Critically Assessing the Unanswered Questions of How, Where, and When to Induce Plasticity in the Posttraumatic Stress Disorder Network with Transcranial Magnetic Stimulation.

Extinction of traumatic memory, a primary treatment approach (termed exposure therapy) in post-traumatic stress disorder (PTSD), occurs through relearning and may be subserved at the molecular level by long-term potentiation (LTP) of relevant circuits. In parallel, repetitive transcranial magnetic stimulation (rTMS) is thought to work through LTP-like mechanisms and may provide a novel, safe, and effective treatment for PTSD. Our recent failed randomized controlled trial (1) emphasizes the necessity of correctly identifying cortical targets, directionality of TMS protocol, and role of memory activation. Here we provide a systematic review of TMS for PTSD to further identify how, where, and when TMS treatment should be delivered to alleviate PTSD symptoms. We conducted a systematic review of the literature searching for rTMS clinical trials involving PTSD patients and outcomes. We searched MEDLINE through October 25th, 2023 for "TMS and PTSD" and "transcranial magnetic stimulation and posttraumatic stress disorder." Thirty-one publications met our inclusion criteria (k=17 randomized controlled trials (RCTs), k=14 open label). RCT protocols were varied in TMS protocols, cortical TMS targets, and memory activation protocols. There was no clear superiority across protocols of low-frequency (k=5) vs. high-frequency protocols (k=6), or by stimulation location. Memory provocation or exposure protocols (k=7) appear to enhance response. Overall, TMS appears to be effective in treating PTSD symptoms across a variety of TMS frequencies, hemispheric target differences, and exposure protocols. Disparate protocols may be conceptually harmonized when viewed as potentiating proposed anxiolytic networks or suppressing anxiogenic networks.

Behavioral and Functional Brain Activity Alterations Induced by TMS Coils with Different Spatial Distributions.

Previous investigation of cognitive processes using transcranial magnetic stimulation (TMS) have explored the response to different stimulation parameters such as frequency and coil location. In this study, we attempt to add another parameter by exploiting the spatial profiles of TMS coils to infer regional information concerning reward-related behavior. We used different TMS coils to modulate activity in the prefrontal cortex (PFC) and examined resulting changes in behavior and associated brain activity. More specifically, we used the Figure-8 coil to stimulate a portion of the dorsolateral PFC (DLPFC) and the H-Coil to stimulate a larger volume within the lateral PFC (LPFC). Healthy human volunteers completed behavioral questionnaires (n = 29) or performed a reward-related decision-making functional MRI (fMRI) task (n = 21) immediately before and after acute high-frequency stimulation (10 Hz) with either a Figure-8 coil, H-Coil, or a sham coil. Stimulation was found to induce behavioral changes as well as changes in brain activation in key nodes of the reward network. Right LPFC, but not right DLPFC or sham, stimulation was found to induce changes in both behavioral scores and brain activation in key nodes of the reward system. In conclusion, this study supports the role of the right LPFC in reward-related behavior and suggest that the pathways through which the observed effects were generated are located outside the area of the DLPFC that is traditionally targeted with TMS. These results demonstrate the use of TMS coils with different spatial profiles as an informative tool to investigate anatomic and functional correlates of behavior.

A randomized sham controlled comparison of once vs twice-daily intermittent theta burst stimulation in depression: A Canadian rTMS treatment and biomarker network in depression (CARTBIND) study.

BACKGROUND: Intermittent theta burst stimulation (iTBS) is a newer form of repetitive transcranial magnetic stimulation (rTMS) for patients with treatment resistant depression (TRD). Applying multiple daily iTBS sessions may enable patients to achieve remission more rapidly. OBJECTIVE: We compared the efficacy and tolerability of a twice-daily versus once-daily iTBS protocol in patients with TRD. We hypothesized that twice-daily iTBS would result in a greater improvement in depression scores compared to once-daily iTBS. METHODS: 208 participants (131 females) with TRD were randomized to receive either iTBS (600 pulses) delivered twice-daily with a 54-min interval between treatments or once-daily (1200 pulses) with 1 sham treatment with the same interval between treatments, to ensure equal levels of daily therapeutic contact and blinding of patients and raters. The primary outcome measure was change in depression scores on the Hamilton Rating Scale for Depression (HRSD-17) after 10 days of treatment and 30 days of treatments. RESULTS: HRSD-17 scores improved in both the twice-daily and once-daily iTBS groups; however, these improvements did not significantly differ between the two groups at either the 10-day or 30-day timepoints. Response and remission rates were low (<10%) in both groups after 10 days and consistent with prior reports at 30 days; these rates did not differ between the treatment groups. CONCLUSIONS: These results suggest that twice-daily iTBS does not accelerate response to iTBS and is not different from once-daily treatment in terms of improving depressive symptoms in patients with TRD. Clinicaltrials.gov ID: NCT02729792 (https://clinicaltrials.gov/ct2/show/NCT02729792).

