medication (i.e., temporal association with
gambling or hypersexuality medication and trial of decreasing medications)
2. Decrease or discontinue implicated medications
3. If preoperative changes in medications not tolerated or behaviors persist, may
proceed cautiously with surgery with informed consent on potential risk of
persisting behavioral symptoms; decision dependent on factors such as cognitive
status, likely association with dopaminergic medications, patient supports, capacity
for behavioral controls, and access to postoperative neurobehavioral management
Algorithms are most relevant for subthalamic stimulation given potential interactions between stimulation and medications.
ing set of psychosocial concerns or disappointments will present the evidence is inconclusive. Some studies sug-
create another set of unique challenges. gest that adverse neuropsychiatric events may be more
Information is beginning to emerge on potential dif- common in the STN compared to GPi patients. Alterna-
ferences between STN and GPi stimulation. However, at tively, some neuropsychiatric symptoms may be more

S322 V. VOON ET AL.
TABLE 5. Postoperative management for psychiatric symptoms following deep brain stimulation for Parkinson’s disease
Depression Early
1. Increase levodopa
2. Antidepressants ⫾ psychotherapy if not responsive or partially responsive
3. Consider trial or restart/dose increase of dopamine agonist with mood-elevating properties
(e.g., pramipexole)
4. Evaluation for suicidal ideation
5. Consider psychiatric referral
Late
1. Trial of increase levodopa
2. Antidepressants and/or psychotherapy if not responsive or partially responsive
3. Consider trial of dopamine agonist with mood-elevating properties
4. Evaluation for suicidal ideation
5. Assess for primary apathy or cognitive deficits
6. Consider psychiatric referral
Suicidal ideation: refer to psychiatry (see section on suicidal ideation)
Treatment-refractory depression: optimization of pharmacological management with adequate
dosing and duration of treatment, switching of antidepressant classes, and combination
and augmentation strategies; augmentation with atypical antipsychotics is not
recommended; safety of the use of electroconvulsive therapy in patients with implanted
stimulators is not known, although a case report has been published describing the safety
and efficacy of electroconvulsive therapy utilized in the treatment of depression in a PD
patient following DBS surgery125
Hypomania/mania 1. Assess for suicidal ideation, risk-taking behaviors (driving, finances, excessive spending,
sexual behaviors): concurrent referral to psychiatry if risk-taking behaviors present for
capacity and safety assessments, potential hospitalization, treatment
2. Assess for necessity for treatment
Mild: time-limited, none of the above behaviors, responsive to interventions
1. No treatment required
2. Consider decreasing dopaminergic medications or decreasing stimulation
Persistent or moderate to severe
1. Decrease dopaminergic medications or decrease stimulation
2. Discontinue antidepressants
3. Clozapine and/or mood stabilizer (carbamezapine, valproic acid)
Apathy Early
1. Increase levodopa
2. Assess for depression (including dysthymia, subsyndromal or minor depression)
3. Antidepressant if depression present
Late
1. Trial of increasing levodopa
2. Assess for depression (including dysthymia, subsyndromal or minor depression)
3. Antidepressant if present or trial of antidepressant if uncertain
4. Assess for cognitive status
a. Cholinesterase inhibitor if dementia present
b. Caregiver psychoeducation on apathy symptoms
c. Multidisciplinary approach for dementia management
Suicidal ideation 1. Referral to psychiatry (note that the management of comorbid psychiatric symptoms is
affected by dopaminergic withdrawal symptoms and the presence of stimulation; see
appropriate sections for management)
2. Assessment for postoperative depression, hypomania/mania, psychotic symptoms with
management as outlined in previous sections
3. Standard psychiatric management of suicidal ideation
Hallucinations/psychosis 1. Adjustment of antiparkinsonian medications
2. Trial of decreasing stimulation parameters
3. Atypical antipsychotics if needed: clozapine or quetiapine
4. Assessment for cognitive deficits: cholinesterase inhibitors if dementia present
Pathological gambling/hypersexuality 1. Decrease or discontinue any implicated dopaminergic medication (e.g., dopamine agonist)
and/or decrease total dopaminergic medication dose
2. Rule out medication- or stimulation-related hypomania/mania (see management of
postoperative hypomania/mania)
3. Trial of decreasing stimulation
4. Consider atypical antipsychotics (clozapine or quetiapine)
5. Multidisciplinary addiction management
Algorithms are most relevant for subthalamic stimulation given potential interactions between stimulation and medications.

