Medical Hypotheses 81 (2013) 611–618

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Medical Hypotheses

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One ring to rule them all? – Temporospatial specificity of deep brainstimulation for treatment-resistant depression

0306-9877/$ - see front matter � 2013 Elsevier Ltd. All rights reserved.http://dx.doi.org/10.1016/j.mehy.2013.07.014

⇑ Corresponding author. Tel.: +49 62117032360; fax: +49 17032405E-mail address: carolin.hoyer@zi-mannheim.de (C. Hoyer).

Carolin Hoyer a,⇑, Alexander Sartorius a, Lucas Lecourtier b, Karl L. Kiening c,Andreas Meyer-Lindenberg a, Peter Gass a

a Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, J5, 68159 Mannheim, Germanyb Laboratoire d’Imagerie et de Neurosciences Cognitives, FRE 3289, Université de Strasbourg-CNRS, 12 rue Goethe, Strasbourg, Francec Division of Stereotactic Neurosurgery, Department of Neurosurgery, Heidelberg University, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany

a r t i c l e i n f o a b s t r a c t

Article history:Received 2 April 2013Accepted 5 July 2013

Deep brain stimulation (DBS) for intractable cases of depression has emerged as a valuable therapeuticoption during the last decade. While several locations have been intensely investigated in recent years,the literature is lacking an all-encompassing perspective thereupon asking if and how these stimulationsites relate to each other and what this may imply for the underlying mechanisms of action of this treat-ment modality.

We aim at proposing a model of DBS mechanism of action with particular focus on several puzzlingaspects regarding an apparent temporo-spatial specificity of antidepressant action, i.e. the discrepancybetween protracted response after initiation of stimulation and rapid relapse upon discontinuation, aswell as differential effects on psychopathology. We suggest that the pre-treatment depressive state isdetermined by the interaction of individual traits with dysfunctional adaptive processes as responsesto stress, resulting in a disease-associated, overtly dysfunctional, equilibrium. The antidepressant actionof DBS is thought to modify and re-set this equilibrium in a temporospatially distinct manner by influ-encing the activity states of two different brain circuitries.

The idea of sequential and temporospatially distinct mechanisms of action bears implications for theassessment of psychopathology and behavior in clinical and preclinical studies as well as investigationsinto brain circuit activity states.

� 2013 Elsevier Ltd. All rights reserved.

Introduction

Deep brain stimulation (DBS) for intractable cases of certainpsychiatric disorders has been receiving increasing amounts ofattention during the last decade. Since the pioneering work ofMayberg and colleagues, who applied DBS to the subgenual ante-rior cingulate cortex [1], further stimulation sites have been inves-tigated and further showed the potential of the procedure forimproving the condition of patients with otherwise treatment-resistant depression (TRD). Despite growing clinical expertise, anumber of questions are currently still unanswered. One puzzlingaspect that has hitherto not yet been adequately explained con-cerns the time-course of improvement and recurrence of depres-sive symptoms after initiation and termination of DBS,respectively: Regardless of stimulation site, clinical remission usu-ally requires prolonged periods of stimulation, mostly weeks, eventhough some symptoms may improve more rapidly. In line withthe conceptualization of depression as a disorder of disrupted or

dysfunctional neuronal network activity, we propose a model forDBS-mediated antidepressant action aimed at explaining thesetime course-related peculiarities. We suggest that the pre-treatment depressive state is determined by the interaction of indi-vidual traits with dysfunctional adaptive processes as responses tostress, resulting in a disease-associated, overtly dysfunctional,equilibrium. The antidepressant action of DBS is thought to modifyand re-set this equilibrium in a temporospatially distinct mannerby influencing the activity states of two different brain circuitries.

Local and network mechanisms of DBS action

The pioneering work of Benabid [2] suggested that the thera-peutic effects of DBS result from the initiation of a functional lesionthought to be mediated by different mechanisms (reviewed in [3])such as depolarization blockade, synaptic inhibition or synapticdepression, presumably acting together to produce neuronal ef-fects [4,5].

