The effect of deep brain stimulation on the non-motor symptoms of Parkinson's disease: a critical review of the current evidence

Abstract

The benefit of deep brain stimulation (DBS) in controlling the motor symptoms of Parkinson's disease is well established, however, the impact on the non-motor symptoms (NMS) remains to be elucidated, although the growing investigative efforts are promising. This article reviews the reported data and considers the level of evidence available with regard to the effect of DBS on NMS total burden and on the cognitive, neuropsychiatric, sleep, pain, dysautonomic, and weight domains. Multiple case series suggest that DBS improves the burden of NMS by reducing prevalence, intensity, and non-motor fluctuations. There is level I evidence on the effect of DBS on cognition and mood. Slight cognitive decline has been reported in most class I studies, although the functional effect is probably minimal. Two randomized prospective studies reported no change in depression while improvement of anxiety has been reported by a class I trial. Prospective cohort studies point to improvement of hyperdopaminergic behaviors, such as impulse control disorders, while others report that hypodopaminergic states, like apathy, can appear after DBS. There is only class III evidence supporting the benefit of DBS on other NMS such as nocturnal sleep, pain, dysautonomia (urinary, gastrointestinal, cardiovascular, and sweating), and weight loss. Although preliminary results are promising, randomized prospectively controlled trials with NMS as primary end points are necessary to further explore the effect of DBS on these often invalidating symptoms and offer conclusions about efficacy.

http://www.nature.com/npjparkd

Web End =www.nature.com/npjparkd

REVIEW ARTICLE OPEN

The effect of deep brain stimulation on the non-motor symptoms of Parkinsons disease: a critical review of the current evidence

Mnica M Kurtis1, Thadshani Rajah2, Luisa F Delgado3 and Haidar S Dafsari4

The benet of deep brain stimulation (DBS) in controlling the motor symptoms of Parkinsons disease is well established, however, the impact on the non-motor symptoms (NMS) remains to be elucidated, although the growing investigative efforts are promising. This article reviews the reported data and considers the level of evidence available with regard to the effect of DBS on NMS total burden and on the cognitive, neuropsychiatric, sleep, pain, dysautonomic, and weight domains. Multiple case series suggest that DBS improves the burden of NMS by reducing prevalence, intensity, and non-motor uctuations. There is level I evidence on the effect of DBS on cognition and mood. Slight cognitive decline has been reported in most class I studies, although the functional effect is probably minimal. Two randomized prospective studies reported no change in depression while improvement of anxiety has been reported by a class I trial. Prospective cohort studies point to improvement of hyperdopaminergic behaviors, such as impulse control disorders, while others report that hypodopaminergic states, like apathy, can appear after DBS. There is only class III evidence supporting the benet of DBS on other NMS such as nocturnal sleep, pain, dysautonomia (urinary, gastrointestinal, cardiovascular, and sweating), and weight loss. Although preliminary results are promising, randomized prospectively controlled trials with NMS as primary end points are necessary to further explore the effect of DBS on these often invalidating symptoms and

offer conclusions about efcacy.

npj Parkinson's Disease (2017) 2, 16024; doi:http://dx.doi.org/10.1038/npjparkd.2016.24

Web End =10.1038/npjparkd.2016.24 ; published online 12 January 2017

INTRODUCTIONThe efcacy of deep brain stimulation (DBS) on the control of motor symptoms in Parkinsons disease (PD) has been consistently demonstrated in Class I clinical trials and is thus well established.13 In the past two decades there is a growing recognition that non-motor symptoms (NMS) are fundamental to the concept of PD as they dominate the premotor stage and are prevalent throughout disease progression.4 A single NMS, like pain or depression, can overshadow the clinical picture in some patients, and NMS burden (NMSB) as a whole has been recently identied as the most important factor in determining the quality of life of PD patients.5 The importance of NMS makes the need for effective therapies increasingly evident and thus behooves the scientic community to investigate the effect of DBS on these symptoms. There are previous reviews concerning this topic,68

but the need for an updated critical review of the current data is warranted as the number of publications regarding NMS and DBS has grown exponentially in the past years. To give the reader an analytical overview, studies are reviewed in depth and classied according to the quality of evidence they provide: level I (large randomized controlled trials and meta-analysis), level II (small randomized trials and controlled prospective trials), and level III (prospective uncontrolled case series), following parameters established by the evidence-based task force commissioned by the Movement Disorders Society.9

This review includes clinical studies considering NMS as a primary or secondary outcome from DBS intervention and focusing on NMSB, non-motor uctuations (NMF), cognition, neuropsychiatric symptoms (depression and anxiety, suicide attempts, apathy, and impulse control disorders (ICDs)), sleep, pain, autonomic (urinary, gastrointestinal, cardiovascular, and sweating), and weight gain.

THE PATHOPYSIOLOGY OF NMS AND DBSThe pathophysiology underlying cognitive and neuropsychiatric manifestations in PD is certainly complex and individually variable. Multiples studies corroborate widespread Lewy type- synucleinopathy (LTS) in the neocortex as an important factor, and limbic and brainstem involvement may also have a role, as well as coexisting Alzheimers disease pathology, cerebrovascular disease, and amyloid angiopathy.10 The implication of cortico-basal ganglia (BG) circuitry disorders in the development of these NMS is also gaining attention as understanding of these networks progresses.

On the basis of the model developed by Alexander et al.11 in

1986, it is generally accepted that the BG constitute a part of three distinct functional and anatomical loops involving sensorimotor, associative, and limbic processing.

These networks have a role in weeding out relevant information from noise for the selection of movement patterns, actions, and

1Movement Disorders Unit, Neurology Department, Hospital Ruber Internacional, Madrid, Spain; 2Kings Parkinson's Centre of Excellence, Kings College and Kings College Hospital, London, UK; 3Fundacin Universitaria de Ciencias de la Salud, Hospital San JosHospital Infantil Universitario de San Jos, Bogot, Colombia and 4Department of Neurology, University Hospital Cologne, Cologne, Germany.

Correspondence: MM Kurtis (mailto:[email protected]

Web End [email protected])

Received 8 July 2016; revised 15 September 2016; accepted 26 September 2016

Published in partnership with the Parkinson's Disease Foundation

Effect of Parkinson surgery on non-motor symptoms MM Kurtis et al

2

goal-directed behaviors, while neurophysiological and neuroimaging studies have delineated their segregated topographical organization into parallel circuits. It is the ventral striatum and caudate output pathways that project, through the ventromedial globus pallidus, subthalamic nucleus (STN), substantia nigra, and thalamus, to the anterior cingulate and dorsolateral prefrontal and lateral orbitofrontal cortices (which send return pathways to these structures) thus regulating cognitive and behavioral processes. The well-known motor circuit involves the direct and indirect pathways and connects the dorsolateral putamen, globus pallidus interna (GPi), STN, and thalamus to the motor and premotor cortical areas.12,13 The dopamine depletion seen in PD leads to a reduction of selectivity and spacial focalization of this cortico-BG circuitry and thus may be the pathological substrate of, not only motor symptoms such as brdykinesia and rigidity, but also non-motor symptoms such as apathy and dysexecutive functions.

Dopamine replacement therapy may restores the balance. However, because striatal dopamine depletion is heterogeneous, treatment may lead to hypersensitivity of postsynaptic dopamine receptors in selective subterritories of the striatum. If the dorsolateral striatal territory expresses this sensitization, the result can be augmented movements (dyskinesias). If more ventrome-dial regions are implicated, ICDs may arise.12 It is well established that DBS surgery in the main relay centers of the cortico-BG circuitry, such as STN or GPi, has similar clinical effects to dopaminergic therapy. It is thought that DBS high frequency stimulation in the dorsolateral region of the STN facilitates movement by releasing the No Go signal normally exerted by this nucleus on the motor BG circuitry. It is possible that an anteromedial electrode placement or current spread to this area may also release the No Go signal on the limbic and associative circuits13 and thus produce cognitive and affective disinhibition, explaining some of the neuropsychiatric NMS effects seen after DBS.14,15

The pathophysiological basis for DBS effect on other non-motor symptoms such as sleep disorders, pain, and dysautonomia is complex and different mechanisms may have a role. First, adjacent regions near the STN, for example, the pedunculopontine nucleus, could be modulated by DBS, thus resulting in benecial effects on sleep.16 Second, a modulation of BG circuitry may result in effects on autonomic centers of the thalamus, projecting to the anterior cingulate and lateral frontal cortex with benecial effects of symptoms like sweating17 and bladder control.18

DBS EFFECT OF NMSB AS A WHOLENMSB can be evaluated by the NMS Questionnaire (NMSQuest),19 a

qualitative patient completed tool, or measured in a quantitative fashion by the NMS Scale (NMSS).20 However, there have only been a few studies that have specically used validated tools for measuring NMS in relation to DBS in PD (see Table 1). In a small open-label study including 10 PD patients, a 36% overall improvement in the mean NMSS score after STN DBS surgery was reported.21 However, the sample was too small to be able to report any meaningful subgroup/domain analysis. Using the NMSQuest-based scoring system, Nazzarro et al.22 studied 24 patients who underwent bilateral STN DBS and showed that the NMSQuest score decreased from 12 (severe NMSB) pre-surgery to 7 (moderate NMSB) post surgery at 1-year follow-up.22 Subsequently, Dafsari et al.23 have reported the rst multicentre European DBS study of STN stimulation where NMS were the primary outcome.23 This was an open prospective observational study including 60 patients who underwent STN DBS and were evaluated at baseline and at 6-month follow-up with the NMSS. The authors reported a 42% improvement in NMSB, underpinned by a range of signicant improvements in specic NMS (sleep, urinary, and perceptual problems). The immediate effect of DBS on NMSB has also been studied with nonspecic tools. Wolz et al.24 reported on 10 NMS in

34 patients with a median DBS time of 13 months. In this cohort, DBS did not have an immediate effect on the frequencies of a wide range of autonomic, sensory, cognitive, and neuropsychiatric NMS as assessed by a semi-structured interview, and only a signicant improvement of the frequency of inner restlessness was reported.24 However, the severity of most NMS, as measured by Visual Analog Scales, was signicantly improved; particularly fatigue, and inner restlessness in a subset of patients. The methodological differences in these studies including objectives, measuring tools, and follow-up times may account for the variability of results.

