deep brain stimulation for psychiatric disorders – state...

Deep brain stimulation for psychiatricdisorders – state of the art

T. E. SCHL€AAPFER and B. H. BEWERNICK

Brain Stimulation Group, Department of Psychiatry and Psychotherapy,

University Hospital Bonn, Germany and Departments of Psychiatry

and Mental Health, The Johns Hopkins University, MD, USA

With 3 Figures and 4 Tables

Contents

Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38History of deep brain stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39Principles of DBS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40Neurobiology of depression and OCD . . . . . . . . . . . . . . . . . . . . . . . . . . . 41Neurobiology of depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41Neurobiology of OCD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42

Studies of DBS and psychiatric disorders . . . . . . . . . . . . . . . . . . . . . . . . . 43Problems in target selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43Targets in depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43Targets in OCD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46Safety and advantages of DBS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

Ethical aspects and standards in DBS . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51Ethical considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51The path towards mandatory standards for DBS in psychiatric disorders . . . . 52

Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53The future of DBS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54

Abstract

A substantial number of patients suffering from severe neuropsychiatricdisorders do not respond to conventional therapeutic approaches. Results

from functional neuroimaging research and the development of neuromod-ulatory treatments lead to novel putative strategies. Recently, one of thosemethods, deep brain stimulation (DBS) has been applied in selected patientwith major depression and obsessive-compulsive disorder (OCD) and majordepression.

We summarize in this review, the state of art of knowledge about theneurobiology of depression and OCD and historical treatment methods.Principles of DBS and reasons for the use of DBS in neuropsychiatry arediscussed. Different targets have been chosen in a hypothesis-guided wayand first results have demonstrated that DBS might be able to modulate dys-functional neural networks in both major depression and OCD. Although DBSis a unique and promising method for otherwise treatment resistant psychiatricpatients, mandatory treatment standards have to be applied for patient andtarget selection. Therefore, a distinct focus of this review lies on ethical aspectsfor DBS in neuropsychiatric disorders.

Keywords: Deep brain stimulation (DBS); depression; obsessive compulsive disor-ders; neuroethical aspects.

Introduction

Today, different well established forms of drug treatment and psychothera-py are available for the treatment of neuropsychiatric disorders, alone orin combination they are effective in most patients [4, 37]. However, thereremain a sizable number of patients that cannot be helped with theseinterventions. Indeed, 8–13% of patients suffering from major depressionhave a poor outcome after five years of treatment [31]. A more recentstudy found that 63.2% of patients included in the STAR-D study werenot treated to remission in the acute study phase [49]. These patients arecalled ‘‘treatment-resistant’’ and have been treated with several antidepres-sants (e.g., tricyclica, selective serotonine reuptake inhibitors) augmentationagents (e.g., lithium, neuroleptics), psychotherapy and often electroconvul-sive treatment. In obsessive-compulsive disorder (OCD) the number oftreatment-resistant patients is estimated to be 10–40% [30, 16]. Thesepatients have little hope of recovery, are almost always stigmatized andremain in a state of extremely poor quality of life. Treatment resistant psy-chiatric disorders are a significant source of worldwide disability [43]. Thus,it clearly is a moral imperative to develop alternative treatment methods forthese patients.

In this review, we will outline putative new options for treatment-resistantdepression and OCD. A special focus lies on the establishment of mandatoryresearch guidelines.

