Background Noninvasive brain stimulation is typically delivered once daily, but accelerated protocols delivering multiple daily treatments have re-emerged to shorten time to clinical improvement. Methods At the Neuroscience School of Advanced Studies Non-Invasive Brain Stimulation Challenge Workshop (Crans-Montana, Switzerland, October 21-24, 2025), we reviewed the literature on accelerated protocols across noninvasive brain stimulation modalities such as electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), transcranial electrical stimulation (tES), transcranial vagus nerve stimulation (tVNS), and transcranial focused ultrasound (tUS). Accelerated protocols were defined as multiple daily treatments (≥2/day). Results Accelerated ECT protocols date back to the 1960s, when multiple seizure inductions per day produced more rapid clinical improvement but greater cognitive adverse effects. Accelerated TMS protocols emerged in the mid-2000s and gained popularity in the late 2010s, when protocols delivering more than three treatments per day began to show faster antidepressant effects. Accelerated protocols with other modalities or for indications other than major depressive disorder are in early stages. Discussion Accelerated protocols may reduce response latency without diminishing response magnitude. However, the durability of accelerated protocols remains unclear, and systematic exploration of parameter space across modalities is needed.

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.

Electrical conductivity of cortical gray matter governs the magnitude and spatial distribution of electric fields generated by brain stimulation and intrinsic neuronal activity measured with M/EEG and intracortical recordings. However, reported macroscopic conductivity values vary by more than threefold, limiting the fidelity of bioelectromagnetic models and leaving unresolved whether this variability reflects measurement uncertainty or genuine structural heterogeneity of cortical tissue. Here, we present a multiscale computational framework that, for the first time, attempts to derive mesoscale conductivity maps of mouse visual cortex at 50-µm resolution directly from large-volume, segmented nanometer-scale electron microscopy data. The Minnie 65 subvolume of the MICrONS dataset is accurately subdivided into 1,224 50-µm cubic blocks. Each block contains, on average, 40-50 million membrane facets of a highly convoluted and dense cellular structure. Three orthogonal electrode pairs are applied to each isolated block to estimate the three principal components of the conductivity tensor. Quasistatic electric modeling is enabled by an iterative boundary-element fast multipole method (BEM-FMM) under the approximation of non-conducting membranes (DC conductivity). Spatially averaged conductivity values predicted by our framework agree well with prior low-resolution measurements in rats, validating the approach. At the same time, the resulting mesoscale maps reveal pronounced conductivity granularity at 50-100 µm scales as well as significant variations in both radial and tangential directions. These results indicate that mesoscale conductivity heterogeneity could be an intrinsic structural property of the cortex. Limitations and extensions of this study are discussed in detail.

Rationale As neurostimulation devices increasingly incorporate closed-loop functionality, the greater design complexity brings additional requirements for risk management and special considerations to optimize benefit. This manuscript creates a common framework on which all current and planned neuromodulation-based physiologic closed-loop controllers (PCLCs) can be mapped, including integration of the “Technical Considerations of Medical Devices with Physiologic Closed-Loop Control Technology” guidance published in 2023 by the United States Food and Drug Administration, a classification of feedback (reactive) and feedforward (predictive) biomarkers, and control systems theory. Results and Conclusions We explain risk management in the context of this framework and illustrate its applications for three exemplary technologies. This manuscript serves as guidance to the emerging field of PCLCs in neuromodulation, mitigating risk through standardized nomenclature and a systematic outline for rigorous device development, testing, and implementation.