DBS EFFECT ON NON-MOTOR FLUCTUATIONSThe NMF accompany motor uctuations in most cases and are common in PD.25 NMF may exist as NMS symptoms that typically worsen during motor-off periods, that are only present during motor-off periods, or that uctuate independently from the motor state.25 Witjas et al.26 studied NMF in 40 patients who underwent STN DBS surgery and were followed for 1 year.26 They classied NMF into four main groups: cognitive, psychiatric, autonomic, and sensory uctuations. The NMF that improved the most after STN DBS were sensory symptoms and pain, with 84.2% improvement. Other NMF which improved were in the dysautonomic and cognitive domains with 60 and 70% decrease in severity. However, psychiatric uctuations seemed to respond less consistently postoperatively. Ortega-Cubero et al.27 studied 20 patients and reported reduced frequency and severity after 2-year follow-up of both psychiatric and autonomic uctuations after STN DBS surgery, partially supporting the previous observations.27 These open-label data (see Table 1) implying the benet of DBS on NMSB and NMF need to be conrmed in controlled studies. These small sample studies probably included subjects with a range of baseline characteristics regarding their NMF that may explain the differing results. For example, pre-surgical NMF response to levodopa therapy, duration, severity, and frequency may inuence response to DBS.

DBS EFFECT ON COGNITIONCognitive decline is far-reaching in PD and seems an inevitable consequence of disease progression as more than 80% of patients develop dementia after 20-year follow-up.28 A large meta-analysis including more than 600 patients showed that DBS of the STN generates a statistically signicant small decrease in the executive functions and working memory.29 Similarly, a class I study by Witt et al.30 found mild decrease in executive functions in the STN group when compared with the best medical therapy group (BMT) after a 6-month follow-up.30 However, another subsequent meta-analysis including more than 10 000 patients reported that 57% of the included studies did not nd signicant cognitive changes after DBS.31 This was corroborated by a large randomized prospective study by Willams et al.32 comparing a BMT group with an STN surgery group during a 1-year follow-up, and showing no differences in cognitive decline.32 Other prospective uncontrolled studies have found none or clinically irrelevant cognitive decline,3337 while some report a decline in lexical uency.33,3638 Two large randomized studies compared the classic surgical targets for PD and showed no difference between the groups.3,39

These variable results may be partly attributed to patient cohort differences with respect to baseline demographic characteristics, PD symptomatology, surgical techniques, and postoperative management. The main risk factors associated with cognitive decline and surgery have been subdivided into (1) preoperative risk factors: impaired attention, higher levodopa equivalent dosages and motor impairment, older age, higher motor, and severe axial symptoms; (2) intra-operative risk factors such as surgical electrode trajectories (through the frontal lobe and head

npj Parkinson's Disease (2017) 16024 Published in partnership with the Parkinson's Disease Foundation

Effect of Parkinson surgery on non-motor symptoms MM Kurtis et al

3

60OverallNMSSimproved,showingsignicantimprovementin4domains:

sleep/fatigue,perceptualproblems/hallucinations,urinaryandmiscellaneous.

AuthorYearOutcomemeasureTypeofstudyNo.ofpatientsMainoutcomeafterbilateralSTNDBS

Dafsarietal.33 2016Primary:NMSasawhole

NMSS:9domains

NMSQuest

PDQ-8

Cross-sectionalstudy34Nomajorimmediateeffectsonfrequencies,butimprovesseverityofmostNMS,

particularlypsychiatricsymptoms(depression,anxiety,andfatigue).

36monthsprospectivestudy10ShowsholisticandselectivebenecialeffectonaspectsofNMS.Especiallyon5

1-yearprospectivestudy24NMSdecreasedsignicantlywhenassessedwithaNMSQuestandsignicant

improvementinQoL.

Zibettietal.71 2007Primary:NMSasawhole

ClinicalInterview

2-yearprospectivestudy20NMFseverityandfrequencyrelatedtotheoff-statewerereduced.

1-yearprospectivestudy40AlleviationofNMFseen,withsignicantpositiveeffectsonsensory,dysautonomic,

andcognitiveuctuations.Lessconsistentinpsychicresponse.

of the caudate nucleus); and (3) postoperative factors including stimulation parameters, electrode location, and medication changes.14,40

In conclusion, there is level I and II type evidence (see Table 2) consistently reporting a moderate decrease in verbal uency after STN DBS, as well as a mild reduction in abstract reasoning, working memory and executive functions. However, this mild cognitive deterioration is generally not clinically relevant.

DBS EFFECT ON NEUROPSYCHIATRIC SYMPTOMS DepressionPatients with PD may manifest neuropsychiatric symptoms such as depression, anxiety, apathy, impulsiveness, introversion, hopelessness, and suicidal behavior at any stage of the disease. Depression is considered one of the most frequent mood state changes in PD with a prevalence of about 4050%, with major depression occurring in 5 to 10% of cases.8 Two large randomized controlled trials showed that there was no difference between the STN DBS and BMT groups with respect to depression after a 6-month follow-up (See Table 2).1,2 One

randomized study comparing the difference in depressive symptoms between the two classic targets, did not show differences,39 while Follet et al.3 reported worsening of depression after STN DBS when compared with GPi.3 Smaller controlled trials on the immediate effect of DBS41 and

prospective case series with up to 11-year follow-up have reported no change in depression,38,42 or mild

improvement.37,43 In summary, there is level I evidence demonstrating that DBS is not detrimental for depression, and some class II and III studies suggesting it may improve slightly. Differing results may be due to population differences, methodological variations (i.e., measuring tools, follow-up time) and postoperative motor control and medical treatment changes.

AnxietyAnxiety is another frequent NMS, usually coexisting with depression and with motor uctuations, occurring in about 40% of PD patients.8 There is one large randomized controlled study including 156 patients who underwent STN DBS or BMT providing class I data of improvement in anxiety scales at 6-month follow-up after DBS (see Table 2).30 Similarly to depression results, some prospective series suggest that anxiety may benet from STN DBS.41,43

Impulse control disordersICDs are behavioral addictions that include hypersexuality, hyperphagia, pathologic gambling and compulsive shopping. These ICDs affect up to 40% of PD patients with dopamine agonist therapy and approximately 15% of PD patients overall.44

There are conictive results as far as their response to surgery (see Table 3). One of the recognized causes of ICDs relates to a hyperdopaminergic state, related to dopamine replacement therapy. Various large prospective studies suggest that when ICDs are caused by hyperdopaminergic states, they improve after surgery due to drug reduction.43,45,46 Lhomme et al.43 go

as far as proposing that disabling dopaminergic treatment abuse and drug-induced behavioral addictions in PD may be considered a new indication for subthalamic stimulation.43

However, the verdict is still not settled since some cases of de novo impulsivity have been reported after surgery.4749 In a large

retrospective study including 89 patients, Kim et al.49 reported improvement in 13 of 20 patients with ICDs, however nine cases developed de novo ICDs.49 In a survey directed to the Parkinson Study Group centers with the objective of evaluating the

particulardomains:sleep,mood/cognition,urinary,sexual,andmiscellaneous.Other

domainsshownochange.

Nazzaroetal.22 2011Primary:NMSasawhole

NMSQuest,PDQ-39

1224monthsprospectivestudy36Amelioratessleepandconstipation.

Table1.DBSeffectsonnon-motorsymptomsasawholeandnon-motoructuationsinPDpatients

Abbreviations:DBS,deepbrainstimulation;NMS,non-motorsymptoms;NMF,non-motoructuations;NMSS,Non-MotorSymptomsScale;NMSQuest,non-motorsymptomsquestionnaire;QoL,qualityoflife;

PD,Parkinsonsdisease;VAS,VisualAnalogScale;PDQ,Parkinsonsdiseasequestionnaire.

