Sham Transcranial Magnetic Stimulation Research Articles

Brain stimulation over the left DLPFC enhances motivation for effortful rewards in patients with major depressive disorder

BackgroundAmotivation is a typical feature in major depressive disorder (MDD), which produces reduced willingness to exert effort. The dorsolateral prefrontal cortex (DLPFC) is a crucial structure in goal-directed actions and therefore is a potential target in modulating effortful motivation. However, it remains unclear whether the intervention is effective for patients with MDD. MethodsWe employed transcranial magnetic stimulation (TMS), computational modelling and event-related potentials (ERPs) to reveal the causal relationship between the left DLPFC and motivation for effortful rewards in MDD. Fifty patients underwent both active and sham TMS sessions, each followed by performing an Effort-Expenditure for Rewards Task, during which participants chose and implemented between low-effort/low-reward and high-effort/high-reward options. ResultsThe patients showed increased willingness to exert effort for rewards during the DLPFC facilitated session, compared with the sham session. They also had a trend in larger P3 amplitude for motivated attention toward chosen options, larger CNV during preparing for effort exertion, and larger SPN during anticipating a high reward. Besides, while behavior indexes for effortful choices were negatively related to depression severity in the sham session, this correlation was weakened in the active stimulation session. ConclusionsThese findings provide behavioral, computational, and neural evidence for the left DLPFC on effortful motivation for rewards. Facilitated DLPFC improves motor preparation and value anticipation after making decisions especially for highly effortful rewards in MDD. Facilitated DLPFC also has a potential function in enhancing motivated attention during cost-benefit trade-off. This neuromodulation effect provides a potential treatment for improving motivation in clinics.

Harnessing Placebo Effects for the Treatment of Functional Cognitive Disorder: A Feasibility Pilot Study.

Limited research has directly investigated whether and how placebo effects can be harnessed for the treatment of functional neurological disorder (FND), despite a long-standing and controversial history of interest in this area. A small exploratory study was conducted with adults with a cognitive subtype of FND recruited from a single cognitive neurology center in the United States. Participants were given the expectation of receiving cranial stimulation that could benefit their memory symptoms; however, the intervention was sham transcranial magnetic stimulation (placebo). Outcomes included measures of short-term memory testing, subjective memory rating, and state anxiety before and after stimulation. After the study, the true objective and rationale for investigating placebo effects were explained in a scripted debriefing session. Acceptability of the study design and qualitative feedback were collected. Institutional ethics approval and signed consent were obtained. Three patients (female, N=2; male, N=1; average age=57 years) were recruited. Outcome data were analyzed descriptively at the patient level. Trends of improvement in subjective memory rating, but not objective cognitive test scores, and decreases in state anxiety were observed. After the debriefing session, all patients found the study design to be acceptable (ratings of 70%, 90%, and 100%), and two of the three patients believed that withholding mechanistic information about the intervention was needed to leverage placebo effects as treatment. In the first study to prospectively investigate the feasibility of harnessing placebo effects for the treatment of FND, promising preliminary findings were obtained, and methods and resources for use in larger future studies are offered.

A pilot, randomized clinical trial: Left dorsolateral prefrontal cortex intermittent theta burst stimulation improves treatment outcomes in veterans with alcohol use disorder.

Transcranial magnetic stimulation (TMS) offers a promising treatment avenue to modulate brain function in alcohol use disorder (AUD). To the best of our knowledge, this pilot study is the first randomized, double-blind, sham-controlled trial to deliver intermittent theta burst stimulation to the left dorsolateral prefrontal cortex (DLPFC) among US veterans with AUD. We hypothesized that 20 sessions of real TMS are tolerable and feasible. As a secondary line of inquiry, we hypothesized that, relative to sham TMS, individuals receiving real TMS would experience greater reductions in 6-month relapse rates, anhedonia, and alcohol cue-reactivity. Veterans (n = 17, one woman) were enrolled in a double-blind, sham-controlled trial (2-3 sessions/day; 7-10 days; 600 pulses/session; 20 sessions). Pre- and posttreatment assessments included responses to self-report questionnaires and functional magnetic resonance imaging measures of alcohol cue-reactivity. Alcohol consumption was assessed for 6 months. Linear mixed-effects models were constructed to predict posttreatment craving, mood, and cue-reactivity. Individuals who received active iTBS (n = 8) were less likely to relapse within 3 months after treatment than the sham-treated group (n = 9) (OR = 12.0). Greater reductions in anhedonia were observed following active iTBS (Cohen's d = -0.59), relative to sham (d = -0.25). Alcohol cue-reactivity was reduced following active iTBS and increased following sham within the left insula (d = -0.19 vs. 0.51), left thalamus (d = -0.28 vs. 0.77), right insula (d = 0.18 vs. 0.52), and right thalamus (d = -0.06 vs. 0.62). Relative to sham, we demonstrate that 20 sessions of real left DLPFC iTBS reduced the likelihood of relapse for at least 3 months. The potential utility of this approach is underscored by observed decreases in anhedonia and alcohol cue-reactivity-strong predictors of relapse among veterans. These initial data offer a valuable set of effect sizes to inform future clinical trials in this patient population.

