Deep Repetitive Transcranial Magnetic Stimulation Research Articles

The Clinical Efficacy of Accelerated Deep Repetitive Transcranial Magnetic Stimulation in Depression and Obsessive-Compulsive Disorder: Multi-centric Real-World Observational Data.

Background Of late, the interest in accelerated treatment protocols in repetitive transcranial magnetic stimulation (TMS) for the treatment of depression and obsessive-compulsive disorder (OCD) has been gaining momentum. Studies have already found that the patterned theta burst stimulation is non-inferior to the standard high-frequency stimulation in treating depression. The objective of the present study was to evaluate the clinical efficacy of a customized accelerated combination TMS naturalistic setting. Methods Retrospective analysis of pre and post-deep repetitive TMSresponses in depression and OCD patients was performed. About 391 Depression and 239 OCD patients' data was analyzed. Customized treatment protocols consisted oftwice daily high-frequency stimulations intervened by one theta burst stimulation. The outcome measures were a day six score in depression and a day 10 score in OCD, compared to day one baseline scores. Results The overall response rate in depression was 60.86%, estimated as a >50% reduction in the Hamilton Depression Rating Scale (HAM-D) 21 items score, and 62.76% in OCD, estimated as a >35% reduction in the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) score. The mean reduction of YBOCS and HAM-D was statistically significant at p<0.0001(Mann-Whitney U test statistic=9442.5, z=12.66 for YBOCS and 16673.5, z=18.92 for HAM-D). Corresponding effect size estimations revealed Cohen's d value of 1.40 and 1.59, respectively. Conclusions The response rates achieved at day six and day 10 in depression and OCD, respectively, were comparable to previous studies employing standard treatment protocols. The accelerated protocol produced satisfactory short-term clinical outcomes that were effective in the early management of the illness without any serious adverse effects.

Efficacy of insula deep repetitive transcranial magnetic stimulation combined with varenicline for smoking cessation: A randomized, double-blind, sham controlled trial

BackgroundCurrent smoking cessation treatments are limited in terms of efficacy, particularly with regards to long term abstinence. There is a large amount of evidence implicating the insula in nicotine addiction. ObjectiveTo examine the efficacy of bilateral repetitive transcranial magnetic stimulation (rTMS) directed to the insular cortex with the H11 coil, relative to sham stimulation, on smoking abstinence and smoking outcomes in smokers who are receiving standard varenicline treatment. MethodsThis randomized, double-blind, sham controlled trial recruited 42 participants who were randomized to receive either active (n = 24) or sham (n = 18) high frequency rTMS directed to the insula (4 weeks), while receiving varenicline treatment (12 weeks). The primary outcome was 7-day point prevalence abstinence at the end of 12 weeks. ResultsSmokers in the active group had significantly higher abstinence rates than those in the sham group (82.4% vs. 30.7%, p = 0.013) at the end of treatment (Week 12). Secondary outcome measures of abstinence rate at the end of rTMS treatment (Week 4), abstinence rate at 6 months, and smoking outcomes (e.g., craving, withdrawal) showed no significant differences between groups. No differences were found in adverse events reported between the groups. ConclusionThis study provides evidence of the potential benefit of having a combined treatment for smoking cessation using insula rTMS with the H11 coil and varenicline. Maintenance rTMS sessions and continuation of varenicline for those in abstinence may induce longer-term effects and should be considered in future studies.

Safety of Deep Repetitive Transcranial Magnetic Stimulation (drTMS) against Medical Refractory Symptoms in Parkinson Syndromes: First German Real-World Data with a Specific H5 Coil.

So far, deep repetitive transcranial magnetic stimulation (drTMS) has shown promising results as an add-on treatment for Parkinson's disease (PD) but not for non-idiopathic Parkinson Syndromes (PS). We aimed to investigate the safety and feasibility of drTMS application in patients with different Parkinson Syndromes and medical refractory symptoms. Multifaceted real-world data (n = 21) were retrospectively analyzed regarding adverse effects as well as short-term effects of the drTMS treatment on patients' self-rated symptom severity and motor, cognitive, and emotional functions. The drTMS treatment with H5 coil included a sequential 1 Hz primary motor cortex stimulation contralateral to the more-affected body side and a bilateral 10 Hz stimulation of the prefrontal cortex. Overall, drTMS could be safely administered to patients with different PSs and medical refractory symptoms, but large variation was apparent in the rate and severity ratings of the reported adverse event/adverse device effect. The treatment significantly decreased the subjective main symptom severity. This effect was more pronounced in older patients with PD. Furthermore, analysis showed an improvement in depression, but no effect could be established in terms of cognitive performance. drTMS can be safely administered to patients with PS and medical refractory symptoms and can decrease the subjective motor symptom severity and depression.

