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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.

Objectives Abnormal functional brain asymmetry and deficient response inhibition are two core symptoms of attention deficit hyperactivity disorder (ADHD). We investigated whether these symptoms are inter-related and whether they are underlined by altered frontal excitability and by compromised interhemispheric connectivity. Methods We studied these issues in 52 ADHD and 43 non-clinical adults by comparing: (1) stop-signal reaction time (SSRT); (2) frontal asymmetry of the N200 event-related potential component, which is evoked during response inhibition and is lateralised to the right hemisphere; (3) TMS-evoked potential (TEP) in the right frontal hemisphere, which is indicative of local cortical excitability; and (4) frontal right-to-left interhemispheric TMS signal propagation (ISP), which is reversely indicative of interhemispheric connectivity. Results Compared to controls, the ADHD group demonstrated elongated SSRT, reduced N200 right-frontal-asymmetry, weaker TEP, and stronger ISP. Moreover, in the ADHD group, N200 right-frontal-asymmetry correlated with SSRT, with TEP, and with symptoms severity. Conversely, no relationship was observed between ISP and N200 right-frontal-asymmetry, and both TEP and ISP were found to be unrelated to SSRT. Conclusions Our results indicate that abnormal frontal asymmetry is related to a key cognitive symptom in ADHD and suggest that it is underlined by reduced right-frontal excitability.

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.

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.

(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.

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.

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.

Insula responses to drug cues are correlated with cravings, and lesions in this area reduce nicotine seeking. Here, we investigated the potential efficacy of repetitive transcranial magnetic stimulation (rTMS) targeting the insula in alcohol addiction. Treatment-seeking alcohol-dependent patients (Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition; N = 56) participated in this double-blind, sham-controlled, randomized trial. Participants received 10 Hz rTMS or sham using an H8 coil, 5 days a week for 3 weeks. Stimulation targeted insular cortex and overlaying regions bilaterally, while excluding anterior prefrontal areas. Craving and self-reported as well as biomarker-based drinking measures were collected at baseline, during treatment, and through 12 weeks. Resting-state magnetic resonance imaging (rsMRI) data were collected before and after treatment. Task-based MRI was used to probe brain correlates of reward processing, affective responses, and alcohol following completion of treatment. A marked overall decrease in craving and drinking measures was observed during treatment, but did not differ between rTMS or sham stimulation. Both groups equally increased their alcohol use following completion of treatment and through the 12-week follow-up. Analysis using seeds in the insula identified differences in resting-state connectivity between active and sham groups at completion of treatment, potentially indicating an ability of treatment to modify insula function. However, while each task robustly replicated brain responses established in the literature, no effects of rTMS were found. Collectively, this study does not support efficacy of rTMS targeting the insula in alcohol addiction.

Well-functioning error monitoring of the inner and outer environments is essential for adaptively altering behavior, while malfunction characterizes conditions such as obsessive–compulsive disorder (OCD). The underlying brain processing is manifested as Error-Related Negativity (ERN) signal elicited following error comission, and Perceived Error Related Theta Activity (PERTA) signal elicited following detection of discrepancy in the environment. Yet, while enhanced ERN was repeatedly demonstrated in OCD patients and was found to be potentiated among their unaffected first degree relatives, no comparable observations were reported with regard to PERTA. We recorded EEG activity while OCD patients, OCD patients’ siblings (Family), and healthy controls (HC) performed computerized tasks. For the examination of ERN we used the Stroop task and for the examination of PERTA we presented correct and incorrect mathematical equations. Increased ERN (0–120 ms post response) was observed in both the OCD and Family groups, but only the OCD patients’ signal significantly differed from that of HC's. Similarly, modified PERTA activity was observed in both the OCD and Family groups in the N1 peak (65–125 ms post perceived error), but only for the OCD group this activity significantly differed from that of HC. Both ERN and PERTA's N1 are fast occurring peaks, which suggests that OCD is associate with a constantly over-activated detection system that monitors the inner and outer environment and reacts promptly following detection of a mistake. Furthermore, the modified but non-significantly different activity of the Family group suggests that the pathological condition evolves in vulnerable individuals with neuronal predisposition.

