Surgery and Psychiatry

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Peer-Review Reports

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Surgery for Psychiatric DisordersJudy Luigjes1, Bart P. de Kwaasteniet1, Pelle P. de Koning1, Marloes S. Oudijn1, Pepijn van den Munckhof 2,

. Richard Schuurman2, Damiaan Denys1,3

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INTRODUCTION

Surgery in psychiatric disorders involvesablative and stimulation techniques and hasa long and turbulent history. The signifi-cant progress of our understanding of thepathophysiology of psychiatric disorders,

Key words� Addiction� Deep brain stimulation� Major depressive disorder� Obsessive-compulsive disorder� Psychosurgery� Tourette syndrome

Abbreviations and AcronymsALIC: Anterior limb of the internal capsuleAN: Anorexia nervosaDBS: Deep brain stimulationDDS: Dopamine dysregulation syndromeGPi: Globus pallidus

DRS: ●●●

IPG: Internal pulse generatorTP: Inferior thalamic peduncle

DD: Major depressive disorderPFC: Medial prefrontal cortexAc: Nucleus accumbensCD: Obsessive-compulsive disorderFC: Circuits connecting orbitofrontal cortexFC: Orbitofrontal cortexG: Pathologic gamblingCG: Subcallosal cingulate gyrusTN: Subthalamic nucleusRD: Therapy-resistant depression

TS: Tourette syndromeVC/VS: Ventral capsule/ventral striatumY-BOCS: Yale-Brown obsessive-compulsive scale

From the Departments of 1Psychiatry and2Neurosurgery, Academic Medical Center,

niversity of Amsterdam, Amsterdam; and 3The Institutefor Neuroscience, an institute of the Royal NetherlandsAcademy of Arts and Sciences, Amsterdam, TheNetherlands

To whom correspondence should be addressed:Damiaan Denys, M.D., Ph.D. [E-mail: [email protected]]

Citation: World Neurosurg. (2012).http://dx.doi.org/10.1016/j.wneu.2012.03.009

Journal homepage: www.WORLDNEUROSURGERY.org

Available online: www.sciencedirect.com

1878-8750/$ - see front matter © 2012 Elsevier Inc.All rights reserved.

thanks to preclinical and neuroimaging V

WORLD NEUROSURGERY xx [x]: xxx, MON

tudies and the development in technologyf the past decades, has been enabled byermanent deep brain stimulation (DBS).ith DBS, surgically implanted electrodes

eliver controlled electrical pulses to tar-eted areas of the brain. Compared to abla-

ive neurosurgery, DBS is reversible and ad-ustable. The settings of the stimulation cane changed and the electrodes can be re-oved from the brain. The objective of this

eview is to give an overview of the recentesearch in the field of DBS and psychiatry.

e start with a short introduction of theistory of surgery for psychiatric disorders,description of the procedure, and team

equirements for DBS for psychiatric disor-ers.

ISTORY OF SURGERY FOR PSYCHIATRICISORDERS

t the Berlin Medical Congress of 1889, thewiss psychiatrist Gottlieb Burckhardt1836 –1907) presented his operative find-ngs and outcomes of selective removal ofhe left frontotemporal cerebral cortex in amall series of six patients with various di-gnoses, one with chronic mania, one withrimary dementia, and four with primäre

Surgery in psychiatric disorders has ain the past few decades with deep braand reversible neurosurgical interventcontrolled electrical pulses to targetedfor therapy-refractory obsessive-comptrolled and open trials have been condaround 54%. Open trials have shown erefractory depression and case reportaddiction. Another promising indicatioefficacy of DBS is shown by severalFurther research should focus on optimand increasing the number of controllindications for DBS and new target oresearch.

errücktheit, a clinical category equivalent

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o schizophrenia (10). Burckhardt claimedsuccess in three of his six patients but hisunconventional work was heavily criticizedby international medical colleagues, and hediscontinued the project after publicationof his surgical results in 1891 (66). In 1910,the Estonian neurosurgeon Lodovicus Puusepp(1875–1942) disrupted the “association fi-bers” between the frontal and parietal cor-tex in three patients with manic depressionor “epileptic equivalents” (86). It was notuntil 1935 when neurologist Egas Moniz(1874 –1955), regarded by many as thefounder of modern psychosurgery, andneurosurgeon Almeida Lima (1903–1985)performed the first prefrontal leukotomiesin 20 psychiatric patients, suffering fromschizophrenia, bipolar disorder, and anxi-ety disorders (75). The American neurolo-gist Walter Freeman (1895–1972) and neu-rosurgeon James Watts (1904 –1994) beganperforming leukotomies in 1936 (27), andtheir modified lobotomy technique was ad-opted by neurosurgeons around the world.By 1949 it was estimated that 10,000 lobot-omies had been performed in the UnitedStates, with similar numbers collectively inthe United Kingdom (102).

