deep brain stimulation surgery

Peer-Review Reports

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DisAlctutprohig(20United States of America (49). In theGlobalStatus Report from 2004, the World HealthOrganization estimated that about 2 billionpeople worldwide consume alcoholic bev-erages (64). Among those are 76.3 millionwitMo

homoestabocanilepdenmillion deaths (3.2% of total) and a loss of58.3 million (4% of total) of disability-ad-justed life years (63, 64).

According to the Diagnostic and StatisticalManual of Mental DisordersFourth Edition

imthree or more of the seven criteria listed inTable 1, occurring at any time in the same12-month period. Characteristic hallmarks ofdrug addiction in essence are compulsion toseek and take thedrug, loss of control to limit

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WORLDNEUROSURGERY 80 [3/4]: S28.e21-S28.e31, SEPTEMBER/OCTOBER 2013www.WORLDNEUROSURGERY.org S28.e21h diagnosable alcohol use disorders.reover, the global burden related to alco-

(DSM-IV) of the American Psychiatric Asso-ciation (1), the most common and global

intake, and emergence of a negative emo-tional state reecting a motivational with-ep Brain Stimulation Surgeergen Voges, Ulf Mller, Bernhard B

RODUCTION

easeohol dependence or alcoholism consti-es one of the most serious public healthblems worldwide with a comparablyh prevalence of 4.65% related to 1 year012002) for the population of the

wordsddictionravingeep brain stimulationucleus accumbenseward systemtereotaxy

reviations and AcronymsComputed tomography

S: Deep brain stimulation: Dorsal striatumM-IV: Diagnostic and Statistical Manual ofntal Disorders, Fourth EditionHigh frequency: Impulse generator: Local field potentialI: Magnetic resonance imagingc: Nucleus accumbens-R: Hares Psychopathy Check ListRevised: Prefrontal cortexVentral striatum: Ventral tegmental area

From the Departments of StereotacticNeurosurgery, Neurology and Psychiatry, Otto-

Guericke University, Magdeburg; Leibniz Institute forrobiology, Magdeburg; and Department of Neurology,ersity Lbeck, Lbeck, Germany

hom correspondence should be addressed:rgen Voges, M.D., Ph.D.ail: [email protected]]

tion: World Neurosurg. (2013) 80, 3/4:S28.e21-S28.e31.://dx.doi.org/10.1016/j.wneu.2012.07.011

rnal homepage: www.WORLDNEUROSURGERY.org

ilable online: www.sciencedirect.com

8-8750/$ - see front matter Published by Elsevier Inc.for Alcohol Addictionrts, Thomas Mnte, Hans-Jochen He

l consumption expressed in terms ofrbidity or mortality is high. Alcohol isimated, for instance, to cause worldwideut 20%30%of esophageal cancer, livercer, cirrhosis of the liver, homicide, ep-tic seizures, and motor vehicle acci-ts (61). In essence, alcohol causes 1.8

ACKGROUND: The consequencesportant health and economic burdndard treatment (medication and

idence from in vivo investigationsins reward system is critically inv

nce of addictive behavior, suggestingnificantly improve the prognosis o

cidental observation, we used the nuntral position in the dopaminergic rn (DBS) of alcohol addiction.

ETHODS: We report our first exppendence and review the literaturediction.

ESULTS: Five patients were treatedvere alcohol addiction (average follownificant and ongoing improvement oftely abstinent for more than 4 years.

rmanent side effects. Simultaneous reget area and surface electroencepuropsychological tasks gave a hint onohol-related cues.

ONCLUSIONS: To our knowledge, tempt to treat alcohol-addicted patimulation probably counterbalances theoluntarily drug-seeking behavior. Meusing randomized, double-blind, andunderway to corroborate these prelindard in psychiatry and psychology, al-ol dependence, or other drug addiction isracterized as the repeated use of a drugpite recurrent adverse consequences. Al-ol dependence is amaladaptive pattern ofohol use, leading to clinically signicantpairment or distress, as manifested by

ronic alcohol dependence causeworldwide. Relapse rates after

chotherapy) are high. There isfrom studies in patients that thed in the development and mainte-t modification of this system couldictive patients. Motivated by an

us accumbens (NAc), which has ard system for deep brain stimula-

nces with NAc DBS for alcoholessing the mechanisms leading to

-label with bilateral NAc DBS for8 months). All patients experiencedving. Two patients remained com-stimulation was tolerated without

ing of local field potentials from thegraphy while patients performedivotal role of the NAc in processing

ata presented here reflect the firstwith NAc DBS. Electrical NAc

ct of drug-related stimuli triggeringhile, two prospective clinical stud-sover stimulation protocols for DBSry results.stacohchadescohalc

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PEER-REVIEW REPORTS

JUERGEN VOGES ET AL. DBS SURGERY FOR ALCOHOL ADDICTION

S2wal syndrome when access to the drug isvented (33).

nsurgical Treatment of Alcoholdictionnsurgical treatment of alcoholism candivided into two phases, an acute and aond, chronic phase. The aimof the acuteatment phase is detoxication or with-wal of alcohol, which is supported bydications such as benzodiazepine, ifessary. The objective of the secondase is prevention of subsequent relapse. The most frequently applied drugs forapse prevention are disulram, naltrex-e, and acamprosate.Disulram hinders alcohol intake by pro-cing an unpleasant reaction when pa-nts under medication drink alcohol. Thestance interferes with acetaldehyde, aradation product of alcohol blockingther metabolism into acetate. Naltrexonen opioid receptor antagonist, supposedreduce dopamine release associated withohol expectancies and consumption.e presumed clinical effect of naltrexonedication is reduction of heavy drinkingdiminishing the rewarding neurobiolog-l effect of alcohol (53). Acramprosate, athetic compound with a chemical struc-e similar to that of-aminobutyric acid iscically designed to maintain absti-

ependence

olerance

ithdrawal symptoms or clinically definedlcohol withdrawal syndrome

se in larger amounts or for a longer periodan intended

ersistent desire or unsuccessful efforts to cutown on alcohol use

ime is spent obtaining alcohol or recoveringom effects

ocial, occupational, and recreational pursuitsre given up or reduced because of alcohol use

se is continued despite knowledge of alcohol-lated harm

lcohol dependence is diagnosed if at least three ormore of the listed criteria occur at any time withinthe same 12-month period.

