Journal of Parkinson’s Disease 4 (2014) 289–300 289

DOI 10.3233/JPD-130273
IOS Press

Review

An Update of the Impact of Deep Brain

Stimulation on Non Motor Symptoms in
Parkinson’s Disease
Lisa Klingelhoefera,b,∗ , Michael Samuelc , K. Ray Chaudhuria and Keyoumars Ashkand
a National Parkinson Foundation International Centre of Excellence, Department of Neurology, King’s College
Hospital and King’s College, Denmark Hill, London, UK
b Department of Neurology, Technical University Dresden, Dresden, Germany
c National Parkinson Foundation International Centre of Excellence, Department of Neurology, King’s College

Hospital, Denmark Hill, London, UK

d Department of Neurosurgery, King’s College Hospital, Denmark Hill, London, UK

Abstract. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established therapy for patients with
Parkinson’s disease (PD), especially those with advanced motor complications. The effect of STN DBS on non motor symptoms
(NMS) of PD is less well studied. In this article, we review the pertinent literature on the impact of STN DBS on NMS when
they co-exist with disabling motor symptoms in PD patients. We also present evidence that the number and the severity of most
NMS decrease after STN DBS which can have a major impact on patients’ quality of life.

Keywords: Deep brain stimulation, DBS, Parkinson’s disease, PD, subthalamic nucleus, STN, internal globus pallidus, GPi, non
motor symptoms

INTRODUCTION the subthalamic nucleus (STN) [1–3], globus pallidus

Parkinson’s disease (PD) is a chronic progressive
neurodegenerative disorder that presents with the clas-
sic motor signs of tremor, rigidity and bradykinesia
but is associated with a wide variety of non motor
symptoms (NMS). Deep brain stimulation (DBS) is
an established symptomatic treatment procedure for
patients with Parkinson´s disease. Best short-term and
long-term evidence is available for stimulation of
∗ Correspondence to: Lisa Klingelhoefer, MD, Fellow, National
Parkinson Foundation International Centre of Excellence, Depart-
ment of Neurology, King’s College Hospital and King’s College,
Denmark Hill, London SE5 9RS, UK. Tel.: +44 7456786911;
E-mail: lisa.klingelhoefer@nhs.net and Department of Neurol-
ogy, Technical University Dresden, Fetscherstraße 74, Dresden,
Germany.
internus (GPi) [4, 5] and thalamic ventralis intermedius
(VIM) [6]. Previously, the primary endpoints of most
studies were focused on a change in the motor signs and
so are the scales selected to assess the outcome. There
is good evidence on effectiveness of DBS to improve
motor symptoms in advanced Parkinson’s disease with
significant benefits in tremor, rigidity and bradykinesia
[3, 7–9]. Also in PD patients, early at the onset of motor
complications and therefore earlier in the course of the
disease, data showed significant benefits of DBS on
motor symptoms [2]. There is therefore good evidence
that both patients with advanced PD and those at an
early stage of PD with motor complications will ben-
efit from STN DBS with an improvement in UPDRS
III of about 50%, a reduction in off-periods during the
day of 70% and a prolongation of periods with good

ISSN 1877-7171/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved
290 L. Klingelhoefer et al. / An Update of the Impact of Deep Brain Stimulation on Non Motor Symptoms in Parkinson’s Disease
mobility of about 20% [2, 3, 10, 11]. Furthermore com-
plications like dyskinesias, a side effect of levodopa
therapy, decrease by 60–70% after STN DBS [2, 3, 11].
Until now NMS have received limited attention and
are mostly only assessed as secondary endpoints in
randomized studies. Non motor features are common
in PD patients, occur across all disease stages and
whilst well described, are still under recognized in
comparison to their huge impact on patients’ quality of
life [12]. Main non motor symptoms groups are neu-
ropsychiatric, e.g. depression or cognitive dysfunction,
sleep disorders, autonomic symptoms, e.g. bladder dis-
turbances or orthostatic hypotension, gastrointestinal
symptoms, sensory symptoms, e.g. pain and a group of
other symptoms, e.g. fatigue [12]. In the recent years,
effective and validated measuring tools, e.g. the Non
Motor Symptoms Questionnaire (NMSQuest) [13] and
the Non Motor Symptoms Scale (NMSS) [14] have
been developed which allow an accurate measurement
of NMS in PD patients.
Most of the current literature on the effect of DBS
on NMS is based on using STN as the target with little
data on GPi. There is almost no evidence on the effect
of DBS on NMS using the VIM as the target for PD
patients.
It has been shown that NMS are more frequent and
severe in advanced PD [15, 16], but are also present
in early stages of PD, even before dopaminergic med-
ication has been initiated [17]. Both in early stages
and advanced stages of PD, NMS show a greater
impact on health-related quality of life and health status
than motor symptoms [15, 17, 18]. Therefore, ther-
apies investigated in patients with PD, independent
of disease stage, must address motor and non-motor
symptoms to provide optimal quality of life, health
status and individual well being.
STATE OF THE SCIENCE – IMPACT OF
DEEP BRAIN STIMULATION ON NON
MOTOR SYMPTOMS OF PARKINSON’S
DISEASE
Presently there is evidence that some non motor
symptoms improve after STN DBS, some are not influ-
enced by DBS and some deteriorate temporary or long
term after DBS [19, 20]. The overall improvement in
mean NMSS was reported as 36% after STN DBS [21].
The changes in NMS frequency and severity may be
related to the changes in the dopamine replacement
therapy (DRT) that follows DBS, be related to the
surgery itself (e.g. the tract and micro lesion effect)
or be due to the electrical stimulation at the active
electrode contact.
Nazzaro et al. [22] showed that the number of NMS
was significantly reduced one year following STN
DBS (from a mean of 12 to 7 NMS). It appears that
STN DBS does not have a major immediate effect on
frequencies of NMS as assessed by the NMSS, but
severities of most NMS were significantly improved
by an immediate effect of STN DBS in 34 PD patients
[23]. Of interest, there was no correlation between
post DBS changes in NMS and motor improvement,
demographics or medication changes [23]. NMS were
less frequently reported in the long-term follow up of
patients with STN DBS which led to a significantly
positive correlation with quality of life and activities
of daily living [22].
Behavioural disorders like impulsivity can occur
or worsen after STN DBS [24]. The STN probably
provides a global “no-go” signal which may be mod-
ulated by DBS leading to a shortening of the actual
time of decision making under high-conflict conditions
[20, 25, 26]. Nevertheless, postoperative behavioural
changes are seldom caused by stimulation alone.
The mortality in the first year following STN DBS
has been reported at 0.4% and suicide, especially in
patients with postoperative depression and a previ-
ous history of impulse control disorders or compulsive
medication use, has been reported as one of the most
important risks for mortality following DBS in PD
patients [27]. Schuepbach et al. [2] in a random-
ized, multicenter, parallel-group study comparing STN
DBS plus medical therapy with medical therapy alone
(EARLYSTIM study), also found a high frequency of
suicidal behaviour including suicides but without any
difference between patients in the DBS and those in the
best medical treatment groups. They suggested that the
decision to eventually undergo DBS may select a spe-
cific subgroup of patients with a higher risk for suicidal
behaviour than the general population. Therefore not
the DBS as a procedure seems to be associated with a
higher risk of suicide but the personality traits of PD
patients’ deciding for DBS.
In addition, Weintraub et al. [28] observed no sui-
cide behaviours and rare new-onset suicide ideation
when comparing PD patients randomised to DBS ver-
sus best medical therapy (BMT). Rates of suicide
ideation at 6 months were similar for patients ran-
domised to STN versus GPi DBS (1.5% vs. 0.7%),
but several proxy symptoms were worse in the STN
group. Again this study does not support a direct
association between DBS surgery and an increased
risk for suicide ideation and behaviours. Despite these
 L. Klingelhoefer et al. / An Update of the Impact of Deep Brain Stimulation on Non Motor Symptoms in Parkinson’s Disease
findings, behavioural and mood disorders should be
carefully monitored following DBS. Impulse con-
trol disorders (ICD), mainly caused by dopaminergic
medication, improved markedly or disappeared after
STN DBS [20, 29–32]. Lhommee et al. [32] showed
an overall improvement in neuropsychiatric symp-
toms in 63 PD patients after STN DBS and proposed
that disabling non motor fluctuations, dopaminergic
treatment abuse and drug-induced behavioural addic-
tions may be considered as new indications for STN
DBS. This positive effect of STN DBS might be
due to decreased stimulation of dopaminergic cir-
cuits by reduction of dopaminergic medication, a
less pulsatile and non suprathreshold stimulation of
the mesolimbic dopamine receptors or direct modu-
lation by DBS of the reward seeking brain circuitry
[2, 29, 33, 34].