The types of neurons, their interconnections and intra-networkposition will critically determine the actual local and circuit re-sponses to stimulation [6]. Alterations of various neurotransmitter

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systems in the wake of DBS have also been observed in animalstudies, furthermore indicating impending changes in neural activ-ity on a network level [7–9]. Further supported by findings of met-abolic changes remote from the actual stimulation sites [1,10], thecurrently favored theory on mechanisms of DBS action assumesthe modulation of larger-scale brain network activity [11,12]. Thisconceptual stance mirrors the view of disorders amenable to DBStreatment as disorders of specific brain networks, and conse-quently, network dysfunction, rather than reflecting an underlyingpathology primarily related to specific systems of neurotransmis-sion or regions [12]. Such a network-focused view, then, shouldnot discard, but rather embrace and integrate, assumptions aboutlocalized effects. With respect to DBS treatment of movement dis-orders, McIntyre and Hahn [12] attempt to partly reconcile thesedifferent perspectives by suggesting that what Benabid [2] origi-nally conceived of as ‘‘jamming’’, i.e. stimulation-induced func-tional neuronal inhibition, may be reframed as a resetting ofnetwork oscillatory patterns through resonance-triggered regular-ization of neuronal firing rates. In a related vein McCracken andGrace [13] identified changes in local field potential oscillationsand accompanying widespread changes in OCD- and depression-related networks following high-frequency nucleus accumbens(NAcc) DBS in rats.

DBS for treatment-refractory depressive disorder

Anatomical targets

The subgenual anterior cingulate cortex (sgACC) was the firststructure to which investigational DBS for severe depression wassuccessfully applied [1]. Since then, patient cohorts have been ex-tended and followed up for several years [14–17], showing impres-sive stable response and remission rates. A further target structurehas been the NAcc; [10,18,19]. Closely related anatomical foci arethe ventral capsule/ventral striatum [20] and the medial forebrainbundle (MFB; [21]), which accesses the NAcc and striatum, andwhose suitability as a DBS target for TRD is currently evaluated[22]. Further promising sites of successful DBS intervention indepressive disorder are the inferior thalamic peduncle [23,24]and the stria medullaris thalami/lateral habenula [25,26] (for re-cent overviews on clinical efficacy see [27,28]).

Time-course of symptom amelioration

With respect to the onset of DBS antidepressant effects, someimmediate changes were observed: [1] reported contact-specificreproducible and reversible acute clinical changes after the initia-tion of sgACC DBS, including increased interest and awareness.Similar effects were observed with NAcc stimulation, which ini-tially did not pertain to changes in mood per se but rather were re-lated to increases in motivational drive [19]. In some instances,rapid reduction of symptom severity was observed after surgerybut prior to the initiation of a sham stimulation or stimulation con-dition for psychiatric [14,23] and various neurological conditions[29,30]. These insertional effects have been related to the inductionof a microlesion, which in turn has been suggested to involve glialactivation [31] or edema with consecutive local functional inhibi-tion [23,32], as well as psychological factors such as reduced anx-iety after successful surgical intervention [14]. This type of acuteeffect, however, differs from those mentioned before since it is nei-ther specific nor reversible or reproducible.

Despite the impressive clinical improvement of severely af-fected patients under DBS, current experience indicates thatdepressive symptoms re-appear rather rapidly upon terminationof treatment [33]. There is some variety regarding the acuity of

relapse, with some patients experiencing clinical worsening afew days after stimulation was turned off either as a planned pro-cedure of the study protocol [10,14] or accidentally [20,25], whilein one case of sgACC stimulation, carry-over effects of a magnitudeof up to two weeks were noted [1]. Whereas patterns of symptomre-occurrence after termination of stimulation have been system-atically studied in Parkinson’s disease [34,35], no detailed investi-gations of this issue have been performed for depression.Difficulties arise because of ethical concerns associated with dete-rioration of clinical status and associated suicidality [14]; more-over, assessment is complicated by the fact that the magnitudeof latency to symptom alteration is much larger for depressionthan for Parkinson’s disease where some clinical effects of on/offstate manipulations can be seen within only a few minutes [35].However, on the grounds of existing clinical observations, onemay cautiously claim that ongoing stimulation appears to be re-quired for stable and sustained antidepressant effects, thereby par-alleling data for antidepressant drug treatment sincediscontinuation of antidepressant pharmacotherapy considerablyincreases risk of relapse [36,37]. In sum, while some beneficialacute (i.e. presenting within days) effects, interestingly relatingto motivation rather than mood, are observed shortly after initia-tion of DBS, there is a noticeable delay until considerable clinicalimprovement and stability occur. On the other hand, rather rapidworsening upon termination of stimulation has been noted forthe entirety of locations investigated.