Evoked EEG Responses to TMS Targeting Regions Outside the Primary Motor Cortex and Their Test–Retest Reliability

Transcranial magnetic stimulation (TMS)–evoked electroencephalography (EEG) potentials (TEPs) provide unique insights into cortical excitability and connectivity. However, confounding EEG signals from auditory and somatosensory co-stimulation complicate TEP interpretation. Our optimized sham procedure established with TMS of primary motor cortex (Gordon in JAMA 245:118708, 2021) differentiates direct cortical EEG responses to TMS from those caused by peripheral sensory inputs. Using this approach, this study aimed to investigate TEPs and their test–retest reliability when targeting regions outside the primary motor cortex, specifically the left angular gyrus, supplementary motor area, and medial prefrontal cortex. We conducted three identical TMS–EEG sessions one week apart involving 24 healthy participants. In each session, we targeted the three areas separately using a figure-of-eight TMS coil for active TMS, while a second coil away from the head produced auditory input for sham TMS. Masking noise and electric scalp stimulation were applied in both conditions to achieve matched EEG responses to peripheral sensory inputs. High test–retest reliability was observed in both conditions. However, reliability declined for the ‘cleaned’ TEPs, resulting from the subtraction of evoked EEG response to the sham TMS from those to the active, particularly for latencies > 100 ms following the TMS pulse. Significant EEG differences were found between active and sham TMS at latencies < 90 ms for all targeted areas, exhibiting distinct spatiotemporal characteristics specific to each target. In conclusion, our optimized sham procedure effectively reveals EEG responses to direct cortical activation by TMS in brain areas outside primary motor cortex. Moreover, we demonstrate the impact of peripheral sensory inputs on test–retest reliability of TMS-EEG responses.

Adaptive short-term plasticity in the typical reading network

The left temporo-parietal cortex (TPC) is crucial for phonological decoding, i.e., for learning and retaining sound-letter mappings, and appears hypoactive in dyslexia. Here, we tested the causal contribution of this area for reading in typical readers with transcranial magnetic stimulation (TMS) and explored the reading network's response with fMRI. By investigating the underlying neural correlates of stimulation-induced modulations of the reading network, we can help improve targeted interventions for individuals with dyslexia. 28 typical adult readers overtly read simple and complex words and pseudowords during fMRI after effective and sham TMS over the left TPC. To explore differences in functional activation and effective connectivity within the reading network, we performed univariate and multivariate analyses, as well as dynamic causal modeling. While TMS-induced effects on reading performance and brain activation showed large individual variability, multivariate analyses revealed a shift in activation in the left inferior frontal cortex for pseudoword reading after effective TMS. Furthermore, TMS increased effective connectivity from the left ventral occipito-temporal cortex to the left TPC. In the absence of effects on reading performance, the observed changes in task-related activity and the increase in functional coupling between the two core reading nodes suggest successful short-term compensatory reorganization in the reading network following TMS-induced disruption. This study is the first to explore neurophysiological changes induced by TMS to a core reading node in typical readers while performing an overt reading task. We provide evidence for remote stimulation effects and emphasize the relevance of functional interactions in the reading network.