There are however also reports [35] of new onset
post operative ICDs or of patients whose pre-existing
ICDs worsened after DBS. The time period between
DBS and the development of ICD varied from imme-
diately after surgery to months later. Most of the ICDs
were transient and resolved within a year of their devel-
opment. The reasons for the development of ICDs after
DBS remain unknown and different hypothesis have
been proposed:
1. Direct modulation due to DBS: As the STN
mediates not only motor but also cognitive and
emotional functions, the stimulation of the STN
might increase impulsivity [36, 37].
2. Current spread to adjoining structures beyond the
STN: Studies have shown that the stimulation of
different contacts of the same electrode can influ-
ence the performance on decision making tasks
and behaviour [25, 38–41].
3. Side effects of dopaminergic medication: Patients
undergoing DBS usually have a higher cumula-
tive exposure to dopaminergic medication due to
longer duration and greater severity of PD. DBS
may further sensitize the brain to neuropsychi-
atric side effects of dopaminergic medication. In
patients with pre-existing ICDs therefore a sig-
nificant reduction of dopaminergic medication
needs to be achieved before any improvement in
ICDs is seen [30, 39, 41–44].
4. The improvement of motor function after DBS
may facilitate the full expression of behavioural
abnormalities or premorbid latent psychiatric
symptoms that had been developed, for exam-
ple due to the use of dopaminergic medication,
before DBS [45].
291
Table 1 summarises the current literature on DBS
and ICDs.
Pre-existing drug induced psychotic symptoms like
hallucinations disappear after STN DBS in nearly all
PD patients following reduction of DRT [59]. On
the other hand, transient psychotic symptoms such as
delirium may be seen in the immediate post-operative
period as the direct result of surgery, possibly related
to peri-electrode oedema.
Apathy occurring in the postoperative period may
be caused primarily by the withdrawal of DRT [55, 60]
because in many patients, a complete reversal of apathy
after treatment with dopaminergic therapy could be
shown [33, 61]. Given that apathy is not reversed in all
PD patients following DRT, STN DBS in itself may
be the cause of apathy in a proportion of patients [62].
The topic warrants further investigations, especially as
the most recent STN DBS studies report an increase in
frequency and severity of apathy post surgery [62–64].
As apathy after STN DBS develops progressively in
some patients, the role of dopaminergic desensitization
rather than a direct stimulation effect has also been
postulated [55]. Given the diversity of the literature
on the association between STN DBS and apathy, we
suggest that different types of apathy such as transient
direct postoperative apathy, apathy in association with
depression and/or cognitive deficits, might be caused
by different mechanisms (e.g. reduction of DRT, STN
DBS effects).
There are differing data with respect to the effect of
STN DBS on mood disorders like depression, mania
and anxiety with improvement [23, 26, 65], no change
[66] and worsening of symptoms [2, 67] reported com-
pared to the preoperative condition. Again these may
be partly due to postoperative DRT changes and partly
due to stimulation effect itself [68]. Positive immediate
and long term effects of STN DBS on mood includ-
ing depression and anxiety might be mediated through
direct involvement of the STN in fear processing and
non motor limbic circuits and/or indirect dopaminergic
effects of the STN DBS [23, 26]. The anatomical local-
isation of the electrodes, e.g. in ventral-medial limbic
portion of the STN can cause both behavioural disor-
ders such as impulsivity and mood disorders such as
mania [48, 53, 69–71]. Current spread to the adjacent
limbic circuits may also lead to mood problems like
depression and mania and reprogramming of the DBS
system should be considered in an attempt to improve
the problem [68, 69, 72].
Multiple studies and meta-analysis have consis-
tently shown that STN DBS does not impair overall
cognition, although there is a selective decrease in
 292
Table 1
A summary of current publications related to development of impulse control disorders (ICDs) and deep brain stimulation (DBS) in patients with Parkinson’s disease (PD)
Reference Number of PD patients with ICD Type of impulse control disorder (ICD) DBS target Outcome after DBS
{Total sample size of patients}
Krause et al. 2001 3 {18} increased libido STN (1) GPi (2) 2 patients treated in an inpatient psychiatric clinic,
[46] further outcome not described
Houeto et al. 2002 2 {24} behavioural disorder with sexual deviancy, STN not resolved
[45] exhibitionism, heightened libido
Romito et al. 2002 4 {22} increased sexuality STN transient, completely resolved after some months
[47]
Romito et al. 2002 3 {30} increased sexuality STN transient, completely resolved after up to 18 months
[48]
Kleiner-Fisman et al. 2 {25} hypersexuality STN transient (1), persistent (1)
2003 [49]
Funkiewitz et al. 2004 2 {77} aggressive impulsive episodes STN developed after DBS but only transient
[50]
Krause et al. 2004 1 {24} increased libido STN medical treatment for 6 months, afterwards stable
[51] over years
Sensi et al. 2004 [38] 1 {1} aggressive behaviour disorder with disturbed STN gradually subsided completely
impulse control
Machado et al. 2005 1 {1} Trichotillomania (pre-existing DBS) STN Pre-existing active before DBS and ongoing
[52] problem after DBS
Witjas et al. 2005 [30] 1 {1} hypersexuality (pre-existing DBS) STN resolved after DBS
Ardouin et al. 2006 7 {598} pathological gambling (pre-existing DBS) STN resolved after DBS after 18 months, transient
[29] worsening in 2 patients.
Bandini et al. 2007 2 {2} pathological gambling STN dramatically improved after DBS
[44]
Contarino et al. 2007 2 {11} hypersexuality STN developed after DBS but only transient
[53]
Smeding et al. 2007 1 {1} pathological gambling STN developed after DBS but disappeared after
[39] discontinuation of pergolide and changing of
stimulation parameters
Doshi and Bhargava 2 {2} hypersexuality STN developed after DBS
2008 [54]
Halbig et al. 2009 [43] 3 {16} impulse control disorder STN developed after DBS
L. Klingelhoefer et al. / An Update of the Impact of Deep Brain Stimulation on Non Motor Symptoms in Parkinson’s Disease

Reference Number of PD patients with ICD
{Total sample size of patients}
Lim et al. 2009 [20]
Thobois et al. 2010
[55]
Zahodne et al. 2011
[56]
Lhommee et al. 2012
[32]
Moum et al. 2012 [57]
Shotbolt et al. 2012
[31]
Eusebio et al. 2013
[58]
Table 1
(Continued)
Type of impulse control disorder (ICD) DBS target Outcome after DBS
2 {21} pathological gambling STN developed after DBS (1), resolved pre-operatively
and did not recur after DBS (1)
17 {63} several pathological behavioural addictions STN disappeared after STN in all patients at follow up of
12 months
4 {22} binge eating STN increase after DBS (2), stable after DBS (2)
17 {63} preoperative behavioural addictions such as STN disappeared after STN in all patients at follow up of
hypersexuality, pathological gambling, 12 months
compulsive shopping, excessive eating behaviour
7 {159} hypersexuality, pathological gambling, excessive STN (4) GPi (3) 3/7 resolved (2 STN, 1 GPi), 2/7 with new dopamine
chocolate craving (pre-existing DBS in all 7 dysregulation syndrome after STN DBS, 2/7 no
patients) change of ICD after DBS. New ICD after DBS in
17 patients: initially unilateral DBS 11/17 (7/11
GPi, 4/11 STN DBS) of whom 5/11 went on for
bilateral DBS and of these 4/5 the new ICD
resolved completely; initially bilateral DBS 6/17
(4/6 STN and 2/6 GPi DBS)
3 and 1 {50} hypersexuality and hypersexuality / dopamine STN stable (1) or no recurrence (3)
dysregulation syndrome (pre-existing DBS)
18 {110} pathological gambling, hypersexuality, excessive STN pre-existing ICD resolved after DBS or significantly
shopping, binge eating (pre-existing DBS in all 18 improved after DBS in 16/18 patients, 2/18 were
patients) lost to follow up. New ICD in 7 patients after DBS
(1 pathological gambling, 2 excessive shopping, 1
hypersexuality, 3 binge eating) at follow up of 12
months.