Deep Transcranial Magnetic Stimulation Combined With Brief Exposure for Posttraumatic Stress Disorder: A Prospective Multisite Randomized Trial.

BACKGROUND: Posttraumatic stress disorder (PTSD) is both prevalent and debilitating. While deep transcranial magnetic stimulation (dTMS) has shown preliminary efficacy, exposure therapy remains the most efficacious, though limited, treatment in PTSD. The medial prefrontal cortex (mPFC) is implicated in extinction learning, suggesting that concurrent mPFC stimulation may enhance exposure therapy. In this randomized controlled multicenter trial, the efficacy and safety of mPFC dTMS combined with a brief exposure procedure were studied in patients with PTSD. METHODS: Immediately following exposure to their trauma narrative, 125 outpatients were randomly assigned to receive dTMS or sham. Twelve sessions were administered over 4 weeks, with a primary end point of change in 5-week Clinician-Administered PTSD Scale for DSM-5 score. This clinical study did not include biological markers. RESULTS: Clinician-Administered PTSD Scale for DSM-5 score improved significantly in both groups at 5 weeks, though the improvement was smaller in the dTMS group (16.32) compared with the sham group (20.52; p = .027). At 9 weeks, improvement continued in Clinician-Administered PTSD Scale for DSM-5 score in both groups but remained smaller in dTMS (19.0) versus sham (24.4; p = .024). CONCLUSIONS: Both groups showed significant PTSD symptom improvement, possibly from the brief script-driven imagery exposure. While our design was unable to rule out placebo effects, the magnitude and durability of improvement suggest that repeated ultrabrief exposure therapy alone may be an effective treatment for PTSD, warranting additional study. The surprising and unexpected effect in the dTMS group also suggests that repeated mPFC stimulation with the H7 coil may interfere with trauma memory-mediated extinction. Our results provide new insight for dTMS approaches for possible future avenues to treat PTSD.

Electroconvulsive therapy with a memory reactivation intervention for post-traumatic stress disorder: A randomized controlled trial.

BACKGROUND: Post-traumatic Stress Disorder (PTSD) often does not respond to available treatments. Memories are vulnerable to disruption during reconsolidation, and electroconvulsive therapy (ECT) has amnestic effects OBJECTIVE/HYPOTHESIS: To test the use of ECT to disrupt the reconsolidation of traumatic memories as a potential treatment for PTSD METHODS: Participants were adults from the civilian population and were referred for ECT treatment for severe depression with comorbid PTSD symptoms. Twenty-eight participants were randomly assigned to reactivation of a traumatic or non-traumatic memory using audio script driven imagery prior to each ECT treatment. Primary outcomes were change in scores on the Modified PTSD Symptom Scale - Self Report (MPSS-SR) and the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5). Secondary outcomes included a comparison of the change in heart rate while listening to the script RESULTS: Twenty-five female patients who completed a post-ECT assessment were included in the analysis. No significant group differences were found in the MPSS-SR or CAPS-5 scores from pre-ECT to post-ECT or 3-month follow-ups. However, both groups improved at post-ECT and 3-month follow up. Partial eta squared estimates of effect size showed large effect sizes for all outcomes (η2 > 0.13). Changes in heart rate were not significantly different between groups or over time CONCLUSIONS: ECT paired with pre-treatment traumatic memory reactivation was not more effective for treating PTSD symptoms than ECT with non-traumatic memory reactivation. While our primary hypothesis was not supported, our data provides further support for the efficacy of ECT for improving symptoms of PTSD with comorbid depression. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04027452. IDENTIFIER: NCT04027452.

Clinical Effectiveness of Maintenance Electroconvulsive Therapy in Patients with Schizophrenia: A Retrospective Cohort Study.

