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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 bilat­eral 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 (X(2)=5.655, p=0.017). Among completers (N=169), the CQR until Week 18 was 28.0% and 11.7%, respectively (X(2)=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 smok­ing cessation for adults.

Obsessive-compulsive disorder (OCD) is a chronic and disabling condition that often responds unsatisfactorily to pharmacological and psychological treatments. Converging evidence suggests a dysfunction of the cortical-striatal-thalamic-cortical circuit in OCD, and a previous feasibility study indicated beneficial effects of deep transcranial magnetic stimulation (dTMS) targeting the medial prefrontal cortex and the anterior cingulate cortex. The authors examined the therapeutic effect of dTMS in a multicenter double-blind sham-controlled study.At 11 centers, 99 OCD patients were randomly allocated to treatment with either high-frequency (20 Hz) or sham dTMS and received daily treatments following individualized symptom provocation, for 6 weeks. Clinical response to treatment was determined using the Yale-Brown Obsessive Compulsive Scale (YBOCS), and the primary efficacy endpoint was the change in score from baseline to posttreatment assessment. Additional measures were response rates (defined as a reduction of ≥30% in YBOCS score) at the posttreatment assessment and after another month of follow-up.Eighty-nine percent of the active treatment group and 96% of the sham treatment group completed the study. The reduction in YBOCS score among patients who received active dTMS treatment was significantly greater than among patients who received sham treatment (reductions of 6.0 points and 3.3 points, respectively), with response rates of 38.1% and 11.1%, respectively. At the 1-month follow-up, the response rates were 45.2% in the active treatment group and 17.8% in the sham treatment group. Significant differences between the groups were maintained at follow-up.High-frequency dTMS over the medial prefrontal cortex and anterior cingulate cortex significantly improved OCD symptoms and may be considered as a potential intervention for patients who do not respond adequately to pharmacological and psychological interventions.

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) 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 TMSHere 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).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.

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

Chronic treatment resistant depression takes a substantial toll on patients' quality of life and alternative treatment options are limited. This prospective multicenter study evaluated the safety, tolerability and efficacy of four weeks of thrice-a-week deep transcranial magnetic stimulation (dTMS) in combination with selective serotonin reuptake inhibitors (SSRIs).Forty patients who failed to respond during a 16-week double-blind placebo controlled (DBPC) trial of dTMS or sham dTMS as monotherapy were screened and started a treatment of previously tolerable but ineffective SSRI. After ten days of medication, high frequency dTMS was added three times a week for four weeks.dTMS combined with SSRIs was well tolerated, with only headaches as a related adverse event (n = 4), which did not cause drop outs. Six patients were excluded from analysis: 1 was missing screening data and 5 received less than 10 sessions. Out of 34 patients included in this study, 12 (35.3%) patients remitted (HDRS-21 10). No significant differences were found between patients who had received sham or active dTMS in the earlier DBPC multicenter trial.This was a small scale open study of dTMS with SSRIs in patients that failed to respond during a DBPC dTMS trial, although a carryover effect cannot be excluded. Comparative efficacy of dTMS with and without SSRIs and specific dosing and protocol parameters warrant specifically-designed large-scale controlled studies.Thrice weekly dTMS at 120% motor threshold(MT), 10 HZ, 3‑s trains, 20‑s intervals, 2400 daily pulses, can augment formerly ineffective SSRI treatment.

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.

Proper neuronal function requires strict maintenance of the brain&rsquo, s extracellular environment. Therefore, passage of molecules between the circulation and brain neuropil is tightly regulated by the blood&ndash, 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.

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.

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.

Low frequency repetitive TMS (rTMS) of a cortical seizure focus is emerging as an antiepileptic treatment. While conventional rTMS stimulators activate only superficial cortical areas, reaching deep epileptic foci, for example in temporal lobe epilepsy (TLE), is possible using specially designed H-coils. We report the results of rTMS in a young adult with pharmacoresistant bilateral TLE who underwent three courses (of 10, 15, and 30 daily sessions) of unilateral rTMS over the hemisphere from which seizures originated most often. Seizure frequency was assessed before and after each block of rTMS sessions, as was the tolerability of the procedure. Seizure frequency declined significantly, by 50 to 70% following each rTMS course. All sessions were well-tolerated.

