Repetitive Transcranial Magnetic Stimulation (rTMS) is a widely used noninvasive brain stimulation technique that has been approved for treatment-resistant depression (TRD) in many countries. A growing divergence in national health authority positions has reignited debate over the role of rTMS in the treatment of treatment-resistant depression (TRD). While numerous countries—including the United States, Canada, and Australia—have endorsed and reimbursed rTMS based on robust meta-analytic evidence, other jurisdictions have issued more restrictive or inconclusive recommendations. These contrasting stances reflect significant variability in how health authorities interpret the clinical and cost-effectiveness data, leading to inconsistent access and coverage worldwide. This heterogeneity has sparked ongoing controversies in multiple countries, including recent policy discussions in Australia and Europe, highlighting the need for clearer, evidence-aligned guidance at the international level. The striking contrast between the evidence for efficacy of rTMS in TRD and the lack of recommendation from some national health authorities raises particularly important questions since it leads to many serious consequences from public health and medico-economic standpoints. In this article, we argue that health authority endorsement of rTMS for TRD is justified on clinical, safety, and economic grounds. We further propose that such endorsement should be linked to three prerequisites—training certification, defined therapeutic positioning, and standardized clinical protocols. Training and accreditation frameworks should be implemented at scale to facilitate the approval of rTMS by health authorities, enabling widespread, high-quality delivery, optimizing outcomes, and generating health economic returns.

Brain disorders-encompassing neurological, mental, and substance use disorders-account for 10 of the top 25 causes of disability worldwide according to the Global Burden of Disease (GBD) 2021 study. Despite such an impact, they have not been centrally analyzed in prior GBD studies. This paper synthesizes the latest disability-focused GBD study to quantify the prevalence and disability burden of 35 conditions from 2010 to 2021, a period marking the first decline in global health outcomes in three decades. It further incorporates disability metrics from 2021 to 2023 to contextualize post-pandemic trends. The paper covers the prevalence and disability burden of neurological, mental, and substance use disorders along with COVID-19 using disability-adjusted life-years (DALYs) and years lived with disability (YLDs) metrics. From 2010-2021, Parkinson's, Alzheimer's, and migraine (in neurological disorders), major depressive, anxiety, and eating disorders (in mental disorders), and opioid and drug use disorders (in substance use disorders) showed the greatest increases in age-adjusted prevalence rates across both sexes. In 2021, neurological disorders were the largest contributor to DALYs among brain-disorder categories, while depressive and anxiety disorders ranked as the 2nd and 6th leading causes of global YLDs. Alzheimer's disease/dementias, Parkinson's disease, autism spectrum disorder (ASD), depressive and anxiety disorders, and opioid and drug use disorders showed the largest increases in burden within their respective categories between 2010 and 2021. In both 2021 and 2023, females had higher prevalence rates of overall neurological disorders, headache/migraine, multiple sclerosis, depressive/anxiety disorders, and anorexia nervosa, while males had higher rates of stroke, Parkinson's disease, ASD/ADHD, and substance use disorders. In DALY/YLD metrics, females showed higher rates for anorexia nervosa and multiple sclerosis, and males for ASD, certain neurological disorders, COVID-19, and substance use disorders. In the 2021-2023 extension analysis, disability data showed increases in prevalence and disability of several brain disorders, mostly anxiety disorders, while the COVID-19 disability burden declined markedly by 2023. Further sex-specific disability burden metrics, key insights from each disorder, and limitations/confounds are discussed.

Transcranial magnetic stimulation (TMS) is a non-invasive technique to stimulate the brain, while electroencephalography (EEG) is a non-invasive technique to record its electrical activity. Their combined use (TMS-EEG) has been established only relatively recently, after successful development of TMS-compatible EEG amplifiers. TMS-EEG offers the unparalleled opportunity to directly perturb the brain with TMS and simultaneously record its response with EEG. This allows inferences on causal input-output relationships, therefore going critically beyond purely observational techniques, such as resting-state EEG or functional MRI, in the study of brain dynamics. This consensus review updates the work of Tremblay and coworkers [Clin Neurophysiol 2019; 130: 802-844]. Since then, substantial advances have been made in understanding contamination of TMS-EEG signals by physiological and non-physiological artifacts, as well as in developing strategies to avoid or control them. In parallel, new insights have emerged regarding the physiological mechanisms underlying TMS-EEG responses and their diagnostic and prognostic utility in a broad range of psychiatric and neurological disorders. As such, TMS-EEG is rapidly shaping a dynamic new field in clinical neurophysiology and neuroscience. This review provides a critical and comprehensive synthesis of current knowledge, including practical guidance for implementing TMS-EEG in the clinical setting.