Moniz was awarded the Nobel Prize in

history and has regained momentumimulation (DBS). DBS is an adjustableusing implanted electrodes to deliveras of the brain. It holds great promisee disorder. Several double-blind con-d and the response rate is estimated

uraging results with DBS for therapy-ve shown potential effects of DBS on

Tourette syndrome, where potentiale series and a few controlled trials.g DBS with respect to target locationouble-blinded trials. In addition, newns should be explored in preclinical

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1949 for the “discovery of the therapeutic

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value of prefrontal leukotomy in certainpsychoses,” but, at that time, the procedurewas already regarded as unethical and un-scientific. Beside the often-expressed fun-damental moral reservations, the technicalprocedure itself, with operations merelyperformed by eye, was also discredited. In1949, the French neurosurgeon Talairach(1911–2007) therefore presented the use of astereotactic frame to selectively coagulatethe frontothalamic fibers in the anteriorlimb of the internal capsule at the IVth In-ternational Congress of Neurology in Paris(103). Hereafter, stereotactic psychosur-gery quickly replaced the prefrontal lobot-omy, and was applied for various psychiat-ric disorders: anterior capsulotomy forgeneral anxiety disorder and obsessive-compulsive disorder (OCD), cingulotomyfor addiction, bipolar disorder, depression,OCD, schizoaffective disorder and schizo-phrenia, subcaudate tractotomy for depres-sion, OCD and schizophrenia, anterior cal-losotomy for schizoaffective disorder andschizophrenia (see Leiphart and Valone[57] for review), thalamotomy for Tourettesyndrome (TS) (36), hypothalamotomy foraddiction (17), aggressiveness (93) and sex-ual disorders (89), and amygdalotomy foraggressive behavior associated with mentalimpairment (77). Although stereotacticpsychosurgery in the early years almost ex-clusively used ablative lesions, experimen-tal DBS in psychiatric patients was alreadyperformed in the 1950s by research groupsat the Mayo Clinic in Rochester and TulaneUniversity in New Orleans (8, 37).

Since the introduction of psychoactivedrugs like chlorpromazine, reserpine, lith-ium, haloperidol, imipramine, and diaze-pam in the 1950s and 1960s, the number ofpatients requiring stereotactic psychosur-gery decreased enormously. At present, it isonly applied in treatment-refractory psychi-atric disorders. Since the 1987 publicationfrom Benabid et al. (6) on thalamic DBS inparkinsonian patients with tremor, DBShas virtually replaced ablative lesions in ste-reotactic neurosurgery for both movementand psychiatric disorders.

Procedure for ImplantationFor electrode implantation, a stereotactichead frame is attached to the patient’s skull.Then, the patient is imaged with the frameon to localize the target(s) on magnetic res-
onance imaging or computed tomography.
2 www.SCIENCEDIRECT.com

After burr holes are made in the patient’sskull, stereotactic frame guidance is used toplace the leads in the targeted area. The leadis then connected to an extension cable andtunneled under the scalp and skin of theneck to a subcutaneous pocket in the sub-clavicular or abdominal area that holds theinternal pulse generator (IPG). The IPG’slife depends on parameter settings, afterwhich it needs to be surgically replaced.Since DBS in psychiatric disorders generallyrequires high amperages, IPGs are often re-placed after 9 –18 months. The recent devel-opment of rechargeable IPGs has pro-longed their life significantly.

Administering StimulationThe implantable IPG contains a battery forpower and a microchip to regulate the stim-ulation settings. The activity of the elec-trodes can be programmed externally with aportable appliance communicating withthe pulse generator through telemetry. Theelectrodes have various contact points(mostly four), which can be stimulated sep-arately, thereby enabling adjustment of theanatomic reach of the stimulation area. Fre-quency, intensity, and pulse width are alsoprogrammable. The programming facilityhas the advantage that, after implantation,the stimulation can be optimized to in-crease the therapeutic effects and to de-crease side effects.

Team RequirementsDBS in psychiatric disorders requires a mul-tidisciplinary collaboration between the de-partments of neurosurgery and psychiatry.Careful patient selection is key in DBS treat-ment. Therefore, a psychiatrist with exper-tise in the specific psychiatric disorder ofthe DBS indication is needed to diagnosethe severity of symptoms, presence of co-morbidity, and to evaluate criteria and theirexclusion. Patients should only be includedwhen all other available treatments for thedisorder were administered. In addition,psychological and social evaluation is re-quired preferably by psychologists and spe-cialized nurses to assess the patient’s moti-vation, the patient’s support structure, andhis/her social functioning. The last step inthe patient selection is to exclude medicalconditions or structural brain abnormali-
ties contraindicative for surgery.
WORLD NEUROSURGERY, http://d

The surgery is performed by a neurosur-gical team with specific expertise in stereo-tactic and functional neurosurgery. Per-forming neurosurgery on awake patientsposes challenges for the surgical team. Psy-chological assistance from the psychiatricteam who is familiar with the patient istherefore recommended as long as the pa-tient is awake.

DBS programming is carried out duringregular follow-up visits by an expert psychi-atrist and a team including psychologists orspecialized nurses. The team has to betrained to assess symptoms and side ef-fects, and has to understand the technicalaspects of DBS. For some patients, it can bebeneficial to optimize the effect of DBS withthe help of cognitive behavioral therapy, forwhich trained behavioral therapists areneeded.

Since DBS for psychiatric disorders isstill an experimental treatment, systematicinvestigation of its efficacy, possible sideeffects, and underlying mechanisms of ac-tion are needed (52), and this needs to becarried out by a multidisciplinary investiga-tional team.

DBS IN THERAPY-REFRACTORY OCD

RationaleOCD is characterized by anxiety-provokingintrusive thoughts and repetitive behaviorthat are severe and time consuming (�1hour/day) and causes distinct distress. Ifleft untreated, it can have a devastating ef-fect on occupational functioning, relation-ships, and social activities. Specific treat-ments for OCD, such as pharmacotherapywith serotonin reuptake inhibitors and cog-nitive behavioral therapy, provide 40%–60% symptom reduction in half of thepatients. Approximately 10% of patients re-main severely affected and suffer fromtreatment-refractory OCD (15). For a smallproportion of these treatment-refractory pa-tients, DBS may be appropriate. It is estimatedthat since 1999 more than 100 patients withOCD have received experimental DBS in fivedifferent brain targets: the anterior limb of theinternal capsule (ALIC), nucleus accumbens(NAc), ventral capsule/ventral striatum (VC/VS), subthalamic nucleus (STN), and inferiorthalamic peduncle (ITP).

