Neuromodulation: Technology at the Neural Interface

Background: The mechanisms driving cervical dystonia remain unclear, limiting effective, non-invasive treatment development. Lesion network mapping previously localized a brain network derived from lesions causing cervical dystonia, with a network hub in the somatosensory cortex, a viable target for non-invasive brain stimulation. Objectives: We conducted a randomized, sham-controlled, crossover trial administering continuous theta-burst stimulation (cTBS) to the S1 lesion network hub, testing whether modulating this network reduces CD symptoms. Methods: Thirteen idiopathic cervical dystonia patients (57.85 {+/-} 10.85 years) received two 10-session blocks of bilateral somatosensory cortex cTBS (active or sham; counterbalanced). The primary outcome was change in cervical dystonia symptoms, measured by the Toronto Western Spasmodic Torticollis Scale (TWSTRS). A wearable motion sensor objectively measured change in head and neck movement patterns. Motor evoked potentials and resting-state fMRI assessed cTBS-induced changes in corticospinal excitability and functional connectivity, respectively. Results: Active cTBS did not significantly reduce cervical dystonia symptoms compared to sham (condition x timepoint interaction: p = .149). Range of motion significantly increased with active, versus sham, cTBS (p = .015). Corticospinal excitability decreased following sham (p = .042), but not active, cTBS. No significant connectivity changes were seen from the somatosensory cortex stimulation site after active cTBS; however, significant changes emerged from the globus pallidus interna. Conclusion: This study prospectively tested the effects of neuromodulation on a lesion network mapping-derived target. Active cTBS did not significantly improve TWSTRS scores relative to sham. The intervention was well tolerated by all patients, and future studies could consider higher-dose or alternative protocols to this target.

Objective: This computational modeling study quantified the influence of sex and race-related cranial anatomy on predicted brain-wide current flow during electroconvulsive therapy (ECT) across conventional (bifrontal (BF), bitemporal/bilateral (BL), right unilateral (RUL)) and experimental (focal electrically administered seizure therapy (FEAST) and frontomedial (FM)) electrode montages. The objective was to determine whether race-associated variability meaningfully contributes to differences in ECT stimulation metrics across montages. Methods: Finite element head models of Chinese, Black, and Caucasian subjects were developed using high-resolution magnetic resonance imaging and analyzed using the Realistic vOlumetric- Approach-based Stimulator for Transcranial electric stimulation (ROAST) pipeline (N = 150 total; n = 50 per cohort, comprising 25 M and 25 F, age range: 20-30 years). Five ECT montages were simulated under a constant-current condition (900mA). Stimulation strength (Ebrain/Eth) was quantified as 90th percentile of brain-wide E-field magnitude (Ebrain) relative to neuronal activation threshold (Eth = 0.25 V/cm) quantified stimulation strength. Overall focality was evaluated as a percentage of brain volume stimulated above the neural activation threshold (Ebrain [≥] Eth), while laterality was quantified as the median right-to-left hemispheric E-field magnitude ratio. The effects of race, sex, and montage on stimulation strength, focality, and hemispheric laterality were statistically analyzed. Results: Substantial race- and sex-related differences observed in cranial anatomy resulted in systematic variation in predicted ECT-induced E-field intensity. Brain-wide E-field magnitude varied by both race and montage, with the largest fields generally observed in Caucasian head models and during BL stimulation. Montage exerted the strongest effect on stimulation strength (Ebrain/Eth) with BL and FEAST producing the highest stimulation strengths, followed by RUL and FM, while BF produced the lowest. Caucasian subjects generally predicted higher stimulation strengths than Black and Chinese subjects, whereas females predicted modestly higher stimulation strengths than males. Laterality was primarily determined by montage, with FEAST producing the greatest hemispheric asymmetry, followed by RUL. Chinese subjects demonstrated higher laterality ratios than both Black and Caucasian subjects. BL, RUL, and FEAST stimulated substantially larger brain volumes above neural activation threshold (less focal stimulation) than BF. Lower focality was observed in Caucasian subjects relative to Black and Chinese subjects, and in females relative to males. Conclusions: Electrode montage was the primary determinant of predicted ECT stimulation strength, focality, and laterality. Race-related anatomical differences and, to a lesser extent, sex-related differences systematically altered stimulation patterns, supporting consideration of individualized anatomy in ECT dosing and treatment optimization.