Slowly up but quickly down – mapping sequentialtemporospatial DBS effects

With respect to the application of DBS for neurological disor-ders such as Parkinson’s disease, stark differences are observed be-tween alleviation of distal symptoms and tremor, which oftenrequire only seconds of stimulation, and postural and locomotorimprovement, which need longer times of stimulation. Theseobservations have been linked to qualitative differences of bothsymptom pathophysiology and therapeutic mechanisms [34]. Sucha clear-cut distinction cannot be made with respect to DBS for psy-chiatric disorders because the underlying pathophysiology is morecomplex, and the magnitude of latency to observable and stable ef-fects is larger.

Regarding depression, the time-courses associated with theinduction of treatment effects have hitherto been interpreted asreflecting the sequential action of different mechanisms underly-ing and mediating therapeutic effects: While short-term improve-ment is seen as resulting from the acute disruption of pathologicalcortico-striato-thalamo-cortical (CSTC) network activity implied inthe disorder [38–40], the progressive, and presumably cumulative,effects of longer stimulation have been attributed to longer-termplastic changes [33,41,42] as well as changes in regional connectiv-ity and synaptic transmission rates [41]. This, however, leavesunexplained why clinical state deteriorates so quickly when stim-ulation is turned off. In what follows, we build on implications ofthe underlying assumption that network effects of DBS are criticalin mediating its therapeutic efficacy with regard to time- and pre-sumably location specificity of the treatment modality and suggestthat DBS initiates a stepwise recalibration of pathological circuitactivity.

The pre-treatment depressive state as an evolved equilibrium

How disease-related longer-term structural and functionalmood circuit changes are evaluated methodologically has criticalimplications on the conceptualization of the pre-DBS status quo.This is an important point to consider because the patient

a

b

c

Fig. 1. Schematic representation of the inner, fast response (red), and outer, slower-response (blue), regulatory loops. = DBS stimulation site, AMY = amygdala, BG/Th = basal ganglia, thalamus, dsp = dorsal striato-pallidal connections, fr = fasciculus retroflexus, Hipp = hippocampus, DRN = dorsal raphe nuclei, LC = locus coeruleus,LHb = lateral habenula, mfb = medial forebrain bundle, NAcc = nucleus accumbens, sgACC = subgenual anterior cingulate cortex, sm = stria medullaris thalami, SN = sub-stantia nigra, VS = ventral striatum, VSP = ventral striato-pallidal connections, VTA = ventral tegmental area (a) overview on regulatory loops, structures and pathways, (b)inner regulatory loop and current DBS stimulation sites, (c) outer regulatory loop. (For interpretation of the references to color in this figure legend, the reader is referred tothe web version of this article.)

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population eligible to investigational DBS treatment is normallyrequired to have a history of chronic debilitating disease with inad-equate efficacy of several treatments including electroconvulsivetherapy [43]. In the largest-to-date sample [15,16], the first diseasemanifestation was 20 years prior to DBS treatment with thecurrent depressive episode lasting 6.9 years. Moreover, uponadmission to surgery, patients were receiving more than four med-ications. In another study [14], the total number of previous anti-depressant treatments was 22 for patients with major depressivedisorder. Thus, the baseline state of patients presenting for DBSvery likely represents a mixture of state-, trait- [44] and quitepossibly also treatment-related features [45], which has beensuggested to lie at the root of the pronounced phenomenologicalheterogeneity of depression [39].