Circuits connecting orbitofrontal cortex(OFC), medial prefrontal cortex (mPFC),
basal ganglia and thalamus are central to
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OCD pathophysiology (33). OCD is associ-ated with hyperactivity of this cortical-stria-tal-pallidal-thalamic-cortical network (72).Although the exact mechanism of DSB isunknown, it is hypothesized that DBS in-hibits or functionally overrides this patho-logical hyperactivity (88). Although studiescombining imaging and DBS that may con-firm the inhibitory characteristics of DBS,are sparse, it is suggested that hyperactivityin the OFC correlates with the severity ofOCD, and that OFC activity normalizes afterDBS (1, 56).

Efficacy of DBS for OCDWe identified four open and seven con-trolled studies with a blinded on– off phase.The inclusion ratio per study ranged from4 –27 patients with OCD (Table 1). Consid-ering the amount of larger studies with DBSin OCD, case studies were excluded. Onestudy (31) was omitted from final efficacyanalysis because of its design that includedresults from earlier studies.

Anterior Limb of Internal Capsule. The ALICcontains fibers connecting the prefrontalcortex and the subcortical nuclei, includingthe dorsomedial thalamus. The choice ofthe ALIC as a brain target for DBS was basedon the experience with the anterior capsu-lotomy for therapy-refractory OCD. This

Table 1. Overview of Published Studies o

Study Target

Nuttin et al., 1999 (81)† ALIC

Nuttin et al., 2003 (82)† ALIC

Abelson et al., 2005 (1)† ALIC

Sturm et al., 2003 NAc

Denys et al., 2010 (16)† NAc

Huff et al., 2010† Right-NAc

Greenberg et al., 2006 (32) VC/VS

Goodman et al., 2010 (29)† VC/VS

Jiménez-Ponce et al., 2009 (41) ITP

Mallet et al., 2008 (64)† STN

ALIC, the anterior limb of internal capsule; NAc, nucleusResponder definition: �35% Y-BOCS reduction.*Responder definition: �25% Y-BOCS reduction.†Controlled studies.

ablative procedure had shown positive re-


sponse in approximately 50% of partici-pants (74).

In 1999, Nuttin et al. (81) published thefirst article on bilateral ALIC DBS in fourpatients. They reported beneficial effectsin three of four patients. Another study(82) by the same group in 2003 describedsix patients with DBS in the ALIC for aperiod of 21 months. Four patients partic-ipated in a crossover evaluation; threeshowed a 35% or greater reduction insymptoms on the Yale-Brown obsessive-compulsive scale (Y-BOCS) (30). Abelsonet al. (1) reported two responders of fourpatients in a randomized on– off se-quence of four 3-week blocks, followed byan open stimulation phase.

VentralCapsule/VentralStriatum. Subsequently,adjacent structures of the internal capsulewere targeted for DBS. The ventral striatalarea contains the ventral caudate nucleusand NAc. It is thought to be associatedwith motivation and reward. Combinedwith the ventral capsule it is referred to asthe VC/VS region. This brain target waschosen based on the experience with sub-caudate tractotomy (see Leiphart and Val-one [57] for review) and gamma knifecapsulotomy at the ventral region of theALIC for treatment-refractory OCD (1). In2006, Greenberg et al. (32) conducted astudy with 10 patients who underwent bi-

ep Brain Stimulation for Therapy-Refractor

Number of PatientsFollow-up

Period (months)

4 Not mentioned

6 3–31

4 4–23

5 24–30

16 21

10 12

10 36

6 12

5 12

16 3 months of stimulation

ens; VC/VS, ventral capsule/ventral striatum; STN, subthala

lateral stimulation of the VC/VS. Eight pa-

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tients were observed for 3 years. Four ofeight patients were considered respond-ers (�35% symptom reduction). A com-bined study on the long-term results from26 patients with ALIC/VC/VS implanta-tion by the same American and Belgiangroups reported an overall responder rate of62% after a mean of 31.4 months of follow-up(31). Refinement of the implantation site to amore posterior location, toward the junctionof the anterior capsule, anterior commissure,and bed nucleus of the stria terminalis, im-proved the results. A study by Goodman et al.(29), using a blinded, staggered-onset designof six OCD patients with VC/VS DBS, showedfour of six responders after 12 months’ fol-low-up.

Nucleus Accumbens. The NAc is locatedwhere the head of the caudate and the ante-rior portion of the putamen meet, just be-neath the ALIC, and plays a key role in thereward circuitry (18, 19, 49, 96). The NAc isconsidered a promising target for DBS be-cause there is evidence of dysfunction of thereward system in OCD. A study by Figee etal. (24) showed attenuated reward anticipa-tion activity in the NAc of patients with OCDcompared with healthy controls. Sturm etal. (101) published the first DBS results ofunilateral, right-sided NAc implantation infour patients with OCD. This open studyconsidered three of four patients as re-

sessive-Compulsive Disorder

Response

In 3 of 4, some beneficial effects were seen

Responder 50%

Responder 50%

Responder 60% (Y-BOCS scores not mentioned)

Responder 56%

Responder 10%

Responder 40%

Responder 33%

Responder 100%

Responder* 75%

cleus; ITP, inferior thalamic peduncle.