SM-IV, Diagnostic and Statistical Manual of MentalDisordersFourth Edition.8.e22 www.SCIENCEDIRECT.comminobutyric acid agonist. Its mode ofion can simply be described as repair ofbalance between these two transmittertems,which is disturbed by alcohol (26).oth naltrexone and acamprosate haven tested in a high number of random-d controlled trials worldwide. With re-ct to the percentage of patients continu-abstinence undermedication comparedplacebo, the results display a great vari-lity,with relapse rates ranging from30%80%. Cochrane reviews revealed a rathereffect size with Cohens d around 0.25odds ratios in most of the meta-analy-in the order of 1.25 (41).lso great efforts have beenmade to pre-t relapsesby applicationofdifferent psy-therapeutic modalities such as brief in-vention (31 studies), social skills trainingstudies),motivational enhancement (17dies), cognitive therapy (10 studies), anders (24). After a thorough review of therature, the Institute of Medicine, Unitedtes, could not identify a modality beingerior to others tested and recommendedsecutively the combination of the vari-

s approaches together with individual-d treatment strategies (2-4).

ep Brain Stimulation for AlcoholdictionMotivationth high relapse rates after conservativeatment and the adverse effects of chronicohol abuse on the physical, mental, andial performance of these patients are thein reasons to search for alternative ther-es. Since thepioneeringworkofBenabidal. in the 1980s (6), deep brain stimula-n (DBS) became an established methodthe treatment of Parkinson disease (10,

), tremor (38), and generalized or seg-ntal dystonia (37, 56). Meanwhile DBS,ich is an attractive method because of itstential reversibility when the stimulatorwitched off, has been extended for theatment of patients with neuropsychiatriceases during the last years.he motivation for our group to treat al-ol-addicted patients with nucleus ac-bens (NAc) high-frequency (HF) DBS

an open-label study is based principallyan accidental observation published byhn et al. in 2007 (36). These authors re-rted a case treated for severe anxiety dis-er and secondary depressive disorderWORLD NEUROSURGERY, http://dx.drted that with initiation of stimulation,alcohol dependence had improved sub-ntially. Here we summarize our prelimi-y results of a small case series, in whichtreated ve patients with severe alcoholiction refractory to standard therapy bylying off-label HF DBS in the NAc. Allients gave their informed consent toth treatment and examination accordingour study protocol, which we performedh permission of the ethic commission ofr hospital. Results of treatment for threehesevepatientswere alreadypublished, 47).

TIENTS AND METHODS

rgical Candidateslusioncriteriawereasfollows:agerangingm 25 to 60 years, alcohol dependence ac-ding to ICD-10 (international classica-n of diseases) and DSM-IV, history of alco-lism of at least 10 years, inpatientoxication following abstinence of at leasteeks, a minimum of two long-term inpa-t therapies of at least 6 months, and un-cessful therapy with acamprosate or na-xone or disulram. Exclusion criteria werefollows: history of seizures, antisocial per-ality (scoreof20onHares Psychopathyeck ListRevised), brain damage visible onand MRI scans, alcohol-related personal-deprivation,pasthistoryofaddiction toan-er substance or currently using anotherstances of abuse, or additional psychiatricorders (DSM-IV axis I or II) unrelated to al-ol dependence. Furthermore, we per-med neuropsychological tests (listed be-in clinical assessments) before surgery

ensurein addition to the clinical evalua-nthat patients are able to give informedsent and in order to exclude patients withld mental retardation. Patients were ex-ded if the IQ was below 80 or a score wasow 80%of the average score.ersons primarily responsible for indi-ing DBS were the psychiatrist of ourup (B.B.) and the neurosurgeon (J.V.).en both persons had agreed to NAculation, a third, independent psychia-

t controlled the rst decision and gave aal statement. If the latter was negative,ients were not treated with DBS.he off-label use of a technical device,ich means the use other than the oneoi.org/10.1016/j.wneu.2012.07.011

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tactic implantation of the brain electrodes(model 3387;Medtronic,Minnesota,MN,

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PEER-REVIEW REPORTS


WOual case-by-case decision, does not re-ire a vote from an ethic commission.gardless, we treated the patients in ac-d with a positive vote from the ethicmission of the medical faculty of the

iversity of Magdeburg.

rgical Procedureatment planning standards and thegical procedure are, in general, de-ibed elsewhere in detail (57). Briey, adays prior to surgery, patients under-

nt nonstereotactic MRI examination.atment planning was performed usingcial software (Precisis AG, Heidel-

rg, Germany). Sturm et al. originallyrked out targeting of the NAc in 2003). We dened the target referred to thest distal contact of the quadripolar

