Associations Between
Bilateral Subthalamic
The authors explored the associations between
subthalamic nucleus deep brain stimulation (STN-
DBS) and anxiety in Parkinsons disease (PD)
patients. Recent research suggests that anxiety may
be one of the earliest manifestations of PD; however,
the lack of a dopamine-medication control group is
a major limitation of these studies. Authors paired
a group of 31 bilateral STN-DBS PD patients
(STN-DBS group) with 31 dopamine-medicated
PD patients (Medication-control group) and used
various psychological assessment scales for group
evaluations. These were completed 1 month
preoperatively, and 3 weeks, 5 weeks, 2 months, 4
months, 7 months, and 13 months postoperatively.
As compared with the Medication group, the STN-
DBS group improved in motor functioning and
general status after 1 week Stimulator PowerOn;
State-Anxiety improved significantly at 1 week and
1 month after Stimulator PowerOn, but was not
significant at the subsequent time-points. Anxiety
scores remained stable before 3rd-month Stimulator
316 http://neuro.psychiatryonline.org
Nucleus Deep Brain
Stimulation (STN-DBS)
and Anxiety in Parkinsons
Disease Patients: A
Controlled Study
Chongwang Chang, M.D.
Nan Li, M.S.
Yuyan Wu, B.S.
Ning Geng, M.S.
Shunnan Ge, M.S.
Jing Wang, M.S.
Xin Wang, M.S.
Xuelian Wang, M.D.
PowerOn, but got worse after that time. In the
STN-DBS group, SAI was positively related to
motor symptoms and life quality preoperatively and
4 months postoperatively, but, in the Medication
group, this correlation existed throughout the
study. PD-related anxiety decreased in STN-DBS
patients because of the improvement in motor
function for a short time; however, as the voltages
and pulse-widths grew higher with time, the PD-
related anxiety became worse.
(The Journal of Neuropsychiatry and Clinical
Neurosciences 2012; 24:316325)
T raditionally, Parkinsons disease (PD) is considered
a movement disorder. However, there is increas-
ing evidence to indicate that PD is a multidimensional
Received July 20, 2011; revised January 21, February 17, 2012; accepted
February 20, 2012. From the Dept. of Neurosurgery, Tangdu Hospital,
Fourth Military Medical University, 1 Xinsi Road, Xian, Shaanxi
Province 710038, China. Send correspondence to Wang Xuelian, Dept.
of Neurosurgery, Tangdu Hospital, Shaanxi Province, China; e-mail:
tdgnsjwk@126.com
Copyright 2012 American Psychiatric Association
J Neuropsychiatry Clin Neurosci 24:3, Summer 2012