A Case Series of Deep Transcranial Magnetic Stimulation Treatment for Patients with Obsessive-Compulsive Disorder in the Tokyo Metropolitan Area.

Obsessive-compulsive disorder (OCD) is a chronic illness in which patients do not achieve remission sufficiently with conventional medication. Deep repetitive transcranial magnetic stimulation (dTMS) for OCD neuromodulates the bilateral anterior cingulate cortex (ACC) and dorsal medial prefrontal cortex (mPFC), which are known to be impaired in OCD. While dTMS treatment for OCD has shown effective results overseas, TMS treatment for OCD has rarely been implemented in Japan, and its effectiveness is unknown. We conducted an FDA-approved dTMS protocol to 26 patients with OCD. In addition, individual exposure stimulation that elicited each patient’s obsessive thoughts was also combined during dTMS treatment. Before and after 30 sessions of TMS treatment, the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) was used to assess changes in the severity of each patient’s obsessive-compulsive disorder. Response to dTMS treatment in patients with OCD was determined by whether the total score on the Y-BOCS after a course of treatment was reduced by 30% or more compared with the score at baseline. The percentage of responders in this case series following the 30 sessions of dTMS treatment was 53.9%. In addition, total Y-BOCS scores and scores on each item were significantly improved. The percent changes in total Y-BOCS scores did not differ between the sexes or between on- and off-medication patients. No obvious adverse events were observed in this case series. In line with the results of TMS studies for OCD patients reported overseas, dTMS treatment for Japanese patients with OCD may have a favorable therapeutic effect.

Insula deep rTMS and varenicline for smoking cessation: A randomized control trial study protocol.

Background: Current approved therapies for smoking cessation have modest long-term effects for abstinence. The insular cortex has been identified by preclinical and clinical studies as a critical target for addiction treatment. Insula functions can be modulated non-invasively using brain stimulation. It is unknown if deep repetitive transcranial magnetic stimulation (rTMS) of the insula can improve smoking cessation of smokers trying to quit using varenicline. Methods: This will be a randomized, double-blind, sham-controlled clinical trial with 50 nicotine dependent smokers looking to quit. They will be randomly assigned to receive either active (10 Hz) or sham insula deep rTMS. Deep rTMS will be administered for 4 weeks (5 days/week). All participants will receive open label varenicline for 12 weeks. The primary outcome measure will be the 7-day point prevalence abstinence at the end of 12 weeks. The secondary outcomes will be Fagerström Test of Nicotine Dependence, Minnesota Nicotine Withdrawal Scale, Tiffany Questionnaire of Smoking Urges, expired carbon monoxide measurements, cigarettes smoked per day, point prevalence abstinence at end of 4 weeks, prolonged and continuous abstinence at 6 months. The measures will be collected throughout the 3-month treatment period as well as at the 6-month follow up. Discussion: This trial will test for the first time the impact of deep insula rTMS on smoking cessation in smokers treated with varenicline. This trial will use an H-coil specific to the insula, while previous studies have targeted both the insula and prefrontal cortex. This trial will inform on the utility to combine insula deep rTMS with varenicline to improve smoking abstinence rates. Clinical Trial Registration: Trial registered at https://clinicaltrials.gov/ct2/show/NCT04083144 (Identifier: NCT04083144).