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reported. A subsequent double-blind studyby the same group in 2010 with 10 OCDpatients reported only one responder at1-year follow-up, although five patientswere considered partial responders (�25%symptom improvement) (18). In 2010 De-nys et al. (16) published a study on 16 pa-tients with bilateral NAc DBS for OCD. Thisstudy consisted of an open 8-month treat-ment phase, followed by a double-blind,crossover phase with randomly assigned2-week periods of active or sham stimula-tion. It ended with an open 12-month main-tenance phase. Nine of 16 patients were de-fined responders during follow-up.

Subthalamic Nucleus. The STN is part of thebasal ganglia and is located ventral to thethalamus, dorsal to the substantia nigra,and medial to the corticospinal tract. Stud-ies of DBS in Parkinson disease highlightedthe presumable role of the STN in behav-ioral alteration and reducing OCD symp-toms. After initial positive results in casestudies (26, 63), Mallet et al. (64) reportedon the efficacy of bilateral STN stimulationin 16 OCD patients. Twelve of 16 patientswere categorized as responders, althoughresponders were defined by a mean de-crease of 25% or greater in Y-BOCS score inthis study.

Inferior Thalamic Peduncle. The ITP links thethalamus and the OFC and is part of theorbitofrontal-thalamic system. Becausethese structures are central in the patho-physiology of OCD (33), it was hypothe-sized that electrical stimulation of thiswhite matter bundle could reduce OCDsymptoms. The only study on DBS for OCDin the ITP was an open study conducted byJiménez-Ponce et al. (41). They reported fiveof five responders on the Y-BOCS after 12months’ follow-up.

Limitations and SafetySide effects of DBS are related to either thesurgical procedure or to the stimulation it-self. Bleeding rates of DBS surgery are be-tween 0.2% and 5% (94). Other side effectsreported related to the operation are woundinfection and perioperative headache (16).Side effects related to the stimulation varywidely. They are usually reversible by cessa-tion or adjustment of stimulation parame-ters. Acute mood changes during the first
few days of stimulation have been reported,

such as transient sadness, anxiety, and eu-phoria, sometimes to the extent of hypo-manic and manic symptoms (29). Transienthypomania is the side effect most com-monly observed immediately after stimula-tion in DBS for patients with OCD. Tran-sient hypomanic episodes seem to occurmore often in the VC/VS–NAc region.Chronic mood improvement is an unin-tended but favorable side effect of DBS be-cause most treatment-refractory patients withOCD suffer from comorbid major depres-sion. Antidepressive effects were reported af-ter NAc, ALIC, and VC/VS stimulation (1, 16,32). Because no mood improvement was ob-served after STN stimulation (64), this im-provement seems to be related to DBS of theventral striatum in particular. Stimulationcessation can result in severe worsening ofmood. However, this worsening can be re-versed by reactivation of the stimulation.

Conclusion and Future DirectionsDBS is a promising therapy for treatment-re-fractory patients with OCD as 44 of 82 pa-tients were defined responders, resulting inan average overall response rate of 54%. Be-cause of the various study designs with differ-ing outcome measures, duration of follow-up, and limited number of subjects, aclarifying comparison of the efficacy per braintarget remains difficult. Further researchshould focus on optimizing this therapy withrespect to target location, patient selectionand management, and further investigationof its mechanism of action.

DBS IN THERAPY-REFRACTORYDEPRESSION

RationaleMajor depressive disorder (MDD) has a life-time prevalence of 15%–20% (46). With ad-equate treatment, most patients with MDDrecover to a normal level of functioning.However, up to 40% of patients who re-spond to antidepressant treatment developresidual symptoms despite optimized treat-ment (23). Furthermore, up to 33% of pa-tients do not reach remission criteria de-spite adequate sequenced antidepressanttreatment, resulting in therapy-resistantdepression (TRD) (91).

Although the exact pathophysiology of
MDD remains unknown, a convincing net-

work model has been described (70). Ac-cording to this model, there is a dysregulationbetween ventral limbic regions (including an-terior insula, hippocampus, subcallosal cin-gulated, and brainstem) and dorsal corticalregions (including prefrontal cortex, premo-tor area, parietal cortex), with increased lim-bic activity and decreased cortical activity inMDD. Similarly, reversal of this pattern hasbeen found during mood improvement anddepression remission (14, 44, 99).

Efficacy of DBS for DepressionWe identified four open studies using aunique caseload and one study describingthe follow-up results after 3 years (Table 2).The inclusion ratio ranged between 8 and20 patients. At the time of writing, no con-trolled studies on DBS for depression havebeen published.

Ventral Capsule/Ventral Striatum. The VC/VSas a potential DBS target for TRD was basedon research with this target in OCD (32, 81).Depressive symptoms were also improvedin addition to those of OCD. Malone et al.(65) included 15 highly refractory depres-sive patients, in whom electrodes were im-planted bilaterally in the VC/VS region fol-lowing the dorsal-ventral trajectory of theanterior limb of the internal capsule (28).They found a response rate of 40% after 6months and 53.3% at last follow-up (mean23.5 months, �14.9 months). Remissionrates were 20% at 6 months and 40% at lastfollow-up. The mean HDRS score de-creased from 33.1 at baseline to 17.5 after 6months follow-up.