C-STIM: Protocol for a randomized, single-blind, crossover study of cerebellar repetitive transcranial magnetic stimulation (rTMS) for postural instability in people with progressive supranuclear palsy (PSP)

BackgroundMethods for modulating the cerebellum with transcranial magnetic stimulation (TMS) are well established, and preliminary data from our group and others has shown evidence of transient improvements in balance after cerebellar repetitive transcranial magnetic stimulation (rTMS) in progressive suprancuclear palsy (PSP). This study examines extensive posturography measures before and after 10 sessions of cerebellar rTMS and sham TMS in PSP. MethodsThirty subjects with PSP and postural instability will undergo cerebellar active and sham rTMS in a single-blind, crossover design with a randomized order of a 10-day intervention. Primary outcomes will be changes in sway area and medio-lateral range of sway with eyes open while standing on a stationary force-plate, and safety, tolerability, and blindedness. Secondary outcomes will include posturography and gait analysis with body-worn, triaxial inertial sensors, clinical balance scales and questionnaires, and a bedside test of vestibular function. Exploratory outcomes are changes in functional near infrared spectroscopy (fNIRS) signal over the prefrontal, supplementary motor, and primary motor cortices while standing and walking, and speech samples for future analysis. DiscussionThe C-STIM crossover intervention study adds a longer duration of stimulation and extensive posturography measures to more finely measure the improvements in balance and exploratory functional near-infrared spectroscopy (fNIRS) over the prefronal, supplementary motor, and primary motor cortices during balance assessments before and after 10 sessions of cerebellar rTMS and 10 sessions of sham cerebellar TMS. This project will improve our understanding of the importance of the cerebellum for control of postural stability in PSP.

Causal evidence for the role of the sensory visual cortex in visual short-term memory maintenance

The role of the sensory visual cortex during visual short-term memory (VSTM) remains controversial. This controversy is possibly due to methodological issues in previous attempts to investigate the effects of transcranial magnetic stimulation (TMS) on VSTM. The aim of this study was to use TMS, while covering previous methodological deficits. Sixty-four young adults were recruited to participate in two experiments (Experiment 1: n = 36; Experiment 2: n = 28) using a VSTM orientation change-detection task under TMS. Monocular vision was ensured using red-blue goggles combined with red-blue stimuli. Double-pulse TMS was delivered at different times (Experiment 1: 0, 200 or 1000 ms; Experiment 2: 200, 1000 ms) during a 2 s maintenance phase, on one side of the occipital hemisphere. In Experiment 2, a sham TMS condition was introduced. Decreased detection sensitivity (d') in the ipsilateral occipital hemisphere to visual hemifield, and in the real TMS (compared with sham TMS) condition indicated inhibitory TMS effects, and thus, a causal involvement of the sensory visual cortex during early (200 ms) and late (1000 ms) maintenance in VSTM. These findings are aligned with sensory recruitment, which proposes that both perceptual and memory processes rely upon the same neural substrates in the sensory visual cortex. The methods used in this study were preregistered and had received in-principle acceptance on 6 June 2022 (Stage 1 protocol can be found in: https://doi.org/10.17605/OSF.IO/EMPDT).

Excitatory brain stimulation over the left dorsolateral prefrontal cortex enhances voluntary distraction in depressed patients.

While implicit distraction could ameliorate negative feelings in patients with major depressive disorders (MDD), it remains unclear whether patients could benefit from explicit, voluntary distraction. Meanwhile, though the dorsolateral prefrontal cortex (DLPFC) is established as a crucial brain region involved in attentional control, the causal relationship between the DLPFC and voluntary distraction is unexplored in patients. Combing explicit distraction and transcranial magnetic stimulation (TMS), this study investigated whether TMS-activated DLPFC facilitates voluntary distraction in MDD patients. Eighty patients diagnosed with current MDD underwent either active (n = 40) or sham (n = 40) TMS sessions, followed by receiving negative social feedback from other patients, during which they were requied to use distraction strategy to down-regulate their painful feelings. Electroencephalogram was recorded during the task. Both the subjective emotional rating and the amplitude of late positive potential showed that depressed patients successfully down-regulate their negative emotions via voluntary distraction, and the TMS-activated left DLPFC produced a larger benefit of emotion regulation compared to the sham TMS group. Results also revealed that while emotion regulation effect was negatively associated with depressive symptoms in the sham TMS group, this correlation was largely diminished when patients' left DLPFC was activated by TMS during the voluntary distraction. These findings demonstrated that distraction is valuable for emotion regulation in MDD patients and they could be beneficial in voluntary distraction by activating their left DLPFC using neural modulation techniques. This study has valuable implications for clinical treatement of emotional dysregulation in MDD patients.

