Systematic review and meta-analysis of neurofeedback and its effect on posttraumatic stress disorder.

Background: To date, only one systematic review and meta-analysis of randomized controlled trials (RCTs) has evaluated the effect of neurofeedback in PTSD, which included only four studies and found an uncertainty of the effect of EEG-NF on PTSD symptoms. This meta-analysis is an update considering that numerous studies have since been published. Additionally, more recent studies have included fMRI-NF as well as fMRI-guided or -inspired EEG NF. Methods: Systematic literature searches for RCTs were conducted in three online databases. Additional hand searches of each study identified and of systematic reviews and meta-analyses published were also undertaken. Outcomes evaluated the effect of neurofeedback vs. a control (active, sham, and waiting list) on their effects in reducing PTSD symptoms using various health instruments. Meta-analytical methods used were inverse variance random-effects models measuring both mean and standardized mean differences. Quality and certainty of the evidence were assessed using GRADE. Adverse events were also evaluated. Results: A total of 17 studies were identified evaluating a total of 628 patients. There were 10 studies used in the meta-analysis. Results from all studies identified favored neurofeedback's effect on reducing PTSD symptoms including BDI pretest-posttest [mean difference (MD): 8.30 (95% CI: 3.09 to 13.52; P = 0.002; I 2 = 0%)]; BDI pretest-follow-up (MD: 8.75 (95% CI: 3.53 to 13.97; P < 0.00001; I 2 = 0%); CAPS-5 pretest-posttest [MD: 7.01 (95% CI: 1.36 to 12.66; P = 0.02; I 2 = 86%)]; CAPS-5 pretest-follow-up (MD: 10 (95% CI: 1.29 to 21.29; P = 0.006; I 2 = 77%); PCL-5 pretest-posttest (MD: 7.14 (95% CI: 3.08 to 11.2; P = 0.0006; I 2 = 0%); PCL-5 pretest-follow-up (MD: 14.95 (95% CI: 7.95 to 21.96; P < 0.0001; I 2 = 0%). Other studies reported improvements using various other instruments. GRADE assessments of CAPS, PCL, and BDI demonstrated a moderate/high level in the quality of the evidence that NF has a positive clinical effect. Conclusion: Based on newer published studies and the outcomes measured, NF has demonstrated a clinically meaningful effect size, with an increased effect size at follow-up. This clinically meaningful effect appears to be driven by newer fMRI-guided NF and deeper brain derivates of it.

Never Too Late: Safety and Efficacy of Deep TMS for Late-Life Depression.

Repetitive transcranial magnetic stimulation (rTMS) is an effective and well-established treatment for major depressive disorder (MDD). Deep TMS utilizes specially designed H-Coils to stimulate the deep and broad cerebral regions associated with the reward system. The improved depth penetration of Deep TMS may be particularly important in late-life patients who often experience brain atrophy. The aim of this phase IV open-label study was to evaluate the safety and efficacy of Deep TMS in patients with late-life MDD. Data were collected from 247 patients with MDD aged 60-91 at 16 sites who had received at least 20 Deep TMS sessions for MDD. The outcome measures included self-assessment questionnaires (Patient Health Questionnaire-9 (PHQ-9), Beck Depression Inventory-II (BDI-II)) and clinician-based scales (21-item Hamilton Depression Rating Scale (HDRS-21)). Following 30 sessions of Deep TMS, there was a 79.4% response and 60.3% remission rate on the most rated scale. The outcomes on the PHQ-9 were similar (76.6% response and 54.7% remission rate). The highest remission and response rates were observed with the HDRS physician-rated scale after 30 sessions (89% response and a 78% remission rate). After 20 sessions, there was a 73% response and 73% remission rate on the HDRS. Consistent with prior studies, the median onset of response was 14 sessions (20 days). The median onset of remission was 15 sessions (23 days). The treatment was well tolerated, with no reported serious adverse events. These high response and remission rates in patients with treatment-resistant late-life depression suggest that Deep TMS is a safe, well-tolerated and effective treatment for this expanded age range of older adults.

Linguistic and affective characteristics of script-driven imagery for adults with posttraumatic stress order: Associations with clinical outcomes during deep transcranial magnetic stimulation.