Nucleus Accumbens. Bewernick et al. (7) se-lected the NAc as target for DBS in TRD.Similar to the VC/VS area, Denys et al. (16)observed a substantial mood improvementin patients with OCD treated with bilateralNAc DBS. Furthermore, major depressionappears to be associated with hypoactiva-tion of the NAc during reward outcome,which is thought to be associated with theanhedonic aspects of depression (84). TheNAc receives projections from the ventraltegmental area, which produces dopamine,and from regions involved in emotionalprocessing, including the OFC andamygdala (78). Stimulating the NAc couldtherefore modulate neural activity in otheremotion and motivation centers in the brain
(95). Bewernick et al. (7) included 10 TRD
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patients who were implanted with bilateralDBS electrodes. A response was defined as a50% reduction on 28-item HDRS, and re-mission as a score of 10 or lower on HDRS.Response and remission rates after 12months were 50% and 30%, respectively.The mean HDRS score decreased from 32.5at baseline to 20.8 after 12 months of fol-low-up.

Subcallosal Cingulate Gyrus. The subcallosalcingulate gyrus (SCG), which includesBrodmann area 25, is a key hub in themood-regulating circuit (69, 97). Depres-ion is associated with increased activity ofCG during rest and during performance ofmotional tasks (13, 20, 43, 70, 97). Con-ersely, decreased activity in this region af-er antidepressant treatment, transcranial

agnetic stimulation, and electroconvul-ive therapy has been found (3, 71). Thesendings suggest that the SCG is an impor-

ant region in the pathophysiology of de-ression. Therefore this region became of

nterest for DBS (60).Lozano et al. (60) investigated the effects

f DBS in 20 TRD patients by implantingilateral electrodes in the SCG. From base-

ine to 12 months of stimulation, the meanDRS (17-item) score decreased from 24.4

Table 2. Overview of Published Studies oRefractory Depression

Study Target

Malone et al., 2009 (65) VC/VS

Bewernick et al., 2009 NAc

Lozano et al., 2008 (60)Follow-up: Kennedy et al., 2011 (45)

SCGSCG

Puidgemont et al., 2011 (85) SCG

NAc, nucleus accumbens; SCG, subcallosal cingulate gyru*Mean last follow-up was 23.5 � 14.9 months.†Last follow-up between 3 and 6 years.

o 12.6. After 12 months follow-up, they re- t


orted a response rate of 55% and a remis-ion rate of 35%. After 3 years of follow-up,esponse rates were 75%, and remissionates 50% (45). At last follow-up (range,– 6 years), the average response rate was4.3%, and the average remission rate was2.9%. Recently, Puigdemont et al. (85) re-orted on eight TRD patients with DBS in

he same target area. At 6-month follow-up,esponse and remission rates were 87.5%nd 37.5%, respectively, on HDRS 17-item.t 1 year follow-up, these rates were 62.5%nd 50%.

imitations and Safetyide effects directly related to the stimula-ion are limited in DBS for depression.tudies reported an increase of anxiety andension, hypomania, and insomnia (7, 65).ll of these side effects were transient andould be stopped by cessation or adjust-ent of stimulation parameters.

onclusion and Future DirectionsBS is a promising therapy for treatment-

efractory depression, with a comparablehort- and long-term clinical efficacy be-

ep Brain Stimulation for Therapy-

ber ofients

Follow-upPeriod (months) Response

5 6Last follow-up*

Response 40%Remission 20%Response 53.3%Remission 40%

0 12 Response 50%Remission 30%

00

1236

Last follow-up†

Response 55%Remission 35%Response 75%Remission 50%Response 64.3%Remission 42.9%

8 612

Response 87.5%Remission 37.5%Response 62.5%Remission 50%

S, ventral capsule/ventral striatum.

ween the different brain targets. The fact c

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hat DBS is clinically effective in differentrain targets, together with positron emis-ion tomography findings showing de-reased metabolism in SGC and other pre-rontal regions after NAc DBS (7), suggestshat DBS may indeed modulate the patho-ogic neural network involved in depres-ion. However, possible clinical improve-ent due to the placebo effect cannot be

uled out. Furthermore, DBS patients gotore supportive care compared to non-BS patients, with more frequent follow-up

isits. The attention of health care profes-ionals and more frequent visits alone coulde the cause of clinical improvement in DBSatients. Therefore, double-blind con-

rolled crossover studies are needed to de-ermine whether DBS is an efficaciousntidepressant treatment. In addition,euroimaging and neuropsychologictudies of DBS in TRD are needed to im-rove our understanding of the patho-hysiology of depression and the mecha-ism of action of DBS. It is the generallinical impression that reduction of TRDymptoms takes longer than OCD symp-oms after DBS. Another common clinicalbservation is that TRD symptoms during

he optimization period are more prone toxtreme fluctuations, therefore TRD pa-ients are more difficult to stabilize overime than OCD patients. Given the risk foruicide, TRD patients need to be moni-ored very carefully.