The current study investigated the anxiolytic properties of the deep transcranial magnetic stimulation (DTMS) in unipolar major depression using a systematic literature review and meta-analysis. Compared to baseline, large anxiolytic and antidepressant outcomes were obtained after 20 daily sessions of high-frequency DTMS according to data from six open-label studies with 95 patients. Unlike the antidepressant effect, the anxiolytic effect was more heterogeneous among studies and did not depend on concurrent treatment with antidepressants.

Background An acute course of dTMS typically involves treatments delivered 5 days a week, for 4 weeks. Should more treatments be given if the patient has not responded? Data are needed to inform decisions about the best next steps for acute non-responders. Objective To characterize response among acute-phase non-responders in a randomized controlled trial of deep repetitive transcranial magnetic stimulation (dTMS) monotherapy for medication-resistant depression. Methods Summary statistics and Kaplan-Meier curves were used to characterize outcomes of 33 medication-free Brainsway™ dTMS non-responders to double blind but active treatment at the end of 4 weeks (20 sessions), who then continued double blind but active twice–weekly treatment for up to 12 additional weeks. Results 24 participants (72.7%) achieved responder status during at least one rating with dTMS continuation -- 20 (60.6%) within four weeks, with 13 (39.4%) consistently meeting response criteria for the duration of the study. 20 (63.6%) achieved remission status at some point during treatment continuation. Conclusions A significant proportion of acute course non-responders to dTMS treatment eventually respond with continued treatment. Continuing TMS treatment beyond the acute course for non-responders may result in eventual response in over half of these individuals.

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.

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 (dTMS) is a neurostimulation technique for deep brain structures that has recently been successfully applied in the clinic for the treatment of addiction. In contrast to the conventional magnetic stimulation, which uses planar coils [Figure-of-Eight (FoE)] to target specific superficial regions of the brain, dTMS requires the design of complex 3-D coils in order to induce deeply penetrating fields. Recent clinical studies have focused on the use of H4 coils, which utilizes a left–right symmetric structure for bilateral stimulation of the prefrontal cortex, and demonstrated efficacy for therapy such as smoking cessation. The mechanism of activity, however, remains poorly understood, in part because the affected regions of the brain are not known in detail. To this purpose, computational techniques applied to highly detailed inhomogeneous tissue phantoms provide a powerful tool for testing coil efficacy. In this work, we quantified both electric field ${\mathbf E}$ distribution and its penetration depth in the prefrontal cortex, induced by a specific Hesed-coil, H4, designed for the addiction treatment and by the traditional FoE coil for comparison. Results show that H4 coil preferentially targets the insula and cingulate cortex. Moreover, it can induce in the deepest tissues E amplitude ranging between 20% and 40% of the cortical peak, and it can penetrate the cortex up to 4 cm with a E > 50% of the cortical peak, thus noticeably increasing the penetration depth of the traditional TMS systems.

Background Tobacco smoking is the leading cause of preventable death in developed countries. Our previous studies in animal models and humans suggest that repeated activation of cue-induced craving networks followed by electromagnetic stimulation of the dorsal prefrontal cortex (PFC) can cause lasting reductions in drug craving and consumption. We hypothesized that disruption of these circuitries by deep transcranial magnetic stimulation (TMS) of the PFC and insula bilaterally can induce smoking cessation. Methods Adults ( N = 115) who smoke at least 20 cigarettes/day and failed previous treatments were recruited from the general population. Participants were randomized to receive 13 daily sessions of high-frequency, low-frequency or sham stimulation following, or without, presentation of smoking cues. Deep TMS was administered using an H-coil version targeting the lateral PFC and insula bilaterally. Cigarette consumption was evaluated during the treatment by measuring cotinine levels in urine samples and recording participants' self-reports as a primary outcome variable. Dependence and craving were assessed using standardized questionnaires. Results High (but not low) frequency deep TMS treatment significantly reduced cigarette consumption and nicotine dependence. The combination of this treatment with exposure to smoking cues enhanced reduction in cigarette consumption leading to an abstinence rate of 44% at the end of the treatment and an estimated 33% 6 months following the treatment. Conclusions This study further implicates the lateral PFC and insula in nicotine addiction and suggests the use of deep high-frequency TMS of these regions following presentation of smoking cues as a promising treatment strategy.