Current antidepressant therapies predominately target symptom remission in major depressive disorder (MDD) but often overlook social dysfunction, which is a critical determinant of functional recovery. Individualized, accelerated continuous theta burst stimulation (cTBS) targeting the right dorsolateral prefrontal cortex (R.DLPFC) may offer a potential therapeutic approach for concurrently improving clinical and psychosocial outcomes in MDD. In this randomized, double-blind, sham-controlled trial, 70 patients with MDD were randomly assigned to receive either active (n = 37) or sham (n = 33) accelerated cTBS for 2 weeks. The treatments targeted individualized R.DLPFC sites, which were identified by task-evoked brain activation during a social interactive task (Ultimatum Game, UG). Depressive and anxiety symptoms, general social functioning, UG-derived behavioral and computational modeling indices (e.g., learning rates), and effective connectivity in social processing networks were assessed pre- and post-treatment. Active accelerated cTBS significantly outperformed sham stimulation in reducing depressive and anxiety symptoms and improving general social functioning (all ps < 0.001). The active group also demonstrated enhanced cooperation behavior (p = 0.002) and increased learning rates (89% HDI: [0.01, 0.21]). And the active group exhibited increased effective connectivity from the right insula to the R.DLPFC and stable effective connectivity from the anterior cingulate cortex (ACC) to the left insula after treatment, which was different from the sham group (Pp > 0.95). No severe adverse events occurred. Individualized, accelerated cTBS targeting task-evoked activation in the R.DLPFC safely and effectively improves clinical symptoms and social dysfunction in MDD. Altered effective connectivity among the DLPFC, insula and ACC may provide mechanistic insights into its therapeutic effects. Trial Registration: chictr.org.cn; ChiCTR2300068273.

BACKGROUND:Repetitive transcranial magnetic stimulation (rTMS) may have an analgesic effect in neuropathic pain. However, clinical application is notably limited by a variable rate of responders. We aimed to (i) assess the analgesic efficacy of prolonged continuous theta burst stimulation (pcTBS) delivered to M1, (ii) study the analgesic effect of maintenance treatment in responders., and (iii) examine the analgesic efficacy of switching to the left dorsolateral prefrontal cortex (DLPFC) in nonresponders. METHODS:We conducted a randomized, sham-controlled, and double-blind study in chronic neuropathic pain participants (n = 94). In part 1, participants were randomized to receive 5 days of either pcTBS, 10-Hz rTMS, or sham stimulation over the left M1. In the subsequent parts, responders to either active treatment in part 1 continued with biweekly sessions for four weeks (part 2), while nonresponders in part 1 received 5 days of stimulation on the left DLPFC (part 3). Corticospinal excitability was assessed via measurements of motor-evoked potential (MEP) and cortical silent period (CSP) recorded from the right first dorsal interosseous (FDI) muscle. RESULTS:Among the 94 participants randomized into treatment groups, 5 days of M1 stimulation with either pcTBS or 10-Hz rTMS showed significant analgesia compared to baseline (mean [standard deviation {SD}]: 10-Hz 37.9 ± 17.5 vs 48.5 ± 16.0, P < .001; pcTBS 35.1 ± 15.3 vs 47.1 ± 15.1, P < .001), but the two active groups did not differ from each other (P = .16). However, pcTBS induced more rapid corticospinal excitability changes (MEP pcTBS versus Sham: 188.5 ± 39.8 vs 102.2 ± 6.9, P = .044; CSP pcTBS versus Sham: 113.9 ± 3.8 vs 101.7 ± 3.3, P = .039), whereas no significant changes were observed in the 10-Hz group during the same period (MEP 10-Hz versus Sham:115.7 ± 9.3 vs 102.2 ± 6.9, Pcorrected = 1.000; CSP 10-Hz versus Sham: 103.6 ± 2.9 vs 101.7 ± 3.3, Pcorrected = 1.000). In the responder group, additional maintenance sessions further increased analgesia (time effect: Post2 versus Post1: 21.3 ± 2.1 vs 27.1 ± 2.3, P = .006) and maintained analgesic effect for 1 month in both the pcTBS and 10-Hz rTMS treatment groups (follow-up versus Post1: 29.9 ± 2.7 vs 27.1 ± 2.3, P = .74). Additional sessions also increased corticospinal excitability, and this was associated with less pain during the follow-up period (r = -0.48, P = .037). Pain symptoms were improved more by pcTBS (post versus pre: 11.3 ± 5.5 vs 13.1 ± 5.3, P = .020) than by 10-Hz rTMS (post versus pre: 15.9 ± 7.2 vs 15.5 ± 6.4, P = .978) when both were applied to the left DLPFC in initial nonresponders. CONCLUSIONS:This study demonstrates that pcTBS applied to M1 is an effective treatment for chronic neuropathic pain, with analgesic efficacy comparable to conventional 10-Hz rTMS. The protocol offers a substantial reduction in treatment time, opening perspectives for more efficient clinical application.