Objectives: Disorders of consciousness (DOC) affect an estimated 200,000 patients in the United States. Effective treatment options have remained elusive. Focused ultrasound neuromodulation (FUS) of brain regions controlling consciousness, such as the central lateral thalamus (CLT), has emerged as a promising non-invasive treatment. However, prior studies have been limited by broad effective stimulation volumes, missing control conditions, and limited target validation. This study investigated the effects of FUS of the CLT in a non-human primate model of DOC with robust control conditions and more robust targeting than previous experiments. Materials and Methods: Two male rhesus macaques underwent 1-hour propofol anesthesia sessions as a model of DOC. Bilateral CLT targets were sonicated using a stereotactically mounted 256-element phased-array focused ultrasound system. Focused and unfocused (random phases) paradigms were tested in both animals, and a spotlighting (sonicating multiple targets) paradigm was tested in one animal. Arousal was monitored via EEG beta power, pulse oximetry, breathing rate, and movement, and compared between sonication and control sessions for each paradigm. Results: Paired Wilcoxon signed-rank tests showed no significant differences for any of the four measures across the three paradigms (all pFDR [≥] 0.30). The largest observed effect was increased body movement under the unfocused paradigm (rrb = +0.58), though this did not reach statistical significance. Animals remained physiologically stable throughout sessions and recovery periods, with no clinically significant changes in heart rate, breathing rate, blood oxygen saturation, or other safety concerns. Conclusions: Under the tested parameters, FUS of the CLT did not produce measurable changes in arousal. The absence of adverse physiological effects supports the safety of this FUS paradigm. The largest effect occurring under spatially distributed sonication, consistent with prior evidence that broader stimulation volumes produce stronger arousal responses, suggests that distributed network stimulation may warrant investigation as an alternative to focal targeting. Future studies should investigate this possibility and should include robust control conditions to properly quantify effects.

Transcranial low-intensity focused ultrasound (LIFU) offers a rare ability to noninvasively modulate human brain activity in superficial and deep neural structures. Yet the field still cannot reliably predict how a given acoustic protocol will affect a specific brain target. We synthesize 230 LIFU experiments targeting the human cerebrum from 136 articles reporting sufficient acoustic information and neuromodulatory outcomes. We compare associations between acoustic parameters and reported outcomes across cortical and subcortical targets. This reveals divergent parameter-effect landscapes across cortical and subcortical targets. Cortical outcomes follow a nonmonotonic organization across pulse repetition frequency and duty cycle, with distinct zones associated with facilitation, suppression, and null or ambiguous effects. Subcortical outcomes instead vary predominantly along duty cycle, shifting from suppression at lower values toward facilitation at higher values. Intensity and dose factors do not provide a consistent target-independent explanation for outcome polarity, and current evidence is insufficient to identify parameters promoting lasting effects. These findings challenge the assumption that acoustic protocols have generalizable effects across the brain and identify anatomical target as a central dimension that should inform LIFU protocol design. We provide SonoMap, an open, interactive web resource that supports a more systematic, evidence-based approach to human LIFU neuromodulation.

