Abstract
Although deep brain stimulation (DBS) is an established treatment choice for Parkinson’s disease (PD), essential tremor and movement disorders, its effectiveness for the management of treatment-resistant depression (TRD) remains unclear. Herein, we conducted an integrative review on major neuroanatomical targets of DBS pursued for the treatment of intractable TRD. The aim of this review article is to provide a critical discussion of possible underlying mechanisms for DBS-generated antidepressant effects identified in preclinical studies and clinical trials, and to determine which brain target(s) elicited the most promising outcomes considering acute and maintenance treatment of TRD. Major electronic databases were searched to identify preclinical and clinical studies that have investigated the effects of DBS on depression-related outcomes. Overall, 92 references met inclusion criteria, and have evaluated six unique DBS targets namely the subcallosal cingulate gyrus (SCG), nucleus accumbens (NAc), ventral capsule/ventral striatum or anterior limb of internal capsule (ALIC), medial forebrain bundle (MFB), lateral habenula (LHb) and inferior thalamic peduncle for the treatment of unrelenting TRD. Electrical stimulation of these pertinent brain regions displayed differential effects on mood transition in patients with TRD. In addition, 47 unique references provided preclinical evidence for putative neurobiological mechanisms underlying antidepressant effects of DBS applied to the ventromedial prefrontal cortex, NAc, MFB, LHb and subthalamic nucleus. Preclinical studies suggest that stimulation parameters and neuroanatomical locations could influence DBS-related antidepressant effects, and also pointed that modulatory effects on monoamine neurotransmitters in target regions or interconnected brain networks following DBS could have a role in the antidepressant effects of DBS. Among several neuromodulatory targets that have been investigated, DBS in the neuroanatomical framework of the SCG, ALIC and MFB yielded more consistent antidepressant response rates in samples with TRD. Nevertheless, more well-designed randomized double-blind, controlled trials are warranted to further assess the efficacy, safety and tolerability of these more promising DBS targets for the management of TRD as therapeutic effects have been inconsistent across some controlled studies.
Similar content being viewed by others
Introduction
Major depressive disorder (MDD) is a chronic and disabling condition associated with significant morbidity, with an estimated lifetime prevalence of 14.6 and 11.1% in high- and low-to-middle-income countries, respectively.1, 2 Standard antidepressant drugs are thought to primarily act inhibiting or otherwise modulating monoamine neurotransmission.3, 4 Only approximately a third of patients with MDD achieve remission after an adequate trial with a first-line antidepressant agent.5, 6 The failure to respond to one or more adequate antidepressant trials (that is, with adequate doses and duration) indicates the presence of treatment-resistant depression (TRD), although the definition for TRD has varied across trials.7, 8, 9 Moreover, the use of first-line antidepressants is associated with safety and tolerability concerns.10 TRD is associated with elevated health-care costs, morbidity, reduced quality of life and work productivity, and thus meaningfully contributes to the overall burden of MDD.11 Therefore, the search for mechanistically novel therapeutic options for TRD is currently a research priority.12 In last decade, accumulating evidence indicates that ketamine is efficacious and may provide rapid antidepressant effects for patients with TRD.13, 14 Nevertheless, its long-term efficacy remains unclear, and benefits should be weighed against untoward effects including but not limited to dissociative effects, potential for abuse and deleterious cognitive side effects at higher or repeated doses.15 Given the significant public health impact of TRD, and the limited effectiveness of available psychological and pharmacological treatments for chronic TRD patients, the field has witnessed an increasing interest in exploring the therapeutic potential of non-pharmacological interventions like repetitive transcranial magnetic stimulation, transcranial direct current stimulation, vagus nerve stimulation, epidural cortical stimulation, electroconvulsive therapy (ECT) and deep brain stimulation (DBS) as therapeutic options for TRD.16, 17, 18, 19, 20 Herein, we provide an integrative review of preclinical and clinical studies that have assessed DBS, a relatively recent neuromodulatory treatment modality, within different neuroanatomical targets as a putative treatment for TRD. Details of the search strategy and criteria for selection of references are provided in the supporting online material.
Deep brain stimulation
In DBS surgery, the electrode is stereotactically implanted into specific neuroanatomical targets where stimulation is provided via a pacemaker-like stimulator device that delivers continuous electrical stimulation.21 A schematic representation of the apparatus is provided in Figure 1. Benabid and Pollak pioneered modern DBS over ablative surgery for the treatment of movement disorders by targeting the thalamic nucleus ventralis intermedius, globus pallidus internus and subthalamic nucleus (STN).22, 23 Because of the tremendous clinical success of DBS as a treatment for movement disorders and reported concurrent beneficial effects on neuropsychiatric manifestations, this neuromodulatory approach has also been explored as a possible treatment for many mental disorders including obsessive–compulsive disorder and intractable depression.24, 25, 26 Interestingly, ketamine’s rapid antidepressant and anti-anhedonic effects are associated with alterations in glucose metabolism in brain structures, that are also serving as potential targets for DBS, like the habenula, insula, prefrontal cortex (PFC) and anterior cingulate cortex in patients with TRD.27, 28 Despite the incomplete understanding of the underlying mechanisms of action (MOA) involved in the therapeutic response to DBS among patients with TRD,29 several brain targets have been tested, and thus DBS has evolved to become a promising strategy for the management of TRD.3, 24, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39
Clinical and preclinical outcomes
Clinical studies have assessed putative therapeutic effects of DBS in participants with TRD across several major brain targets namely Brodmann area 25 or subcallosal cingulate gyrus (SCG), nucleus accumbens (NAc), ventral capsule/ventral striatum (VC/VS) or ventral part of anterior limb of the internal capsule (vALIC), medial forebrain bundle (MFB), lateral habenular complex (LHb), and inferior thalamic peduncle (ITP). The names of the respective pioneering institutions that conducted DBS manipulations across these brain targets for the treatment of TRD are presented in Figure 1. The ideal settings for achieving optimum antidepressant effects in humans remain unclear, although it is worthy to note that therapeutic effects may vary as a function of respective DBS targets and stimulation parameters, and also according to clinical characteristics of individual patients.40 The exploratory meta-analysis conducted by Smith41 suggests that active DBS applied to some of the above brain targets could be 71% more efficacious than sham treatment (summary effect size: 1.71; 95% confidence interval: 1.47–1.96) for TRD. However, only eight studies were available, and effect sizes could not be separated according to specific brain targets. Detailed information pertaining to clinical and preclinical central nervous system targets chosen for DBS as a treatment for depression is provided in the following sections, and is briefly summarized in Tables 1 and 2.
Details of neuroanatomical substrates tested across preclinical DBS studies for depression-like phenotypes are diagrammatically depicted in Figure 2. As presented in Table 2, stimulation parameters markedly varied across preclinical investigations. Yet, settings between 60 and 130 Hz for frequency, 60 and 200 μs for pulse width and 50 and 300 μA for amplitude exhibited promising antidepressant-like effects across various DBS targets. Preclinical studies have also pointed that different stimulation parameters and neuroanatomical locations may influence antidepressant-related effects. However, at least in part because of the complex and multifactorial pathophysiology of human depression, currently no animal model meets all validity criteria (including predictive validities),42, 43 and hence limitations of preclinical models should be considered when inferences pertaining to depression in humans are made.
DBS of the SCG
Clinical studies
The SCG may have a pivotal role in the regulation of sadness and negative emotions occurring in both depressed and healthy subjects.24, 44, 45, 46 Clinical outcomes for this DBS target are summarized in Table 1. Mayberg and coworkers24 initially reported that four out of six patients with TRD achieved antidepressant response after 6 months of open-label SCG-DBS. Afterwards, Lozano et al.47 reported that 40% of participants with TRD (n=20) achieved response after 1 week of stimulation, whereas 60 and 55% of patients met response criteria at 6 and 12 months, respectively, in an open-label trial that tested SCG-DBS. A few case reports also demonstrated efficacy for this target in the TRD patients.48, 49, 50, 51, 52 Long-term outcomes of SCG-DBS for the aforementioned open-label trial were subsequently reported, with 55–60 and 64.3% response rates after 1–3 and 3-6 years’ follow-up visits, respectively,53 and four participants either committed or attempted suicide over the course of study, although because of uncontrolled design of this study it could not be established whether this serious adverse effect was related to DBS or to illness evolution per se. Holtzheimer et al.54 replicated those findings in an uncontrolled study involving 17 participants with TRD after SCG-DBS. This trial reported 43.6–70.1% response rates (assessed with the Hamilton depression rating scale) following 24-week, 1-year and 2-year follow-up visits. Although this study was uncontrolled, it should be noted that the blinded discontinuation of SCG-DBS resulted in the full relapse of depressive episodes in all three patients in which this was attempted, whereas depressive symptoms improved once stimulation was reinstated.54 Furthermore, these robust therapeutic benefits and brain metabolic changes have been further replicated in a preliminary uncontrolled observation;55, 56 seven out of eight TRD patients achieved antidepressant response after SCG-DBS at a 6-month follow-up visit. In a more recent randomized, double-blind, sham-controlled crossover trial Puigdemont et al.57 reported reversal of depressive scores after active SCG-DBS application in five participants with TRD,57 and long-term high frequency stimulation (HFS) exhibited better antidepressant response.58
Berlim et al.59 conducted an exploratory meta-analysis of four observational studies, and verified that response and remission rates following SCG-DBS were 36.6 and 16.7%, 53.9 and 24.1%, and 39.9 and 26.3% at 3-, 6- and 12-month follow-up periods, respectively. Moreover, open-label studies reported remission rates ranging from 29 to 58% after chronic stimulation of the SCG for up to 12–36 months,60, 61, 62 although evidence suggests that longer pulse durations could influence pathways farther from the SCG, and activation of the SCG–NAc network may contribute to antidepressant response after SCG-DBS.31 Patient-specific tractography modeling provided relevant insights for the identification of electrode location and critical neuronal tracts that could mediate antidepressant responses to SCG-DBS, and may also mitigate inter-individual variability in the direct effects of stimulation on brain circuitry.45, 63, 64 Using tractography-based surgical targeting, Riva-Posse et al.45 demonstrated 72.7% (8 of 11 participants) and 81.8% (9 of 11 participants) response rates at 6 months and 1 year after SCG-DBS, respectively, whereas six patients were in remission at both time points.