Pre-frontal stimulation does not reliably increase reward responsiveness.

Depression is the leading cause of disability worldwide and its effects can be fatal, with over 800,000 people dying by suicide each year. Neuromodulatory treatments such as transcranial magnetic stimulation (TMS) are being used to treat depression. Despite its endorsement by two regulatory bodies: NICE (2016) and the FDA (2008), there are major questions about the treatment efficacy and biological mechanisms of TMS. Ahn etal.'s (2013) justified the use of TMS in a clinical context in an important study indicating that excitatory TMS increases reward responsiveness. A pseudo-replication of this study by Duprat etal., (2016) also found a similar effect of active TMS, but only with the addition of an exploratory covariate to the analyses-trait reward responsiveness. Here we replicate Ahn etal.'s (2013) key study, and to test the reliability of the effects, and their dependency on trait reward responsiveness as described by Duprat etal., (2016). Using excitatory and sham TMS, we tested volunteers using the probabilistic learning task to measure their reward responsiveness both before and after stimulation. We also examined affect (positive, negative) following stimulation. Irrespective of TMS, the task was shown to be sensitive to reward responsiveness. However, we did not show TMS to be effective in increasing reward responsiveness and we did not replicate Ahn etal., (2013) or Duprat etal., (2016)'s key findings for TMS efficacy, where we provide evidence favouring the null. Moreover, exploratory analyses suggested following active stimulation, positive affect was reduced. Given our findings, we question the basic effects, which support the use of TMS for depression, particularly considering potential deleterious effects of reduced positive affect in patients with depression.

The functional relevance of right DLPFC and VMPFC in risk-taking behavior.

The prefrontal cortex can be partialized in various anatomical and functional sub regions. Among those regions, both right dorsolateral prefrontal cortex (rDLPFC) and ventromedial prefrontal cortex (VMPFC) have been associated with risk-taking behavior based on neuroimaging studies. Noninvasive brain stimulation (NIBS) studies aiming at demonstrating the functional relevance of neural activity in these areas almost exclusively focused on the rDLPFC, where its experimental stimulation with a (generally) inhibitory protocol lead to a measurable increase in risk-taking behavior due to reduced cognitive control. The functional relevance of VMPFC in risk-taking behavior has not yet been addressed using NIBS, although multiple neuroimaging studies correlate this area's activity with valuation. Here, we used NIBS to investigate the functional relevance of both, the rDLPFC and VMPFC in risk-taking behavior. We hypothesized that, compared to sham stimulation, VMPFC suppression leads to a reduction in risk-taking behavior by reducing the appeal to higher value options and consequently the attractiveness of riskier options, whereas rDLPFC suppression leads to an increase in risk taking, replicating previous findings. We applied continuous theta burst stimulation (cTBS), a generally inhibitory protocol, to stimulate either VMPFC or DLPFC before the execution of the computerized Maastricht Gambling Task (MGT) in a within-subject design with 30 participants. The MGT allowed the analysis of potential brain region-specific effects of cTBS on risk-taking behavior such as participants' choices of average values, probabilities, and response time. cTBS applied to either rDLPFC or VMPFC both led to an increase in risk-taking behavior and in the average value chosen as compared to sham transcranial magnetic stimulation. No effect on the choice of probabilities was found. A significant increase in response time was observed exclusively after suppressing rDLPFC. We speculate that these similar behavioral consequences following cTBS over DLPFC and VMPFC are likely due to the strong anatomical and functional interconnection between both brain regions.

Neuromodulatory effects of transcranial magnetic stimulation on language performance in healthy participants: Systematic review and meta-analysis.