38 T. E. SCHL€AAPFER and B. H. BEWERNICK

History of deep brain stimulation

Directly neurosurgical interventions for psychiatric indications have a long andsomewhat tainted history [34]. Psychiatric neurosurgery began in the 30s of thelast century when Egas Moniz performed the first frontal lobotomy [42]. Thismethod was further developed and widely used in the 1940s, when Freemanand Watts performed frontal lobotomies lacking any other treatment for severemental disorders [13]. These operations were crude, not guided by scientifichypotheses, were associated with high mortality and lead to unacceptable ad-verse effects. With the invention of psychotropic drugs in 1954 and their broadapplication, the interest for surgery waned [13]. Due to severe side effects ofpsychopharmacological medications and the availability of new operating tech-niques (stereotactic surgery), interest in functional neurosurgery for psychiatricdisorders returned [13]. Today, stereotactic operations allow reaching a targetprecisely with minimal lesions and minimal side effects. Methods are cingulot-omy (bilateral lesioning of cingulate gyrus) for OCD, major depression andpain disorders [25, 55], capsulotomy (anterior limb of the internal capsule asrelay between cortex and thalamus) for OCD, subcaudate tractotomy (inter-rupts cortical pathways to striatum and to thalamus) for OCD and depression[25, 55] and limbic leucotomy (combination of cingulotomy and a ventral lesionsimilar to that of subcaudate tractotomy) for OCD, depression and self-muti-lation [25, 47, 55]. The efficacy of neurosurgery for otherwise therapy resistantpatients lies between 30 and 70%, depending on the disorder and the selectedtarget [13].

Electric stimulation of the brain probably had its beginnings in 1879, wherelimb movement were elicited by stimulating the motor cortex in dogs, humanstudies followed in 1884 [22]. The first chronic brain stimulation was per-formed in the mid 20th century, when the Nucleus Caudatus was stimulatedfor eight weeks in a case of a severe depressed patient [17].

Insights from lesioning studies, imaging studies and animal models havecontributed to the development of deep brain stimulation (DBS). Adams was avery early pioneer who stimulated the internal capsule for relief of chronic pain[2]. The technique of chronic DBS used today was invented in the 80s byBenabid and coworkers for the treatment of movement disorders [10]. Today,this method is clinically used for the treatment of tremor associated withParkinson’s disease, chronic pain and dystonia. The observation of inducedpsychiatric side effects (e.g., changes in mood, hypomania, reduction of anxiety)gave the impulse to try DBS also for psychiatric disorders [36]. Another im-pulse was the fact that the effective but irreversible ablative neurosurgicalinterventions could now be emulated using DBS with a focused, fully reversibleand titratable technique (see Fig. 1). Insights from a somewhat different meth-od of electric brain stimulation (vagal nerve stimulation) further encouraged thedevelopment of DBS [52].

Deep brain stimulation for psychiatric disorders – state of the art 39

Principles of DBS

Deep brain stimulation is achieved by an implanted, battery powered neuro-stimulator, placed subcutaneously usually in the chest area. One or two leadsconnect to the actual stimulating electrodes in the brain. The exact neurobio-logical mechanisms by which DBS exerts modulatory effects on brain tissue arenot yet fully understood [26]. On the neuronal level, excitatory and inhibitoryprocesses might play a role [40]. It has been suggested, that DBS leads to afunctional lesion of the surrounding tissue. Depolarisation blockade of currentdependent ion channels [12], exhaustion of the neurotransmitter pool [66] orsynaptic inhibition [15] are suggested mechanisms of action. Neural activationin the stimulated areas has been described as well [28].

It is unknown which part of the neuronal structure (e.g., cell body, axon) isprimarily modulated by DBS. The effect of DBS on neurons obviouslydepends on different factors: the physiological properties of the surroundingbrain tissue, the geometric configuration of the electrode as well as the dis-tance and orientation of the neuronal elements towards the electrode [32].Stimulation parameters (frequency, amplitude, pulse width, duration) also clear-ly have an impact on the effect: a nonlinear relationship between stimulusduration (pulse width) and amplitude (voltage=current) has been observed[48]. Thus, the stimulation volume is not a fixed area around the electrodeand the effect on neuronal tissue is variable. With commonly used parameters,a relatively large volume of neural tissue is influenced [32].

Neurophysiologic recordings during stimulation in patients with movementdisorders have demonstrated, that the oscillatory activity occuring betweencortex and midbrain is modulated by DBS [32]. Changes in neurotransmitterrelease (Glutamate, Dopamine) have been reported in some studies [27, 59].

Functional neuroimaging data have demonstrated that DBS changes theactivity of brain areas far beyond the targeted region. Thus, complex neural

Fig. 1. Actual location of the electrode leads in the post-operative control X-ray in a

DBS study for depression [54]


networks are modulated [32, 39, 56, 60]. These results go well in line with thelong-term changes described in psychiatric patients.