disease. In addition to motor deficits, it is also associ-
ated with a number of non-motor symptoms, including
anxiety, which can precede the classical motor features
of PD by years; these contribute substantially to a de-
terioration in quality of life for PD patients.1,2 Epidemi-
ological studies have reported that the prevalence of
anxiety in PD ranged from 5% to 69%.3,4 This variabil-
ity in results may be caused by the use of different
assessment tools and methods. The anxiety of the PD
patient cannot be detected unless there are severe clinical
manifestations.3 It not only worsens the symptoms of
PD,5 but also makes the PD patient afraid of stepping
forward due to the fear of tumbling.6
Although the relationship between dopaminergic
transmission and clinical anxiety disorders is complex
and poorly understood,7 there is evidence that anxiety in
PD is associated with abnormalities in dopaminergic
transmission.8,9 Dopamine (DA)-depleted rodents man-
ifest increased anxiety-like behaviors.10,11 Furthermore,
recent evidence suggests that the noradrenergic and
serotonergic systems may play a more significant role in
the manifestation of PD-related anxiety than previously
thought.12 According to the Braak et al.13 and Del Tredici
et al.14 staging of PD pathology, serotonergic cell loss in
the raphe nuclei is evident before nigrostriatal dopami-
nergic degeneration.14 Noradrenaline (NA) dysfunction
is also likely to occur before pronounced degeneration of
DA neurons.13 In general, PD-related anxiety seems to be
related to the dopaminergic, noradrenergic, and seroto-
nergic systems and is manifested before the motor
dysfunction of PD. On the other hand, the theory related
to the etiology of anxiety symptoms in PD argues that
PD-related anxiety is reactive and secondary to the
psychosocial stress of a chronic disease and the asso-
ciated disability, as they are usually diagnosed after the
PD.15
Subthalamic nucleus (STN) deep brain stimulation
(DBS) is known to be an effective treatment for motor
symptoms of PD. An increasing number of studies are
now focusing on the influence of STN-DBS on non-
motor symptoms. Most researchers have reported that
the STN-DBS worsens cognition,1618 apathy,19 and impulse-
control disorder 16,2022 in PD patients. Researchers are
increasingly bound up in the discussion of the influence
of STN-DBS on depression in PD patients;2326 however,
few researchers have focused specifically on changes in
PD-related anxiety after STN-DBS; most only mention
incidental changes in anxiety as a part of follow-
up research. In a 72-case, 15-month follow-up study by
J Neuropsychiatry Clin Neurosci 24:3, Summer 2012
CHANG et al.
Castelli et al.27 and a 41-case, 12-month follow-up study
by Thierry et al.,26 it was found that the anxiety of the
STN-DBS PD patients was stable during the pre- and
post-operative follow-up period. However, in a 33-case,
15-month follow-up study by Kalteis et al.,28 anxiety was
reported to be significantly improved. The common
limitation of these studies is the lack of a control group,
which consequently meant that the researchers were
unable to minimize the influence of other effects.
To overcome this limitation and try to elucidate the
influence of STN-DBS on PD-related anxiety, the current
study compared the changes in anxiety within a DA
(Medication) control group and a bilateral STN-DBS
group. Based on the probable pathological mechanism of
PD-related anxiety, this article first hypothesized that
anxiety might be decreased in STN-DBS patients because
of the pronounced improvement of motor functioning
associated with STN-DBS. However, because of the
unchangeable nigrostriatal dopaminergic degeneration
in PD, the second hypothesis is that STN-DBS cannot
change PD-related anxiety in the long term. Further-
more, PD-related anxiety might continue to worsen with
the progression of PD disease.
METHOD
Subjects
The experimental subjects were patients who received
bilateral STN-DBS implantation between January 2008
and June 2009 in the Research Center of Functional
Brain Disease (a research institute of the Department of
Neurosurgery, Tangdu Hospital, Fourth Military Med-
ical University) and who agreed to participate in the study.
The inclusion criteria were a diagnosis of idiopathic PD
(U.K. brain bank); Hoehn-Yahr (modified) Grades $2.5;
normal preoperative brain MRI; and preoperative
improvement rate of the Madopar Impact Test $40%.
The exclusion criteria were: Mini-Mental State Exam
(MMSE) score #24; any distinct mental disorders
detected by psychological assessment and psychia-
trists; any anxiolytic drugs being used; and any normal
surgical contraindications. During the study period, the
following subjects were rejected: those whose combina-
tion of antiparkinsonian medications exceeded about
10 mg/day of levodopa equivalent; those who needed
the treatment of antipsychotics, anxiolytics, and anti-
depressants; those whose contact positions of the STN-
DBS needed to be readjusted for inaccurate location or
http://neuro.psychiatryonline.org 317
STN-DBS AND ANXIETY IN PD
drifting; those who needed removal of the STN-DBS for
any reason; and, for members of the Medication control
group, those who wanted to accept the STN-DBS
implantation.
The study applied the paired-control method. Once
a PD patient was enrolled as a member of the STN-DBS
group, another PD patient from the outpatient databank
of our center, who was receiving pharmacotherapy
only, was paired to an STN-DBS patient and assigned to
the Medication group. The pairing criteria were match-
ing gender and Hoehn-Yahr (modified) grade, age
(within 1 year), medical history (within 1 year), years
of education (within 1 year), and the daily levodopa
equivalent of antiparkinsonian medications (plus-or-
minus 100 mg/day).
All patients were told that the levodopa equivalent of
their current antiparkinsonian medications would not
change during the study period. As this study aimed to
investigate the optimal therapeutic doses of levodopa,
and as a reward for participation in the study, levodopa
was provided to subjects free of charge. Patients were
informed clearly that they had the right to withdraw
from the study at any time.
The patients were unaware of the aims of the study,
and the assessors and program-controllers of the DBS
were blind as to patient-group assignment. Furthermore,
the designer of the study did not participate in the
implementation or assessment procedures. This study
was approved by the ethics committee of the Fourth
Military Medical University, China.
Assessment Scales
The Hamilton Anxiety Scale (Ham-A; 14-item version)
and the StateTrait Anxiety Inventory (STAI) were used
to assess the severity of anxiety. Three of the questions in
the Ham-A relate to the inner experience of anxiety, such
as inquietude, tension, and fear; one is about depression
experience; the rest relate to clinical manifestations of
anxiety, such as agrypnia, memory deterioration, other
physical symptoms (including those that relate to
musculature, sensory system, cardiovascular system,
gastrointestinal tract, respiratory tract, genitourinary
system, and vegetative nervous system), and general
performance when talking. The higher the Ham-A
scores, the worse the anxiety. The STAI is comprised of
two subscales: state anxiety (SAI) and trait anxiety
(TAI); with 20 items each. SAI is mainly a measure of
current anxiety experience, whereas TAI is mainly an
assessment of recent past/general anxiety experiences;
318 http://neuro.psychiatryonline.org
the higher the scores of the two subscales, the greater the
anxiety symptoms.
The third part, the motor component of the Unified
Parkinsons Disease Rating Scale (UPDRS-III), was used
to assess the severity of motor symptoms in the PD
patients; higher scores are indicative of more severe PD
motor symptoms. The PDQ-39 assesses the quality of life
for PD patients; a higher score denotes a worse quality of
life.
Evaluation Time-Points
The patients were assessed in the On state of
levodopa. In order to minimize the influence of
operation-related stress, the pre-operative assessment
was conducted 1 month before the operation. To assess
the post-operative edema reaction and DBS powerOn
stress reactions, the study carried out the first post-
operative assessment at the 3rd week after the operation;
that is, 1 week before Stimulator PowerOn. The second
postoperative assessment was carried out at the 5th
week after the operation/1 week after the Stimulator
powerOn, to observe the short-term changes in anxiety
after Stimulator powerOn. To observe the transitory
and long-term changes in anxiety after Stimulator power
On, subsequent assessments were carried out at 2 months
post-operatively/1 month after Stimulator powerOn,
4 months post-operatively/3 months after Stimulator
powerOn, 7 months post-operatively/6 months after
Stimulator powerOn, and 13 months post-operatively/
12 months after Stimulator powerOn. The evaluation
time-points for the Medication group were strictly
synchronized with the STN-DBS group. Two psycholo-
gists with clinical qualifications approved by the National
Ministry of Health and $2 years of clinical experience
were responsible for the mental and scale assessments.
The average of the scores ascertained by the two assessors
was taken as the final result for each patient.
Surgical Procedures
All of the PD patients in the STN-DBS group under-
went the bilateral STN-DBS operation under the guide
of magnetic resonance imaging (MRI). First, the PD
patients had a Leksell stereotactic frame installed under
local anesthesia. An MRI (GE 3.0 T) with thin slice (2-mm
thickness, 0-mm interval) was then carried out. The
imaging data were transferred to Elekta SurgiPlan
software for target location. In accordance with the
Schaltenbrand-Wahren Brain Anatomy Atlas and using
the coronal images, the target lateral dorsal part of the
J Neuropsychiatry Clin Neurosci 24:3, Summer 2012