OBJECTIVES:Spinal cord stimulation (SCS) has become increasingly widespread in recent years for the management of refractory chronic pain, primarily owing to the development of novel waveform technology allowing variable spinal cord modulation, and indication expansion. The existing literature suggests that despite having favorable initial responses, the efficacy of SCS sometimes is reduced over time. To restore analgesic efficacy, a strategy of altering stimulation waveforms known as salvage therapy has been used. Here, we consolidate the existing evidence and describe the efficacy of salvage therapy. MATERIALS AND METHODS:A literature search using relevant keywords was conducted on PubMed, Web of Sciences, and Cochrane Library data bases, yielding a total of 809 articles. After a full text review and screening for consistency with eligibility criteria were conducted, 22 studies with a collective sample size of 1591 patients were included in the final analysis. Data extraction was performed by six reviewers, with a secondary reviewer verifying each entry. RESULTS:Of the 1591 patients included in our review, the most frequent indication for salvage therapy was loss of waveform efficacy and paresthesia coverage. In most studies, patients received salvage therapy after experiencing loss of efficacy with a single waveform. Most studies also did not strictly control the phase in which salvage therapy was implemented, with only eight of 22 studies reporting exclusively trial phase interventions. The efficacy of salvage therapy was found to be favorable, with 685 of 879 salvage therapy trials (77.9%) being reported as successful. CONCLUSION:New waveform technologies in SCS have expanded therapeutic options for patients with refractory chronic pain. Available evidence suggests that waveform switching may restore analgesic benefit in a subset of patients who experience loss of efficacy after an initial favorable response. However, many salvage strategies involve device revision or generator replacement, and the long-term durability of these interventions remains uncertain. Further prospective studies are needed to better define patient selection, timing of intervention, and long-term outcomes after waveform-based salvage strategies.

The use of noninvasive transcranial brain stimulation methods, such as transcranial electrical stimulation (tES), transcranial magnetic stimulation (TMS), transcranial focused ultrasound stimulation (tFUS), and electroconvulsive therapy (ECT), has grown significantly over the past two decades. Evidence indicates that the dose-response relationship in brain stimulation is neither straightforward nor monotonic, with outcomes influenced by factors such as the brain state, anatomical variability, and neurophysiological mechanisms. Despite advancements in the field, there is still no consensus on standards for estimating and reporting delivered and received stimulation doses or defining dose-response relationships. This paper addresses these gaps by discussing four key areas: (1) factors influencing the delivered dose (stimulation parameters applied at the scalp), (2) quantification of the received dose (electric or acoustic fields delivered to brain tissue), (3) characterization of physiological, behavioral, and molecular responses to specific delivered/received doses, and (4) the dose-response relationship, which describes how variations in dose modulate brain function and behavior. Drawing on evidence from human and animal studies conducted in silico, in vitro, and in vivo, we outline challenges, propose solutions, and summarize current consensus standards. By promoting rigorous methodologies and transparent reporting, this paper aims to advance the reproducibility, safety, and efficacy of research on dose-response assessment in transcranial brain stimulation and its clinical applications.

Background: Transcranial direct current stimulation (tDCS) devices adjust output voltage to maintain the target current despite varying impedance. Pulsatile blood flow produces beat-synchronous changes in tissue impedance. Objective: To determine whether impedance-derived heart rate (IHR), heart rate variability (IHRV), and respiration (IDR) can be estimated from tDCS output voltage without additional physiological sensors. Methods: A custom analog front-end acquires the tDCS output voltage across its full dynamic DC range and superimposed AC fluctuations with high precision. Beats detected from the AC-coupled signal yielded normal-to-normal intervals for HR, HRV, and interval-derived respiration. Accuracy was quantified as mean absolute error (MAE) in 10 healthy laboratory participants against ECG and respiration-monitor references, and against chest-strap RR intervals in 19 at-home sessions from 10 participants with mild-to-moderate depression. Results: Laboratory MAEs versus ECG were 0.57 bpm for HR, 9.40 ms for SDNN, and 18.90 ms for RMSSD (r = 0.995, 0.859, and 0.778; N = 10); respiratory-rate MAE was 1.36 breaths/min (r = 0.852; N = 6). Across 1-5 mA of tDCS, the cardiac voltage ΔV cardiac (t) amplitude scaled linearly with current (slope, 0.073 mV/mA; p < 0.001). The pulsatile impedance ΔZ cardiac (t) = (ΔV cardiac (t)/I applied ) amplitude averaged 0.080 ± 0.029 Ω (mean ± SD) across 50 participant-current observations, with no significant dependence on intensity (slope, -0.002 Ω/mA, p = 0.086). At-home MAEs were 1.43 bpm for HR, 8.86 ms for SDNN, and 24.92 ms for RMSSD (r = 0.995, 0.767, and 0.680; 19 sessions). Conclusions: tDCS output voltage contains a recoverable cardiac-synchronous signal arising from pulsatile impedance, enabling HR, HRV, and respiratory monitoring without additional physiological sensors.