Figure 1. Displayed are intraoperative(CT) examination of case 6 after transThe latter shows the distal contacts (shell and NAc core as intended.RLDNEUROSURGERY 80 [3/4]: S28.e21-dsagittal plane, 34 mm ventral and8 mm lateral of the midline. Coordi-tes were taken from amicroscopic atlasthe human brain (40). If necessary, wedied the atlas standard coordinatesording to landmarks displayed in theividual treatment planning MRI, andicated the border of the NAc region.portant landmarks, which can bearly visualized on coronal MRI scans-weighted sequences, 1.5 T; Intera,ilips, Best, The Netherlands), are thetical limb of Brocas diagonal band,ich is located medially to the NAc, andolfactory tubercle as the ventral bor-

r of the target region. The target wasally dened in projection onto thedo-medial, subventricular part of thec, which according to histochemicalteria represents the remnant of thell area in the primate (54). For stereo-

tactic x-ray images of the skull (A, B) and the postion into the preoperative treatment planning magne window) of the implanted leads in projectionS28.e31, SEPTEMBER/OCTOBER 2013www.WORLDA) with the patient in general anesthe-, we used a modied Riechert-Mund-er stereotactic frame. Intraoperativelyperformed a stereotactic CT examina-n integrating the preoperative treat-nt planning MRI images via image fu-n. The electrode localization wascumented by stereotactic x-ray imagingng x-ray tubes installed in the operatingm. In addition, we performed postoper-ve CT examination. CT as well as x-rayageswere fusedwith theplanningMRI inh case, displaying that the distal con-ts of theDBS electrodewere placed in thedo-medial NAc as intended, the thirdtact within the transition area to theme-l border of the abutting internal capsulethe highest, or the fourth, contact at a

int in themostmedial part of the capsulein the transition area to the caudate. CTages also excluded any intracranial hem-

ative computed tomographicresonance imaging series (C).he nucleus accumbens (NAc)mi6naofmoaccindindImcle(T1PhverwhthedencauNAcrishe

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relapses and abstinence intervals. Beforesurgery, the patients underwent inpatientdetphstaceiingpo

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PEER-REVIEW REPORTS


S2hage. Figure 1 displays the nal elec-de position of case 6.n cases 1 and 2, the electrode leads wereernalized, allowing electrical test stimu-ion and recording of local eld potentialsPs) from the depth contacts in differentropsychological tasks during ve post-

erative days. In all patients, electrodeds were connected to an impulse gener-r (IPG; Kinetra, Medtronic, Minneapolis,nnesota, USA) placed subcutaneously be-th the right clavicle on the pectoral mus-. Stimulation was started using the mosttal two electrode contacts in a bipolarde with stimulation parameters validatedNAc-DBS in obsessive-compulsive disor-(OCD) patients (130Hz, 4.5 V, 90s) (8).

nical Assessmentse Alcohol Dependence Scale was ap-ed for preoperative testing only. Preop-tively and at 6 and 12 months aftertiation of DBS, we used the follow-tests: Obsessive-Compulsive Drink-Scale, Alcohol UrgeQuestionnaire, Rey

ditory Verbal Learning Test (using aGer-n translation), Hamburg Wechsler In-ligence Test for adults, Subtest 3 of theistungspruefsystem,Multiple Choicerd TestB, as well as Trail Making Testnd B.re- andpostsurgical assessment also in-ded the Symptom Check List90 as wellclinical interviews to follow up on possi-changes in psychopathology. In addi-

n, we took routine blood samples andcumented the number and duration of

atients Treated with Bilateral High-requency NAc-DBS for Severelcohol Dependence

aseumber

Age(years)

Follow-upTime

(months)*

Time ofAlcohol

Intake (years)

36 48 24

37 44 26

40 48 22

51 34 41

56 32 18

Follow-up time is defined as the time from date ofsurgery until September 31, 2011.8.e24 www.SCIENCEDIRECT.comoxication followed by an abstinencease of at least 2 weeks. After surgery andrt of NAc DBS, the patients did not re-ve additional psychotherapy or anti-crav-medication; however, attending sup-

rt groups was recommended.

uropsychological Tests andctrophysiologyr a detailed description of the methodol-y, and of the neurophysiological tech-ue in particular, we refer to a previousblication by our group (23). Summa-ed, immediately after operation but priorconnection of the stimulation electrodesthe IPG, we registered LFPs from the ex-nalized brain electrodes in patients 1 andhile they performed cognitive tasks ad-ssing action monitoring and incentiveience of drug-related cues. In addition,also obtained surface electroencephalo-phic activity (Fz, F3, F4, Cz, Pz, P3, andreferenced to the rightmastoid process).he action monitoring study was per-med in case 1 using a typical anker task.ring rapid presentation of letter stringsHHHH,SSSSS,HHSHH,SSHSS), thepa-nt had to react by button press on theplayed center letter with either the leftd (for letter S) or the right hand (for

terH).Wepresenteda total of 880 stimuli0 congruent, duration 100 ms, stimulusset asynchrony 9001100 ms) over a pe-d of 20 minutes. Registered were errorscorrect trials and the overall error rate;

th conditions were differentiated intorect compatible and correct incompati-trials. In addition, we computed post-or slowing as an index of behavioral ad-ation after a performance error (42).or the incentive salience test, we used ak developed to address visual selectioncesses in amodied version (25). In oneies the patient was presented two col-d pictures (targets), which had to be at-ded by the patient and required a deci-n (living or non-living object), andgray pictures (distracters), and in 50%atrary condition (e.g., target: living,tracter: non-living)was displayed con-lateral to the attended target picture,ereas in the other 50% alcohol-relateds were presented (e.g., a bottle of beer, a). Importantly, because of special ar-gement of the visual stimuli, the task perWORLD NEUROSURGERY, http://dx.dted outside the patients attentional fo-.