In summary, effects of DBS crucially depend on the target and the stimu-lation parameters. Short time processes might well explain acute effects inmovement disorder. Especially in psychiatric disorders, long-term changes insymptoms have been described. This can only result from long-lasting, com-plex modulation of neural networks [40].

Neurobiology of depression and OCD

Neurobiology of depression

Symptoms of depression include sadness, lack of interest and motivation, an-hedonia, disturbances in sleep and appetite, hopelessness, suicidal thoughts,psychomotor slowing and the feeling of guilt as well as cognitive deficits.Major depression can be conceptualized by the interaction of genetic, neuro-biological, environmental and psychological factors [9]. The relevance of trans-mitters (e.g., Serotonine, Noradrenaline and Dopamine) has been shown [11].Family studies point to the involvement of several genes in the genesis ofdepression, for example genes for glucocorticoid receptors and for brain-de-rived neurotrophic factor [57] as well as circadian genes [11]. However, up totoday evidence of the involvement of specific genes is less than convincing. Lifeevents and daily hassles clearly are examples of psychological factors contrib-uting to the etiology of depression [58].

In contrast to neurological disorders, the pathological interplay of severalbrain regions contributes to the development of this disease. Metabolic studiessuggest that different symptoms are mediated by different brain regions [65]. Anetwork-model of depression that integrates biochemical, electrophysiological,imaging and animal studies, has been described by Mayberg [38]. According tothis model, depression results from a dysregulation of limbic-cortical connec-tions: pathological changes in dorsal brain regions (including the dorsolateralprefrontal cortex, inferior parietal cortex and striatum) were associated withcognitive symptoms (e.g., apathy, anhedonia, hopelessness, deficits in attentionand executive function), changes in ventral areas (hypothalamic-pituitary-adre-nal axis, Insula, subgenual cingulate and brainstem) contribute to the vegetativeand somatic aspects of depression (e.g., sleep disturbance, appetite, endocrinedysregulation). This model underlines the role of the rostral cingulate cortex inregulating the network [38]. The involvement of further regions in depressionare discussed: the hippocampus contributes to memory deficits, the nucleusaccumbens was associated with anhedonia and lack of motivation, the amyg-dala plays a role in the processing of aversive stimuli and avoidance [11] (seeFig. 2). Animal and imaging data point towards an involvement of the habenula


in depression: Sartorius and Henn [50] suggested that overactivation of thelateral habenula leads to down regulation of serotonergic, noradrenergic anddopaminergic systems and stimulation of the hypothalamic-pituitary-adrenalaxis in depression.

Neurobiology of OCD

OCD is characterized by anxiety-provoking thoughts (obsessions) and repeat-ed, time-consuming behaviours (compulsions) [61]. As in most psychiatricdisorders, a complex interplay of genetic factors, neurotransmitter changesand psychosocial characteristics contribute to the development of this disease.Changes in dopamine and serotonine have been reported [61]. Dysfunctionsin a network connecting the cortex and basal ganglia are supposed to underlieOCD. Probably, overactivation of the direct pathway of the cortico-striatal-pallidal-thalamic-cortical loop lead to intrusive thoughts and other OCDsymptoms [8] (see Fig. 3). Imaging data demonstrated changes in orbitofron-tal cortex, anterior cingulate cortex and caudate nucleus in OCD [7].

Fig. 2. Circuit of mood in depression [11]


Studies of DBS and psychiatric disorders

Problems in target selection

Hypotheses-guided search for a target is fundamental in DBS studies. In psychi-atric disorders, targets have been chosen in a hypothesis guided way usingknowledge derived from lesion and imaging studies as well as from currentunderstanding of the pathophysiology of the respective disorder. In the contraryto neurological diseases, there is not a single pathological structure in psychiatricillness. Several brain structures presumably play different roles in the develop-ment as well as in the maintenance of symptoms. Some targets are in closeanatomical or functional relationship (neural networks) and an overlap of effectis plausible. Thus, different targets might manipulate the pathological network atdifferent nodes. It has been shown, that several targets can lead to remission.