Cathodal transcranial direct current stimulation (C-tDCS) is a potential neuroprotective method in the hyperacute phase of ischemic stroke. We aimed to assess safety, tolerability, feasibility, and potential efficacy of C-tDCS in stroke patients with salvageable penumbra. DICAST-SF was a double-blind, randomized, sham-controlled (3 active: 1 sham), 3 + 3 dose-escalation trial. Inclusion criteria were stroke due to occlusion of the internal carotid or middle cerebral artery, last known well time within 24 h, substantial penumbra on CT perfusion, and ineligibility for mechanical thrombectomy. We applied C-tDCS at six dose tiers over the affected primary motor cortex. The primary safety outcome was the symptomatic intracranial hemorrhage (SICH) rate at 24 h post-stimulation. Secondary outcomes included the rates of asymptomatic intracranial hemorrhage (AICH), early neurological deterioration, serious adverse events, and 90-day mortality. Tolerability was assessed by completion rate and questionnaires. Feasibility threshold was defined as median randomization-to-C-tDCS start time within 10 min in the last ten patients. Twenty five patients were enrolled (19 active, 6 sham), mean age 81 (SD 12) years, 16 women, median NIHSS 8 (IQR 6-16). Ten active and 4 sham patients were treated with thrombolysis. No SICH occurred. Three AICH (2 post-thrombolysis) occurred in the active arm. Rates of early deterioration, serious adverse events, and mortality (4 active vs. 2 sham) were comparable. C-tDCS was well tolerated and feasible, median randomization-to-C-tDCS start time was 8 (7-9) min. C-tDCS in hyperacute stroke was safe, well tolerated, and feasible. Findings support further evaluation in larger efficacy trials. TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04801446.

Non-invasive brain stimulation (NIBS) includes a growing set of techniques aimed at modulating brain activity without surgery or implants. Transcranial magnetic (TMS) and electrical stimulation (tES) are among the most established methods. tES delivers low-intensity current via scalp electrodes, offering a cheaper and portable option, especially for home-based use. Clinical evidence suggests that the effects of tES are cumulative with consecutive applications needed to achieve meaningful changes. The therapeutic application of the clinic-based tES usually involves a minimum of two weeks of daily visits to the clinical institute, which poses a large burden and stress on patients. Home-based tES, e.g. under remote supervision (RS-tES), following adequate training by trained professionals paves the path to increasing the accessibility of the technology to patients. In 2025, the US FDA approved the first home-based tDCS system for the treatment of "moderate to severe major depressive disorder in the current episode, either as monotherapy or as an adjunctive treatment, in patients 18 years and older who are not considered treatment refractory to medication. In this work, the latest knowledge related to home-use of tES is introduced, including the methodology, most frequent clinical applications, advances and limitations.

Objective:Chronic non-specific lower back pain (cNSLBP) is a prevalent and disabling condition, imposing a substantial socioeconomic burden due to high healthcare costs and productivity losses, with limited accessible and effective long-term treatment options. Automated Thermo-mechanical Therapy (ATT) is a promising, non-drug intervention that leverages innovative technical advances to provide multimodal pain relief, offering accessibility and low-cost delivery. This study tested ATT for immediate pain relief in individuals with cNSLBP in a single-session, double-blind, randomized controlled trial. Methods:Forty participants with cNSLBP were assigned to receive either active ATT (n = 20) or control ATT (n = 20) in a 40-min session with urn randomization. The active device applied heated cylindrical rollers along the spine, using far-infrared heat and mechanical tissue stimulation tailored to spinal alignment. In the control condition, the device used minimal mechanical therapy intensity without heat, targeting only the cervical area to avoid lower back therapeutic effects. Pre- and post-intervention assessments measured changes in pain intensity (primary outcome) via a 100-mm Visual Analog Scale for Pain (VAS-P100), alongside secondary outcomes assessing pain characteristics, anxiety, and functional mobility. Results:The active ATT group showed a significant reduction in pain on the VAS-P100, with an average decrease of 46.8%, compared to 17.0% in the control group. Participants in the active group also reported significantly greater subjective pain relief (p = 7.88e-05). Secondary outcomes demonstrated significant improvements in lumbar flexibility (Modified-Modified Schober Test, MMST) for the active ATT group compared to the control group (p = 0.0031). No adverse events were reported, and all participants tolerated the intervention well. Conclusions:A single session of ATT provides immediate, significant pain relief in individuals with cNSLBP, supporting its potential as a safe, non-invasive option for managing chronic back pain. Future studies should examine the long-term benefits of repeated ATT sessions and explore mechanistic insights into thermo-mechanical stimulation's effects on pain and function. Clinical Trial Registration:ClinicalTrials.gov, identifier: NCT06769321.