Brief exposure to traumatic memories using script-driven imagery (SDI) has been proposed as a promising treatment for posttraumatic stress disorder (PTSD). This study investigated the effect of SDI plus active versus sham deep transcranial magnetic stimulation (TMS) in a secondary analysis of a randomized controlled trial for adults with PTSD (N = 134). Linguistic features of scripts and self-reported distress during a 12-session deep TMS treatment protocol were examined as they related to (a) baseline PTSD symptom severity, (b) trauma characteristics, and (c) treatment outcomes. Linguistic Inquiry and Word Count (LIWC) software was used to analyze the following linguistic features of SDIs: negative emotion, authenticity, and cognitive processing. More use of negative emotion words was associated with less severe self-reported and clinician-rated baseline PTSD symptom severity, r = -.18, p = .038. LIWC features did not differ based on index trauma type, range: F(3, 125) = 0.29-0.49, ps = .688-.831. Between-session reductions in self-reported distress across SDI trials predicted PTSD symptom improvement across both conditions at 5-week, B = -15.68, p = .010, and 9-week endpoints, B = -16.38, p = .011. Initial self-reported distress and linguistic features were not associated with treatment outcomes. The findings suggest that individuals with PTSD who experience between-session habituation to SDI-related distress are likely to experience a corresponding improvement in PTSD symptoms.

Real world efficacy and safety of various accelerated deep TMS protocols for major depression.

There is growing interest in accelerated rTMS dosing regimens, wherein multiple sessions of rTMS are applied per day. This Phase IV study evaluated the safety, efficacy, and durability of various accelerated Deep TMS protocols used in clinical practice. Data were aggregated from 111 patients with major depressive disorder (MDD) at 4 sites. Patients received one of several accelerated Deep TMS protocols (2x/day, 3x/day, 5x/day, 10x/day). Self-assessment questionnaires (PHQ-9, BDI-II) and clinician-based rating scales (HDRS-21, MADRS) were collected. On average, accelerated TMS led to an 80.2% response and 50.5% remission rate in the first month based on the most rated scale for each patient. There was no significant difference between protocols (Response: 2x/day:89.6%; 3x/day:75%; 5x/day:81%; 10x/day:67.6%). Response occurred after 10 (3x/day), 20 (5x/day), and 31 sessions (10x/day) on average- all of which occur on day 3-4 of treatment. Of patients with longer term follow up, durability was found in 86.7% (n = 30; 60 days) and 92.9% (n = 14; 180 days). The protocols were well-tolerated with no reported serious adverse events. Accelerated Deep TMS protocols are found to be safe, effective therapeutic options for MDD. They offer treatment resistant patients a treatment option with a rapid onset of action and with long durability.

Transcranial Magnetic Stimulation as a Tool to Promote Smoking Cessation and Decrease Drug and Alcohol Use.

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive, drug-free, neural-circuit-based therapeutic tool that was recently cleared by the United States Food and Drug Associate for the treatment of smoking cessation. TMS has been investigated as a tool to reduce consumption and craving for many other substance use disorders (SUDs). This review starts with a discussion of neural networks involved in the addiction process. It then provides a framework for the therapeutic efficacy of TMS describing the role of executive control circuits, default mode, and salience circuits as putative targets for neuromodulation (via targeting the DLPFC, MPFC, cingulate, and insula bilaterally). A series of the largest studies of TMS in SUDs are listed and discussed in the context of this framework. Our review concludes with an assessment of the current state of knowledge regarding the use of rTMS as a therapeutic tool in reducing drug, alcohol, and nicotine use and identifies gaps in the literature that need to be addressed in future studies. Namely, while the presumed mechanism through which TMS exerts its effects is by modulating the functional connectivity circuits involved in executive control and salience of drug-related cues, it is also possible that TMS has direct effects on subcortical dopamine, a hypothesis that could be explored in greater detail with PET imaging.

Deep TMS H1 Coil treatment for depression: Results from a large post marketing data analysis.