Multicenter,open,6-month

prospectivestudy

Wolzetal.24 2012Primary:NMSasawhole

Semi-structured

questionnaire

VAS

Reichetal.21 2011Primary:NMSasawhole

NMSS

Witjasetal.26 2007Primary:NMF

2013Primary:NMF

Questionnaire

Questionnaire

Ortega-Cubero

etal.27

Published in partnership with the Parkinson's Disease Foundation npj Parkinson's Disease (2017) 16024

Effect of Parkinson surgery on non-motor symptoms

MM Kurtis et al

4

26STNRemarkabledeclineinphonologicaluency,slightdecline

incognition.Nosignicantchangesindepression.

Contradictoryresultsinanxiety.

NostatisticallysignicantdifferencebetweenGPiandSTN

groups.

63STNOverallcognitionunchanged.Reductioninverbaluency.

ImprovementinMWCST.Depressionandanxiety

improved.

McDonaldetal.41 2012Primary:mood

VAMS

Mood,anxiety,apathyandfatigueimprovewithSTNDBS

ON.

SimilarlyslightdecrementsincognitivefunctioninSTN

andGPiDBSgroup.DepressionworsenedafterSNT-DBS

andimprovedafterGPiDBS.

Williamsetal.32 2010Secondary:cognition

NodifferencebetweenSTN-DBSandBMTgroupsinDRS-II

scores.SmallsignicantdecreaseinverbaluencyinSTN

versusBMT.

Weaveretal.2 2009Secondary:cognitionandmood

Neithertreatmentwasassociatedwithsignicantchange

incognitionordepression.

STNDBSdoesnotreduceoverallcognition.Selective

decreaseinfrontalcognitivefunctions.Anxietyimproves

intheSTNgroupcomparedtoBMTgroup.

Kaiseretal.42 2008Primary:Moodandpsychosocialfunction

POMS,BDI,STAI-X1/X2,SCL-90-RandSIP

3-yearprospective33STNNochangeinmoodorpsychosocialfunctioning.Acluster

analysisrevealed4differentpsychosocialprolesthat

remainstableaftersurgery.

Applebyetal.31 2007Secondary:cognition,depression,behavior

10,339DBSReportedratesofdepression,cognitiveimpairment,

mania,andbehaviorchangesarelow.Highrateofsuicide

inpatientstreatedwithDBS.

Deuschletal.1 2006Secondary:cognitionandmood

Emotionalandcognitivemeasuresdidnotdiffer

signicantly.

612STNSTN-DBSresultsinslightdecreaseinexecutivefunctions

andworkingmemory.

15-monthprospective72STNNooverallcognitivechange.Milddecreaseinverbal

12-monthprospective20STNNochangeinglobalcognitivefunction.

uency.Smallimprovementindepressionandobsessive-

compulsiveandparanoidpersonalitytraits.

ResultsafterDBS

3-yearprospective77STNNoglobalcognitivedeterioration.Verbaluencydecline.

5-yearprospective49STNCognitivefunctionchangesbetweenyear15are

consistentwithprogressionofPD.

Danieleetal.35 2003Primary:cognitive

AuthorYearOutcomemeasureTypeofstudyNo.of

patients

(63GPi)

(65STN)

(23STN)

(11BMT)

(152GPi)

(147STN)

(182STN)

(183BMT)

(60STN)

(61GPi)

(134BMT)

(60STN)

(63BMT)

78BMT

128

299

366

255

123

78STN

34

156

11-yearprospective

multicenter

1-yearrandomizedcontrolled

trial

1-yearprospective

Multicenter

Cross-sectional

On/offDBS

2-yearrandomized

prospectivemulticenter

1-yearrandomized

prospectiveopen-label

6monthsrandomized

controlled

6monthsrandomized

multicentre

Meta-analysis

546articlespublished

between19962005

6-monthrandomized-pairs

trial

20articlespublishedbetween

19902005

Meta-analysis

Table2.DBSeffectsoncognitiveimpairmentandmoodinpatientswithPD

Rizzoneetal.38 2014Secondary:cognitionandmood

MMSE,RPM,digitspanforward,phonologicaluency,Corsis

block-tappingtestforward/backward

MWCST,RAVLT,SAS,SDS,BDIandSTAI

Compositescore(cognitivetests,lossofprofessionalactivity,

work,orjob;lossofimportantrelationships;psychosis,

2013Primary:cognitionandmood

depression,oranxietyfor3monthsorlongerasbyMINI)

2012Secondary:cognitionmood,behaviorandNMF.

MDRS,FrontalScore(MWCST,verbaluency,graphicand

motorseries)MINI,ArdouinScale,BDI,BAIandSAS1

Follettetal.3 2010Secondary:cognitionandmood

WAISIIIandBDI-II

MDRS,WAIS,verbalassociativeuency,StroopTest,WCST,

BostonNamingTest,BriefVisuospatialMemoryTest,Hopkins

VerbalLearningTest.BDI

Bentonvisualretention,strooptest,verbaluency

MDRS,MontgomeryandAsbergDRS,BriefPsychiatricRating

Scale

Test,Paired-AssociateLearning,TrailMaking-B,NMCST,verbal

uencytasks,BDI,STAIandSCID-II

MDRS,WCST,verbaluencygraphicandmotorseries,BDI,

UPDRSI

MDRS,RAVLT(German),WAIS

Neuropsychiatrictests,psychiatricsideeffects

RCM,BisyllabicWordRepetitionTest,Corsi'sBlock-Tapping

DRS-II,D-KEFSandWAIS

Neuropsychiatrictests

Wittetal.30 2008Primary:cognition

Parsonsetal.29 2006Primary:cognition

Castellietal.37 2006Primary:Cognition,mood,psychdisorders

Funkiewitzetal.36 2004Primary:cognition,moodandbehavior

Kracketal.34 2003Secondary:cognition

MDRS,BDI,Clinicalinterview

MMSEandMWCST

Oderkerken

etal.39

Lhommeetal.43

Seeref.51

npj Parkinson's Disease (2017) 16024 Published in partnership with the Parkinson's Disease Foundation

Effect of Parkinson surgery on non-motor symptoms MM Kurtis et al

5

STNpatientshadnocognitivedecitat12months,except

forlexicaluency.TherewasnodifferentialeffectofSTN

Abbreviations:BAI,BeckAnxietyInventory;BDI,BeckDepressionInventory;BMT,bestmedicaltherapy;UNI,unilateral;CANTAB,CambridgeNeuropsychologicalTestAutomatedBattery;D-KEFS,Delis-Kaplan

Executivefunctionsystem;DBS,deepbrainstimulation;DRS,DepressionRatingScale;DRS-II,dementiaratingscale-II;DSM-IV,DiagnosticandStatisticalManualofMentalDisorders,fourthedition;GPi,globus

pallidusinterna;MDRS,MattisDementiaRatingScale;MINI,Mini-internationalNeuropsychiatricInterview;MMSE,Mini-MentalStateExam;MWCST,ModiedWisconsinCardSortingTest;NMCST,Nelson

orGPistimulation.WithSTNDBSon:mildbutsignicant

improvementinpsychomotorspeedandworking

memory.

ModiedCardSortingTest;NMF,non-motoructuations;POMS,ProleofMoodScale;RAVLT,ReysAuditoryVerbalLearningTest;RPM,RavensProgressiveMatrices;SAS,ZungsSelf-ratingAnxietyScale;SAS1,

StarksteinApathyScale;SCID-II,StructuredClinicalInterviewfortheDSM-III-RAxisIIDisorders;SCL-90-R,Self-ReportSymptomInventory90Items-Revised;SDS,ZungsSelf-ratingDepressionScale;SIP,Sickness

ImpactProle(SIP);STAI,StateTraitAnxietyInventory;STN,subthalamicnucleus;UPDRS,UniedParkinson'sDiseaseRatingScale;VAMS,VisualAnalogMoodScale;WAISIII,WechslerAdultIntelligenceScalesIII.

patients

(48-STN)

(8-GPi)

20

(15STN)

(5GPi)

56

1-yearprospective

multicenter+cross-sectional

(off/onDBS)

prevalence and screening of ICDs pre and post DBS, 67% of the centers observed at least one case of de novo ICD occurrence after surgery.50 These seemingly contradictory results may be due to differing underlying pathophysiological mechanisms. ICDs that are related to a hyperdopaminergic state clearly improve with medication adjustments after DBS. However, in a subset of patients with greater mesolimbic degeneration, DBS itself may produce alterations in the limbic BG-loop and lead to hyperactivation of the ventral striatum and development of ICDs.

ApathyApathy is a behavioral disorder characterized by decreased motivation, emotional involvement, and goal-directed and self-driven behaviors. It has been described in about 40% of patients with PD51 and has recently been classied into four subtypes relating to a (1) reward deciency syndrome, (2) emotional distress, (3) executive dysfunction, and (4) autoactivation decit.52

Improvement in apathy has been reported after starting dopaminergic therapy and after turning on STN DBS.41 However, worsening of apathy after surgery has also been reported, more than a decade ago,36 and in a more recent prospective study including 63 patients, Thobois et al.51 described how 34 patients developed apathy in the rst months (mean 4.7 months, 3.38.2 months) post surgery (see Table 3). In this seminal study, the authors related the de novo apathy cases to a rapid withdrawal of dopaminergic drugs after surgery. However, medication changes do not explain the whole story in postsurgical apathy and preexisting risk factors such as greater dopaminergic mesolimbic degeneration,12 NMF,51 and dyskinesias may have a role.53 Similar to the post-DBS results for ICDs, these seemingly contradictory results probably depend on the subtype of apathy and its pathophysiological basis.