Deep transcranial magnetic stimulation (dTMS) is a relatively new technique that uses different coils for the treatment of different neuropathologies. The coils are made of soft copper windings in multiple planes that lie adjacent to the skull. They are located within a special helmet so that their magnetic fields combine and improve depth penetration. The H1 dTMS coil is designed to stimulate bilateral prefrontal cortices with greater effective stimulation over the left than the right. By positioning the left side of the coil close to the left dorsolateral prefrontal cortex (DLPFC), the H1 coil was used in a multisite study, leading to FDA approval for treatment-resistant depression. In this same position, the H1 coil was also explored as a possible treatment for negative symptoms of schizophrenia, bipolar depression, and migraine. When moved to different positions over the subject's skull, the H1 coil was also explored as a possible treatment for other conditions. Such manipulation of the H1 coil was demonstrated for PTSD and alcohol dependence by positioning it over the medial prefrontal cortex (mPFC), for anxiety by positioning it over the right prefrontal cortex (rPFC), for auditory hallucinations and tinnitus by positioning it over the temporoparietal junction (TPJ), and for Parkinson's and fatigue from multiple sclerosis (MS) by positioning it over the motor cortex (MC) and PFC. Corresponding electrical field diagrams measured with an oscilloscope through a saline-filled head are included.

Objective To compare the ability of an H-coil and figure-8 coil to stimulate different motor cortex regions. Methods The resting (rMT) and active (aMT) motor thresholds were measured for the right hand APB and leg AHB muscles in 10 subjects, using an H-coil and a figure-8 coil. The electric field distribution induced by the coils was measured in a head model. The combination of the hand and leg MTs with the field measurements was used to determine the depth of hand and leg motor areas via the intersection points. Results The rMT and aMT of both APB and AHB were significantly lower for the H-coil. The ratio and difference between the leg and hand rMT and aMT were significantly lower for the H-Coil. Electric field measurements revealed significantly more favorable depth profile and larger volume of stimulation for the H-coil. The averaged intersection for the APB was at a distance from coil of 1.83 ± 0.54 cm and at an intensity of 97.8 ± 21.4 V/m, while for the AHB it was at a distance of 2.73 ± 0.44 cm and at an intensity of 118.6 ± 21.3 V/m. Conclusion The results suggest a more efficient activation of deeper motor cortical regions using the H-coil. Significance The combined evaluation of MTs by H- and figure-8 coils allows measurement of the individual depth of different motor cortex regions. This could be helpful for optimizing stimulation parameters for TMS treatment.

Deep transcranial magnetic stimulation (dTMS) utilizes different H-coils to study and treat a variety of psychiatric and neurological conditions with identifiable brain targets. The availability of this technology is dramatically changing the practice of psychiatry and neurology as it provides a safe and effective way to treat even drug-resistant patients. However, up until now, no effort was made to summarize the different types of H-coils that are available, and the conditions for which they were tested. Areas covered: Here we assembled all peer reviewed publication that used one of the H-coils, together with illustrations of the effective field they generate within the brain. Currently, the technology has FDA clearance for depression and European clearance for additional disorders, and multi-center trials are exploring its safety and effectiveness for OCD, PTSD, bipolar depression and nicotine addiction. Expert commentary: Taken together with positive results in smaller scale experiments, dTMS coils represent a non-invasive way to manipulate pathological activity in different brain structures and circuits. Advances in stimulation and imaging methods can now lead to efficacious and logical treatments. This should reduce the stigma associated with mental disorders, and improve access to psychiatric treatment.