The causal relationships between neural substrates and human language have been investigated by transcranial magnetic stimulation (TMS). However, the robustness of TMS neuromodulatory effects is still largely unspecified. This study aims to systematically examine the efficacy of TMS on healthy participants' language performance. For this meta-analysis, we searched PubMed, Web of Science, PsycINFO, Scopus, and Google Scholar from database inception until October 15, 2022 for eligible TMS studies on language comprehension and production in healthy adults published in English. The quality of the included studies was assessed with the Cochrane risk of bias tool. Potential publication biases were assessed by funnel plots and the Egger Test. We conducted overall as well as moderator meta-analyses. Effect sizes were estimated using Hedges'g (g) and entered into a three-level random effects model. Thirty-seven studies (797 participants) with 77 effect sizes were included. The three-level random effects model revealed significant overall TMS effects on language performance in healthy participants (RT: g = 0.16, 95% CI: 0.04-0.29; ACC: g = 0.14, 95% CI: 0.04-0.24). Further moderator analyses indicated that (a) for language tasks, TMS induced significant neuromodulatory effects on semantic and phonological tasks, but didn't show significance for syntactic tasks; (b) for cortical targets, TMS effects were not significant in left frontal, temporal or parietal regions, but were marginally significant in the inferior frontal gyrus in a finer-scale analysis; (c) for stimulation parameters, stimulation sites extracted from previous studies, rTMS, and intensities calibrated to the individual resting motor threshold are more prone to induce robust TMS effects. As for stimulation frequencies and timing, both high and low frequencies, online and offline stimulation elicited significant effects; (d) for experimental designs, studies adopting sham TMS or no TMS as the control condition and within-subject design obtained more significant effects. Overall, the results show that TMS may robustly modulate healthy adults' language performance and scrutinize the brain-and-language relation in a profound fashion. However, due to limited sample size and constraints in the current meta-analysis approach, analyses at a more comprehensive level were not conducted and results need to be confirmed by future studies. [https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=366481], identifier [CRD42022366481].

Treatment Response of Transcranial Magnetic Stimulation in Intellectually Capable Youth and Young Adults with Autism Spectrum Disorder: A Systematic Review and Meta-Analysis.

To examine current clinical research on the use of transcranial magnetic stimulation (TMS) in the treatment of pediatric and young adult autism spectrum disorder in intellectually capable persons (IC-ASD). We searched peer-reviewed international literature to identify clinical trials investigating TMS as a treatment for behavioral and cognitive symptoms of IC-ASD. We identified sixteen studies and were able to conduct a meta-analysis on twelve of these studies. Seven were open-label or used neurotypical controls for baseline cognitive data, and nine were controlled trials. In the latter, waitlist control groups were often used over sham TMS. Only one study conducted a randomized, parallel, double-blind, and sham controlled trial. Favorable safety data was reported in low frequency repetitive TMS, high frequency repetitive TMS, and intermittent theta burst studies. Compared to TMS research of other neuropsychiatric conditions, significantly lower total TMS pulses were delivered in treatment and neuronavigation was not regularly utilized. Quantitatively, our multivariate meta-analysis results report improvement in cognitive outcomes (pooled Hedges' g = 0.735, 95% CI = 0.242, 1.228; p = 0.009) and primarily Criterion B symptomology of IC-ASD (pooled Hedges' g = 0.435, 95% CI = 0.359, 0.511; p < 0.001) with low frequency repetitive TMS to the dorsolateral prefrontal cortex. The results of our systematic review and meta-analysis data indicate that TMS may offer a promising and safe treatment option for pediatric and young adult patients with IC-ASD. However, future work should include use of neuronavigation software, theta burst protocols, targeting of various brain regions, and robust study design before clinical recommendations can be made.

Theta-Burst Stimulation Combined With Virtual-Reality Reconsolidation Intervention for Methamphetamine Use Disorder: Study Protocol for a Randomized-Controlled Trial.