OBJECTIVE: This study aimed to assess the clinical effectiveness and cognitive effects of maintenance electroconvulsive therapy (mECT) in patients with schizophrenia or schizoaffective disorder and explore factors associated with both outcomes. METHODS: In this retrospective cohort study, we examined clinical records of 47 patients with a Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) diagnosis of schizophrenia or schizoaffective disorder treated with mECT at an academic mental health hospital between April 2010 and July 2016. Sixty-two mECT courses were reviewed. We assessed clinical effectiveness and cognitive effects as well as factors associated with response to treatment, including psychiatric diagnosis, concomitant pharmacological treatment, and previous treatment response. RESULTS: Maintenance electroconvulsive therapy was able to maintain clinical response in 48 (77%) treatment courses. Significant cognitive adverse effects were reported in 7 (11%) of the courses. Use of antipsychotic, antidepressant or benzodiazepine medications, psychiatric disorder, and sex were not associated with response. CONCLUSION: This study shows meaningful clinical effectiveness and good tolerability of mECT in patients with resistant schizophrenia over extended periods.

Simple Electroencephalographic Treatment-Emergent Marker Can Predict Repetitive Transcranial Magnetic Stimulation Antidepressant Response-A Feasibility Study.

OBJECTIVES: Prefrontal repetitive transcranial magnetic stimulation (rTMS) repeated daily for 4 to 6 weeks is used to treat major depressive disorder, but more than 50% of patients do not achieve significant response. Here we test the validity of a simple electroencephalographic (EEG) marker that predicts nonresponse to rTMS. Such a marker could potentially increase rTMS effectiveness by directing nonresponders to alternative treatments or by guiding early modification of stimulation parameters. METHODS: We retrospectively analyzed 2-channel EEG data captured in the OPT-TMS National Institute of Mental Health-sponsored, multicenter study. Cumulative Brain Engagement Index (cBEI), a measure derived from template matching that allows scoring EEG dynamics along treatment, was computed. RESULTS: Six hundred sixty-five EEG recordings were analyzed. In the rTMS group, the median cBEI was found to increase in the responder group but remained unchanged in the nonresponder group. The difference between the cBEI of the groups became statistically significant by the third valid EEG sample. Within 5 samples, 91% of the responders presented with a cBEI above a preset threshold. Within 9 samples, 17% of the nonresponders had a cBEI above the threshold. CONCLUSIONS: This study demonstrates the feasibility of a simple-to-capture EEG marker as a treatment-emergent marker of response to rTMS treatment of depression. In the OPT-TMS study, discontinuing treatment when the cBEI dropped below the threshold between the fifth to ninth treatment potentially could have avoided administration of 485 (63%) of 765 treatments. Because the marker can be generated online, it would be of interest to evaluate, in future studies, whether it could be used to tune treatment parameters and improve remission rates.

Bilateral Repetitive Transcranial Magnetic Stimulation Decreases Suicidal Ideation in Depression.

OBJECTIVE: The purpose of this study was to evaluate the effects of repetitive transcranial magnetic stimulation (rTMS) on suicidal ideation in patients with treatment-resistant major depression (TRD) (patients who failed to clinically respond to at least 2 medication trials). METHODS: We pooled data from 2 published prospective randomized controlled trials of rTMS applied to the dorsolateral prefrontal cortex in patients with TRD. We compared the effect of bilateral, left unilateral, and sham rTMS on suicidal ideation as measured by the suicide item of the 17-item Hamilton Depression Rating Scale (HDRS) (N = 156). RESULTS: Suicidal ideation resolved in 40.4%, 26.8%, and 18.8% of participants randomized to bilateral, left unilateral, and sham rTMS, respectively. The difference between bilateral and sham was significant (OR = 3.03; 95% CI, 1.19-7.71; P = .02), unlike the difference between left unilateral and sham (OR = 1.59; 95% CI, 0.61-4.12; P = .33). There was a modest correlation between change in suicidal ideation and change in depression severity (Pearson r = 0.38; P < .001) and no difference in change of HDRS-16 score between suicide remitters and nonremitters (P = .32). CONCLUSIONS: Bilateral rTMS was superior to sham rTMS in reducing suicidal ideation in patients with TRD. Only a small portion of the reduction in suicidal ideation was attributable to the reduction in depressive symptoms. These data suggest that suicidal ideation could be a specific target symptom construct for rTMS. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT01515215 and NCT00305045.