Suicide riskThe increased risk of suicidal behaviors after DBS remains an open-ended question. Attention was drawn to this subject by a large meta-analysis reviewing the rst decade of DBS results, which described a completed suicide rate of 0.160.32% after DBS.31 This issue was further explored by Voon et al.54 in a multicenter retrospective case series, including 5311 patients, that reported an attempted suicide rate of 0.9% and a completed suicide rate of 0.45% in the rst postoperative.54 These alarming results were not corroborated in a later randomized controlled trial by Weintraub and colleagues55 comparing a BMT group including 299 patients and a DBS group (including both STN and GPi targets) of 255 patients.55 However, this trial was possibly underpowered owing to the rarity of suicidal events. The risk factors for suicidal ideation and behaviors proposed by this group included selection bias of personality traits in surgical patients, depression, previous history of ICDs, and unrealistic expectations of surgery.

DBS EFFECT ON SLEEPPD patients commonly report sleep problems, suffering from insomnia, excessive daytime sleepiness, restless legs syndrome, and REM sleep behavior disorder (RBD).56,57 Several studies have investigated the effect of DBS on sleep dysfunction in PD (see Table 4). Iranzo and colleagues58 were pioneers in showing objective improvement in sleep quality studied by polysomnography after STN DBS. They reported increased continuous sleep time and a decreased arousal index in 11 patients at 6-month follow-up.58 Hjort et al.59 reported improvement of overall sleep quality after STN DBS as they found signicant improvement in the mean total Parkinson Disease Sleep Scale after 3 months.59

They did not observe change in nocturia or excessive daytime sleepiness despite medication reduction. In another study in a

ResultsafterDBS

AuthorYearOutcomemeasureTypeofstudyNo.of

Corsisblock-tappingtest,RAVLT

ClinicalInterview

MDRS,GroberandBuschke,MWCST,Strooptest,trailmaking,

verbaluency,CANTAB

BDI

PillonBetal.33 2000Primary:cognition

Table2.(Continued)

Published in partnership with the Parkinson's Disease Foundation npj Parkinson's Disease (2017) 16024

Effect of Parkinson surgery on non-motor symptoms

MM Kurtis et al

6

Retrospective89STNICDsmayresolveorimprove,ornewonesappearafterSTNDBS.

Differenceinriskfactorsforpreoperativeversuspostoperative

ICDs.

Lhommeetal.43 2012Secondary:Cognitionmood,behaviorand

NMF

Abbreviations:BAI,BeckAnxietyInventory;BDI,BecksDepressionInventory;DBS,deepbrainstimulation;HAS,HamiltonAnxietyScale;HDS,HamiltonDepressionScale;ICD,impulsecontroldisorders;GPi,

Apathyaggravated.NMFimproved.Hyperdopaminergic

behaviorsandappetitivefunctioningimproved.

Samecohortasref.44.

ICDresolvedin2of7individualsafterunilateralorbilateralDBS.

17patientsdevelopedICDdiagnosespostoperatively.

1741monthprospective29STNPre-surgery:4patientshadICDs.Allresolvedaftersurgerybut1

recurredafter18months.

1-yearprospectivemulticenter63STN34patientsdevelopedapathyatmean4.7(3.38.2)monthsafter

DBSthatwasreversiblein17at1-yearfollow-up.17developed

transientdepressionafter5.7(4.79.3)months.Apathy,

depressionandanxietycanoccuraftersurgeryasadelayed

dopaminewithdrawalsyndrome.

Ardouinetal.45 2006Primary:ICDs:Pathologicalgambling

598STNPathologicalgamblingandothersymptomsofthedopamine

dysregulationsyndromeimprovedfollowingsurgery.Apathy

scorestendedtoincreasesystematicallyaftersurgeryand2

patientshadapathologicalscoreontheapathyscaleinthelong

term.

Funkiewitz

etal.36

AuthorYearOutcomemeasureTypeofstudyNo.ofpatientsMainoutcomeafterDBS

Kimetal.49 2013Primary:ICDs

3-yearprospective77STNApathyscoresmildlyincreased.Behavioralchangeswererare

andtransient.

cohortasref.44

1-yearprospectivemulticenter63STNsame

globuspallidusinterna;MDRS,MattisDementiaRatingScale;MIDI,MinnesotaImpulsiveDisordersInterview;MINI,Mini-InternationalNeuropsychiatricInterview;MMSE,Mini-MentalStateExam;WCST,

WisconsinCardSortingTest;NMF,non-motoructuations;SAS1 ,StarksteinApathyScale;STN,subthalamicnucleus;UPDRS,UniedParkinson'sDiseaseRatingScale.

NASTNorGPi

159

3-monthto6-year(mean18months)

retrospectivedatabaseanalysis

multicenter

Retrospective

Chartreview

Table3.DBSeffectsonapathyandICDsinpatientswithPD

MMSE,BDI,modiedMIDI

MDRS,FrontalScore(MWCST,verbaluency,

graphicandmotorseries)MINI,Ardouin

Scale,BDI,BAIandSAS1

Chartreviewusingcurrentdiagnostic

criteria

ArdouinScale,BDI,BAIandSAS1

Systematicopeninterviewbypsychiatrist

Secondaryoutcomes:cognitionandmood

MDRS,SAS1 andBDI-II

2004Primary:cognition,moodandbehavior

MDRSandWCST

Categoryandliteraluencyandgraphicand

motorseriesBDI,UPDRSpartI

Psychiatristinterview

HDS,HASandBDI

Moumetal.48 2012Primary:ICDs

Shotboltetal.46 2012Primary:ICDs

2010Primary:Apathyandmood

ThoboisSetal.51

Seeref.43

npj Parkinson's Disease (2017) 16024 Published in partnership with the Parkinson's Disease Foundation

Effect of Parkinson surgery on non-motor symptoms MM Kurtis et al

7

Table 4. DBS effects on sleep and pain

Author Year Outcome measure Type of study No. of patients

Main outcome after DBS

Amara et al.60 2012 Primary: sleepPSQI questionnaire

6 months prospective

53 Unilateral STN DBS improves subjective sleep quality.

Lyons and Pahwa61 2006 Primary: sleepEpworth sleepiness Scale

24 months prospective

43 Bilateral STN DBS improved sleep quality. Early morning dystonia and nocturnal akinesia improved. No change in excessive daytime sleepiness.

Hjort et al.59 2004 Primary: sleepPDSS

3 months prospective

10 Bilateral STN DBS improved sleep quality, but no change in excessive daytime sleepiness or nocturia.

Iranzo et al.58 2002 Primary: sleepPSQI questionnaire Polysomnography

6 months prospective

11 Subjective and objective improvement in sleep quality (decreased arousal index).

Cury et al.64 2014 Primary: painNMSS, Visual Analog Scale

1-year prospective

44 Bilateral STN DBS shows improvement in pain intensity, particularly dystonic and musculoskeletal pain. Motor and non-motor symptoms did not correlate with pain relief.

Kim et al.63 2012 Primary: painClinical Interview

2-year prospective

21 Bilateral STN DBS improves pain, sustained for 24 months. However, de novo primarily musculoskeletal pain developed during follow-up.

Gierthmhlen et al.65

2010 Primary: pain

QST

6 months prospective

17 Bilateral STN DBS shows improvement in pain, however no objective change in pain sensitivity.

Loher et al.62 2002 Secondary: pain

MMS, HDS

16 Unilateral and bilateral GPi shows improvement in pain at 3-month and 12-month follow-up.

Abbreviations: DBS, deep brain stimulation; HDS, Hamilton Depression Scale; MMS, Mini-Mental Scale; NMSS, Non-Motor Symptoms Scale; PDSS, Parkinsons Disease Sleep Scale; PSQI, Pittsburgh Sleep Quality Index Questionnaire; QST, quantitative sensory testing; STN, subthalamic nucleus.

12 months prospective

larger cohort, Amara et al.60 reported subjective sleep quality improvement after unilateral STN DBS as measured by the Pittsburgh Sleep Quality Index.60 Dafsari et al.23 also provide signicant evidence of subjective sleep improvement after DBS.23

The long-term benet of sleep after DBS is supported by an early study by Lyons and Pahwa61 that found consistent improvement for up to 2 years.61 As previously reported, this group did not nd change in excessive daytime sleepiness.61 In summary, there is level III type evidence suggesting that STN DBS may improve nocturnal sleep in PD patients, particularly sleep quality. Most authors hypothesize that sleep benet after DBS could result from improved nocturnal mobility and reduced sleep fragmentation. Current data do not report any reduction in REM sleep behavior disorder or improvement of excessive daytime sleepiness.