L. Klingelhoefer et al. / An Update of the Impact of Deep Brain Stimulation on Non Motor Symptoms in Parkinson’s Disease
293
294 L. Klingelhoefer et al. / An Update of the Impact of Deep Brain Stimulation on Non Motor Symptoms in Parkinson’s Disease
the frontal cognitive functions [2, 71, 73]. These
changes do not affect the improvements in quality of
life which accompanies STN DBS [5, 74, 75] and in
fact in self-assessed questionnaire studies, a signifi-
cant improvement in cognition has been reported after
STN DBS [2]. Videnovic et al. in a meta-analysis of
47 studies, representing 1154 patients, and focusing
on the prevalence of adverse events (AEs) after DBS in
PD patients, reported that the most common procedure
related AEs were mental status / behavioural changes.
These were present in 18.4% of patients after STN
and in 9.3% after GPi DBS [76]. Within this category,
however, direct postoperative transient confusion was
the most frequent AE, affecting 10.2% patients with
STN and 6.2% with GPi DBS. Cognitive decline (1.3%
with STN, 0.9% with GPi DBS) was far less com-
mon [76]. Short- and long-term follow-up data have
however indicated postoperative decline on phonemic
and semantic verbal fluency [53, 77, 78] and a signif-
icant but slight decline in tasks of abstract reasoning,
episodic memory and executive function [66, 78, 79].
Marshall et al. [80] demonstrated a greater decline
on the cued phonemic/phonemic fluency and the un-
cued phonemic/semantic fluency tasks in STN DBS
patients compared to non DBS PD patients. They con-
cluded that these changes in alternating fluency were
not related to disease progression alone as STN DBS
patients demonstrated greater declines over time than
non DBS PD patients. Therefore the decline in ver-
bal fluency may be a result of an inability to switch
from one semantic or phonemic subcategory to another
during verbal fluency [81]. The significant negative
influence of STN DBS on verbal fluency was further
shown by a decline solely in phonemic verbal flu-
ency one year [82] and three years [83] in PD patients
after STN DBS in comparison to those treated medi-
cally, whilst the other cognitive domains did not show
significant change. Of note though, single case anal-
ysis highlighted that a subgroup comprising 15% of
STN DBS patients showed significantly more cog-
nitive decline 1 year after surgery compared to the
medically treated patients. The only differentiating fac-
tor in the STN DBS group, between the 15% who
showed cognitive deterioration and the 85% who did
not, was the fact that the former group had significantly
more severe motor PD symptoms [82]. In a large meta-
analysis of 28 cohort studies including 612 patients,
however, no factors underlying the reported changes
in verbal fluency could be detected. Specifically, the
changes were not related to patient age, disease dura-
tion, stimulation parameters or change in dopaminergic
dose after surgery [78]. Several theories have been
postulated to explain the possible changes in different
cognitive domains after STN DBS:
1. Surgical micro-lesioning effects on the cortical-
basal ganglionic circuits involved in word
retrieval processes are thought to be partly
responsible for direct post-surgical decline in ver-
bal fluency in PD patients and can be transient
[71, 83, 84].
2. The stimulation itself might cause decreased
activity of frontotemporal cortical areas as mea-
sured by regional cerebral blood flow in the left
cerebral hemisphere, resulting in the long term
decreased verbal fluency after STN DBS [85].
3. Current spread to non motor areas of the STN
may led to decline in cognitive function. To this
end, Frankemolle et al. [86] used a patient specific
computational model for stimulation program-
ming after STN DBS in advanced PD patients.
The use of this model-based stimulation in com-
parison to a clinically determined stimulation
resulted in less cognitive AEs [86].
4. The postoperative reduction of DRT might also
play a part as changes in the level of dopamine
stimulation affect performance of PD patients
in frontal assessments with influence on differ-
ent cognitive domains including verbal fluency
[61, 87].
In conclusion, STN DBS is a safe procedure with
respect to cognitive morbidity over short- and long-
term follow-up in carefully selected patients [65, 66,
83, 88]. Table 2 provides an overview of the effect of
DBS at the two main PD targets of STN and GPi on
different cognitive domains. The evidence is also now
emerging that DBS of new targets, with the primary
aim of modification of cognitive functions in PD, may
also be possible. Thus improvement in cognition and
apraxia after DBS of the nucleus basalis of Meynert has
been reported in one PD patient with dementia [89, 90].
There are only few studies focusing on the effect of
STN DBS on autonomic dysfunction. Furthermore it
is difficult to distinguish between the direct effect of the
stimulation and the indirect effects, e.g. an improve-
ment in the mobility or the reduction of DRT with
disappearance of side effects.
Halim et al. [103] reported on a small case series
of a marked improvement of sweating and/or blad-
der and bowel function after STN DBS in early-onset
PD patients. In contrast, in a series of 34 PD patients,
assessed by the NMSS, there was no change in the fre-
quency or severity of excessive sweating in DBS “on”
and “off” states [23]. Consistent improvement in blad-
 L. Klingelhoefer et al. / An Update of the Impact of Deep Brain Stimulation on Non Motor Symptoms in Parkinson’s Disease 295

Table 2
Effect of subthalamic nucleus (STN) and internal globus pallidus (GPi) deep brain stimulation (DBS) on different cognitive domains of patients
with Parkinson’s disease (PD): - impairment; 0 no effect; + improvement, (D) secondary to drug reduction, (S) due to direct effect of stimulation,
{} rarely. References in square brackets
Cognitive domains Subthalamic nucleus Internal globus pallidus
General Intellect 0 or +(D) [2, 3, 73, 91–94] 0 [91, 94]
Memory Functions 0 or +(D)/(S) [5, 19, 50, 53, 65, 73, 91, 95, 96] 0 [5, 19, 91, 95, 97]
Language Functions 0 or – [50, 73, 91, 95, 97, 98] 0 or –(S) [91, 95, 97]
Visuospatial / Perceptual Functions 0 {or –} [50, 73, 75, 95, 97, 99] 0 [95, 97]
Executive Functions: Verbal fluency {0} or –(D)/(S) [5, 19, 50, 53, 65, 66, 73, 75, 78, 91, 92, 95–98, 100–102] 0 or –(S) [5, 19, 91, 95, 97]
Attention 0 or +(D) [50, 91, 95–97] 0 [91, 95, 97]

der and bowel function in DBS “on” state has been
reported one year after STN DBS [22, 23].
A positive direct effect of STN stimulation on blad-
der state has been observed. This is suggested by
a significant interaction between bladder state, using
urodynamic measures, and increased cerebral blood
flow (rCBF) in lateral frontal cortex measured by PET
with STN DBS. The improvement in bladder dysfunc-
tion after STN DBS is thought to be partly due to
a delay in the first desire to void and partly due to
an increase in bladder capacity [104]. Furthermore,
it has been shown that STN DBS leads to significant
enhancement of afferent urinary bladder information
processing in brain areas involved in bladder control
[105]. A subjective improvement in symptoms of over-
active bladder, assessed by a questionnaire, has been
reported by PD patients after STN DBS [21], even
when urodynamic parameters did not change signifi-
cantly before and after STN DBS, and with and without
the stimulation on [106].
Arai et al. [107] reported on the effectiveness of STN
DBS in improving gastrointestinal dysfunction in PD
patients whereas levodopa/decarboxylase inhibitor did
not influence gastric emptying.
STN DBS appears to have a positive effect on
cardiovascular dysautonomia by increasing peripheral
vasoconstriction and baroreflex sensitivity, thus sta-
bilising the blood pressure and improving postural
hypotension in PD patients [108]. Sumi et al. [109]
showed that the vagal component in cardiac auto-
nomic dysfunction improved after STN DBS in a study
of 28 PD patients. There were however no statisti-
cally significant differences in the vagally mediated
arterial-cardiac baroreflex function between the on-
and off-stimulation states. Liu et al. [110] further
suggested an effect of STN DBS on sympathetic regu-
lation after showing significantly increased variability
in heart rate in stimulation “on” condition.
Sleep problems and fatigue are one of the most
frequent NMS in PD patients [111]. Studies using
polysomnography showed an objective improvement
in sleep through an increase in sleep efficiency and
quality, increase in continuous sleep time, decrease
in the arousal index, decrease in nocturnal and early
morning dystonia and improvement of nocturnal
mobility after STN DBS [112]. Evaluation by NMSS,
NMSQuest and PSQI showed subjective improvement
in sleep in PD patients after STN DBS [113, 114]. The
positive effects of DBS on sleep are also noted on long-
term follow up [115]. The stimulation seems to have
a direct effect on sleep regulatory centres by increas-
ing slow wave sleep and rapid eye movement (REM)
sleep but not changing the relative percentage of sleep
stages [116]. Furthermore other effects of DBS such
as reduction in DRT or improvement of mobility and
daytime somnolence may indirectly have additional
benefits with respect to sleep [115, 117, 118]. Wolz et
al. [23] reported on immediate positive effect of STN
DBS on fatigue. REM sleep behaviour disorder, on the
other hand, could not be shown to improve after DBS
[112, 119].
