Moshe Isserles

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.

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.

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.

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.

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.

Effectiveness of a second deep TMS in depression: a brief report.

OBJECTIVES Deep transcranial magnetic stimulation (DTMS) is an emerging and promising treatment for major depression. In our study, we explored the effectiveness of a second antidepressant course of deep TMS in major depression. We enrolled eight patients who had previously responded well to DTMS but relapsed within 1 year in order to evaluate whether a second course of DTMS would still be effective. METHODS Eight depressive patients who relapsed after a previous successful deep TMS course expressed their wish to be treated again. Upon their request, they were recruited and treated with 20 daily sessions of DTMS at 20 Hz using the Brainsways H1 coil. The Hamilton depression rating scale (HDRS), Hamilton anxiety rating scale (HARS) and the Beck depression inventory (BDI) were used weekly to evaluate the response to treatment. RESULTS Similar to the results obtained in the first course of treatment, the second course of treatment (after relapse) induced significant reductions in HDRS, HARS and BDI scores, compared to the ratings measured prior to treatment. The magnitude of response in the second course was smaller relative to that obtained in the first course of treatment. CONCLUSIONS Our results suggest that depressive patients who previously responded well to deep TMS treatment are likely to respond again. However, the slight reduction in the magnitude of the response in the second treatment raises the question of whether tolerance or resistance to this treatment may eventually develop.

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.

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.

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.

Response to “The Site of Transcranial Magnetic Stimulation for Post-Traumatic Stress Disorder”

Fig. S2 illustrates that in the model system the h-coil stimulates a volume of brain enormously greater than mPFCdmuch of it at higher intensity. Of the 10 coronal slices in that figure, only the oddly-asymmetric images 2 and 3 suggest the motor threshold zone extending to a depth that might possibly include mPFC. Even with the h-coil, more superficial brain regions inevitably receive a higher intensity of stimulation than deeper ones [2e4]. Yet the text gives no hint that large areas of cortical surface, extending 10 cm anterioreposterior in the frontal lobe and perhaps 12e15 cm transversely, are subject to stronger electric fields than mPFC. Under these circumstances, asserting that the treatment effect occurred specifically at the smaller and more weakly activated mPFC represents a triumph of hope over physics.