Deep brain stimulation (DBS) of the subcallosal cingulate white matter has shown promise as an intervention for patients with chronic, unremitting depression. To test the safety and efficacy of DBS for treatment-resistant depression, a prospective, randomised, sham-controlled trial was conducted.
Methods
Participants with treatment-resistant depression were implanted with a DBS system targeting bilateral subcallosal cingulate white matter and randomised to 6 months of active or sham DBS, followed by 6 months of open-label subcallosal cingulate DBS. Randomisation was computer generated with a block size of three at each site before the site started the study. The primary outcome was frequency of response (defined as a 40% or greater reduction in depression severity from baseline) averaged over months 4–6 of the double-blind phase. A futility analysis was performed when approximately half of the proposed sample received DBS implantation and completed the double-blind phase. At the conclusion of the 12-month study, a subset of patients were followed up for up to 24 months. The study is registered at ClinicalTrials.gov, number NCT00617162.
Findings
Before the futility analysis, 90 participants were randomly assigned to active (n=60) or sham (n=30) stimulation between April 10, 2008, and Nov 21, 2012. Both groups showed improvement, but there was no statistically significant difference in response during the double-blind, sham-controlled phase (12 [20%] patients in the stimulation group vs five [17%] patients in the control group). 28 patients experienced 40 serious adverse events; eight of these (in seven patients) were deemed to be related to the study device or surgery.
Interpretation
This study confirmed the safety and feasibility of subcallosal cingulate DBS as a treatment for treatment-resistant depression but did not show statistically significant antidepressant efficacy in a 6-month double-blind, sham-controlled trial. Future studies are needed to investigate factors such as clinical features or electrode placement that might improve efficacy.
Funding
Abbott (previously St Jude Medical).
Introduction
Brodmann area 25 (BA25) within the subcallosal cingulate has been strongly implicated in the pathophysiology of treatment-resistant depression.1 In patients with depression who respond to antidepressant treatments, BA25 activity shows a consistent change associated with antidepressant response. However, in patients with treatment-resistant depression, BA25 activity does not change with adequate antidepressant treatment compared with treatment responders. Anatomically, BA25 shows a pattern of structural connectivity that supports its role in the pathophysiology of depression and treatment-resistant depression, with monosynaptic connections to the medial prefrontal cortex, perigenual and dorsal anterior cingulate gyri, hippocampus, amygdala, ventral striatum, thalamus, hypothalamus, and monoaminergic nuclei within the brainstem.1 Therefore, direct modulation of BA25, and especially its white matter connections to other brain regions involved in depression, is a potential treatment approach for patients with treatment-resistant depression.
Deep brain stimulation (DBS) of the subcallosal cingulate white matter has shown promising safety and efficacy for patients with treatment-resistant depression.2, 3, 4, 5, 6, 7, 8, 9 Open-label, chronic, high-frequency (>100 Hz) subcallosal cingulate DBS has demonstrated response at 6 months in about 50% of patients and long-term remission (for 2–6 years) in about 50% of patients.4, 5, 6, 7, 10 Patients enrolled in these studies were highly treatment resistant (typically not responding to at least four antidepressant medications in the current episode, and no consistent response to psychotherapy or electroconvulsive therapy), chronically depressed (average episode duration of about 5 years), and severely ill due to their treatment-resistant depression, with the vast majority effectively disabled. These preliminary findings are clinically meaningful and compare favourably to response and remission rates in patients with treatment-resistant depression receiving treatment as usual, or other neuromodulation interventions or ablative procedures such as cingulotomy.11, 12, 13, 14, 15, 16, 17 Given these encouraging open-label data, a prospective, randomised, double-blind, sham-controlled trial of subcallosal cingulate DBS for treatment-resistant depression was conducted. It was hypothesised that 6 months of subcallosal cingulate DBS would be associated with statistically significant antidepressant efficacy compared with sham stimulation.
Research in context
Evidence before this study
We searched PubMed from Jan 1, 2005, to Dec 31, 2016, with the terms “deep brain stimulation”, “DBS”, “depression”, and “psychiatric”. Additionally, we reviewed proceedings of relevant conferences since 2003, including the Society of Biological Psychiatry, American College of Neuropsychopharmacology, and American Society for Stereotactic and Functional Neurosurgery. Multiple open-label reports of deep brain stimulation (DBS) of various brain targets were identified. The target with the most data supporting safety and preliminary efficacy was the subcallosal cingulate white matter.
