different modalities of neuromodulation such as repetitive transcranial magnetic stimulation ( schlaepfer et al . , 2003 ; george , 2010 ) , vagus nerve stimulation ( kosel and schlaepfer , 2003 ; schlaepfer et al . , 2008b ) , and magnetic seizure therapy ( lisanby et al . , 2001 ; kayser et al . , 2010 ) have been proposed and systematically studied in psychiatric different disorders ( schlaepfer et al . , 2010 ) . both clinically and scientifically the most promising method of neuromodulation might be deep brain stimulation ( dbs ) . dbs refers to the stereotaxic placement of unilateral or bilateral electrodes connected to a permanently implanted neurostimulator ( schlaepfer and lieb , 2005b ) . the exact neurobiological mechanisms by which dbs exerts effects on brain tissue are not yet fully understood ( hardesty and sackeim , 2007 ) . various mechanisms have been discussed , on the neuronal level , excitatory and inhibitory processes might play a role ( mcintyre et al . , 2004 ) . today , it is unknown which part of the neuron ( e.g. , cell body , axon ) is primarily modulated by dbs . certainly , the stimulation volume is not a fixed area around the electrode and the effect on neuronal tissue is variable . stimulation parameters ( frequency , amplitude , pulse width , duration ) also clearly have an impact on the effect ( ranck , 1975 ) . with commonly used parameters , a relatively large volume of neural tissue side effects in dbs are either related to the operation itself ( e.g. , bleeding , local infections at the chest ) or to the stimulation ( e.g. , elevation of mood , anxiety , motor slowing ) . fortunately , the safety of the stereotactic operation technique has been extremely improved in the last years with the help of neuroimaging . on the other hand , dbs has many advantages over traditional therapy methods : clinical effects can be achieved without irreversible lesioning , stereotactic operation is the most minimal neurosurgical method and electrodes can be completely removed if necessary . furthermore , dbs offers the opportunity to continuously adjust stimulation variables for each patient in order to optimize therapy . the patient can turn off stimulation immediately if side effects occur . dbs is the only neurosurgical method that allows blinded studies for therapy control . in comparison to antidepressant medication , nor side effects such as extrapyramidal effects , weight gain , that substantially effect compliance and patient s quality of life , are reported . also no long - time side effects as in antidepressant treatments ( geddes et al . , 2003 ; furukawa et al . nonetheless , dbs can be associated with side effects due to stimulation that are transient and can be counteracted by a change in stimulation parameters ( see table 1 ) . but until it has been proven that dbs has the same clinical effect as pharmacotherapy , the latter together with psychotherapy must be the first treatment choice . thus , dbs could become an exciting method in the treatment of depression and obsessive  compulsive disorder ( ocd ) and offers unique possibilities to gain more insight into the underlying neurobiology of psychiatric disorders . different modalities of neuromodulation such as repetitive transcranial magnetic stimulation ( schlaepfer et al . , 2003 ; george , 2010 ) , vagus nerve stimulation ( kosel and schlaepfer , 2003 ; schlaepfer et al . , 2008b ) , and magnetic seizure therapy ( lisanby et al . , 2001 ; kayser et al . , 2010 ) have been proposed and systematically studied in psychiatric different disorders ( schlaepfer et al . , 2010 ) . both clinically and scientifically the most promising method of neuromodulation might be deep brain stimulation ( dbs ) . dbs refers to the stereotaxic placement of unilateral or bilateral electrodes connected to a permanently implanted neurostimulator ( schlaepfer and lieb , 2005b ) . the exact neurobiological mechanisms by which dbs exerts effects on brain tissue are not yet fully understood ( hardesty and sackeim , 2007 ) . various mechanisms have been discussed , on the neuronal level , excitatory and inhibitory processes might play a role ( mcintyre et al . , 2004 ) . today , it is unknown which part of the neuron ( e.g. , cell body , axon ) is primarily modulated by dbs . certainly , the stimulation volume is not a fixed area around the electrode and the effect on neuronal tissue is variable . stimulation parameters ( frequency , amplitude , pulse width , duration ) also clearly have an impact on the effect ( ranck , 1975 ) . with commonly used parameters , a relatively large volume of neural tissue side effects in dbs are either related to the operation itself ( e.g. , bleeding , local infections at the chest ) or to the stimulation ( e.g. , elevation of mood , anxiety , motor slowing ) . fortunately , the safety of the stereotactic operation technique has been extremely improved in the last years with the help of neuroimaging . on the other hand , dbs has many advantages over traditional therapy methods : clinical effects can be achieved without irreversible lesioning , stereotactic operation is the most minimal neurosurgical method and electrodes can be completely removed if necessary . furthermore , dbs offers the opportunity to continuously adjust stimulation variables for each patient in order to optimize therapy . the patient can turn off stimulation immediately if side effects occur . dbs is the only neurosurgical method that allows blinded studies for therapy control . in comparison to antidepressant medication , nor side effects such as extrapyramidal effects , weight gain , that substantially effect compliance and patient s quality of life , are reported . also no long - time side effects as in antidepressant treatments ( geddes et al . , 2003 ; furukawa et al . nonetheless , dbs can be associated with side effects due to stimulation that are transient and can be counteracted by a change in stimulation parameters ( see table 1 ) . but until it has been proven that dbs has the same clinical effect as pharmacotherapy , the latter together with psychotherapy must be the first treatment choice . thus , dbs could become an exciting method in the treatment of depression and obsessive  compulsive disorder ( ocd ) and offers unique possibilities to gain more insight into the underlying neurobiology of psychiatric disorders . the main focus of studies on the underlying neurobiology of major depression ( md ) has focused on the description of biological differences between patients and healthy subjects such as alterations of monoaminergic or endocrine systems . the relative importance of the various biological changes has not been elucidated ; correlation with specific symptoms of the disease has rarely been attempted . psychotropic drugs work by altering neurochemistry to a large extent in widespread regions of the brain , many of which may be unrelated to depression . in contrast to some neurological disorders , the pathological interplay of several brain regions contributes to the behavioral , emotional , and cognitive symptoms of psychiatric disorders . metabolic studies suggest that different symptoms are mediated by different brain regions ( berton and nestler , 2006 ; yurgelun - todd et al . , 2007 ; krishnan and nestler , 2008 ) a convincing network - model of depression integrating biochemical , electrophysiological , imaging , and animal studies , has been described by mayberg ( 1997 ) . according to this model , depression results from a dysregulation of limbic  cortical connections : pathological changes in dorsal brain regions ( including the dorsolateral prefrontal cortex , inferior parietal cortex , and striatum ) were associated with cognitive symptoms ( e.g. , apathy , anhedonia , hopelessness , deficits in attention , and executive function ) , changes in ventral areas ( hypothalamic  pituitary  adrenal axis , insula , subgenual cingulate , and brainstem ) contribute to the vegetative and somatic aspects of depression ( e.g. , sleep disturbance , appetite , endocrine dysregulation ) . this model underlines the role of the rostral cingulate cortex in regulating the network ( mayberg , 1997 ) . the involvement of further regions in depression is discussed : the hippocampus contributes to memory deficits , the nucleus accumbens was associated with anhedonia and lack of motivation , the amygdala plays a role in the processing of aversive stimuli and avoidance ( berton and nestler , 2006 ) . obsessive  compulsive disorder is characterized by obsessions ( anxiety - provoking thoughts ) and compulsions ( repeated , time - consuming behaviors ; stein , 2002 ) . as in most psychiatric disorders , a complex interplay of genetic factors , neurotransmitter changes and psychosocial characteristics contribute to the development of this disease . dysfunctions in a network connecting the cortex and basal ganglia are supposed to underlie ocd . imaging data demonstrated changes in orbitofrontal cortex , anterior cingulate cortex and caudate nucleus in ocd ( baxter , 1990 ) . emerging evidence suggests that different alternations of the ocd circuitry subserve different symptom subtypes ( kopell and greenberg , 2008 ) . it has been hypothesized that an over activation of the direct pathway of the cortico - striatal  pallidal  thalamic  cortical loop leads to intrusive thoughts ( baxter et al . , 2001 ) . these novel conceptualizations of both ocd and md , brought about mainly by advances in functional neuroimaging but also electrophysiological and molecular studies and their synthesis have paved