Phase IV study evaluated Deep TMS for major depression in community settings. Data were aggregated from 1753 patients at 21 sites, who received Deep TMS (high frequency or iTBS) using the H1 coil. Outcome measures varied across subjects and included clinician-based scales (HDRS-21) and self-assessment questionnaires (PHQ-9, BDI-II). 1351 patients were included in the analysis, 202 received iTBS. For participants with data from at least 1 scale, 30 sessions of Deep TMS led to 81.6% response and 65.3% remission rate. 20 sessions led to 73.6% response and 58.1% remission rate. iTBS led to 72.4% response and 69.2% remission. Remission rates were highest when assessed with HDRS (72%). In 84% of responders and 80% of remitters, response and remission was sustained in the subsequent assessment. Median number of sessions (days) for onset of sustained response was 16 (21 days) and for sustained remission 17 (23 days). Higher stimulation intensity was associated with superior clinical outcomes. This study shows that beyond its proven efficacy in RCTs, Deep TMS with the H1 coil is effective for treating depression under naturalistic conditions, and the onset of improvement is usually within 20 sessions. However, initial non-responders and non-remitters benefit from extended treatment.

Transcranial Magnetic Stimulation in Obsessive-Compulsive Disorder.

Obsessive-compulsive disorder (OCD) patients need novel therapeutic interventions since most experience residual symptoms despite treatment. Converging evidence suggest that OCD involves dysfunction of limbic cortico-striato-thalamo-cortical loops, including the medial prefrontal cortex (mPFC) and dorsal anterior cingulate cortex (dACC), that tends to normalize with successful treatment. Recently, three repetitive transcranial magnetic stimulation (rTMS) coils were FDA-cleared for treatment-refractory OCD. This review presents on-label and off-label clinical evidence and relevant physical characteristics of the three coils. The Deep TMS™ H7 Coil studies' point to efficacy of mPFC-dACC stimulation, while no clear target stems from the small heterogenous D-B80 and figure-8 coils studies.

Revisiting the Rotational Field TMS Method for Neurostimulation.

Transcranial magnetic stimulation (TMS) is a non-invasive technique that has shown high efficacy in the treatment of major depressive disorder (MDD) and is increasingly utilized for various neuropsychiatric disorders. However, conventional TMS is limited to activating only a small fraction of neurons that have components parallel to the induced electric field. This likely contributes to the significant variability observed in clinical outcomes. A novel method termed rotational field TMS (rfTMS or TMS 360°) enables the activation of a greater number of neurons by reducing the sensitivity to orientation. Recruitment of a larger number of neurons offers the potential to enhance efficacy and reduce variability in the treatment of clinical indications for which neuronal recruitment and organization may play a significant role, such as MDD and stroke. The potential of the method remains to be validated in clinical trials. Here, we revisit and describe in detail the rfTMS method, its principles, mode of operation, effects on the brain, and potential benefits for clinical TMS.

Pursuing personalized medicine for depression by targeting the lateral or medial prefrontal cortex with Deep TMS.

BACKGROUNDMajor depressive disorder (MDD) can benefit from novel interventions and personalization. Deep transcranial magnetic stimulation (Deep TMS) targeting the lateral prefrontal cortex (LPFC) using the H1 coil was FDA cleared for treatment of MDD. However, recent preliminary data indicate that targeting the medial prefrontal cortex (MPFC) using the H7 coil might induce outcomes that are as good or even better. Here, we explored whether Deep TMS targeting the MPFC is noninferior to targeting the LPFC and whether electrophysiological or clinical markers for patient selection can be identified.METHODSThe present prospective, multicenter, randomized study enrolled 169 patients with MDD for whom antidepressants failed in the current episode. Patients were randomized to receive 24 Deep TMS sessions over 6 weeks, using either the H1 coil or the H7 coil. The primary efficacy endpoint was the change from baseline to week 6 in Hamilton Depression Rating Scale scores.RESULTSClinical efficacy and safety profiles were similar and not significantly different between groups, with response rates of 60.9% for the H1 coil and 64.2% for the H7 coil. Moreover, brain activity measured by EEG during the first treatment session correlated with clinical outcomes in a coil-specific manner, and a cluster of baseline clinical symptoms was found to potentially distinguish between patients who can benefit from each Deep TMS target.CONCLUSIONThis study provides a treatment option for MDD, using the H7 coil, and initial guidance to differentiate between patients likely to respond to LPFC versus MPFC stimulation targets, which require further validation studies.TRIAL REGISTRATIONClinicalTrials.gov NCT03012724.FUNDINGBrainsWay Ltd.