STN was directly localized on the axial image, and the
coordinate values of the target were calculated. Two
burr-holes were drilled in front of the coronal suture
and 2.53 cm. perpendicular from the midline bi-
laterally. The intra-operative Medtronic Leadpoint
microelectrode recording system was used to record
electrophysiological signals of STN neurons to help
locate the target accurately. An electrical stimulation test
was used routinely to observe efficacy and side effects.
Once a satisfactory test result was obtained, the DBS
quadripolar electrode (model 3389; Medtronic Inc.,
Minneapolis, MN, U.S.A.) was implanted and fixed at
the burr-hole. After the electrical stimulation test had
been repeated to confirm the therapeutic effect and the
absence of side effects, an extension wire (Lead 7482-51)
and an implantable pulse-generator (Kinetra 7428; Med-
tronic, Inc.) was implanted in a subcutaneous pocket,
under general anesthesia. One month post-operatively,
the pulse-generator was turned on and programmed with
the following parameter ranges: pulse width at 60 mS,
90 mS, and 120 mS; frequency at 130185 Hz; and voltage
at 1.43.5 V.
Statistical Methods
SPSS 11.0 software was used for data processing and
statistical analysis. Mean values were used in the cal-
culation of the bilateral STN-DBS stimulating parame-
ters of voltage, pulse-width, and frequency. The data in
the study are expressed as mean (standard deviation
[SD]). Statistical methods included analysis of variance,
paired-samples t-tests, independent-samples t-tests, cor-
relation analysis, and regression analysis. For compar-
isons between the two groups, p,0.05 was considered
significant. For comparisons of multiple time-points,
p,0.01 was considered significant.
RESULTS
Demographic Data for the Two Patient Groups
During the study period, information was obtained
from a total of 36 pairs of patients. Five pairs failed to
complete the 14-month follow-up. In two pairs, the
patients in the Medication control group chose STN-DBS
implantation treatment. In one pair, the dose of levo-
dopa was significantly adjusted. In the other two pairs,
the electrode was removed because of infection. Valid
data were obtained for 31 pairs of cases for the final
analysis (efficiency: 86.11%). The demographic data for
J Neuropsychiatry Clin Neurosci 24:3, Summer 2012
CHANG et al.
the two groups of patients are shown in Table 1. There
were no statistical differences in demographics be-
tween the STN-DBS group and the Medication group
(p.0.05).
3.2. Stimulation Parameters and Assessment Scale Data for
the Two Groups at Various Time-Points
The results of the average-difference tests are shown in
Table 2. There were no differences in the averages of the
data for the two groups at the baseline level of 1 month
pre-operatively and 3 weeks post-operatively.
Comparisons Between the STN-DBS Group and the Medica-
tion Group at Various Time-Points Compared with the
Medication group, the UPDRS-III and PDQ-39 of the
STN-DBS group showed improvement after 1 week
Stimulator powerOn (p,0.05); the SAI improved
significantly at 1 week and 1 month after Stimulator
powerOn (p,0.05), but the difference was not signif-
icant at the subsequent time-points (p.0.05). The TAI
and Ham-A scores became worse after 3 months with
Stimulator powerOn (p,0.05).
Comparisons of the Stimulation Parameters and Assess-
ment Scales at Various Time-Points for the STN-DBS
Group Compared with 1-month pre-operation and
the 3rd week post-operatively, the UPDRS-III and
PDQ-39 scores for the STN-DBS group were im-
proved at 1 week and at all subsequent time-points
after Stimulator powerOn (p,0.05). The SAI scores
showed improvement from 1 week to 6 months after
Stimulator powerOn (p,0.05), but then anxiety
worsened at the 12th month after Stimulator power
On (p,0.05). The TAI and Ham-A showed signifi-
cant deterioration from the 3rd month to the 12th
month after Stimulator powerOn (p,0.05).
The voltage and pulse-width of the STN-DBS group
increased significantly at 1 month and at all subsequent
time-points after Stimulator powerOn, as compared
with 1 week after Stimulator powerOn (p,0.05). The
frequency increased significantly from the 3rd month to
the 12th month after Stimulator powerOn (p,0.05),
whereas no significant change was observed at the 1st
month (p.0.05).
Comparisons of the Stimulation Parameters and Assess-
ment Scales at Various Time-Points for the Medication
Group Compared with the pre-operation and Stimu-
lator powerOn time-points, the UPDRS-III scores for
http://neuro.psychiatryonline.org 319
STN-DBS AND ANXIETY IN PD
TABLE 1. Basic Information About the Patients in the STN-DBS Group and the Medication Group, mean (standard deviation)