SULTS

mOctober 2007 throughFebruary 2009,treated ve male patients with NAc-HFS for severe alcohol addiction (Table 2).e median age of the ve patients was 44rs (range: 3665 years). Four of the veients started drinking at teenage, oneject at the age of 38. Alcohol Depen-ce Scale scores ranged from29 to 41.Onrage, the total time since drinking wasyears, ranging from 18 to 41 years. Theual follow-up ranges from 31 to 47nths (average: 38 months) if referred totember 30, 2011.

se Reportsree of these patients were published inail by one of the coauthors (U.M.) (47).e two patients (cases 1 and 2) mentionedthis report who have remained abstinentl remain so after more than 4 years andortanongoingabsenceofcravingforalco-l. Both patients were unemployed beforeS therapy and went back into full-timeployment. The follow-up of the third pa-nt is almost identical. Even though hesome episodes of drinking, the overall

quency of relapses and the amount ofnks have reduced on treatment withc-DBS. Currently, this patient is servingil sentence due to a revoked suspendedtence related to a crime committed be-e DBS therapy was started. Whereas henotmanage to remain abstinent servingrensic therapy a couple of years prior toc-DBS, now he reports no craving or in-est in drinking, although there woulde been numerous possibilities to drinkjail.he scores for Alcohol Dependencele,Global Severity Indexof theSymptomeck List90 summary score, Alcoholge Questionnaire and the OCDC-G (sep-ted for alcohol-related thoughts andpulsion) of these three patients mea-

edpreoperatively andduring a 12-monthservation period after initiation of NAc-S are summarized in Table 3. Unsurpris-ly, in case 3, Obsessive-Compulsiveinking Scale scores did not constantlyoi.org/10.1016/j.wneu.2012.07.011

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Table 3. Patient Scores of the Alcohol Dependence Scale, Global Severity Index of the Symptom-Checklist-90, Alcohol UrgeQ rinki lcohoB

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PEER-REVIEW REPORTS


WOp down to zero but increased repeatedlyvalues ranging from 5 to 10 (drinkingughts) and from9 to 15 (drinkingbehav-) in the context of relapses.The fourth patient was 51 years old whenunderwent surgery for NAc-DBS in De-ber 2008 andhadbeen addicted to alco-

l for almost 20 years. Initially, he con-ed alcohol on a steady basis (delta

oholic). However, over time this drink-pattern changed and he increasingly

nk heavy amounts at once with loss oftrol. He underwent numerous detoxi-ion treatments, two long-term inpatientrapies, and one long-term outpatient re-ilitation treatment without permanentcess. Reasons for relapses before NAc-S were craving for alcohol or personaless. After initiation of DBS therapy, thisient reported immediate and ongoingence of craving. After staying abstinentmore than 16 months, he had a few veryrt relapses over the next 12 months be-se of personal stress. Approximately 2.5rs after DBS surgery, the patient wasdenly almost lost to follow-up and expe-nced a prolonged relapse. Fourteennths later, he was referred to our hospi-because of generalized seizure. At ad-ssion, surgical dressing for several scalperations was necessary. At that time theient reported that compared to the previ-s year, the stimulation never reached theect he had experienced at the beginningDBS therapy.We, therefore, performed aexamination with 2-mm slices. Transfor-tion of these images with the treatmentnning MRI series showed caudoventrallocation of both brain electrodes (10-mmference compared with postoperative

uestionnaire, and Obsessive-Compulsive Dehavior

aseumber

ADS GSI of the SC

Preoperation Preoperation 6-m

41 68 5

28 62 3

NA NA N

alues were obtained preoperatively and 6 and 12 months afDS, Alcohol Dependence Scale; GSI, Global Severity Index; SNA, not assessed.

OCDS scores dropped down to zero but periodically increaseRLDNEUROSURGERY 80 [3/4]: S28.e21-trol images). Surgery for replacement ofelectrodes was performed. Intraopera-ly, we found both brain electrodeshtly xed in scar tissue, indicating thatctrode displacement most probably hadurred quite some time ago. Since thislacement, the patient reports an effectparable to what he had already experi-ed during the time of clinically effectivec-DBS.hefthpatientwas55 yearsoldwhenherted his DBS therapy in February 2009.had been addicted to alcohol for aboutyears. Similar to the fourth patient, het started drinking on a steady basis; inyears before DBS, he experienced veryvy relapses with loss of control. With-wal treatments were sometimes compli-ed by delirium that required treatmenth haloperidol in addition to diazepam.occasion of the last relapse before werted withNAc-DBS, the patient had to beitted to the intensive care unit because

coma due to a blood alcohol level of4%. Reasons for relapse before DBSre craving for alcohol or personal stress.ain, following DBS, this patient reportedimmediate and ongoing absence of crav-. Since initiation of DBS, the patient hasfour short relapses of 13 days each duepersonal stress but remains abstinenterwise.umming up, to our knowledge, thesent clinical study is the rst attempt toat alcohol addictive patients with NAc-S. All patients included were severely af-ted. They had taken large amounts of al-ol for a long time and all of them haderienced multiple unsuccessful treat-nt cycles combining standard medica-

ng ScaleGerman version Separated for A

Score AUQ

12-month Preoperation 6-month 12-

56 29 8

36 53 8

NA 37 10

iation of NAc-DBS.Symptom-Checklist-90; AUQ, Alcohol Urge Questionnaire; OC

alues ranging from 5 to 10 (drinking thoughts) and from 9 tS28.e31, SEPTEMBER/OCTOBER 2013www.WORLDn therapy with psychotherapy prior toS treatment. The most signicant posi-effect of NAc stimulation was completeappearance of craving, which we collec-ly observed in the entire cohort. In addi-n, two of ve patients remained com-tely abstinent for more than 4 years. Inthree cases with stress-related relapses,

th frequency of the events and the inten-of the relapses were considerably re-

ced compared with the time before NAc-S. Prior to study inclusion, all patientsre unemployed or had part-time jobsly, whereas under NAc stimulation, fourthe ve patients are fully employed now.e fth patient (case 3) has to serve a sen-ce for a crime committed before werted DBS therapy.