Background As advances in neuroimaging further our understanding of the brain's functional connectivity, neuropsychology has moved away from a regional approach of attributing behavior to a specific region towards a network approach, attributing behavior to interconnected regions. A prime example of this is the suggested relevance of frontal asymmetry of the lateral prefrontal cortex (LPFC) in emotional processing. Yet, while neuroimaging defines relevant networks, it can only establish correlations and not causality. Objective We address this deficiency by applying cortico-cortical paired associative stimulation (ccPAS) to twenty-seven healthy, human participants (both genders represented equally). ccPAS involves TMS applied to two brain regions contemporaneously, changing the connectivity via Hebbian mechanisms. Methods We evaluate modifications in connectivity following ccPAS between the right and left LPFC that are dependent on the direction of ccPAS, i.e., which hemisphere is stimulated first. Participants performed an emotional reactivity task, assessed by measuring attentional bias, and brain activity was recorded with electroencephalogram (EEG) both at rest and in response to TMS pulses. Results We find that ccPAS modulates attentional bias bidirectionally depending on the order of stimulation. Furthermore, this modulation is accompanied by a change in frontal asymmetry. Measuring the direction of the information flow using TMS evoked potentials provides evidence that ccPAS strengthens inhibition from the hemisphere stimulated first to the hemisphere stimulated second. Conclusions Our findings provide causal evidence for the role of frontal asymmetry in emotional processing and establish ccPAS combined with the EEG measures as a tool to causally characterize functionality of neuronal circuits.

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

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.

BACKGROUND: Alcohol addiction is associated with a high disease burden, and treatment options are limited. In a proof-of-concept study, we used deep repetitive transcranial magnetic stimulation (dTMS) to target circuitry associated with the pathophysiology of alcohol addiction. We evaluated clinical outcomes and explored associated neural signatures using functional magnetic resonance imaging. METHODS: This was a double-blind, randomized, sham-controlled trial. A total of 51 recently abstinent treatment-seeking patients with alcohol use disorder (moderate to severe) were randomized to sham or active dTMS, using an H7 coil targeting midline frontocortical areas, including the medial prefrontal and anterior cingulate cortices. Treatment included 15 sessions over 3 weeks, followed by five sessions over 3 months of follow-up. Each session delivered 100 trains of 30 pulses at 10 Hz. The primary predefined outcome was reduction in percentage of heavy drinking days, obtained using timeline follow-back interviews. Secondary analyses included self-reports of craving, ethyl glucuronide in urine, and brain imaging measures. RESULTS: Both craving after treatment and percentage of heavy drinking days during follow-up were significantly lower in the active versus sham control group (percentage of heavy drinking days = 2.9 +/- 0.8% vs. 10.6 +/- 1.9%, p = .037). Active dTMS was associated with decreased resting-state functional connectivity of the dorsal anterior cingulate cortex with the caudate nucleus and decreased connectivity of the medial prefrontal cortex to the subgenual anterior cingulate cortex. CONCLUSIONS: We provide initial proof-of-concept for dTMS targeting midline frontocortical structures as a treatment for alcohol addiction. These data strongly support a rationale for a full-scale confirmatory multicenter trial. Therapeutic benefits of dTMS appear to be associated with persistent changes in brain network activity. Funding Agencies|European Union [668863-SyBil-AA]; Swedish Research Council [2013-07434]

In a pilot study involving methamphetamine dependents receiving deep Transcranial Magnetic Stimulation (dTMS) targeting the medial prefrontal and cingulate cortices with H7 coil (Brainsway, Israel), we assessed clinical outcomes from patients receiving 20 sessions of dTMS treatments over 4 weeks (5 days on, 2 days off). Although the primary outcome was the behavioral changes related to addiction, we encountered a phenomenon of robust increases in sexual dreams and emission in a patient recruited for this study, which may inform alterations in cortical excitability following dTMS treatment.