Clinical Effectiveness and Tolerability of Electroconvulsive Therapy in Patients with Neuropsychiatric Symptoms of Dementia.

BACKGROUND: Dementia frequently presents with aggression, agitation, and disorganized behavior for which current treatment is partially effective and is associated with significant adverse effects. OBJECTIVE: The aim of this study was to retrospectively assess the clinical effectiveness and tolerability of electroconvulsive therapy (ECT) in a sample of patients with neuropsychiatric symptoms of dementia (NPS) and to explore factors associated with response and with cognitive adverse effects. METHODS: We examined the clinical records of 25 patients with dementia and a pre-existing psychiatric disorder treated with ECT at an academic mental health hospital between April 1, 2010 and January 28, 2016. Twenty-nine acute ECT courses and fifteen maintenance courses were reviewed. We assessed treatment effectiveness and cognitive adverse effects as well as factors associated with response to treatment, including pre-existing psychiatric disorders, concomitant pharmacological treatment and types of dementia. RESULTS: ECT resulted in a clinically meaningful response in 72% of acute treatment courses. Cognitive adverse effects affecting functioning were reported in 7% of the acute treatment courses. Maintenance treatment was effective in sustaining the response in 87% of treatment courses with two reports of significant cognitive adverse effects. One patient fell and experienced a hip fracture a day after treatment. Use of antipsychotic or antidepressant medications, pre-existing psychiatric disorder, or gender were not associated with response. CONCLUSION: This study shows meaningful clinical effectiveness and good tolerability of ECT in patients with severe NPS of dementia. Furthermore, maintenance ECT was effective in sustaining treatment response.

Neuromodulation of Attentional Control in Major Depression: A Pilot DeepTMS Study.

While Major Depressive Disorder (MDD) is primarily characterized by mood disturbances, impaired attentional control is increasingly identified as a critical feature of depression. Deep transcranial magnetic stimulation (deepTMS), a noninvasive neuromodulatory technique, can modulate neural activity and induce neuroplasticity changes in brain regions recruited by attentional processes. This study examined whether acute and long-term high-frequency repetitive deepTMS to the dorsolateral prefrontal cortex (DLPFC) can attenuate attentional deficits associated with MDD. Twenty-one MDD patients and 26 matched control subjects (CS) were administered the Beck Depression Inventory and the Sustained Attention to Response Task (SART) at baseline. MDD patients were readministered the SART and depressive assessments following a single session (n = 21) and after 4 weeks (n = 13) of high-frequency (20 Hz) repetitive deepTMS applied to the DLPFC. To control for the practice effect, CS (n = 26) were readministered the SART a further two times. The MDD group exhibited deficits in sustained attention and cognitive inhibition. Both acute and long-term high-frequency repetitive frontal deepTMS ameliorated sustained attention deficits in the MDD group. Improvement after acute deepTMS was related to attentional recovery after long-term deepTMS. Longer-term improvement in sustained attention was not related to antidepressant effects of deepTMS treatment.

Anatomical and functional connectivity in the default mode network of post-traumatic stress disorder patients after civilian and military-related trauma.

Posttraumatic stress disorder (PTSD) is characterized by unwanted intrusive thoughts and hyperarousal at rest. As these core symptoms reflect disturbance in resting-state mechanisms, we investigated the functional and anatomical involvement of the default mode network (DMN) in this disorder. The relation between symptomatology and trauma characteristics was considered. Twenty PTSD patients and 20 matched trauma-exposed controls that were exposed to a similar traumatic event were recruited for this study. In each group, 10 patients were exposed to military trauma, and 10 to civilian trauma. PTSD, anxiety, and depression symptom severity were assessed. DMN maps were identified in resting-state scans using independent component analysis. Regions of interest (medial prefrontal, precuneus, and bilateral inferior parietal) were defined and average z-scores were extracted for use in the statistical analysis. The medial prefrontal and the precuneus regions were used for cingulum tractography whose integrity was measured and compared between groups. Similar functional and anatomical connectivity patterns were identified in the DMN of PTSD patients and trauma-exposed controls. In the PTSD group, functional and anatomical connectivity parameters were strongly correlated with clinical measures, and there was evidence of coupling between the anatomical and functional properties. Type of trauma and time from trauma were found to modulate connectivity patterns. To conclude, anatomical and functional connectivity patterns are related to PTSD symptoms and trauma characteristics influence connectivity beyond clinical symptoms. Hum Brain Mapp 37:589-599, 2016. © 2015 Wiley Periodicals, Inc.