Targets in depression

DBS has been applied to the subgenual cingulate cortex (Brodman Area cg25)[39]. This region has probably dysfunctional connections to the dorsal and

Fig. 3. Circuit of OCD [35]


ventral compartments of the emotion regulation circuit in depression [38] andplays a critical role in remission. Mayberg and colleagues could demonstrate,that two months after surgery, 5=6 patients met the response criterion (base-line score in the Hamilton Depression Rating Scale (HDRS) minus 50%),after 6 months, four patients showed sustained response [39]. Differentneuropsychological parameters that were impaired at baseline were signifi-cantly improved. A reduction in the pathological hyperactivity in this regionhas also been demonstrated using Positron Emission Tomography (PET) inthis study. During the blinded sham stimulation phase (n¼ 1), the patient’scondition worsened considerably. No adverse events due to stimulation wereobserved [39].

Another group studies the effect of DBS in depression using as target theanterior limb of the capsula interna. Historic lesion studies contributed to thehypothesis that the inactivation of larger brain areas inhibits dysfunctionalconnections through this region. After one month, there has been a substantialreduction in depression in the majority of patients patients, reflected in theMontgomery-Asberg Depression Rating Scale. This outcome remained stablewith some fluctuation over half a year [23].

Table 1. DBS targets for major depression

Target Hypothesis Hypothesis based on

Anterior Gyrus

Cinguli (Brodmanarea Cg25)

Inactivation of Cg25 leads

to recovery

Functional

neuroimagingfindings

Anterior Limb of

Capsula Interna

Inactivation of dysfunctional

connections

Clinically effective

neurosurgical

interventions for

OCD and depression

Nucleus

Accumbens

Modulation of the Nucleus

Accumbens, which is a central

structure in the reward system,leads to improvement of anhedonia

Clinical experience

neurobiology of

reward system

Habenula inhibition of the lateral

Habenula leads to upregulation

of serotonergic, noradrenergic,

dopaminergic system and

downregulation of HPA axis

Functional

neuroimaging

findings animal

studies

Thalamus Dysfunctional connection between

thalamic system and orbitofrontalin depression

Functional neuroimaging

findings animal studies

Disruption of overactivation

of frontal cortex with DBS


Table

2.DBSstudiesin

majordep

ression

Referen

cen

Comorbidity

Target

Studydesign

Stim

ulation

param

eters

Effect

Sideeffects

[39]

6not

reported

anterior

cingulate

gyrus(Cg25)

system

atic

param

eter

search

acute

off-on-off-on

trials,blinding

phase,

6months

follow-up

monopolar

stim

ulation130Hz

60ms

voltag

e

increasedto

9Vat

each

contact

mean

param

etersat

6months:4V,

130Hz,

60ms

Rem

issionofdep

ression

in4=6patients,all

patients

reported

acute

effects,

onepatientmet

response

criteria

during

first4months,

norm

alizationofbrain

metab

olism

inCg25

dose-dep

enden

d

adverseeffects

(lightheaded

ness,

headache,

psychomotor

slowing)at

highlocal

skin

irritations(2=6)

dueto

whichthe

system

needed

tobe

explantedskin

pressure

necrosis(1=6)

[5]

1OCD

Ven

tral

N.Cau

datus

(contacts2,3),

N.Accumben

s

(contacts0,1)

sixmonths

observation,

noblinding

phase

Rem

issionof

dep

ression(HDRS<7);

stim

ulationofall

contactsnecessary

failure

ofthepulse

gen

eratorbattery

improvedvisual

and

verbal

mem

ory

[29]

1Borderline

personality

disorder,

bulim

ia

nervosa

Lower

Stem

ofTh

alam

us

24months

observation,

blindingphase

2.5

V,130Hz,

450ms

Rem

issionof

dep

ression,(Decrease

ofHDRSfrom

42

to10)

tran

sien

tdecrease

inlearning-to-learn

capab

ilities

(WCST)

improvemen

tin

verbal

andnonverbal

mem

ory

andab

stractiontests

[54]

3none

Nucleu

s

Accumben

s

3months

observation

Red

uctionofan

hed

onia

ratings,Norm

alization

ofbrain

metab

olism

inN.Accumben

s


We selected the Nucleus Accumbens as target for DBS because of itsprominent role in the reward system. We could demonstrate, that modulationof this structure was associated with changes in the symptom of anhedoniaand mood in 3 depressed patients [54]. Stimulation current correlated nega-tively with anhedonia ratings. Normalization of brain metabolism in fronto-striatal networks as result of stimulation was also observed [54]. No side effectsdue to stimulation occurred. Results from a total of ten patients in thisstudy show acute as well as long-term antidepressant effects of DBS at thistarget [14].