SCG-DBS may also improve memory as well as executive and motor functioning in participants with TRD, without meaningful adverse effects upon cognitive measures.65, 66, 67, 68, 69, 70, 71 Moreover, patients with TRD may exhibit transient emotional hypersensitivity and a predictable worsening of depressive symptom scores at the initial phases of SCG-DBS,55 thus long-term treatment could be critical for central nervous system remodeling and neuroplasticity, and hence to therapeutic benefits.72 In SCG-DBS-operated participants with TRD, the most frequently observed surgery-associated adverse events were hardware-related (11.4%), suicidality (9.3%)73 and risk of partial seizures.74 In addition, a multicenter, randomized controlled trial (RCT) of SCG-DBS for TRD (BROADEN study) was prematurely interrupted based on results of an interim futility analysis (St Jude Medical Clinical Study).38, 75 Recently, Holtzheimer et al.75 published results of multisite, randomized, double-blind, sham-controlled SCG-DBS study in 90 TRD participants. They did not observe statistically significant effects in the primary efficacy outcome between the stimulation (20%) and control group (17%), similarly in a double-blind study of eight participants Merkl et al.76 reported no difference between active versus sham group. However, 33–48% participants displayed an antidepressant response and 25% achieved remission with up to 2 years of open-label SCG-DBS.75, 76 Nevertheless, the lack of therapeutic response in TRD patients after SCG-DBS may be due to the wrong placement of electrodes or misleading points of stimulation.45 Preliminary evidence for site-specific clinical responses following SCG-DBS was provided in the small open-label trial conducted by Accolla et al.77 that enrolled five participants with TRD; noticeable antidepressant responses following stimulation of the posterior gyrus rectus region in one patient with TRD was observed, although none of the participants in whom DBS was applied to the originally planned Brodmann area 25 were considered responders.
Preclinical studies
The infralimbic cortex, which is part of the rodent ventromedial PFC (vmPFC) is thought to represent the rodent homologous of the human SCG (Brodmann area 25).78 Preclinical studies indicate that DBS applied to the vmPFC may lead to antidepressant-like effects across several preclinical models including the forced swimming test (FST), sucrose preference test and novelty suppressed feeding (Table 2).79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90 Electrical stimulation of this neuroanatomical target has also been shown to increase hedonic and motivational states in animal models of depression,91, 92 and to reverse depressive-like phenotypes induced by chronic unpredictable stress (CUS), chronic social defeat stress, olfactory bulbectomy and in a putative therapy-refractory depressive-like rat line.82, 87, 88, 89, 93, 94, 95
Hamani et al.79 characterized the optimal brain stimulation settings for DBS applied to the vmPFC in rats. DBS targeted to the infralimbic cortex also resulted in antidepressant-like effects, may be through a reversal of synaptic metaplasticity and increments in mitosis.85, 96, 97, 98 In another study, DBS applied to prelimbic mPFC led to different functional brain alterations.99 Moreover, chronic DBS applied to the vmPFC may reverse stress-induced behavioral deficits in the sucrose preference test, FST, novelty suppressed feeding and elevated plus maze models, and may also increase brain-derived neurotrophic factor levels, blood vessel size, synaptic density and astrocyte size in the hippocampus.82, 100, 101, 102 Altogether, these data suggest that stimulation parameters need to be precisely set for achieving meaningful responses after prelimbic or infralimbic PFC-DBS.
Hamani and colleagues80, 82, 103 provided preclinical data to support a putative role for the serotonergic system as a mediator of the antidepressant-like effects of vmPFC-DBS. Moreover, vmPFC stimulation was found to produce antidepressant, anxiolytic and hedonic effects through the modulation of dorsal raphe nucleus (DRN) circuitry in the CUS animal model of depression.86, 87, 94, 104 Furthermore, adjuvant treatment with monoamine oxidase inhibitors was reported to potentiate behavioral effects of vmPFC-DBS in the FST.81 However, co-administration of buspirone, pindolol or risperidone did not significantly alter antidepressant-like effects of DBS.105 This further suggests that vmPFC-DBS might involve the modulation of prefrontal projections to the DRN, which is a brain region involved in serotonin (5-HT) synthesis and release. Apart from the DRN, neurostimulation of the vmPFC may also remotely affect activity of the ventral tegmental area (VTA) and locus coeruleus.106, 107
Possible MOA
Depression has been associated with increased activity of the SCG and dysregulated corticolimbic networks.30, 96, 108, 109, 110, 111 Furthermore, SCG neurons are preferentially more responsive to negative (unpleasant) emotions.112 SCG-DBS may ameliorate depressive symptoms or more specifically anhedonia in patients with TRD.113 Antidepressant response to SCG-DBS in participants with TRD has been associated with frontal asymmetry, higher frontal theta cordance (θ) and local field potential broad α-band activity.114, 115, 116 Suppression of gamma oscillations and increased θ-gamma coupling by active SCG-DBS stimulation may also enhance gamma-aminobutyric acid neurotransmission.117 Therefore, it seems that SCG-DBS stimulation may have a key role in normalizing spectral rhythms in brain networks related to depression neurobiology.
DBS applied to the NAc
Clinical studies
Anhedonia was one of the first manifestations to improve during NAc stimulation in participants with TRD, which also reported a heightened perception of pleasurable activities.34, 36, 113, 118 The ideal parameters of electrical stimulation that could provide adequate antidepressant responses are summarized in Table 1. Schlaepfer et al.34 reported short-term outcomes in three patients with TRD who underwent NAc-DBS. Twelve months of chronic, open-label NAc-DBS led to a decrease in the metabolism of the SCG, amygdala and prefrontal regions with 45 and 9% response and remission rates, respectively, in 10 participants with TRD.118 The long-term open-label trial conducted by Bewernick et al.36 reported a sustained antidepressant effect for NAc-DBS in 11 participants with TRD (45.5% response rate at 48-month follow-up). Yet, only five participants completed this 4-year trial.36 Moreover, there was no evidence of cognitive deterioration in agreement with data from the same research group.36, 119 An open-label trial with six participants reported 50% responders, and did not show signs of cognitive deterioration.120 Altogether, these data suggest that NAc-DBS could be efficacious for the management of TRD.
Preclinical studies
Application of DBS to the NAc-shell triggered impulsive behaviors accompanied by significant increases in dopamine and 5-HT levels in the NAc. However, DBS applied to the NAc core led to antidepressant-like effects without significantly altering levels of 5-HT and dopamine,121, 122 although 2 consecutive days of bilateral stimulation elicited a rapid increase in dopamine and 5-HT release in the orbital PFC.123 HFS or low frequency stimulation of the NAc-DBS also produced distinct region-specific and frequency band-specific changes in local field potential oscillations,124 therefore, suggesting that different stimulation parameters may engage distinct brain areas, which could then influence antidepressant responses to NAc-DBS. Furthermore, a recent study reported that DBS applied to the lateral NAc-shell reduced motivation for sucrose, whereas stimulation of the medial NAc–shell selectively increased the intake of chow.125 These findings suggest that subdivisions of the NAc–shell may influence motivational eating behavior, and may point to dissociable effects of NAc-DBS in alleviating anhedonia in depression. Yet, the field awaits further investigations. Recently, Lim et al.87 observed reduced anxiety-like behaviors and increase in motivation for chow intake in the CUS depression model after HFS of the NAc–core as compared to that in the NAc–shell.
Accumulating evidence indicates that NAc-DBS may decrease depressive-like behavior in CUS-induced animal model of depression.86, 87, 93, 126, 127 Similar results were documented in the high anxiety-related behavior mouse model and in a chronic adrenocorticotropic hormone model of TRD after NAc stimulation.91, 128 Hamani et al.126 observed comparable antidepressant-like effects after stimulation either the vmPFC or the NAc in the FST. Nevertheless, only NAc-DBS influenced different subcortical relay centers in the brain reward circuitry. In contrast, in another study vmPFC-DBS outperformed NAc-DBS.127 Antidepressant-like effects were significantly higher after interrupted stimulation of the NAc compared with intermittent stimulation,128, 129 which was associated with decreased levels of tyrosine hydroxylase, dopamine and norepinephrine in the PFC. Although acute DBS-NAc did not significantly alter hippocampal neurogenesis,130 DBS-NAc–core lowered CUS-induced increase in c-Fos expression in the magnocellular part of the medial vestibular nucleus compared with CUS sham.131
Possible MOA
Consistent with imaging studies in humans, a significant increase in blood oxygenation level-dependent signal in the insula, thalamus and parahippocampal cortex and a decrease in the SCG and PFC during stimulation of the NAc functional magnetic resonance imaging was reported in a pig model.132 Moreover, modulation of the NAc may normalize disease-related hypermetabolism in the SCG and in prefrontal regions including the orbitofrontal cortex, with possible procognitive effects,118 which are similar metabolic decreases observed in patients undergoing SCG-DBS.47 Thus, it has been hypothesized that effects on the SCG could also mediate antidepressant effects of NAc-DBS.118 In addition, as reviewed in the section above, site-specific effects on monoamine neurotransmission have been implicated as a putative antidepressant mechanism of NAc-DBS.
DBS applied to the VC/VS or vALIC
Clinical studies
Application of DBS to the VC/VS (also referred as vALIC in some studies) significantly decreased anxiety and depressive symptoms in participants with obsessive–compulsive disorder, thus providing a rationale for testing its efficacy in samples with TRD.65, 133, 134 Obsessive–compulsive disorder patients who underwent DBS of the VC/VS showed a reduction of cerebral blood flow in the SCG, which appears to be metabolically hyperactive in patients with MDD.30 An open-label pilot trial conducted by Malone et al.32, 135 assessed the efficacy of VC/VS-DBS in 17 patients with TRD. Response rates of 53 and 71% at 12 month and last (14–67 months) follow-up visits, respectively, and a 40% remission rate at last follow-up (6–51 months) were observed. A case report described smoking cessation in a single responder after VC/VS-DBS.136 However, double-blind, randomized, sham-controlled trials of VC/VS-DBS for MDD have thus far provided inconsistent findings.137, 138 In a 16-week sham-controlled randomized trial followed by an open-label continuation phase, Dougherty et al.137 did not observe significant differences in treatment response rates in the active DBS group. The same research group subsequently reported that vALIC-DBS did not influence cognitive function compared with sham.139 In addition, adverse events were more severe for vALIC-DBS compared with the sham group (Table 3). Nevertheless, 25 participants underwent 52-week open-label vALIC-DBS (optimization phase), and 10 participants out of 25 with TRD were classified as responders (40%).140, 141 Sixteen participants were subsequently randomized to active-sham or sham-active groups in a cross-over design, and participants scored significantly lower during active rather than during sham DBS.140 Therefore, the antidepressant efficacy of DBS primarily applied to the VC/VS (or vALIC, a brain structure slightly anterior and ventral to the VC/VS) remains to be established.