In line with a general definition of disorder as ensuing frommalfunctioning adaptive mechanisms [46], the structural, neuro-physiological and neurochemical changes associated with manifestdepressive disorder can partly be viewed as the results of multipleinstances of accommodative processes resulting from prolonged orrepeated exposure to stressors. Accommodation, then, causes a dy-namic and gradual shift of set points, and thus, equilibria, overtime [47–49] towards a disease-associated state of balance. Thiscondition may further be favored by failure to initiate or sustainbeneficial corrective and adaptive processes, as has been suggestedfor the subpopulation of patients with TRD [39].

The interplay of change and stability is also mirrored in disease-associated epigenetic alterations [50] induced by a dynamicmachinery that is responsive of and thus adaptive to environmen-tal changes. On a more local level, it surfaces in discussions on therelative weight and influence of neuronal network-modifying and -stabilizing forces [51,52]: targets of Hebbian plasticity, whichtends to exert somewhat destabilizing effects, are suggested tobe regulated by mechanisms inducing homeostasis.

Within such an adaptationist framework, it was recently sug-gested that neural circuits and brain monoamines are underhomeostatic or allostatic control [53,54]. Based on the claim thatsensor and feedback machinery of monoamine homeostasis re-main intact in depression, it was further proposed that antidepres-sant drug treatment actually perturbs existing homeostasis [55],giving rise to oppositional tolerance [45] through efforts to pre-serve the evolved equilibrium. Oppositional forces have been ar-gued to be proportional to the perturbing effects ofantidepressant drug treatment, indexed by the degree to whichmonoamine levels are altered through treatment [55]. Since DBShas also been shown to alter brain monoamine levels [7–9,56],we analogously argue that DBS is a treatment modality which dis-turbs an evolved, at-present disease-associated, equilibrium of, forexample, neurochemical or electrophysiological features. We sug-gest that oppositional forces are a relevant reason why continuousand long-term DBS for depression is necessary.

The regulatory circuitry of inner and outer loops

In keeping with the conceptualization of depression as a sys-tems-level disorder critically impacting on CSTC circuitry, we pro-pose, first, two regulatory loops to be differentially affected by DBSand, second, that the activation states of these loops co-operate indetermining clinical condition and outcome, eventually.

The inner loopAn inner, fast-response functional loop includes central midline

structures such as the thalamus, the lateral habenula nuclei, brain-stem monoaminergic nuclei (ventral tegmental area, VTA; dorsalraphe nucleus, DRN; substantia nigra, SN; locus coeruleus LC),the ventral striatum/NAcc and the sgACC, as well as fiber connec-tions between these structures: the stria medullaris thalami,

fasciculus retroflexus [57,58] are the major afferent and efferenthabenular pathways, the medial forebrain bundle [59], ventral stri-ato-pallidal pathways and pathways connecting the ventral stria-tum/NAcc and the frontal cortex (Fig. 1).

Spanning midline as well as cortico-striatal structures and path-ways, the inner loop comprises components which have beenimplicated in recent models of depression-associated network dys-function [39,60] and, importantly, targeted by DBS for treatment-refractory depressive disorder. With the NAcc and the habenula,the inner loop contains two structures at the motor-limbic inter-face highly relevant for motivation [22,58]. Moreover, these twomodify mesocorticolimbic dopaminergic circuitry, which criticallymediates motivation, reward and fear and has been implicated indepression pathophysiology [61].

In our framework, the finding of rapid amelioration of amotiva-tion and anhedonia in particular in the wake of NAcc stimulationcan thus be seen as a consequence of primary modification of innerloop activity. Moreover, fast improvement of certain aspects ofdepressive symptomatology following sgACC DBS may be medi-ated via its connections with the NAcc and associated pathways[19]. On the other hand, fast improvement of motivational and he-donic aspects was not seen in the patient receiving DBS of the lat-eral habenula, or more precisely, its main afferent pathway, thestria medullaris thalami [25]. It bears mentioning that the haben-ula is assumed to suppress motor activity following negativelyapprehended consequences and as such to mediate disappoint-ment [58,62,63]. The medial forebrain bundle (MFB), throughwhich efferent monoaminergic nuclei fibers ascend to cortico-striatal and limbic destinations, is another important inner-looppathway to consider in the interplay of motivation and moodand has recently been suggested as a novel target for DBS fordepression [21]. Identified as the causative structure for the induc-tion of hypomania in subthalamic nucleus (STN) stimulation forParkinson’s disease [64,65] the MFB also plays a central role inreward processes, further extending to the rewarding effects ofdrugs of abuse and resultant habit-formation [59]. Hence, stimula-tion of the MFB bears the danger of being addictive, this risk, how-ever, may be reduced by the presence of anhedonia in depression.