Two single-case studies in OCD patients with comorbid depression haveshown antidepressant effects at different targets:bilateral stimulation of theventral nucleus caudatus in combination with Nucleus Accumbens for OCDlead to remission of depression (HDRS_17<7) after six month. No neuro-psychological deterioration was reported [5].

Bilateral stimulation of the lower thalamus stem also lead to remissionin one depressed patient (HDRS 42!10). The effect remained stable for24 months [29]. During blinded discontinuation of stimulation, the patient’scondition aggravated. The lower thalamus stem is the connection be-tween unspecific thalamic system and orbitofrontal cortex. Dysregulation ofthis system seem to play an important role in the development of depression[29].

The habenula has been proposed recently as target for DBS in depressionby Sartorius and Henn [50]. Animal data and imaging studies have shown, thatthis regions controls serotonergic fibers from the dorsal raphe nuclei andnoradrenergic fibers from the locus coeruleus. The authors hypothesize thatover activation of the habenula is related to depression [50].

In summary, five different targets sites are currently under research forDBS in depression therapy. Due to very small sample sizes, it cannot bedecided about most effective target sites yet. First results have shown sustainedantidepressant effects, making DBS a putative therapy option for treatment-resistant depression (see Tables 1 and 2).

Targets in OCD

In OCD, there have been proposed different targets according to the underly-ing pathological network (see Table 3). The orbitofrontal cortex and the ante-rior cingulate cortex are part of the OCD circuit. Unfortunately, these regionsare very large and not well circumscribed in relation to this disease. Thus thesize of cortex region that needs to be modulated would be too large [35]. Inmost studies, the anterior limb of the internal capsule was the target for eitherunilateral or bilateral stimulation [1, 3, 21, 44, 46, 62]. All studies reported onpromising results ranging from response to complete remission (see Table 4).In terms of side effects, some studies reported on induced, directly stimulation


related symptoms of hypomania which all ceased completely after reduction ofstimulation intensity [24, 44, 46].

The Nucleus thalamicus- zona incerta has been studied at three patientswith Parkinson’s disease and comorbid OCD [18, 36]. Both studies reportedconsiderable amelioration of OCD symptoms. The Nucleus Accumbens andNucleus Caudatus were target in one case study with comorbid depression(see above) [5]. This patient achieved remission status [5]. Unilateral stimulationof the N. Acc lead to good results in 14 implanted patients [33]. Stimulation ofthe ventral capsule=ventral striatum lead to major improvement in 50% of thepatients [24]. Side effects related to the stimulation were transient hypomaniaand increased anxiety which could be counteracted by parameter change [24].

In summary, there are promising effects for different targets, but as world-wide sample sizes are small, it is too early to select one favourable target if thereis any. As OCD is a heterogeneous disease, there might be different optimaltargets for different symptom clusters.

Safety and advantages of DBS

In DBS, complications are either related to the operation itself (e.g., bleeding,local infections at the chest) and transient side effects are related to the stimu-lation (e.g., elevation of mood, anxiety, motor slowing). Fortunately, the safetyof the stereotactic operation technique has been extremely improved in the lastyears with the help of neuroimaging. Bleeding rate of DBS surgeries are be-tween 0, 2 and 5% [33]. It has to be underlined, that no side effects such asextrapyramidal effects, weight gain, that substantially effect compliance, arereported.

On the other hand, DBS has many advantages over traditional therapymethods: clinical effects can be achieved without irreversible lesioning, stereo-tactic operation is the most minimal neurosurgical method and electrodes canbe completely removed if necessary. Brain activity can be changed in a direct,controlled manner.