Efficacy and safety of deep transcranial magnetic stimulation for major depression: a prospective multicenter randomized controlled trial.

Major depressive disorder (MDD) is a prevalent and disabling condition, and many patients do not respond to available treatments. Deep transcranial magnetic stimulation (dTMS) is a new technology allowing non-surgical stimulation of relatively deep brain areas. This is the first double-blind randomized controlled multicenter study evaluating the efficacy and safety of dTMS in MDD. We recruited 212 MDD outpatients, aged 22-68 years, who had either failed one to four antidepressant trials or not tolerated at least two antidepressant treatments during the current episode. They were randomly assigned to monotherapy with active or sham dTMS. Twenty sessions of dTMS (18 Hz over the prefrontal cortex) were applied during 4 weeks acutely, and then biweekly for 12 weeks. Primary and secondary efficacy endpoints were the change in the Hamilton Depression Rating Scale (HDRS-21) score and response/remission rates at week 5, respectively. dTMS induced a 6.39 point improvement in HDRS-21 scores, while a 3.28 point improvement was observed in the sham group (p=0.008), resulting in a 0.76 effect size. Response and remission rates were higher in the dTMS than in the sham group (response: 38.4 vs. 21.4%, p=0.013; remission: 32.6 vs. 14.6%, p=0.005). These differences between active and sham treatment were stable during the 12-week maintenance phase. dTMS was associated with few and minor side effects apart from one seizure in a patient where a protocol violation occurred. These results suggest that dTMS constitutes a novel intervention in MDD, which is efficacious and safe in patients not responding to antidepressant medications, and whose effect remains stable over 3 months of maintenance treatment.

Effectiveness of deep transcranial magnetic stimulation combined with a brief exposure procedure in post-traumatic stress disorder--a pilot study.

BACKGROUND: Post-traumatic stress disorder (PTSD) is a debilitating anxiety disorder induced by traumatic experiences. To date, psychotherapy and drug treatment achieve only partial success, indicating need for further development of treatment strategies. Recent research has found that impaired acquired fear extinction capability serves as an important factor at the pathogenesis of the disorder. Medial prefrontal cortex (mPFC) hypo-activity has been implicated in this extinction impairment, providing insight as to why some trauma exposed individuals will develop PTSD. OBJECTIVE: To test whether fear extinction can be facilitated and therapeutic effect achieved by repeated mPFC deep transcranial magnetic stimulation (DTMS) of PTSD patients resistant to standard treatment. METHODS: In a double-blind study, 30 PTSD patients were enrolled and randomly assigned into 3 treatment groups: A) DTMS after brief exposure to the traumatic event with the script-driven imagery procedure; B) DTMS after brief exposure to a non-traumatic event; C) sham stimulation after brief exposure to the traumatic event. RESULTS: Significant improvement was demonstrated in the intrusive component of the CAPS scale in patients administered DTMS after exposure to the traumatic event script, while patients in the control groups showed no significant improvement. Similar trend was demonstrated in the Total-CAPS score as in the other rating scales. A significant reduction in the HR response to the traumatic script was evident in group A, further supporting the above results. CONCLUSIONS: Combining brief script-driven exposure with DTMS can induce therapeutic effects in PTSD patients. A wide multi-center study is suggested to substantiate these findings. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00517400.

Differential effects of deep TMS of the prefrontal cortex on apathy and depression.

