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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.

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.

BACKGROUND Major 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.METHODS The 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.RESULTS Clinical 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.CONCLUSION This 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 REGISTRATION ClinicalTrials.gov NCT03012724.FUNDING BrainsWay Ltd.

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.

TMS contaminates concurrent EEG recordings with Auditory Evoked Potentials (AEPs), which are caused by the perceived impulsive acoustic noise of the TMS coils. We hereby introduce a novel and perceptually motivated/tuned method for the suppression of auditory evoked EEG artifacts of rTMS under the name of “Auditory Fine-Tuned Suppressor of TMS-Clicks” (TMS-click AFTS). The proposed method is based on the deployment of a psychophysically-matched wide-band noise (WBN) masking stimulus, whose parametric synthesis and presentation are based upon adaptive psychophysical optimization. The masking stimulus is constructed individually for each patient/subject, thus facilitating aspects of precision medicine. A specially designed automation software is used for the realization of an adaptive procedure for optimal parameterization of masking noise level, optimizing both the subject’s comfort and the degree of AEP reduction. The proposed adaptive procedure also takes into account the combined effect of TMS intensity level and can as well account for any possibly available subject’s hearing acuity data. To assess the efficacy of the proposed method in reducing the acoustic effects of TMS, we performed TMS-EEG recordings with a 60 channel TMS-compatible EEG system in a cohort of healthy subjects (n = 10) and patients with epilepsy (n = 10) under four conditions (i.e., resting EEG with and without acoustic mask and sham TMS-EEG with and without acoustic mask at various stimulus intensity levels). The proposed approach shows promising results in terms of efficiency of AEP suppression and subject’s comfort and warrants further investigation in research and clinical settings.

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

Background: Transcranial magnetic stimulation (TMS) is a rapidly expanding technology utilized in research and neuropsychiatric treatments. Yet, conventional TMS configurations affect primarily neurons that are aligned parallel to the induced electric field by a fixed coil, making the activation orientation-specific. A novel method termed rotational field TMS (rfTMS), where two orthogonal coils are operated with a 90° phase shift, produces rotation of the electric field vector over almost a complete cycle, and may stimulate larger portion of the neuronal population within a given brain area. Objective: To compare the physiological effects of rfTMS and conventional unidirectional TMS (udTMS) in the motor cortex. Methods: Hand and leg resting motor thresholds (rMT), and motor evoked potential (MEP) amplitudes and latencies (at 120% of rMT), were measured using a dual-coil array based on the H7-coil, in 8 healthy volunteers following stimulation at different orientations of either udTMS or rfTMS. Results: For both target areas rfTMS produced significantly lower rMTs and much higher MEPs than those induced by udTMS, for comparable induced electric field amplitude. Both hand and leg rMTs were orientation-dependent. Conclusions: rfTMS induces stronger physiologic effects in targeted brain regions at significantly lower intensities. Importantly, given the activation of a much larger population of neurons within a certain brain area, repeated application of rfTMS may induce different neuroplastic effects in neural networks, opening novel research and clinical opportunities.

Transcranial magnetic stimulation (TMS) in humans induces electric fields (E-fields, EF) that perturb and modulate the brain’s endogenous neuronal activity and result in the generation of TMS-evoked potentials (TEPs). The exact relation of the characteristics of the induced E-field and the intensity of the brains’ response, as measured by electroencephalography (EEG), is presently unclear. In this pilot study, conducted on three healthy subjects and two patients with generalized epilepsy (total: 3 males, 2 females, mean age of 26 years; healthy: 2 males, 1 female, mean age of 25.7 years; patients: 1 male, 1 female, mean age of 26.5 years), we investigated the temporal and spatial relations of the E-field, induced by single-pulse stimuli, and the brain’s response to TMS. Brain stimulation was performed with a deep TMS device (BrainsWay Ltd., Jerusalem, Israel) and an H7 coil placed over the central area. The induced EF was computed on personalized anatomical models of the subjects through magneto quasi-static simulations. We identified specific time instances and brain regions that exhibit high positive or negative associations of the E-field with brain activity. In addition, we identified significant correlations of the brain’s response intensity with the strength of the induced E-field and finally prove that TEPs are better correlated with E-field characteristics than with the stimulator’s output. These observations provide further insight in the relation between E-field and the ensuing cortical activation, validate in a clinically relevant manner the results of E-field modeling and reinforce the view that personalized approaches should be adopted in the field of non-invasive brain stimulation.

(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.

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.

Diffusion-weighted magnetic resonance imaging (DWMRI) is sensitive to tissues' biophysical characteristics, including apparent diffusion coefficients (ADCs) and volume fractions of water in different populations. In this work, we evaluate the clinical efficacy of DWMRI and high diffusion-weighted magnetic resonance imaging (HDWMRI), acquired up to b = 4000 sec/mm2 to amplify sensitivity to water diffusion properties, in pretreatment prediction of brain tumors' response to radiotherapy. Twelve patients with 20 brain lesions were studied. Six ring-enhancing lesions were excluded due to their distinct diffusion characteristics. Conventional and DWMRI were acquired on a 0.5-T MRI. Response to therapy was determined from relative changes in tumor volumes calculated from contrast-enhanced Ti-weighted MRI, acquired before and a mean of 46 days after beginning therapy. ADCs and a diffusion index, RD, reflecting tissue viability based on water diffusion were calculated from DWMRIs. Pretreatment values of ADC and RD were found to correlate significantly with later tumor response/nonresponse (r = 0.76, P < .002 and r = 0.77, P < .001). This correlation implies that tumors with low pretreatment diffusion values, indicating high viability, will respond better to radiotherapy than tumors with high diffusion values, indicating necrosis. These results demonstrate the feasibility of using DWMRI for pretreatment prediction of response to therapy in patients with brain tumors undergoing radiotherapy.