Pain and sensory symptoms are frequent NMS in
PD patients and are often associated with PD motor
symptoms [120]. Therefore they can occur during “on”
and “off” motor states, are often associated with dys-
tonia and can also fluctuate during the day. In general it
seems that STN DBS improves pain and sensory symp-
toms, especially those associated with “off” conditions
and dystonia in PD [121]. This beneficial effect of the
DBS persisted on a long term follow-up of 24 months,
even when new, mainly musculoskeletal pain, devel-
oped [122]. Objectively, sensitivity to pain, as assessed
by quantitative sensory testing (QST), was not altered
by STN DBS suggesting against direct modulation of
central pain processing by DBS [120].
CONCLUSION
Available evidence indicates that STN DBS is a
safe procedure with regard to most NMS based on
long-term follow-up of carefully selected patients [65].
The number and the severity of most NMS decrease
296 L. Klingelhoefer et al. / An Update of the Impact of Deep Brain Stimulation on Non Motor Symptoms in Parkinson’s Disease
significantly after STN DBS [23]. This is associated
with a significant improvement in quality of life of PD
patients. Worsening of NMS, especially in the neu-
ropsychological and psychiatric domains, may occur
and is most often seen transiently in the immediate
post-operative period after STN DBS, possibly related
to the changes in DRT or the surgery itself. Fur-
ther work, specifically focused on NMS is, however,
required in order to fully understand the mechanisms
and impact of STN DBS on these symptoms. This is
important as it will inform and rationalise patients’ and
physicians’ understanding and expectations of changes
in NMS post DBS. It may also, in time, allow clear
definition of NMS, not as an add-on, but a primary
indication for DBS.
REFERENCES
[1] Benabid AL, Pollak P, Gross C, Hoffmann D, Benazzouz
A, Gao DM, Laurent A, Gentil M, & Perret J (1994) Acute
and long-term effects of subthalamic nucleus stimulation
in Parkinson’s disease. Stereotact Funct Neurosurg, 62,
76-84.
[2] Schuepbach WM, Rau J, Knudsen K, Volkmann J, Krack
P, Timmermann L, Halbig TD, Hesekamp H, Navarro SM,
Meier N, Falk D, Mehdorn M, Paschen S, Maarouf M,
Barbe MT, Fink GR, Kupsch A, Gruber D, Schneider GH,
Seigneuret E, Kistner A, Chaynes P, Ory-Magne F, Brefel
Courbon C, Vesper J, Schnitzler A, Wojtecki L, Houeto JL,
Bataille B, Maltete D, Damier P, Raoul S, Sixel-Doering F,
Hellwig D, Gharabaghi A, Kruger R, Pinsker MO, Amtage
F, Regis JM, Witjas T, Thobois S, Mertens P, Kloss M,
Hartmann A, Oertel WH, Post B, Speelman H, Agid Y,
Schade-Brittinger C, & Deuschl G (2013) Neurostimulation
for Parkinson’s disease with early motor complications. N
Engl J Med, 368, 610-622.
[3] Deuschl G, Schade-Brittinger C, Krack P, Volkmann J,
Schafer H, Botzel K, Daniels C, Deutschlander A, Dill-
mann U, Eisner W, Gruber D, Hamel W, Herzog J, Hilker R,
Klebe S, Kloss M, Koy J, Krause M, Kupsch A, Lorenz D,
Lorenzl S, Mehdorn HM, Moringlane JR, Oertel W, Pinsker
MO, Reichmann H, Reuss A, Schneider GH, Schnitzler A,
Steude U, Sturm V, Timmermann L, Tronnier V, Trotten-
berg T, Wojtecki L, Wolf E, Poewe W, & Voges J (2006) A
randomized trial of deep-brain stimulation for Parkinson’s
disease. N Engl J Med, 355, 896-908.
[4] Rodriguez-Oroz MC, Obeso JA, Lang AE, Houeto JL, Pol-
lak P, Rehncrona S, Kulisevsky J, Albanese A, Volkmann J,
Hariz MI, Quinn NP, Speelman JD, Guridi J, Zamarbide I,
Gironell A, Molet J, Pascual-Sedano B, Pidoux B, Bonnet
AM, Agid Y, Xie J, Benabid AL, Lozano AM, Saint-Cyr J,
Romito L, Contarino MF, Scerrati M, Fraix V, & Van Bler-
com N (2005) Bilateral deep brain stimulation in Parkinson’s
disease: A multicentre study with 4 years follow-up. Brain,
128, 2240-2249.
[5] Follett KA, Weaver FM, Stern M, Hur K, Harris CL, Luo
P, Marks WJ, Jr., Rothlind J, Sagher O, Moy C, Pahwa R,
Burchiel K, Hogarth P, Lai EC, Duda JE, Holloway K, Samii
A, Horn S, Bronstein JM, Stoner G, Starr PA, Simpson R,
Baltuch G, De Salles A, Huang GD, Reda DJ (2010) Pallidal
versus subthalamic deep-brain stimulation for Parkinson’s
disease. N Engl J Med, 362, 2077-2091.
[6] Hariz MI, Krack P, Alesch F, Augustinsson LE, Bosch A,
Ekberg R, Johansson F, Johnels B, Meyerson BA, N’Guyen
JP, Pinter M, Pollak P, von Raison F, Rehncrona S, Speelman
JD, Sydow O, & Benabid AL (2008) Multicentre Euro-
pean study of thalamic stimulation for parkinsonian tremor:
A 6 year follow-up. J Neurol Neurosurg Psychiatry, 79,
694-699.
[7] Ashkan K, Wallace B, Bell BA, & Benabid AL (2004) Deep
brain stimulation of the subthalamic nucleus in Parkinson’s
disease 1993-2003: Where are we 10 years on? Br J Neuro-
surg, 18, 19-34.
[8] Krack P, Batir A, Van Blercom N, Chabardes S, Fraix V,
Ardouin C, Koudsie A, Limousin PD, Benazzouz A, LeBas
JF, Benabid AL, & Pollak P (2003) Five-year follow-up of
bilateral stimulation of the subthalamic nucleus in advanced
Parkinson’s disease. N Engl J Med, 349, 1925-1934.
[9] Williams A, Gill S, Varma T, Jenkinson C, Quinn N, Mitchell
R, Scott R, Ives N, Rick C, Daniels J, Patel S, & Wheatley
K (2010) Deep brain stimulation plus best medical therapy
versus best medical therapy alone for advanced Parkinson’s
disease (PD SURG trial): A randomised, open-label trial.
Lancet Neurol, 9, 581-591.
[10] Kuopio AM, Marttila RJ, Helenius H, Toivonen M, & Rinne
UK (2000) The quality of life in Parkinson’s disease. Mov
Disord, 15, 216-223.
[11] Kleiner-Fisman G, Herzog J, Fisman DN, Tamma F, Lyons
KE, Pahwa R, Lang AE, & Deuschl G (2006) Subthalamic
nucleus deep brain stimulation: Summary and meta-analysis
of outcomes. Mov Disord, 21(Suppl 14), S290-304.
[12] Chaudhuri KR, & Schapira AH (2009) Non-motor
symptoms of Parkinson’s disease: Dopaminergic patho-
physiology and treatment. Lancet Neurol, 8, 464-474.
[13] Chaudhuri KR, Martinez-Martin P, Schapira AH, Stocchi F,
Sethi K, Odin P, Brown RG, Koller W, Barone P, MacPhee G,
Kelly L, Rabey M, MacMahon D, Thomas S, Ondo W, Rye
D, Forbes A, Tluk S, Dhawan V, Bowron A, Williams AJ,
& Olanow CW (2006) International multicenter pilot study
of the first comprehensive self-completed nonmotor symp-
toms questionnaire for Parkinson’s disease: The NMSQuest
study. Mov Disord, 21, 916-923.
[14] Chaudhuri KR, Martinez-Martin P, Brown RG, Sethi K,
Stocchi F, Odin P, Ondo W, Abe K, Macphee G, Macmahon
D, Barone P, Rabey M, Forbes A, Breen K, Tluk S, Naidu
Y, Olanow W, Williams AJ, Thomas S, Rye D, Tsuboi Y,
Hand A, & Schapira AH (2007) The metric properties of
a novel non-motor symptoms scale for Parkinson’s disease:
Results from an international pilot study. Mov Disord, 22,
1901-1911.