Literature studies showed the ability to treat neuropsychiatric disorders using H1 coil, developed for the deep Transcranial Magnetic Stimulation (dTMS). Despite the positive results of the clinical studies, the electric field (E) distributions inside the brain induced by this coil when it is positioned on the scalp according to the clinical studies themselves are not yet precisely estimated. This study aims to character- ize the E distributions due to the H1 coil in the brain of two realistic human models by computational electromagnetic techniques and to compare them with the ones due to the figure-of-8 coil, traditionally used in TMS and positioned as such to simulate the clinical experiments. Despite inter-individual differences, our results show that the dorsolateral prefrontal cortex is the region preferentially stimulated by both H1 and figure-of-8 coil when they are placed in the position on the scalp according to the clinical studies, with a more broad and non-focal distribution in the case of H1 coil. Moreover, the H1 coil spreads more than the figure-of-8 coil both in the prefrontal cortex and medial prefrontal cortex and towards some deeper brain structures and it is characterized by a higher penetration depth in the frontal lobe. This work highlights the importance of the knowledge of the electric field distribution in the brain tissues to interpret the outcomes of the experimental studies and to optimize the treatments.

In the last few years, deep transcranial magnetic stimulation (dTMS) has been used for the treatment of depressive disorders, which affect a broad category of people, from adolescents to aging people. To facilitate its clinical application, particular shapes of coils, including the so-called Hesed coils, were designed. Given their increasing demand and the lack of studies which accurately characterize their use, this paper aims to provide a picture of the distribution of the induced electric field in four realistic human models of different ages and gender. In detail, the electric field distributions were calculated by using numerical techniques in the brain structures potentially involved in the progression of the disease and were quantified in terms of both amplitude levels and focusing power of the distribution. The results highlight how the chosen Hesed coil (H7 coil) is able to induce the maxima levels ofEmainly in the prefrontal cortex, particularly for the younger model. Moreover, growing levels of induced electric fields with age were found by going in deep in the brain, as well as a major capability to penetrate in the deepest brain structures with an electric field higher than 50%, 70%, and 90% of the peak found in the cortex.

The H1-Coil is a novel transcranial magnetic stimulation (TMS) device capable of inducing a magnetic field with a deeper and wider distribution than standard coils. This pilot study evaluated the safety and feasibility of the H1-Coil as adjuvant treatment for bipolar depression (BPD).Nineteen patients diagnosed as having BPD and under treatment with psychotropic medication were enrolled in the study. They received daily prefrontal repetitive TMS (rTMS: 20 Hz, 2 s on, 20 s off, totaling 1680 stimuli) every weekday for four consecutive weeks. The primary outcome measure was the change from baseline in the Hamilton Depression Rating Scale (HDRS-24) score a week after the last treatment session.A significant mean decrease of 12.9 points in the HDRS-24 scale (P0.001) was found. Response rate was 63.2% and remission rate was 52.6%. Treatment was well tolerated in terms of headache and overall discomfort, and there were no significant change in cognitive functioning or mood switches. One patient had a short induced generalized seizure without complications.An add-on H-coil rTMS treatment protocol in BPD subjects indicated improvement in bipolar depression symptoms. Sham-control studies to further determine the efficacy and safety of the H-Coil for BPD are warranted.

Efficient stimulation of deeply located brain regions with transcranial magnetic stimulation (TMS) poses many challenges, arising from the fact that the induced field decays rapidly and becomes less focal with depth. We propose a new method to improve the efficiency of TMS of deep brain regions that combines high permeability cores, to increase focality and field intensity, with a coil specifically designed to induce a field that decays slowly with increasing depth. The performance of the proposed design was investigated using the finite element method to determine the total electric field induced by this coil/core arrangement on a realistically shaped homogeneous head model. The calculations show that the inclusion of the cores increases the field's magnitude by as much as 25% while also decreasing the field's decay with depth along specific directions. The focality, as measured by the area where the field's norm is greater than 1/sq.rt.2 of its maximum value, is also improved by as much as 15% with some core arrangements. The coil's inductance is not significantly increased by the cores. These results show that the presence of the cores might make this specially designed coil even more suited for the effective stimulation of deep brain regions.