Preclinical studies
As ALIC is not well developed in rodents, Hamani et al.126 had chosen white matter fibers of the frontal region for electrical stimulation as this neuroanatomical structure resemble the ALIC in human. Application of DBS in white matter fiber influenced the large brain regions of the cortical and subcortical structures, without producing a significant antidepressant-like effect in FST.126
Possible MOA
Neuroimaging studies conducted in participants with obsessive–compulsive disorder who underwent DBS in this target demonstrated modulation of different nodes of the cortico–striatal–thalamic–cortical circuitry, including the orbitofrontal cortex, basal ganglia, along with a reduction in metabolic hyperactivity of the SCG, observed particularly in participants with co-occurring MDD.142, 143 In addition, the VS encompasses structures like the bed nucleus of the stria terminalis (BNST) and the NAc, which are regions putatively involved in the regulation of stress and reward-motivational pathways in individuals with depression.144, 145 Nevertheless, the antidepressant efficacy as well as possible MOA of VC/VS-DBS remains unclear.
DBS of the MFB
Clinical studies
Three different academic institutions have assessed the efficacy of MFB-DBS in samples with TRD (Figure 1 and Table 1). However, evidence for putative antidepressant effects of MFB-DBS remains relatively unexplored as only data from 11 participants with TRD were provided from two uncontrolled studies.33, 35, 39 Despite these limitations, findings suggest that MFB-DBS could confer rapid and long-lasting antidepressant effects. Short-term bilateral stimulation of the superolateral-MFB showed a rapid reduction in the severity of depressive symptoms in six out of seven participants within 2 days of stimulation, and four out of seven patients met criteria for treatment response after 1-week stimulation,33 whereas at the last observation (after 12–33 weeks) six participants (85.7%) were treatment responders. Fenoy et al.39 also reported in their interim analysis a robust and rapid antidepressant response in an open-label trial of bilateral MFB-DBS, in which three out of four participants with TRD were responders after 1 week of DBS initiation, and two of four participants displayed >80% decrease in MADRS scores after 26 weeks of stimulation. Recently, Bewernick et al.35 provided long-term data for their open-label trial.33 At the time of analysis, six out of eight participants (75%) were treatment responders at 12-month follow-up; these antidepressant effects remained stable for up to 4 years. Furthermore, no evidence of cognitive impairments were noted even after several months of stimulation in this target.35, 39 The most frequently reported adverse effect associated with MFB-DBS were oculomotor disturbances (Table 3), which in most cases diminished over time. In a recent case study, a 58-year-old patient perceived marked mood improvement effect after 1 week of MFB-DBS.146 However, this patient experienced oculomotor side effects that failed to remit over time. The patient was re-operated after 2 years, and responded to DBS applied to the BNST without troublesome oculomotor side effects. These data provide further evidence that in selected clinical situations this adverse effect could be a reason for discontinuing MFB-DBS.39 Taken together, these preliminary data suggest that MFB-DBS could be efficacious for the management of TRD. Thus, the design of a randomized, sham-controlled trial is warranted to confirm those promising findings.
Preclinical studies
Similarly to the NAc, the MFB has a critical role in the regulation of motivation, and thus may contribute to anhedonia.147 In preclinical studies, the MFB-HFS generated antidepressant-like effects was associated long-lasting neural adaptation in target regions of the mesolimbic–mesocortical circuitry (Table 2).92, 148, 149 When Flinders sensitive line rats received bilateral HFS to the MFB, antidepressant-like effects in the FST were observed.92 Similar antidepressant-like effects were reported following bilateral HFS in rats accompanied by an increase in expression of the immediate early gene, zif268, in the piriform cortex, prelimbic cortex, NAc shell, anterior regions of the caudate/putamen and the VTA.150 However, no significant changes in the release of either dopamine or serotonin at the level of the NAc were observed. Although MFB-DBS was reported to mitigate depressive-like behaviors and increase pleasurable or rewarding experiences after mild VTA lesion in rats, it was unable to reverse a despair phenotype after severe VTA lesions in rats.151 Recently, rapid antidepressant-like effects and increased expression of dopamine D2 receptors in the PFC have been reported following acute stimulation of MFB in rats.152
Possible MOA
The MFB is a central component of the mesolimbic–mesocortical dopamine reward system,153, 154, 155 and it is interconnected with several other DBS targets.24, 34, 156, 157 MFB-DBS may activate the mesocorticolimbic system by increasing neuronal activity within these regions through the modulation of dopaminergic and glutamatergic neurotransmission.33, 39, 158, 159 Recently, optogenetic activation of VTA dopaminergic neurons led to increased functional magnetic resonance imaging blood oxygenation level-dependent signals in the NAc concomitantly with an increase in motivational behavior in rats.160 It is thought that modulation of the MFB via DBS may recruit descending glutamatergic fibers from the mPFC to the VTA, and may thus indirectly modulate dopaminergic firing at the VTA.161 MFB-DBS may also modulate upstream cortical regions.33 Yet, the precise MOA underlying putative antidepressant effects of MFB-DBS remain to be elucidated.
DBS of the LHb
Clinical studies
Hyperactivity of neurons at the LHb has been suggested to have a pathophysiological role in MDD.83, 162 Bilateral LHb-DBS may decrease activation within this neuroanatomical region.163 Sartorius et al.163 observed a sustained remission of depressive symptoms after 4 months of DBS in a patient with TRD. A marked re-emergence of depressive symptoms elapsed after the erroneous cessation of stimulation, further pointing to the potential therapeutic usefulness of LHb-DBS for TRD. As evidence from single case report is available, more studies would decide the relevance of this target for TRD.
Preclinical studies
LHb-DBS has been shown to reverse depressive-like behaviors in the CUS as well as in the chronic adrenocorticotropic hormone and learned helplessness models of TRD.83, 84, 87, 164, 165 DBS applied at the LHb gradually increased peripheral and brain levels of norepinephrine, dopamine and 5-HT, which peaked after 28 days of treatment.84 In a comparative study of vmPFC-DBS versus LHb-DBS, Lim et al.87 showed that, although vmPFC-DBS produced a fourfold increase in hippocampal 5-HT release, LHb stimulation produced an ~55–70% increase in striatal 5-HT release. Moreover, HFS of the LHb was reported to counteract depressive-like behavior in the CUS animal model.87
Possible MOA
Electrical stimulation of the LHb was found to significantly inhibit the firing of dopaminergic neurons in the substantia nigra pars compacta and the VTA.166, 167 In a genetic animal model of TRD, a significant alteration of regional cerebral blood volume was observed within the LHb.168 Furthermore, the antidepressant effects of LHb-DBS may involve monoamine pathways as there are strong interactions and direct efferents from the LHb to the DRN, locus coeruleus and the VTA.169
DBS of the ITP
The ITP encompasses a bundle of fibers connecting the dorsomedial thalamus to the orbitofrontal cortex,170 which is dysregulated in participants with MDD.171 Moreover, surgical lesions to the ITP may disrupt the inhibitory action of the thalamo–orbitofrontal system, and may also promote antidepressant-like effects in preclinical models.172 Two case reports have described the results of ITP-DBS in a single patient with TRD.173, 174, 175 A significant decrease in Hamilton depression rating scale scores (from 42 to 6) without side effects at high-frequency DBS settings of 3.5 V and 450 μs of pulse width was verified.173 Recently, antidepressant efficacy of ITP and ALIC/BNST stimulation were compared in blinded crossover study.176 Although no superiority of either targets were noticed, 6/7 patients preferred stimulation in ALIC/BNST.176 Clearly, this brain target deserves further exploration in clinical trials.
DBS of the STN
Acute treatment with STN-DBS significantly improved depression-like behaviors in preclinical models (Table 2).177, 178 Similarly, post hoc clinical evidence suggested possible antidepressant effects following STN-DBS in samples with Parkinson’s disease (PD).179, 180, 181, 182, 183 In contrast, worsening of depressive-like behaviors in rats, and an increased risk of transient cognitive and psychiatric complications have been reported after STN-DBS for PD.184, 185, 186 However, depressive symptoms were less frequent after pallidal-DBS compared with STN-DBS in PD patients.187 In a case report, an increase in current frequency of STN-DBS from 60 to 185 Hz led to a significant improvement of depressive symptoms with complete resolution of his suicidal thoughts in a PD patient.188 In sum, divergent findings in both the clinical and preclinical literature have diminished enthusiasm in the field for further testing this target in clinical trials involving participants with TRD.
Conclusion
Evidence indicates that DBS can be delivered to discrete brain targets and may directly modulate brain activity in a limited brain structure and also activity of interconnected (that is, more distant) brain networks. Furthermore, available evidence suggests that it could be a relatively safe and well-tolerated non-pharmacological therapeutic option for TRD.24, 39, 47, 189, 190 Six prominent DBS targets have been tested for the management of TRD. Interestingly, in most circumstances those targets have been tested in clinical trials prior to the conduction of preclinical studies. However, the underlying mechanisms of DBS-related antidepressant effects remain elusive, and may vary as a function of the primary brain target as well as with stimulation parameters. In addition, clinical trials to date have methodological shortcomings such as a lack of proper randomization, the lack of a control (that is, sham-stimulated) group, small sample sizes, heterogeneity of participants across trials (for example, different definitions of TRD) as well as a lack of consensus algorithms for DBS delivery.40 Herein, the underlying mechanisms for putative antidepressant effects of DBS identified in clinical trials and preclinical studies are reviewed. We sought to determine which brain target(s) most consistently elicited antidepressant responses. Out of six DBS targets, only VC/VS and the SCG have been investigated in multicenter, randomized, sham-controlled trials. However, these trials failed to confirm the efficacy of those targets in participants with TRD.57, 75, 137 On the other hand, open-label clinical studies verified high response rates (ranging from 60 to 78%) in participants with TRD after the application of DBS to several targets.191 Furthermore, discrepant findings across these open-label trials may be ascribed to interpersonal anatomical differences (size and shape) of DBS targets, which could be rectified by mapping the internal neuroanatomical structure of individual patients.35, 39, 45, 77, 192, 193 Taken together, detailed characterization of the anatomical, physiological and neurochemical substrates underlying the effects of DBS may delineate suitable brain targets for the management of TRD.
