Why are clinical trials of deep brain stimulation terminated? An analysis of clinicaltrials.gov.

Background: Although deep brain stimulation (DBS) has established uses for patients with movement disorders and epilepsy, it is under consideration for a wide range of neurologic and neuropsychiatric conditions. Objective: To review successful and unsuccessful DBS clinical trials and identify factors associated with early trial termination. Methods: The ClinicalTrials.gov database was screened for all studies related to DBS. Information regarding condition of interest, study aim, trial design, trial success, and, if applicable, reason for failure was collected. Trials were compared and logistic regression was utilized to identify independent factors associated with trial termination. Results: Of 325 identified trials, 79.7% were successful and 20.3% unsuccessful. Patient recruitment, sponsor decision, and device issues were the most cited reasons for termination. 242 trials (74.5%) were interventional with 78.1% successful. There was a statistically significant difference between successful and unsuccessful trials in number of funding sources (p = 0.0375). NIH funding was associated with successful trials while utilization of other funding sources (academic institutions and community organizations) was associated with unsuccessful trials. 83 trials (25.5%) were observational with 84.0% successful; there were no statistically significant differences between successful and unsuccessful observational trials. Conclusion: One in five clinical trials for DBS were found to be unsuccessful, most commonly due to patient recruitment difficulties. The source of funding was the only factor associated with trial success. As DBS research continues to grow, understanding the current state of clinical trials will help design successful future studies, thereby minimizing futile expenditures of time, cost, and patient engagement.

Thalamo-cortical evoked potentials during stimulation of the dentato-rubro-thalamic tract demonstrate synaptic filtering.

Essential tremor DBS targeting the ventral intermediate nucleus (Vim) of the thalamus and its input, the dentato-rubro-thalamic tract (DRTt), has proven to be an effective treatment strategy. We examined thalamo-cortical evoked potentials (TCEPs) and cortical dynamics during stimulation of the DRTt. We recorded TCEPs in primary motor cortex during clinical and supra-clinical stimulation of the DRTt in ten essential tremor patients. Stimulation was varied over pulse amplitude (2-10 â€‹mA) and pulse width (30-250 â€‹µs) to allow for strength-duration testing. Testing at clinical levels (3 â€‹mA, 60 â€‹µs) for stimulation frequencies of 1-160 â€‹Hz was performed and phase amplitude coupling (PAC) of beta phase and gamma power was calculated. Primary motor cortex TCEPs displayed two responses: early and all-or-none (<20 â€‹ms) or delayed and charge-dependent (>50 â€‹ms). Strength-duration curve approximation indicates that the chronaxie of the neural elements related to the TCEPs is <200 â€‹µs. At the range of clinical stimulation (amplitude 2-5 â€‹mA, pulse width 30-60 â€‹µs), TCEPs were not noted over primary motor cortex. Decreased pathophysiological phase-amplitude coupling was seen above 70 â€‹Hz stimulation without changes in power spectra and below the threshold of TCEPs. Our findings demonstrate that DRTt stimulation within normal clinical bounds does not excite fibers directly connected with primary motor cortex but that supra-clinical stimulation can excite a direct axonal tract. Both clinical efficacy and phase-amplitude coupling were frequency-dependent, favoring a synaptic filtering model as a possible mechanism of action.

Brain metabolic changes and clinical response to superolateral medial forebrain bundle deep brain stimulation for treatment-resistant depression.

Deep brain stimulation (DBS) to the superolateral branch of the medial forebrain bundle is an efficacious therapy for treatment-resistant depression, providing rapid antidepressant effects. In this study, we use 18F-fluorodeoxyglucose-positron emission tomography (PET) to identify brain metabolic changes over 12 months post-DBS implantation in ten of our patients, compared to baseline. The primary outcome measure was a 50% reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) score, which was interpreted as a response. Deterministic fiber tracking was used to individually map the target area; probabilistic tractography was used to identify modulated fiber tracts modeled using the cathodal contacts. Eight of the ten patients included in this study were responders. PET imaging revealed significant decreases in bilateral caudate, mediodorsal thalamus, and dorsal anterior cingulate cortex metabolism that was evident at 6 months and continued to 12 months post surgery. At 12 months post-surgery, significant left ventral prefrontal cortical metabolic decreases were also observed. Right caudate metabolic decrease at 12 months was significantly correlated with mean MADRS reduction. Probabilistic tractography modeling revealed that such metabolic changes lay along cortico-limbic nodes structurally connected to the DBS target site. Such observed metabolic changes following DBS correlated with clinical response provide insights into how future studies can elaborate such data to create biomarkers to predict response, the development of which likely will require multimodal imaging analysis.