Background: Pilot open-label application of high-frequency repetitive transcranial magnetic stimulation (rTMS) with H-coil in Parkinson's Disease (PD) have shown promising results.Objective: To evaluate safety and efficacy of high-frequency rTMS with H-coil in PD in a double-blind, placebo-controlled, randomized study.Methods: Sixty patients with PD were randomized into 3 groups: M1-PFC (real stimulation on primary motor-M1 and pre-frontal cortices-PFC), M1 (real rTMS on M1, sham on PFC), Sham (apparent stimulation). Primary outcome was baseline-normalized percent improvement in UPDRS part III OFF-therapy at the end of treatment (12 rTMS sessions, 4 weeks). Secondary outcomes were improvement in UPDRS part III sub-scores, timed tests, and neuropsychological tests. Statistical analysis compared improvement following real and sham stimulation at the end of the protocol using either a t-test or a Mann-Whitney test.Results: All patients tolerated the treatment and concluded the study. One patient from M1-PFC group was excluded from the analysis due to newly discovered uncontrolled diabetes mellitus. No serious adverse effect was recorded. At the end of treatment, patients receiving real rTMS (M1-PFC and M1 combined) showed significantly greater improvement compared to sham in UPDRS part III total score (p = 0.007), tremor subscore (p = 0.011), and lateralized sub-scores (p = 0.042 for the more affected side; p = 0.012 for the less affected side). No significant differences have been oserved in safety and efficacy outcomes between the two real rTMS groups. Notably, mild, not-distressing and transient dyskinesias occurred in 3 patients after real rTMS in OFF state.Conclusions: The present findings suggest that high-frequency rTMS with H-coil is a safe and potentially effective procedure and prompt larger studies for validation as add-on treatment in PD.

This article is based on a consensus conference, promoted and supported by the International Federation of Clinical Neurophysiology (IFCN), which took place in Siena (Italy) in October 2018. The meeting intended to update the ten-year-old safety guidelines for the application of transcranial magnetic stimulation (TMS) in research and clinical settings (Rossi et al., 2009). Therefore, only emerging and new issues are covered in detail, leaving still valid the 2009 recommendations regarding the description of conventional or patterned TMS protocols, the screening of subjects/patients, the need of neurophysiological monitoring for new protocols, the utilization of reference thresholds of stimulation, the managing of seizures and the list of minor side effects. New issues discussed in detail from the meeting up to April 2020 are safety issues of recently developed stimulation devices and pulse configurations; duties and responsibility of device makers; novel scenarios of TMS applications such as in the neuroimaging context or imaging-guided and robot-guided TMS; TMS interleaved with transcranial electrical stimulation; safety during paired associative stimulation interventions; and risks of using TMS to induce therapeutic seizures (magnetic seizure therapy). An update on the possible induction of seizures, theoretically the most serious risk of TMS, is provided. It has become apparent that such a risk is low, even in patients taking drugs acting on the central nervous system, at least with the use of traditional stimulation parameters and focal coils for which large data sets are available. Finally, new operational guidelines are provided for safety in planning future trials based on traditional and patterned TMS protocols, as well as a summary of the minimal training requirements for operators, and a note on ethics of neuroenhancement.

ADHD is one of the most prevalent neurocognitive disorders. Deep Transcranial Magnetic Stimulation (dTMS) is a non-invasive neuromodulation tool that holds promise in treatment of neurocognitive disorders. Hypoactivity of the prefrontal cortex (PFC) has been observed in ADHD. This study examined the clinical, cognitive, and neural effects of dTMS to the PFC in adults with ADHD by using functional magnetic resonance imaging (fMRI). High frequency repetitive dTMS was applied to either the right or left PFC in 62 adults with ADHD in a randomized, double blind, placebo controlled protocol with 3 study groups: 2 treatment arms (rPFC, or lPFC) and a Sham arm. The study included 15 dTMS/cognitive training treatment sessions. Clinical effects were assessed with the Conners Adult ADHD Rating Scale (CAARS) self-report and the Clinical Global Impression score (CGI) as primary outcome measures. Self-report/observer questionnaires and computerized cognitive testing were also performed to assess clinical and cognitive effects. Neural effects were assessed with fMRI using working-memory (WM) and resting-state paradigms. While the study did not show improvement in the primary endpoints, significant improvements were observed in the CAARS (self-report) inattention/memory sub-scale, as well as increased activations in the rDLPFC, right parietal-cortex and right insula/IFG during WM conditions after treatment in the right stimulation group. Increased rDLPFC activation was associated with larger symptom improvement in the right stimulation group. This study indicates that dTMS is effective in modulating attention related brain networks, and is a feasible technique that may improve attention symptoms in adults with ADHD.