Objective: The H-coils are a new development in transcranial magnetic stimulation (TMS) research, allowing direct stimulation of deeper neuronal pathways than does standard TMS. This study assessed possible health risks, and some cognitive and emotional effects, of two H-coil versions designed to stimulate deep portions of the prefrontal cortex, using several stimulation frequencies. Methods: Healthy volunteers (n = 32) were randomly assigned to one of four groups: each of two H-coil designs (H1/H2), standard figure-8 coil, and sham-coil control. Subjects were tested in a pre–post design, during three increasing (single pulses, 10 Hz, and 20 Hz) stimulation sessions, as well as 24–36 h after the last stimulation. Results: The major finding of the present study is that stimulation with the novel H-coils was well tolerated, with no adverse physical or neurological outcomes. Computerized cognitive tests found no deterioration in cognitive functions, except for a transient short-term effect of the H1-coil on spatial recognition memory on the first day of rTMS (but not in the following treatment days). On the other hand, spatial working memory was transiently improved by the H2-coil treatment. Finally, the questionnaires showed no significant emotional or mood alterations, except for reports on ‘detachment’ experienced by subjects treated with the H1-coil. Conclusions: This study provides additional evidence for the feasibility and safety of the two H-coil designs (H1/H2). Significance: The H-coils offer a safe new tool with potential for both research and clinical applications for psychiatric and neurological disorders associated with dysfunctions of deep brain regions. � 2007 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

The H-coils are a novel development in transcranial magnetic stimulation (TMS), designed to achieve effective stimulation of deep neuronal regions without inducing unbearable fields cortically, thus broadly expanding the potential feasibility of TMS for research and for treating various neurologic disorders. This study compared the field distribution of two H-coil versions, termed H1 and H2, and of a standard figure-of-eight coil. Three-dimensional electrical field distributions of the H1 and H2-coils, designed for effective stimulation of prefrontal regions, and of a standard figure-8 coil, were measured in a head model filled with physiologic saline solution. With stimulator output at 120% of the hand motor threshold, suprathreshold field is induced by the H1-coil at lateral and medial frontal regions at depths of up to 4 to 5 cm, and by the H2-coil at medial prefrontal regions up to 2 to 3 cm, and at lateral frontal regions up to 5 to 6 cm. The figure-8 coil induced suprathreshold field focally under the coil's central segment, at depths of up to 1.5 cm. The ability of the H-coils to stimulate effectively deeper neuronal structures is obtained at the cost of a wider electrical field distribution in the brain. However, the H-coils enable simultaneous stimulation of several brain regions, whereas the depth penetration in each region can be controlled either by adjusting the stimulator output, and/or by varying the distance between various coil elements and the skull.

In the last years, deep transcranial magnetic stimulation (dTMS) has become the main tool for the treatment of several neuropsychiatric disorders that involve deep brain regions. These pathologies include for example unipolar and bipolar disorders [1], major depressive disorders [2][3], post stroke [4] and vascular [5] depression, memory dysfunctions [6], diabetic neuropathy [7], Parkinson disease [8]. The physical principle that allows the therapeutic use of this technique is based on the induction of an electric field (E), through the coils placed close to the scalp, which safely modulate the activity of the cerebral structure of interest. Depending on the parameter of stimulation, that field can modify the excitability of the brain target. The effectiveness of this stimulation technique is univocally linked to the coil configurations, which should enable the activation of deep targets. This is even more critical for the pathologies listed above, which usually disturb elderly people. That is because they could be affected by the presence of prefrontal atrophy, which implies an increase of the distance between scalp and cortex, making even more difficult to reach deeper structures. Lately, great efforts have been carried on to develop specific coils, such as the family of the so called Hesed (H) coils, that are based on certain design principles and have larger dimension compared to conventional coils, to the specific purpose of improving the penetration depth of the stimulation. Despite clinical studies have attained positive outcomes of dTMS, the mechanism lying below them is not yet completely clear. In order to clarify this issue, the knowledge of the detailed E distribution induced inside cerebral tissues is the main and first step to be performed.

Noninvasive magnetic stimulation of the human central nervous system has been used in research and the clinic for several years. However, the coils used previously stimulated mainly the cortical brain regions but could not stimulate deeper brain regions directly. The purpose of the current study was to develop a coil to stimulate deep brain regions. Stimulation of the nucleus accumbens and the nerve fibers connecting the prefrontal cortex with the nucleus accumbens was one major target of the authors' coil design. Numeric simulations of the electrical field induced by several types of coils were performed and accordingly an optimized coil for deep brain stimulation was designed. The electrical field induced by the new coil design was measured in a phantom brain and compared with the double-cone coil. The numeric simulations show that the electrical fields induced by various types of coils are always greater in cortical regions (closer to the coil placement); however, the decrease in electrical field within the brain (as a function of the distance from the coil) is markedly slower for the new coil design. The phantom brain measurements basically confirmed the numeric simulations. The suggested coil is likely to have the ability of deep brain stimulation without the need to increase the intensity to levels that stimulate cortical regions to a much higher extent and possibly cause undesirable side effects.