A narrative review on invasive brain stimulation for treatment-resistant depression

While most patients with depression respond to pharmacotherapy and psychotherapy, about one-third will present treatment resistance to these interventions. For patients with treatment-resistant depression (TRD), invasive neurostimulation therapies such as vagus nerve stimulation, deep brain stimulation, and epidural cortical stimulation may be considered. We performed a narrative review of the published literature to identify papers discussing clinical studies with invasive neurostimulation therapies for TRD. After a database search and title and abstract screening, relevant English-language articles were analyzed. Vagus nerve stimulation, approved by the U.S. Food and Drug Administration as a TRD treatment, may take several months to show therapeutic benefits, and the average response rate varies from 15.2-83%. Deep brain stimulation studies have shown encouraging results, including rapid response rates (> 30%), despite conflicting findings from randomized controlled trials. Several brain regions, such as the subcallosal-cingulate gyrus, nucleus accumbens, ventral capsule/ventral striatum, anterior limb of the internal capsule, medial-forebrain bundle, lateral habenula, inferior-thalamic peduncle, and the bed-nucleus of the stria terminalis have been identified as key targets for TRD management. Epidural cortical stimulation, an invasive intervention with few reported cases, showed positive results (40-60% response), although more extensive trials are needed to confirm its potential in patients with TRD.

Deep brain stimulation of the "medial forebrain bundle": sustained efficacy of antidepressant effect over years.

Deep brain stimulation (DBS) to the superolateral branch of the medial forebrain bundle (MFB) has emerged as a quite efficacious therapy for treatment resistant depression (TRD), leading to rapid antidepressant effects. In this study, we complete our assessment of our first 10 enrolled patients throughout one year post-implantation, showing sustained antidepressant effect up to 5 years. The primary outcome measure was a 50% reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) score, which was interpreted as a response. Deterministic fiber tracking was used to individually map the target area. An insertional effect was seen during the 4-week sham stimulation phase (29% mean MADRS reduction, p = 0.02). However, after 2 weeks of initiating stimulation, five patients met response criteria (47% mean MADRS reduction, p < 0.001). One patient withdrew from study participation at 6 weeks. Twelve weeks after initiating stimulation, six of nine remaining patients had a >50% decrease in MADRS scores relative to baseline (52% mean MADRS reduction, p = 0.001); these same six patients continued to meet response criteria at 52 weeks (63% overall mean MADRS reduction, p < 0.001). Four of five patients who achieved the 5-year time point analysis continued to be responders (81% mean MADRS reduction, p < 0.001). Evaluation of modulated fiber tracts reveals significant common prefrontal/orbitofrontal connectivity to the target region in all responders. Key points learned from this study that we can incorporate in future protocols to better elucidate the effect of this therapy are a longer blinded sham stimulation phase and use of scheduled discontinuation concomitant with functional imaging.

Frameless Robot-Assisted vs Frame-Based Awake Deep Brain Stimulation Surgery: An Evaluation of Technique and New Challenges.

BACKGROUND: Methodological approaches to deep brain stimulation (DBS) continue to evolve from awake frame-based to asleep frameless procedures with robotic assistance, primarily directed to optimize operative efficiency, lead accuracy, and patient comfort. Comparison between the 2 is scarce. OBJECTIVE: To analyze the impacts of methodological differences on operative efficiency and stereotactic accuracy using a frame compared with a frameless robotic platform while maintaining the awake state and use of multiple microelectrode recording (MER) trajectories. METHODS: Thirty-four consecutive patients who underwent bilateral awake frameless robot-assisted DBS were compared with a previous cohort of 30 patients who underwent frame-based surgery. Patient demographics, operative times, and MER data were collected for both cohorts. Two-dimensional radial errors of lead placements were calculated. RESULTS: Preoperative setup, surgical, and total operating room times were all significantly greater for the robot-assisted cohort (P < .001). The need for computed tomography imaging when referencing the robotic fiducials led to increased setup duration because of patient transport, unnecessary for the frame-based cohort. Multiple simultaneous MER trajectories increased surgical time (mean 26 min) for the robot-assisted cohort only. The mean radial errors in the robot-assisted and frame cohorts were 0.98 ± 0.66 and 0.74 ± 0.49 mm (P = .03), respectively. CONCLUSION: The use of a truly frameless robotic platform such as the Mazor Renaissance (Mazor Robotics Ltd) presented challenges when implementing techniques used during awake frame-based surgery. Maintaining good accuracy, intraoperative reference imaging, and limited MER trajectories will help integrate frameless robot assistance into the awake DBS surgical workflow.