BS IN THERAPY-REFRACTORYDDICTION

ationalerug addiction has detrimental effects on

he affected individuals and their environ-ent and it possess a heavy burden on soci-

ty as a whole. Addiction is a new indicationor DBS, but the rationale to consider DBSs a potentially effective treatment for ad-iction is similar to that in depression andCD and can be summarized in three main

easons. (1) Case reports and animal re-earch have shown promising results forBS for addiction (e.g., Kuhn et al. [54],assoler et al. [105]). (2) Preclinical re-earch and neuroimaging studies in theast two decades have increased our under-tanding of the underlying pathophysio-ogic mechanisms behind addiction byhowing affected salience attribution and

f De

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ognitive control in addiction (25, 107). The


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main brain structures involved in theseprocesses are the ventral tegmental area,OFC, striatum, insula, amygdala, cingu-lated gyrus, dorsalateral prefrontal cortex,and inferior frontal gyrus (50). (3) Relapserates after treatment for addiction are high(50%–70% after 1 year of completing treat-ment) and many patients do not respond atall to treatments. It is therefore important tokeep searching for new interventions (73,83).

Efficacy of DBS for AddictionWe identified three studies in which the in-dication of DBS treatment was addictionand 10 other studies in which the remissionof addiction was an unintended side effectof DBS in patients who were treated for adifferent disorder (Table 3). No controlledstudies on DBS and addiction have thus farbeen published.

Subthalamic Nucleus. The first studies to re-port a possible effect of DBS on addictionwere studies on STN DBS in Parkinson dis-

Table 3. Overview of Published Studies o

Study Addiction

Müller et al., 2009 (76) Alcohol

Kuhn et al., 2009 Alcohol

Kuhn et al., 2011 (53) Alcohol

Zhou et al., 2011 (110) Heroin

Kuhn et al., 2007 (54) Nicotine

Neuner et al., 2009 (80) Nicotine

Mantione, 2010 (67) Nicotine

Ardouin et al., 2006 (4) PG

Smeding et al., 2007 (100) PG

Bandini et al., 2007 PG, DDS

Witjas et al., 2005 (109) DDS

Knobel et al., 2008 (48) DDS

Lim et al., 2008 DDS

AD, anxiety disorder; DBS, deep brain stimulation; DDS,disorder; PG, pathologic gambling; STN, subthalamic n

ease. In patients with Parkinson disease, do- h


amine replacement therapy can sometimesevelop into addictive use of medicationalled dopamine dysregulation syndromeDDS). In addition, DDS is associated with thenset of impulse control disorders such asathologic gambling (PG), compulsive shop-ing, or hypersexuality (22). The first two caseeries on this subject by Ardouin et al. (4) and

itjas et al. (109) described nine patients withDS or PG, who improved or resolved their

ddiction after STN DBS. Similarly, Knobel etl. (48) described an improvement of DDS af-er STN DBS. However, Smeding et al. (100)escribed the opposite effect: a patient with-ut a history of addictive behaviors developedpattern of PG after STN DBS treatment de-

pite a clear reduction of levodopa and dopa-ine agonist treatment. Lim et al. (58) de-

cribed a mixed outcome in 19 patients withTN DBS: five worsened on their DDS or PGehavior, six resolved their addictive behav-

ors, and in eight patients DDS or PG re-ained unchanged. In many of these pa-

ients, changes in the use of levodopa oropamine agonist treatment after DBS could

ep Brain Stimulation for Therapy-Refractor

etNumber of

PatientsFollow-up

Period (months)

c 3 12–15

c 1 12

c 1 12

c 1 84

c 10 30

c 1 36

c 1 24

7 40 (mean)

1 42

2 6–12

2 18

1 18

19 16 (mean)

ne dysregulation syndrome; DEP, depression; NAc, nucleusTS, Tourette syndrome.

ave influenced their addictive behaviors as c


ell. In the study by Lim et al. (58), there was aelation between poor outcome on behavioralymptoms and the use of higher postopera-ive medication use. It is therefore difficult toeduce from these reports the direct effect ofTN DBS on addictive behaviors.

ucleus Accumbens. Four studies illustratedchange in addiction after NAc DBS in-

ended to treat another psychiatric disorder51, 54, 67). The first study was a single caseeport by Kuhn et al. (54) who described aatient treated for anxiety and depressionith NAc DBS who had comorbid alcoholependence. Although the DBS treatmentad a negligible effect on the anxiety andepressive symptoms, he was able to reduceis alcohol intake to moderate amounts,hich lasted during the 1-year follow-up pe-

iod. In a second report by Kuhn et al. (51)bout patients treated with NAc DBS forsychiatric disorders (OCD, anxiety disor-er, or TS) 3 of 10 smoker patients stoppedmoking after NAc DBS and never relapseduring the 30-month follow-up period, auch higher rate than unaided smoking

diction

Response Comorbid Disorder

olvedroved

—

roved DP/AD

olved —

olved —

olvedhanged

AD/OCD/TS

olved GTS OCD

olved OCD

olved PD

rsened after DBS anded after changinggs � medication

PD

olved PD

olved PD

roved PD

rsenedhangedolved

PD

bens; OCD, obsessive-compulsive disorder; PD, Parkinson

f De y Ad

Targ

NA 2 res1 imp

NA 1 imp

NA 1 res

NA 1 res

NA 3 res7 unc

NA 1 res

NA 1 res

STN 7 res

STN 1 wostoppsettin

STN 2 res

STN 2 res

STN 1 imp

STN 5 wo8 unc6 res

dopami accum

essation in the general population. The

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T4

third and fourth studies are case reportsabout patients who quit smoking and re-mained abstinent in the follow-up periodafter DBS for OCD (67) and TS (80). In con-trast to the first case report, both patientsshowed symptom improvements for theprimary diagnosis.