DBS EFFECT ON PAINThere have been several open label studies addressing the issue of pain, a common NMS of PD and its response to DBS, using either STN or the GPi as targets (see Table 4). Loher et al.62 reported on the effect of unilateral and bilateral GPi DBS in 16 patients: evaluations documented at 3 months indicated pain relief, which was sustained at the 12-month follow-up.62 In another study, Kim et al.63 reported a positive outcome of pain after STN DBS that persisted after 2 years, although some patients developed de novo musculoskeletal pain.63 In their recently published study, the IPMDS NMS study group showed that after 6 months of STN DBS, there was signicant reduction in pain scores as measured by the NMSS.23 It is worth noting that these studies do not specically address the classication of pain in PD. On the other hand, Cury et al.64 investigated a cohort of 41 patients and tackled this issue specically, reporting signicant improvement in pain intensity after 1 year of STN DBS.64 The prevalence of pain decreased from 70 to 21% and the most improved types were dystonic and musculoskeletal pain while central and neuropathic pain did not change. This supports previous ndings with quantitative sensory testing describing that sensitivity to pain was not inuenced by STN DBS and suggesting that DBS may have no direct modulation of central pain processing.65

Pain and DBS studies to date suffer from methodological limitations due to their open label nature and lack of a coherent tool to address the multifactorial nature of pain in PD that is currently possible with the recently validated Kings PD Pain Scale.66 There is only class III evidence supporting the benet of DBS on pain and future randomized controlled studies should take into account the various types of PD-related pain as they may be inuenced differently by DBS.

DBS EFFECT ON THE AUTONOMIC DOMAINUrinary symptomsUrinary symptoms are important constituents of autonomic dysfunction and occur in 3871% of PD patients and are therefore of the most frequent NMS.57 Another review has reported improvement in detrusor hyperreexia and increased bladder capacity after DBS.7 A recent study reported signicant improvement in urinary symptoms from baseline in the urinary domain of the NMSS, which addresses frequency, urgency, and nocturia.23 In

other open label studies studying the immediate effects of turning DBS ON, Seif et al.67 found improved bladder function as measured by objective urodynamic parameters67 and Wolz

et al.24 found that patients reported a positive direct effect on urinary symptoms with DBS on.24 The underlying physiological mechanism may be related to improved cortical control,68 and

improved sensory gating.18 However, these data need to be corroborated in further larger studies as some have reported subjective benet but no change in urodynamic parameters (see Table 5).69

Gastrointestinal symptomsNot many studies have specically looked at the effect of DBS on the gastrointestinal system (see Table 5). The rst study to document evidence was conducted by Arai et al.70 who studied 16 PD patients and measured gastric emptying by the excretion of CO2 in the 13C-acetate breath test.70 They reported improvement of gastric emptying after turning DBS on and speculated on a modulatory role of the dysfunctional vagal neural control in PD.

Published in partnership with the Parkinson's Disease Foundation npj Parkinson's Disease (2017) 16024

Effect of Parkinson surgery on non-motor symptoms

MM Kurtis et al

8

Vagallymediatedarterial-cardiacreeximprovedpostsurgery.No

differencefoundbetweenDBSon/off.

24NoconsiderablepositiveornegativeeffectonANScardiovascular

regulation,althoughsignicantreductioninorthostatichypotension.

Trachanietal.17 2010Primary:sweating

Abbreviations:BP,bloodpressure;BMT,bestmedicaltherapy;BRS,baroreexsensitivity;DBS,deepbrainstimulation;RRI,RRinterval;SBF,respirationandskinbloodow.

MainoutcomeafterSTNDBS

16Improvedgastricemptying.

1966.7%subjectiveimprovement.Noobjectiveimprovement.

2-yearprospective16Subjectiveimprovementbutnoobjectiveimprovementfound.

14Increasedperipheralvasoconstrictiononstimulation,improving

posturalhypotensioninpatients.

16Firsturgetovoidandmaximumbladdercapacityimproved

signicantlyintheONstate.

patients

(28STN)

AuthorYearOutcomemeasureTypeofstudyNo.of

41

(13BMT)

Araietal.70 2012Primary:gastrointestinalsymptoms13 C-acetatebreathtest.3months

Controlled

Prospective

DBSon/off

prospective

6months

prospective

6months

prospective

Cross-sectional

DBSon/off

Cross-sectional

DBSon/off

The study by Dafsari et al.23 supports the above-mentioned ndings of improved gastrointestinal emptying after STN DBS.23

Another study by Zibetti et al.71 reported the positive effects of STN DBS in improving salivation and constipation in a 1- and 3-year follow-up of 36 patients.71 There is therefore class III evidence suggesting some benet in gastrointestinal symptoms after DBS. Future studies should take into account the complexity of underlying pathological mechanisms. For example, constipation may depend on a central component (mediated by neural loss and LTS in the dorsal motor nucleus of the vagus nerve and spinal cord) and a peripheral component (mediated by a rostralcaudal gastrointestinal gradient of LTS). Patients with more brainstem pathology, may obtain a benet not seen in others.

Troche et al.72 reviewed nine studies that specically addressed the effect of STN DBS on dysphagia and found no effect.72

However, in a recent manometric study in 16 PD patients, Derrey et al.73 found signicant improvement in esophageal body contractions and enhancement of lower esophageal sphincter opening. Again, dysphagia in PD is a complex symptom that may be caused by alterations in the oral, pharyngeal, or esophageal phases of swallowing. On the basis of a small series of autopsy studies, dysphagia probably depends on LTS pathology of the pharyngeal nerves and localized muscle atrophy10 and thus one would not expect to see an effect by DBS.10 However, some patients may also show abnormal esophageal peristaltic movements, which could be modulated by DBS through the vagal nerve, but whether this translates into clinical benet remains to be elucidated.74

Orthostatic hypotensionAn early study in a small cohort indicated instant improvement of orthostatic hypotension after turning STN DBS on,75 but failed to report any change in cardiovascular control (see Table 5). These ndings were supported by a more recent controlled study that reported improved orthostatic hypotension in PD patients after DBS.76 Another controlled study including 28 PD patients proposed that the vagal component of the arterial-cardiac baroreex improved postoperatively.77 Dafsari et al.23 suggested that STN DBS may have a long-term effect on cardiovascular symptoms, and opine that further studies are needed.23

HyperhidrosisThere have been contradictory outcomes on the effect of STN DBS on sweating function, where some studies show positive results and others fail to observe differences (see Table 5). Wolz et al.24

found no change after immediate stimulation;24 whereas Dafsari et al.23 found signicant improvement in hyperhidrosis at 6-month follow-up.23 In another 6-month study including 19 patients, Trachani et al.17 indicated that there was subjective improvement in sweating, however, no objective reduction in hyperhidrosis was demonstrated.17 These studies were limited by the small number of included subjects, and offer class III evidence that DBS probably does not worsen sweating spells. Contradictory results can partially be explained by differences in baseline characteristics (e.g., sweating spells clearly related with dyskinesias, off periods, or nighttime akinesia may benet from DBS due to motor improvement), measuring tools (there is no validated tool that takes into account sweating uctuations, subjective perception, and objective ndings) and postsurgical medication changes.

OLFACTIONAlthough odor detection78 and identication79 seems to not be inuenced by DBS, odor discrimination seems to be improved as a result of DBS,78 possibly owing to improved cognitive odor information processing.80 In a recent open-label, prospective

Sumietal.77 2012Primary:cardiovascularsymptoms

Spectralandtransferfunctionanalysesofcardiovascular

variability.

Trachanietal.76 2012Primary:cardiovascularsymptoms

Questionnaire,BPmonitoringandneurophysiologicaltests

Semi-structuredquestionnaire,Sympatheticskinresponse

Questionnaires:InternationalProstateSymptomScoreand

DanishProstateSymptomScore

Urodynamicinvestigation

Stemperetal.75 2006Primary:cardiovascularsystem

Headuptilttesting,(BP),RRintervals(RRI),respiration,and

skinbloodow(SBF).Baroreexsensitivity(BRS)

Table5.DBSeffectsonautonomicsymptomsinPD

Wingeetal.69 2007Primary:urinarysymptoms

Seifetal.67 2004Primary:urinarysystem

Urodynamicinvestigation

npj Parkinson's Disease (2017) 16024 Published in partnership with the Parkinson's Disease Foundation

Effect of Parkinson surgery on non-motor symptoms MM Kurtis et al

9

study including 60 patients with PD, patients experienced a subjective improvement of the ability to smell and taste.23

DBS EFFECT ON BODY WEIGHTGenerally, patients with PD lose weight gradually as the disease progresses.81 The effect of DBS on body weight is still a matter under discussion; however, in recent years, many observational studies (see Table 6) have reported that patients gain weight after surgery and this may adversely affect their metabolic status.82 In a

retrospective review including 182 patients with a range of movement disorders and DBS targets, Strowd et al.83 described a mean weight gain of about 1 kg per year for 2 years following surgery.83 In a recent retrospective casecontrol study, this same group reported a mean weight gain of 2.9 kg in the STN DBS group, signicantly more than in the control group on BMT, with mean loss of 1.8 kg.84 An early prospective study showed a 4.7 kg. increase in PD patients after surgery at 1-year follow-up.85 Other groups have reported weight gain ranging from 4.3 to 14 kg.86

One study explored this weight gain by gender and found that men gained lean body mass, whereas women gained weight at the expense of fat, but mean weight gain was similar.87 Another study evaluated the difference between STN DBS patients and BMT, showing greater weight gain in the surgical group.88 There are different hypotheses attempting to explain postsurgical weight gain, relating it to dopaminergic therapy modications, increased food intake related to changes in the hypothalamus,89

decreased energy expenditure by better control of dyskinesias,90

and improvement of motor symptoms.85 In summary, there is Class III evidence suggesting that PD patients gain weight after STN DBS.

