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Transcranial magnetic stimulation is an increasingly popular FDA-approved treatment for resistant depression, migraines, and OCD. Research is also underway for its use in various other psychiatric and medical disorders. Although rare, seizures are a potential adverse event of TMS treatment. In this article, we discuss TMS-related seizures with the various coils used to deliver TMS, the risk factors associated with seizures, the differential diagnosis of its presentations, the effects of sleep deprivation and alcohol use on seizures, as well as seizure risks with protocols for traditional TMS, theta-burst stimulation, and accelerated TMS. A discussion is presented comparing the potential risk of seizures with various psychotropic medications versus TMS. Included are case reports of TMS seizures in the child/adolescent patient, bipolar disorder patients, patients with a history of a traumatic brain injury, and those with epilepsy. Reports are also shared on TMS use without seizures in patients with a history of head injuries and TMS's continued use if patients have a seizure during their TMS treatment. Findings generated in this review suggest the following. Seizures, if present, are usually self-limiting. Most treatment recommendations for TMS-related seizures are supportive in nature. The risk of TMS-related seizures is <1% overall. TMS has successfully been used in patients with epilepsy, traumatic brain injuries, and those with a prior TMS-related seizure. The rate of TMS-related seizures is comparable to that of most psychotropic medications. While having a seizure is a rare but serious adverse effect of TMS, the benefits of treating refractory depression with TMS may outweigh the risk of suicidal ideation and other significant complications of depression.

Treatment-resistant major depressive disorder is common; repetitive transcranial magnetic stimulation (rTMS) by use of high-frequency (10 Hz) left-side dorsolateral prefrontal cortex stimulation is an evidence-based treatment for this disorder. Intermittent theta burst stimulation (iTBS) is a newer form of rTMS that can be delivered in 3 min, versus 37·5 min for a standard 10 Hz treatment session. We aimed to establish the clinical effectiveness, safety, and tolerability of iTBS compared with standard 10 Hz rTMS in adults with treatment-resistant depression. In this randomised, multicentre, non-inferiority clinical trial, we recruited patients who were referred to specialty neurostimulation centres based at three Canadian university hospitals (Centre for Addiction and Mental Health and Toronto Western Hospital, Toronto, ON, and University of British Columbia Hospital, Vancouver, BC). Participants were aged 18–65 years, were diagnosed with a current treatment-resistant major depressive episode or could not tolerate at least two antidepressants in the current episode, were receiving stable antidepressant medication doses for at least 4 weeks before baseline, and had an HRSD-17 score of at least 18. Participants were randomly allocated (1:1) to treatment groups (10 Hz rTMS or iTBS) by use of a random permuted block method, with stratification by site and number of adequate trials in which the antidepressants were unsuccessful. Treatment was delivered open-label but investigators and outcome assessors were masked to treatment groups. Participants were treated with 10 Hz rTMS or iTBS to the left dorsolateral prefrontal cortex, administered on 5 days a week for 4–6 weeks. The primary outcome measure was change in 17-item Hamilton Rating Scale for Depression (HRSD-17) score, with a non-inferiority margin of 2·25 points. For the primary outcome measure, we did a per-protocol analysis of all participants who were randomly allocated to groups and who attained the primary completion point of 4 weeks. This trial is registered with ClinicalTrials.gov, number NCT01887782. Between Sept 3, 2013, and Oct 3, 2016, we randomly allocated 205 participants to receive 10 Hz rTMS and 209 participants to receive iTBS. 192 (94%) participants in the 10 Hz rTMS group and 193 (92%) in the iTBS group were assessed for the primary outcome after 4–6 weeks of treatment. HRSD-17 scores improved from 23·5 (SD 4·4) to 13·4 (7·8) in the 10 Hz rTMS group and from 23·6 (4·3) to 13·4 (7·9) in the iTBS group (adjusted difference 0·103, lower 95% CI −1·16; p=0·0011), which indicated non-inferiority of iTBS. Self-rated intensity of pain associated with treatment was greater in the iTBS group than in the 10 Hz rTMS group (mean score on verbal analogue scale 3·8 [SD 2·0] vs 3·4 [2·0] out of 10; p=0·011). Dropout rates did not differ between groups (10 Hz rTMS: 13 [6%] of 205 participants; iTBS: 16 [8%] of 209 participants); p=0·6004). The most common treatment-related adverse event was headache in both groups (10 Hz rTMS: 131 [64%] of 204; iTBS: 136 [65%] of 208). In patients with treatment-resistant depression, iTBS was non-inferior to 10 Hz rTMS for the treatment of depression. Both treatments had low numbers of dropouts and similar side-effects, safety, and tolerability profiles. By use of iTBS, the number of patients treated per day with current rTMS devices can be increased several times without compromising clinical effectiveness. Canadian Institutes of Health Research.

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.