Table 3. DBS target sites for OCD

Target Hypothesis Hypothesis based on

Ventral=anterior

Capsula Interna

Relay between Cortex

and Thalamus

Anterior capsulotomy

N. Caudatus modulates both direct and

indirect OCD pathways

Subcaudate tractotomy

Volumetric studies Metabolic

studies Imaging studies

N. Subthalamicus– Modulates indirect OCD pathway Imaging studiesN. Accumbens overactivation of the direct

pathway provokes OCD symptoms

Imaging studies


Table

4.DBSstudiesOCD

Referen

ces

ncomorbidity

Target

Studydesign

Parameter

effect

Sideeffects=problems

[44,46]

6So

matoform

disorder,

major

dep

ression,

histrionic

andnarcistic

personality

disorder

Anterior

Cap

sule

Double

blind;

on-offfor

3months

(4patients),

21months

follow-up,

Differentparam

eters

individually

adjusted

,

upto

10.5

V,100Hz,

450ms

66%

ofpatients

responded

;acute

effect

inonepatient

(red

ucedan

xiety,

dep

ression,an

d

obsessivethoughts),

worsen

ingin

stim

ulation-off-

phase

Sensationofthelead

san

d

thestim

ulatorfatigue,

acute

worsen

ingofan

xiety

withsomeparam

eters,

weightchan

ges,at

high

amplitude:

cognitivean

d

beh

aviouraldisinhibition

(reversedwhen

stim

ulationam

plitude

was

decreased

)short

battery

life(5

months)

[36]

2Parkinson’s

disease

N.Su

b-

thalam

icus

Clinical

observations

onemonth

before

surgery

andafter

6months

Pt1:3V,185Hz,

60ms;Pt2:3V,

130Hz,

90ms

58%

improvemen

t

inpatient1,64%

improvemen

tin

patient2in

Y-BOCS

after2weeks

[3]

1AxisII:

deferred

Anterior

Limbof

Cap

sula

Interna

Casestudy;

param

etersset

at2weeks

after

implantation,

review

edat

6weeks

and

3months

At2weeks:2V,

100Hz,

210ms

Positive

case

report;

decreasein

Y-BOCS

from

34=40to

7=40

(continued

)


Table

4(continued

)

Referen

ces

ncomorbidity

Target

Studydesign

Parameter

effect


[21]

3So

matoform

disorder

Anterior

Cap

sule

15–33months

follow-up

Higham

plitude

66%

ofPatien

ts

responded

[62]

4N.

Accumben

s

Clinical

observations,

24–30months

follow-up

2–6.5

V75%

ofpatients

responded

[5]

1Major

dep

ression

N.

Cau

datus=

N.

Accumben

s

Casestudy

15months

follow-up

Stim

ulation

intensity

increased!

2V,

130Hz,

90ms

(deepestcontacts

usedbilaterally)

twoupper

contacts

added

andvoltag

e

increasedupto

4Van

d120ms

Positive

case

report;

remissionof

dep

ressivesymptoms

at6months;delayed

remissionofOCD

at

12–15months

[18]

1Parkinson’s

disease

N.Su

b-

thalam

icus

Casereport

sixmonths

follow-up

Leftelectrode:

3.5

V,

rightelectrode:

1,3

V;185Hz,

60ms

Chronicmonopolar

stim

ulation

positive

case

report,

PDmotorsymptoms

improved,OCD

symptoms

disap

peared,

decreased

anxiety

(continued

)


Table

4(continued

)

Referen

ces

ncomorbidity

Target

Studydesign

Parameter

effect


[1]

4MD(3=4),

social

phobia,

pastan

orexia,

bulim

ia

Anterior

Cap

sule

Double-blindfor

2�3

weeks,

open

label

testingphase,

4–34months

follow-up

5–10.5

V,

4–23months

follow-up

25%

ofpatients

responded

onesuicide,

judged

tobeunrelatedto

stim

ulation

[24]

10

Major

dep

ression

(8=10)

Ven

tral

Cap

sule=

Ven

tral

Striatum

Patien

tswere

blinded

Intrao

perative:

Different

param

eters,

Best

results:

ventral

contact

(0

and=or1)

neg

ative,

100–130Hz,

90–210ms,

8–17mA

50%

ofpatients

responded

(YBOCS

scoresan

dlevelof

global

functioning)

Implantation:intracereb

ral

hem

orrhag

eafterlead

insertion,asingle

tonic-

clonic

seizure,superficial

surgical

woundinfection,

alltreatedsuccessfully,

stim

ulation:acute

effects

onmood(in

creasedan

xiety);

moodelevation=hypoman

ia:

increaseden

ergy,speech

production,social

interactions;DBS

interruption(dueto

battery

dep

letion):worsen

ingin

dep

ressed

moodan

dOCD

symptoms;

Empty

batteries

after

5.5–13months,

onepatientdieddueto

recurringbreastcancer


Furthermore, DBS offers the opportunity to continuously adjust stimula-tion variables for each patient in order to optimize therapy. The patient canturn off stimulation immediately if side effects occur. DBS is the only neuro-surgical method that allows blinded studies for therapy control.

Thus, DBS is an exciting method and offers unique possibilities to gainmore insight into the underlying neurobiology of psychiatric disorders.

Ethical aspects and standards in DBS

Ethical considerations

Referring to the difficult history of psychosurgery, there have to be applied thehighest ethical standard for DBS. High mortality, immense suffering and lowquality of life as well as the social burden are in favour for the use of thismethod for therapy-resistant patients. In addition, the potential benefit forthe understanding of pathological principles in mental disorders is high.Nonetheless, some ethical aspects have to be considered more closely [19,20, 53, 63, 64].

The following fundamental ethical concerns are mostly applicable for allclinical interventions (e.g., pharmacotherapy, psychotherapy) as well as for DBSin neurological disorders: are patients able to give confirmed consent? It hasbeen demonstrated, that depressed patients showed few impairments in theirability to give informed consent to participate in research [6]. Another questionis, how far should we manipulate human nature [20]? Especially long-termeffects of DBS cannot be evaluated yet, but in comparison to pharmacothera-py, brain stimulation is a more specific and reversible intervention. So far, thereare no harming effects (or changes in personality) reported. Most people wouldagree that trying to heal illnesses is a fruitful manipulation of human nature.More problematic is the danger of misuse, e.g., for mind control or for overenhancing normal (healthy) cognitive functions (neuro enhancement) [19, 20].As clinical researchers on therapeutics in psychiatry, our aim is to help patientsto lead a normal life which implies normal cognitive function and autonomy ofthe patient.

Practical ethical issues are the availability of alternative treatment options(e.g., pharmacotherapy, ECT, psychotherapy). As this method is only applied totreatment-resistant patients, there is no hope of other treatment approachescurrently available.

The reversibility of the method and the potential benefit are strong ethicalarguments for the use of DBS in psychiatric disorders [63, 64].

On the other side, there are substantial risks (bleeding, infection, etc.) andthe efficacy is not yet established. Thus, each case has to be evaluated carefullyand obligatory ethical standards have to be established in form of inclusion andexclusion criteria. This also prevents researcher to ‘‘jump on the bandwagon’’.


In summary, it would be unethical to abandon a possible beneficial methodbefore its scientific evaluation only for historical reasons. Until this method willbe scientifically evaluated, obligatory standards for patient inclusion and theselection of targets have to be established.

The path towards mandatory standards for DBS in psychiatricdisorders

The different ethical aspects discussed above lead to the proposal of criteria forthe application of DBS. In 2002, Nuttin and colleagues have put forwardminimum requirements for the use of DBS in psychiatric diseases [45].These include an ethics committee that approves the study protocol and over-sees the ongoing project. They also propose a committee for the patient selec-tion. It is questionable, if a committee with limited access to the individualpatient should make this decision or if an external gate keeper who is notinvolved otherwise in the study, is more suitable for this task. It has to betaken into account that in case of patient selection, responsibility cannot beshared.