Deep brain stimulation of the "medial forebrain bundle": a strategy to modulate the reward system and manage treatment-resistant depression.

The medial forebrain bundle-a white matter pathway projecting from the ventral tegmental area-is a structure that has been under a lot of scrutinies recently due to its implications in the modulation of certain affective disorders such as major depression. In the following, we will discuss major depression in the context of being a disorder dependent on multiple relevant networks, the pathological performance of which is responsible for the manifestation of various symptoms of the disease which extend into emotional, motivational, physiological, and also cognitive domains of daily living. We will focus on the reward system, an evolutionarily conserved pathway whose underperformance leads to anhedonia and lack of motivation, which are key traits in depression. In the field of deep brain stimulation (DBS), different "hypothesis-driven" targets have been chosen as the subject of clinical trials on efficacy in the treatment-resistant depressed patient. The "medial forebrain bundle" is one such target for DBS, and has had remarkably rapid success in alleviating depressive symptoms, improving anhedonia and motivation. We will review what we have learned from pre-clinical animal studies on defining this white matter tract, its connectivity, and the complex molecular (i.e., neurotransmitter) mechanisms by which its modulation exerts its effects. Imaging studies in the form of tractographic depictions have elucidated its presence in the human brain. Such has led to ongoing clinical trials of DBS targeting this pathway to assess efficacy, which is promising yet still lack in sufficient numbers. Ultimately, one must confirm the mechanism of action and validate proof of antidepressant effect in order to have such treatment become mainstream, to promote widespread improvement in the quality of life of suffering patients.

A narrative review on invasive brain stimulation for treatment-resistant depression.

While most patients with depression respond to pharmacotherapy and psychotherapy, about one-third will present treatment resistance to these interventions. For patients with treatment-resistant depression (TRD), invasive neurostimulation therapies such as vagus nerve stimulation, deep brain stimulation, and epidural cortical stimulation may be considered. We performed a narrative review of the published literature to identify papers discussing clinical studies with invasive neurostimulation therapies for TRD. After a database search and title and abstract screening, relevant English-language articles were analyzed. Vagus nerve stimulation, approved by the U.S. Food and Drug Administration as a TRD treatment, may take several months to show therapeutic benefits, and the average response rate varies from 15.2-83%. Deep brain stimulation studies have shown encouraging results, including rapid response rates (> 30%), despite conflicting findings from randomized controlled trials. Several brain regions, such as the subcallosal-cingulate gyrus, nucleus accumbens, ventral capsule/ventral striatum, anterior limb of the internal capsule, medial-forebrain bundle, lateral habenula, inferior-thalamic peduncle, and the bed-nucleus of the stria terminalis have been identified as key targets for TRD management. Epidural cortical stimulation, an invasive intervention with few reported cases, showed positive results (40-60% response), although more extensive trials are needed to confirm its potential in patients with TRD.

Surgical Management for Dystonia: Efficacy of Deep Brain Stimulation in the Long Term.