Added value of this study
To our knowledge, this trial is the first randomised, double-blind, sham-controlled study of subcallosal cingulate DBS for treatment-resistant depression. Also, to date, it is the largest study of DBS for any psychiatric disorder. Although the sham-controlled study is negative, these findings, including the long-term follow-up data, could provide guidance for further investigation of DBS as a potential treatment for severe, refractory depression.
Implications of all the available evidence
Open-label studies of subcallosal cingulate DBS have demonstrated sustained response and remission rates that are clinically significant and greater than would be expected with treatment as usual. The open-label component of this trial is consistent with this past experience, with a high long-term response rate with ongoing stimulation with optimised parameter changes. Although the controlled phase of this study was negative, it is notable that the sample on average had more chronic depression than in previous studies, which could provide an explanation for the negative 6 month, placebo-controlled results. Additionally, since this trial was initiated, a proof-of-concept study has demonstrated that individualised targeting using diffusion tensor imaging could significantly improve the efficacy of subcallosal cingulate DBS for depression. Taken together, the available evidence strongly supports further investigation of DBS of the subcallosal cingulate white matter as a potential therapy for treatment-resistant depression, a highly prevalent and disabling medical condition.
A 6 month, multicentre, randomised, double-blind, sham-controlled trial was conducted to evaluate the safety and efficacy of subcallosal cingulate DBS (Libra XP Deep Brain Stimulation System; St Jude Medical, Plano, TX, USA) for patients with treatment-resistant depression. A 6-month open-label phase followed the double-blind phase. Planned enrolment was 201 participants randomised at up to 20 sites.
Inclusion criteria included: men and women aged 21–70 years; unipolar, non-psychotic major depressive disorder diagnosed before age 45 years with a current episode at least 12 months in duration; lack of antidepressant response (via medical or pharmacy records) to a minimum of four adequate antidepressant treatments, including at least three medications from three different classes, evidence-based psychotherapy, or electroconvulsive therapy; lack of sustained response to a course of psychotherapy; Montgomery-Åsberg Depression Rating Scale (MADRS) score more than 22 at each of three separate baseline visits, rated by two separate psychiatrists (baseline visits 2 and 3 separated by no more than 6 weeks), and eligible participants must have demonstrated absence of notable improvement (≤20% lessening of MADRS score) between these visits; Global Assessment of Function (GAF) score less than 50; Mini-Mental State Examination (MMSE) score more than 24; medication free or current antidepressant or psychotropic medication regimen stable for at least 4 weeks before study entry; and able and willing to give written informed consent.
Exclusion criteria included: bipolar or psychotic disorder; obsessive compulsive disorder; post-traumatic stress disorder; panic disorder; bulimia or anorexia nervosa; generalised anxiety disorder as the primary diagnosis during the current depressive episode; substance use disorder (excluding caffeine or nicotine) within the past 12 months; borderline or antisocial personality disorder; substantial risk of suicide; received electroconvulsive therapy within 3 months before enrolment, or likely to require electroconvulsive therapy during the study; CNS disease impairing motor, sensory, or cognitive function or requiring intermittent or chronic medication; fibromyalgia, chronic fatigue syndrome, or current condition requiring chronic narcotic use; unstable, uncontrolled medical illness; past ablative or other intracranial surgery; contraindication to MRI scanning; contraindication to general anaesthesia or DBS surgery; pregnant, intending to get pregnant during the study, or breastfeeding; currently participating in another investigational device, drug, or surgical trial; or unable to comply with study visit schedule and timeline.
Participants could continue psychotherapy and medications during the study but were required to maintain a stable medication regimen as well as regularly scheduled psychotherapy visits. Medication changes or the initiation of psychotherapy were not allowed during the 6-month double-blind phase. Minor adjustments to sedative, hypnotic, and anxiolytic medications were allowed.