e Effects, IPG Replacementthe present small case series, no adversents related to surgery occurred. High-quency stimulation of the NAcwas toler-d without permanent side effects. Onlye patient (case 2) had a transient episodeh hypomania when bipolar stimulations initialized according to the protocol.er readjustment of IPG settings, choos-the most distal contact for monopolarulation and concomitantly reducingstimulation energy (130 Hz, 3.5 V, 90

), the symptoms disappeared. Impulseerators were replaced in all four pa-

nts, stimulating in the bipolar mode26 months after rst surgery, when onasion of scheduled visits the externaltrol device indicated remaining batteryacity of approximately 10%. Three pa-nts did not notice low battery capacity.

l-Related Thoughts and Drinking

OCDS-G (ObsessionCompulsion)

Preoperation 6-month 12-month

11/18 0 0

18/19 0 0

11/20 (0)* (0)*

Obsessive-Compulsive Drinking ScaleGerman version;

rinking behavior) in context of relapses.Aganinghadtooth

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PEER-REVIEW REPORTS


S2uropsychological Testse following summarizes the results ofneuropsychological tests and electro-ysiological data obtained from the ex-nalized brain electrodes and surfacectroencephalography registration whenpatients performed the tests. For de-

ls, we refer the reader to our previousblication (23).

ion Monitoring Study. Registration of av-ged surface event-related potentialsectrode Cz referenced against mastoidcess) and bipolar averaged LFPs ob-ned time-locked to the erroneous motorponse displayed a typical error-relatedativity followed by the so-called error-

ated positivity in the event-related poten-ls (signicant differences, P 0.005). InNAc on both sides, similar error-relateddulations were seen, which were muchre pronounced in the bipolar recordingsween the two most distant electrodetacts 0 and 3 than in the recordings be-en contacts 2 and 3. Activity from bothes was very similar. Cross-correlationlysis comparing depth and surface elec-de activity showed that in both hemi-eres, error-related negativity obtainedm the NAc preceded the surface error-ated activity by 39 ms.

entive Salience Task. When patients 1 anderformed the visual selection test, wepared trials with an alcohol-related ortral distracter stimulus on the side con-lateral to the target stimulus. In LFPs re-ded from the left NAc (bipolar recordingweenelectrode contacts 0 and3),we reg-red a rather early difference betweenveforms obtained to stimulus arrayswitheutral distracter and those with an alco-l-relateddistracter. The emergenceof theistered waves was statistically signi-t. LFPs obtained from the right NAc,wever, did not show reliable differencesween the two conditions in this task.

CUSSION

velopment of Alcohol Addictiondiction is the continued use of a mood-ering substance or behavior despite ad-8.e26 www.SCIENCEDIRECT.comer theories explaining the developmentaddiction, however, focused only onchanisms related to the acute impact of ag on neural networks. Pleasurable effectser drug consumption are considered tove mainly the desire for repeated reward.thermore, frequent drug consumptionulates tolerance development, which de-

ases the reinforcing properties of a sub-nce and bears the risk for increases in dos-. Besides positive reinforcement, negativenforcementmechanismsalsoare involved.negative reinforcement, acute or pro-ged withdrawal symptoms, such as theergenceof anegative emotional state (e.g.,phoria, anxiety, irritability)when intakeofrug is prevented, result in continueduse aseans toavoid theaversive consequencesofgwithdrawal (13, 35).einforcement or conditioning theoriesconsidered to provide explanations forinitiation and maintenance of compul-

e drug use but are insufcient to fullylain relapses. Relapses, the most prob-atic aspect of drug addiction, can occurn after long periods of abstinence orn if the individual has the strong will totain. More recently presented theoriesposed a concept of disequilibrium in theins reward system in consequence oferal neuroadaptation steps initiated bylonged drug use. One conceptualiza-n of motivational changes associatedh addiction is the incentive sensitiza-n theory brought forward by Robin-and Berridge (51). They hypothesizedt drugs utilize systems in the brain thatnormally involved with incentive moti-ion and reward for natural appetitive re-orcers, directing individuals or animalsstimuli with salience for preservation ofspecies. Enduring hypersensitivity not

ly to the drug itself but also to drug-associ-d stimuli (cues) leads to a shift from drugng (thehedonic aspect of drugconsump-n) todrugwanting,withprolongedcom-lsive drug-seeking patterns (51).ther theories focusing on particular as-ts of drug-induced neuroadaptationsh less or more overlap between the dif-ent perspectives address primarily thelowing: (a) formation of ingrained drugits as a consequence of aberrant stimu-response learning (12, 59, 61); (b) alter-ons in prefrontal cortical (PFC) activity,WORLD NEUROSURGERY, http://dx.doverlaps between limbic and cortical ar-involved in addiction andmemory (27),ich cause maladaptive associative learn-(11).manating froma conceptualization thatg addiction has aspects of both (a) im-lse control disorders, which are largelyociatedwith positive reinforcement, andcompulsive disorders, which can be re-ed to negative reinforcement mecha-ms and automaticity, Koob proposed aniction cycle composed of three stages:binge/intoxication stage, the with-wal/negative affect stage, and the pre-upation/anticipation stage. Theseee stages interact with each other, be-e more intense, and nally lead to the

hological state known as addiction (32,). In a comprehensive review, Koob andlkow (35) focused on the brain neurocir-try engaged at each of the above-men-ned states, as well as on changes within

on interactions among their singlets as a consequence of drug abuse. Thest vulnerable structure in the binge/in-ication state is the ventral tegmentala (VTA) and themesolimbic dopaminer-system. The authors stated that most

pamine-mediated reinforcement occursthe level of the NAc because this brainion hasmultiple inputs fromother brainuctures, which are also critically involvedreinforcement such as the central nu-us of the amygdala (CeA) and the ventrallidum. With some delay, the interactionween ventral striatum (VS), dorsal stria-(DS), and the thalamus will lead to the

elopment of compulsive drug-seekingavior (35).