[15] Martinez-Martin P, Rodriguez-Blazquez C, Kurtis MM, &
Chaudhuri KR (2011) The impact of non-motor symptoms
on health-related quality of life of patients with Parkinson’s
disease. Mov Disord, 26, 399-406.
[16] Leonardi M, Raggi A, Pagani M, Carella F, Soliveri P,
Albanese A, & Romito L (2012) Relationships between
disability, quality of life and prevalence of nonmotor symp-
toms in Parkinson’s disease. Parkinsonism Relat Disord, 18,
35-39.
[17] Muller B, Assmus J, Herlofson K, Larsen JP, & Tysnes OB
(2013) Importance of motor vs. non-motor symptoms for
health-related quality of life in early Parkinson’s disease.
Parkinsonism Relat Disord, 19, 1027-1032.
[18] Hinnell C, Hurt CS, Landau S, Brown RG, & Samuel M
(2012) Nonmotor versus motor symptoms: How much do
 L. Klingelhoefer et al. / An Update of the Impact of Deep Brain Stimulation on Non Motor Symptoms in Parkinson’s Disease
they matter to health status in Parkinson’s disease? Mov
Disord, 27, 236-241.
[19] Fasano A, Daniele A, & Albanese A (2012) Treatment of
motor and non-motor features of Parkinson’s disease with
deep brain stimulation. Lancet Neurol, 11, 429-442.
[20] Lim SY, O’Sullivan SS, Kotschet K, Gallagher DA, Lacey
C, Lawrence AD, Lees AJ, O’Sullivan DJ, Peppard RF,
Rodrigues JP, Schrag A, Silberstein P, Tisch S, & Evans AH
(2009) Dopamine dysregulation syndrome, impulse control
disorders and punding after deep brain stimulation surgery
for Parkinson’s disease. J Clin Neurosci, 16, 1148-1152.
[21] Reich MM, Chaudhuri KR, Ashkan K, Hulse N, Costello
A, Moriarty J, & Samuel M (2011) Changes in the non-
motor symptom scale in Parkinson’s disease after deep brain
stimulation. Basal Ganglia, 1, 131-133.
[22] Nazzaro JM, Pahwa R, & Lyons KE (2011) The impact of
bilateral subthalamic stimulation on non-motor symptoms
of Parkinson’s disease. Parkinsonism Relat Disord, 17, 606-
609.
[23] Wolz M, Hauschild J, Fauser M, Klingelhofer L, Reich-
mann H, & Storch A (2012) Immediate effects of deep brain
stimulation of the subthalamic nucleus on nonmotor symp-
toms in Parkinson’s disease. Parkinsonism Relat Disord, 18,
994-997.
[24] Kim YE, Kim HJ, Lee JY, Yun JY, Kim JY, SH, & Jeon P,
BS (2013) Impulse control and related behaviors after bilat-
eral subthalamic stimulation in patients with Parkinson’s
disease. J Clin Neurosci, 20, 964-969.
[25] Frank MJ, Samanta J, Moustafa AA, & Sherman SJ (2007)
Hold your horses: Impulsivity, deep brain stimulation, and
medication in parkinsonism. Science, 318, 1309-1312.
[26] Volkmann J, Daniels C, & Witt K (2010) Neuropsychiatric
effects of subthalamic neurostimulation in Parkinson dis-
ease. Nat Rev Neurol, 6, 487-498.
[27] Voon V, Krack P, Lang AE, Lozano AM, Dujardin K, Schup-
bach M, D’Ambrosia J, Thobois S, Tamma F, Herzog J,
Speelman JD, Samanta J, Kubu C, Rossignol H, Poon YY,
Saint-Cyr JA, Ardouin C, & Moro E (2008) A multicentre
study on suicide outcomes following subthalamic stimula-
tion for Parkinson’s disease. Brain, 131, 2720-2728.
[28] Weintraub D, Duda JE, Carlson K, Luo P, Sagher O, Stern M,
Follett KA, Reda D, & Weaver FM (2013) Suicide ideation
and behaviours after STN and GPi DBS surgery for Parkin-
son’s disease: Results from a randomised, controlled trial. J
Neurol Neurosurg Psychiatry, 84, 1113-1118.
[29] Ardouin C, Voon V, Worbe Y, Abouazar N, Czernecki V,
Hosseini H, Pelissolo A, Moro E, Lhommee E, Lang AE,
Agid Y, Benabid AL, Pollak P, Mallet L, & Krack P (2006)
Pathological gambling in Parkinson’s disease improves on
chronic subthalamic nucleus stimulation. Mov Disord, 21,
1941-1946.
[30] Witjas T, Baunez C, Henry JM, Delfini M, Regis J, Cherif
AA, Peragut JC, & Azulay JP (2005) Addiction in Parkin-
son’s disease: Impact of subthalamic nucleus deep brain
stimulation. Mov Disord, 20, 1052-1055.
[31] Shotbolt P, Moriarty J, Costello A, Jha A, David A, Ashkan
K, & Samuel M (2012) Relationships between deep brain
stimulation and impulse control disorders in Parkinson’s dis-
ease, with a literature review. Parkinsonism Relat Disord, 18,
10-16.
[32] Lhommee E, Klinger H, Thobois S, Schmitt E, Ardouin
C, Bichon A, Kistner A, Fraix V, Xie J, Aya Kombo M,
Chabardes S, Seigneuret E, Benabid AL, Mertens P, Polo G,
Carnicella S, Quesada JL, Bosson JL, Broussolle E, Pollak
P, & Krack P (2012) Subthalamic stimulation in Parkinson’s
297
disease: Restoring the balance of motivated behaviours.
Brain, 135, 1463-1477.
[33] Thobois S, Lhommee E, Klinger H, Ardouin C, Schmitt E,
Bichon A, Kistner A, Castrioto A, Xie J, Fraix V, Pelissier
P, Chabardes S, Mertens P, Quesada JL, Bosson JL, Pol-
lak P, Broussolle E, & Krack P (2013) Parkinsonian apathy
responds to dopaminergic stimulation of D2/D3 receptors
with piribedil. Brain, 136, 1568-1577.
[34] Weintraub D, & Potenza MN (2006) Impulse control disor-
ders in Parkinson’s disease. Curr Neurol Neurosci Rep, 6,
302-306.
[35] Demetriades P, Rickards H, & Cavanna AE (2011) Impulse
control disorders following deep brain stimulation of
the subthalamic nucleus in Parkinson’s disease: Clinical
aspects. Parkinsons Dis, 2011, 658415.
[36] Mallet L, Schupbach M, N’Diaye K, Remy P, Bardinet E,
Czernecki V, Welter ML, Pelissolo A, Ruberg M, Agid Y,
& Yelnik J (2007) Stimulation of subterritories of the sub-
thalamic nucleus reveals its role in the integration of the
emotional and motor aspects of behavior. Proc Natl Acad
Sci U S A, 104, 10661-10666.
[37] Temel Y, Kessels A, Tan S, Topdag A, Boon P, &
Visser-Vandewalle V (2006) Behavioural changes after
bilateral subthalamic stimulation in advanced Parkinson dis-
ease: A systematic review. Parkinsonism Relat Disord, 12,
265-272.
[38] Sensi M, Eleopra R, Cavallo MA, Sette E, Milani P, Qua-
trale R, Capone JG, Tugnoli V, Tola MR, Granieri E, & Data
PG (2004) Explosive-aggressive behavior related to bilat-
eral subthalamic stimulation. Parkinsonism Relat Disord,
10, 247-251.
[39] Smeding HM, Goudriaan AE, Foncke EM, Schuurman PR,
Speelman JD, & Schmand B (2007) Pathological gambling
after bilateral subthalamic nucleus stimulation in Parkinson
disease. J Neurol Neurosurg Psychiatry, 78, 517-519.
[40] Cavanagh JF, Wiecki TV, Cohen MX, Figueroa CM,
Samanta J, Sherman SJ, & Frank MJ (2011) Subthalamic
nucleus stimulation reverses mediofrontal influence over
decision threshold. Nat Neurosci, 14, 1462-1467.
[41] Rodriguez-Oroz MC, Lopez-Azcarate J, Garcia-Garcia D,
Alegre M, Toledo J, Valencia M, Guridi J, Artieda J, &
Obeso JA (2011) Involvement of the subthalamic nucleus
in impulse control disorders associated with Parkinson’s
disease. Brain, 134, 36-49.