Traumatic brain injury (TBI) is linked to persistent cognitive and functional impairment, yet its long-term effects on the spatiotemporal organization of brain activity remain unclear. Electroencephalography (EEG) studies have reported spectral power and functional connectivity (FC) abnormalities following TBI, but little is known about whether injury also disrupts propagating oscillatory activity such as travelling waves. Resting-state EEG was analysed from a large clinical dataset (Temple University Hospital EEG Corpus) including 174 individuals with TBI and 174 age- and sex-matched non-TBI clinical controls. FC was estimated using the debiased weighted phase lag index and tested using network-based statistic. Spectral power differences were computed with cluster-based permutation. Travelling waves were quantified along left- and right-lateral electrode lines using two-dimensional Fast Fourier Transforms to extract forward (posterior-to-anterior) and backward (anterior-to-posterior) propagation in theta and alpha bands. TBI participants exhibited lower alpha-band connectivity (p < 0.001) and higher theta-band connectivity (p = 0.011) relative to controls. Spectral analyses revealed stronger theta power (p = 4.6 × 10-4) and weaker posterior alpha power (p = 0.008). Critically, travelling-wave analyses showed weaker backward theta waves in TBI across hemispheres, surviving multiple comparison correction in the left (p = 0.007), but not right (p = 0.018). These findings link TBI to altered oscillatory power, disrupted FC, and weaker backward travelling theta waves, consistent with impaired top-down coordination. The opposing pattern of theta hyperconnectivity alongside alpha hypoconnectivity may reflect compensatory but inefficient large-scale communication. Travelling-wave analysis thus provides a novel complement to conventional EEG measures for characterising electrophysiological alterations following TBI in a heterogenous clinical sample with limited clinical metadata.

We use connectome modeling to map polysynaptic fiber pathways underlying transcranial magnetic stimulation (TMS) therapy for depression. We propose putative cortical and subcortical routes that connect stimulation sites in the dorsolateral prefrontal cortex to the subgenual cingulate cortex via intermediate regions. Here we show that route length explains both TMS treatment response in two independent patient cohorts and the clinical efficacy of functional magnetic resonance imaging-guided TMS targeting. Our results illuminate the neuroanatomical basis of TMS therapy for depression.

Background Anxiety disorders and treatment-resistant major depressive disorder (TRD) are often comorbid. Studies suggest ketamine has anxiolytic and antidepressant properties. Aims To investigate if subcutaneous racemic ketamine, delivered twice weekly for 4 weeks, reduces anxiety in people with TRD. Method The Ketamine for Adult Depression Study was a multisite 4-week randomised, double-blind, active (midazolam)-controlled trial. The study initially used fixed low dose ketamine (0.5 mg/kg, cohort 1), before protocol revision to flexible, response-guided dosing (0.5–0.9 mg/kg, cohort 2). This secondary analysis assessed anxiety using the Hamilton Anxiety (HAM-A) scale (primary measure) and ‘inner tension’ item 3 of the Montgomery–Åsberg Depression Rating Scale (MADRS), at baseline, 4 weeks (end treatment) and 4 weeks after treatment end. Analyses of change in anxiety between ketamine and midazolam groups included all participants who received at least one treatment (n = 174), with a mixed effects repeated measures model used to assess the primary anxiety measure. The trial was registered at www.anzctr.org.au (ACTRN12616001096448). Results In cohort 1 (n = 68) the reduction in HAM-A score was not statistically significant: −1.4 (95% CI [−8.6, 3.2], P = 0.37), whereas a significant reduction was seen for cohort 2 (n = 106) of −4.0 (95% CI [−10.6, −1.9], P = 0.0058), favouring ketamine over midazolam. These effects were mediated by total MADRS and were not maintained at 4 weeks after treatment end. MADRS item 3 was also significantly reduced in cohort 2 (P = 0.026) but not cohort 1 (P = 0.96). Conclusion Ketamine reduces anxiety in people with TRD when administered subcutaneously in adequate doses.