Clinical implications and future directions
The use of DBS in the management of TRD remains at investigational stages. How research in this treatment modality for depression should continue and improve from this point represents a meaningful challenge for neuroclinicians.38, 40, 194 As most neuroanatomical centers regulating affect and motivation are interconnected,3, 195, 196, 197 DBS could influence distant brain networks regardless of the initial target.198 Tractography and other imaging techniques could provide valuable resources to guide surgical procedures, and also for post-surgery monitoring.39, 40, 45, 47, 72, 118 The identification of individual clinical characteristics as well as biomarkers of treatment response within the emerging framework of precision psychiatry also provides a relevant yet relatively unexplored research direction.114, 115, 165, 193, 199 It should be noted that the effectiveness of unilateral versus bilateral DBS of brain targets warrant confirmation in randomized, double-blind, sham-controlled trials.39, 79, 80, 152, 200 Importantly, it is yet debatable whether non-responders to one target might benefit from DBS delivered to an alternative target. Taken together, the selection of patients, target brain regions, parameters of stimulation and identification of early biomarkers are necessary steps to be taken to provide more consistent evidence for this promising treatment modality for intractable depression. It should be noted that RCTs of DBS applied to the SCG, VC/VS or vALIC have thus far provided inconsistent results. Therefore, adequately powered and well-designed double-blind RCTs are warranted to provide a more accurate assessment of the efficacy and safety for DBS delivered at different brain targets as a therapeutic option for TRD.
References
Bromet E, Andrade LH, Hwang I, Sampson NA, Alonso J, de Girolamo G et al. Cross-national epidemiology of DSM-IV major depressive episode. BMC Med 2011; 9: 90.
Kessler RC, Bromet EJ . The epidemiology of depression across cultures. Annu Rev Public Health 2013; 34: 119–138.
Anderson RJ, Frye MA, Abulseoud OA, Lee KH, McGillivray JA, Berk M et al. Deep brain stimulation for treatment-resistant depression: efficacy, safety and mechanisms of action. Neurosci Biobehav Rev 2012; 36: 1920–1933.
Rosenblat JD, McIntyre RS, Alves GS, Fountoulakis KN, Carvalho AF . Beyond monoamines-novel targets for treatment-resistant depression: a comprehensive review. Curr Neuropharmacol 2015; 13: 636–655.
Rush AJ, Trivedi MH, Wisniewski SR, Stewart JW, Nierenberg AA, Thase ME et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med 2006; 354: 1231–1242.
Carvalho AF, Berk M, Hyphantis TN, McIntyre RS . The integrative management of treatment-resistant depression: a comprehensive review and perspectives. Psychother Psychosom 2014; 83: 70–88.
Souery D, Papakostas GI, Trivedi MH . Treatment-resistant depression. J Clin Psychiatry 2006; 67 (Suppl 6): 16–22.
McIntyre RS, Filteau MJ, Martin L, Patry S, Carvalho A, Cha DS et al. Treatment-resistant depression: definitions, review of the evidence, and algorithmic approach. J Affect Disord 2014; 156: 1–7.
Berlim MT, Turecki G . What is the meaning of treatment resistant/refractory major depression (TRD)? A systematic review of current randomized trials. Eur Neuropsychopharmacol 2007; 17: 696–707.
Carvalho AF, Sharma MS, Brunoni AR, Vieta E, Fava GA . The safety, tolerability and risks associated with the use of newer generation antidepressant drugs: a critical review of the literature. Psychother Psychosom 2016; 85: 270–288.
Mrazek DA, Hornberger JC, Altar CA, Degtiar I . A review of the clinical, economic, and societal burden of treatment-resistant depression: 1996-2013. Psychiatr Serv 2014; 65: 977–987.
Papakostas GI, Ionescu DF . Towards new mechanisms: an update on therapeutics for treatment-resistant major depressive disorder. Mol Psychiatry 2015; 20: 1142–1150.
Zarate CA Jr., Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 2006; 63: 856–864.
Papadimitropoulou K, Vossen C, Karabis A, Donatti C, Kubitz N . Comparative efficacy and tolerability of pharmacological and somatic interventions in adult patients with treatment-resistant depression: a systematic review and network meta-analysis. Curr Med Res Opin 2017; 33: 701–711.
Sanacora G, Frye MA, McDonald W, Mathew SJ, Turner MS, Schatzberg AF et al. A consensus statement on the use of ketamine in the treatment of mood disorders. JAMA Psychiatry 2017; 74: 399–405.
Dumitriu D, Collins K, Alterman R, Mathew SJ . Neurostimulatory therapeutics in management of treatment-resistant depression with focus on deep brain stimulation. Mount Sinai J Med 2008; 75: 263–275.
Mohr P, Rodriguez M, Slavickova A, Hanka J . The application of vagus nerve stimulation and deep brain stimulation in depression. Neuropsychobiology 2011; 64: 170–181.
Rizvi SJ, Donovan M, Giacobbe P, Placenza F, Rotzinger S, Kennedy SH . Neurostimulation therapies for treatment resistant depression: a focus on vagus nerve stimulation and deep brain stimulation. Int Rev Psychiatry 2011; 23: 424–436.
Blumberger DM, Mulsant BH, Daskalakis ZJ . What is the role of brain stimulation therapies in the treatment of depression? Curr Psychiatr Rep 2013; 15: 368.
Kopell BH, Halverson J, Butson CR, Dickinson M, Bobholz J, Harsch H et al. Epidural cortical stimulation of the left dorsolateral prefrontal cortex for refractory major depressive disorder. Neurosurgery 2011; 69: 1015–1029, discussion 1029.
Tye SJ, Frye MA, Lee KH . Disrupting disordered neurocircuitry: treating refractory psychiatric illness with neuromodulation. Mayo Clin Proc 2009; 84: 522–532.
Benabid AL, Benazzouz A, Hoffmann D, Limousin P, Krack P, Pollak P . Long-term electrical inhibition of deep brain targets in movement disorders. Mov Disord 1998; 13 (Suppl 3): 119–125.
Benabid AL, Pollak P, Louveau A, Henry S, de Rougemont J . Combined (thalamotomy and stimulation) stereotactic surgery of the VIM thalamic nucleus for bilateral Parkinson disease. Applied Neurophysiol 1987; 50: 344–346.
Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C et al. Deep brain stimulation for treatment-resistant depression. Neuron 2005; 45: 651–660.
Kuhn J, Huff W . Will deep brain stimulation be as successful in major depression as it has been in Parkinson's disease? Exp Rev Neurother 2010; 10: 1363–1365.
Alonso P, Cuadras D, Gabriels L, Denys D, Goodman W, Greenberg BD et al. Deep brain stimulation for obsessive-compulsive disorder: a meta-analysis of treatment outcome and predictors of response. PLoS ONE 2015; 10: e0133591.
Lally N, Nugent AC, Luckenbaugh DA, Ameli R, Roiser JP, Zarate CA . Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression. Transl Psychiatry 2014; 4: e469.
Carlson PJ, Diazgranados N, Nugent AC, Ibrahim L, Luckenbaugh DA, Brutsche N et al. Neural correlates of rapid antidepressant response to ketamine in treatment-resistant unipolar depression: a preliminary positron emission tomography study. Biol Psychiatry 2013; 73: 1213–1221.
McIntyre CC, Savasta M, Kerkerian-Le Goff L, Vitek JL . Uncovering the mechanism(s) of action of deep brain stimulation: activation, inhibition, or both. Clin Neurophysiol 2004; 115: 1239–1248.
Mayberg HS, Liotti M, Brannan SK, McGinnis S, Mahurin RK, Jerabek PA et al. Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am J Psychiatry 1999; 156: 675–682.
Johansen-Berg H, Gutman DA, Behrens TE, Matthews PM, Rushworth MF, Katz E et al. Anatomical connectivity of the subgenual cingulate region targeted with deep brain stimulation for treatment-resistant depression. Cereb Cortex 2008; 18: 1374–1383.
Malone DA Jr., Dougherty DD, Rezai AR, Carpenter LL, Friehs GM, Eskandar EN et al. Deep brain stimulation of the ventral capsule/ventral striatum for treatment-resistant depression. Biol Psychiatry 2009; 65: 267–275.
Schlaepfer TE, Bewernick BH, Kayser S, Madler B, Coenen VA . Rapid effects of deep brain stimulation for treatment-resistant major depression. Biol Psychiatry 2013; 73: 1204–1212.
Schlaepfer TE, Cohen MX, Frick C, Kosel M, Brodesser D, Axmacher N et al. Deep brain stimulation to reward circuitry alleviates anhedonia in refractory major depression. Neuropsychopharmacology 2008; 33: 368–377.
Bewernick BH, Kayser S, Gippert SM, Switala C, Coenen VA, Schlaepfer TE . Deep brain stimulation to the medial forebrain bundle for depression- long-term outcomes and a novel data analysis strategy. Brain Stimul 2017; 10: 664–671.
Bewernick BH, Kayser S, Sturm V, Schlaepfer TE . Long-term effects of nucleus accumbens deep brain stimulation in treatment-resistant depression: evidence for sustained efficacy. Neuropsychopharmacology 2012; 37: 1975–1985.
Taghva AS, Malone DA, Rezai AR . Deep brain stimulation for treatment-resistant depression. World Neurosurg 2013; 80: S27 e17-24.
Morishita T, Fayad SM, Higuchi MA, Nestor KA, Foote KD . Deep brain stimulation for treatment-resistant depression: systematic review of clinical outcomes. Neurotherapeutics 2014; 11: 475–484.
Fenoy AJ, Schulz P, Selvaraj S, Burrows C, Spiker D, Cao B et al. Deep brain stimulation of the medial forebrain bundle: distinctive responses in resistant depression. J Affect Disord 2016; 203: 143–151.
Mayberg HS, Riva-Posse P, Crowell AL . Deep brain stimulation for depression: keeping an eye on a moving target. JAMA Psychiatry 2016; 73: 439–440.