STN-DBS Group
Mean age (SD), years
Men
Women
Education, years
Medical history, years
Hoehn-Yahr (modified) grade
Mean levodopa daily equivalent of anti-parkinsonian 814.31 (195.49)
drugs, mg.
Mini-Mental State Exam (MMSE)
STN-DBS: subthalamic nucleus deep brain stimulation.
the Medication group were poor at all time-points after
the 5th month of the study (p,0.05). The scores for the
PDQ-39 were significantly poorer at the 14th month of the
study (p,0.05). The SAI, TAI, and Ham-A scores for
the Medication group showed no significant changes at
any time-points during the study (p.0.05).
Correlations Between Stimulation Parameters and
Assessment Scales
The results of the correlation coefficients and significance
tests between the UPDRS-III, PDQ-39, and stimulation
parameters, and the SAI, TAI, and Ham-A are shown
in Table 3.
For the Medication group, both the UPDRS-III and
PDQ-39 were positively related to SAI, but not to the
TAI or Ham-A during the study period p,0.05).
For the STN-DBS group, the UPDRS-III was posi-
tively related to the SAI at and before the 3rd month
after Stimulator powerOn (p,0.05). The PDQ-39 was
positively related to the SAI at and before 3 weeks
postoperatively (p,0.05), but was uncorrelated at sub-
sequent time-points (p.0.05). The UPDRS-III and PDQ-
39 were not related to the TAI and Ham-A during
the study period (p.0.05). The SAI was not related to
voltage, frequency, or pulse-width after Stimulator
powerOn, whereas both the TAI and Ham-A were
positively related to voltage and pulse-width (p,0.05).
Regression Analysis for the Influence of Stimulation
Parameters on Anxiety Scales in the STN-DBS Group
We analyzed and tested the significance of the stan-
dard regression equation and standard regression
coefficients in accordance with the findings of the
correlation analyses. The UPDRS-III and PDQ-39
were the independent variables, and the SAI was the
dependent variable. Voltage and pulse-width were
320 http://neuro.psychiatryonline.org
Range Medication Group Range
58.32 (4.18) 5363 57.83 (4.23) 5462
20 20
11 11
10.39 (3.14) 614 10.76 (4.47) 614
5.77 (2.62) 38 5.83 (2.85) 38
3.62 (1.22) 2.54.0 3.62 (1.22) 2.54.0
6201,010 826.86 (218.05) 6101,040
27.73 (2.91) 2530 27.55 (2.38) 2530
independent variables, and the Ham-A and TAI were
dependent variables. The results are shown in Table 4.
The effects of the UPDRS-III and PDQ-39 on the SAI
binary standard regression equation were established
at 1 month pre-operation and the 3rd week post-
operatively (1 week before Stimulator powerOn). The
effect of the UPDRS-III on the SAI standard unitary
regression equation was established from 1 week to 3
months after Stimulator powerOn. The effect of voltage
and pulse-width on the TAI binary standard regres-
sion equation was established during 12 months after
Stimulator powerOn. The effects of voltage and pulse-
width on the Ham-A binary standard regression equa-
tion were established during 12 months after Stimulator
powerOn.
DISCUSSION
The results of this study revealed that the UPDRS-III
scores progressively increased for the Medication group,
indicating that the symptoms of PD continued to worsen
when using the unchanged dosage of dopamine during
the study period. Also, for the STN-DBS group, wherein
the parameters of the electrical stimulation were contin-
ually adjusted and the dosage of dopamine was un-
changed, the symptoms of PD became progressively
worse. These findings both indicate that the progression
of PD cannot be controlled by dopamine or STN-DBS.
The study found that SAI was related to motor
symptoms and life quality pre-operatively and 4 months
post-operatively for the STN-DBS group, but, in the
Medication group, this correlation existed during the
entire study period. This indicates that state-anxiety was
influenced by the severity of the motor symptoms and
the level of life quality. The results therefore verify the
J Neuropsychiatry Clin Neurosci 24:3, Summer 2012
 TABLE 2. Comparisons of the Stimulation Parameters and Assessment Scales Between the Two Patient Groups at Different Time-Points, mean (standard deviation)
Scores
Evaluation Time-Points
Items
1 Month Pre- 3 Weeks Post- 5 Weeks Post- 2 Months Post- 4 Months Post- 7 Months Post- 13 Months Post-
Groups Operation Operation Operation Operation Operation Operation Operation F
abc abc abc abc abc
UPDRS-III STN-DBS group 26.61 (9.79) 26.54 (9.58) 9.29 (3.21) 9.90 (3.61) 10.68 (3.56) 11.97 (3.54) 12.97 (4.79) 101.17e
Medication 25.77 (8.64) 25.81 (8.78) 25.77 (8.64) 26.19 (8.26) 26.52 (8.47)bc 27.19 (8.46)bc 27.90 (8.76)bc 12.59)e
group
SAI STN-DBS group 47.58 (6.15) 47.55 (6.39) 39.61 (7.21)abc 44.29 (7.04)abc 45.84 (6.98)bc 47.26 (6.59)bc 48.06 (6.39)bc 69.34)e