The outer loopWe furthermore propose a second, outer, loop to partly overlap

with the inner loop along the lateral habenula/brainstem nuclei/MFB portion connecting brainstem monoaminergic nuclei to thefrontal cortical areas and to additionally encompass temporo-lim-bic structures such as the amygdala and hippocampus and respec-tive connections [66–68], which were shown to critically partakein mediating sgACC DBS antidepressant responses [68].

A place for neuroplasticity?

Neurogenesis and neuroplasticity have been argued to criticallyimpact on both depression pathophysiology and treatment [69],and coupling of excitation and neurogenesis was found in adulthippocampal stem cells [70]. Accordingly, neuroplastic processeshave been investigated in the wake of electrical stimulation ofthe anterior thalamic nuclei (ATN), a central component of limbiccircuitry [71,72], and an increase of the number of proliferatingcells in the hippocampal dentate gyrus was found. Moreover, NAccDBS in rodents induced dendritic plasticity as well as neurochem-ical alterations, which accompanied increased exploratory and re-duced anxiety-like behavior [73]. These effects may be mediatedthrough ATN-cingulate cortical or NAcc-VTA pathways, respec-tively [74,75], as well as hippocampal connections [68]. Moreover,stimulation of the ventral prelimbic cortex [76], the ventromedialPFC [77] and the ventral tegmental area [78] in rodents causedan increase in brain-derived neurotrophic factor (BDNF) as a

depression severity, e.g. HAMD score

remission

time

pre-treatment state DBS started DBS terminated

pathological activity of inner and outer loop

manifest depression

beginning normalization of inner loop activity

improvement of anhedonia and amotivation

stepwise normalization of outer loop activity driven by inner loop

remission of depressivesymptomatology

recurrence of inner loop pathological activity

relapse of depression

Fig. 2. Temporospatially distinct DBS action: different activity states of the inner and outer loops co-operate in determining clinical condition and outcome. Blue circlesrepresent the outer loop, red circles represent the inner loop. Thickness of circle drawing represents loop activity states (from left to right: thick = pathological loop over-activity, stepwise thinning = normalization of loop activity, stepwise thickening = return to disease-associated states of over-activation). (For interpretation of the referencesto color in this figure legend, the reader is referred to the web version of this article.)

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further marker of neuroplastic changes [79]. Long-term observa-tion of a patient receiving DBS of the lateral habenula further sug-gests that DBS contributes to increases in BDNF [80].

Alterations of clinical condition in response to DBS treatment asreflections of different activity states of the inner and outer loops

Improvement of depressive psychopathology after commencingDBS initially concerns mainly anhedonia and amotivation, whichprecede actual mood alterations. Moreover, most clinical studiesreport a steady improvement of depressive symptomatology witha plateau reached after approximately three to five months. Simi-larly, in rodents, behavioral changes in the open field test, indicat-ing increased exploration and attenuated anxiety-like behavior, aswell as increases in brain monoamine concentrations, in the wakeof lateral habenula stimulation were more pronounced withincreasing duration of the stimulation [8]. Finally, pharmacologicalinhibition of the lateral habenula in a genetic rat model of depres-sion did not have immediate antidepressant effects, supporting theidea of a staged functional and behavioral response [81].

The observation of staged and duration-dependent clinical-behavioral as well as neurochemical changes suggests the underly-ing circuitry to be modified in a location- and/or time-dependentway, an assumption in accordance with models mapping facetsof depression symptomatology to different brain circuits or loca-tions (e.g. [27,39,82]. In line with this, we propose a dynamic inter-action of activity states of the inner and outer loops in shaping DBSoutcome.