[42] Weintraub D, Koester J, Potenza MN, Siderowf AD, Stacy
M, Voon V, Whetteckey J, Wunderlich GR, & Lang AE
(2010) Impulse control disorders in Parkinson disease: A
cross-sectional study of 3090 patients. Arch Neurol, 67, 589-
595.
[43] Halbig TD, Tse W, Frisina PG, Baker BR, Hollander E,
Shapiro H, Tagliati M, Koller WC, & Olanow CW (2009)
Subthalamic deep brain stimulation and impulse control in
Parkinson’s disease. Eur J Neurol, 16, 493-497.
[44] Bandini F, Primavera A, Pizzorno M, & Cocito L (2007)
Using STN DBS and medication reduction as a strategy to
treat pathological gambling in Parkinson’s disease. Parkin-
sonism Relat Disord, 13, 369-371.
[45] Houeto JL, Mesnage V, Mallet L, Pillon B, Gargiulo M, du
Moncel ST, Bonnet AM, Pidoux B, Dormont D, Cornu P, &
Agid Y (2002) Behavioural disorders, Parkinson’s disease
and subthalamic stimulation. J Neurol Neurosurg Psychia-
try, 72, 701-707.
[46] Krause M, Fogel W, Heck A, Hacke W, Bonsanto M,
Trenkwalder C, & Tronnier V (2001) Deep brain stimula-
tion for the treatment of Parkinson’s disease: Subthalamic
298 L. Klingelhoefer et al. / An Update of the Impact of Deep Brain Stimulation on Non Motor Symptoms in Parkinson’s Disease
nucleus versus globus pallidus internus. J Neurol Neurosurg
Psychiatry, 70, 464-470.
[47] Romito LM, Scerrati M, Contarino MF, Bentivoglio AR,
Tonali P, & Albanese A (2002) Long-term follow up of
subthalamic nucleus stimulation in Parkinson’s disease.
Neurology, 58, 1546-1550.
[48] Romito LM, Raja M, Daniele A, Contarino MF, Bentivoglio
AR, Barbier A, Scerrati M, & Albanese A (2002) Transient
mania with hypersexuality after surgery for high frequency
stimulation of the subthalamic nucleus in Parkinson’s dis-
ease. Mov Disord, 17, 1371-1374.
[49] Kleiner-Fisman G, Fisman DN, Sime E, Saint-Cyr JA,
Lozano AM, & Lang AE (2003) Long-term follow up of
bilateral deep brain stimulation of the subthalamic nucleus
in patients with advanced Parkinson disease. J Neurosurg,
99, 489-495.
[50] Funkiewiez A, Ardouin C, Caputo E, Krack P, Fraix V,
Klinger H, Chabardes S, Foote K, Benabid AL, & Pollak
P (2004) Long term effects of bilateral subthalamic nucleus
stimulation on cognitive function, mood, and behaviour in
Parkinson’s disease. J Neurol Neurosurg Psychiatry, 75,
834-839.
[51] Krause M, Fogel W, Mayer P, Kloss M, & Tronnier V (2004)
Chronic inhibition of the subthalamic nucleus in Parkinson’s
disease. J Neurol Sci, 219, 119-124.
[52] Machado AG, Hiremath GK, Salazar F, & Rezai AR (2005)
Fracture of subthalamic nucleus deep brain stimulation hard-
ware as a result of compulsive manipulation: Case report.
Neurosurgery, 57, E1318; discussion E1318.
[53] Contarino MF, Daniele A, Sibilia AH, Romito LM, Ben-
tivoglio AR, Gainotti G, & Albanese A (2007) Cognitive
outcome 5 years after bilateral chronic stimulation of subtha-
lamic nucleus in patients with Parkinson’s disease. J Neurol
Neurosurg Psychiatry, 78, 248-252.
[54] Doshi P, & Bhargava P (2008) Hypersexuality following
subthalamic nucleus stimulation for Parkinson’s disease.
Neurol India, 56, 474-476.
[55] Thobois S, Ardouin C, Lhommee E, Klinger H, Lagrange
C, Xie J, Fraix V, Coelho Braga MC, Hassani R, Kistner
A, Juphard A, Seigneuret E, Chabardes S, Mertens P, Polo
G, Reilhac A, Costes N, LeBars D, Savasta M, Tremblay L,
Quesada JL, Bosson JL, Benabid AL, Broussolle E, Pollak
P, & Krack P (2010) Non-motor dopamine withdrawal syn-
drome after surgery for Parkinson’s disease: Predictors and
underlying mesolimbic denervation. Brain, 133, 1111-1127.
[56] Zahodne LB, Susatia F, Bowers D, Ong TL, Jacobson CEt,
Okun MS, Rodriguez RL, Malaty IA, Foote KD, & Fer-
nandez HH (2011) Binge eating in Parkinson’s disease:
Prevalence, correlates and the contribution of deep brain
stimulation. J Neuropsychiatry Clin Neurosci, 23, 56-62.
[57] Moum SJ, Price CC, Limotai N, Oyama G, Ward H, Jacob-
son C, Foote KD, & Okun MS (2012) Effects of STN and
GPi deep brain stimulation on impulse control disorders and
dopamine dysregulation syndrome. PLoS One, 7, e29768.
[58] Eusebio A, Witjas T, Cohen J, Fluchere F, Jouve E, Regis
J, & Azulay JP (2013) Subthalamic nucleus stimulation and
compulsive use of dopaminergic medication in Parkinson’s
disease. J Neurol Neurosurg Psychiatry, 84, 868-874.
[59] Umemura A, Oka Y, Okita K, Matsukawa N, & Yamada
K (2011) Subthalamic nucleus stimulation for Parkinson
disease with severe medication-induced hallucinations or
delusions. J Neurosurg, 114, 1701-1705.
[60] Antonini A, Isaias IU, Rodolfi G, Landi A, Natuzzi F, Siri
C, & Pezzoli G (2011) A 5-year prospective assessment of
advanced Parkinson disease patients treated with subcuta-
neous apomorphine infusion or deep brain stimulation. J
Neurol, 258, 579-585.
[61] Czernecki V, Schupbach M, Yaici S, Levy R, Bardinet E,
Yelnik J, Dubois B, & Agid Y (2008) Apathy following
subthalamic stimulation in Parkinson disease: A dopamine
responsive symptom. Mov Disord, 23, 964-969.
[62] Kirsch-Darrow L, Zahodne LB, Marsiske M, Okun MS,
Foote KD, & Bowers D (2011) The trajectory of apathy after
deep brain stimulation: From pre-surgery to 6 months post-
surgery in Parkinson’s disease. Parkinsonism Relat Disord,
17, 182-188.
[63] Le Jeune F, Drapier D, Bourguignon A, Peron J, Mesbah
H, Drapier S, Sauleau P, Haegelen C, Travers D, Garin
E, Malbert CH, Millet B, & Verin M (2009) Subthalamic
nucleus stimulation in Parkinson disease induces apathy: A
PET study. Neurology, 73, 1746-1751.
[64] Denheyer M, Kiss ZH, & Haffenden AM (2009) Behavioral
effects of subthalamic deep brain stimulation in Parkinson’s
disease. Neuropsychologia, 47, 3203-3209.
[65] Witt K, Daniels C, Reiff J, Krack P, Volkmann J, Pinsker
MO, Krause M, Tronnier V, Kloss M, Schnitzler A, Wojtecki
L, Botzel K, Danek A, Hilker R, Sturm V, Kupsch A, Karner
E, & Deuschl G (2008) Neuropsychological and psychiatric
changes after deep brain stimulation for Parkinson’s dis-
ease: A randomised, multicentre study. Lancet Neurol, 7,
605-614.
[66] Fasano A, Romito LM, Daniele A, Piano C, Zinno M, Ben-
tivoglio AR, & Albanese A (2010) Motor and cognitive
outcome in patients with Parkinson’s disease 8 years after
subthalamic implants. Brain, 133, 2664-2676.
[67] Pinsker M, Amtage F, Berger M, Nikkhah G, & van Elst
LT (2013) Psychiatric side-effects of bilateral deep brain
stimulation for movement disorders. Acta Neurochir Suppl,
117, 47-51.
[68] Raucher-Chene D, Charrel CL, de Maindreville AD, &
Limosin F (2008) Manic episode with psychotic symptoms
in a patient with Parkinson’s disease treated by subthalamic
nucleus stimulation: Improvement on switching the target.