J Neuropsychiatry Clin Neurosci 24:3, Summer 2012

Medication 48.13 (5.81) 48.10 (6.02) 46.45 (7.94) 48.42 (6.66) 49.03 (6.68) 48.10 (6.55) 48.32 (6.69) 2.08
group
TAI STN-DBS group 42.77 (9.26) 42.81 (9.29) 45.45 (9.66) 47.39 (9.75) 49.00 (9.98)bc 50.42 (10.14)bc 51.81 (10.21)abc 12.99e
Medication 41.81 (9.18) 42.84 (9.36) 42.39 (8.41) 42.06 (8.80) 41.84 (8.83) 42.00 (8.48) 42.29 (8.66) 4.17
group
Ham-A STN-DBS group 12.35 (2.68) 12.32 (2.65) 12.10 (2.31) 12.65 (2.14) 13.03 (2.46)bc 13.48 (2.90)bc 14.29 (3.13)abc 16.86e
Medication 12.90 (2.47) 12.87 (2.45) 12.61 (2.01) 12.77 (2.08) 13.00 (1.88) 13.10 (1.80) 13.42 (1.89) 5.65
group
PDQ-39 STN-DBS group 77.58 (14.87) 77.52 (15.14) 38.87 (16.08)abc 41.45 (14.78)abc 42.77 (15.48)abc 43.13 (15.53)abc 45.06 (15.55)abc 93.01e
Medication 77.06 (15.81) 77.03 (16.05) 77.32 (15.00) 79.19 (15.67) 81.32 (15.99) 83.10 (16.24) 85.10 (16.13)bc 6.81
group
Mean 2.22 (0.40) 2.37 (0.36)d 2.58 (0.23)d 2.69 (0.20)d 2.87 (0.16)d 8.62e
voltage
Mean 61.94 (7.49) 64.84 (11.22) 68.71 (13.84)d 76.45 (20.26)d 82.26 (21.86)d 12.99e
frequency
Mean pulse- 133.94 (2.80) 137.87 (3.11)d 140.84 (4.15)d 143.10 (4.42)d 145.03 (4.31)d 13.69e
width

For the STN-DBS group, Stimulator powerOn occurred 1 month post-operation; hence, 5 weeks post-operation is equivalent to 1 week after Stimulator powerOn; accordingly, 2
months post-operatively is equivalent to 1 month after Stimulator powerOn; 4 months post-operatively is equivalent to 3 months after Stimulator powerOn; 7 months post-
operatively is equivalent to 6 months after Stimulator powerOn; and 13 months post-operatively is equivalent to 12 months after Stimulator powerOn.
a
p,0.05, compared with the Medication group, by independent-samples t-test.
b
p,0.05, compared with 1 month before the surgery, by paired-samples t-test.
c
p,0.05, compared with 3 weeks post-surgery, by paired-samples t-test.
d
p,0.05, compared with 5 weeks post-surgery, by paired-samples t-test.
e
p,0.01, from F-tests at different time-points.

321http://neuro.psychiatryonline.org
CHANG et al.
STN-DBS AND ANXIETY IN PD

TABLE 3. Correlations Among UPDRS-III, PDQ-39, and Stimulation Parameters, and the SAI, TAI, and Ham-A, for the Two Patient
Groups
Correlation Coefficients
Evaluation Time-Points
1 Month 3 Weeks 5 Weeks 2 Months 4 Months 7 Months 13 Months
Pre- Post- Post- Post- Post- Post- Post-
Items Groups Operation Operation Operation Operation Operation Operation Operation
UPDRS-III SAI STN-DBS 0.401a 0.404a 0.362a 0.438a 0.405a 0.331 0.300
Medication 0.472a 0.464a 0.414a 0.391a 0.425a 0.420a 0.442a
TAI STN-DBS 0.248 0.251 0.297 0.235 0.213 0.191 0.242
Medication 0.151 0.166 0.185 0.203 0.180 0.203 0.190
Ham-A STN-DBS 0.204 0.203 0.194 0.166 0.157 0.135 0.139
Medication 0.310 0.300 0.341 0.321 0.346 0.330 0.340
PDQ-39 SAI STN-DBS 0.397a 0.380a 0.285 0.104 0.185 0.205 0.207
Medication 0.413a 0.409a 0.417a 0.369a 0.370a 0.383a 0.389a
TAI STN-DBS 0.304 0.310 0.326 0.308 0.302 0.316 0.333
Medication 0.218 0.226 0.210 0.208 0.224 0.216 0.209
Ham-A STN-DBS 0.298 0.294 0.154 0.126 0.132 0.135 0.107
Medication 0.222 0.210 0.264 0.333 0.231 0.227 0.267
Mean SAI 0.255 0.248 0.193 0.200 0.162
voltage TAI 0.508b 0.497b 0.501b 0.404a 0.408a
Ham-A 0.451a 0.380a 0.352a 0.416a 0.573b
Mean SAI 0.215 0.238 0.224 0.268 0.228
frequency TAI 0.065 0.045 0.048 0.053 0.055
Ham-A 0.102 0.137 0.129 0.119 0.127
Mean SAI 0.051 0.031 0.036 0.071 0.075
pulse- TAI 0.426a 0.445a 0.451a 0.462a 0.454a
width Ham-A 0.450a 0.700b 0.786b 0.831b 0.862b
a
Significance of relative factors: p,0.05.
b
Significance of relative factors: p,0.01.