Focal repetitive transcranial magnetic stimulation (rTMS) has been applied to improve cognition in Alzheimer's disease (AD) with conflicting results. We applied rTMS in AD in a pilot placebo-controlled study using the H2-coil. H-coils are suitable for targeting wider neuronal structures compared with standard focal coils, in particular the H2-coil stimulates simultaneously the frontal-parietal-temporal lobes bilaterally. Thirty patients (mean age 70.9 year, SD 8.1; mean MMSE score 16.9, SD 5.5) were randomized to sham or real 10 Hz rTMS stimulation with the H2-coil. Each patient underwent 3 sessions/week for 4 weeks, followed by 4 weeks with maintenance treatment (1 session/week). Primary outcome was improvement of ADAS-cog at 4 and 8 weeks compared with baseline. A trend toward an improved ADAS-cog score over time was observed for patients undergoing real rTMS, with actively treated patients experiencing a mean decrease of −1.01 points at the ADAS-Cog scale score per time point (95% CIs −0.02 to −3.13, p < 0.04). This trend was no longer evident 2 months after the end of treatment. Real rTMS showed no significant effect on MMSE and BDI changes over time. These preliminary findings suggest that rTMS with H-coil is feasible and safe in patients with probable AD and might provide beneficial, even though transient, effects on cognition. This study prompts larger studies in the early stages of AD, combining rTMS and cognitive rehabilitation.Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT04562506.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation method that is increasingly used to treat psychiatric disorders, primarily depression. Initial studies suggest that rTMS may help treat addictions, but evaluation is required in a multicenter randomized controlled trial (RCT). METHODS: Here, we tested in chronic smokers whether repeated bilateral rTMS of the lateral prefrontal and insular cortices reduces cigarette craving and consumption and increases quit rates. This multicenter RCT included 14 sites and 262 chronic smokers who received Active or Sham rTMS. Participants received three weeks of daily rTMS sessions following cue-induced craving and were monitored up to four months. The primary outcome was the four-week continuous quit rate (CQR) measured by daily smoking diaries and verified by urine cotinine measures. Secondary outcome measures included changes in cigarette consumption and craving. This trail is registered at ClinicalTrials.gov, number NCT02126124. RESULTS: In the intent to treat analysis set, CQR was 19·4% following Active and 8·7% following Sham rTMS (χ 2 = 5·655, p=0·017). Among completers (N=169), CQR was 28·0% and 11·7%, respectively (χ 2 = 7·219, p=0·007). CQR within the first six weeks was 25·3% (Active) and 6·4% (Sham) (χ 2 = 11·885, p=0·0006), of which 63% (Active) and 50% (Sham) remained abstinent for at least four months (χ 2 =8·46, p=0·003). Significant between-group differences in cigarette consumption and craving emerged as early as two weeks into treatment. CONCLUSIONS: This study establishes a safe treatment protocol that promotes smoking cessation by stimulating the relevant brain circuits. It represents the first large multicenter RCT of brain stimulation for addiction medicine. Funded by: BrainsWay Declaration of Interest: Oscar Morales occasional reports consult work for Brainsway; Dr. Tendler reports personal fees from Brainsway, other from Advanced Mental Health Care Inc./DTMS Center LLC, outside the submitted work; Dr. Roth reports personal fees from Brainsway, outside the submitted work; In addition, Dr. Roth has a patent US 7,407,478 with royalties paid; Mr. Deutsch reports personal fees from Brainsway, during the conduct of the study; personal fees from Brainsway, outside the submitted work; David Feifel reports he is a member of Brainsway's Scientific Advisory Board (non-compensated); Dr. Duffy reports other from Brainsway, during the conduct of the study; other from Alivation Health LLC and Alivation Research LLC, outside the submitted work; Prof. Abraham Zangen is an inventor of Deep TMS coils which were patented by the NIH and other academic institutions where Abraham Zangen worked. These patents were licensed to BrainsWay and Abraham Zangen receives royalties from these patents. In addition Prof. Zangen serves as consultant for BrainsWay and has finanacial insterests in BrainsWay; Dr. Todder reports other from BRAINSWAY, during the conduct of the study; all other authors have nothing to disclose. Ethical Approval:The trial protocol (Supplementary Materials; SM 1.1) was approved by local institutional review boards and was registered at clinicaltrials.gov (NCT02126124). The study was conducted in the United States (12 sites) and Israel (two sites), with active enrollment from August 2014 through August 2019. The trial was supported by industry (BrainsWay).

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.