INTRODUCTION: Dystonia is a movement disorder substantially affecting the quality of life. Botulinum Neurotoxin (BoNT) is used intramuscularly as a treatment for dystonia; however, not all dystonia patients respond to this treatment. Deep brain stimulation (DBS) is an established treatment for Parkinson's disease (PD) and essential tremor, but it can help in dystonia as well. OBJECTIVES: We studied a total of 67 dystonia patients who were treated with DBS over a period of 7 years to find out the long-term efficacy of DBS in those patients. First, we calculated patient improvement in post-surgery follow-up programs using the Global Dystonia Severity scale (GDS) and Burke-Fahn-Marsden dystonia rating scale (BFMDRS). Secondly, we analyzed the scales scores to see if there was any statistical significance. METHODS: In our study we analyzed patients with ages from 38 to 78 years with dystonia who underwent DBS surgery between January 2014 and December 2020 in four different centers (India, Kuwait, Egypt, and Turkey). The motor response to DBS surgery was retrospectively measured for each patient during every follow-up visit using the GDS and the BFMDRS scales. RESULTS: Five to 7 years post-DBS, the mean reduction in the GDS score was 30 ± 1.0 and for the BFMDRS score 26 ± 1.0. The longitudinal change in scores at 12 and 24 months post-op was also significant with mean reductions in GDS and BFMDRS scores of 68 ± 1.0 and 56 ± 1.0, respectively. The p-values were <0.05 for our post-DBS dystonia patients. CONCLUSIONS: This study illustrates DBS is an established, effective treatment option for patients with different dystonias, such as generalized, cervical, and various brain pathology-induced dystonias. Although symptoms are not completely eliminated, continuous improvements are noticed throughout the post-stimulation time frame.

Influence of Intraoperative Microelectrode Recording in Deep Brain Stimulation.

BACKGROUND: There is considerable debate regarding the use of intraoperative microelectrode recording (MER) in deep brain stimulation (DBS). OBJECTIVE: To determine if the use of intraoperative MER impacts the final position of the lead implant in DBS of the subthalamic nucleus (STN) and globus pallidus (GPi) and to evaluate the incidence of complications. METHODS: The authors conducted a retrospective chart review of all patients who underwent STN and GPi DBS with MER, at the University of Texas Health Science Center in Houston from June 1, 2009 to October 1, 2013 to compare initial and final coordinates. Hemorrhagic and infectious complications were reviewed. RESULTS: A total of 90 lead implants on 46 patients implanted at the center during this time period were reviewed and included in the study. A statistically significant difference between the initial and final coordinates was observed in the superior-inferior direction with a mean difference of 0.40 mm inferiorly (±0.96 mm, P<0.05) and 0.96 mm inferiorly (±1.32 mm, P<0.05) in the STN and GPi locations, respectively. A nonstatistically significant difference was also observed in the anterior-posterior direction in both locations. There were no intraparenchymal hemorrhages on postoperative computed tomography. Two patients developed postoperative seizures (7.4%). One STN electrode (1.1%) required revision because of a suboptimal response. CONCLUSIONS: Intraoperative MER in STN and GPi DBS implant does not seem to have a higher rate of surgical complications compared with historical series not using MER and might also be useful in determining the final lead location.

Case report of hyperacute edema and cavitation following deep brain stimulation lead implantation.

BACKGROUND: Postoperative cerebral edema around a deep brain stimulation (DBS) electrode is an uncommonly reported complication of DBS surgery. The etiology of this remains unknown, and the presentation is highly variable; however, the patients generally report a good outcome. CASE DESCRIPTION: Here, we report an unusual presentation of postoperative edema in a 66-year-old female who has bilateral dentatorubrothalamic tract (specifically, the ventral intermediate nucleus) DBS for a mixed type tremor disorder. Initial postoperative computed tomography (CT) was unremarkable and the patient was admitted for observation. She declined later on postoperative day (POD) 1 and became lethargic. Stat head CT scan performed revealed marked left-sided peri-lead edema extending into the centrum semiovale with cystic cavitation, and trace right-sided edema. On POD 2, the patient was alert, but with global aphasia, right-sided neglect, and a plegic right upper extremity. Corticosteroids were started and a complete infectious workup was unremarkable. She was intubated and ultimately required a tracheostomy and percutaneous gastrostomy tube. She returned to the clinic 3 months postoperatively completely recovered and ready for battery implantation. CONCLUSION: While this is an unusual presentation of cerebral edema following DBS placement, ultimately, the outcome was good similar to other reported cases. Supportive care and corticosteroids remain the treatment of choice for this phenomenon.

Deep Brain Stimulation of the Pedunculopontine Nucleus Area in Parkinson Disease: MRI-Based Anatomoclinical Correlations and Optimal Target.