Background Repetitive transcranial magnetic stimulation (rTMS) has several advantages compared to other interventions for neurological and psychological disorders. However, various adverse effects have been reported in rTMS research, and little is known about who is most susceptible to rTMS adverse effects, or how they can be minimized. Aims We aimed to identify risk factors for adverse effects reported in a recent clinical trial examining rTMS as a treatment for Alzheimer’s disease (AD). We hypothesized that higher stimulation intensity would be associated with experiencing unspecified pain/discomfort, dental pain, headache, jaw pain, and muscle contractions, but not be associated with other adverse effects. Methods Using detailed notes from treatment sessions, 10 adverse effects were identified. Spearman correlations were conducted to assess relationships between the highest applied stimulation intensity and normalized frequency of each adverse effect amongst those who experienced that adverse effect. Demographic information, cognitive scores, and withdrawal status were compared between the binarized groups of participants who experienced adverse effects versus those who did not. Spearman correlations were also conducted on the binarized adverse effects and the highest applied stimulation intensity. Logistic regressions were conducted to identify potential risk factors. Results In both the sham and active treatment groups, unspecified pain/discomfort was the most common adverse effect, followed by muscle contractions and dizziness. In both the active and sham treatment groups, stimulation intensity was positively associated with muscle contractions, but was not significantly related to any other adverse effect. In evaluating groups with/without adverse effects, we found there was a significantly higher proportion of males reporting adverse effects in both the active treatment group and the sham treatment group compared to females. Conclusion The findings of this study are a step toward understanding how researchers can minimize such adverse effects, and thereby, create a less aversive experience for rTMS participants.

Background: Treatment-resistant depression (TRD) poses a substantial clinical challenge, with nearly half of patients failing to respond to initial therapies. While accelerated regimens of intermittent theta-burst stimulation (a-iTBS), particularly Stanford Neuromodulation Therapy (SNT), demonstrate promising efficacy, the protracted daily treatment schedule (~10 hours) may limit clinical adoption. Central to the premise of SNT is a dose-response curve. However, the characteristics of this curve remain theoretical and unexplored. Understanding this dose-relation may assist in optimising SNT treatment efficiency and enhancing clinical tractability. Methods: To this effect, we first characterised the cortical effects of a-iTBS using concurrent TMS-EEG (Study 1, n=41 healthy individuals). Findings revealed a clear dose-response curve, which plateaued at 5-7 daily. These results were absent in sham stimulation. Informed by this neural dynamic, we designed an abbreviated 6-session protocol (a-iTBS-6) and tested it against the standard 10-session regimen (a-iTBS-10) and sham stimulation in a randomised controlled trial involving TRD patients (Study 2, n= 45, 15 in each arm). Findings: Critically, both active protocols demonstrated significant and comparable antidepressant efficacy. The a-iTBS-6 protocol yielded response rates of 60.0% at post-treatment and 73.3% at 4-week follow-up, showing no significant differences compared to the a-iTBS-10 protocol (60.0% and 60.0%, respectively). These two accelerated iTBS programs were safe with minor side effects. Interpretation: Based on this exploratory clinical evaluation, our findings establish an abbreviated and effective accelerated iTBS paradigm for TRD individuals. This treatment is expected to increase feasibility, reduce clinical and patient burden, and is likely to facilitate broader adoption of SNT.