Obesity is associated with food and eating addiction (FA), but the biobehavioral markers of this condition are poorly understood. To characterize FA, we recruited 18 healthy controls and overweight/obese adults with (n = 31) and without (n = 17) FA (H-C, FAOB, NFAOB, respectively) to assess alpha brain asymmetry at rest using electroencephalogram, event-related potentials following exposure to high-calorie food (HCF), low-calorie food (LCF), and nonfood (NF) images in a Stroop paradigm, reaction time reflective of the Stroop bias, and symptoms of depression and disordered eating behavior. The FAOB group had the greatest emotional and uncontrollable eating, depressive, and binge-eating symptoms. The FAOB group displayed lower resting left alpha brain asymmetry than that of the NFAOB group. Differently from the other groups, the FAOB group presented attenuated Stroop bias following exposure to HCF relative to NF images, as well as a lower late positive potential component (LPPb, 450&ndash, 495 ms) in both frontal and occipital regions. In the total cohort, a correlation was found between the Stroop bias and the LPPb amplitude. These results point to biobehavioral hypervigilance in response to addictive food triggers in overweight/obese adults with FA. This resembles other addictive disorders but is absent in overweight/obesity without FA.

Background/objectives Repetitive transcranial magnetic stimulation (rTMS) has been recognized as a promising intervention for the treatment of post-stroke motor deficits. Here, we explore safety, feasibility, and potential effectiveness of high-frequency rTMS (HF-rTMS) delivered with the Hesed coil (H-coil) during active cycling on paretic lower extremity (LE) motor function in chronic stroke. Materials and methods Twelve subjects with a first-ever stroke were recruited in this double-blind, placebo controlled, crossover study. Eleven sessions of HF-rTMS (40 2s-trains of 20 Hz at 90% resting leg motor threshold) were delivered over the LE motor areas using the H-coil during active cycling for three weeks. Each subject underwent both real and sham rTMS treatments separated by a four-week washout period, in a random sequence. Vital signs were recorded before and after each rTMS session. Any discomfort related to stimulation and side effects were recorded. LE function was also evaluated with Fugl-Meyer assessment (FMA-LE), spasticity was assessed with modified-Ashworth scale and measures of gait speed and endurance (10-meter and 6-min walk tests, respectively) were recorded. Results No participant reported serious adverse effects. During real rTMS, 4 of 12 subjects reported mild side effects including transitory dizziness and muscle twitches on shoulder, so that intensity of stimulation initially set at 90% of RMT was reduced to 80% of RMT on average in these four subjects. Only real treatment was associated with a significant and sustained improvement in FMA-LL (67% responders vs. 9% of the sham). Spasticity significantly ameliorated only after the real rTMS. Real treatment did not offer advantages on walking timed measures when compared with sham. Conclusions This exploratory study suggests that bilateral HF-rTMS combined with cycling is safe and potentially effective in ameliorating paretic LE motor function and spasticity, rather than gait speed or endurance, in chronic stroke.

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.

Attention deficit hyperactivity disorder (ADHD) is a prevalent disorder with effective pharmacological treatment that benefits most patients. However, about one-third fail to benefit while others search non-pharmacological alternatives, and for those options are scarce. One alternative treatment option is to alter abnormal right prefrontal cortex (rPFC) activity, given that rPFC abnormality has been repeatedly implicated in ADHD neurophathology. Here, we evaluated whether targeting the rPFC with multiple sessions of repetitive transcranial magnetic stimulation (rTMS), which can modulate neuronal excitability, activity, and plasticity in a non-invasive manner, will affect clinical symptoms in adults suffering from ADHD. Concomitantly, we used EEG to characterize electrophysiological alterations induced by treatment and to search for correlation between baseline neuronal activity and clinical response. Forty-three drug free adults with ADHD were randomized to receive either Real, Active Control, or Sham treatment (13 females, age ranging 21-46; n = 15, 14, 14, respectively), and underwent three weeks of daily high-frequency (18 Hz) stimulation sessions. We found that Real treatment was safe and resulted in significant improvement of symptoms (η2p = 0.34; Cohen's d(against Sham) = 0.96; Cohen's d(against AC) = 0.68; p = 0.00085). Furthermore, based on EEG recorded within the first treatment session we established a novel biomarker, composed of the Alpha and Low-gamma power, which highly correlated the magnitude of the clinical outcome (r = 0.92, p = 0.0001). Taken together, the results of this pilot study indicate safety and effectiveness of rTMS directed to the rPFC for treatment of adult ADHD patients. The biomarker is suggested to reflect the responsiveness of the cortex to this rTMS intervention. Following validation of the results in larger samples, this study may represent a step towards a non-pharmacological treatment for adults with ADHD using EEG-based selection of optimal candidates for treatment.

