Glutamate-Mediated Blood-Brain Barrier Opening: Implications for Neuroprotection and Drug Delivery.

UNLABELLED: The blood-brain barrier is a highly selective anatomical and functional interface allowing a unique environment for neuro-glia networks. Blood-brain barrier dysfunction is common in most brain disorders and is associated with disease course and delayed complications. However, the mechanisms underlying blood-brain barrier opening are poorly understood. Here we demonstrate the role of the neurotransmitter glutamate in modulating early barrier permeability in vivo Using intravital microscopy, we show that recurrent seizures and the associated excessive glutamate release lead to increased vascular permeability in the rat cerebral cortex, through activation of NMDA receptors. NMDA receptor antagonists reduce barrier permeability in the peri-ischemic brain, whereas neuronal activation using high-intensity magnetic stimulation increases barrier permeability and facilitates drug delivery. Finally, we conducted a double-blind clinical trial in patients with malignant glial tumors, using contrast-enhanced magnetic resonance imaging to quantitatively assess blood-brain barrier permeability. We demonstrate the safety of stimulation that efficiently increased blood-brain barrier permeability in 10 of 15 patients with malignant glial tumors. We suggest a novel mechanism for the bidirectional modulation of brain vascular permeability toward increased drug delivery and prevention of delayed complications in brain disorders. SIGNIFICANCE STATEMENT: In this study, we reveal a new mechanism that governs blood-brain barrier (BBB) function in the rat cerebral cortex, and, by using the discovered mechanism, we demonstrate bidirectional control over brain endothelial permeability. Obviously, the clinical potential of manipulating BBB permeability for neuroprotection and drug delivery is immense, as we show in preclinical and proof-of-concept clinical studies. This study addresses an unmet need to induce transient BBB opening for drug delivery in patients with malignant brain tumors and effectively facilitate BBB closure in neurological disorders.

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.

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.

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.

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.

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.

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.

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.

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.

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 for the treatment of auditory hallucinations: a preliminary open-label study.

BACKGROUND: Schizophrenia is a chronic and disabling disease that presents with delusions and hallucinations. Auditory hallucinations are usually expressed as voices speaking to or about the patient. Previous studies have examined the effect of repetitive transcranial magnetic stimulation (TMS) over the temporoparietal cortex on auditory hallucinations in schizophrenic patients. Our aim was to explore the potential effect of deep TMS, using the H coil over the same brain region on auditory hallucinations. PATIENTS AND METHODS: Eight schizophrenic patients with refractory auditory hallucinations were recruited, mainly from Beer Ya'akov Mental Health Institution (Tel Aviv university, Israel) ambulatory clinics, as well as from other hospitals outpatient populations. Low-frequency deep TMS was applied for 10 min (600 pulses per session) to the left temporoparietal cortex for either 10 or 20 sessions. Deep TMS was applied using Brainsway's H1 coil apparatus. Patients were evaluated using the Auditory Hallucinations Rating Scale (AHRS) as well as the Scale for the Assessment of Positive Symptoms scores (SAPS), Clinical Global Impressions (CGI) scale, and the Scale for Assessment of Negative Symptoms (SANS). RESULTS: This preliminary study demonstrated a significant improvement in AHRS score (an average reduction of 31.7% ± 32.2%) and to a lesser extent improvement in SAPS results (an average reduction of 16.5% ± 20.3%). CONCLUSIONS: In this study, we have demonstrated the potential of deep TMS treatment over the temporoparietal cortex as an add-on treatment for chronic auditory hallucinations in schizophrenic patients. Larger samples in a double-blind sham-controlled design are now being preformed to evaluate the effectiveness of deep TMS treatment for auditory hallucinations. TRIAL REGISTRATION: This trial is registered with clinicaltrials.gov (identifier: NCT00564096).

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.

Application of transcranial magnetic stimulation for major depression: Coil design and neuroanatomical variability considerations.

High-frequency repeated transcranial magnetic stimulation (rTMS) as a treatment for major depressive disorder (MDD) has received FDA clearance for both the figure-of-8 coil (figure-8 coil) and the H1 coil. The FDA-cleared MDD protocols for both coils include high frequency (10-18 Hz) stimulation targeting the dorsolateral prefrontal cortex (dlPFC) at an intensity that is 120% of the right-hand resting motor threshold. Despite these similar parameters, the two coils generate distinct electrical fields (e-fields) which result in differences in the cortical stimulation they produce. Due to the differences in coil designs, the H1 coil induces a stimulation e-field that is broader and deeper than the one induced by the figure-8 coil. In this paper we review theoretical and clinical implications of these differences between the two coils and compare evidence of their safety and efficacy in treating MDD. We present the design principles of the coils, the challenges of identifying, finding, and stimulating the optimal brain target of each individual (both from functional and connectivity perspectives), and the possible implication of stimulating outside that target. There is only one study that performed a direct comparison between clinical effectiveness of the two coils, using the standard FDA-approved protocols in MDD patients. This study indicated clinical superiority of the H1 coil but did not measure long-term effects. Post-marketing data suggest that both coils have a similar safety profile in clinical practice, whereas effect size comparisons of the two respective FDA pivotal trials suggests that the H1 coil may have an advantage in efficacy. We conclude that further head-to-head experiments are needed, especially ones that will compare long-term effects and usage of similar temporal stimulation parameters and similar number of pulses.

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.