This study analyzed the impact of high-definition transcranial direct current stimulation (HD-tDCS) on gaze behavior in professional female basketball players during free-throw shooting preparation. Gaze fixation duration was identified using a mobile eye tracker from free throws shooting preparation (n = 2,233). Multi-channel HD-tDCS (cathodic and sham) was applied for 20 minutes before shooting preparation. The shots were classified as code 1 (successful without hitting the rim or backboard), code 2 (the ball hit the rim before going in), and code 3 (missed shots). There were significant differences between sham and cathodic conditions in percentage changes (pre-to post-intervention) of gaze fixation duration for all three codes (p < 0.001), with increases for sham and decreases for cathodic. Interaction effects (condition × time × shooting code) were observed (p < 0.001). The present findings suggest that HD-tDCS can decrease gaze fixation duration towards a functional inward-out role related to improving neural efficiency.

The MNI152 template is widely treated as a representative average brain in neuroimaging, computational modeling, and neuromodulation research, yet its fidelity to true population morphology has not been systematically evaluated. In this study, we compared the MNI152 template to 430 individual MRI scans from a publicly available dataset spanning Asian, Black, and White participants. We additionally compared the MNI152 template with the independently developed US200 template, which was generated using a modern diffeomorphic template-building framework, to assess whether a contemporary template better represents human brain morphology. We conducted affine registrations and deformation-based morphometry to detect and quantify gross morphological differences as well as local voxel-level deformations. The MNI152 template consistently required consistent global contraction, and its Jacobian fields revealed spatially heterogeneous deformations, indicating systematic mismatches in both size and shape. In contrast, the US200 template showed mean scaling and deformation values near 1.0, reflecting closer correspondence to real human anatomy. These findings suggest that the MNI152 template is less representative of the morphology of this study population than the US200 template and that linear registration alone cannot eliminate these systematic differences. Reliance on MNI152 may therefore introduce anatomical bias in applications requiring high morphological fidelity. These results further support continued development of modern, unbiased, and potentially demographic-specific templates.

BACKGROUND:Spinal Cord Stimulation (SCS) is a therapeutic option for chronic pain conditions, such as persistent spinal pain syndrome, complex regional pain syndrome, painful diabetic peripheral neuropathy, and radiculopathy. The treatment typically involves a temporary trial phase before permanent implantation. Despite showing efficacy, trial phase failure and long-term SCS outcomes remain important considerations. The aim of this review was to quantify three key SCS outcomes-(1) trial phase nonresponse, (2) annual explantation rates after permanent implantation up to three years, and (3) annual <50% pain reduction rates among patients who retain their implant up to three years. MATERIALS AND METHODS:A systematic literature review was conducted across PubMed, Embase, and Cochrane data bases to identify studies reporting on SCS outcomes. Studies were included if they reported quantitative data on at least one of the three outcomes. Data were extracted and summarized across studies. A three-level binomial generalized linear mixed model with logit link was used to calculate pooled rates across included studies. Risk of bias was assessed using the Risk of Bias 2 tool and National Institutes of Health quality assessment tools as appropriate, and certainty of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation framework. RESULTS:A total of 38 studies were included in the analysis. The pooled trial phase failure rate was 16.2%. Pooled explant rates were 4.0%, 7.0%, and 11.9% at one, two, and three years respectively. Pooled rates of <50% pain reduction were 24.2%, 27.0%, and 32.8% at one, two, and three years respectively. CONCLUSIONS:We aggregate and analyze the durability of SCS outcomes according to a defined rubric. Outcomes were not stratified by factors that could influence response, such as waveform. 16.2% of patients assessed for SCS eligibility did not proceed past the trial phase. On average, at three years post implantation, 44.7% of patients with permanent implants had undergone explantation or reported <50% pain relief.