Study procedures were approved by the institutional review board at each site and the US Food and Drug Administration under an investigational device exemption (G070107, sponsored by St Jude Medical). The study was monitored by an independent data and safety monitoring board, and all participants gave written informed consent.
Potential participants were screened according to the eligibility criteria. At least 2 years of medical records were reviewed. Potential participants were given a detailed informed consent document, had an initial screening, and completed three baseline evaluations. These evaluations occurred no less than 2 weeks apart from each other, and baseline visits 2 and 3 were not separated by more than 6 weeks. The first two baseline visit evaluations were performed by independent psychiatrists. Baseline assessments included the MADRS; the 17-item Hamilton Depression Rating Scale (HRSD-17); the Self-Rated Quick Inventory of Depressive Symptomatology (QIDS-SR); subsection for cluster B personality disorder of the structured Clinical Interview for DSM-IV Personality Disorders (SCID-II); Systematic Assessment for Treatment Emergent Events (SAFTEE); the 30-item Inventory of Depressive Symptomatology (IDS-C30); the Young Mania Rating Scale (YMRS); the Work and Social Adjustment Scale (WSAS); GAF; the short-form Quality of Life Enjoyment and Satisfaction Questionnaire (QOL); Clinical Global Impression of Severity and Improvement (CGI); Patient Global Impression Index (PGI); Health and Labor Questionnaire (HLQ); Hamilton Anxiety Rating Scale (HAM-A); and Columbia Suicide Severity Rating Scale (C-SSRS). After the baseline visit was completed, the lead study psychiatrist (PEH) performed an external review of the participants' data to ensure eligibility. After the third baseline visit, a neuropsychological battery was administered to assess attention, working memory, and other executive functions. A high-resolution MRI scan and presurgical evaluation were also performed.
The DBS system consisted of two leads, extension wires, and an implantable pulse generator. Each DBS lead consisted of a four-electrode array with a 3 mm electrode at the tip and three 1·5 mm electrodes, each separated by 1·5 mm. At least two of three experts (HSM, CH, PEH) manually selected and agreed on the optimal surgical target, defined as a region in the subcallosal cingulate white matter approximately 75% of the distance from the anterior commissure to the plane defined by the grey matter edge of the genu of the corpus callosum and in the transition from the white matter to the grey matter in the medial–lateral axis.2, 3, 18 Target selection was done in native MRI space (ie, not in an atlas-defined space) and involved identifying a target region at the area of transition between grey and white matter in the subcallosal cingulate gyrus. Optimal target location was provided to the site neurosurgeon to assist with surgical targeting, and each neurosurgeon was trained on targeting by a team of experts (HSM, CH, AML).
Bilateral DBS system implantation occurred no less than 2 weeks and no more than 4 weeks after the final baseline evaluation using the standard stereotactic surgical procedures at each site. Impedance of the system was tested intraoperatively, but no stimulation was delivered during surgery.
Postoperative CT was obtained to assess for intracranial haemorrhage and lead localisation. The postoperative CT scan was then merged with the preoperative high-resolution MRI used for initial target selection. At least two of three expert consultants (HSM, CH, PEH) reviewed these merged images and selected an optimal contact sequence for chronic monopolar stimulation. The first contact chosen was the one in closest proximity to the predefined target, and the second contact chosen was the one in the next closest proximity to the predefined target. No participant had more than two contacts within the predefined target region. Four participants had an additional surgery to reposition the leads due to the leads not being in the ideal target region; in all cases, this repositioning occurred before randomisation. Post-operative CT scans were merged with baseline MRI scans.
Approximately 2 weeks after device implantation, participants were randomly assigned to receive immediate active stimulation (stimulation group) or 6-month delayed stimulation (sham group) in a 2:1 ratio. Randomisation was computer generated (SAS version 9.2) with a block size of three at each site before the site started the study. At each site, an unblinded DBS programmer was informed of treatment allocation; all other team members and patients were masked to treatment allocation.
For participants randomised to the stimulation group, stimulation was initiated at the completion of the randomisation visit (week 2 following implantation). Initial parameters included monopolar stimulation at the optimal first contact selected on each side at 130 Hz, 91 microsecond pulse width, 4 mA. For patients in the control group, a sham programming session was done, but stimulation was not initiated. Participants were not formally assessed for whether they had acute effects from stimulation.