Background Low frequency (≤1 Hz) repetitive transcranial magnetic stimulation (rTMS) has been shown to suppress cortical excitability and is beginning to be trialed for the treatment of refractory epilepsy. Purpose As a step toward a larger trial, the current pilot study was aimed to test the tolerability and safety of temporal lobe rTMS using H-coil for the treatment of temporal lobe epilepsy (TLE). Research Design 1800 pulses of active or sham rTMS were applied 5 days a week for 2 weeks over the temporal lobe of the affected hemisphere. Results Nine participants were enrolled and randomized to verum or sham stimulation. One participant dropped out from the sham group after 5 rTMS sessions. In-session, 3 patients had typical seizures during sham stimulation. One patient had seizures also during active stimulation (albeit fewer than during sham). Minor reported adverse events during stimulation otherwise included transient neck pain and headache, and were reported in equal numbers in both groups. Major adverse events were not reported. Our results indicate that H-coil rTMS was well-tolerated. Conclusion Given the relatively high prevalence of individuals with TLE who are treatment-resistant and the preliminary results of this study, we suggest that a larger safety and efficacy trial of 1 Hz rTMS for the treatment of TLE is warranted.

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.

Late-life depression (LLD) is a growing worldwide problem due to demographic changes, with limited treatment options due to high rates of pharmacotherapy adverse effects, accessibility of psychotherapy, and tolerability of electroconvulsive therapy. Novel neuromodulation techniques, such as repetitive transcranial magnetic stimulation (rTMS), may overcome these limitations. The objective of this study is to determine the efficacy, tolerability, and cognitive effects of high-dose deep rTMS in LLD. In this study we randomized older adults between 60 and 85 years old with major depressive disorder (MDD) to sham or active deep rTMS (H1 coil, 6012 pulses, 18 Hz, 120% of resting motor threshold) delivered over the dorsolateral and ventrolateral prefrontal cortex 5 days per week over 4 weeks. Our primary outcome was remission of depression in an intention-to-treat analysis. We also assessed change in cognitive functioning with rTMS treatment and tolerability based on adverse effects. Fifty-two participants were randomized to active (n = 25) or sham H1 coil (n = 27). Remission rate was significantly higher with active than sham rTMS (40.0% vs 14.8%) with a number needed to treat of 4.0 (95% CI: 2.1-56.5). There was no change on any measure of executive function and no serious adverse events. Adverse effect profiles were similar between active and sham rTMS, except for reports of pain being significantly more common in the active condition (16.0% vs 0%). High-dose deep rTMS appears to be safe, well tolerated, and efficacious in the treatment of LLD.

Background Dorsolateral prefrontal cortex (DLPFC) is critically involved in mood and alcohol use disorders. Objective : We aimed to investigate the safety of intervention with add-on bilateral prefrontal high-frequency deep transcranial magnetic stimulation (dTMS) and between-group differences in treatment response in patients with different types of depressive episodes, including major depressive episodes in the course of major depressive disorder (MDD), bipolar disorder, type I (BD-I), and MDD with alcohol use disorder (MDAUD). Methods We conducted a 6-month open-label study, involving 82 patients with DSM-5 Depressive Episode. Of these, 41 had diagnosis of MDD, 20 BD-I, and 21 MDAUD. All patients received standard drug treatment and add-on dTMS over the bilateral DLPFC with left prevalence for four weeks, with five sessions in each week. We rated mood state with the Hamilton Depression Rating Scale (HDRS) at baseline, one-month, and six-month follow-up visits. Results Mean total HDRS scores dropped from 22.8 (SD = 5.9) at baseline to 10.4 (SD = 3.6) at 1 month, to 10.0 (SD = 4.5) at 6 months, while response/remission were 70.73% ( N = 58) and 19.51% ( N = 16) at 1 month and 76.83% ( N = 63) and 32.93% (27) at 6 months, respectively, with no between-group differences. No patient experienced any side effects. Conclusions High-frequency DLPFC dTMS was well tolerated and did not significantly differ on improvement of depression in MDD, BD-I, and MDAUD.