Abstract Background Transcutaneous auricular vagus nerve stimulation (taVNS) depends on activating afferent vagal pathways, leading to central and physiological (parasympathetic) modulation. Explaining how taVNS changes cardiorespiratory physiology requires systematic characterization of the effects of electrode location and stimulation waveform using rigorous experimental controls. Objective To determine the acute effects of four taVNS stimulation configurations (left unilateral 25 Hz, 100 Hz, burst, and bilateral 25 Hz) on physiological markers of parasympathetic activation compared with configuration-matched earlobe stimulation in healthy subjects at rest. Methods Customized 8-mm ear-clip electrodes delivered monophasic 500 μs pulses (anode anterior) to the tragus or a configuration-matched earlobe control across four stimulation configurations (left unilateral 25 Hz, 100 Hz, burst, and bilateral 25 Hz). Twenty-five healthy participants completed a randomized, single-blind, within-subject crossover study, undergoing both active and control stimulation for all four configurations (200 sessions total). Each session consisted of five 60-second stimulation blocks (1,000 stimuli total). Heart rate (HR), heart rate variability (HRV; RMSSD), and respiration were recorded continuously. Linear mixed-effects models compared physiological responses between tragus and earlobe stimulation during the first stimulation block (primary analysis), across 5-second HR intervals (secondary analysis), and averaged across all five stimulation blocks (post hoc analysis). Results During the first stimulation block, HRV was significantly higher during unilateral left 25 Hz tragus stimulation than during the matched earlobe control (β = −10.34, t(33) = −2.63, p = .01, 95% CI [−18.05, −2.64]), consistent with increased parasympathetic activity. No significant differences were observed for HRV with the other stimulation configurations, or for HR or respiration under any configuration. Analysis of 5-second HR intervals likewise revealed no significant temporal effects for block one. Analysis of 5-second heart rate intervals across the five blocks identified differences between tragus and earlobe at discrete time points but did not show a consistent temporal pattern across the stimulation period. Across all five stimulation blocks, unilateral left 25 Hz tragus stimulation remained associated with higher HRV (β = −6.56, t(124) = −3.85, p < .01, 95% CI [−9.90, −3.22]) and also produced an increase in HR relative to earlobe stimulation (β = −1.05, t(24) = −2.57, p = .01, 95% CI [−1.85, −0.24]). Respiration was unaffected throughout. Conclusion In this systematic study, unilateral left 25 Hz tragus stimulation produced physiological modulation consistent with vagal target engagement. These findings underscore the importance of rigorous dose-specific taVNS studies to establish reproducible physiological biomarkers.

BACKGROUND:Neuromodulation is a rapidly advancing field in pain medicine, providing targeted, reversible interventions for patients with chronic pain unresponsive to conventional therapies. Advances in waveform technology, device design, and stimulation strategies have shifted neuromodulation from a last-resort approach to a core element of multidisciplinary pain management. Despite its growing adoption, variability in training, terminology, and clinical implementation underscores the need for consensus-driven frameworks to ensure safety, efficacy, and uniformity across practice settings. OBJECTIVES:This review aims to define current and emerging concepts in neuromodulation, summarize the supporting evidence, and offer clinicians an evidence-informed framework for individualized application in chronic pain management. STUDY DESIGN:Narrative review. METHODS:We conducted a comprehensive synthesis of neuromodulation strategies spanning spinal cord stimulation (SCS), dorsal root ganglion stimulation (DRGS), peripheral nerve stimulation (PNS), motor cortex stimulation (MCS), deep brain stimulation (DBS), and targeted drug delivery (TDD). The review integrates data from published studies and reviews to cover emerging concepts, classifications, indications, technological advancements, device features, clinical applications, and practical guidance for patient-specific decision-making. RESULTS:Over the past decade, neuromodulation use has expanded significantly, driven by technological and mechanistic innovations. Peripheral nerve stimulation (PNS) has become increasingly precise for focal neuropathic pain, demonstrating efficacy in migraine, hemiplegic shoulder pain, persistent spinal pain syndrome, post-amputation neuropathic pain, trigeminal neuralgia, plexus injuries, and multifidus dysfunction. SCS remains a mainstay for widespread neuropathic pain, including CRPS, painful diabetic neuropathy, and post-surgical syndromes, with innovations such as 10-kHz high-frequency and burst stimulation offering paresthesia-free analgesia and improved patient satisfaction. DRGS provides targeted relief for localized neuropathic pain, including post-herniorrhaphy and post-thoracotomy syndromes, with more predictable outcomes. Neurophysiological refinements, including differential target multiplexed (DTM) stimulation and closed-loop systems with evoked compound action potential (ECAP) feedback, enable real-time spinal control and consistent analgesia. Multiphase and surround-inhibition paradigms further enhance segmental coverage, energy efficiency, and rapid analgesic onset. TDD has evolved into a precise adjunctive therapy, with programmable pumps delivering morphine, baclofen, and ziconotide safely, minimizing systemic exposure while allowing individualized dosing. Collectively, these innovations support precision-guided, personalized neuromodulation with durable efficacy and improved patient-centered outcomes across diverse chronic pain conditions. LIMITATIONS:Heterogeneity in published evidence and the lack of large-scale, head-to-head randomized trials for certain waveforms and technologies limit the conclusions of this review. CONCLUSIONS:Neuromodulation continues to advance at the intersection of neuroscience, bioengineering, and clinical practice. Harmonizing definitions, classifications, and education will guide future innovation and help ensure that neuromodulation fulfills its promise of safe, effective, and equitable patient care.