For participants receiving active stimulation, programming changes were made on the basis of change in MADRS from the previous rating. 2 weeks after the initial programming session, no parameter changes were made if the MADRS score reduction was 10% or more from the previous evaluation. If the MADRS value was less than 10% lower than that on the previous evaluation, amplitude was increased to 6 mA. After another 4 weeks (if the MADRS was again <10% lower than that from the previous evaluation), the amplitude was increased to 8 mA. After another 4 weeks, if the MADRS was again less than 10% lower than that from the previous evaluation, the second contact from the preselected contact sequence would be added for monopolar stimulation (ie, the patient would have two contacts providing active monopolar [8 mA] stimulation in each hemisphere). If intolerable side-effects occurred after a parameter change, parameters were returned to the previous settings. No modifications were allowed in pulse width or frequency. No further parameter changes were allowed beyond 10 weeks following initiation of stimulation. Participants randomly assigned to sham had similar programming visits, but stimulation remained off during the double-blind phase.
After randomisation, participants returned for evaluations at weeks 4, 6, and 8, then every month until the 6-month endpoint. At each visit, the following evaluations were completed: MADRS; SAFTEE; DBS programming form; IDS-C30; QIDS-SR; WSAS; GAF; CGI; PGI; HAM-A; and C-SSRS. At the 3-month and 6-month visits, the following additional evaluations were completed: HRSD-17; YMRS; QOL; and HLQ. The neuropsychological battery was repeated at the 6-month visit. Outside of regularly scheduled, in-person assessments, each patient was contacted by phone or in person by study personnel every 1–2 weeks to assess for safety. Participants experiencing worsening of suicidal ideation could remain in the study if stability (so-called rescue) could be achieved within 7 days. Participants experiencing a 25% or greater worsening in MADRS score from baseline were considered treatment failures and either enrolled in the open-label or long-term follow-up study (depending on whether or not they were already receiving active stimulation) or exited from the study.
Following the 6-month double-blind phase, participants entered the 6-month open-label phase. All participants in the control group had stimulation initiated at this time with the algorithm used for contact and parameter selection and changes as described above for the active treatment group. Participants in the stimulation group continued with active stimulation. In the open-label phase, patients and study staff (except the unblinded programmer) were not provided any information about randomisation status during the first 6 months of the study. At each monthly visit, the following evaluations were completed: DBS programming form; MADRS; IDS-C30; QIDS-SR; WSAS; GAF; CGI; PGI; HAM-A; and C-SSRS. At the 9-month and 12-month visits, the following additional evaluations were completed: SAFTEE; YMRS; QOL; and HLQ. The neuropsychological battery was performed again at the 12-month visit. Parameter adjustments were constrained as described above. Changes in medications and psychotherapy were allowed in this open-label phase.
Participants completing the 12-month study were invited to continue in a long-term, naturalistic follow-up study. Study visits occurred every 6 months. Changes in stimulation parameters, medications, and psychotherapy were allowed. For patients continuing with chronic DBS, a rechargeable battery was provided as needed.
The primary efficacy endpoint for the study was defined as difference in proportion of patients achieving a response between the stimulation and control groups. Response was defined as a 40% or greater reduction in MADRS and no worsening in GAF from baseline (average of three baseline MADRS assessments) to the average scores at months 4, 5, and 6. The average of months 4, 5, and 6 was chosen as the primary endpoint due to the aim to assess for a sustained change over time. Secondary measures of efficacy included changes from baseline to endpoint for HRSD-17, IDS-C30, QIDS-SR, WSAS, PGI, CGI, QOL, and HAM-A. For the 6-month open-label and long-term follow-up studies, response was defined as a 40% or greater reduction in MADRS from the baseline average to the score at the timepoint of interest (eg, 12 months, 18 months, 24 months). Remission at all timepoints was defined as a MADRS score of 10 or lower.
The occurrence of all adverse events (eg, suicidal ideation or behaviour, unanticipated medical treatment for psychiatric reasons, device-related events, and hospital admission due to worsening depression) across the study duration was used as the primary safety endpoint for the study.