BACKGROUND: Experimental studies led to testing of deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) as a new therapy to treat freezing of gait (FOG) in Parkinson disease (PD). Despite promising initial results fueling a growing interest toward that approach, several clinical studies reported heterogeneity in patient responses. Variation in the position of electrode contacts within the rostral brainstem likely contributes to such heterogeneity. OBJECTIVE: To provide anatomoclinical correlations of the effect of DBS of the caudal mesencephalic reticular formation (cMRF) including the PPN to treat FOG by comparing the normalized positions of the active contacts among a series of 11 patients at 1- and 2-yr follow-up and to provide an optimal target through an open-label study. METHODS: We defined a brainstem normalized coordinate system in relation to the pontomesencephalic junction. Clinical evaluations were based on a composite score using objective motor measurements and questionnaires allowing classification of patients as "bad responders" (2 patients), "mild responders" (1 patient) and "good responders" (6 patients). Two patients, whose long-term evaluation could not be completed, were excluded from the analysis. RESULTS: Most effective DBS electrode contacts to treat FOG in PD patients were located in the posterior part of the cMRF (encompassing the posterior PPN and cuneiform nucleus) at the level of the pontomesencephalic junction. CONCLUSION: In the present exploratory study, we performed an anatomoclinical analysis using a new coordinate system adapted to the brainstem in 9 patients who underwent PPN area DBS. We propose an optimal DBS target that allows a safe and efficient electrode implantation in the cMRF.

Medial Forebrain Bundle Deep Brain Stimulation Reverses Anhedonic-Like Behavior in a Chronic Model of Depression: Importance of BDNF and Inflammatory Cytokines.

Deep brain stimulation (DBS) of the medial forebrain bundle (MFB) displays a promising antidepressant effects in patients with treatment-refractory depression; however, a clear consensus on underlying mechanisms is still enigmatic. Herein, we investigated the effects of MFB-DBS on anhedonic-like behavior using the Froot Loops® consumption in a chronic unpredictable mild stress (CUS) model of depression, biochemical estimation of peripheral and central inflammatory cytokines, stress hormone, and brain-derived neurotrophic factor (BDNF). Seven days of MFB-DBS significantly reversed the 42-day CUS-generated anhedonic-like phenotype (p < 0.02) indicated by an increase in Froot Loops® consumption. Gross locomotor activity and body weight remained unaffected across the different groups. A dramatic augmentation of adrenocorticotropic hormone levels was seen in the plasma and cerebrospinal fluid (CSF) samples of CUS rats, which significantly reduced following MFB-DBS treatment. However, C-reactive protein levels were found to be unaffected. Interestingly, decreased levels of BDNF in the CUS animals were augmented in the plasma, CSF, and hippocampus following MFB-DBS, but remained unaltered in the nucleus accumbens (NAc). While multiplex assay revealed no change in the neuronal levels of inflammatory cytokines including IL-1α, IL-4, IL-10, IL-12, IL-13, and IL-17 in the neuroanatomical framework of the hippocampus and NAc, increased levels of IL-1ß, IL-2, IL-5, IL-6, IL-7, IL-18, TNF-α, and INF-γ were seen in these brain structures after CUS and were differentially modulated in the presence of MFB stimulation. Here, we show that there is dysregulation of BDNF and neuroimmune mediators in a stress-driven chronic depression model, and that chronic MFB-DBS has the potential to undo these aberrations.

Comparison of tractography-assisted to atlas-based targeting for deep brain stimulation in essential tremor.

BACKGROUND: Direct targeting of the dentato-rubro-thalamic tract is efficacious in DBS for tremor suppression. OBJECTIVES: We sought to compare outcomes and optimal stimulation parameters for tremor control using the technique of directly targeting the dentato-rubro-thalamic tract to those who underwent indirect targeting of the ventral intermediate nucleus thalamus. METHODS: Twenty consecutive essential tremor patients obtained preoperative diffusion MRIs, where the dentato-rubro-thalamic tract was individually drawn and used to directly target the ventral intermediate nucleus of the thalamus during surgery. These patients were compared to an earlier cohort of 20 consecutive patients who underwent surgery using atlas-based coordinates. Baseline and 1-year postsurgery tremor amplitude using The Essential Tremor Rating Assessment Scale was recorded, as were the parameters needed for successful tremor control. RESULTS: The indirectly targeted group had greater baseline and postop tremor severity relative to those directly targeted (baseline, 2.9 vs. 2.6; P = 0.02; postop, 1.1 vs. 0.8; P = 0.03). Mean voltage, pulse width, and frequency for optimal tremor control in the directly targeted group (38 electrodes) = 2.8 V, 80 µs, 153 Hz; the parameters for the indirectly targeted group (38 electrodes) = 2.9 V, 86 µs, 179 Hz (significantly greater, P < 0.001). Both groups had significant improvement in arm tremor amplitude from baseline (P < 0.001) without sustained side effects. CONCLUSION: Direct targeting of the dentato-rubro-thalamic tract provides excellent tremor control, comparable to indirectly targeting the ventral intermediate nucleus of the thalamus. Use of lower stimulation parameters, especially frequency, to control tremor in the directly targeted group suggests that it is a more efficient targeting methodology, which may minimize battery depletion. © 2018 International Parkinson and Movement Disorder Society.