BACKGROUND: Apathy is one hallmark of major depression (MDD). It is distinguished by lack of emotion, whereas other aspects of depression involve considerable emotional distress. Investigating both apathy and depression may increase the degree of treatment efficacy for both ailments together and apart. OBJECTIVE: Evaluate the differential effects of deep transcranial magnetic stimulation (DTMS) over the prefrontal cortex (PFC) on apathy and other aspects of depression in patients suffering from a depressive episode. METHODS: Fifty-four treatment-resistant MDD patients were evaluated with the Hamilton Rating Scale for Depression (HRSD), and then treated with DTMS. Apathy-related items from HRSD (ApHRSD) were compared with the remaining items from HRSD (DepHRSD). Antidepressant medications were withdrawn and active DTMS treatment was administered at 20 Hz, 5 days a week for 4 weeks. Changes in HRSD were recorded. Primary efficacy time point was 1 week after the end of active treatment. RESULTS: At screening, ApHRSD distribution was unimodal (moderate apathy), with low correlation (r = 0.17) between ApHRSD and DepHRSD. After treatment, a third had remitted apathy, and the correlation between ApHRSD and DepHRSD had dramatically increased (r = 0.83). Severe ApHRSD (≥ 7) at screening correlated with nonremission for both ApHRSD (R(2) = 0.1993, P = .0012) and DepHRSD (R(2) = 0.0860, P = .0334). CONCLUSIONS: DTMS over the PFC improved both apathy and depression similarly. However, DTMS did not lead to MDD remission if ApHRSD at screening was ≥ 7 of 12. Further investigation using a larger sample will determine whether screening apathy at baseline could be used to predict efficacy of DTMS in MDD patients.

Cognitive-emotional reactivation during deep transcranial magnetic stimulation over the prefrontal cortex of depressive patients affects antidepressant outcome.

BACKGROUND: Transcranial magnetic stimulation (TMS) enables non-surgical activation of specific brain areas. TMS over the prefrontal cortex (PFC) is emerging as a significant tool that can augment or replace non/partially effective antidepressant medications. Deep TMS (DTMS) utilizes newly developed coils that enable effective stimulation of deeper cortical layers involved in the pathophysiology of depression. OBJECTIVES: We aimed to assess the H1-DTMS coil as an add-on to antidepressants in treating patients with major depression. We also intended to evaluate whether the antidepressant outcome of DTMS treatment is affected by a cognitive-emotional procedure performed during stimulation. METHODS: 57 patients were enrolled in the study that included 4 weeks of daily 20 Hz stimulation sessions and additional 4 weekly sessions as a short maintenance phase. Two subgroups of patients received either positive or negative cognitive-emotional reactivation along with the stimulation sessions. RESULTS: 21 of 46 patients (46%) who received at least 10 stimulation sessions achieved response (improvement of ≥ 50% in the Hamilton Depression Rating Scale (HDRS)) and 13 of them (28%) achieved remission (HDRS-24 ≤ 10) by the end of the daily treatment phase. Improvements were smaller in the negatively reactivated group and Beck Depression Inventory scores were not significantly improved in this group. CONCLUSIONS: DTMS over the PFC proved to be safe and effective in augmenting antidepressant medications. Negative cognitive-emotional reactivation can disrupt the therapeutic effect of DTMS. A large sham controlled study is required to further establish the effectiveness of DTMS as an augmentation treatment and the role of cognitive reactivation during stimulation.

Site-specific antidepressant effects of repeated subconvulsive electrical stimulation: potential role of brain-derived neurotrophic factor.

BACKGROUND: Electroconvulsive therapy (ECT) is a very effective treatment for major depression. This method involves robust nonfocal stimulation of the brain and can normalize both neurochemical alterations and depressive behavior in animal models. We hypothesized that short stimulation sessions of specific reward-related brain sites might induce similar effects. METHODS: In the present study we compared behavioral and neurochemical effects produced by ECT and by repeated stimulation of reward-related brain sites, in a widely used rat model for depressive behavior induced by chronic mild stress (CMS). Different groups of rats received 10 sessions of either electroconvulsive shocks or subconvulsive electrical stimulation (SCES) of specific brain sites with an implanted electrode. The SCES temporal parameters were similar to those used in transcranial magnetic stimulation studies in humans. A battery of behavioral tests and measurements of brain-derived neurotrophic factor (BDNF) levels were used to assess the effectiveness of these treatments relative to sham treatments. RESULTS: Repeated SCES of either the nucleus accumbens (NAC) or the ventral but not the dorsal prelimbic cortex (PLC) reversed the main behavioral deficit and the reduction of BDNF levels in the hippocampus that were induced by CMS. The ECT was more effective because it also normalized a behavioral deficit associated with anxiety but produced a learning and memory impairment. CONCLUSIONS: This study implicates the ventral PLC and the NAC in the pathophysiology of depressive behavior and suggests that local intermittent SCES can induce an antidepressant effect similar to that of ECT, without the cognitive impairment caused by the convulsive treatment.