On the basis of preliminary data,7 response in 40% or greater of patients was anticipated for the group assigned to active subcallosal cingulate DBS, with response in 18·5% or fewer of patients in the control group expected.12 Therefore, 159 participants randomised in a 2:1 ratio (106 in the active group and 53 in the sham group) would provide 80% power to reject the primary efficacy null hypothesis at a 5% significance level. Sample size calculations were performed based on the Z test method with pooled variance using PASS 2005. To allow for a dropout rate as high as 20%, the sample size for recruitment was increased to 201 participants (134 in the active stimulation group and 67 in the sham stimulation group).
For analysis of the primary outcome, participants who were missing one or two of the assessments at months 4, 5, or 6 had data from the available visits used. Participants missing MADRS scores for months 4, 5, and 6 were considered non-responders. A logistic regression model including effects of treatment group, study site, level of treatment resistance (as defined by Antidepressant Treatment History Form criteria), and baseline MADRS was fitted. Data from study sites with fewer than three participants in either treatment group were pooled. The primary outcome was assessed in all randomly allocated participants except for those who exited the study before month 6. In approving this study, the US Food and Drug Administration required a futility analysis be completed once at least 75 participants had reached the primary endpoint by either completing the month 6 visit or exiting the study. No more than 125 participants could be enrolled before the futility analysis. The futility analysis was performed using the average of the revised alternative hypothesis and the observed interim results. With the estimated sample size of 201 participants, the alternative hypothesis was response in 40% of participants receiving active stimulation and 20·7% of participants receiving sham (the proportions providing 80% power to reject the primary hypothesis given the smaller sample size at the time of the futility analysis). On the basis of these revised population proportions, 5000 sets of simulation results among the remaining approximately 84 stimulation participants and 42 control group participants were run. Each set of simulated results was added to the observed results, and a two-tailed Fisher's exact p value was calculated. The probability of a successful outcome of the study was the proportion of these p values less than 0·05. If the probability of a successful study outcome was less than 10%, the study would be stopped for futility. Additionally, the study could be stopped at the sponsor's discretion, even if this formal definition for futility was not met.
Abbott (previously known as St Jude Medical) financially supported the study, contributed to the design and conduct of the study, and contributed to the collection, monitoring, and management of the data. PEH and HSM had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Section snippets
Results
A total of 128 participants were enrolled (ie, signed informed consent) from 15 investigational sites before the completion of the futility analysis between April 10, 2008, and Nov 21, 2012 (figure 1). Of the 128 participants enrolled into the study, only 90 from 13 investigational sites received DBS system implantation and were randomly assigned to treatment. Of these participants, 60 were randomly assigned to active stimulation, and 30 were randomly assigned to sham stimulation. There were no
Discussion
This study helps confirm the feasibility and safety of subcallosal cingulate DBS as a treatment for patients with treatment-resistant depression. However, this study did not demonstrate that 6 months of active versus sham stimulation was associated with statistically significant antidepressant effects. Additionally, participants initially treated with sham stimulation during the first 6 months of the study did not show statistically significant antidepressant benefit with an additional 6 months
Closed-loop deep brain stimulation (DBS) system offers a promising approach for treatment-resistant depression, but identifying universally accepted electrophysiological biomarkers for closed-loop DBS systems targeting depression is challenging. There is growing evidence suggesting a strong association between the lateral habenula (LHb) and depression. Here, we took LHb as a key target, utilizing multi-site local field potentials (LFPs) to study the acute and chronic changes in electrophysiology, functional connectivity, and brain network characteristics during the formation of a chronic restraint stress (CRS) model. Furthermore, our model combining the electrophysiological changes of LHb and interactions between LHb and other potential targets of depression can effectively distinguish depressive states, offering a new way for developing effective closed-loop DBS strategies.
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.
To review successful and unsuccessful DBS clinical trials and identify factors associated with early trial termination.
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.
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.
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.
A seminal study found higher subgenual frontal cortex resting-state connectivity with 2 left ventral frontal regions and the dorsal midbrain to predict better response to psychotherapy versus medication in individuals with treatment-naïve major depressive disorder (MDD). Here, we examined whether these subgenual networks also play a role in the pathophysiology of clinical outcomes in MDD with early treatment resistance in primary care.