the road to hypothesis - guided studies on targeted reversible neuromodulation with dbs in these disorders . the subgenual cingulate cortex ( brodmann area cg25 ) has probably dysfunctional connections to the dorsal and ventral compartments of the emotion regulation circuit in depression ( mayberg , 1997 ) . the subgenual cingulate cortex modulates negative mood states ( mayberg et al . , 2005b ) . it has been involved in acute sadness and in antidepressive treatment effects ( mayberg et al . the rostral part of the cingulate cortex seems to play a key role in modulating the network of depression ( mayberg , 1997 ) . ( 2005b ) could demonstrate , that 2  months after surgery , 5/6 patients met the response criterion [ baseline score in the hamilton depression rating scale ( hdrs ) minus 50% ] , after 6  months , four patients showed sustained response . different neuropsychological parameters that were impaired at baseline were significantly improved . a reduction in the pathological hyperactivity in this region has also been demonstrated using positron emission tomography ( pet ) in this study . during the blinded sham stimulation phase ( n  =  1 ) , the patient s condition worsened considerably . no adverse events due to stimulation were observed ( mayberg et al . , 2005b ) . ( 2009 ) investigated the use of dbs at the ventral capsule / ventral striatum ( vc / vs ) . the vc / vs was targeted , because former studies targeting the vc / vs in ocd patients ( nuttin et al . , 1999 ; greenberg et al . , 2006 ) showed improvement not only for ocd symptoms but also for depressive symptoms . this finding was supported by the fact that the vs has complex architecture and includes structures such as the bed nucleus of the stria terminalis and the nucleus accumbens , which are regions believed to be involved with stress - related and reward  motivation components of depression ( forray and gysling , 2004 ; epstein et al . , 2006 ) . once stimulation was titrated to therapeutic benefit and the absence of adverse effects , patients received significant improvements in depressive symptoms measured by the hdrs . responder rates of 40% at 6  months ( n  =  15 ) and 53.3% at last follow - up ( mean last follow - up of 23.5    14.9  months ) receiving continuous dbs stimulation are referred . remission rates were reported 20% at 6  months and 40% at last follow - up with the hdrs . so the results of this study suggest that dbs of the vc / vs could also provide benefit in highly treatment - refractory patients with depression . however , since the larger contacts of the vc / vs leads have twice the surface area of standard leads used in other dbs applications , more frequent battery replacements or rather implanting recharging batteries should be considered ( malone et al . , 2009 ) . we selected the nucleus accumbens as target for dbs because of its prominent role in the reward system . the nucleus accumbens is known to act as motivational gateway between systems involved in motor control and limbic systems in charge of emotion processing ; especially the ventral striatum is uniquely located to modulate other regions of the brain ( schlaepfer et al . , 2008a ) . by targeting one site in a network of brain regions implicated in processing of affective stimuli , it was possible to manipulate anhedonia in particular . it could be demonstrated that modulation of this structure was associated with changes in the symptoms of anhedonia and mood in three depressed patients . normalization of brain metabolism in fronto - striatal networks as result of stimulation was also observed ( schlaepfer et al . results from a total of nine patients in this study show acute as well as long - term antidepressant effects of dbs at this target have been published recently , demonstrating a responder rate of 50% ( bewernick et al . , the habenula has been proposed recently as target for dbs in depression ( sartorius and henn , 2007 ) . animal data and imaging studies have shown , that this regions controls serotonergic fibers from the dorsal raphe nuclei and noradrenergic fibers from the locus coeruleus ( winter et al . the authors hypothesize that over activation of the habenula is related to depression and recently reported on the course of depression after dbs to the habenula in a case report ( sartorius et al . , 2010 ) . another putative target site for md has been proposed very recently , the medial forebrain bundle ( coenen et al . , 2011 ) . magnetic resonance diffusion tensor imaging ( dti ) can visualize distinct functional circuits in the living human brain on the basis of the anisotropy of the brain tissue . this technique has been applied to an analysis of the different dbs sites for md and lead to the hypothesis - guided development of yet another site with