Deep rTMS of the insula and prefrontal cortex in smokers with schizophrenia: Proof-of-concept study

Patients with schizophrenia have a high prevalence of cigarette smoking and respond poorly to conventional treatments, highlighting the need for new therapies. We conducted a mechanistic, proof-of-concept study using bilateral deep repetitive transcranial magnetic stimulation (dTMS) of insular and prefrontal cortices at high frequency, using the specialized H4 coil. Feasibility of dTMS was tested for disruption of tobacco self-administration, insula target engagement, and insula circuit modulation, all of which were a priori outcomes of interest. Twenty patients completed the study, consisting of weekday dTMS sessions (randomization to active dTMS or sham; double-blind; 10 patients per group), a laboratory tobacco self-administration paradigm (pre/post assessments), and multimodal imaging (three MRI total sessions). Results showed that participants assigned to active dTMS were slower to initiate smoking their first cigarette compared with sham, consistent with smoking disruption. The imaging analyses did not reveal significant Time × Group interactions, but effects were in the anticipated directions. In arterial spin labeling analyses testing for target engagement, an overall decrease in insula blood flow, measured during a post-treatment MRI versus baseline, was numerically more pronounced in the active dTMS group than sham. In fMRI analyses, resting-state connectivity between the insula and default mode network showed a numerically greater change from baseline in the active dTMS group than sham, consistent with a functional change to insula circuits. Exploratory analyses further suggested a therapeutic effect of dTMS on symptoms of psychosis. These initial observations pave the way for future confirmatory studies of dTMS in smoking patients with schizophrenia.

Differential Placebo Responses for Pharmacotherapy and Neurostimulation in Late-Life Depression

BackgroundThe magnitude of the placebo response depends on both the modality used as the “placebo” and the intervention with which it is compared, both of which can complicate the interpretation of randomized controlled trials (RCTs) for depression in late life. Given that neurostimulation and pharmacotherapy are among the most common interventions studied for late-life depression, comparing the relative placebo responses in studies of these interventions can aid interpretation of relative effect sizes. Materials and MethodsWe analyzed data from two RCTs of adults aged ≥60 years in an episode of treatment-resistant major depression, one comparing aripiprazole and matching placebo pills and the other comparing deep repetitive transcranial magnetic stimulation (rTMS) and sham rTMS. In both RCTs, depression was assessed using the 17-item Hamilton Depression Rating Scale (HDRS-17). The primary comparison occurred after four weeks using analysis of covariance (ANCOVA) of HDRS-17 scores in participants who received placebo pills or sham rTMS. Relevant covariates included years of education, duration of depressive episode, and baseline HDRS-17 score. ResultsAccounting for covariates, there was a larger reduction of HDRS-17 after four weeks in the sham rTMS group (estimated marginal mean ± SE: −5.90 ± 1.45; 95% CI: [−8.82, 2.98]) than in the placebo pills group (−1.07 ± 1.45; [−3.98, 1.85]). There were no significant differences between these groups in the binary outcome analysis of response and remission rates at four weeks or any outcome at trial end point comparison. ConclusionsSham rTMS may have a larger placebo response than placebo pills early in the treatment of older adults with treatment-resistant depression. Differential placebo responses should be considered in both the interpretation and design of RCTs.

Repetitive Transcranial Magnetic Stimulation in Alcohol Dependence: A Randomized, Double-Blind, Sham-Controlled Proof-of-Concept Trial Targeting the Medial Prefrontal and Anterior Cingulate Cortices

BackgroundAlcohol 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. MethodsThis 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. ResultsBoth 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. ConclusionsWe 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.

Deep rTMS of the insula disrupts cigarette self-administration and modulates insula-centric brain function in smokers with schizophrenia

Background: While cigarette smoking has plummeted in the general population, rates have stagnated in patients with schizophrenia. We tested a 3-week regimen of deep repetitive transcranial magnetic stimulation (dTMS) capable of reaching the insula, which plays an important role in maintaining smoking.

Effects of cerebellar transcranial magnetic stimulation on ataxias: A randomized trial

IntroductionCerebellar ataxia remains a neurological symptom orphan of treatment interventions, despite being prevalent and incapacitating. We aimed to study, in a double-blind design, whether cerebellar modulation could improve ataxia. MethodsWe included patients with diagnosis of spinocerebellar ataxia type 3, multiple systems atrophy cerebellar type, or post-lesion ataxia. Patients received five sessions each of sham and active cerebellar 1 Hz deep repetitive transcranial magnetic stimulation in randomized order. Our primary outcome was the decrease in the Scale for the Assessment and Rating of Ataxia when comparing phases (active x sham). Secondary outcomes measures included the International Cooperative Ataxia Rating Scale, and other motor, cognitive, and quality of life scales. This study was registered at clinicaltrials.gov (protocol NCT03213106). ResultsTwenty-four patients aged 29–74 years were included in our trial. After active stimulation, the Scale for the Assessment and Rating of Ataxia score was significantly lower than the score after sham stimulation [median (interquartile range) of 10.2 (6.2, 16.2) versus 12.8 (9.6, 17.8); p = 0.002]. The International Cooperative Ataxia Rating Scale score also improved after active stimulation versus sham [median (interquartile range) of 29.0 (21.0, 43.5) versus 32.8 (22.0, 47.0); p = 0.005]. Other secondary outcomes were not significantly modified by stimulation. No patient presented severe side effects, and nine presented mild and self-limited symptoms. ConclusionsOur protocol was safe and well-tolerated. These findings suggest that cerebellar modulation may improve ataxic symptom and provide reassurance about safety for clinical practice.