Mindfulness meditation has been linked to differences in attention and executive function, which may be related to differences in neural activity patterns. To explore this, we used an electroencephalography (EEG)-based event-related potential (ERP) paradigm to examine brain responses associated with conflict monitoring and attention in experienced meditators, compared to non-meditators. We measured N2 and P3 ERPs associated with conflict monitoring and attention processes from 35 meditators and 29 non-meditators across both an easy and a hard Go/Nogo task (50 η_p^2 = 0.11). The fronto-midline N2 ERP was also larger following Nogo trials than Go trials in the harder task condition and was associated with correct responses. Meditators also exhibited a more frontally distributed P3 ERP in the easy task compared to the hard task, while non-meditators showed a more frontally distributed P3 ERP in the hard task (pFDR = 0.015, η_p^2 = 0.08). Meditation experience was associated with distinct topographical patterns of neural activity, without corresponding differences in global amplitudes. Exploratory analyses of relationships between task parameters, behavioural performance, and the neural activities of interest indicated these meditation-related effects appear to be more closely associated with attentional processes than with processes specific to conflict monitoring or stimulus expectancy, although we acknowledge that the ERP components examined reflect multiple overlapping cognitive processes. This study was not preregistered.

OBJECTIVE:Mindfulness-based interventions (MBIs) show promise in managing chronic pain but often require substantial time commitments, leading to high attrition and concerns about acceptability. This meta-analysis evaluated attrition rates in MBIs for chronic pain and examined moderators contributing to participant withdrawal. METHODS:Following PRISMA guidelines, we searched relevant databases for studies of MBIs for pain. Eligible studies included randomised controlled trials, controlled trials, and quasi-experimental designs that reported attrition data for adults (≥18 y) with chronic pain lasting over 3 months. Data extraction covered attrition metrics, program characteristics, and participant demographics. Statistical analyses included random-effects meta-analyses of proportions, sensitivity analyses, meta-regression, and publication bias assessments. RESULTS:Forty-four studies (45 intervention conditions) were included. The pooled attrition rate was 30.1% (95% CI: 24.5%- 37.3%) with substantial heterogeneity ( I ²=89.0%). Attrition increased with stricter completion thresholds (minimum sessions required for programme completion status) ( P <0.001, R ²=28.1%): 18.0% (≥3 to 4 sessions), 31.6% (≥5 to 6 sessions), and 49.7% (>6 sessions). Online delivery showed higher attrition (51.0%) than in-person delivery (25.6%, P =0.002, R ²=17.1%). Individually delivered MBIs were also associated with higher attrition than group formats (β=0.216, P =0.039, R ²=5.5%). Publication bias analyses suggested minor influence on the pooled effect, which remained robust after adjustment. DISCUSSION:Attrition rates for MBIs in chronic pain vary widely. Higher attrition is associated with stricter completion criteria, online delivery, and individual formats. These findings highlight the need to optimise MBI programme structure for management of pain.

OBJECTIVES:Electroencephalography (EEG) can be used to assess functional brain connectivity (FC). However, there is considerable variability in the methods used for FC measurement across different studies, which may contribute to heterogeneity in research outcomes. We aimed to assess how different EEG pre-processing steps impact EEG-FC measurement when applied to real EEG data. METHODS:Using the BrainClinics.com open-source EEG data repository we investigated how different pre-processing steps impacted the ability to detect age-related differences in alpha band FC and the test-retest reliability of FC measures. The pre-processing steps tested included artifact reduction techniques (Independent Component Analysis (ICA), wavelet-enhanced ICA (wICA), and Multi-channel Wiener Filters (MWF)), different epoch lengths (epochs that were 2 s versus 6 s in length), and different re-referencing montages (the common average reference (CAR) versus current source density (CSD) re-referencing). We also assessed different FC metrics including imaginary coherence (iCOH), real magnitude squared coherence (rMSC), and weighted phase lag index (wPLI) metrics. RESULTS:The best performing pipeline at detecting age-related differences in alpha FC and providing high test-retest reliability included artifact reduction by ICA or wICA, data re-referenced using the CSD method, and FC measured by rMSC. CONCLUSION & SIGNIFICANCE:This paper presents evidence for an EEG pre-processing pipeline that provides good detection of meaningful effects and high test-retest reliability for sensor space EEG alpha frequency FC.