Smith DF . Exploratory meta-analysis on deep brain stimulation in treatment-resistant depression. Acta Neuropsychiatr 2014; 26: 382–384.
Hamani C, Nobrega JN . Deep brain stimulation in clinical trials and animal models of depression. Eur J Neurosci 2010; 32: 1109–1117.
Nestler EJ, Hyman SE . Animal models of neuropsychiatric disorders. Nat Neurosci 2010; 13: 1161–1169.
Drevets WC, Savitz J, Trimble M . The subgenual anterior cingulate cortex in mood disorders. CNS Spectr 2008; 13: 663–681.
Riva-Posse P, Choi KS, Holtzheimer PE, Crowell AL, Garlow SJ, Rajendra JK et al. A connectomic approach for subcallosal cingulate deep brain stimulation surgery: prospective targeting in treatment-resistant depression. Mol Psychiatry 2017 article in press.
Riva-Posse P, Holtzheimer PE, Garlow SJ, Mayberg HS . Practical considerations in the development and refinement of subcallosal cingulate white matter deep brain stimulation for treatment-resistant depression. World Neurosurg 2013; 80: S27 e25–S27 e34.
Lozano AM, Mayberg HS, Giacobbe P, Hamani C, Craddock RC, Kennedy SH . Subcallosal cingulate gyrus deep brain stimulation for treatment-resistant depression. Biol Psychiatry 2008; 64: 461–467.
Puigdemont D, Portella MJ, Perez-Egea R, de Diego-Adelino J, Gironell A, Molet J et al. Depressive relapse after initial response to subcallosal cingulate gyrus-deep brain stimulation in a patient with a treatment-resistant depression: electroconvulsive therapy as a feasible strategy. Biol Psychiatry 2009; 66: e11–e12.
Neimat JS, Hamani C, Giacobbe P, Merskey H, Kennedy SH, Mayberg HS et al. Neural stimulation successfully treats depression in patients with prior ablative cingulotomy. Am J Psychiatry 2008; 165: 687–693.
Torres CV, Ezquiaga E, Navas M, de Sola RG . Deep brain stimulation of the subcallosal cingulate for medication-resistant type I bipolar depression: case report. Bipolar Disord 2013; 15: 719–721.
Funayama M, Kato M, Mimura M . Disappearance of treatment-resistant depression after damage to the orbitofrontal cortex and subgenual cingulate area: a case study. BMC Neurol 2016; 16: 198.
Holtzheimer PE 3rd, Mayberg HS . Deep brain stimulation for treatment-resistant depression. Am J Psychiatry 2010; 167: 1437–1444.
Kennedy SH, Giacobbe P, Rizvi SJ, Placenza FM, Nishikawa Y, Mayberg HS et al. Deep brain stimulation for treatment-resistant depression: follow-up after 3 to 6 years. Am J Psychiatry 2011; 168: 502–510.
Holtzheimer PE, Kelley ME, Gross RE, Filkowski MM, Garlow SJ, Barrocas A et al. Subcallosal cingulate deep brain stimulation for treatment-resistant unipolar and bipolar depression. Arch Gen Psychiatry 2012; 69: 150–158.
Puigdemont D, Perez-Egea R, Portella MJ, Molet J, de Diego-Adelino J, Gironell A et al. Deep brain stimulation of the subcallosal cingulate gyrus: further evidence in treatment-resistant major depression. Int J Neuropsychopharmacol 2012; 15: 121–133.
Martin-Blanco A, Serra-Blasco M, Perez-Egea R, de Diego-Adelino J, Carceller-Sindreu M, Puigdemont D et al. Immediate cerebral metabolic changes induced by discontinuation of deep brain stimulation of subcallosal cingulate gyrus in treatment-resistant depression. J Affect Disord 2015; 173: 159–162.
Puigdemont D, Portella M, Perez-Egea R, Molet J, Gironell A, de Diego-Adelino J et al. A randomized double-blind crossover trial of deep brain stimulation of the subcallosal cingulate gyrus in patients with treatment-resistant depression: a pilot study of relapse prevention. J Psychiatr Neurosci 2015; 40: 224–231.
Eitan R, Fontaine D, Benoit M, Giordana C, Darmon N, Israel Z et al. One year double blind study of high vs low frequency subcallosal cingulate stimulation for depression. J Psychiatr Res 2018; 96: 124–134.
Berlim MT, McGirr A, Van den Eynde F, Fleck MP, Giacobbe P . Effectiveness and acceptability of deep brain stimulation (DBS) of the subgenual cingulate cortex for treatment-resistant depression: a systematic review and exploratory meta-analysis. J Affect Disord 2014; 159: 31–38.
Merkl A, Schneider GH, Schonecker T, Aust S, Kuhl KP, Kupsch A et al. Antidepressant effects after short-term and chronic stimulation of the subgenual cingulate gyrus in treatment-resistant depression. Exp Neurol 2013; 249: 160–168.
Ramasubbu R, Anderson S, Haffenden A, Chavda S, Kiss ZH . Double-blind optimization of subcallosal cingulate deep brain stimulation for treatment-resistant depression: a pilot study. J Psychiatr Neurosci 2013; 38: 325–332.
Lozano AM, Giacobbe P, Hamani C, Rizvi SJ, Kennedy SH, Kolivakis TT et al. A multicenter pilot study of subcallosal cingulate area deep brain stimulation for treatment-resistant depression. J Neurosurg 2012; 116: 315–322.
Lujan JL, Chaturvedi A, Choi KS, Holtzheimer PE, Gross RE, Mayberg HS et al. Tractography-activation models applied to subcallosal cingulate deep brain stimulation. Brain Stimul 2013; 6: 737–739.
Riva-Posse P, Choi KS, Holtzheimer PE, McIntyre CC, Gross RE, Chaturvedi A et al. Defining critical white matter pathways mediating successful subcallosal cingulate deep brain stimulation for treatment-resistant depression. Biol Psychiatry 2014; 76: 963–969.
Holtzheimer PE, Mayberg HS . Deep brain stimulation for psychiatric disorders. Annu Rev Neurosci 2011; 34: 289–307.
Moreines JL, McClintock SM, Kelley ME, Holtzheimer PE, Mayberg HS . Neuropsychological function before and after subcallosal cingulate deep brain stimulation in patients with treatment-resistant depression. Depress Anxiety 2014; 31: 690–698.
Bogod NM, Sinden M, Woo C, Defreitas VG, Torres IJ, Howard AK et al. Long-term neuropsychological safety of subgenual cingulate gyrus deep brain stimulation for treatment-resistant depression. J Neuropsychiatr Clin Neurosci 2014; 26: 126–133.
Hilimire MR, Mayberg HS, Holtzheimer PE, Broadway JM, Parks NA, DeVylder JE et al. Effects of subcallosal cingulate deep brain stimulation on negative self-bias in patients with treatment-resistant depression. Brain Stimul 2015; 8: 185–191.
Serra-Blasco M, de Vita S, Rodriguez MR, de Diego-Adelino J, Puigdemont D, Martin-Blanco A et al. Cognitive functioning after deep brain stimulation in subcallosal cingulate gyrus for treatment-resistant depression: an exploratory study. Psychiatr Res 2015; 225: 341–346.
McInerney SJ, McNeely HE, Geraci J, Giacobbe P, Rizvi SJ, Ceniti AK et al. Neurocognitive predictors of response in treatment resistant depression to subcallosal cingulate gyrus deep brain stimulation. Front Hum Neurosci 2017; 11: 74.
McNeely HE, Mayberg HS, Lozano AM, Kennedy SH . Neuropsychological impact of Cg25 deep brain stimulation for treatment-resistant depression: preliminary results over 12 months. JNerv Ment Dis 2008; 196: 405–410.
Crowell AL, Garlow SJ, Riva-Posse P, Mayberg HS . Characterizing the therapeutic response to deep brain stimulation for treatment-resistant depression: a single center long-term perspective. Front Integr Neurosci 2015; 9: 41.
Saleh C, Fontaine D . Deep brain stimulation for psychiatric diseases: what are the risks? Curr Psychiatr Rep 2015; 17: 33.
Richieri R, Borius PY, Lagrange G, Faget-Agius C, Guedj E, Mc Gonigal A et al. Unmasking partial seizure after deep brain stimulation for treatment-resistant depression: a case report. Brain Stimul 2016; 9: 636–638.
Holtzheimer PE, Husain MM, Lisanby SH, Taylor SF, Whitworth LA, McClintock S et al. Subcallosal cingulate deep brain stimulation for treatment-resistant depression: a multisite, randomised, sham-controlled trial. Lancet Psychiatry 2017; 4: 839–849.
Merkl A, Aust S, Schneider GH, Visser-Vandewalle V, Horn A, Kuhn AA et al. Deep brain stimulation of the subcallosal cingulate gyrus in patients with treatment-resistant depression: a double-blinded randomized controlled study and long-term follow-up in eight patients. J Affect Disord 2017; 227: 521–529.
Accolla EA, Aust S, Merkl A, Schneider GH, Kuhn AA, Bajbouj M et al. Deep brain stimulation of the posterior gyrus rectus region for treatment resistant depression. J Affect Disord 2016; 194: 33–37.
Wallis JD . Cross-species studies of orbitofrontal cortex and value-based decision-making. Nat Neurosci 2011; 15: 13–19.
Hamani C, Diwan M, Isabella S, Lozano AM, Nobrega JN . Effects of different stimulation parameters on the antidepressant-like response of medial prefrontal cortex deep brain stimulation in rats. J Psychiatr Res 2010a; 44: 683–687.
Hamani C, Diwan M, Macedo CE, Brandao ML, Shumake J, Gonzalez-Lima F et al. Antidepressant-like effects of medial prefrontal cortex deep brain stimulation in rats. Biol Psychiatry 2010b; 67: 117–124.
Hamani C, Giacobbe P, Diwan M, Balbino ES, Tong J, Bridgman A et al. Monoamine oxidase inhibitors potentiate the effects of deep brain stimulation. Am J Psychiatry 2012a; 169: 1320–1321.
Hamani C, Machado DC, Hipolide DC, Dubiela FP, Suchecki D, Macedo CE et al. Deep brain stimulation reverses anhedonic-like behavior in a chronic model of depression: role of serotonin and brain derived neurotrophic factor. Biol Psychiatry 2012b; 71: 30–35.