There are only three published articleswho describe addiction as indication forDBS treatment, all of them using the NAc astarget area. The choice of the NAc as targetarea was based on these reports, animal re-search (38, 47, 59, 105), and the central rolethe NAc is thought to play in affected re-ward processing in addiction (50). A caseseries by Muller et al. (76) reported threepatients with severe refractory alcohol de-pendence receiving bilateral NAc DBS. In allpatients craving disappeared, two patientsremained abstinent during 1 year follow-up,and the other patient reduced his alcoholconsumption considerably. Using a similarapproach, another case report by Kuhn et al.(53) described a patient with alcohol depen-dency who reduced his alcohol use to occa-sional consumption after 8 months of DBSand completely stopped drinking after 1year of treatment. The third case report byZhou et al. (110) described a patient suffer-ing from chronic heroin dependence whorefrained from drug use after NAc DBS dur-ing a follow-up period of 6 years. Interest-ingly, the patient remained drug free after2–3 years of DBS treatment when the IPGwas turned off and later removed.

Limitations and SafetyA major limitation is that most of the re-ported patients were treated primarily foranother disorder, which makes it difficultto determine whether the found effect onaddiction is caused directly by the DBS, orwhether it is an indirect result after im-provement of the main disorder, such aslifestyle changes or altered medication use.Most side effects reported were transient. Inthe articles describing STN DBS, mild apa-thy was reported in two patients (4) andemotional instability and vivid dreaming inone patient (100). In the articles describingNAc DBS, a hypomanic episode of 2 weekswas reported in one patient (76), and mildconfusion and urinary incontinence in the12 hours after surgery in another patient(110). To explore and establish the efficacy
and safety of DBS in addiction, the results of

careful explorative studies have to beawaited.

Conclusions and Future ResearchDBS might be a promising therapy fortreatment-refractory addiction; however,at present no controlled trials with DBSfor addiction have been published. TheNAc seems a promising target area for DBSin addiction, as we have shown in a recentreview of both animal and human research(61).

DBS IN THERAPY-REFRACTORY TS

TS is a childhood-onset condition charac-terized by motor and vocal tics that arechronic (duration, �1 year) (55). Psychopa-thology is common and includes a wide va-riety of disorders, including OCD, attentiondeficit hyperactivity disorder, and variousdegrees of personality disorders (35). Al-though symptoms mostly improve by earlyadulthood, a significant number of patientsfail to respond to standard pharmacologicor behavioral therapies (12). TS is consid-ered a movement disorder, but has psychi-atric components and therefore will be dis-cussed in this review. The application ofDBS in therapy refractory TS was pioneeredby Vandewalle et al. in 1999 (104). About 60patients with TS have thus far been treatedby DBS (Table 4), targeting different areasof the thalamus, different areas of the inter-nal segment of the globus pallidus (GPi),the NAc, the STN, and the ALIC. The ratio-nale behind the different targets varies.Some studies target sensimotor areas to me-diate movement dysfunctionality, whereasothers target areas in the corticostriatal net-work to mediate the compulsive element ofthe disorder, especially in patients with co-morbid OCD. Three studies (2, 62, 108; withunique case load) have used a double-blindcontrolled design for testing the efficacy ofDBS, two studies (68, 98) used an open labeldesign in a larger group of patients (5 and 18,respectively), other studies are case reports orcase series. Two double-blind (2, 62) con-trolled studies used the thalamus as targetarea and showed moderate improvement inthe blinded condition (14% and 37%, respec-tively), with further improvement in the openfollow-up assessment phase (44% and 49%).The third blinded controlled study (108) com-
pared the effects of thalamic stimulation, GPi
TH 2012

stimulation, stimulation in both areas, andsham stimulation in three patients and foundthe best effects for GPi stimulation. Further-more, an improvement of symptoms is re-ported in all but two other studies. One studyfirst reported no change in symptoms in onepatient (21) and another reported a worseningof symptoms in one patient (11). Side effectsthat are reported using the different target ar-eas include psychosis, anxiety, depression, ef-fects on libido, and decreased energy (39, 62,106, 108). In one case report, a suicide attemptwas described after several years of NAc DBSin a patient with TS who had a decrease of44% on the Yale global tic severity scales (79).Together these studies show promising re-sults for the application of DBS in TS; how-ever, the amount of stimulation targets usedand the wide variety of stimulation parametersettings make it difficult to compare studiesand to decide which target area is most effec-tive and safe. Additional complications in thesearch for best target area are the differentcomorbidities that accompany many of thesepatients and the phenotypic variability of thedisorder (35). In further research, larger andmore blinded controlled trials will be neededto establish the efficacy of DBS in TS and todecide on which target area is most suitable.

NEW INDICATIONS FOR DBS

Modulating the functionality of brain areasinvolved in the regulation of food intake bymeans of DBS could be a promising newtreatment option in eating disorders likeobesity (34) and also anorexia nervosa(AN). In obesity, both the hypothalamusand NAc are considered as potential targets.Several animal studies have investigated theefficacy of DBS in the lateral hypothalamusor in the ventromedial hypothalamus onfood intake and weight loss in animal mod-els (9, 90, 92). In 1974, Quaade et al. (87)reported suppression of appetite and mini-mal weight loss after stereotactic electroco-agulation of the lateral hypothalamus inthree obese patients. In addition, Mantioneet al. (67) reported a 44-kg weight loss in apatient with severe OCD who underwent bi-lateral NAc DBS. However, hypotheses re-garding the possible positive effects of DBSon obesity are mainly generated by animalstudies, and by conceptual frameworksbased on the current knowledge of the neu-
robiology of the regulation of feeding.