Social cognition, particularly theory of mind (ToM) is important for understanding and engaging with the social environment. The continual development and improvement of these skills can be of broad benefit. However, current social cognitive training methods are time intensive and have limited ecological validity. Virtual reality (VR) combined with transcranial alternating current stimulation (tACS) may provide a more ecologically valid and efficient alternative. The current study investigated the effects of theta tACS to the right temporoparietal junction (rTPJ) on VR social cognition training in a group of 21 healthy adults. Outcome measures were behavioural (attribution of intentions ToM task) and neurophysiological (spectral power and event related potentials). Participants completed two identical lab sessions each. One session included VR training concurrent with active theta tACS and the other, with sham theta tACS. Participants completed resting state electroencephalography (EEG) and ToM tasks with concurrent EEG pre and post VR-tACS in each session. tACS condition was randomised and all assessments were double-blinded. VR and active tACS, but not VR and sham tACS, improved ToM task accuracy. ToM task response times improved pre versus post VR-tACS regardless of tACS condition (active vs sham). Resting state theta power increased significantly across the cortex post VR-tACS regardless of tACS condition. This study provides the first evidence for the feasibility of a combined VR-tACS protocol for social cognition. Future research in larger samples, and with multiple sessions, in both healthy and clinical populations are recommended. ### Competing Interest Statement KEH was a past founder of Resonance Therapeutics. PBF has received reimbursement for educational activities from Otsuka Australia Pharmaceutical Pty Ltd and equipment for research from Brainsway Ltd. ### Clinical Trial ACTRN12621001649808 ### Funding Statement KG was supported by a Monash University Departmental Scholarship, an Australian Government Research Training Program (RTP) Scholarship and an Epworth HealthCare Capacity Building Grant. KEH was supported by a National Health and Medical Research Council (NHMRC) fellowship (1135558). PBF is supported by an MHMRC Leadership Award. ATH was supported by and Alfred Deakin Postdoctoral Research Fellowship. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Monash Health Human Research Ethics Committee gave ethical approval for this work. Monash University Human Research Ethics Committee, Alfred Health and Epworth HealthCare provided governance approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

BACKGROUND:Repetitive transcranial magnetic stimulation (rTMS) over the cerebellum has shown therapeutic potential for spinocerebellar ataxia type 3 (SCA3). However, the underlying electrophysiological mechanisms remain unclear. Here, we aimed to utilize single-pulse TMS combined with electroencephalography co-registration (TMS-EEG) to probe cerebellar projections underlying the effects of rTMS in SCA3 patients. METHODS:A group of 38 SCA3 patients and 35 healthy controls underwent baseline TMS-EEG to assess cerebellar projections. Patients were evaluated using the International Cooperative Ataxia Rating Scale (ICARS) and then randomized to receive either a 3-week course of active intermittent theta burst stimulation (iTBS) or sham iTBS applied to the cerebellum. ICARS assessments were then performed at post-treatment and 3-month follow-up, with additional TMS-EEG performed post-treatment. RESULTS:ICARS scores were improved by iTBS treatment than the Sham stimulation at post-treatment (2.67 [95 %CI, 0.53-4.81]; p = 0.016) and 3-month follow-up (4.11 [95 %CI, 1.02-7.20]; p = 0.011). iTBS restored cerebello-cortical inhibition over the contralateral motor cortex as reflected by enhanced N45 amplitude (1.31 [95 %CI, 0.08-2.53]; p = 0.038), which covaried with better clinical improvement (p = 0.005). iTBS also reorganized beta band oscillation, that potentially underlies the cerebello-cortical inhibition in SCA3 individuals. At the source level, cerebellar rTMS normalized the impaired cerebello-cortical inhibition characterized by the evoked current density over the motor cortex. CONCLUSIONS:Our findings indicate that cerebellar iTBS alleviates clinical ataxia severity in SCA3 potentially by restoring cerebello-cortical inhibition and reorganizing beta-band activity. N45 amplitude may serve as a potential biomarker for treatment response in SCA3.

OBJECTIVE:Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for depression, but not for all patients. Accurate treatment response prediction could lower treatment burden. Research suggests machine learning trained with electroencephalography (EEG) data may predict response, but a limited range of features have been tested. We tested whether a combination of > 7000 time-series features were predictive of response in training and test and independent datasets. METHODS:Pre-treatment EEG from 188 patients with depression treated with rTMS were decomposed into five principal components (PCs). The highly comparative time-series analysis toolbox was used to extract 7304 time-series features from each participant and PC. A classification algorithm was trained to predict responders from these features separately for each PC. The classifier was applied to an independent dataset (N = 58) to test generalizability. RESULTS:Within the training and test dataset, the third PC showed above-chance classification accuracy (69.4 %, pFDR = 0.005). The model generalized to the independent dataset with above-chance accuracy (60 %, p = 0.046). Analysis of feature-clusters suggested responders showed more high frequency relative power relative, and a more negative skew in the distribution of time-series values. CONCLUSIONS:Results suggest our methods could be used to inform treatment selection. SIGNIFICANCE:Our methods may enable better outcomes than 'one-size-fits-all' treatment approaches.