At the outset, ongoing – and overtly dysfunctional – processesacting on top of primary disease-associated traits (e.g. [83,84] haverendered the relevant circuitry into a state of pathological activity(Fig. 2; pre-treatment state), thereby giving rise to depressivesymptoms. Supporting this, several aspects of disease-associatedneurobiology as well as clinical phenomenology and treatment re-sponse were demonstrated to be related to illness duration [85–87]. As outlined above, we assume this pre-treatment status to

be kept up by an intact homeostatic machinery with altered set-points or states of equilibrium.

DBS of any of the fast-response inner-loop structures sequen-tially alters metabolism and functional connectivity in a temporo-spatially distinct manner (Fig. 2, DBS started): in the early phase oftreatment, pathological circuit activity of the inner loop is normal-ized, i.e. begins to approach physiological levels of functioning.Continuous stimulation is required in order to counteract opposi-tional forces attempting to keep the evolved, ‘‘dysfunctional‘‘, equi-librium. At this point, our proposal would predict depressivesymptomatology to improve particularly with respect to motiva-tional drive and hedonism since these are mapped to the inner loop[10,19].

After several weeks, functional coupling of inner- and outerloop activity occurs in the sense of a beginning normalization ofouter-loop activity, which, however, does not immediately andcompletely resort to a regular physiological level. We suggest thatthis coupling happens via the shared structures and pathways ofboth loops (see Fig. 1). Since oppositional forces are also at workin the outer loop, and the reversal of outer loop activity to physio-logical functioning requires the inner loop to drive it, the outerloop response is lagging behind. With cognitive aspects of depres-sion such as biased information processing and -evaluation associ-ated to frontal cortical and limbic circuitry [88–90], these would bepredicted to improve later during the course of treatment. Thesame implication would hold for vegetative symptoms and anxi-ety, which are also assumed to be located in limbic circuitry[39,91]. If both loops are kept in a forced state of altered activityby ongoing DBS, steady improvement and remission from depres-sion is expected to occur.

If stimulation is terminated, both loops fall back from forcedfunctional states into their pre-treatment equilibria (Fig. 2, DBSterminated). This echoes the increased risk of relapse upon discon-tinuation of antidepressant drug treatment and increased resis-tance effects and high rates of relapse after termination ofelectroconvulsive therapy in patients with longer disease duration

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[37,92]. While changes in the slower outer loop may not instanta-neously disappear upon DBS termination – after all, neuroplasticchanges have most likely been induced – the fast-response innerloop will return more readily to the pathological equilibrium whenno countering force is applied. If the return of either loop to thepre-treatment state is a necessary and sufficient condition for re-lapse into depression, this change of inner loop activity state willbe accompanied by worsening of the clinical condition. With theinner loop first reverting to a pathological functional state, de-creased interest and motivation would be predicted to occur first.Confirming this expectation, [1] observed a clinical course in asgACC DBS patient where loss of interest, motivation and initiativewere noted despite continuing euthymic mood after cessation ofstimulation. We propose that the psychopathology observedshortly after DBS discontinuation mainly reflects the return ofthe inner loop to the evolved disease-associated state.

Finally, we suggest that the different modalities through whichDBS mediates antidepressive effects in fact pair with these loops inthat fast occurring functional mechanisms such as synaptic inhibi-tion [93] or the synchronization of pathological oscillatory activity[12] primarily manifest in the inner loop, whereas outer-loop alter-ations induce slower, i.e. synapto- and neuroplastic, changes,determining its longer delay in DBS response. The lateral habenulaas a shared component of the inner loop is critically involved incontrolling monoaminergic, especially dopaminergic and seroto-nergic, neurotransmission [63] and may thus play a critical rolein inducing more rapid changes associated to inner loop function-ing but also cause changes of outer loop activity. Such a functionalcoupling, for example, may happen through a serotonin/BDNFinteraction: serotonin impacts on BDNF expression, and there isevidence for genetic epistasis of the two systems in different spe-cies [94]. Serotonin was also demonstrated to induce epigeneticchanges in BDNF promoter regions related to cortical plasticityon adult rats [95]. There are currently no data regarding the poten-tial role of epigenetic changes in DBS antidepressant action, how-ever, chromatin remodeling and altered BDNF expression in rathippocampus were observed after electroconvulsive therapy [96].