Li B, Piriz J, Mirrione M, Chung C, Proulx CD, Schulz D et al. Synaptic potentiation onto habenula neurons in the learned helplessness model of depression. Nature 2011; 470: 535–539.
Meng H, Wang Y, Huang M, Lin W, Wang S, Zhang B . Chronic deep brain stimulation of the lateral habenula nucleus in a rat model of depression. Brain Res 2011; 1422: 32–38.
Perez-Caballero L, Perez-Egea R, Romero-Grimaldi C, Puigdemont D, Molet J, Caso JR et al. Early responses to deep brain stimulation in depression are modulated by anti-inflammatory drugs. Mol Psychiatry 2014; 19: 607–614.
Lim LW, Janssen ML, Kocabicak E, Temel Y . The antidepressant effects of ventromedial prefrontal cortex stimulation is associated with neural activation in the medial part of the subthalamic nucleus. Behav Brain Res 2015a; 279: 17–21.
Lim LW, Prickaerts J, Huguet G, Kadar E, Hartung H, Sharp T et al. Electrical stimulation alleviates depressive-like behaviors of rats: investigation of brain targets and potential mechanisms. Transl Psychiatry 2015b; 5: e535.
Jimenez-Sanchez L, Castane A, Perez-Caballero L, Grifoll-Escoda M, Lopez-Gil X, Campa L et al. Activation of AMPA receptors mediates the antidepressant action of deep brain stimulation of the infralimbic prefrontal cortex. Cereb cortex 2016a; 26: 2778–2789.
Jimenez-Sanchez L, Linge R, Campa L, Valdizan EM, Pazos A, Diaz A et al. Behavioral, neurochemical and molecular changes after acute deep brain stimulation of the infralimbic prefrontal cortex. Neuropharmacology 2016b; 108: 91–102.
Rea E, Rummel J, Schmidt TT, Hadar R, Heinz A, Mathe AA et al. Anti-anhedonic effect of deep brain stimulation of the prefrontal cortex and the dopaminergic reward system in a genetic rat model of depression: an intracranial self-stimulation paradigm study. Brain Stimul 2014; 7: 21–28.
Schmuckermair C, Gaburro S, Sah A, Landgraf R, Sartori SB, Singewald N . Behavioral and neurobiological effects of deep brain stimulation in a mouse model of high anxiety- and depression-like behavior. Neuropsychopharmacology 2013; 38: 1234–1244.
Edemann-Callesen H, Voget M, Empl L, Vogel M, Wieske F, Rummel J et al. Medial forebrain bundle deep brain stimulation has symptom-specific anti-depressant effects in rats and as opposed to ventromedial prefrontal cortex stimulation interacts with the reward system. Brain Stimul 2015; 8: 714–723.
Gersner R, Toth E, Isserles M, Zangen A . Site-specific antidepressant effects of repeated subconvulsive electrical stimulation: potential role of brain-derived neurotrophic factor. Biol Psychiatry 2010; 67: 125–132.
Veerakumar A, Challis C, Gupta P, Da J, Upadhyay A, Beck SG et al. Antidepressant-like effects of cortical deep brain stimulation coincide with pro-neuroplastic adaptations of serotonin systems. Biol Psychiatry 2014; 76: 203–212.
Moshe H, Gal R, Barnea-Ygael N, Gulevsky T, Alyagon U, Zangen A . Prelimbic stimulation ameliorates depressive-like behaviors and increases regional bdnf expression in a novel drug-resistant animal model of depression. Brain Stimul 2016; 9: 243–250.
Etievant A, Oosterhof C, Betry C, Abrial E, Novo-Perez M, Rovera R et al. Astroglial control of the antidepressant-like effects of prefrontal cortex deep brain stimulation. EBioMedicine 2015a; 2: 898–908.
Insel N, Pilkiw M, Nobrega JN, Hutchison WD, Takehara-Nishiuchi K, Hamani C . Chronic deep brain stimulation of the rat ventral medial prefrontal cortex disrupts hippocampal-prefrontal coherence. Exp Neurol 2015; 269: 1–7.
Bezchlibnyk YB, Stone SS, Hamani C, Lozano AM . High frequency stimulation of the infralimbic cortex induces morphological changes in rat hippocampal neurons. Brain Stimul 2017; 10: 315–323.
Parthoens J, Verhaeghe J, Stroobants S, Staelens S . Deep brain stimulation of the prelimbic medial prefrontal cortex: quantification of the effect on glucose metabolism in the rat brain using [(18) F]FDG microPET. Mol Imaging Biol 2014; 16: 838–845.
Dournes C, Beeske S, Belzung C, Griebel G . Deep brain stimulation in treatment-resistant depression in mice: comparison with the CRF1 antagonist, SSR125543. Progr Neuropsychopharmacol Biol Psychiatry 2013; 40: 213–220.
Bambico FR, Bregman T, Diwan M, Li J, Darvish-Ghane S, Li Z et al. Neuroplasticity-dependent and -independent mechanisms of chronic deep brain stimulation in stressed rats. Transl Psychiatry 2015; 5: e674.
Chakravarty MM, Hamani C, Martinez-Canabal A, Ellegood J, Laliberte C, Nobrega JN et al. Deep brain stimulation of the ventromedial prefrontal cortex causes reorganization of neuronal processes and vasculature. NeuroImage 2016; 125: 422–427.
Bregman T, Nona C, Volle J, Diwan M, Raymond R, Fletcher PJ et al. Deep brain stimulation induces antidepressant-like effects in serotonin transporter knockout mice. Brain Stimul 2018; 11: 423–425.
Srejic LR, Hamani C, Hutchison WD . High-frequency stimulation of the medial prefrontal cortex decreases cellular firing in the dorsal raphe. Eur J Neurosci 2015; 41: 1219–1226.
Laver B, Diwan M, Nobrega JN, Hamani C . Augmentative therapies do not potentiate the antidepressant-like effects of deep brain stimulation in rats. J Affect Disord 2014; 161: 87–90.
Bruchim-Samuel M, Lax E, Gazit T, Friedman A, Ahdoot H, Bairachnaya M et al. Electrical stimulation of the vmPFC serves as a remote control to affect VTA activity and improve depressive-like behavior. Exp Neurol 2016; 283 (Pt A): 255–263.
Torres-Sanchez S, Perez-Caballero L, Mico JA, Celada P, Berrocoso E . Effect of Deep Brain Stimulation of the ventromedial prefrontal cortex on the noradrenergic system in rats. Brain Stimul 2017; 11: 222–230.
Mayberg HS . Limbic-cortical dysregulation: a proposed model of depression. J Neuropsychiatr Clin Neurosci 1997; 9: 471–481.
Hamani C, Mayberg H, Stone S, Laxton A, Haber S, Lozano AM . The subcallosal cingulate gyrus in the context of major depression. Biol Psychiatry 2011; 69: 301–308.
Etievant A, Lucas G, Dkhissi-Benyahya O, Haddjeri N . The role of astroglia in the antidepressant action of deep brain stimulation. Front Cell Neurosci 2015b; 9: 509.
Hamani C, Nobrega JN . Reply to: deep brain stimulation for depression: is it a gray or white "matter"? Biol Psychiatry 2016; 80: e45.
Laxton AW, Lipsman N, Lozano AM . Deep brain stimulation for cognitive disorders. Handb Clin Neurol 2013; 116: 307–311.
Eggers AE . Treatment of depression with deep brain stimulation works by altering in specific ways the conscious perception of the core symptoms of sadness or anhedonia, not by modulating network circuitry. Med Hypotheses 2014; 83: 62–64.
Broadway JM, Holtzheimer PE, Hilimire MR, Parks NA, Devylder JE, Mayberg HS et al. Frontal theta cordance predicts 6-month antidepressant response to subcallosal cingulate deep brain stimulation for treatment-resistant depression: a pilot study. Neuropsychopharmacology 2012; 37: 1764–1772.
Neumann WJ, Huebl J, Brucke C, Gabriels L, Bajbouj M, Merkl A et al. Different patterns of local field potentials from limbic DBS targets in patients with major depressive and obsessive compulsive disorder. Mol Psychiatry 2014; 19: 1186–1192.
Quraan MA, Protzner AB, Daskalakis ZJ, Giacobbe P, Tang CW, Kennedy SH et al. EEG power asymmetry and functional connectivity as a marker of treatment effectiveness in DBS surgery for depression. Neuropsychopharmacology 2014; 39: 1270–1281.
Sun Y, Giacobbe P, Tang CW, Barr MS, Rajji T, Kennedy SH et al. Deep brain stimulation modulates gamma oscillations and theta-gamma coupling in treatment resistant depression. Brain Stimul 2015; 8: 1033–1042.
Bewernick BH, Hurlemann R, Matusch A, Kayser S, Grubert C, Hadrysiewicz B et al. Nucleus accumbens deep brain stimulation decreases ratings of depression and anxiety in treatment-resistant depression. Biol Psychiatry 2010; 67: 110–116.
Grubert C, Hurlemann R, Bewernick BH, Kayser S, Hadrysiewicz B, Axmacher N et al. Neuropsychological safety of nucleus accumbens deep brain stimulation for major depression: effects of 12-month stimulation. World J Biol Psychiatry 2011; 12: 516–527.
Millet B, Jaafari N, Polosan M, Baup N, Giordana B, Haegelen C et al. Limbic versus cognitive target for deep brain stimulation in treatment-resistant depression: accumbens more promising than caudate. Eur Neuropsychopharmacol 2014; 24: 1229–1239.
Sesia T, Bulthuis V, Tan S, Lim LW, Vlamings R, Blokland A et al. Deep brain stimulation of the nucleus accumbens shell increases impulsive behavior and tissue levels of dopamine and serotonin. Exp Neurol 2010; 225: 302–309.
van Dijk A, Mason O, Klompmakers AA, Feenstra MG, Denys D . Unilateral deep brain stimulation in the nucleus accumbens core does not affect local monoamine release. J Neurosci Methods 2011; 202: 113–118.
van Dijk A, Klompmakers AA, Feenstra MG, Denys D . Deep brain stimulation of the accumbens increases dopamine, serotonin, and noradrenaline in the prefrontal cortex. J Neurochem 2012; 123: 897–903.