According to Nuttin and colleagues, inclusion criteria are severity, chronic-ity, disability and treatment refractoriness [45]. These criteria need to be furtherspecified for each disease. Mink and colleagues already developed some forTourette disorder [40]. Our group applied the following criteria [51]:

Inclusion criteria:

� Major depression (MD), severe, unipolar type German mother tongue:� Hamilton Depression Rating Scale (HDRS24) score of >20:� Global Assessment of Function (GAF) score of <45:� At least 4 episodes of MD or chronic episode >2 years:� 5 years after first episode of MD:� Failure to respond to �adequate trials (>5 weeks at the maximum recom-mended or tolerated dose) of primary antidepressants from at least 3 differ-ent classes:– Adequate trials (>3 weeks at the usually recommended or maximum tolerat-

ed dose) of augmentation=combination of a primary antidepressant using atleast 2 different augmenting=combination agents (lithium, T3, stimulants,neuroleptics, anticonvulsants, buspirone, or a second primary antidepressant);

– an adequate trial of electroconvulsive therapy [ECT] (>6 bilateral treat-ments); and

– an adequate trial of individual psychotherapy (>20 sessions with an expe-rienced psychotherapist).

� Able to give written informed consent� No medical comorbidity� Drug free or on stable drug regimen at least 6 weeks before study entry


Exclusion criteria:

� Current or past nonaffective psychotic disorder� Any current clinically significant neurological disorder or medical illness af-

fecting brain function, other than motor tics or Gilles de la Tourette syndrome� Any clinically significant abnormality on preoperative magnetic resonance

imaging (MRI)� Any surgical contraindications to undergoing DBS� Current or unstably remitted substance abuse (aside from nicotine)� Pregnancy and women of childbearing age not using effective contraception� History of severe personality disorder

Another important aspect of quality in DBS research is patient management:clinical experience has shown that it is extremely important to clarify thepatient’s expectations before surgery, and to closely follow the patients afterthe operation in order to avoid stress, catastrophic thinking, hypomania orsuicidality, especially in case of suboptimal acute therapy effect. In case ofno response, hospitalization or other treatment options (change in medication,ECT, psychotherapy) should be offered.

Some issues have to be taken into account regarding the adjustment of stim-ulation parameters: as a broad variety of possible settings is available and thereusually is not an immediate response, but changes need several weeks, parametersshould be changed only after several weeks. This can be compared to pharmaco-therapy. With parameter changes, all other therapies should be kept constant.

The quality of the research team is also one main factor in DBS therapy:patient selection, baseline psychiatric and neuropsychological assessment andthe operation and follow-up requires a team of surgeons, psychiatrists andneuropsychologists which are experts in the field of the respective disease.Each case has to be documented according to scientific standards (standardiseddiagnostic with clinical scales, evaluation of cognitive parameters with psycho-logical tests, report of parameter changes, other therapies, additional neuroim-aging etc.). These requirements can only be fulfilled in special academic centreswhere all these resources are available. Fundamental guidelines for study designshould also be agreed on (e.g., randomized controlled trials? Blinding phase?Period for follow-up?). Last but not least, standards for target selection alsoneed to be established (e.g., strong anatomical and functional hypotheses). It isour task as neuroscientists together with legal authorities to work out standardsto guarantee for the quality of research in this field.

Conclusions

A substantial percentage of therapy-resistant psychiatric patients require newtherapy approaches. Deep brain stimulation offers the possibility to manipulate


pathological neuronal networks in a very precise way. First studies showed verypromising effects in depression and OCD. There are no fundamental ethicobjections to its use in psychiatric disorders, but until substantial clinical datais available, mandatory standards are needed for patient and target selection,quality of research centre and study protocol.

The future of DBS

DBS is a unique and very promising method for the treatment of therapy-resistant psychiatric patients. Nonetheless, the duration of the battery limits thechoice of stimulation parameters, increases the risk of infection and raisestreatment costs. Rechargeable batteries are currently under development.Actual technology allows mainly continuous stimulation with little possibilityfor dynamic adjustment. Recording signals from the DBS electrode and com-bining DBS with imaging in order to map the spatiotemporal unfolding ofDBS-elicited whole brain activity are rich research tools. Imaging techniquescan be used with DBS to reveal the fundamental mechanism of pathologicalbrain function.

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