Summary and conclusion

Our proposal accomplishes several things:

1. With the assumption of time- and location-dependent sequen-tial DBS-induced changes, it accounts for various observationsregarding DBS therapeutic mechanisms, both short-term andlong-term, and allows them to be incorporated into a unifiedmodel without exclusive reliance on either of these.

2. It offers an explanation for the peculiar time course of symptomalleviation and re-occurrence with respect to stimulation on/offstates.

3. With the idea of an underlying loop system, the fact that stim-ulation of different targets in comparable patient populationsrenders similar results may be explicable with activation ofone and the same pathway, or system of pathways, emanatingfrom different origins.

4. The induction of widespread changes following DBS treatmentis compatible with the notion of functional circuitries connect-ing different structures. For example, stimulation of the NAcchas been associated with changes in PET studies in the senseof decreased activity in prefrontal regions such as the orbito-frontal cortex as well as cingulate regions, thalamus, and cau-date nucleus and increase in the precentral gyrus [10,19].Similarly, over-activity of the sgACC in depressed patients wasreduced in the wake of DBS and was accompanied with variousmetabolic changes in limbic and cortical sites including the

frontal cortices and the ventral striatum. Moreover, while thesgACC is integrated within a medial-limbic-striatal-network, italso projects to the amygdala/hippocampus region [97], andthe antidepressant effects of sgACC DBS may be mediated viastrong fiber connections to cingulate regions as well as hypo-thalamus, NAcc and the amygdala/hippocampus regions [68].

5. It provides a blueprint of DBS therapeutic action in depressionaspects of which are testable and as such may fruitfully stimu-late further preclinical and clinical research.

The idea of sequential and temporspatially distinct therapeuticmechanisms of DBS has several implications for further researchon the subject. For example, the assessment of patients’ psychopa-thology should be detailed enough to differentiate changes inmotivation and hedonic functioning [98] from mood alterationsduring the course of treatment. On the other hand, while mosttests for animal behavioral assessment focus on features likeexploration, which relates to both anxiety as well as motivation,the investigation of cognitive aspects of emotion assessment inanimals such as biased attention or interpretation [99,100] hasbeen largely neglected. Thus, finer-grained approaches to thequantification of affective state and behavior in animal models willbe highly informative as to the manner and order of symptomimprovement. A major drawback of, in particular genetic, animalmodels of depression concerns the fact that long-term adaptivechanges in mood- and motivation-related circuitry, as they mostlikely exist in the patient population eligible for DBS, may be diffi-cult to model in an adequate way.

The assumption that abnormal activity of either loop structureis a necessary and sufficient requirement for a clinical depressedstate may be tested with functional imaging analyses in animalsand humans, comparing pre-treatment abnormalities (e. g.[101,102] with the identification of stimulation-induced changes.Moreover, animal models can be used to assess region-specificstructural as well as neurobiochemical changes related to differentdurations of stimulation. In conjunction with a thorough behav-ioral analysis of depression-like behavior, predictions aboutsequential ordering of various DBS mechanisms of action can betested. In this regard, optogenetic tools, in particular, have been[103] and will continue to be employed in delineating relations be-tween proposed circuitries and behavior more precisely [104].

We are well aware of the still small number of studies on whichour proposal is grounded. Hence, it is of necessity speculative but,to the best of our knowledge, it is the first attempt at unifyingnumerous, as yet disparate, observations and assumptions aboutDBS-antidepressant action into a model with testable hypothesesin both preclinical and clinical investigations. Regardless ofwhether aspects of it will finally be refuted or confirmed, we hopeit provides a valuable incentive for future focused and hypothesis-driven research.

Conflict of interest

None.

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