Bilateral deep transcranial magnetic stimulation of motor and prefrontal cortices in Parkinson's disease: a comprehensive review.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by both motor and non-motor symptoms, many of which are resistant to currently available treatments. Since the discovery that non-invasive transcranial magnetic stimulation (TMS) can cause dopamine release in PD patients, there has been growing interest in the use of TMS to fill existing gaps in the treatment continuum for PD. This review evaluates the safety and efficacy of a unique multifocal, bilateral Deep TMS protocol, which has been evaluated as a tool to address motor and non-motor symptoms of PD. Six published clinical trials have delivered a two-stage TMS protocol with an H-Coil targeting both the prefrontal cortex (PFC) and motor cortex (M1) bilaterally (220 PD patients in total; 108 from two randomized, sham-controlled studies; 112 from open label or registry studies). In all studies TMS was delivered to M1 bilaterally (Stage 1) and then to the PFC bilaterally (Stage 2) with approximately 900 pulses per stage. For Stage 1 (M1), two studies delivered 10 Hz at 90% motor threshold (MT) while four studies delivered 1 Hz at 110% MT. For Stage 2 (PFC), all studies delivered 10 Hz at 100% MT. The results suggest that this two-stage Deep TMS protocol is a safe, moderately effective treatment for motor symptoms of PD, and that severely impaired patients have the highest benefits. Deep TMS also improves mood symptoms and cognitive function in these patients. Further research is needed to establish optimal dosing and the long-term durability of treatment effects.

Detailed measurements and simulations of electric field distribution of two TMS coils cleared for obsessive compulsive disorder in the brain and in specific regions associated with OCD.

The FDA cleared deep transcranial magnetic stimulation (Deep TMS) with the H7 coil for obsessive-compulsive disorder (OCD) treatment, following a double-blinded placebo-controlled multicenter trial. Two years later the FDA cleared TMS with the D-B80 coil on the basis of substantial equivalence. In order to investigate the induced electric field characteristics of the two coils, these were placed at the treatment position for OCD over the prefrontal cortex of a head phantom, and the field distribution was measured. Additionally, numerical simulations were performed in eight Population Head Model repository models with two sets of conductivity values and three Virtual Population anatomical head models and their homogeneous versions. The H7 was found to induce significantly higher maximal electric fields (p<0.0001, t = 11.08) and to stimulate two to five times larger volumes in the brain (p<0.0001, t = 6.71). The rate of decay of electric field with distance is significantly slower for the H7 coil (p < 0.0001, Wilcoxon matched-pairs test). The field at the scalp is 306% of the field at a 3 cm depth with the D-B80, and 155% with the H7 coil. The H7 induces significantly higher intensities in broader volumes within the brain and in specific brain regions known to be implicated in OCD (dorsal anterior cingulate cortex (dACC), dorsolateral prefrontal cortex (dlPFC), inferior frontal gyrus (IFG), orbitofrontal cortex (OFC) and pre-supplementary motor area (pre-SMA)) compared to the D-B80. Significant field ≥ 80 V/m is induced by the H7 (D-B80) in 15% (1%) of the dACC, 78% (29%) of the pre-SMA, 50% (20%) of the dlPFC, 30% (12%) of the OFC and 15% (1%) of the IFG. Considering the substantial differences between the two coils, the clinical efficacy in OCD should be tested and verified separately for each coil.

Efficacy and Safety of Deep Transcranial Magnetic Stimulation for Obsessive-Compulsive Disorder: A Prospective Multicenter Randomized Double-Blind Placebo-Controlled Trial.

(Appeared originally in American Journal of Psychiatry 2019; 176:931-938) Reprinted with permission from American Psychiatric Association Publishing.

Deep Transcranial Magnetic Stimulation Effects on the Electrophysiological Parameters in Obsessive-Compulsive Disorder.

Backgrounds. Deep Transcranial Magnetic Stimulation (dTMS) is a non-invasive treatment cleared by FDA as a safe and efficient intervention for the treatment of depression and obsessive-compulsive disorder (OCD). Objectives. In this retrospective single-center study, the effects of dTMS on the electrophysiological parameters and the clinical outcomes of patients with OCD were tested. Methods. Thirty sessions of dTMS were administered to 29 OCD patients (15 female and 14 male). Quantitative electroencephalography (QEEG) recordings and Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) were measured at baseline and endpoint. Paired sample t-test was used to measure the change in Y-BOCS scores and QEEG activity after dTMS practice. Results. All 29 patients responded to the dTMS intervention by indicating at least 35% reduction in Y-BOCS scores. QEEG recordings revealed a significant decrease in theta, alpha and the beta rhythms. The decrease in the severity of OCD symptoms correlated with the decrease in beta activity at left central region. Conclusions. Historically, excess fast oscillations in OCD are correlated with the unresponsiveness to selective serotonin reuptake inhibitor (SSRI) treatment. We hypothesize that the decrease in the power of beta bands by deep TMS is related to the mechanism of the therapeutic response.