chanismse NAc has two morphologically distinctunits, shell and core, which are distin-

ished by differential expression of neuro-tides and synaptic afferent inputs (45).odents, these anatomical subunits displayctional differences also. The core is sug-ted to be involved in guiding behavior to-rd a specic goal based on learning; thell seems to be crucial for unconditionedard-seekingbehaviors(18).Stimulationofer theNAc shell or core region in the nor-l brain of rodents can elicit different ef-ts. In Wistar rats, for instance, high-fre-ency NAc-DBS of the accumbens coreoi.org/10.1016/j.wneu.2012.07.011

prevented the inductionof long-termpotenti-ation in the dentate gyrus of the hippocam-puinctiateff

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blinded stimulation protocol. The reasonfor this practicewas the off-label use ofDBSbassiopatpleseeplativeriofecbrainvanoceb

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PEER-REVIEW REPORTS


WOs, and stimulation of the accumbens shellreased themagnitude of long-term poten-ion inductiondemonstrating opposingects on this plastic phenomenon (39).In contrast with rodents, the shell arearegressed in the primate and is no lon-clearly distinguishable, except for the

t that it carries the typical receptors1D3 dopamine receptors, opiate recep-s, receptors for a multitude of bioactiveteins and peptides). It is supposed thatthe primate and the human brain, thell and core function together in a kind ofcerted action rather than independentlym each other, as elaborated in Sturm et(54).Analysis ofNAc function,which togetherh the olfactory tubercle and the islandsCalleja represents the ventral subregionhe striatum, revealed that this region is aotal center within brain systems regulat-motivation and reward. Reward is sug-ted to be an important mechanism fordevelopment of addictive behavior (34).

bstances of abuse such as alcohol occupybrain networks belonging to the brainard system represented by two mainro-chemical pathways, themesocorticalthe mesolimbic pathway, the latter ex-

ding from the ventral tegmental area ofmidbrain via the medial forebrain bun-to the NAc. Natural rewards, but alsost drugswith addiction potential includ-alcohol, lead to increased extracellular

pamine concentration in the NAc. Intrast to natural rewards, however, dopa-ne activity does not adapt or habituate toeated drug exposure (62). Moreover, re-ted drug exposure induces sensitizationdopamine transmission in the NAc (50).these mechanisms, substances with ad-tive potential can become a powerful re-rding, discriminative, and reinforcingulus (35). Because of its functional andtomical position, the NAc has a centralsition within the brain areas and neuro-cuitries involved in the development ofiction such as VTA, lateral hypothala-s, VS and DS, amygdala, hippocampus,prefrontal/cingular cortex. Thus, electri-stimulation of this targetmay give the op-rtunity to modulate or correct neuroadap-changes caused by substance abuse.

McCracken and Grace investigating theect of electrical stimulation of the NAc inRLDNEUROSURGERY 80 [3/4]: S28.e21-enhanced slow LFP oscillations in theitofrontal cortex via antidromic activa-n of corticostriatal recurrent inhibition). Data from another study of these au-rs recording simultaneously LFPs fromltiple sites in the rat brain, suggesting thatNAc-DBS, which is considered to berapeutically active, and low-frequencyc-DBS, which is regarded as a possibleeterious stimulation pattern, producetinct region-specic and frequencyd-specic changes in LFP oscillations.h-frequency NAc-DBS, for instance, se-tively affected spontaneous and evokedP oscillatory power and coherencewithinbetween themedial PFC (mPFC), lateralitofrontal cortex, mediodorsal thala-s, and NAc. The authors concluded thatc-DBS might achieve therapeutic effectsenhancing rhythmicity and synchronousibition within and between afferentuctures, thereby normalizing the func-n of a neural circuit that has aberrantease-specic activity (44).wo animal studies provided evidencet electrical manipulation of the NAc cancically improve behavior associatedh addiction, such as uncontrolled drugake, craving, and relapse. Knapp et al.) used an in vivo self-administrationdel for their investigation. Rats with freeess to either water or a 10% ethanolter solution that developed stable alcoholsumption within 5 to 7 weeks and weren treated with daily HFDBS applied eitherheNAc shell or theNAccore for 5minutesuced alcohol intake signicantly. Thisulation effect was independent of theulation site, shell or core, anddidnot im-

r the consumption of water (31).assoler et al. (55) demonstrated in ratst electrical stimulation with 160 Hz inNAc shell attenuated signicantly the

nstatement of drug seeking precipitatedhigher cocaine doses but did not affectreinstatement of food seeking. How-r, stimulation of the DS did not changeaine reinstatement. Thus, the authorscluded that the observed NAc-DBS ef-t was both anatomically and reinforcercic.

nical Datae disadvantage of the present pilot studyhat the patients were treated with a non-S28.e31, SEPTEMBER/OCTOBER 2013www.WORLDing on individual case-by-case deci-ns. However, the long follow-up of theients treated so far with ongoing com-te response referred to craving can ben as one argument against a signicantcebo effect. In addition, the postopera-course of case 4 who experienced dete-

ration of a previously good treatment ef-t in context with displacement of thein electrodes can be interpreted as anoluntary treatment-free interval and asther argument against a bias due to pla-o effects.y contrast, Zhou et al. (66) reported aient treated successfully with bilateralc-DBS for heroin addiction, who re-ined abstinent for another 3.5 years evenen the stimulator was removed at the re-est of the patient and his family after 2.5rs of continuous stimulation (145Hz, 90, 2.5 V). The brain electrodes were ste-tactically placed using coordinates com-able to the presented alcohol study, ex-t for the anterior distance to the AC (7.5instead of 2.5 mm) (66).