Disruption in reciprocal connectivity between the right anterior insula and the left dorsolateral prefrontal cortex is associated with depression and may be a target for neuromodulation. In a five-center, parallel, double-blind, randomized controlled trial we personalized resting-state functional magnetic resonance imaging neuronavigated connectivity-guided intermittent theta burst stimulation (cgiTBS) at a site based on effective connectivity from the right anterior insula to the left dorsolateral prefrontal cortex. We tested its efficacy in reducing the primary outcome depression symptoms measured by the GRID Hamilton Depression Rating Scale 17-item over 8, 16 and 26 weeks, compared with structural magnetic resonance imaging (MRI) neuronavigated repetitive transcranial magnetic stimulation (rTMS) delivered at the standard stimulation site (F3) in patients with ‘treatment-resistant depression’. Participants were randomly assigned to 20 sessions over 4–6 weeks of either cgiTBS ( n  = 128) or rTMS ( n  = 127) with resting-state functional MRI at baseline and 16 weeks. Persistent decreases in depressive symptoms were seen over 26 weeks, with no differences between arms on the primary outcome GRID Hamilton Depression Rating Scale 17-item score (intention-to-treat adjusted mean, −0.31, 95% confidence interval (CI) −1.87, 1.24, P  = 0.689). Two serious adverse events were possibly related to TMS (mania and psychosis). MRI-neuronavigated cgiTBS and rTMS were equally effective in patients with treatment-resistant depression over 26 weeks (trial registration no. ISRCTN19674644). A randomized controlled trial found that functional connectivity-guided approaches to intermittent theta burst stimulation and repetitive transcranial magnetic stimulation both reduced depressive symptoms in patients with moderate to severe treatment-resistant depression over 26 weeks.

Cognition is commonly affected in brain disorders. Non-invasive brain stimulation (NIBS) may have procognitive effects, with high tolerability. This meta-analysis evaluates the efficacy of transcranial magnetic stimulation (TMS) and transcranial Direct Current Stimulation (tDCS) in improving cognition, in schizophrenia, depression, dementia, Parkinson's disease, stroke, traumatic brain injury, and multiple sclerosis. A PRISMA systematic search was conducted for randomized controlled trials. Hedges' g was used to quantify effect sizes (ES) for changes in cognition after TMS/tDCS v. sham. As different cognitive functions may have unequal susceptibility to TMS/tDCS, we separately evaluated the effects on: attention/vigilance, working memory, executive functioning, processing speed, verbal fluency, verbal learning, and social cognition. We included 82 studies (n = 2784). For working memory, both TMS (ES = 0.17, p = 0.015) and tDCS (ES = 0.17, p = 0.021) showed small but significant effects. Age positively moderated the effect of TMS. TDCS was superior to sham for attention/vigilance (ES = 0.20, p = 0.020). These significant effects did not differ across the type of brain disorder. Results were not significant for the other five cognitive domains. Our results revealed that both TMS and tDCS elicit a small trans-diagnostic effect on working memory, tDCS also improved attention/vigilance across diagnoses. Effects on the other domains were not significant. Observed ES were small, yet even slight cognitive improvements may facilitate daily functioning. While NIBS can be a well-tolerated treatment, its effects appear domain specific and should be applied only for realistic indications (i.e. to induce a small improvement in working memory or attention).

The concurrent use of transcranial magnetic stimulation with electroencephalography (TMS–EEG) is growing in popularity as a method for assessing various cortical properties such as excitability, oscillations and connectivity. However, this combination of methods is technically challenging, resulting in artifacts both during recording and following typical EEG analysis methods, which can distort the underlying neural signal. In this article, we review the causes of artifacts in EEG recordings resulting from TMS, as well as artifacts introduced during analysis (e.g. as the result of filtering over high-frequency, large amplitude artifacts). We then discuss methods for removing artifacts, and ways of designing pipelines to minimise analysis-related artifacts. Finally, we introduce the TMS–EEG signal analyser (TESA), an open-source extension for EEGLAB, which includes functions that are specific for TMS–EEG analysis, such as removing and interpolating the TMS pulse artifact, removing and minimising TMS-evoked muscle activity, and analysing TMS-evoked potentials. The aims of TESA are to provide users with easy access to current TMS–EEG analysis methods and to encourage direct comparisons of these methods and pipelines. It is hoped that providing open-source functions will aid in both improving and standardising analysis across the field of TMS–EEG research. •TMS pulses result in numerous artifacts in concurrent EEG recordings.•We review the origins of these artifacts and methods for removing them.•We also introduce TESA, an open-source EEGLAB extension for TMS-EEG analysis.

Background: The Canadian Network for Mood and Anxiety Treatments (CANMAT) conducted a revision of the 2009 guidelines by updating the evidence and recommendations. The scope of the 2016 guidelines remains the management of major depressive disorder (MDD) in adults, with a target audience of psychiatrists and other mental health professionals. Methods: Using the question-answer format, we conducted a systematic literature search focusing on systematic reviews and meta-analyses. Evidence was graded using CANMAT-defined criteria for level of evidence. Recommendations for lines of treatment were based on the quality of evidence and clinical expert consensus. “Neurostimulation Treatments” is the fourth of six sections of the 2016 guidelines. Results: Evidence-informed responses were developed for 31 questions for 6 neurostimulation modalities: 1) transcranial direct current stimulation (tDCS), 2) repetitive transcranial magnetic stimulation (rTMS), 3) electroconvulsive therapy (ECT), 4) magnetic seizure therapy (MST), 5) vagus nerve stimulation (VNS), and 6) deep brain stimulation (DBS). Most of the neurostimulation treatments have been investigated in patients with varying degrees of treatment resistance. Conclusions: There is increasing evidence for efficacy, tolerability, and safety of neurostimulation treatments. rTMS is now a first-line recommendation for patients with MDD who have failed at least 1 antidepressant. ECT remains a second-line treatment for patients with treatment-resistant depression, although in some situations, it may be considered first line. Third-line recommendations include tDCS and VNS. MST and DBS are still considered investigational treatments.