reactive and secondary theory of PD-related anxiety 15
and, to some extent, support the first hypothesis of this
article (i.e., that PD-related anxiety may be decreased
in STN-DBS patients because of the improvement of
motor functioning associated with STN-DBS surgery).
The motor symptoms of PD were fluctuating, and levels
of anxiety paralleled these fluctuations. The lack of a
correlation between SAI and motor symptoms after 4
months postoperatively for the STN-DBS group may be
because of changes in the STN-DBS stimulating param-
eters. This study also revealed that state-anxiety was
unrelated to the STN-DBS stimulating parameters. One
might infer from this that the stimulating parameters
were not related to the symptoms of PD.
The more interesting result was that trait-anxiety and
Ham-A scores were correlated with the changes in
voltage and pulse-width during the study period. This
result conflicted with the second hypothesis (i.e., that
STN-DBS will not change PD-related anxiety in the
long term because of the unchangeable nigrostriatal
dopaminergic degeneration in PD). However, when the
hypotheses were formulated, we only considered the
unceasing nigrostriatal dopaminergic degeneration of
PD patients, and neglected the impact of the STN-DBS or
the stimulating target (STN).
Recent research has confirmed that within human and
primate brains, there are five circuits that connect the
cortex to the basal ganglia, the thalamus, and back to
the cortex. The associative circuit and limbic circuit are
closely related to cognitive, emotional, and behavioral
regulation. The STN is, anatomically, at the center of
these loops, and, as such, is an effective regulator of
these circuits.29,30 The STN can be anatomically divided
into three functional subregions: the dorsolateral motor
subregion, the ventromedial associative subregion, and
the medial limbic subregion, which are related to motor
functions, the associative circuit, and the limbic circuit,
respectively.29,3134 Neuroanatomical research35 has shown
that the middle part of the STN connects to the limbic part
of the globus pallidus and striatum and also links to the
prefrontal lobe and cingulate gyrus. These connections
suggest that the STN is involved in the information-
processing of the limbic system. Greenhouse et al.36
showed that stimulation of the dorsal subregion led to
a more significant improvement of motor symptoms, as

322 http://neuro.psychiatryonline.org J Neuropsychiatry Clin Neurosci 24:3, Summer 2012

 CHANG et al.

TABLE 4. Regression-Analysis Factors for the Influence of UPDRS-III, PDQ-39, Voltage and Pulse-Width on Anxiety Scales in the STN-
DBS Group
Correlation Coefficients
Evaluation Time-Points
1 Month Pre- 3 Weeks Post- 5 Weeks Post- 2 Months Post- 4 Months Post- 7 Months Post- 13 Months Post-
Items Operation Operation Operation Operation Operation Operation Operation
UPDRS-III SAI 0.401a 0.404a 0.362a 0.438a 0.405a 0.331 0.300
PDQ-39 0.397a 0.380a 0.285 0.104 0.185 0.205 0.207
Mean voltage TAI 0.510b 0.502b 0.506b 0.411a 0.409a
Mean pulse- 0.408a 0.417a 0.411a 0.405a 0.403a
width
Mean voltage Ham-A 0.405a 0.451a 0.416a 0.552b 0.573b
Mean pulse 0.451a 0.689b 0.773b 0.824b 0.857b
width
a
test of the significance of the standard regression factor, p,0.05, by t-test.
b
test of the significance of the standard regression factor, p,0.01.