P188 Inducing motor cortical plasticity in Parkinson’s disease using subthalamic deep brain stimulation and repetitive transcranial magnetic stimulation

P188 Inducing motor cortical plasticity in Parkinson’s disease using subthalamic deep brain stimulation and repetitive transcranial magnetic stimulation

A Method to Provoke Obsessive Compulsive Symptoms for Basic Research and Clinical Interventions.

The efficacy of deep repetitive transcranial magnetic stimulation (dTMS) for obsessive compulsive disorder (OCD) was recently confirmed in a Food and Drug Administration-regulated, multicenter, sham-controlled study. In this study, patients who failed pharmacotherapy underwent individually tailored provocations just prior to each stimulation session, in the attempt to activate the relevant circuitry and making it labile to change. The procedure that was developed reliably evoked moderate intensity symptoms, making it effective on the one hand and mild enough to allow the patient to continue with the dTMS session on the other. This methodology article describes in a detailed step wise fashion how to evaluate the patient’s specific symptoms and design the individualized provocations. Additionally, the article explains how to instruct relevant personnel to administer the provocations, gauge their efficacy, and overcome possible obstacles. This method, apart from its ongoing role in the clinical treatment of OCD by dTMS, may be used for provocation of symptoms in basic studies [e.g., imaging with Electroencephalogram (EEG) or Functional magnetic resonance imaging fMRI] as well as other treatments.

Personality traits and antidepressant effects of deep repetitive transcranial magnetic stimulation (DTMS)

Background Previous studies have shown safety and efficacy of deep repetitive transcranial magnetic stimulation (DTMS) in treatment-resistant depression. However, little is known about predictors of response; i.e. it is difficult to predict which patients will benefit from the treatment. The aim of this study was to investigate the role of personality traits in predicting antidepressant effects of DTMS. Methods A total of 68 consecutive patients diagnosed with major depressive disorder (MDD) were treated with daily DTMS over the left dorsolateral prefrontal cortex for 4 weeks. At baseline, patients completed the IPIP50 (a five-factor assessment of major personality dimensions), Brief COPE (assessment of a broad range of coping responses), and LOTR-R test (measure of optimism versus pessimism). Antidepressant effects of DTMS were measured using the 21-item Hamilton Depression Rating Scale (HAMD) at baseline and at the conclusion of the treatment. Results Clinical remission (HAMD ≤ 9) was observed in 73% of the patients. Those who achieved remission had significantly higher baseline levels of conscientiousness, intellect/imagination and optimism, as well as higher scores on using humour, acceptance and religion as coping strategies, compared to other patients. Also, correlations were calculated between scores on personality traits and percentage improvement in HAMD scores. Significant positive associations were observed for dimensions of conscientiousness and intellect/imagination, and coping mechanisms: positive reframing, humour and acceptance. Conclusions The assessment of personality traits may have prognostic value in DTMS treatment for MDD. Further studies are needed to better clarify these preliminary findings.

Decrease in frequency of ketamine infusions after dTMS in a 19 year old patient with treatment resistant depression: Case report

Objective: Describe treatment and durability with deep repetitive transcranial magnetic stimulation (dTMS) in a highly treatment refractory depression patient allowing decreased frequency of ketamine infusions.