Bipolar depression (BD) is a highly prevalent condition with limited therapeutic options. Deep (H1-coil) transcranial magnetic stimulation (dTMS) is a novel TMS modality with established efficacy for unipolar depression. We conducted a randomized sham-controlled trial to evaluate the efficacy and safety of dTMS in treatment-resistant BD patients. Patients received 20 sessions of active or sham dTMS over the left dorsolateral prefrontal cortex (H1-coil, 55 18 Hz 2 s 120% MT trains). The primary outcome was changes in the 17-item Hamilton Depression Rating Scale (HDRS-17) from baseline to endpoint (week 4). Secondary outcomes were changes from baseline to the end of the follow-up phase (week 8), and response and remission rates. Safety was assessed using a dTMS adverse effects questionnaire and the Young Mania Rating Scale to assess treatment-emergent mania switch (TEMS). Out of 50 patients, 43 finished the trial. There were 2 and 5 dropouts in the sham and active groups, respectively. Active dTMS was superior to sham at end point (difference favoring dTMS=4.88; 95% CI 0.43 to 9.32, p=0.03) but not at follow-up. There was also a trend for greater response rates in the active (48%) vs sham (24%) groups (OR=2.92; 95% CI=0.87 to 9.78, p=0.08). Remission rates were not statistically different. No TEMS episodes were observed. Deep TMS is a potentially effective and well-tolerated add-on therapy in resistant bipolar depressed patients receiving adequate pharmacotherapy.

Uncertainty surrounding ohmic tissue conductivity impedes accurate calculation of the electric fields generated by non-invasive brain stimulation. We present an efficient and generic technique for uncertainty and sensitivity analyses, which quantifies the reliability of field estimates and identifies the most influential parameters. For this purpose, we employ a non-intrusive generalized polynomial chaos expansion to compactly approximate the multidimensional dependency of the field on the conductivities. We demonstrate that the proposed pipeline yields detailed insight into the uncertainty of field estimates for transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), identifies the most relevant tissue conductivities, and highlights characteristic differences between stimulation methods. Specifically, we test the influence of conductivity variations on (i) the magnitude of the electric field generated at each gray matter location, (ii) its normal component relative to the cortical sheet, (iii) its overall magnitude (indexed by the 98th percentile), and (iv) its overall spatial distribution. We show that TMS fields are generally less affected by conductivity variations than tDCS fields. For both TMS and tDCS, conductivity uncertainty causes much higher uncertainty in the magnitude as compared to the direction and overall spatial distribution of the electric field. Whereas the TMS fields were predominantly influenced by gray and white matter conductivity, the tDCS fields were additionally dependent on skull and scalp conductivities. Comprehensive uncertainty analyses of complex systems achieved by the proposed technique are not possible with classical methods, such as Monte Carlo sampling, without extreme computational effort. In addition, our method has the advantages of directly yielding interpretable and intuitive output metrics and of being easily adaptable to new problems.

Meta-analyses have shown that high-frequency (HF) repetitive transcranial magnetic stimulation (rTMS) has antidepressant properties when compared with sham rTMS. However, its overall response and remission rates in major depression (MD) remain unclear. Thus, we have systematically and quantitatively assessed the efficacy of HF-rTMS for MD based on randomized, double-blind and sham-controlled trials (RCTs). We searched the literature from 1995 through to July 2012 using MEDLINE, EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials, SCOPUS, and ProQuest Dissertations & Theses. We used a random-effects model, odds ratios (ORs) and the number needed to treat (NNT). Data from 29 RCTs were included, totaling 1371 subjects with MD. Following approximately 13 sessions, 29.3% and 18.6% of subjects receiving HF-rTMS were classified as responders and remitters, respectively (compared with 10.4% and 5% of those receiving sham rTMS). The pooled OR was 3.3 (p < 0.0001) for both response and remission rates (with associated NNTs of 6 and 8, respectively). Furthermore, we found HF-rTMS to be equally effective as an augmentation strategy or as a monotherapy for MD, and when used in samples with primary unipolar MD or in mixed samples with unipolar and bipolar MD. Also, alternative stimulation parameters were not associated with differential efficacy estimates. Moreover, baseline depression severity and drop-out rates at study end were comparable between the HF-rTMS and sham rTMS groups. Finally, heterogeneity between the included RCTs was not statistically significant. HF-rTMS seems to be associated with clinically relevant antidepressant effects and with a benign tolerability profile.