BackgroundCraving associated with drug-related memory is one of the key factors that induce the relapse of methamphetamine (MA). Disruption or modulation of the reconsolidation of drug-related memory may serve as an option for clinical treatment of MA addiction. This protocol proposes to use virtual reality (VR) to retrieve drug-associated memory and then use transcranial magnetic stimulation (TMS) at the neural circuit that encodes the reward value of drug cues to provide a non-invasive intervention during reconsolidation. We aim to evaluate the effectiveness of TMS treatment after VR retrieval on the reduction of cue reactivity and craving of MA.MethodsThis is a randomized, double-blind, sham-controlled, parallel group trial, targeting participants with MA use disorder aged from 18 to 45 years old. Forty-five eligible volunteers in Shanxi Drug Rehabilitation Center will be recruited and be randomly allocated into three parallel groups, receiving either 1) MA-related cues retrieval in VR combined with active TMS (MA VR scene + TBS) or 2) sham TMS (MA VR scene + sham TBS), or 3) neutral cues retrieval in VR combined with active TMS (neutral VR scene + TBS). Two sessions of post-VR-retrieval TBS will be scheduled on two separate days within 1 week. The primary outcome will detect the memory-related activity by the electroencephalography (EEG) reactivity to drug cues in VR scenes. Secondary outcomes are the self-reported MA craving in VR scene, the physiological parameter (cue-induced heart rate) and the scores of psychological questionnaires including anxiety, depression, and mood. All primary and secondary outcomes will be assessed at baseline, 1-week, and 1-month post-intervention. Assessments will be compared between the groups of 1) MA VR scene + TBS, 2) MA VR scene + sham TBS and 3) neutral VR scene + TBS.DiscussionThis will be the first study to examine whether the TMS modulation after VR retrieval can reduce self-reported craving and drug-related cue reactivity. It will promote the understanding of the neural circuit mechanism of the reconsolidation-based intervention and provide an effective treatment for MA use disorder patients.Clinical Trial Registration[Chinese Clinical Trial Registry], identifier [ChiCTR1900026902]. Registered on 26 October 2019.

The Efficacy and Safety of Transcranial Magnetic Stimulation in Treatment-Resistant Bipolar Depression.

The aim of the current study is to investigate the efficacy and safety of Transcranial magnetic stimulation (TMS) treatment, a non-invasive brain stimulation technique, on depressive symptoms in treatment-resistant bipolar depression (TRBD). The study included 29 patients between the ages of 18-65, with bipolar disorder depressive episode according to DSM-5 and with the decision of non-response to treatment according to the Canadian Mood and Anxiety Treatment Network (CANMAT). Patients were divided into two groups double-blind-randomly, 20 sessions of TMS and 20 sessions of sham TMS were applied crossover. Hamilton Depression Rating Scale (HAM-D), Beck Depression Inventory (BDI), Young Mania Rating Scale (YMRS) and TMS Side Effect Questionnaire were applied to the patients before the treatment, at the 2nd week which is the crossover phase, and at the end of the treatment at 4th week. In both groups, the severity of depression was decreased significantly according to HAM-D and BDI scores after the procedure. As well as active stimulation, some positive placebo effects were observed with sham stimulation. But the decreases seen in HAM-D and BDI scores and response to the treatment were higher during the weeks when the groups received active stimulation (respectively p=0.000, p=0.001, p=0.005). At the end of the study, according to HAM-D, 55.7% of the patients showed response to the treatment, 24.13% partial response. According to BDI, 41.37% of the patients showed response to the treatment, and 31.03% partial response. No associations were found between TMS response and sociodemographic - clinical features, or type of the disease (p>0.05). During the study, no serious adverse effects such as seizures or manic / hypomanic switches were observed. The results of our study showed that TMS treatment is an effective and safe treatment for patients with treatment-resistant bipolar depression.

Repetitive Transcranial Magnetic Stimulation Promotes Rapid Psychiatric Stabilization in Acutely Suicidal Military Service Members.

This study presents data for using accelerated transcranial magnetic stimulation (TMS) as an intervention for suicidal crisis (SC). This prospective, single-site, randomized, double-blind trial enrolled active-duty military participants with SC to receive either active TMS (n = 59) or sham TMS (n = 61) 3 times per day for 3 consecutive days. Our primary outcome, the Beck Scale for Suicidal Ideation-current (SSI-C), was measured before each session of TMS. Secondary outcomes measured both the SSI-C and the Beck Scale for Suicidal Ideation-total daily for the 3 intervention days and at 1, 3, and 6 months of follow-up. In the modified intention to treat (mITT) analysis of SSI-C changes over treatment sessions, the TMS active group had accelerated decline in suicidal ideation as compared with sham: β for interaction was 0.12 points greater SSI-C decline per session (standard error [SE], 0.06) in TMS versus sham (P = 0.04). In both the mITT and per-protocol active TMS groups, the mean final SSI-C scores were below 3. These scores remained below 3 for the entire 6-month follow-up period. In this military trial of suicidal patients, we found that both active and sham accelerated TMS rapidly reduces SC. Moreover, in the mITT analysis, there was a statistically significant antisuicidal benefit of active TMS versus sham TMS in the primary outcome. Both the mITT and per-protocol groups moved from higher to approximately 7 times lower suicide risk strata and remained there for the duration of the study. Further studies are warranted to understand accelerated TMS' full potential as a treatment for SC.