Repetitive transcranial magnetic stimulation for smoking cessation: a pivotal multicenter double-blind randomized controlled trial.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation method increasingly used to treat psychiatric disorders, primarily depression. Initial studies suggest that rTMS may help to treat addictions, but evaluation in multicenter randomized controlled trials (RCTs) is needed. We conducted a multicenter double-blind RCT in 262 chronic smokers meeting DSM-5 criteria for tobacco use disorder, who had made at least one prior failed attempt to quit, with 68% having made at least three failed attempts. They received three weeks of daily bilat-eral active or sham rTMS to the lateral prefrontal and insular cortices, followed by once weekly rTMS for three weeks. Each rTMS session was administered following a cue-induced craving procedure, and participants were monitored for a total of six weeks. Those in abstinence were monitored for additional 12 weeks. The primary outcome measure was the four-week continuous quit rate (CQR) until Week 18 in the intent-to-treat efficacy set, as determined by daily smoking diaries and verified by urine cotinine measures. The trial was registered at ClinicalTrials.gov (NCT02126124). In the intent-to-treat analysis set (N=234), the CQR until Week 18 was 19.4% following active and 8.7% following sham rTMS (X2 =5.655, p=0.017). Among completers (N=169), the CQR until Week 18 was 28.0% and 11.7%, respectively (X2 =7.219, p=0.007). The reduction in cigarette consumption and craving was significantly greater in the active than the sham group as early as two weeks into treatment. This study establishes a safe treatment protocol that promotes smoking cessation by stimulating relevant brain circuits. It represents the first large multicenter RCT of brain stimulation in addiction medicine, and has led to the first clearance by the US Food and Drug Administration for rTMS as an aid in smok-ing cessation for adults.

Real-world efficacy of deep TMS for obsessive-compulsive disorder: Post-marketing data collected from twenty-two clinical sites.

BACKGROUND: Deep transcranial magnetic stimulation (dTMS) with the H7-coil was FDA cleared for obsessive-compulsive disorder (OCD) in August 2018 based on multicenter sham-controlled studies. Here we look at the efficacy of dTMS for OCD in real world practices. METHODS: All dTMS clinics were asked to supply their data on treatment details and outcome measures. The primary outcome measure was response, defined by at least a 30% reduction in the Yale Brown Obsessive Compulsive Scale (YBOCS) score from baseline to endpoint. Secondary outcome measures included first response, defined as the first time the YBOCS score has met response criteria, and at least one-month sustained response. Analyses included response rate at the endpoint (after 29 dTMS sessions), number of sessions and days required to reach first response and sustained response. RESULTS: Twenty-two clinical sites with H7-coils provided data on details of treatment and outcome (YBOCS) measures from a total of 219 patients. One-hundred-sixty-seven patients who had at least one post-baseline YBOCS measure were included in the main analyses. Overall first and sustained response rates were 72.6% and 52.4%, respectively. The response rate was 57.9% in patients who had YBOCS scores after 29 dTMS sessions. First response was achieved in average after 18.5 sessions (SD = 9.4) or 31.6 days (SD = 25.2). Onset of sustained one-month response was achieved in average after 20 sessions (SD = 9.8) or 32.1 days (SD = 20.5). Average YBOCS scores demonstrated continuous reduction with increasing numbers of dTMS sessions. CONCLUSIONS: In real-world clinical practice, the majority of OCD patients benefitted from dTMS, and the onset of improvement usually occurs within 20 sessions. Extending the treatment course beyond 29 sessions results in continued reduction of OCD symptoms, raising the prospect of value for extended treatment protocols in non-responders.

Deep transcranial magnetic stimulation for obsessive-compulsive disorder is efficacious even in patients who failed multiple medications and CBT.

OCD is a chronic and disabling disease with a lifetime prevalence of 2%-3%. About 40-60% of these patients do not adequately respond to pharmacotherapy and CBT. Deep transcranial magnetic stimulation (dTMS) was shown to be safe and effective as a treatment alternative for OCD and recently received regulatory approvals. Yet it is unclear whether patients who failed numerous medications and/or CBT can still benefit from dTMS. Here, we analyzed recent data from a double-blind multicenter dTMS study and found efficacy of this novel treatment even in OCD patient cohorts who previously failed to respond to multiple medications and CBT.

TMS-Induced Controlled BBB Opening: Preclinical Characterization and Implications for Treatment of Brain Cancer.

Proper neuronal function requires strict maintenance of the brain's extracellular environment. Therefore, passage of molecules between the circulation and brain neuropil is tightly regulated by the blood-brain barrier (BBB). While the BBB is vital for normal brain function, it also restricts the passage of drugs, potentially effective in treating brain diseases, into the brain. Despite previous attempts, there is still an unmet need to develop novel approaches that will allow safe opening of the BBB for drug delivery. We have recently shown in experimental rodents and in a pilot human trial that low-frequency, high-amplitude repetitive transcranial magnetic stimulation (rTMS) allows the delivery of peripherally injected fluorescent and Gd-based tracers into the brain. The goals of this study were to characterize the duration and safety level of rTMS-induced BBB opening and test its capacity to enhance the delivery of the antitumor growth agent, insulin-like growth factor trap, across the BBB. We employed direct vascular and magnetic resonance imaging, as well as electrocorticography recordings, to assess the impact of rTMS on brain vascular permeability and electrical activity, respectively. Our findings indicate that rTMS induces a transient and safe BBB opening with a potential to facilitate drug delivery into the brain.