compared with stimulation of the ventral subregion, but
it induced negative emotions much more often.
The best improvement in motor symptoms is pro-
duced when one stimulates the dorsolateral subregion
of the STN in PD patients,36,37 which was chosen as the
target region in the current study. If continuously
stimulated, the dorsolateral subregion of the STN may
trigger a variety of moods, such as panic and worry, and
bring about physical changes symptomatic of anxiety,
such as a rapid heartbeat, muscle tension, and shivers.
Also, as the STN connects to the limbic system, the
stimulated STN will influence the limbic system, which
may affect the amygdaloid nucleus, and instigate moods
such as anxiety.
The stimulation parameters of DBS include voltage,
frequency, pulse-width, and the selection of contacts.
In this study, the dorsolateral motor subregion of the
STN was used as a stimulating target for all cases,
and all stimulating patterns were single-contact stim-
uli. The position of the contacts was identified by the
effect of the motor symptoms via programming-
control of the DBS and the post-operative MRI. If the
electrodes were located inaccurately or drifted from
the target, the patients were rejected from the study.
Therefore, all of the targets that are affected by all
electrode contacts can be regarded as the same. For this
reason, the contact-selection itself had nothing to do
with the anxiety state.38 The voltage and pulse-width
of DBS mainly affect the current strength. Frequency
mainly refers to the timing of stimulations and has
little to do with the current strength. Theoretically,
when the voltage and pulse-width are higher, the current
that is generated by the DBS stimulator is stronger, and,
as a result, the functional brain area that is influenced
by the current is larger. If the current grew stronger, it
may affect more subregions within or outside the STN.
In such cases, anxiety symptoms will increase in severity.
Also, the stronger current may be identified by the
brain as a harmful stimulation, and subsequently arouse
anxiety, an instinctive response to danger.
The financial burden of the DBS device and the battery
loss of the pulse-generator were also psychologically
distressing to PD patients and their families. Higher
voltage and pulse-width meant greater loss of pulse-
generator battery power, more money, greater psycho-
logical distress, and increased anxiety.
The results of this research differed from those of
previous studies.2628 The main reason for this may be
that the previous studies2628 had not controlled for the
influence of DA on PD-related anxiety. The present
study remedied this shortcoming. Moreover, this study
addresses the influence of the stimulating parameters
of STN-DBS on PD-related anxiety, the discussion
of which has not appeared in the published literature
to-date. However, in this type of research, the mean
values adopted for the bilateral stimulators parame-
ters will be problematic when the differences between
the bilateral stimulators parameters are great, an effect
that we will continue to monitor in future studies.
Nevertheless, despite the limitations associated with
this research, which also include the short time-course
(because of ethical considerations), the small number of
cases, and the incomplete random sample, the current

J Neuropsychiatry Clin Neurosci 24:3, Summer 2012 http://neuro.psychiatryonline.org 323