A longitudinal study on deep brain stimulation of the medial forebrain bundle for treatment-resistant depression.

Deep brain stimulation (DBS) to the superolateral branch of the medial forebrain bundle (MFB) has been reported to lead to rapid antidepressant effects. In this longitudinal study, we expand upon the initial results we reported at 26 weeks (Fenoy et al., 2016), showing sustained antidepressant effects of MFB DBS on six patients with treatment-resistant depression (TRD) over 1 year. The Montgomery-Åsberg Depression Rating Scale (MADRS) was used as the primary assessment tool. Deterministic fiber tracking was used to individually map the target area; analysis was performed to compare modulated fiber tracts between patients. Intraoperatively, upon stimulation at target, responders reported immediate increases in energy and motivation. An insertional effect was seen during the 4-week sham stimulation phase from baseline (28% mean MADRS reduction, p = 0.02). However, after 1 week of initiating stimulation, three of six patients had a > 50% decrease in MADRS scores relative to baseline (43% mean MADRS reduction, p = 0.005). One patient withdrew from study participation. At 52 weeks, four of remaining five patients have > 70% decrease in MADRS scores relative to baseline (73% mean MADRS reduction, p = 0.007). Evaluation of modulated fiber tracts reveals significant common orbitofrontal connectivity to the target region in all responders. Neuropsychological testing and 18F-fluoro-deoxyglucose-positron emission tomography cerebral metabolism evaluations performed at baseline and at 52 weeks showed minimal changes and verified safety. This longitudinal evaluation of MFB DBS demonstrated rapid antidepressant effects, as initially reported by Schlaepfer et al. (2013), and supports the use of DBS for TRD.

Increased dopamine receptor expression and anti-depressant response following deep brain stimulation of the medial forebrain bundle.

BACKGROUND: Among several potential neuroanatomical targets pursued for deep brain stimulation (DBS) for treating those with treatment-resistant depression (TRD), the superolateral-branch of the medial forebrain bundle (MFB) is emerging as a privileged location. We investigated the antidepressant-like phenotypic and chemical changes associated with reward-processing dopaminergic systems in rat brains after MFB-DBS. METHODS: Male Wistar rats were divided into three groups: sham-operated, DBS-Off, and DBS-On. For DBS, a concentric bipolar electrode was stereotactically implanted into the right MFB. Exploratory activity and depression-like behavior were evaluated using the open-field and forced-swimming test (FST), respectively. MFB-DBS effects on the dopaminergic system were evaluated using immunoblotting for tyrosine hydroxylase (TH), dopamine transporter (DAT), and dopamine receptors (D1-D5), and high-performance liquid chromatography for quantifying dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in brain homogenates of prefrontal cortex (PFC), hippocampus, amygdala, and nucleus accumbens (NAc). RESULTS: Animals receiving MFB-DBS showed a significant increase in swimming time without alterations in locomotor activity, relative to the DBS-Off (p<0.039) and sham-operated groups (p<0.014), indicating an antidepressant-like response. MFB-DBS led to a striking increase in protein levels of dopamine D2 receptors and DAT in the PFC and hippocampus, respectively. However, we did not observe appreciable differences in the expression of other dopamine receptors, TH, or in the concentrations of dopamine, DOPAC, and HVA in PFC, hippocampus, amygdala, and NAc. LIMITATIONS: This study was not performed on an animal model of TRD. CONCLUSION: MFB-DBS rescues the depression-like phenotypes and selectively activates expression of dopamine receptors in brain regions distant from the target area of stimulation.