McCracken CB, Grace AA . Nucleus accumbens deep brain stimulation produces region-specific alterations in local field potential oscillations and evoked responses in vivo. J Neurosci 2009; 29: 5354–5363.
van der Plasse G, Schrama R, van Seters SP, Vanderschuren LJ, Westenberg HG . Deep brain stimulation reveals a dissociation of consummatory and motivated behaviour in the medial and lateral nucleus accumbens shell of the rat. PLoS ONE 2012; 7: e33455.
Hamani C, Amorim BO, Wheeler AL, Diwan M, Driesslein K, Covolan L et al. Deep brain stimulation in rats: different targets induce similar antidepressant-like effects but influence different circuits. Neurobiol Dis 2014; 71: 205–214.
Rummel J, Voget M, Hadar R, Ewing S, Sohr R, Klein J et al. Testing different paradigms to optimize antidepressant deep brain stimulation in different rat models of depression. J Psychiatr Res 2016; 81: 36–45.
Kim Y, McGee S, Czeczor JK, Walker AJ, Kale RP, Kouzani AZ et al. Nucleus accumbens deep brain stimulation efficacy in ACTH-pretreated rats: alterations in mitochondrial function relate to antidepressant-like effects. Transl Psychiatry 2016a; 6: e842.
Falowski SM, Sharan A, Reyes BA, Sikkema C, Szot P, Van Bockstaele EJ . An evaluation of neuroplasticity and behavior after deep brain stimulation of the nucleus accumbens in an animal model of depression. Neurosurgery 2011; 69: 1281–1290.
Winter C, Bregman T, Voget M, Raymond R, Hadar R, Nobrega JN et al. Acute high frequency stimulation of the prefrontal cortex or nucleus accumbens does not increase hippocampal neurogenesis in rats. J Psychiatr Res 2015; 68: 27–29.
Huguet G, Kadar E, Temel Y, Lim LW . Electrical stimulation normalizes c-Fos expression in the deep cerebellar nuclei of depressive-like rats: implication of antidepressant activity. Cerebellum 2017; 16: 398–410.
Knight EJ, Min HK, Hwang SC, Marsh MP, Paek S, Kim I et al. Nucleus accumbens deep brain stimulation results in insula and prefrontal activation: a large animal FMRI study. PLoS ONE 2013; 8: e56640.
Aouizerate B, Cuny E, Martin-Guehl C, Guehl D, Amieva H, Benazzouz A et al. Deep brain stimulation of the ventral caudate nucleus in the treatment of obsessive-compulsive disorder and major depression. Case report. J Neurosurg 2004; 101: 682–686.
van den Munckhof P, Bosch DA, Mantione MH, Figee M, Denys DA, Schuurman PR . Active stimulation site of nucleus accumbens deep brain stimulation in obsessive-compulsive disorder is localized in the ventral internal capsule. Acta Neurochir Suppl 2013; 117: 53–59.
Malone DA Jr. . Use of deep brain stimulation in treatment-resistant depression. Cleveland Clin J Med 2010; 77 (Suppl 3): S77–S80.
Strong DR, Haber SN, Tyrka AR, Bernier JA, Rassmussen SA, Greenberg BD . Reversible increase in smoking after withdrawal of ventral capsule/ventral striatum deep brain stimulation in a depressed smoker. J Addict Med 2012; 6: 94–95.
Dougherty DD, Rezai AR, Carpenter LL, Howland RH, Bhati MT, O'Reardon JP et al. A randomized sham-controlled trial of deep brain stimulation of the ventral capsule/ventral striatum for chronic treatment-resistant depression. Biol Psychiatry 2015; 78: 240–248.
Richardson RM, Ghuman AS, Karp JF . Results of the first randomized controlled trial of deep brain stimulation in treatment-resistant depression. Neurosurgery 2015; 77: N23–N24.
Kubu CS, Brelje T, Butters MA, Deckersbach T, Malloy P, Moberg P et al. Cognitive outcome after ventral capsule/ventral striatum stimulation for treatment-resistant major depression. J Neurol Neurosurg Psychiatry 2017; 88: 262–265.
Bergfeld IO, Mantione M, Hoogendoorn ML, Ruhe HG, Notten P, van Laarhoven J et al. Deep brain stimulation of the ventral anterior limb of the internal capsule for treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry 2016; 73: 456–464.
Bergfeld IO, Mantione M, Hoogendoorn MLC, Ruhe HG, Horst F, Notten P et al. Impact of deep brain stimulation of the ventral anterior limb of the internal capsule on cognition in depression. Psychol Med 2017; 47: 1647–1658.
Rauch SL, Dougherty DD, Malone D, Rezai A, Friehs G, Fischman AJ et al. A functional neuroimaging investigation of deep brain stimulation in patients with obsessive-compulsive disorder. J Neurosurg 2006; 104: 558–565.
Van Laere K, Nuttin B, Gabriels L, Dupont P, Rasmussen S, Greenberg BD et al. Metabolic imaging of anterior capsular stimulation in refractory obsessive-compulsive disorder: a key role for the subgenual anterior cingulate and ventral striatum. J Nucl Med 2006; 47: 740–747.
Forray MI, Gysling K . Role of noradrenergic projections to the bed nucleus of the stria terminalis in the regulation of the hypothalamic-pituitary-adrenal axis. Brain Res Brain Res Rev 2004; 47: 145–160.
Epstein J, Pan H, Kocsis JH, Yang Y, Butler T, Chusid J et al. Lack of ventral striatal response to positive stimuli in depressed versus normal subjects. Am J Psychiatry 2006; 163: 1784–1790.
Blomstedt P, Naesstrom M, Bodlund O . Deep brain stimulation in the bed nucleus of the stria terminalis and medial forebrain bundle in a patient with major depressive disorder and anorexia nervosa. Clin Case Rep 2017; 5: 679–684.
Mavridis IN . Deep brain stimulation for psychiatric disorders: Are nucleus accumbens and medial forebrain bundle two branches of the same tree? Neurosci Biobehav Rev 2015; 56: 345–346.
Furlanetti LL, Coenen VA, Aranda IA, Dobrossy MD . Chronic deep brain stimulation of the medial forebrain bundle reverses depressive-like behavior in a hemiparkinsonian rodent model. Exp Brain Res 2015a; 233: 3073–3085.
Furlanetti LL, Dobrossy MD, Aranda IA, Coenen VA . Feasibility and safety of continuous and chronic bilateral deep brain stimulation of the medial forebrain bundle in the naive Sprague-Dawley rat. Behav Neurol 2015b; 2015: 256196.
Bregman T, Reznikov R, Diwan M, Raymond R, Butson CR, Nobrega JN et al. Antidepressant-like effects of medial forebrain bundle deep brain stimulation in rats are not associated with accumbens dopamine release. Brain Stimul 2015; 8: 708–713.
Furlanetti LL, Coenen VA, Dobrossy MD . Ventral tegmental area dopaminergic lesion-induced depressive phenotype in the rat is reversed by deep brain stimulation of the medial forebrain bundle. Behav Brain Res 2016; 299: 132–140.
Dandekar MP, Luse D, Hoffmann C, Cotton P, Peery T, Ruiz C et al. Increased dopamine receptor expression and anti-depressant response following deep brain stimulation of the medial forebrain bundle. J Affect Disord 2017; 217: 80–88.
Coenen VA, Honey CR, Hurwitz T, Rahman AA, McMaster J, Burgel U et al. Medial forebrain bundle stimulation as a pathophysiological mechanism for hypomania in subthalamic nucleus deep brain stimulation for Parkinson's disease. Neurosurgery 2009; 64: 1106–1114, discussion 1114-1105.
Cho YT, Fromm S, Guyer AE, Detloff A, Pine DS, Fudge JL et al. Nucleus accumbens, thalamus and insula connectivity during incentive anticipation in typical adults and adolescents. NeuroImage 2013; 66: 508–521.
Galvez JF, Keser Z, Mwangi B, Ghouse AA, Fenoy AJ, Schulz PE et al. The medial forebrain bundle as a deep brain stimulation target for treatment resistant depression: a review of published data. Progr Neuropsychopharmacol Biol Psychiatry 2015; 58: 59–70.
Coenen VA, Panksepp J, Hurwitz TA, Urbach H, Madler B . Human medial forebrain bundle (MFB) and anterior thalamic radiation (ATR): imaging of two major subcortical pathways and the dynamic balance of opposite affects in understanding depression. J Neuropsychiatr Clin Neurosci 2012a; 24: 223–236.
Coenen VA, Schlaepfer TE, Maedler B, Panksepp J . Cross-species affective functions of the medial forebrain bundle-implications for the treatment of affective pain and depression in humans. Neurosci Biobehav Rev 2011; 35: 1971–1981.
Sesack SR, Pickel VM . Prefrontal cortical efferents in the rat synapse on unlabeled neuronal targets of catecholamine terminals in the nucleus accumbens septi and on dopamine neurons in the ventral tegmental area. J Comp Neurol 1992; 320: 145–160.
You ZB, Chen YQ, Wise RA . Dopamine and glutamate release in the nucleus accumbens and ventral tegmental area of rat following lateral hypothalamic self-stimulation. Neuroscience 2001; 107: 629–639.
Ferenczi EA, Zalocusky KA, Liston C, Grosenick L, Warden MR, Amatya D et al. Prefrontal cortical regulation of brainwide circuit dynamics and reward-related behavior. Science 2016; 351: aac9698.
Taber MT, Das S, Fibiger HC . Cortical regulation of subcortical dopamine release: mediation via the ventral tegmental area. J Neurochem 1995; 65: 1407–1410.
Sartorius A, Henn FA . Deep brain stimulation of the lateral habenula in treatment resistant major depression. Med Hypotheses 2007; 69: 1305–1308.
Sartorius A, Kiening KL, Kirsch P, von Gall CC, Haberkorn U, Unterberg AW et al. Remission of major depression under deep brain stimulation of the lateral habenula in a therapy-refractory patient. Biol Psychiatry 2010; 67: e9–e11.
Friedman A, Lax E, Dikshtein Y, Abraham L, Flaumenhaft Y, Sudai E et al. Electrical stimulation of the lateral habenula produces an inhibitory effect on sucrose self-administration. Neuropharmacology 2011; 60: 381–387.
Kim Y, Morath B, Hu C, Byrne LK, Sutor SL, Frye MA et al. Antidepressant actions of lateral habenula deep brain stimulation differentially correlate with CaMKII/GSK3/AMPK signaling locally and in the infralimbic cortex. Behav Brain Res 2016b; 306: 170–177.