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Table 4. Overview of Published Studies of Deep Brain Stimulation for Therapy-Refractory Tourette Syndrome.

Study TargetNumber of

PatientsFollow-up Period

(months) Response (reduction on YGTSS) Comorbidity

Vanderwalle et al., 2003†Follow-up:Ackermans et al., 2010

CM-Pf VoiCM-Pf Voi

32

8-6072-120

Mean82% Tic reduction85 Tic reduction

Servello et al., 2008 (98)Follow-up:Porta et al., 2009

CM-Pf VoiCM-Pf Voi

1815

3-1824

65%52%

OCD/DEP/ aggression

Bajwa et al., 2007 CMPf Voi 1 24 66%

Maciunas et al., 2007 (62)* CM-Pf Voi 5 3 Mean14% (blinded comparison)44% follow-up

OCD/DEP/ ADHD

Vernaleken et al., 2009 CM-Pf Voi 1 6 36% OCD/ADHD/ DEP symptoms

Ackermans et al., 2011 (2)* CM-Pf Voi 6 3 � 6 (blinded comparison)12

Mean37% (blinded comparison)49% follow-up

Lee et al., 2011 CM-Pf Voi 1 18 58%

Ackermans et al., 2006‡ CMPf VoiGPi

2 12 85% tic reduction93% tic reduction

Ackermans et al., 2006‡ CMPf VoiGPi

2 12 85% tic reduction93% tic reduction

Welter et al., 2008 (108)§* CM-Pfand GPi

3 20-60 MeanGPi: 78%CM-Pf: 45%Both: 60%

Flaherty et al., 2005Shields et al., 2008�

ALICCM-Pf Voi

1 183

23%46%

Servello et al., 2009 ALIC/NAc 4 10-44 Mean 66% OCD

Burdick et al., 2010 (11) ALIC/NAc 1 30 17% worsening OCD

Kuhn et al., 2007 (54) NAc 1 30 41% on OCD

Zabek et al., 2008 Right NAc 1 28 80%

Neuner et al., 2009 (80)¶ NAc 1 36 44% OCD

Diederich et al., 2005 GPi 1 14 47%

Gallagher et al., 2006 GPi right 1 Several months Improvement of tics contralateraland continuation of tics ipsilateralto electrode

Shahed et al., 2007 GPi 1 6 84% PD, impulsivity

Dehning et al., 2008 GPi 1 12 88%

Dueck et al., 2009 (21) GPi 1 12 No benefit Mental retardation

Martinez-Fernández et al., 2011 (68) GPi 5 3-24 Mean 29% Dystonia/ ADHD

Martinez-Torres et al., 2009 STN 1 12 97% tic improvement PD

ADHD, attention deficit hyperactivity disorder; ALIC, anterior limb of internal capsule; CM-Pf, center median parafascicular complex; DEP, depression; GPi, globus pallidus internus; OCD,obsessive-compulsive disorder; NAc, nucleus accumbens; PD, Parkinson disorder; STN, subthalamic nucleus; Voi, ventralis oralis internus.

*Controlled studies.†Includes 1 patient from Vanderwalle et al. 1999.‡Includes 1 patient from Vanderwalle et al. 2003.§Includes 1 patient from Huerto et al. 2005.�1 patient receiving DBS two times in different target areas.
¶Neuner et al. 2010 reports suicide attempt in follow-up study.
8 www.SCIENCEDIRECT.com WORLD NEUROSURGERY, http://dx.doi.org/10.1016/j.wneu.2012.03.009

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Human imaging studies in patients withAN show ventral (limbic) and dorsal (cogni-tive) neural circuit dysfunction, which re-semble dysfunctions in psychiatric disor-ders like OCD and MDD (42). Given thesymptomatic similarities between AN andOCD, and the efficacy of NAc DBS in OCD,the NAc or associated brain areas in the cor-tico-striato-thalamo-cortical circuits maybe effective targets for DBS in AN. Alterna-tively, Israël et al. (40) observed a lastingremission of chronic AN after DBS in thesubgenual cingulated cortex for severetreatment-refractory depression, and Bar-bier et al. (5) described a case of successfulanterior capsulotomy in AN and OCD. Fur-ther (pre)clinical research is needed to ex-plore how promising DBS may be in thetreatment of obesity and AN.

FINAL CONCLUSIONS

The application of DBS in psychiatric disor-ders has a promising prospect but still re-mains investigational. OCD and TS are theonly disorders in which double-blindedcontrolled trials have been used to examinethe efficacy of DBS. In both disorders, moreresearch is needed to find the most effectivetarget area(s), which may consist of morethan one neuroanatomic location due tovariability in the phenomenology of the dis-order. DBS in depression and addiction ispromising as well; however, double-blinded controlled trials are needed to con-firm this effect. In addiction, it is too early todraw conclusions as only case reports or se-ries have been published. In addition, moreresearch into the mechanisms of action usingneuroimaging and animal experiments couldgreatly contribute to optimizing DBS as atreatment in psychiatry in terms of target loca-tion and stimulation settings.

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onflict of interest statement: The authors declare that therticle content was composed in the absence of anyommercial or financial relationships that could beonstrued as a potential conflict of interest.

udy Luigjes and Bart P. de Kwaasteniet are co–firstuthors.

eceived 14 October 2011; accepted 28 March 2012

itation: World Neurosurg. (2012).ttp://dx.doi.org/10.1016/j.wneu.2012.03.009

ournal homepage: www.WORLDNEUROSURGERY.org

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