DISCUSSIONThis review of the current data investigating the impact of DBS on the NMS suggests that some symptoms may improve, others remain unchanged and some worsen, corroborating previous ndings.68 There is high-quality evidence demonstrating that DBS is generally a safe procedure with regard to cognition and behavioral morbidity. Data support the improvement of anxiety, and possibly also depression and ICDs. The benet on sleep, dystonic, and musculoskeletal pain, urinary and gastrointestinal symptoms, and weight loss has also been suggested by prospective uncontrolled studies. Overall, cognitive function generally remains stable, while some small studies suggest that REM sleep behavior disorder, excessive daytime sleepiness, and dysphagia also remain unchanged by DBS. On the other hand, after surgery, decreased verbal uency is consistently reported and apathy possibly worsens, as suggested by prospective series.

In interpreting postsurgical results, the reader must bear in mind the limitations of each type of study (Table 16). Even in high-quality studies, it is difcult to extrapolate the direct impact of DBS from the possible indirect effects that may be modulated by changes in medication, motor symptom improvement, or management of therapeutic expectations, among many other variables.

Substantial progress has been made in recent years to further our understanding of the NMS. Development of disease-specic patient-reported questionnaires, such as the NMSQuest19 or

questionnaire for impulsive-compulsive disorders in Parkinson's disease,91 and disease-specic scales, like the NMSS,20 the REM Sleep Behavior Disorder Severity Scale,92 and Kings PD Pain Scale,66 have provided the necessary tools to measure NMS, thus enabling an increasing number of clinical trials to include specic NMS and NMS as a whole as primary end points. DBS multi-disciplinary investigative efforts combining functional neuroimaging, neurophysiology, and clinical data provide a unique opportunity in advancing toward understanding the

Table6.DBSeffectsonbodyweightinpatientswithPD

STN-DBSgroup:WGmean2.9kgversusBMTgroupmeanWlossof

1.8kg(1.826.9kg).NodifferencebetweenuniandbilSTN.

182MeanWGof1.8kgat24monthfollow-upinthewholesample.In

thePDsubpopulation,meanWGof2.3kg.

Walkeretal.88 2009Weight1-yearcasecontrol39uniSTN

40BMT

STNDBS(case)meanWGof4.3kgcomparedwithcontrols(BMT).

24NormalizationofenergymetabolismafterDBS-STNimplantation

mayfavorbodyWG.Mengainedprimarilyfat-freemass.Women

gainedmainlyfatmass.

Maciaetal.90 2004WeightandBMICasecontrol19STN

14BMT

TheSNT-DBSgrouphadasignicantweightgain(9.77kg)and

BMIincrease(4.7kg/m2 )vs.controlgroup.

AuthorYearOutcomemeasureTypeofstudyNo.ofpatientsMainoutcomeafterDBS

1-yearprospective27MeanWGwas4.7kgaftersurgery.Signicantcorrelationbetween

WGandimprovementofdyskinesias.Majorityofpatientsreferred

WGasadverseevent.

35STN(10uni,

25bil)

34BMT

69;

Strowdetal.84 2016Height,weightandBMI2yearsretrospective

casecontrol

Strowdetal.83 2010Weight2yearsretrospective

DBSforPD,ET,dystonia

4monthsprospective

open

Abbreviations:BC,bodycomposition;bil,bilateral;BMI,bodymassindex;BMT,basalmetabolicrate;DBS,deepbrainstimulation;ET,essentialtremor;PD,Parkinsonsdisease;STN,subthalamicnucleus;uni,

unilateral;W,weight;WG,weightgain.

DualX-rayabsorptiometryandenergyexpenditure

weremeasuredover36hincalorimetricchambers.

Montaurieretal.87 2007Bodycomposition

Gironelletal.85 2002Questionnaireaboutseverityandetiologyofweight

again

Published in partnership with the Parkinson's Disease Foundation npj Parkinson's Disease (2017) 16024

Effect of Parkinson surgery on non-motor symptoms MM Kurtis et al

10

neurophysiological mechanisms behind NMS. A key point in the future may be to understand how the somatotopy of the BG loops inuences various non-motor outcomes. Neuropsychiatric and cognitive results probably depend more highly on cortico-BG circuitry than other non-motor symptoms, such as pain and dysautonomia, that may have a central and peripheral component, as suggested by neuropathologic ndings of LTS at both levels.10

Of the classic DBS targets, most of the data pertains to the subthalamic nucleus (STN), with a paucity of studies regarding the GPi, and null investigations specically looking at the effect of thalamic ventroimtermediate stimulation. There are few comparative studies available for non-motor effects of STN and GPi DBS. Although some data suggest, advantages of GPi DBS on mood and behavior,55,93,94 little is known on other non-motor symptoms

such as autonomic dysfunctions, pain or sleep symptoms. Future studies comparing STN and GPi DBS effects should not only focus on the quality of life and motor symptoms but also on a wide range of non-motor symptoms. This requires the utilization of scores covering a wide range of NMS such as the NMS Scale, the NMS Questionnaire, and laboratory-assisted evaluation of NMS with, e.g., cognitive tests such as the verbal uency for executive dysfunctions, polysomnography for sleep, CO2 excretion measurement for gastrointestinal functions, urometric tests for urinary symptoms, etc.

DBS was initially developed to target medical refractory motor symptoms such as severe dyskinesias and uctuations. However, we have since learned that NMS in PD may affect patient quality of life to a higher degree than motor symptoms5 and current effective medical treatments are lacking. Recent DBS technology developments have provided directional stimulation systems (Boston Scientic and Medtronic development center Eindhoven), which allow current steering towards specic subareas of anatomic target structures. Case reports95 and smaller scope96 studies pioneering this technology in patients with PD have provided evidence of its clinical usefulness to achieve optimized motor effects and avoid side effects of DBS. On the basis of the anatomy and functional circuitry of the BG, there is a rationale to examine the non-motor effects of DBS in subareas of the target region in a similar experimental design as in these studies on motor effects of directional stimulation.

We advocate that future randomized controlled studies in DBS should (1) include NMS as primary end points, (2) involve large cohorts that can be divided into subtypes,97 and (3) specically analyze volumes of tissue activated in context of patients individual BG anatomy/somatotopy and thus advance towards therapies tailored personally, based on motor and non-motor symptom prole.

CONTRIBUTIONS

M.M.K. performed the bibliographical search and wrote the nal draft of the manuscript and tables. T.R. wrote the rst draft of the sleep, pain, and dysautonomia sections and tables and contributed to the bibliographic search. L.F.D. wrote the rst draft of the cognitive, neuropsychiatric, and weight sections and tables. H.S.D. reviewed the nal draft and contributed to the bibliographic search.

COMPETING INTERESTS

The authors declare no conict of interest.

REFERENCES1. Deuschl, G. et al. A randomized trial of deep-brain stimulation for Parkinsons disease. N. Engl. J. Med. 355, 896908 (2006).

2. Weaver, F. M. et al. Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial. JAMA 301, 6373 (2009).

3. Follett, K. A. et al. Pallidal versus subthalamic deep-brain stimulation for Parkinsons disease. N. Engl. J. Med. 362, 20772091 (2010).

4. Chaudhuri, K. R. & Schapira, A. H. V. Non-motor symptoms of Parkinsons disease: dopaminergic pathophysiology and treatment. Lancet Neurol. 8, 464474 (2009).

5. Martinez-Martin P., Rodriguez-Blazquez C., Kurtis M. M., Chaudhuri K. R., NMSS Validation Group. The impact of non-motor symptoms on health-related quality of life of patients with Parkinsons disease. Mov. Disord. 26: 399406 (2011).

6. Klingelhoefer, L., Samuel, M., Chaudhuri, K. R. & Ashkan, K. An update of the impact of deep brain stimulation on non motor symptoms in Parkinsons disease.J. Parkinsons Dis. 4, 289300 (2014).7. Wang, X.-H. et al. Target selection recommendations based on impact of deep brain stimulation surgeries on nonmotor symptoms of Parkinsons disease. Chin. Med. J. (Engl) 128, 33713380 (2015).

8. Kim, H., Jeon, B. S. & Paek, S. H. Nonmotor symptoms and subthalamic deep brain stimulation in Parkinsons disease. Mov. Disord. 8, 8391 (2015).

9. Lang, A. E. & Lees, A. Management of Parkinsons disease: an evidence-based review. Mov. Disord. 17, S1S6 (2002).

10. Adler, C. H. & Beach, T. G. Neuropathological basis of nonmotor manifestations of Parkinsons disease. Mov. Disord. 31, 11141119 (2016).