Background Currently available TMS stimulators have a single channel operating a single coil. Objective To outline and present physical and physiological benefits of a novel convenient multi-channel stimulator, comprising five channels, where the stimulation parameters of each channel are independently controllable. Methods Simultaneous and sequential operation of various channels was tested in healthy volunteers. Paired pulses schemes with various inter-stimulus intervals (ISIs) were studied for the hand APB and the leg AH muscles. Energy consumption and coil heating rates with simultaneous operation of 4 channels was compared to a single figure-8 coil. Results Repetitive operation of separate channels with different stimulation parameters is demonstrated. The operations of various channels can be combined simultaneously or sequentially to induce multiple pulses with ISIs of μs resolution. A universal pattern of inhibition and facilitation as a function of ISI was found, with some dependence on coils configurations and on pulse widths. A strong dependence of the induced inhibition on the relative orientation of the conditioning and test pulses was discovered. The ability of this method to induce inhibition in shallow brain region but not in deeper region, thus focusing the effect in the deep brain region, is demonstrated. A significant saving in energy consumption and a reduction in coil heating were demonstrated for several channels operated simultaneously compared to a standard single channel figure-8 coil. Conclusions The multi-channel stimulator enables the synchronized induction of different excitability modulations to different brain regions using different stimulation patterns in various channels. Multiple pulses operation with coils with various depth profiles can increase the focality of TMS effect in deep brain regions.

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).

Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation technique that activates neurons via generation of brief pulses of high-intensity magnetic field. If these pulses are applied in a repetitive fashion (rTMS), persistent modulation of neural excitability can be achieved. The technique has proved beneficial in the treatment of a number of neurological and psychiatric conditions. However, the effect of rTMS on excitability and the other performance indicators shows a considerable degree of variability across different sessions and subjects. The frequency of stimulation has always been considered as the main determinant of the direction of excitability modulation. However, interactions exist between frequency and several other stimulation parameters that also influence the degree of modulation. In addition, the spatial interaction of the transient electric field induced by the TMS pulse with the cortical neurons is another contributor to variability. Consideration of all of these factors is necessary in order to improve the consistency of the conditioning effect and to better understand the outcomes of investigations with rTMS. These user-controlled sources of variability are discussed against the background of the mechanisms that are believed to drive the excitability changes. The mechanism behind synaptic plasticity is commonly accepted as the driver of sustained excitability modulation for rTMS and indeed, plasticity and rTMS share many characteristics, but definitive evidence is lacking for this. It is more likely that there is a multiplicity of mechanisms behind the action of rTMS. The different mechanisms interact with each other and this will contribute to the variability of rTMS-induced excitability changes. This review investigates the links between rTMS and synaptic plasticity, describes their similarities and differences, and highlights a neglected contribution of the membrane potential. In summary, the principal aims of this review are (i) to discuss the different experimental and subject-related factors that contribute to the variability of excitability modulation induced by rTMS, and (ii) to discuss a generalized underlying mechanism for the excitability modulation.

Stimulation of deep brain regions with Transcranial Magnetic Stimulation (TMS) may have an important role as a therapy to treat chemical dependency and depression. The coils traditionally used in TMS, however, have a poor performance in stimulating deep neurons. In this work we study the usage of high permeability cores combined with coils specifically designed to induce fields that decay slowly with depth. By using the finite elements method we show that the use of such cores increases the field's magnitude, decreases its decay rate and improves its focality. Such improvements make these high permeability core coils more suited to stimulate deep brain regions.

Repetitive transcranial magnetic stimulation (rTMS) is an established technique for noninvasive brain stimulation and widely used in basic and clinical neurophysiology. Yet, brain stimulation using