J Neurol Sci, 273, 116-117.
[69] Ulla M, Thobois S, Llorca PM, Derost P, Lemaire JJ,
Chereau-Boudet I, de Chazeron I, Schmitt A, Ballanger B,
Broussolle E, & Durif F (2011) Contact dependent repro-
ducible hypomania induced by deep brain stimulation in
Parkinson’s disease: Clinical, anatomical and functional
imaging study. J Neurol Neurosurg Psychiatry, 82, 607-614.
[70] Bejjani BP, Damier P, Arnulf I, Thivard L, Bonnet AM,
Dormont D, Cornu P, Pidoux B, Samson Y, & Agid Y (1999)
Transient acute depression induced by high-frequency deep-
brain stimulation. N Engl J Med, 340, 1476-1480.
[71] Okun MS, Fernandez HH, Wu SS, Kirsch-Darrow L, Bow-
ers D, Bova F, Suelter M, Jacobson CEt, Wang X, Gordon
CW, Jr., Zeilman P, Romrell J, Martin P, Ward H, Rodriguez
RL, & Foote KD (2009) Cognition and mood in Parkin-
son’s disease in subthalamic nucleus versus globus pallidus
interna deep brain stimulation: The COMPARE trial. Ann
Neurol, 65, 586-595.
[72] Pariwatcharakul P, Clough C, Shotbolt P, Morris R, Hulse
N, Costello A, Samuel M, & Ashkan K (2013) Pathological
crying after subthalamic nucleus stimulation. Mov Disord,
28, 1348-1349.
[73] Yagüez L, Costello A, Moriarty J, Hulse N, Selway R,
Clough C, Samuel M, & Ashkan K (2014) Cognitive pre-
dictors of cognitive change following bilateral subthalamic
nucleus deep brain stimulation in Parkinson’s disease. J Clin
Neurosci, 21, 445-450.
 L. Klingelhoefer et al. / An Update of the Impact of Deep Brain Stimulation on Non Motor Symptoms in Parkinson’s Disease
[74] Weaver FM, Follett K, Stern M, Hur K, Harris C, Marks
WJ, Jr., Rothlind J, Sagher O, Reda D, Moy CS, Pahwa R,
Burchiel K, Hogarth P, Lai EC, Duda JE, Holloway K, Samii
A, Horn S, Bronstein J, Stoner G, Heemskerk J, & Huang
GD (2009) Bilateral deep brain stimulation vs best medi-
cal therapy for patients with advanced Parkinson disease: A
randomized controlled trial. JAMA, 301, 63-73.
[75] Alegret M, Junque C, Valldeoriola F, Vendrell P, Pilleri M,
Rumia J, & Tolosa E (2001) Effects of bilateral subthalamic
stimulation on cognitive function in Parkinson disease. Arch
Neurol, 58, 1223-1227.
[76] Videnovic A, & Metman LV (2008) Deep brain stimulation
for Parkinson’s disease: Prevalence of adverse events and
need for standardized reporting. Mov Disord, 23, 343-349.
[77] Daniele A, Albanese A, Contarino MF, Zinzi P, Barbier A,
Gasparini F, Romito LM, Bentivoglio AR, & Scerrati M
(2003) Cognitive and behavioural effects of chronic stimula-
tion of the subthalamic nucleus in patients with Parkinson’s
disease. J Neurol Neurosurg Psychiatry, 74, 175-182.
[78] Parsons TD, Rogers SA, Braaten AJ, Woods SP, & Troster
AI (2006) Cognitive sequelae of subthalamic nucleus deep
brain stimulation in Parkinson’s disease: A meta-analysis.
Lancet Neurol, 5, 578-588.
[79] Costello A, Al Khamees H, Moriarty J, Hulse N, Malik I,
Selway R, Clough C, Ashkan K, & Samuel M (2011) Non-
amnestic mild cognitive impairment is a prominent aspect
in Parkinson’s disease patients being considered for deep
brain stimulation. Basal Ganglia, 1, 213-220.
[80] Marshall DF, Strutt AM, Williams AE, Simpson RK,
Jankovic J, & York MK (2012) Alternating verbal fluency
performance following bilateral subthalamic nucleus deep
brain stimulation for Parkinson’s disease. Eur J Neurol, 19,
1525-1531.
[81] De Gaspari D, Siri C, Di Gioia M, Antonini A, Isella V,
Pizzolato A, Landi A, Vergani F, Gaini SM, Appollonio
IM, & Pezzoli G (2006) Clinical correlates and cognitive
underpinnings of verbal fluency impairment after chronic
subthalamic stimulation in Parkinson’s disease. Parkinson-
ism Relat Disord, 12, 289-295.
[82] Castelli L, Rizzi L, Zibetti M, Angrisano S, Lanotte M, &
Lopiano L (2010) Neuropsychological changes 1-year after
subthalamic DBS in PD patients: A prospective controlled
study. Parkinsonism Relat Disord, 16, 115-118.
[83] Zangaglia R, Pacchetti C, Pasotti C, Mancini F, Servello
D, Sinforiani E, Cristina S, Sassi M, & Nappi G (2009)
Deep brain stimulation and cognitive functions in Parkin-
son’s disease: A three-year controlled study. Mov Disord,
24, 1621-1628.
[84] Obeso I, Casabona E, Bringas ML, Alvarez L, & Jahan-
shahi M (2012) Sematic and phonemic verbal fluency in
Parkinsonś disease: Influence of clinical and demographic
variables. Behav Neurol, 25, 111-118.
[85] Schroeder U, Kuehler A, Lange KW, Haslinger B, Tronnier
VM, Krause M, Pfister R, Boecker H, & Ceballos-Baumann
AO (2003) Subthalamic nucleus stimulation affects a
frontotemporal network: A PET study. Ann Neurol, 54,
445-450.
[86] Frankemolle AM, Wu J, Noecker AM, Voelcker-Rehage
C, Ho JC, Vitek JL, McIntyre CC, & Alberts JL (2010)
Reversing cognitive-motor impairments in Parkinson’s dis-
ease patients using a computational modelling approach to
deep brain stimulation programming. Brain, 133, 746-761.
[87] Gotham AM, Brown RG, & Marsden CD (1988) ’Frontal’
cognitive function in patients with Parkinson’s disease ‘on’
and ‘off’ levodopa. Brain, 111(Pt 2), 299-321.
299
[88] Wu B, Han L, Sun BM, Hu XW, & Wang XP (2014) Influ-
ence of deep brain stimulation of the subthalamic nucleus
on cognitive function in patients with Parkinson’s disease.
Neurosci Bull, 30, 153-161.
[89] Freund HJ, Kuhn J, Lenartz D, Mai JK, Schnell T,
Klosterkoetter J, & Sturm V (2009) Cognitive functions in a
patient with Parkinson-dementia syndrome undergoing deep
brain stimulation. Arch Neurol, 66, 781-785.
[90] Barnikol TT, Pawelczyk NB, Barnikol UB, Kuhn J, Lenartz
D, Sturm V, Tass PA, & Freund HJ (2010) Changes in apraxia
after deep brain stimulation of the nucleus basalis Meynert
in a patient with Parkinson dementia syndrome. Mov Disord,
25, 1519-1520.
[91] Ardouin C, Pillon B, Peiffer E, Bejjani P, Limousin P,
Damier P, Arnulf I, Benabid AL, Agid Y, & Pollak P (1999)
Bilateral subthalamic or pallidal stimulation for Parkinson’s
disease affects neither memory nor executive functions: A
consecutive series of 62 patients. Ann Neurol, 46, 217-223.
[92] Williams AE, Arzola GM, Strutt AM, Simpson R, Jankovic
J, & York MK (2011) Cognitive outcome and reliable change
indices two years following bilateral subthalamic nucleus
deep brain stimulation. Parkinsonism Relat Disord, 17, 321-
327.
[93] Chou KL, Taylor JL, & Patil PG (2013) The MDS-UPDRS
tracks motor and non-motor improvement due to subtha-
lamic nucleus deep brain stimulation in Parkinson disease.
Parkinsonism Relat Disord, 19, 966-969.
[94] Odekerken VJ, van Laar T, Staal MJ, Mosch A, Hoffmann
CF, Nijssen PC, Beute GN, van Vugt JP, Lenders MW,
Contarino MF, Mink MS, Bour LJ, van den Munckhof P,
Schmand BA, de Haan RJ, Schuurman PR, & de Bie RM
(2013) Subthalamic nucleus versus globus pallidus bilat-
eral deep brain stimulation for advanced Parkinson’s disease
(NSTAPS study): A randomised controlled trial. Lancet
Neurol, 12, 37-44.