Forty-five people with current MDD who had not responded to ≥2 serotonergic antidepressants (n = 43, meeting predefined functional magnetic resonance imaging minimum quality thresholds) were enrolled and followed over 4 months of standard care. Functional magnetic resonance imaging resting-state connectivity between the preregistered subgenual frontal cortex seed and 3 previously identified left ventromedial, ventrolateral prefrontal/insula, and dorsal midbrain regions was extracted. The clinical outcome was the percentage change on the self-reported 16-item Quick Inventory of Depressive Symptomatology.
We observed a reversal of our preregistered hypothesis in that higher resting-state connectivity between the subgenual cortex and the a priori ventrolateral prefrontal/insula region predicted favorable rather than unfavorable clinical outcomes (rs39 = −0.43, p = .006). This generalized to the sample including participants with suboptimal functional magnetic resonance imaging quality (rs43 = −0.35, p = .02). In contrast, no effects (rs39 = 0.12, rs39 = −0.01) were found for connectivity with the other 2 preregistered regions or in a whole-brain analysis (voxel-based familywise error–corrected p < .05).
Subgenual connectivity with the ventrolateral prefrontal cortex/insula is relevant for subsequent clinical outcomes in current MDD with early treatment resistance. Its positive association with favorable outcomes could be explained primarily by psychosocial rather than the expected pharmacological changes during the follow-up period.
Treatment-resistant depression (TRD) occurs more commonly in women. Deep brain stimulation (DBS) is an emerging treatment for TRD, and its efficacy continues to be explored. However, differences in treatment outcomes between males and females have yet to be explored in formal analysis.
A PRISMA-compliant systematic review of DBS for TRD studies was conducted. Patient-level data were independently extracted by two authors. Treatment response was defined as a 50 % or greater reduction in depression score. Percent change in depression scores by gender were evaluated using random-effects analyses.
Of 737 records, 19 studies (129 patients) met inclusion criteria. The mean reduction in depression score for females was 57.7 % (95 % CI, 64.33 %–51.13 %), whereas for males it was 35.2 % (95 % CI, 45.12 %–25.23 %) (p < 0.0001). Females were more likely to respond to DBS for TRD when compared to males (OR = 2.44, 95 % CI 1.06, 1.95). These differences varied in significance when stratified by DBS anatomical target, age, and timeframe for responder classification.
Studies included were open-label trials with small sample sizes.
Our findings suggest that females with TRD respond at higher rates to DBS treatment than males. Further research is needed to elucidate the implications of these results, which may include connectomic sexual dimorphism, depression phenotype variations, or unrecognized symptom reporting differences. Methodological standardization of outcome scales, granular demographic data, and individual subject outcomes would allow for more robust comparisons between trials.
Deep brain stimulation (DBS) is currently under investigation as a potential therapeutic approach for managing major depressive disorder (MDD) and ventromedial prefrontal cortex (vmPFC) is recognized as a promising target region. Therefore, the present study aimed to investigate a preclinical paradigm of bilateral vmPFC DBS and examine the molecular mechanisms underlying its antidepressant-like effects using chronic unpredictable stress (CUS) model in rats.
Male rats were subjected to stereotaxic surgery and deep brain stimulation paradigm in non-stressed and CUS rats respectively, and the therapeutic effect of DBS were assessed by a series of behavioral tests including sucrose preference test, open field test, elevated plus maze test, and forced swim test. The potential involvement of the BDNF/TrkB signaling pathway and its downstream effects in this process were also investigated using western blot.
We identified that a stimulation protocol consisting of 130 Hz, 200 μA, 90 μs pulses administered for 5 h per day over a period of 7 days effectively mitigated CUS-induced depressive-like and anxiety-like behaviors in rats. These therapeutic effects were associated with the enhancement of the BDNF/TrkB signaling pathway and its downstream ERK1/2 activity.
These findings provide valuable insights into the potential clinical utility of vmPFC DBS as an approach of improving the symptoms experienced by individuals with MDD. This evidence contributes to our understanding of the neurobiological basis of depression and offers promise for the development of more effective treatments.