BackgroundHearing aids and cochlear implants (CIs) are the primary interventions for sensorineural hearing loss, restoring auditory function through amplification and intracochlear electrical stimulation, respectively. For those with residual low-frequency hearing, the combined electric-acoustic stimulation (EAS) has demonstrated superior speech perception, particularly in noisy environments, compared to either modality. However, CI surgery carries inherent risks, including postoperative hearing loss, which undermines EAS benefits and limits future rehabilitation options. To overcome these limitations, we propose a non-invasive alternative: extracochlear electric and acoustic stimulation (EEAS), delivering electrical stimulation via transcutaneous electrodes without surgery. Here, we present a first systematic investigation of non-invasive extracochlear electrical stimulation using ear canal electrode montages, evaluating its feasibility, perceptual effects, and key parameters across diverse hearing statuses. MethodsWe conducted a controlled, within-subject study with 15 participants: 5 with normal hearing (NH), 5 with high-frequency hearing loss (HI), and 5 with severe-to-profound deafness (PL). We used charge-balanced sinusoidal stimuli (125-4000 Hz) applied via an ear canal electrode and four return electrode montages, including contralateral ear canal, contralateral mastoid, ipsilateral mastoid, and forehead electrodes. Participants rated auditory sensations, including loudness, sound quality, and lateralization, as well as side effects on separate 0-10 scales, with current intensity increased up to 2 mA/cm{superscript 2}. Thresholds and perceptual responses were analyzed across frequencies, electrode configurations, and hearing groups. ResultsReliable auditory percepts were elicited across all groups. NH participants reported pure-tone sensations, whereas HI and PL participants perceived broadband, noise-like sounds. Loudness decreased with increasing frequency, particularly for HI and PL, with minimal responses in the high-frequency range. The current threshold increased with stimulation frequency, whereas the threshold expressed as charge per phase remained constant, suggesting that charge per phase primarily determines neural activation, whereas current amplitude is more closely associated with the intensity of auditory and side effect perception. Contralateral montages produced significantly higher loudness ratings than ipsilateral or forehead configurations. The forehead montage was poorly tolerated, leading to early termination due to discomforting side effects. Sound lateralization was predominantly central or bilateral with contralateral setups, while ipsilateral and forehead configurations yielded ipsilateral perceptions. ConclusionsNon-invasive extracochlear electrical stimulation via ear canal electrodes is feasible and perceptually effective across a spectrum of hearing statuses. Perceptive outcomes are strongly influenced by electrode montage and residual hearing, with evidence of electrophonic excitation in NH individuals and electroneural activation in HI and PL participants. Contralateral mastoid electrode configurations offer the optimal balance of perceptual strength, tolerability, and spatial localization. These findings establish a critical foundation for the development of EEAS devices, demonstrating that non-invasive electrical stimulation can generate meaningful auditory percepts, paving the way for safe, accessible, and integrated hearing rehabilitation solutions. This work informs future EEAS developments and advances the path toward clinically viable, non-invasive cochlear stimulation.

Objectives: Non-invasive brain stimulation (NIBS) holds significant promise for treating neurological and neuropsychiatric conditions, yet translation into routine clinical practice remains limited. We aimed to explore stakeholder perceptions of NIBS and barriers to its clinical adoption. Methods: We conducted focus-group interviews with 33 participants across three key stakeholder groups in the UK: (1) people with lived experience of brain injury, depression, or dementia; (2) healthcare professionals; and (3) researchers. Reflexive thematic analysis was used to identify themes in the data. Findings: Seven key themes emerged spanning preferences, hope and disappointment, communication, accessibility, infrastructure, ethical/regulatory uncertainty, and the evidence base. Across groups, NIBS was viewed positively and with cautious optimism, but substantial barriers were highlighted, including limited public and clinical awareness, challenges in demonstrating cost-effectiveness, infrastructure constraints, and difficulties navigating regulatory and translational pathways. Participants emphasised the importance of clear communication, improved education, and stronger interdisciplinary collaboration to support adoption. Notably, stakeholders prioritised evidence of clinical efficacy and usability over detailed mechanistic understanding. Conclusions: These findings provide actionable insights into the translational gap in NIBS and highlight priorities for facilitating its integration into clinical care.