This guideline summarizes updated safety data (2017-2025) and provides expert recommendations on the use of low intensity transcranial electrical stimulation (tES) in humans. tES encompasses several techniques including transcranial direct current stimulation (tDCS), oscillatory transcranial direct current stimulation (otDCS), transcranial alternating current stimulation (tACS), transcranial random noise stimulation (tRNS), transcranial temporal interference stimulation (tTIS), and their combinations or variations. Across over 300,000 sessions involving healthy individuals, patients with neuropsychiatric conditions, and other clinical populations, no tES-related serious adverse events (AEs) have been reported. Moderate AEs are rare and limited to a small range of specific applications. Mild AEs are common and include transient symptoms such as localized sensations (e.g., tingling or burning), headaches, and fatigue. Similar mild AEs are also reported by individuals receiving placebo stimulation. The frequency, magnitude, and type of AEs are comparable across healthy, clinical, and vulnerable groups, including children, elderly, or pregnant women. Combined interventions (e.g., co-application with EEG, TMS, or neuroimaging) have not shown increased safety risks. Safety is well-established for both bipolar and multichannel tES when applied up to 4 mA and up to 60 min per day. Higher intensities and longer stimulation durations may also be safe. Nevertheless, the number of studies using intensities above 4 mA or stimulating longer than 60 min is low. Home-based use of treatments is growing rapidly, leveraging remote supervision to provide patients with greater access and enable repeated, sustained dosing paradigms. We recommend using screening and AE questionnaires in future controlled studies, in particular when planning to extend the stimulation parameters applied. We discuss recent regulatory and ethical issues.

BACKGROUND:Accelerated forms of repetitive transcranial magnetic stimulation (rTMS) are proving to be a safe and effective for treatment-resistant depression (TRD). However, the likelihood of treatment response remains difficult to predict. It is possible to assess inadequate treatment responses early in treatment courses to predict eventual non-response by course end. METHODS:Post-hoc analysis of prospective clinical trial data was conducted (N = 298). Participants were randomized to one of three treatment arms: daily, unilateral 10 Hz rTMS to the left dorsolateral prefrontal cortex or accelerated bilateral theta-burst stimulation (TBS) at either 80 % or 120 % resting motor threshold stimulation intensity. Clinical response was assessed using the Quick Inventory of Depressive Symptomatology (QIDS). Negative predictive values (NPVs) were generated at week 1 using various QIDS percentage improvement cut-offs to predict eventual non-response. RESULTS:Participants who showed a ≤ 10 % or ≤ 20 % improvement in QIDS score by week 1 had NPVs ranging from 70.0 % to 97.5 %. Higher NPVs were found for participants randomized to low-intensity accelerated TBS than 10 Hz daily rTMS at week 1. LIMITATIONS:Accelerated TBS and standard rTMS courses featured relatively short courses of 20 sessions. Analyses predict eventual treatment response using only change in QIDS severity without subscale analysis. CONCLUSIONS:Early treatment non-response potentially has predictive utility, including in an accelerated TBS protocol. Further studies should determine whether there is clinical benefit in reviewing and/or adapting treatment protocols in view of these findings.

The inhibitory effect of interhemispheric signal propagation (ISP) is believed to be aligned with GABA(B) receptor mediated inhibitory neurotransmission and related to interhemispheric connectivity. Repetitive Transcranial magnetic stimulation (rTMS) is a safe and potent strategy for altering brain connectivity. However, it remains unclear if rTMS modulates ISP. With pretreatment of baclofen, a GABA(B) receptor agonist, this study characterized rTMS effects on ISP and the influence of GABA(B) receptor neurotransmission. ISP was measured with TMS and electroencephalography co-registration (TMS-EEG). Excitatory rTMS (> 5 Hz) was found to increase interhemispheric inhibition indexed by ISP. This effect was reduced by baclofen pretreatment, potentially reflecting competition for GABA(B) receptors neurotransmission between baclofen and rTMS. Beyond evoked potentials, our data also identified TMS-evoked gamma oscillation as a reliable indicator of intracortical inhibition. These novel findings help to clarify the effects of rTMS on interhemispheric connectivity, which may help to optimize rTMS treatments for various psychiatric disorders.