What intensity of deep repetitive transcranial magnetic stimulation is necessary to remit treatment resistant depression

What intensity of deep repetitive transcranial magnetic stimulation is necessary to remit treatment resistant depression

Alternative antidepressant deep transcranial magnetic stimulation protocols

Background: The remission rate for patients with pharmacotherapy resistant depression who undergo standard deep repetitive transcranial magnetic stimulation (dTMS) is almost 50%. This protocol consists of twenty daily treatments utilizing high-frequency (18Hz, 1980 pulses) stimulation to the left PFC (L-PFC). Its remission rate is second only to electroconvulsive therapy, which has significant cognitive side effects and poor durability. Nevertheless, alternative treatments for non-responders should be explored.

S156. Cognitive Effects of Deep Transcranial Magnetic Stimulation for Late-Life Depression

Late-life depression (LLD) is a growing global public health issue due to demographic changes. LLD is associated with cognitive functioning impairment. Deep repetitive transcranial magnetic stimulation (rTMS) is an emerging treatment for depression in younger adults associated with improved cognition; however, the impact of deep rTMS on cognition in LLD has not been explored.

The role of the prefrontal cortex in freezing of gait in Parkinson's disease: insights from a deep repetitive transcranial magnetic stimulation exploratory study.

Freezing of Gait (FOG) is one of the most debilitating gait impairments in Parkinson's disease (PD), leading to increased fall risk and reduced health-related quality of life. The utility of parkinsonian medications is often limited in the case of FOG and it frequently becomes dopamine resistant. Recent studies have suggested that pre-frontal cortex (PFC) dysfunction contributes to FOG; however, most previous findings provide only indirect evidence. To better understand the role of the PFC, we aimed to investigate the impact of high frequency, deep, repetitive transcranial magnetic stimulation (drTMS) of the medial PFC on FOG and its mediators. Nine patients with advanced PD participated in a randomized, cross-over exploratory study. We applied drTMS over the medial PFC for 16weeks, with real and sham conditions; each condition included an intensive (i.e., 3 times a week) phase and a maintenance (once a week) phase. Scores on a FOG-provoking test, the motor part of the Unified Parkinson's Disease Rating Scale, and gait variability significantly improved after real drTMS, but not after the sham condition. Self-report of FOG severity and cognitive scores did not improve. Due to discomfort and pain during treatment, two patients dropped out and the study was halted. These initial findings support the cause-and-effect role of the pre-frontal cortex in FOG among patients with PD. Due to the small sample size, findings should be interpreted cautiously. Further studies are needed to more fully assess the role of the medial PFC in the underlying mechanism of FOG and the possibility of using non-invasive brain stimulation to modify FOG.

61% of unmedicated treatment resistant depression patients who did not respond to acute TMS treatment responded after four weeks of twice weekly deep TMS in the Brainsway pivotal trial

BackgroundAn 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. ObjectiveTo characterize response among acute-phase non-responders in a randomized controlled trial of deep repetitive transcranial magnetic stimulation (dTMS) monotherapy for medication-resistant depression. MethodsSummary 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. Results24 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. ConclusionsA 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.

ID 295 – Deep repetitive transcranial magnetic stimulation with the H-coil in Alzheimer’s disease: A placebo-controlled, double-blind study

Objective Focal rTMS in Alzheimer’s disease (AD) revealed cognitive benefits. H-coil depolarize deeper and wider structures compared with focal coils, maybe targeting widespread networks involved in neurodegenerative disorders. We explored H-coil safety and efficacy in AD. Methods Thirty AD subjects (70.21 ± 8.66 y.o.), randomized in real or sham groups, underwent 16 rTMS sessions (3/week for 4 weeks, 1/week for other 4 weeks), over fronto-parieto-temporal lobes (10 Hz). Neuropsychological assessment was performed at baseline, after 4 weeks (4 w), at the end (8 w). Primary outcome: improvement in Alzheimer’s disease Scale-cognitive (ADAS-cog). Four subjects were excluded (1 acute myocardial infarction in the sham group, 1 misdiagnosis, 2 missing data), thus statistical analysis included 26 subjects. Results No serious side effects were reported. At 4 w, percent ADAS-cog improvement from baseline (4 w%) was greater in the real compared with the sham group ( p = 0.042). The relationship between baseline ADAS-cog and 4 w% differed between the two groups ( p = 0.009), with higher improvement for less cognitively impaired subjects at baseline only after real stimulation. Conclusions Excitatory deep rTMS appears feasible in AD with a promising safety and efficacy profile and may better impact the course of the disease when administered at earlier stages.