STN-DBS AND ANXIETY IN PD
study provides some representation of the anxiety
experienced by the STN-DBS PD patient population.
Dr. Chang, Nan Li, and Yuyan Wu contributed equally to
this article and are all first-authors.
References
1. Chaudhuri KR, Healy DG, Schapira AH; National Institute for
Clinical Excellence: Non-motor symptoms of Parkinsons
disease: diagnosis and management. Lancet Neurol 2006;
5:235245
2. Reijnders JS, Ehrt U, Lousberg R, et al: The association between
motor subtypes and psychopathology in Parkinsons disease.
Parkinsonism Relat Disord 2009; 15:379382
3. Dissanayaka NN, Sellbach A, Matheson S, et al: Anxiety
disorders in Parkinsons disease: prevalence and risk factors.
Mov Disord 2010; 25:838845
4. Leentjens AF, Dujardin K, Marsh L, et al: Symptomatology and
markers of anxiety disorders in Parkinsons disease: a cross-
sectional study. Mov Disord 2011; 26:484492
5. Routh LC, Black JL, Ahlskog JE: Parkinsons disease compli-
cated by anxiety. Mayo Clin Proc 1987; 62:733735
6. Pasman EP, Murnaghan CD, Bloem BR, et al: Balance problems
with Parkinsons disease: are they anxiety-dependent? Neuro-
science 2011; 177:283291
7. Millan MJ: The neurobiology and control of anxious states.
Prog Neurobiol 2003; 70:83244
8. Stein DJ, Westenberg HG, Liebowitz MR: Social anxiety disorder
and generalized anxiety disorder: serotonergic and dopaminer-
gic neurocircuitry. J Clin Psychiatry 2002; 63(Suppl 6):1219
9. Remy P, Doder M, Lees A, et al: Depression in Parkinsons
disease: loss of dopamine and noradrenaline innervation in the
limbic system. Brain 2005; 128:13141322
10. Eskow Jaunarajs KL, Dupre KB, Ostock CY, et al: Behavioral
and neurochemical effects of chronic L-dopa treatment on non-
motor sequelae in the hemiparkinsonian rat. Behav Pharmacol
2010; 21:627637
11. Taylor TN, Caudle WM, Shepherd KR, et al: Nonmotor
symptoms of Parkinsons disease revealed in an animal model
with reduced monoamine storage capacity. J Neurosci 2009;
29:81038113
12. Eskow Jaunarajs KL, Angoa-Perez M, Kuhn DM, et al: Potential
mechanisms underlying anxiety and depression in Parkinsons
disease: consequences of L-dopa treatment. Neurosci Biobehav
Rev 2011; 35:556564
13. Braak H, Ghebremedhin E, Rb U, et al: Stages in the
development of Parkinsons disease-related pathology. Cell
Tissue Res 2004; 318:121134
14. Del Tredici K, Rb U, De Vos RA, et al: Where does parkinson
disease pathology begin in the brain? J Neuropathol Exp
Neurol 2002; 61:413426
15. Prediger RD, Matheus FC, Schwarzbold ML, et al: Anxiety in
Parkinsons disease: a critical review of experimental and
clinical studies. Neuropharmacology 2012; 62:115124
16. Deuschl G, Schade-Brittinger C, Krack P, et al; German
Parkinson Study Group, Neurostimulation Section: A random-
ized trial of deep-brain stimulation for Parkinsons disease. N
Engl J Med 2006; 355:896908
324 http://neuro.psychiatryonline.org
We thank all the patients and their families who participated
in this study. This work was supported by grants from the
Funding System for Scientific Research of Tangdu Hospital.
Dr. Chang received travel grants from Medtronic. The
other authors have no conflicts of interest.
17. Okun MS, Fernandez HH, Wu SS, et al: Cognition and mood
in Parkinsons disease in subthalamic nucleus versus globus
pallidus interna deep brain stimulation: the COMPARE trial.
Ann Neurol 2009; 65:586595
18. Parsons TD, Rogers SA, Braaten AJ, et al: Cognitive se-
quelae of subthalamic nucleus deep brain stimulation in
Parkinsons disease: a meta-analysis. Lancet Neurol 2006;
5:578588
19. Kirsch-Darrow L, Zahodne LB, Marsiske M, et al: The
trajectory of apathy after deep brain stimulation: from pre-
surgery to 6 months post-surgery in Parkinsons disease.
Parkinsonism Relat Disord 2011; 17:182188
20. Lim SY, Evans AH, Miyasaki JM: Impulse control and related
disorders in Parkinsons disease: review. (review) Ann N Y
Acad Sci 2008; 1142:85107
21. Hlbig TD, Tse W, Frisina PG, et al: Subthalamic deep brain
stimulation and impulse control in Parkinsons disease. Eur J
Neurol 2009; 16:493497
22. Frank MJ, Samanta J, Moustafa AA, et al: Hold your horses:
impulsivity, deep brain stimulation, and medication in parkin-
sonism. Science 2007; 318:13091312
23. Kosel M, Sturm V, Frick C, et al: Mood improvement after deep
brain stimulation of the internal globus pallidus for tardive
dyskinesia in a patient suffering from major depression.
J Psychiatr Res 2007; 41:801803
24. Wang X, Chang C, Geng N, et al: Long-term effects of bilateral
deep brain stimulation of the subthalamic nucleus on de-
pression in patients with Parkinsons disease. Parkinsonism
Relat Disord 2009; 15:587591
25. Strutt AM, Simpson R, Jankovic J, et al: Changes in cognitive-
emotional and physiological symptoms of depression follow-
ing STN-DBS for the treatment of Parkinsons disease. Eur
J Neurol 2012; 19:121127
26. Soulas T, Sultan S, Gurruchaga JM, et al: Depression and
coping as predictors of change after deep brain stimulation in
Parkinsons disease. World Neurosurg 2011; 75:525532
27. Castelli L, Perozzo P, Zibetti M, et al: Chronic deep brain
stimulation of the subthalamic nucleus for Parkinsons disease:
effects on cognition, mood, anxiety and personality traits. Eur
Neurol 2006; 55:136144
28. Kalteis K, Standhardt H, Kryspin-Exner I, et al: Influence of
bilateral STN-stimulation on psychiatric symptoms and psy-
chosocial functioning in patients with Parkinsons disease.
J Neural Transm 2006; 113:11911206
29. Nuti A, Ceravolo R, Piccinni A, et al: Psychiatric comorbidity in
a population of Parkinsons disease patients. Eur J Neurol 2004;
11:315320
30. Temel Y, Visser-Vandewalle V, Aendekerk B, et al: Acute and
separate modulation of motor and cognitive performance in
parkinsonian rats by bilateral stimulation of the subthalamic
nucleus. Exp Neurol 2005; 193:4352
J Neuropsychiatry Clin Neurosci 24:3, Summer 2012

31. Parent A, Hazrati LN: Functional anatomy of the basal ganglia,
I: the cortico-basal ganglia-thalamo-cortical loop. Brain Res
Brain Res Rev 1995; 20:91127
32. Hamani C, Saint-Cyr JA, Fraser J, et al: The subthalamic nucleus
in the context of movement disorders. Brain 2004; 127:420
33. Karachi C, Yelnik J, Tand D, et al: The pallidosubthalamic
projection: an anatomical substrate for nonmotor functions
of the subthalamic nucleus in primates. Mov Disord 2005;
20:172180
34. Zaidel A, Spivak A, Shpigelman L, et al: Delimiting sub-
territories of the human subthalamic nucleus by means of
microelectrode recordings and a Hidden Markov Model. Mov
Disord 2009; 24:17851793
J Neuropsychiatry Clin Neurosci 24:3, Summer 2012
CHANG et al.
35. Groenewegen HJ, Berendse HW: Connections of the subthalamic
nucleus with ventral striatopallidal parts of the basal ganglia
in the rat. J Comp Neurol 1990; 294:607622
36. Greenhouse I, Gould S, Houser M, et al: Stimulation at dorsal
and ventral electrode contacts targeted at the subthalamic
nucleus has different effects on motor and emotion functions in
Parkinsons disease. Neuropsychologia 2011; 49:528534
37. Hershey T, Campbell MC, Videen TO, et al: Mapping Go-No-Go
performance within the subthalamic nucleus region. Brain
2010; 133:36253634
38. York MK, Wilde EA, Simpson R, et al: Relationship between
neuropsychological outcome and DBS surgical trajectory and
electrode location. J Neurol Sci 2009; 287:159171
http://neuro.psychiatryonline.org 325