BACKGROUND:Persistent gait deficits after stroke are prevalent and negatively impact function. Motor learning methods promote neuroplasticity and can produce significant clinical gains, however recovery is limited for many individuals in the chronic phase. Transcranial direct current stimulation(tDCS) can enhance neuroplastic effects of training and can be easily paired with neurorehabilitation. OBJECTIVE:We tested active vs. sham bihemispheric 2 mA tDCS targeting primary motor leg regions paired with gait therapy. METHODS:Individuals(n = 44) were randomized to 10 sessions of active tDCS/sham tDCS paired with motor training. Outcomes were collected at baseline, mid-treatment, post-treatment and 6-week follow-up. TDCS-induced electric field(e-field) and lesion load were calculated using each participant's magnetic resonance imaging (MRI). Statistical methods included longitudinal linear mixed-effects model with treatment group by time interaction effects, Wilcoxon signed rank test and correlation analyses. RESULTS:Thirty-nine individuals completed the study. No difference was observed between treatment groups. Total cohort analysis showed significant improvement (p < 0.05) in the following: Fugl-Meyer, fastest gait speed, preferred gait speed, Timed Up and Go, Functional Gait Assessment, and Gait Assessment and Intervention Tool across time, with maintenance or improvement at 6-week follow-up. E-field in targeted region ranged 0.10-0.29 V/m. Lesion load did not correlate with change in clinical outcomes. CONCLUSIONS:Both groups improved across the clinical outcomes following short duration motor learning-based gait training with and without tDCS. Lesion load was not related to treatment response. E-field in targeted regions was variable across participants. Future studies employing optimized tDCS to ensure consistent dosing across subjects, paired with an effective gait training approach is needed.

Electrical stimulation accelerates wound repair by modulating endogenous bioelectric signals that regulate inflammation, angiogenesis, extracellular matrix remodeling, and cellular responses within the wound microenvironment. However, clinical translation has been hindered by cumbersome devices with procedures that disrupt standard wound-care workflows, direct electrode contact with the wound bed, and/or limited stimulation output. Wearable Disposable Electrotherapy (WDE) integrates an electronics-free printed electrochemical architecture into an mm-thick patch that looks and is applied like a conventional bandage. The device is self-powered and delivers a single electrotherapy dose simply by application to the skin. Device dose-control (electrochemical performance) and efficacy were evaluated in a full-thickness excisional wound model in rats, compared with a sham device and a conventional Constant Current (CC) stimulator. WDE or control treatments were applied daily from day 1 through day 13, with endpoint evaluation on day 14. WDE delivered electrical stimulation comparable to CC while reducing the time required to achieve 50% wound closure by 2.08 days (~29%) relative to sham treatment. Histological and immunofluorescence analyses at day 14 demonstrated enhanced tissue remodeling, including increased collagen deposition (~25%), tissue cellularity (~73%), myofibroblast-associated αSMA expression (~2.6-fold), angiogenesis-associated CD31 expression (~2.0-fold), and increased expression of both M2- (CD206, ~2.0-fold) and M1-associated (iNOS, ~1.7-fold) markers compared with sham. A novel cellular-resolution dosimetry model, leveraging charge-based boundary element method accelerated with the fast multipole method (BEM-FMM), provides a biophysical framework linking electrical stimulation with wound microenvironment and tissue repair mechanisms. Together, these findings establish WDE as a practical bioelectric wound dressing that accelerates wound healing and tissue remodeling, with the simplicity and scalability of disposable bandages.