n addition, bilateral ablation of the NAcformed by Wu et al. in an uncontrolled,spective open-label study in 12 patientss effective to treat alcohol addiction.ese patients had consumed alcohol for aan timeof 15 years (627 years) andwereendent of alcohol for amean time of6rs (range: 310 years). Nine of 12 pa-nts (75%)with a follow-upof6monthsnot relapse and did not consume alco-

l at all. In the remaining three cases, re-ses occurred. Bilateral ablation of thec caused only transient side effects (hy-smia) in one case (65). Taking into con-eration the central position of theNAc inetwork integrating contextual informa-n from the hippocampus, emotional in-mation from the amygdala, with cogni-information from the PFC in selectiongoal-directed behaviors (19), this lowmber of side effects after destruction ofth nuclei is surprising.n two patients treated in the presentdy, we registered simultaneously LFPsm the target area and surface electroen-halography while they performed neu-sychological tasks. The anker tasksen for the action-monitoring study pres-s incongruent anker letters, which givee for a high number of performance er-NEUROSURGERY.org S28.e27

rors. In these experiments, erroneous butnot correct button presses lead to a charac-tertiagenThdepthanegthesulthoeradisprehypgenmedoNAitoweandgoconconleasigpuaddistiocouby

stutivemuIntakvatandinvNAsalindwtenduing

usefunsivbraturtem

units connected with the reward system(e.g., DS, thalamus, PFC) (17, 58).

KdepalcbeeolflealowhigblospocomrelgreregcluulicolnoAlsconexpofcocdoVScreandintofdic

IgradetrotdenducenatethelatsynD2thecanaddatethathaactiessencueis r

Bis a

of drug-related cues (see overview in Gold-stein und Volkow [16]). Comparable to thebloter(vsofconcoranddentiobitdystheinccuePFcreass(20

ItraoupaNAcontwraywitrigreldittioNAtivinctiotheshiingthepapacohactattthemaforranwoifythaimulathe

PEER-REVIEW REPORTS


S2istic negativity of event-related poten-ls, the so-called error-related negativityerated in the anterior cingulated cortex.e comparison of signals recorded fromth and surface electrode activity showedt in both hemispheres, error-relatedativity obtained from the NAc precededsurface error-related activity. Same re-ts were already registered by one coau-r (T.M.) in a patient treated with unilat-l NAc-DBS for obsessive-compulsiveorder (48). Taken together, we inter-ted these data as conrmation of theothesis that the NAc is involved in theeration of a signal triggered by error-diated dopamine release from midbrainpaminergic neurons projecting to thec and being part of a human actionmon-ring system. Given that the NAc mayight information coming from limbicprefrontal regions in order to shape

al-directed behaviors and taking intosideration that action motoring hasceptually been linked to reinforcementrning, malfunction of this nucleus cannicantly drive the development of com-lsive drug seeking,which is a hallmark ofictive behavior (13). On the other side, it

comprehensible that electrical stimula-n of this brain area can substantiallynterbalance neuroadaptations causedlong-lasting drug abuse.One motivation for the incentive saliencedy in the present patients was the incen-sensitization theory of addiction for-

lated by Berridge and Robinson (7, 51).essence, following alcohol or drug in-e, the mesolimbic reward system is acti-ed leading to dopamine release in the VSNAc. Comparable to the mechanisms

olved in reward prediction in animals,c dopamine release attributes incentiveience to drug-associated cues. This cue-uceddopamine release then canmediateanting of substances with addictive po-tial. Drug-related stimuli might also in-ce craving in addicted patients, trigger-drug-seeking behavior.

In the past years, several investigatorsd positron emission tomography orctional MRI (fMRI) to study noninva-ely specic cue-related activation ofin areas, in particular, of those struc-es belonging to the brains reward sys-such as VTA or NAc and of anatomical8.e28 www.SCIENCEDIRECT.comareken et al. used blood oxygen levelendent fMRI to display the response toohol-related olfactory stimuli (odors ofr and whiskey) and non-alcohol-relatedactory stimuli (odors of grass andther) in 10 high-risk drinkers and ve-risk (control group) drinkers. In theh-risk group, the difference between theod oxygen leveldependent signal in re-nse to alcohol-related olfactory stimulipared to that obtained for non-alcohol-

ated olfactory stimuli was signicantlyater in the NAc but also in some voxelsistered from the VTA. The authors con-ded that alcohol-related olfactory stim-might activate the dopamine mesocorti-imbic system to a greater degree thann-alcohol-related olfactory stimuli (30).o active cocaine abusers responded toditioned, cocaine-related cues. Whenosed to videos depicting cocaine scenesindividuals procuring and administeringaine, test subjects exhibited signicantpamine increases in the DS but not in thewhere the NAc is located (59). The dis-pancy in the expected response of the VSthe activation instead of the DS can be

erpreted as reecting the intensicationhabits with increasing chronicity of ad-tion.nterestingly, positron emission tomo-phic imaging studies indicated that afteroxication, overall dopaminergic neu-ransmission in the VS of alcohol-depen-t patients is reduced. In particular, re-

ction of availability and sensitivity oftral dopamine D2 receptors was associ-d with the subsequent relapse risk inse patients. Also alcohol craving corre-ed specically with both low dopaminethesis capacity and reduced dopamine-receptor availability in the VS includingNAc (21, 22). Even thoughspeculative, itbe assumed that in an advanced stage ofiction, the presentation of drug-associ-d cues can still cause dopamine releaset triggers reward craving or relapse, butt, however, other brain areas are moreivated than the NAc itself. Animal stud-, for instance, demonstrated that the pre-tation of alcohol and drug-associateds can lead to relapse even if nodopamineeleased in the VS (52).esides the reward system, the PFC alsoctivated in response to the presentationWORLD NEUROSURGERY, http://dx.dod oxygen leveldependent effect regis-ed for the NAc, the pure taste of alcohol. litchi juice) increased activity in the PFCyoung drinkers also. This result can besidered a specic response because itrelated in addictives with alcohol usecraving (14). By contrast, in non-depen-t alcohol drinkers, alcohol administra-n reduced cue-related activity in the or-ofrontal cortex. In addition, dopaminefunction was correlated not only withseverity of alcohol craving but also withreased processing of alcohol-associateds in the anterior cingulate and medialC (22)brain areas in which an in-asedprocessingof alcohol cues has beenociated with an increased relapse risk).n the actual study, we presented neu-l and alcohol-related images or cuestside the visual eld attended by thetients. In LFPs recorded from the leftc (bipolar recording between electrodetact 0 3) we found a difference be-