hypothetically greater efficacy and even less unwanted effects . single - case studies in ocd patients with comorbid depression have shown antidepressant effects : bilateral stimulation of the ventral nucleus caudatus in combination with nucleus accumbens for ocd led to remission of depression ( hdrs_17 it was supposed that dysregulation of the connection between unspecific thalamic system and orbitofrontal cortex plays an important role in the development of depression ( jimnez et al . , 2005 ) . therefore , bilateral stimulation of the lower thalamus stem was performed one depressed patient and led to remission ( hdrs 42    10 ) . unfortunately , these regions are very large and not well circumscribed in relation to this disease . thus the size of cortex region that needs to be modulated would be too large ( lipsman et al . , 2007 ) . in most studies , the anterior limb of the internal capsule was the target for either unilateral or bilateral stimulation ( anderson and ahmed , 2003 ; gabriels et al . , 2003 ; nuttin et al . , 1999 ; nuttin et al . , 2003 ; all studies reported on promising results ranging from response to complete remission . in terms of side effects , some studies reported on induced , directly stimulation related symptoms of hypomania which all ceased completely after reduction of stimulation intensity . zona incerta has been studied at three patients with parkinson s disease and comorbid ocd ( mallet et al . , 2002 ; the subthalamic nucleus was stimulated in a study ( malone et al . , 2009 ) , this group included 16 patients and received significant lower symptoms of ocd . in a recent ocd study targeting the subthalamic nucleus , ocd symptoms were significantly reduced after the 3-months double - blind stimulation phase compared to the double - blind sham stimulation phase ( mallet et al . , 2008 ) . both studies refer to possible associated risk of serious adverse events ( mallet et al . , 2008 ; malone et al . , the nucleus accumbens and nucleus caudatus were target in one case study with comorbid depression ( s above ) . unilateral stimulation of the nacc in a well - designed , controlled study lead to somewhat less impressive but significant improvements results in 10 patients ( huff et al . , 2010 ) . the stimulation of the vc / vs led to a significant improvement in 50% of the patients side effects related to the stimulation were transient hypomania and increased anxiety , which could be counteracted by parameter change ( greenberg et al . , 2006 ) . recently results of bilateral dbs to the nucleus accumbens in ocd with an open 8-month treatment phase , followed by a double - blind crossover phase with randomly assigned 2-week periods of active or sham stimulation , ending with an open 12-month maintenance phase have been published ( denys et al . , 2010 ) . nine of the 16 patients were classified as responders , indicating that bilateral stimulation of the nucleus accumbens may be an effective and safe treatment in patients with highly refractory ocd . in summary , promising effects for different targets have been demonstrated , but as worldwide sample sizes are small , it is too early to select one favorable target if there is any . as ocd is a heterogeneous disease , there might be different optimal targets for different symptom clusters . the high mortality , low quality of life , and the social burden of inadequately treated serious psychiatric illness favor the use of dbs for treatment - resistant patients . the potential benefit to the understanding of pathological principles in mental disorders is evident ( schlaepfer and lieb , 2005a ; fuchs , 2006 ; ford , 2007 ; synofzik and schlaepfer , 2008 , 2010 ) . fundamental ethical concerns are generally applicable to all clinical interventions ( e.g. , pharmacotherapy , psychotherapy ) including dbs in neurological disorders . foremost , are patients able to give conformed consent ? it has been demonstrated that depressed patients show few impairments in decision - making capacity related to clinical treatment research ( appelbaum et al . , 1999 ) . another concern is , how far human nature may ethically be manipulated ( fuchs , 2006 ) . long - term effects of dbs can not be evaluated yet , but in comparison to pharmacotherapy , brain stimulation is a more specific and reversible intervention . more problematic is the danger of misuse , such as for mind control or for over - enhancement of normal ( healthy ) cognitive function (  brain doping  ; fuchs , 2006 ; ford , 2007 ) . as clinical researchers in psychiatry , our aim is to help patients to lead a normal life , including normal cognitive function and personal autonomy . more practical ethical concerns are the availability of alternative treatment methods ( e.g. , pharmacotherapy , ect , psychotherapy ) . taking to account that dbs is used only with treatment - resistant patients , who have already shown no benefit with other treatment approaches currently available , the apparent reversibility of dbs and its robust potential benefits , as described by prior pilot studies , are strong ethical arguments for considering dbs treatment for resistant psychiatric disorders ( synofzik and schlaepfer , 2008 , 2010 ) . however , there are also some notable risks with dbs , particularly intracerebral bleeding and wound infection and its efficacy is not yet formally and extensively established in controlled trials . therefore , until the dbs treatment method is scientifically validated ; obligatory standards for patient inclusion and exclusion criteria as well as the selection of targets are needed . ( 2009 ) , recommending 16 key points for guiding research and protecting the safety and rights of research subjects , as well as nuttin et al . ( 2002 ) to form a separate committee with only distant access to the individual patient or no direct involvement to the study for reviewing patient selection . it is our belief , that despite any committee review  might it be as thorough and exhaustive as possible  the clinical responsibility remains with the patient s clinicians and can not be shared by review committees . so from our point of view further research regarding obligatory standards in dbs is needed . this is by no means unique to dbs , but this area is particularly vulnerable to bias because of an excessive reliance on single - patient case reports ( schlaepfer and fins , 2010 ) . until cohort studies are routinely performed , the possibility will remain that only positive results will be published at the expense of negative data that might also have important implications . balanced publishing of results is even more important taking to account , that patients and public understanding of the risks and benefits of dbs is strongly shaped by media ( racine et al . , 2007 ) . there are no fundamental ethic objections to its use in psychiatric disorders , but until substantial clinical data is available , mandatory standards are needed for patient and target selection , quality of research center , and study protocol . it is very important to point out that in the actual stage of research ; dbs for psychiatric diseases is clinical research on therapeutics . the benefit of this method has to be proven first , until dbs will be available for many patients . before , much more information about the therapeutic effect , individual predictors of response , possible short and long - time side effects , and neuroethical issues have to be gained . deep brain stimulation is a unique and very promising method for the treatment of therapy  resistant psychiatric patients . nonetheless , the duration of the battery limits the choice of stimulation parameters , increases the risk of infection , and raises treatment costs . a particular advantage of dbs is , that it allows recording signals from the stimulating electrodes ( cohen et al . , 2009a,2009b,2009c ) and combining these data with functional neuroimaging in order to map the spatiotemporal unfolding of dbs - elicited whole brain activity will lead to a much broader knowledge on functional and dysfunctional circuits processing affective stimuli revealing fundamental mechanisms of brain function . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest .
most patients suffering from psychiatric disorders respond to combinations of psycho- and psychopharmacotherapy ; however there are patients who profit little if anything even after many years of treatment . since about a decade different modalities of targeted neuromodulation  among them most prominently  deep brain stimulation ( dbs )  are being actively researched as putative approaches to very treatment - resistant forms of those disorders 
 . 
 recently , promising pilot data have been reported both for major depression ( md ) and obsessive  compulsive disorder ( ocd ) . 
 given the fact that patients included in dbs studies had been treated unsuccessfully for many years with conventional treatment methods , renders these findings remarkable . 
 remarkable is the fact , that in case of the long - term studies underway for md , patients show a stable response . 
 this gives hope to a substantial percentage of therapy  resistant psychiatric patients requiring new therapy approaches . 
 there are no fundamental ethic objections to its use in psychiatric disorders , but until substantial clinical data is available , mandatory standards are needed . 
 dbs is a unique and very promising method for the treatment of therapy  resistant psychiatric patients . 
 the method allows manipulating pathological neuronal networks in a very precise way .