To study the effects of a repetitive deep transcranial magnetic stimulation (rDTMS) in patients with Parkinson disease using the H5 coil for the low-frequency stimulation of the primary motor cortex, followed by the high-frequency rDTMS of the prefrontal cortex.The main outcome measures were the total and motor scores of the Unified Parkinson's Disease Rating Scale (UPDRS). Secondary measures included rating of depression and quantitative motor tasks.Forty-eight patients were randomized 1:1 into real or sham rDTMS treatment arms. Analyses (n = 42) of both UPDRS scores revealed a significant main effect for time between baseline and day 90 (end of treatment), indicating that there was an improvement of both scores over time in the whole sample. Although effects of treatment and time-by-treatment were insignificant, simple effects analysis of both measures was significant in the rDTMS group and reached a P-value of 0.06 in the sham group. The response rate was higher in patients with longer disease duration and higher motor UPDRS scores. Side effects were more common in the rDTMS group but were transient and tolerable.Although rDTMS treatment exhibited some motor improvements, we could not demonstrate an advantage for real treatment over sham. Further research is required to establish stimulation parameters that may induce potentially more beneficial outcomes, probably in patients with longer and more sever disease.

Background Obsessive Compulsive Disorder (OCD) is a chronic and disabling disorder with poor response to pharmacological treatments. Converging evidences suggest that OCD patients suffer from dysfunction of the cortico-striato-thalamo-cortical (CSTC) circuit, including in the medial prefrontal cortex (mPFC) and the anterior cingulate cortex (ACC). Objective To examine whether modulation of mPFC-ACC activity by deep transcranial magnetic stimulation (DTMS) affects OCD symptoms. Methods Treatment resistant OCD participants were treated with either high-frequency (HF; 20 Hz), low-frequency (LF; 1 Hz), or sham DTMS of the mPFC and ACC for five weeks, in a double-blinded manner. All treatments were administered following symptoms provocation, and EEG measurements during a Stroop task were acquired to examine changes in error-related activity. Clinical response to treatment was determined using the Yale-Brown-Obsessive-Compulsive Scale (YBOCS). Results Interim analysis revealed that YBOCS scores were significantly improved following HF (n = 7), but not LF stimulation (n = 8), compared to sham (n = 8), and thus recruitment for the LF group was terminated. Following completion of the study, the response rate in the HF group (n = 18) was significantly higher than that of the sham group (n = 15) for at least one month following the end of the treatment. Notably, the clinical response in the HF group correlated with increased Error Related Negativity (ERN) in the Stroop task, an electrophysiological component that is attributed to ACC activity. Conclusion HF DTMS over the mPFC-ACC alleviates OCD symptoms and may be used as a novel therapeutic intervention. Notwithstanding alternative explanations, this may stem from DTMS ability to directly modify ACC activity.

Objective Here we bring a neurophysiological diagnostic tool, based on pathophysiologically-relevant brain region, that is critical for reducing the variability between clinicians, and necessary for quantitative measures of ADHD severity. Methods 54 healthy and 57 ADHD adults participated in the study. Electroencephalography (EEG) was recorded when combined with transcranial magnetic stimulation (TMS) over the right prefrontal cortex and also recorded during the Stop Signal task. Results TMS evoked potentials (TEPs) and the event related potential (ERP) components in the Stop Signal task were found to be significantly reduced in ADHD relative to the matched healthy controls. Stop signal reaction time (SSRT) and stopping accuracy was found to correlate with the ERP signal, and ADHD severity correlated with the TEP signal. Cortical activity (early TEP and Stop Signal ERP) diagnostic model yielded accuracy of 72%. Conclusion TEPs and ERPs reveal that right PFC excitability was associated with ADHD severity, and with behavioral impulsivity – as a hallmark of ADHD pathology. This electrophysiological biomarker supports the potential of objective diagnosis for ADHD. Significance Such tools would allow better assessment of treatment efficacy and prognosis, may advance understanding of the pathophysiology of the disease and better the public's attitudes and stigma towards ADHD. Trial Registration: Trial to Evaluate the Efficacy of the HLPFC Coil Deep Transcranial Magnetic Stimulation System in Treating Attention Deficit and Hyperactivity Disorder (ADHD) in Adults, https://clinicaltrials.gov/ct2/show/NCT01737476 , ClinicalTrials.gov number NCT01737476