een waveforms obtained to stimulus ar-s with a neutral distracter and thoseh an alcohol-related distracter. In theht NAc, however, we did not observeiable differences between the two con-ions. Seen in the context of the rela-nship between dopamine release in thec and increased attribution of incen-e salience to drug-associated stimuli,reasing motivational value and atten-nal processing of drug-related cues on

one side and dopamine-mediatedft from drug liking to drug want- on the other side, we interpretedse unilateral LFP changes in our twotients as surrogate for cue-induced do-mine-dependent NAc activity. The al-ol-related cues were able to drive NAcivity even when presented outside theentional focus, which suggests thatse cues are processed in a highly auto-tic fashion, thus being uncontrollablethe affected person. Given the long-ge inuence of DBS on neural net-rks and its ability to signicantly mod-signal transmission, it seems feasiblet high-frequency DBS has the ability toprove dysfunction not only at the stim-tion site but also in projection areas ofNAc such as the PFC.oi.org/10.1016/j.wneu.2012.07.011

Future DirectionsData from in vivo investigations, single caserepstuofprothearegooraprodoproin tstamaseawit

gatthemevesounenwilassmethe

NAfunbeddiaBrofunintcermequsurbeNAme

achwitis ntrewittinquadjtiefroproqu

benet as achieved with higher stimulationfrequencies (28), which may also be validfor

Aaddrepmesubstimvattompatabutieimcla

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sch A, Lorenz D, Lorenzl S, Mehdorn HM,Moringlane JR, Oertel W, Pinsker MO, Reichmann

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WOorts, as well as from small case seriesdies provide evidence that modicationthe NAc function can remarkably im-ve addiction behavior. However, to dateresults from clinical application of DBSvery preliminary. Therefore, the rst

al of future activities should be to corrob-te the observed improvement also inspective studies using randomized,uble-blind, and crossover stimulationtocols for DBS. This point is consideredwoprojects, conceptualized and actuallyrted by members of our group. The Ger-n Research Foundation funds both re-rch projects aimed at treating patientsh NAc-DBS for alcohol addiction.Although one project (principal investi-or: B.B.) is a multicentric clinical study,other combines clinical and comple-

ntary in vivo investigations (principal in-tigators:H.-J.H., J. V.). In addition to thetcome measures of relapse and absti-ce, the second project in its clinical partl concentrate primarily on the detailedessment of possible cognitive impair-nts caused by NAc-DBS, in particular inlong term.

The central anatomical position of thec, which is located close to several otherctionally relevant structures such as thenucleus of the stria terminalis, the me-

l forebrain bundle, or the vertical limb ofcas diagonal band (40), and the pivotalctional role of theNAc as amotor limbicerface (46) does not only give rise to con-ns related to possible cognitive impair-nt caused by DBS but also raises theestion as towhich anatomical units in therounding of the stimulation site have toelectrically affected in addition to thec to achieve maximum clinical improve-nt in addictive patients.The stimulation pattern required toieve clinical improvement, in particular,h reference to the stimulation frequency,ot adequately dened to date. Patients

ated for primary generalized dystoniah pallidal DBS, for instance, are rou-ely stimulated with 130 Hz or higher fre-encies, which is comparable to the IPGustment used in alcohol-addicted pa-nts. However, there are a few reportsm patients with dystonia indicating thatbably frequencies around 60 Hz areite sufcient to gain the same clinicalRLDNEUROSURGERY 80 [3/4]: S28.e21-DBS in addiction treatment.nother central question that should beressed in the future is whether the NAcresents a universal site for DBS treat-nt of addiction or if different types ofstance dependence require differentulation targets. Besides clinical obser-

ions, the results from positron emissionographic imaging recording activationterns in response to the substance ofse or drug-related stimuli with the pa-

nts on and off stimulation could be anportant source for information to furtherrify this point.

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Conflict of interest statement: The first author, J.V.,receives occasionally honoraries from Medtronic Inc.(Minneapolis, MN, USA) for activities as contributor. All

others have no financial interests to disclose. There are noconflicts of interest at all.

Received 6 January 2012; accepted 17 July 2012;published online 21 July 2012

Citation: World Neurosurg. (2013) 80, 3/4:S28.e21-S28.e31.http://dx.doi.org/10.1016/j.wneu.2012.07.011

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WORLDNEUROSURGERY 80 [3/4]: S28.e21-S28.e31, SEPTEMBER/OCTOBER 2013www.WORLDNEUROSURGERY.org S28.e31

Deep Brain Stimulation Surgery for Alcohol AddictionIntroductionDiseaseNonsurgical Treatment of Alcohol AddictionDeep Brain Stimulation for Alcohol AddictionMotivation

Patients and MethodsSurgical CandidatesSurgical ProcedureClinical AssessmentsNeuropsychological Tests and Electrophysiology

ResultsCase ReportsSide Effects, IPG ReplacementNeuropsychological TestsAction Monitoring StudyIncentive Salience Task

DiscussionDevelopment of Alcohol AddictionMechanismsClinical DataFuture Directions

References

deep brain stimulation surgery

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