11. Alexander, G. E., DeLong, M. R. & Strick, P. L. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu. Rev. Neurosci. 9, 357381 (1986).

12. Tremblay, L., Worbe, Y., Thobois, S., Sgambato-Faure, V. & Fger, J. Selective dysfunction of basal ganglia subterritories: from movement to behavioral disorders. Mov. Disord. 30, 11551170 (2015).

13. Obeso, J. A. et al. Functional organization of the basal ganglia: therapeutic implications for Parkinsons disease. Mov. Disord. 23, 548559 (2008).

14. Volkmann, J., Daniels, C. & Witt, K. Neuropsychiatric effects of subthalamic neurostimulation in Parkinson disease. Nat. Rev. Neurol. 6, 487498 (2010).

15. Castrioto, A., Lhomme, E., Moro, E. & Krack, P. Mood and behavioural effects of subthalamic stimulation in Parkinsons disease. Lancet Neurol. 13, 287305 (2014).

16. Alessandro, S. et al. Non-motor functions in parkinsonian patients implanted in the pedunculopontine nucleus: focus on sleep and cognitive domains. J. Neurol. Sci. 289, 4448 (2010).

17. Trachani, E. et al. Effects of subthalamic nucleus deep brain stimulation on sweating function in Parkinsons disease. Clin. Neurol. Neurosurg. 112, 213217 (2010).

18. Herzog, J. et al. Improved sensory gating of urinary bladder afferents in Parkinsons Disease following subthalamic stimulation. Brain 131, 132145 (2008).

19. Chaudhuri, K. R. et al. International multicenter pilot study of the rst comprehensive self-completed nonmotor symptoms questionnaire for Parkinsons disease: the NMSQuest study. Mov. Disord. 21, 916923 (2006).

20. Chaudhuri, K. R. et al. The metric properties of a novel non-motor symptoms scale for Parkinsons disease: results from an international pilot study. Mov. Disord. 22, 19011911 (2007).

21. Reich, M. M. et al. Changes in the non-motor symptom scale in Parkinsons disease after deep brain stimulation. Basal Ganglia 1, 131133 (2011).

22. Nazzaro, J. M., Pahwa, R. & Lyons, K. E. The impact of bilateral subthalamic stimulation on non-motor symptoms of Parkinsons disease. Parkinsonism Relat. Disord. 17, 606609 (2011).

23. Dafsari, H. S. et al. Benecial effects of bilateral subthalamic stimulation on non-motor symptoms in Parkinsons disease. Brain Stimul. 9, 7885 (2016).

24. Wolz, M. et al. Immediate effects of deep brain stimulation of the subthalamic nucleus on nonmotor symptoms in Parkinsons disease. Park. Relat. Disord. 18, 994997 (2012).

25. Storch, A. et al. Nonmotor uctuations in Parkinson disease: severity and correlation with motor complications. Neurology 80, 800809 (2013).

26. Witjas, T. et al. Effects of chronic subthalamic stimulation on nonmotor uctuations in Parkinsons disease. Mov. Disord. 22, 17291734 (2007).

27. Ortega-Cubero, S. et al. Effect of deep brain stimulation of the subthalamic nucleus on non-motor uctuations in Parkinsons disease: two-years' follow-up. Parkinsonism Relat. Disord. 19, 543547 (2013).

28. Hely, M. A., Reid, W. G. J., Adena, M. A., Halliday, G. M. & Morris, J. G. L. The Sydney multicenter study of Parkinsons disease: the inevitability of dementia at 20 years. Mov. Disord. 23, 837844 (2008).

29. Parsons, T. D., Rogers, S. A., Braaten, A. J., Woods, S. P. & Trster, A. I. Cognitive sequelae of subthalamic nucleus deep brain stimulation in Parkinsons disease: a meta-analysis. Lancet Neurol. 5, 578588 (2006).

30. Witt, K. et al. Neuropsychological and psychiatric changes after deep brain stimulation for Parkinsons disease: a randomised, multicentre study. Lancet Neurol. 7, 605614 (2008).

npj Parkinson's Disease (2017) 16024 Published in partnership with the Parkinson's Disease Foundation

Effect of Parkinson surgery on non-motor symptoms MM Kurtis et al

11

31. Appleby, B. S., Duggan, P. S., Regenberg, A. & Rabins, P. V. Psychiatric and neuropsychiatric adverse events associated with deep brain stimulation: a meta-analysis of ten years experience. Mov. Disord. 22, 17221728 (2007).

32. Williams, A. et al. Deep brain stimulation plus best medical therapy versus best medical therapy alone for advanced Parkinsons disease (PD SURG trial): a randomised, open-label trial. Lancet Neurol. 9, 581591 (2010).

33. Pillon, B. et al. Neuropsychological changes between off and on STN or GPi stimulation in Parkinsons disease. Neurology 55, 411418 (2000).

34. Krack, P. et al. Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinsons disease. N. Engl. J. Med. 349, 19251934 (2003).

35. Daniele, A. et al. Cognitive and behavioural effects of chronic stimulation of the subthalamic nucleus in patients with Parkinsons disease. J. Neurol. Neurosurg. Psychiatry 74, 175182 (2003).

36. Funkiewiez, A. et al. Long term effects of bilateral subthalamic nucleus stimulation on cognitive function, mood, and behaviour in Parkinsons disease. J. Neurol. Neurosurg. Psychiatry 75, 834839 (2004).

37. Castelli, L. et al. Chronic deep brain stimulation of the subthalamic nucleus for Parkinsons disease: effects on cognition, mood, anxiety and personality traits. Eur. Neurol. 55, 136144 (2006).

38. Rizzone, M. G. et al. Long-term outcome of subthalamic nucleus DBS in Parkinsons disease: from the advanced phase towards the late stage of the disease? Parkinsonism Relat. Disord. 20, 376381 (2014).

39. Odekerken, V. J. et al. Subthalamic nucleus versus globus pallidus bilateral deep brain stimulation for advanced Parkinsons disease (NSTAPS study): a randomised controlled trial. Lancet Neurol. 12, 3744 (2013).

40. Witt, K. et al. Relation of lead trajectory and electrode position to neuropsychological outcomes of subthalamic neurostimulation in Parkinsons disease: results from a randomized trial. Brain 136, 21092119 (2013).

41. McDonald, L. M., Page, D., Wilkinson, L. & Jahanshahi, M. Deep brain stimulation of the subthalamic nucleus improves sense of well-being in Parkinsons disease. Mov. Disord. 27, 372378 (2012).

42. Kaiser, I., Kryspin-Exner, I., Brcke, T., Volc, D. & Alesch, F. Long-term effects of STN DBS on mood: psychosocial proles remain stable in a 3-year follow-up. BMC Neurol. 8, 43 (2008).

43. Lhomme, E. et al. Subthalamic stimulation in Parkinsons disease: restoring the balance of motivated behaviours. Brain 135, 14631477 (2012).

44. Rossi, P. J., Gunduz, A. & Okun, M. S. The subthalamic nucleus, limbic function, and impulse control. Neuropsychol. Rev. 25, 398410 (2015).

45. Ardouin, C. et al. Pathological gambling in Parkinsons disease improves on chronic subthalamic nucleus stimulation. Mov. Disord. 21, 19411946 (2006).46. Shotbolt, P. et al. Relationships between deep brain stimulation and impulse control disorders in Parkinsons disease, with a literature review. Parkinsonism Relat. Disord. 18, 1016 (2012).

47. Demetriades, P., Rickards, H. & Cavanna, A. E. Impulse control disorders following deep brain stimulation of the subthalamic nucleus in Parkinsons disease: clinical aspects. Parkinsons Dis. 2011, 658415 (2011).

48. Moum, S. J. et al. Effects of STN and GPi deep brain stimulation on impulse control disorders and dopamine dysregulation syndrome. PLoS One 7, e29768 (2012).

49. Kim, Y. E. et al. Impulse control and related behaviors after bilateral subthalamic stimulation in patients with Parkinsons disease. J. Clin. Neurosci. 20, 964969 (2013).

50. Hack, N. et al. Impulsive and compulsive behaviors in Parkinson Study Group (PSG) centers performing deep brain stimulation surgery. J. Parkinsons Dis. 4, 591598 (2014).

51. Thobois, S. et al. Non-motor dopamine withdrawal syndrome after surgery for Parkinsons disease: predictors and underlying mesolimbic denervation. Brain 133, 11111127 (2010).

52. Pagonabarraga, J., Kulisevsky, J., Strafella, A. P. & Krack, P. Apathy in Parkinsons disease: Clinical features, neural substrates, diagnosis, and treatment. Lancet Neurol. 14, 518531 (2015).

53. Higuchi, M. et al. Predictors of the emergence of apathy after bilateral stimulation of the subthalamic nucleus in patients with Parkinsons disease. Neuromodulation 18, 113117 (2015).

54. Voon, V. et al. A multicentre study on suicide outcomes following subthalamic stimulation for Parkinsons disease. Brain 131, 27202728 (2008).