[95] Pillon B, Ardouin C, Damier P, Krack P, Houeto JL, Klinger
H, Bonnet AM, Pollak P, Benabid AL, & Agid Y (2000)
Neuropsychological changes between “off” and “on” STN
or GPi stimulation in Parkinson’s disease. Neurology, 55,
411-418.
[96] Perozzo P, Rizzone M, Bergamasco B, Castelli L, Lanotte
M, Tavella A, Torre E, & Lopiano L (2001) Deep brain stim-
ulation of the subthalamic nucleus in Parkinson’s disease:
Comparison of pre- and postoperative neuropsychological
evaluation. J Neurol Sci, 192, 9-15.
[97] Trepanier LL, Kumar R, Lozano AM, Lang AE, & Saint-Cyr
JA (2000) Neuropsychological outcome of GPi pallidotomy
and GPi or STN deep brain stimulation in Parkinson’s dis-
ease. Brain Cogn, 42, 324-347.
[98] Morrison CE, Borod JC, Perrine K, Beric A, Brin MF, Rezai
A, Kelly P, Sterio D, Germano I, Weisz D, & Olanow CW
(2004) Neuropsychological functioning following bilateral
subthalamic nucleus stimulation in Parkinson’s disease.
Arch Clin Neuropsychol, 19, 165-181.
[99] Smeding HM, Speelman JD, Huizenga HM, Schuurman
PR, & Schmand B (2011) Predictors of cognitive and psy-
chosocial outcome after STN DBS in Parkinson’s Disease.
J Neurol Neurosurg Psychiatry, 82, 754-760.
[100] Smeding HM, Speelman JD, Koning-Haanstra M, Schu-
urman PR, Nijssen P, van Laar T, & Schmand B (2006)
Neuropsychological effects of bilateral STN stimulation in
Parkinson disease: A controlled study. Neurology, 66, 1830-
1836.
[101] Dujardin K, Defebvre L, Krystkowiak P, Blond S, & Destee
A (2001) Influence of chronic bilateral stimulation of the
300 L. Klingelhoefer et al. / An Update of the Impact of Deep Brain Stimulation on Non Motor Symptoms in Parkinson’s Disease
subthalamic nucleus on cognitive function in Parkinson’s
disease. J Neurol, 248, 603-611.
[102] Higginson CI, Wheelock VL, Levine D, King DS, Pap-
pas CT, & Sigvardt KA (2009) The clinical significance
of neuropsychological changes following bilateral subthala-
mic nucleus deep brain stimulation for Parkinson’s disease.
J Clin Exp Neuropsychol, 31, 65-72.
[103] Halim A, Baumgartner L, & Binder DK (2011) Effect of
deep brain stimulation on autonomic dysfunction in patients
with Parkinson’s disease. J Clin Neurosci, 18, 804-806.
[104] Herzog J, Weiss PH, Assmus A, Wefer B, Seif C, Braun PM,
Herzog H, Volkmann J, Deuschl G, & Fink GR (2006) Sub-
thalamic stimulation modulates cortical control of urinary
bladder in Parkinson’s disease. Brain, 129, 3366-3375.
[105] Herzog J, Weiss PH, Assmus A, Wefer B, Seif C, Braun PM,
Pinsker MO, Herzog H, Volkmann J, Deuschl G, & Fink GR
(2008) Improved sensory gating of urinary bladder afferents
in Parkinson’s disease following subthalamic stimulation.
Brain, 131, 132-145.
[106] Winge K, Nielsen KK, Stimpel H, Lokkegaard A, Jensen
SR, & Werdelin L (2007) Lower urinary tract symptoms
and bladder control in advanced Parkinson’s disease: Effects
of deep brain stimulation in the subthalamic nucleus. Mov
Disord, 22, 220-225.
[107] Arai E, Arai M, Uchiyama T, Higuchi Y, Aoyagi K,
Yamanaka Y, Yamamoto T, Nagano O, Shiina A, Maruoka
D, Matsumura T, Nakagawa T, Katsuno T, Imazeki F, Saeki
N, Kuwabara S, & Yokosuka O (2012) Subthalamic deep
brain stimulation can improve gastric emptying in Parkin-
son’s disease. Brain, 135, 1478-1485.
[108] Stemper B, Beric A, Welsch G, Haendl T, Sterio D, & Hilz
MJ (2006) Deep brain stimulation improves orthostatic reg-
ulation of patients with Parkinson disease. Neurology, 67,
1781-1785.
[109] Sumi K, Katayama Y, Otaka T, Obuchi T, Kano T, Kobayashi
K, Oshima H, Fukaya C, Yamamoto T, Ogawa Y, & Iwasaki
K (2012) Effect of subthalamic nucleus deep brain stim-
ulation on the autonomic nervous system in Parkinson’s
disease patients assessed by spectral analyses of R-R interval
variability and blood pressure variability. Stereotact Funct
Neurosurg, 90, 248-254.
[110] Liu KD, Shan DE, Kuo TB, & Yang CC (2013) The effects
of bilateral stimulation of the subthalamic nucleus on heart
rate variability in patients with Parkinson’s disease. J Neurol,
260, 1714-1723.
[111] Gallagher DA, Lees AJ, & Schrag A (2010) What are the
most important nonmotor symptoms in patients with Parkin-
son’s disease and are we missing them? Mov Disord, 25,
2493-2500.
[112] Iranzo A, Valldeoriola F, Santamaria J, Tolosa E, & Rumia J
(2002) Sleep symptoms and polysomnographic architecture
in advanced Parkinson’s disease after chronic bilateral sub-
thalamic stimulation. J Neurol Neurosurg Psychiatry, 72,
661-664.
[113] Hwynn N, Ul Haq I, Malaty IA, Resnick AS, Dai Y, Foote
KD, Fernandez HH, Wu SS, Oyama G, Jacobson CEt, Kim
SK, & Okun MS (2011) Effect of deep brain stimulation on
Parkinson’s nonmotor symptoms following unilateral DBS:
A pilot study. Parkinsons Di, 2011, 507416.
[114] Amara AW, Standaert DG, Guthrie S, Cutter G, Watts RL,
& Walker HC (2012) Unilateral subthalamic nucleus deep
brain stimulation improves sleep quality in Parkinson’s dis-
ease. Parkinsonism Relat Disord, 18, 63-68.
[115] Lyons KE, & Pahwa R (2006) Effects of bilateral subthala-
mic nucleus stimulation on sleep, daytime sleepiness, and
early morning dystonia in patients with Parkinson disease.
J Neurosurg, 104, 502-505.
[116] Monaca C, Ozsancak C, Jacquesson JM, Poirot I, Blond S,
Destee A, Guieu JD, & Derambure P (2004) Effects of bilat-
eral subthalamic stimulation on sleep in Parkinson’s disease.
J Neurol, 251, 214-218.
[117] Arnulf I, Bejjani BP, Garma L, Bonnet AM, Houeto JL,
Damier P, Derenne JP, & Agid Y (2000) Improvement of
sleep architecture in PD with subthalamic nucleus stimula-
tion. Neurology, 55, 1732-1734.
[118] Chahine LM, Ahmed A, & Sun Z (2011) Effects of STN
DBS for Parkinson’s disease on restless legs syndrome and
other sleep-related measures. Parkinsonism Relat Disord,
17, 208-211.
[119] Zibetti M, Rizzi L, Colloca L, Cinquepalmi A, Angrisano S,
Castelli L, Lanotte M, & Lopiano L (2010) Probable REM
sleep behaviour disorder and STN-DBS outcome in Parkin-
son’s Disease. Parkinsonism Relat Disord, 16, 265-269.
[120] Gierthmuhlen J, Arning P, Binder A, Herzog J, Deuschl G,
Wasner G, & Baron R (2010) Influence of deep brain stimu-
lation and levodopa on sensory signs in Parkinson’s disease.
Mov Disord, 25, 1195-1202.
[121] Kim HJ, Paek SH, Kim JY, Lee JY, Lim YH, Kim MR,
Kim DG, & Jeon BS (2008) Chronic subthalamic deep brain
stimulation improves pain in Parkinson disease. J Neurol,
255, 1889-1894.
[122] Kim HJ, Jeon BS, Lee JY, Paek SH, & Kim DG (2012) The
benefit of subthalamic deep brain stimulation for pain in
Parkinson disease: A 2-year follow-up study. Neurosurgery,
70, 18-23; discussion 23-14.