Christoph GR, Leonzio RJ, Wilcox KS . Stimulation of the lateral habenula inhibits dopamine-containing neurons in the substantia nigra and ventral tegmental area of the rat. J Neurosci 1986; 6: 613–619.
Ji H, Shepard PD . Lateral habenula stimulation inhibits rat midbrain dopamine neurons through a GABA(A) receptor-mediated mechanism. J Neurosci 2007; 27: 6923–6930.
Kiening K, Sartorius A . A new translational target for deep brain stimulation to treat depression. EMBO Mol Med 2013; 5: 1151–1153.
Geisler S, Trimble M . The lateral habenula: no longer neglected. CNS Spectr 2008; 13: 484–489.
Kopell BH, Greenberg BD . Anatomy and physiology of the basal ganglia: implications for DBS in psychiatry. Neurosci Biobehav Rev 2008; 32: 408–422.
Drevets WC . Functional anatomical abnormalities in limbic and prefrontal cortical structures in major depression. Progr Brain Res 2000; 126: 413–431.
Velasco M, Velasco F, Jimenez F, Carrillo-Ruiz JD, Velasco AL, Salin-Pascual R . Electrocortical and behavioral responses elicited by acute electrical stimulation of inferior thalamic peduncle and nucleus reticularis thalami in a patient with major depression disorder. Clin Neurophysiol 2006; 117: 320–327.
Jimenez F, Velasco F, Salin-Pascual R, Hernandez JA, Velasco M, Criales JL et al. A patient with a resistant major depression disorder treated with deep brain stimulation in the inferior thalamic peduncle. Neurosurgery 2005; 57: 585–593, discussion 585-593.
Jimenez F, Velasco F, Salin-Pascual R, Velasco M, Nicolini H, Velasco AL et al. Neuromodulation of the inferior thalamic peduncle for major depression and obsessive compulsive disorder. Acta Neurochir Suppl 2007; 97 (Pt 2): 393–398.
Jimenez F, Nicolini H, Lozano AM, Piedimonte F, Salin R, Velasco F . Electrical stimulation of the inferior thalamic peduncle in the treatment of major depression and obsessive compulsive disorders. World Neurosurg 2013; 80: S30 e17–25.
Raymaekers S, Luyten L, Bervoets C, Gabriels L, Nuttin B . Deep brain stimulation for treatment-resistant major depressive disorder: a comparison of two targets and long-term follow-up. Transl Psychiatry 2017; 7: e1251.
Faggiani E, Delaville C, Benazzouz A . The combined depletion of monoamines alters the effectiveness of subthalamic deep brain stimulation. Neurobiol Dis 2015; 82: 342–348.
Creed MC, Hamani C, Nobrega JN . Effects of repeated deep brain stimulation on depressive- and anxiety-like behavior in rats: comparing entopeduncular and subthalamic nuclei. Brain Stimul 2013; 6: 506–514.
Schneider F, Habel U, Volkmann J, Regel S, Kornischka J, Sturm V et al. Deep brain stimulation of the subthalamic nucleus enhances emotional processing in Parkinson disease. Arch Gen Psychiatry 2003; 60: 296–302.
Funkiewiez A, Ardouin C, Caputo E, Krack P, Fraix V, Klinger H et al. Long term effects of bilateral subthalamic nucleus stimulation on cognitive function, mood, and behaviour in Parkinson's disease. J Neurol Neurosurg Psychiatry 2004; 75: 834–839.
Czernecki V, Pillon B, Houeto JL, Welter ML, Mesnage V, Agid Y et al. Does bilateral stimulation of the subthalamic nucleus aggravate apathy in Parkinson's disease? J Neurol Neurosurg Psychiatry 2005; 76: 775–779.
Campbell MC, Black KJ, Weaver PM, Lugar HM, Videen TO, Tabbal SD et al. Mood response to deep brain stimulation of the subthalamic nucleus in Parkinson's disease. J Neuropsychiatr Clin Neurosci 2012; 24: 28–36.
Eisenstein SA, Dewispelaere WB, Campbell MC, Lugar HM, Perlmutter JS, Black KJ et al. Acute changes in mood induced by subthalamic deep brain stimulation in Parkinson disease are modulated by psychiatric diagnosis. Brain Stimul 2014; 7: 701–708.
Temel Y, Wilbrink P, Duits A, Boon P, Tromp S, Ackermans L et al. Single electrode and multiple electrode guided electrical stimulation of the subthalamic nucleus in advanced Parkinson's disease. Neurosurgery 2007; 61 (5 Suppl 2): 346–355, discussion 355-347.
Aono M, Iga J, Ueno S, Agawa M, Tsuda T, Ohmori T . Neuropsychological and psychiatric assessments following bilateral deep brain stimulation of the subthalamic nucleus in Japanese patients with Parkinson's disease. J Clin Neurosci 2014; 21: 1595–1598.
Bejjani BP, Houeto JL, Hariz M, Yelnik J, Mesnage V, Bonnet AM et al. Aggressive behavior induced by intraoperative stimulation in the triangle of Sano. Neurology 2002; 59: 1425–1427.
Sako W, Miyazaki Y, Izumi Y, Kaji R . Which target is best for patients with Parkinson's disease? A meta-analysis of pallidal and subthalamic stimulation. J Neurol Neurosurg Psychiatry 2014; 85: 982–986.
Mahgoub NA, Kotbi N . Acute depression and suicidal attempt following lowering the frequency of deep brain stimulation. J Neuropsychiatr Clin Neurosci 2009; 21: 468.
Appleby BS, Duggan PS, Regenberg A, Rabins PV . Psychiatric and neuropsychiatric adverse events associated with deep brain stimulation: A meta-analysis of ten years' experience. Mov Disord 2007; 22: 1722–1728.
Narang P, Retzlaff A, Brar K, Lippmann S . Deep brain stimulation for treatment-refractory depression. Southern Med J 2016; 109: 700–703.
Zhou C, Zhang H, Qin Y, Tian T, Xu B, Chen J et al. A systematic review and meta-analysis of deep brain stimulation in treatment-resistant depression. Progr Neuropsychopharmacol Biol Psychiatry 2018; 82: 224–232.
Hamani C, Mayberg H, Snyder B, Giacobbe P, Kennedy S, Lozano AM . Deep brain stimulation of the subcallosal cingulate gyrus for depression: anatomical location of active contacts in clinical responders and a suggested guideline for targeting. J Neurosurg 2009; 111: 1209–1215.
Schlaepfer TE . Deep brain stimulation for major depression-steps on a long and winding road. Biol Psychiatry 2015; 78: 218–219.
Schlaepfer TE, Bewernick BH, Kayser S, Hurlemann R, Coenen VA . Deep brain stimulation of the human reward system for major depression—rationale, outcomes and outlook. Neuropsychopharmacology 2014; 39: 1303–1314.
Nestler EJ, Carlezon WA Jr. . The mesolimbic dopamine reward circuit in depression. Biol Psychiatry 2006; 59: 1151–1159.
Krishnan V, Nestler EJ . Linking molecules to mood: new insight into the biology of depression. Am J Psychiatry 2010; 167: 1305–1320.
Coenen VA, Schlaepfer TE, Allert N, Madler B . Diffusion tensor imaging and neuromodulation: DTI as key technology for deep brain stimulation. Int Rev Neurobiol 2012b; 107: 207–234.
Hoyer C, Sartorius A, Lecourtier L, Kiening KL, Meyer-Lindenberg A, Gass P . One ring to rule them all?—Temporospatial specificity of deep brain stimulation for treatment-resistant depression. Med Hypotheses 2013; 81: 611–618.
Fernandes BS, Williams LM, Steiner J, Leboyer M, Carvalho AF, Berk M . The new field of 'precision psychiatry'. BMC Med 2017; 15: 80.
Guinjoan SM, Mayberg HS, Costanzo EY, Fahrer RD, Tenca E, Antico J et al. Asymmetrical contribution of brain structures to treatment-resistant depression as illustrated by effects of right subgenual cingulum stimulation. J Neuropsychiatr Clin Neurosci 2010; 22: 265–277.
Acknowledgements
The Translational Psychiatry Program (USA) is funded by the Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth). Laboratory of Neurosciences (Brazil) is one of the centers of the National Institute for Molecular Medicine (INCT-MM) and one of the members of the Center of Excellence in Applied Neurosciences of Santa Catarina (NENASC). Its research is supported by grants from CNPq (JQ), FAPESC (JQ); Instituto Cérebro e Mente (JQ) and UNESC (JQ). JQ is a 1A CNPq Research Fellow. Dr Jair C Soares has received grants/research supports from the Pat Rutherford, Jr Endowed Chair in Psychiatry (JCS), John S Dunn Foundation from United States (JCS) and NIMH (R01MH085667-01A1; JCS), Stanley Medical Research Institute, and NIH.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
JCS received research/grant support from Bristol-Meyers Squibb, Forest Laboratories, Merck, Elan Pharmaceuticals, J&J, Stanley Medical Research Institute and has served as a consultant for Pfizer, Abbot and Astellas Pharma. The remaining authors declare no conflict of interest.
PowerPoint slides
Rights and permissions
About this article
Cite this article
Dandekar, M., Fenoy, A., Carvalho, A. et al. Deep brain stimulation for treatment-resistant depression: an integrative review of preclinical and clinical findings and translational implications. Mol Psychiatry 23, 1094–1112 (2018). https://doi.org/10.1038/mp.2018.2
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/mp.2018.2
- Springer Nature Limited
This article is cited by
-
Social experience in adolescence shapes prefrontal cortex structure and function in adulthood
Molecular Psychiatry (2024)
-
Deep brain stimulation of habenula reduces depressive symptoms and modulates brain activities in treatment-resistant depression
Nature Mental Health (2024)
-
Normalized affective responsiveness following deep brain stimulation of the medial forebrain bundle in depression
Translational Psychiatry (2024)
-
A review of diffusion MRI in mood disorders: mechanisms and predictors of treatment response
Neuropsychopharmacology (2024)
-
Linking connectivity of deep brain stimulation of nucleus accumbens area with clinical depression improvements: a retrospective longitudinal case series
European Archives of Psychiatry and Clinical Neuroscience (2024)