likely to be improved by STN stimulation since it affords 5. Volkmann J, Allert N, Voges J, Weiss PH, Freund HJ, Sturm V.
Safety and efficacy of pallidal or subthalamic nucleus stimulation
a greater reduction or elimination of dopaminergic med- in advanced PD. Neurology 2001;56:548 –551.
ications and STN stimulation itself may play a role in 6. Anderson VC, Burchiel KJ, Hogarth P, et al., Pallidal versus
improving certain symptoms (e.g., obsessive– compul- subthalamic deep brain stimulation in Parkinson’s disease. Arch
Neurol 2005;62:554 –560
sive symptoms). Thus, pending the outcomes of larger 7. Rodriguez-Oroz MC, Obeso JA, Lang AE, et al., Bilateral deep
well-documented randomized controlled studies, preop- brain stimulation in Parkinson’s disease: a multicenter study with
erative neuropsychiatric comorbidity may 1 day play a 4 years followup. Brain 2005;128;2240 –2249.
8. Volkmann J, Allert N, Voges J, Weiss PH, Freund HJ, Sturm V.
role in target selection. Safety and efficacy of pallidal or subthalamic nucleus stimulation
The postoperative cognitive and psychiatric states fol- in advanced PD. Neurology 2001;56:548 –551.
lowing stimulation for PD are poorly understood and 9. Krack P, Fraix V, Mendes A, Benabid AL, Pollak P. Postopera-
tive management of subthalamic nucleus stimulation for Parkin-
understudied. Patients with severe PD who undergo son’s disease. Mov Disord 2002;17(Suppl. 3):S188 –S197.
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tunity to study potential biological and psychosocial ulation for Parkinson’s disease: a review of initial studies and
recommendations for future research. Brain Cogn 2000;42:268 –
variables underlying several cognitive and psychiatric 293.
symptoms prospectively. Such studies can provide fur- 11. Woods SP, Fields JA, Tröster AI. Neuropsychological sequelae
ther insight not only into symptoms associated with PD, of subthalamic nucleus deep brain stimulation in Parkinson’s
disease: a critical review. Neuropsychol Rev 2002;12:111–126.
but also into drug withdrawal mechanisms and poten- 12. Moretti R, Torre P, Antonello RM, et al. Neuropsychological
tially mood, addiction, and behavioral disorders unre- changes after subthalamic nucleus stimulation: a 12 month fol-
lated to PD. The range of cognitive and psychiatric low-up in nine patients with Parkinson’s disease. Parkinsonism
Relat Disord 2003;10:73–79.
symptoms observed in PD patients following DBS and 13. Morrison CE, Borod JC, Perrine K, et al. Neuropsychological func-
the paucity of available literature provides a fertile tioning following bilateral subthalamic nucleus stimulation in Par-
ground for further pathophysiological and clinical kinson’s disease. Arch Clin Neuropsychol 2004;19:165–181.
14. Gironell A, Kulisevsky J, Rami L, Fortuny N, Garcia-Sanchez C,
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Stimulation for advanced PD is effective and safe lamic stimulation on cognitive function in Parkinson disease: a
for the vast majority of well-selected patients. The controlled comparative study. J Neurol 2003;250:917–923.
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majority of the observed psychiatric symptoms is tran- subthalamic stimulation on cognitive function in Parkinson dis-
sient and manageable and ideally, if appropriately ease. Arch Neurol 2001;58:1223–1227.
understood and managed, preventable. Studies with 16. Ardouin C, Pillon B, Peiffer E, et al. Bilateral subthalamic or
pallidal stimulation for Parkinson’s disease affects neither mem-
appropriate control groups with advanced PD on high ory nor executive functions: a consecutive series of 62 patients.
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into further context. This article is intended as a com- 17. Burchiel KJ, Anderson VC, Favre J, Hammerstad JP. Comparison
of pallidal and subthalamic nucleus deep brain stimulation for
panion to the preoperative and postoperative issues advanced Parkinson’s disease: results of a randomized, blinded
papers in this supplement on DBS for PD. Further pilot study. Neurosurgery 1999;45:1375–1382.
information on cognitive and behavioral clinical issues 18. Krack P, Batir A, Van Blercom N, et al. Five-year follow-up of
bilateral stimulation of the subthalamic nucleus in advanced Par-
can be found elsewhere in this issue. kinson’s disease. N Engl J Med 2003;349:1925–1934.
19. Perozzo P, Rizzone M, Bergamasco B, et al. Deep brain stimu-
Acknowledgments: We gratefully acknowledge the assis- lation of the subthalamic nucleus in Parkinson’s disease: compar-
tance of Dr. Jean Saint-Cyr and Dr. Jerome Yelnik in their ison of pre- and postoperative neuropsychological evaluation.
comments on the anatomical table. J Neurol Sci 2001;192:9 –15.
20. Pillon B, Ardouin C, Damier P, et al. Neuropsychological
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Movement Disorders

Vol. 21, Suppl. 14, 2006, pp. S305–S326

Deep Brain Stimulation: Neuropsychological and

OUTCOME STUDIES Subthalamic Stimulation

Movement Disorders, Vol. 21, Suppl. 14, 2006

Movement Disorders, Vol. 21, Suppl. 14, 2006

Movement Disorders, Vol. 21, Suppl. 14, 2006

Movement Disorders, Vol. 21, Suppl. 14, 2006

Movement Disorders, Vol. 21, Suppl. 14, 2006

Movement Disorders, Vol. 21, Suppl. 14, 2006

Movement Disorders, Vol. 21, Suppl. 14, 2006

Movement Disorders, Vol. 21, Suppl. 14, 2006

Adapted from Voon and colleagues.45

PATHOPHYSIOLOGY OF PSYCHIATRIC AND neurodegenerative process and involvement of nondo-

Movement Disorders, Vol. 21, Suppl. 14, 2006

Adapted from Funkiewiez and colleagues.96

Movement Disorders, Vol. 21, Suppl. 14, 2006

Movement Disorders, Vol. 21, Suppl. 14, 2006

Movement Disorders, Vol. 21, Suppl. 14, 2006

Movement Disorders, Vol. 21, Suppl. 14, 2006

Apathy Visual Hallucinations

Movement Disorders, Vol. 21, Suppl. 14, 2006

Movement Disorders, Vol. 21, Suppl. 14, 2006

Movement Disorders, Vol. 21, Suppl. 14, 2006

Movement Disorders, Vol. 21, Suppl. 14, 2006

Movement Disorders, Vol. 21, Suppl. 14, 2006

Movement Disorders, Vol. 21, Suppl. 14, 2006

Movement Disorders, Vol. 21, Suppl. 14, 2006

Movement Disorders, Vol. 21, Suppl. 14, 2006

Movement Disorders, Vol. 21, Suppl. 14, 2006

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