The causal role of the bilateral ventrolateral prefrontal cortices on emotion regulation of social feedback.

The ventrolateral prefrontal cortices (VLPFC) are crucial regions involved in voluntary emotion regulation. However, the lateralization of the VLPFC in downregulating negative emotions remains unclear; and whether the causal role of the VLPFC is generalizable to upregulating positive emotions is unexplored. This study used transcranial magnetic stimulation (TMS) to examine the causal relationship between the left/right VLPFC and social emotion reappraisal. One hundred and twenty participants were randomly assigned to either active (left and right VLPFC groups, n = 40/40) or sham (vertex, n = 40) TMS groups. Participants were instructed to passively receive social feedback or use reappraisal strategies to positively regulate their emotions. While the subjective emotional rating showed that the bilateral VLPFC facilitated the reappraisal success, the electrophysiological measure of the late positive potential (LPP) demonstrated a more critical role of the right VLPFC on social pain relief (decreased LPP amplitudes) and social reward magnification (enhanced LPP amplitudes). In addition, the influence of emotion regulation on social evaluation was found to be mediated by the memory of social feedback, indicating the importance of memory in social behavioral shaping. These findings suggest clinical protocols for the rehabilitation of emotion‐regulatory function in patients with affective and social disorders.

Motor cortex oscillates at its intrinsic post-movement beta rhythm following real (but not sham) single pulse, rhythmic and arrhythmic transcranial magnetic stimulation

We aimed to test the idea that rhythmic transcranial magnetic stimulation (TMS) entrains cortical oscillations. To do this, we examined oscillatory responses in the electroencephalogram (EEG) to TMS over primary motor cortex. In particular, we contrasted responses to real TMS with those to sham TMS in order to dissociate the contributions of direct (transcranial) activation and indirect activation (via auditory/sensory input) of the brain. We first showed that real single pulse TMS elicited a brief (∼200 ms) increase in sensorimotor beta power whose frequency closely matched that of each individual's post-movement beta rebound (PMBR, ∼18 Hz). Sham TMS triggered minimal oscillatory activity. Together this implies that real TMS interacts with endogenous oscillations via direct brain activation. We then showed that although trains of real rhythmic TMS delivered at each individuals PMBR frequency produced a brief increase in beta power at the same frequency, real arrhythmic TMS also elicited an equivalent increase in beta. The implication is that the oscillatory response is independent of the rhythm of stimulation. By contrast, sham stimulation elicited minimal activity in the beta band, and the responses to rhythmic and arrhythmic sham TMS were broadly similar, showing that sham rhythmic stimulation did not produce entrainment via sensory rhythms. Together, the data demonstrate that the beta oscillatory response of M1 to real TMS predominantly reflects direct activation of the underlying cortex. However, the data do not support the notion of rhythmic TMS enhancing oscillatory activity via entrainment-like mechanisms, at least within the constraints of the current experimental set-up.

A structured ICA-based process for removing auditory evoked potentials

Transcranial magnetic stimulation (TMS)-evoked potentials (TEPs), recorded using electroencephalography (EEG), reflect a combination of TMS-induced cortical activity and multi-sensory responses to TMS. The auditory evoked potential (AEP) is a high-amplitude sensory potential—evoked by the “click” sound produced by every TMS pulse—that can dominate the TEP and obscure observation of other neural components. The AEP is peripherally evoked and therefore should not be stimulation site specific. We address the problem of disentangling the peripherally evoked AEP of the TEP from components evoked by cortical stimulation and ask whether removal of AEP enables more accurate isolation of TEP. We hypothesized that isolation of the AEP using Independent Components Analysis (ICA) would reveal features that are stimulation site specific and unique individual features. In order to improve the effectiveness of ICA for removal of AEP from the TEP, and thus more clearly separate the transcranial-evoked and non-specific TMS-modulated potentials, we merged sham and active TMS datasets representing multiple stimulation conditions, removed the resulting AEP component, and evaluated performance across different sham protocols and clinical populations using reduction in Global and Local Mean Field Power (GMFP/LMFP) and cosine similarity analysis. We show that removing AEPs significantly reduced GMFP and LMFP in the post-stimulation TEP (14 to 400 ms), driven by time windows consistent with the N100 and P200 temporal characteristics of AEPs. Cosine similarity analysis supports that removing AEPs reduces TEP similarity between subjects and reduces TEP similarity between stimulation conditions. Similarity is reduced most in a mid-latency window consistent with the N100 time-course, but nevertheless remains high in this time window. Residual TEP in this window has a time-course and topography unique from AEPs, which follow-up exploratory analyses suggest could be a modulation in the alpha band that is not stimulation site specific but is unique to individual subject. We show, using two datasets and two implementations of sham, evidence in cortical topography, TEP time-course, GMFP/LMFP and cosine similarity analyses that this procedure is effective and conservative in removing the AEP from TEP, and may thus better isolate TMS-evoked activity. We show TEP remaining in early, mid and late latencies. The early response is site and subject specific. Later response may be consistent with TMS-modulated alpha activity that is not site specific but is unique to the individual. TEP remaining after removal of AEP is unique and can provide insight into TMS-evoked potentials and other modulated oscillatory dynamics.