Efficacy of Deep TMS with the H1 Coil for Anxious Depression.

(1) Background: While the therapeutic efficacy of Transcranial Magnetic Stimulation (TMS) for major depressive disorder (MDD) is well established, less is known about the technique's efficacy for treating comorbid anxiety. (2) Methods: Data were retrospectively analyzed from randomized controlled trials (RCTs) that used Deep TMS with the H1 Coil for MDD treatment. The primary endpoint was the difference relative to sham treatment following 4 weeks of stimulation. The effect size was compared to literature values for superficial TMS and medication treatments. (3) Results: In the pivotal RCT, active Deep TMS compared with sham treatment showed significantly larger improvements in anxiety score (effect size = 0.34, p = 0.03 (FDR)) which were sustained until 16 weeks (effect size = 0.35, p = 0.04). The pooled effect size between all the RCTs was 0.55, which compares favorably to alternative treatments. A direct comparison to Figure-8 Coil treatment indicated that treatment with the H1 Coil was significantly more effective (p = 0.042). In contrast to previously reported studies using superficial TMS and medication for which anxiety has been shown to be a negative predictor of effectiveness, higher baseline anxiety was found to be predictive of successful outcome for the H1-Coil treatment. (4) Conclusions: Deep TMS is effective in treating comorbid anxiety in MDD and, unlike alternative treatments, the outcome does not appear to be adversely affected by high baseline anxiety levels.

Moderators of the response to deep TMS for smoking addiction.

Introduction: Deep repetitive transcranial magnetic stimulation (Deep TMS™) was recently cleared by the FDA as a short-term treatment for smoking cessation. However, it is unknown which participants are more likely to benefit from the treatment. Methods: We evaluated the data from the published randomized controlled trial of 262 participants 22-70 years old that led to the FDA clearance to characterize demographic and smoking history factors that moderate Deep TMS treatment efficacy. The current analysis included 75 completers in the active TMS group and 94 completers in the sham TMS group. Results: We found that participants younger than 40 had four times the quit rate than those older than 40. Additionally, participants who quit following treatment smoked 10 years less than non-quitters. Moreover, Caucasian participants had two times the quit rate than African-American participants. Strikingly, participants with more than 12 years of education had 7 times the quit rate than participants with less education. Conclusion: Three weeks of Deep TMS has a higher smoking addiction quit rate in participants who are younger, more educated, Caucasian and with less extensive smoking history. Participants who are older, with less education and more extensive smoking history may need a longer treatment course and/or combined treatment modalities. Potential reasons may be related to the challenges of inducing neuronal modifications in those with greater physical and psychological dependence. Further investigation is warranted.

Deep TMS H7 Coil: Features, Applications & Future.

INTRODUCTION: Transcranial magnetic stimulation (TMS) uses magnetic pulses to induce electrical current in the underlying neuronal tissue. A variety of TMS coils exist on the market, differing primarily in configuration, orientation, and flexibility of the wire windings of the coil. Deep TMSTM utilizes H-Coils, flexible coils with different configurations for stimulating different brain regions implicated in different neuropsychiatric disorders. The H7 Coil, designed to target primarily the medial prefrontal cortex and the anterior cingulate cortex, is FDA-cleared for obsessive-compulsive disorder (OCD). It was chosen as the focus of this review since it recently showed promise in various neuropsychiatric populations in addition to growing understanding of its mechanism of action (MOA). AREAS COVERED: Here we assembled all peer-reviewed publications on the H7 Coil to showcase its efficacy in: (a) various OCD patient populations (e.g., different degrees of symptom severity, treatment resistance, comorbidities) (b) other neuropsychiatric populations (e.g., addiction, major depressive disorder and autism spectrum disorder). EXPERT OPINION: While substantial evidence pertaining to the H7 Coil's efficacy as well as its MOA has accumulated, much work remains. In the final section of this review, we highlight areas of ongoing and future research that will further elucidate the coil's MOA as well as its full efficacy potential.