55. Weintraub, D. et al. Suicide ideation and behaviours after STN and GPi DBS surgery for Parkinsons disease: results from a randomised, controlled trial.J. Neurol. Neurosurg. Psychiatry 84, 11131118 (2013).56. Chaudhuri, K. R. & Martinez-Martin, P. Clinical assessment of nocturnal disability in Parkinsons disease: the Parkinson's Disease Sleep Scale. Neurology 63, S17S20 (2004).

57. Chaudhuri, K. R. & Healy, D. G. Schapira AHV. Non-motor symptoms of Parkinsons disease: diagnosis and management. Lancet Neurol. 5, 235245 (2006).

58. Iranzo, A., Valldeoriola, F., Santamara, J., Tolosa, E. & Rumi, J. Sleep symptoms and polysomnographic architecture in advanced Parkinsons disease after chronic bilateral subthalamic stimulation. J. Neurol. Neurosurg. Psychiatry 72, 661664 (2002).

59. Hjort, N., stergaard, K. & Dupont, E. Improvement of sleep quality in patients with advanced Parkinsons disease treated with deep brain stimulation of the subthalamic nucleus. Mov. Disord. 19, 196199 (2004).

60. Amara, A. W. et al. Unilateral subthalamic nucleus deep brain stimulation improves sleep quality in Parkinsons disease. Parkinsonism Relat. Disord. 18, 6368 (2012).

61. Lyons, K. E. & Pahwa, R. Effects of bilateral subthalamic nucleus stimulation on sleep, daytime sleepiness, and early morning dystonia in patients with Parkinson disease. J. Neurosurg. 104, 502505 (2006).

62. Loher, T. J., Burgunder, J.-M., Weber, S., Sommerhalder, R. & Krauss, J. K. Effect of chronic pallidal deep brain stimulation on off period dystonia and sensory symptoms in advanced Parkinsons disease. J. Neurol. Neurosurg. Psychiatry 73, 395399 (2002).

63. Kim, H.-J., Jeon, B. S., Lee, J.-Y., Paek, S. H. & Kim, D. G. The benet of subthalamic deep brain stimulation for pain in Parkinson disease: a 2-year follow-up study. Neurosurgery 70, 1823 (2012).

64. Cury, R. G. et al. Effects of deep brain stimulation on pain and other nonmotor symptoms in Parkinson disease. Neurology 83, 14031409 (2014).

65. Gierthmhlen, J. et al. Inuence of deep brain stimulation and levodopa on sensory signs in Parkinsons disease. Mov. Disord. 25, 11951202 (2010).

66. Chaudhuri, K. R. et al. Kings Parkinson's disease pain scale, the rst scale for pain in PD: an international validation. Mov. Disord. 30, 16231631 (2015).

67. Seif, C. et al. Effect of subthalamic deep brain stimulation on the function of the urinary bladder. Ann. Neurol. 55, 118120 (2004).

68. Herzog, J. et al. Subthalamic stimulation modulates cortical control of urinary bladder in Parkinsons disease. Brain 129, 33663375 (2006).

69. Winge, K. et al. Lower urinary tract symptoms and bladder control in advanced Parkinsons disease: effects of deep brain stimulation in the subthalamic nucleus. Mov. Disord. 22, 220225 (2007).

70. Arai, E. et al. Subthalamic deep brain stimulation can improve gastric emptying in Parkinsons disease. Brain 135, 14781485 (2012).

71. Zibetti, M. et al. Motor and nonmotor symptom follow-up in parkinsonian patients after deep brain stimulation of the subthalamic nucleus. Eur. Neurol. 58, 218223 (2007).

72. Troche, M. S., Brandimore, A. E., Foote, K. D. & Okun, M. S. Swallowing and deep brain stimulation in Parkinsons disease: a systematic review. Parkinsonism Relat. Disord. 19, 783788 (2013).

73. Derrey, S. et al. Impact of deep brain stimulation on pharyngo-esophageal motility: a randomized cross-over study. Neurogastroenterol. Motil. 27, 12141222 (2015).

74. Suttrup, I. & Warnecke, T. Dysphagia in Parkinsons disease. Dysphagia 31, 2432 (2016).

75. Stemper, B. et al. Deep brain stimulation improves orthostatic regulation of patients with Parkinson disease. Neurology 67, 17811785 (2006).

76. Trachani, E. et al. Heart rate variability in Parkinsons disease unaffected by deep brain stimulation. Acta Neurol. Scand. 126, 5661 (2012).

77. Sumi, K. et al. Effect of subthalamic nucleus deep brain stimulation on the autonomic nervous system in Parkinsons disease patients assessed by spectral analyses of R-R interval variability and blood pressure variability. Stereotact. Funct. Neurosurg. 90, 248254 (2012).

78. Hummel, T., Jahnke, U., Sommer, U., Reichmann, H. & Mller, A. Olfactory function in patients with idiopathic Parkinsons disease: effects of deep brain stimulation in the subthalamic nucleus. J. Neural Transm. 112, 669676 (2005).

79. Fabbri, M. et al. Subthalamic deep brain stimulation effects on odor identication in Parkinsons disease. Eur. J. Neurol. 22, 207210 (2015).

80. Guo, X. et al. Effects of bilateral deep brain stimulation of the subthalamic nucleus on olfactory function in Parkinsons disease patients. Stereotact. Funct. Neurosurg. 86, 237244 (2008).

81. Chen, H., Zhang, S. M., Hernn, M. A., Willett, W. C. & Ascherio, A. Weight loss in Parkinsons disease. Ann. Neurol. 53, 676679 (2003).

82. Rieu, I. et al. Body weight gain and deep brain stimulation. J. Neurol. Sci. 310, 267270 (2011).

83. Strowd, R. E. et al. Weight change following deep brain stimulation for movement disorders. J. Neurol. 257, 12931297 (2010).

84. Strowd, R. E. et al. Association between subthalamic nucleus deep brain stimulation and weight gain: results of a case-control study. Clin. Neurol. Neurosurg. 140, 3842 (2016).

85. Gironell, A., Pascual-Sedano, B., Otermin, P. & Kulisevsky, J. Weight gain after functional surgery for Parkinsons disease. Neurologia 17, 310316 (2002).

86. Foubert-Samier, A. et al. A long-term follow-up of weight changes in subthalamic nucleus stimulated Parkinsons disease patients. Rev. Neurol. 168, 173176 (2012).

Published in partnership with the Parkinson's Disease Foundation npj Parkinson's Disease (2017) 16024

Effect of Parkinson surgery on non-motor symptoms MM Kurtis et al

12

87. Montaurier, C. et al. Mechanisms of body weight gain in patients with Parkinsons disease after subthalamic stimulation. Brain 130, 18081818 (2007).

88. Walker, H. C. et al. Weight changes associated with unilateral STN DBS and advanced PD. Parkinsonism Relat. Disord. 15, 709711 (2009).

89. Nirenberg, M. J. & Waters, C. Compulsive eating and weight gain related to dopamine agonist use. Mov. Disord. 21, 524529 (2006).

90. Macia, F. et al. Parkinsons disease patients with bilateral subthalamic deep brain stimulation gain weight. Mov. Disord. 19, 206212 (2004).

91. Weintraub, D. et al. Validation of the questionnaire for impulsive-compulsive disorders in Parkinsons disease. Mov. Disord. 24, 14611467 (2009).

92. Sixel-Dring, F., Schweitzer, M., Mollenhauer, B. & Trenkwalder, C. Intraindividual variability of REM sleep behavior disorder in Parkinsons disease: a comparative assessment using a new REM sleep behavior disorder severity scale (RBDSS) for clinical routine. J. Clin. Sleep Med. 7, 7580 (2011).

93. Okun, M. S. et al. Cognition and mood in Parkinsons disease in subthalamic nucleus versus globus pallidus interna deep brain stimulation: the COMPARE trial. Ann. Neurol. 65, 586595 (2009).

94. Anderson, V. C., Burchiel, K. J., Hogarth, P., Favre, J. & Hammerstad, J. P. Pallidal vs subthalamic nucleus deep brain stimulation in Parkinson disease. Arch. Neurol. 62, 554560 (2005).

95. Reker, P., Dembek, T. A., Becker, J., Visser-Vandewalle, V. & Timmermann, L. Directional deep brain stimulation: a case of avoiding dysarthria with bipolar directional current steering. Parkinsonism Relat. Disord. 31, 156158 (2016).

96. Steigerwald, F., Mller, L., Johannes, S., Matthies, C. & Volkmann, J. Directional deep brain stimulation of the subthalamic nucleus: a pilot study using a novel neurostimulation device. Mov. Disord. 31, 12401243 (2016).

97. Marras, C. & Chaudhuri, K. R. Nonmotor features of Parkinsons disease subtypes. Mov. Disord. 31, 10951102 (2016).

This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the articles Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

Web End =http://creativecommons.org/licenses/ http://creativecommons.org/licenses/by/4.0/

Web End =by/4.0/

The Author(s) 2017

npj Parkinson's Disease (2017) 16024 Published in partnership with the Parkinson's Disease Foundation