Safety of transcranial magnetic stimulation in unipolar depression: A systematic review and meta-analysis of randomized-controlled trials

BackgroundTo study the safety and patients’ tolerance of transcranial magnetic stimulation (TMS), we conducted a systematic review and meta-analysis of the major depressive disorder population. MethodsOur study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched the literature published before April 30th, 2021 and performed a random-effects meta-analyses which included drop-out due to adverse events, serious adverse events and other non-serious adverse events as primary and secondary outcomes. ResultsA total of 53 randomized sham-controlled trials with 3,273 participants were included. There was no increased risk of drop-out due to an adverse event (active TMS intervention group=3.3%, sham TMS intervention group=2.3%, odds ratio = 1.30, 95% CI= 0.78–2.16, P = 0.31) or a serious adverse event (active TMS intervention group=0.9%, sham TMS intervention group=1.5%, odds ratio = 0.67, 95% CI= 0.29–1.55, P = 0.35). Our findings suggest that TMS intervention may significantly increase the risk of non-serious adverse events including: headaches (active TMS intervention group=22.6%, sham TMS intervention group=16.2%, odds ratio = 1.48, 95% CI= 1.15–1.91, P = 0.002), discomfort (active TMS intervention group=10.9%, sham TMS intervention group=5.0%, odds ratio 1.98, 95% CI= 1.22–3.21, P = 0.006) and pain (active TMS intervention group=23.8%, sham TMS intervention group=5.2%, odds ratio= 8.09, 95% CI= 4.71–13.90, P < 0.001) at the stimulation site, but these non-serious events were mostly mild and transient after TMS treatment. ConclusionsThese findings provide evidence for the safety and patients’ tolerance of transcranial magnetic stimulation technique as an alternative monotherapy or as an add-on treatment for major depressive disorder.

Intensity dependency of peripheral nerve stimulation in spinal LTP induced by paired associative corticospinal-motoneuronal stimulation (PCMS).

Paired associative corticospinal-motoneuronal stimulation (PCMS) induces plasticity at synapses between corticospinal tracts (CSTs) and spinal motoneurons (SMs). We investigated the effects of peripheral nerve electrical stimulation (PNS) intensity on PCMS-induced plasticity. PCMS consisted of 180 paired stimuli of transcranial magnetic stimulation (TMS) over the left primary motor cortex with PNS on the right ulnar nerve at the wrist. We compared effects induced by different PNS intensities: supramaximal, twice and three times sensory threshold intensities. For evaluating efficacy of the synapse between CSTs and SMs, single-pulse TMS was delivered at cervicomedullary junction level, and cervicomedullary motor-evoked potentials (CMEPs) were recorded from the right first-dorsal interosseous muscle before and after PCMS. PCMS with the supramaximal PNS intensity increased CMEP amplitude. The facilitatory effect of PCMS with the supramaximal PNS was larger than those of PCMS with weaker PNS intensities. Sham TMS with the supramaximal PNS showed no CMEP changes after the intervention. PNS intensity of PCMS influences the magnitude of synaptic plasticity induction between the CSTs and SMs at the spinal level, and the supramaximal intensity is the best for induction of long-term potentiation-like effects. The PNS intensity may influence the number of activated SMs by axonal backpropagating pulses with PNS which must overlap with descending volleys induced by TMS.