OBJECTIVES:Epidural stimulation of the spinal cord evokes distinct electrophysiologic responses that can be recorded epidurally. Here, we characterized evoked compound action potentials (ECAPs), doublets (secondary or tertiary ECAPs, probably of different physiologic origin from primary ECAPs), evoked synaptic activity potentials (ESAPs), and electromyographic (EMG) signals in preclinical models. Our objective was to clarify the features and distinct physiologic origins of these signals, to advance mechanistic studies and support clinical applications of spinal cord stimulation (SCS) therapy. MATERIALS AND METHODS:Adult male Sprague-Dawley rats (300-440 g) were implanted with two epidural leads (caudal and rostral; each with eight electrodes) and received monopolar, biphasic stimulation (200-μs pulse width) at 2 and 50 Hz, with current increased stepwise to motor threshold. Rhesus macaques (11.5 and 10.2 kg) were implanted with a single 12-electrode epidural lead and stimulated using either tripolar, triphasic pulses at 10 Hz (100 μs) or tripolar, biphasic pulses at 3 Hz (80 μs) up to 3 × ECAP threshold. Recordings were taken from nonstimulating electrodes. RESULTS:ECAPs and EMG signals were recorded across multiple spinal segments in both rats (L1-T7) and macaques (L2-T11). Doublets presented as complex waveforms with multiple negative peaks, two in rats and three in macaques, likely representing distinct ECAPs at T11-T6 in a rat and L1-T11 in macaques. ESAPs, detectable in rats, showed anatomical specificity over the L1/T13 vertebrae, with peak responses at L1. Signal analysis included activation thresholds, amplitudes, latencies, and conduction velocities. CONCLUSIONS:This study outlines electrophysiologic signals evoked by SCS in terms of their waveform, recruitment thresholds, and putative physiologic origins. We propose that to some extent, these signals reflect different aspects of spinal processing and may serve as biomarkers of dysregulated nociceptive pathways, and as indicators of SCS efficacy or potential side effects.

Obsessive-compulsive disorder (OCD) is a condition with substantial disability and subclinical obsessive-compulsive behaviors affect up to 1 billion people globally. Transcranial electrical stimulation (tES) is emerging as a potential treatment for OCD, yet its effectiveness is uncertain due to the limited number of randomized controlled trials conducted so far. Here we applied 3 meta-analytic approaches to evaluate the pooled therapeutic effect size of included randomized controlled trials (n(tDCS) = 15, n(tACS) = 1) (pair-wise meta-analysis), compare the efficacy of various tES interventions (network meta-analysis), and explore how treatment effect size correlates with induced electrical field in the target brain regions (meta-modeling). With these 3 distinct meta-analytic approaches, we first show a significant moderate effect of tES interventions (standardized mean difference 0.61; 95% confidence interval [0.37 to 0.85]; P < 0.001) as a whole on reducing OCD severity, with larger therapeutic effects of twice-daily intervention, and with other stimulation parameters also moderating efficacy. Next, we identify specific tES interventions with superior indicated and estimated effects, including entraining alpha frequency alternating stimulation of the medial prefrontal cortex, excitability-diminishing cathodal stimulation over the supplementary motor area and orbitofrontal cortex, and excitability-enhancing anodal stimulation of the lateral prefrontal cortex. Finally, we show based on computational approaches that longer stimulation targeting the medial prefrontal and frontopolar cortices has greater therapeutic effects and suggest an optimized intervention accordingly. We finally discuss other potentially effective tES interventions according to the latest neurobiological theory of OCD. The results contribute to establishing the clinical efficacy of tES for OCD treatment while suggesting future studies to further evaluate current and future approaches to enhance the efficacy of interventions.