Magnetic Resonance guided High Intensity Focused Ultrasound (MRgHIFU) has been demonstrated to be a safe and effective minimally invasive therapy for essential tremor (ET). However, it is not clear whether older adults ([&ge;]70 years old) or individuals with comorbidities exhibit similar safety and efficacy. This IRB approved project collected EPIC EMR data on patients that underwent MRgHIFU at Parkview Regional Medical Center from January 2023 to November 2025. 68 patients were assessed for tremor severity using Clinical Rating Scale for Tremor (CRST), quality of life using Quality of life in ET Questionnaire (QUEST), and safety profile via reported post-procedure side effects. CRST and QUEST scores improved up to 1 year from baseline in our patient cohort and efficacies in older ([&ge;]70 years of age) and younger (<70 years of age) patients up to 3 months post MRgHIFU were not statistically different. Effects of comorbidities on CRST or QUEST scores improvements were all transient or did not affect endpoints. Older patients showed fewer total side effects at 3 months (1.17 (95% CI: 0.47-1.87) vs 0.21 (95% CI: -0.09-0.51), p=0.017) as did patients with pulmonary disease at 1 month (1.9 (95% CI: 1.6-2.2) vs 1.1 (95% CI: 0.9-1.3), p=0.036) while patients with family history of tremor showed more side effects at day 1 (1.5 (95% CI: 0.8-2.2) vs 2.5 (95% CI: 2.1-2.9), p=0.025). Age and comorbidities were not detected to adversely affect safety or efficacy following MRgHIFU in ET patients.

Purpose: Fibromyalgia involves chronic widespread pain and heightened movement evoked pain (MEP), which can limit access to resistance training's functional and psychological benefits by hindering exercise participation and adherence. This study aimed to determine whether transcutaneous electrical nerve stimulation (TENS) applied during resistance exercise reduces MEP in women with fibromyalgia. Materials and methods: 21 women with fibromyalgia performed 2 sets of 10 leg press repetitions at 60% predicted 1 RM while receiving randomized active TENS (100 Hz) or sham TENS. Pain intensity and unpleasantness (0 to 10 numerical rating scales) were assessed at baseline, immediately post exercise, 15 min post-exercise, end-of-day, and 24h later. Results: Active TENS led to a greater reduction in post-exercise pain than sham, with 90% of participants experiencing at least a 15% decrease in whole body pain 15 minutes post-exercise, compared to none in the sham group. No group differences were observed at the end of the day or 24h after the exercise session. Conclusion: These results suggest that a single session of high frequency TENS during resistance exercise can produce short term reductions in MEP in women with fibromyalgia. While effects did not persist at 24h, these short-term effects may help mitigate acute exercise related pain and support early training adherence.

Background: Neuropathic pain (NP) remains a therapeutic challenge, with conventional repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex (M1) yielding a response rate of approximately 40%. Personalised targeting based on dysfunctional neurocircuitry offers a promising strategy to enhance efficacy, yet its application in NP is unexplored. This open-label trial investigated a novel targeting approach guided by the recently described cingulo-opercular and somato-cognitive action (CON-SCAN) network, a circuit integrating cognitive and affective dimensions of pain. Methods: Twenty patients with NP received 10 sessions of M1-rTMS over two weeks, with the stimulation site individually localised based on maximal functional connectivity to a CON template. Results: Increased CON-SCAN connectivity from baseline to post-treatment was associated with reduction in pain interference, anxiety and depression scores. The response rate was 50% post-treatment, which was maintained at the 1-month follow-up. Improvements were also observed in neuropathic pain symptoms, negative affect, and overall health. Conclusions: As the first connectivity-guided rTMS trial for NP, this study provides preliminary evidence that personalised targeting of the CON-SCAN network is feasible and associated with the analgesic effects of M1-rTMS, supporting further investigation in randomised controlled trials. Trial registration: Chinese Clinical Trial Registry, ChiCTR2500104679. Registered 20 June 2025, http://www.chictr.org.cn. Chinese Clinical Trial Registry, ChiCTR2400094568. Registered 24 December 2024, http://www.chictr.org.cn. Keywords: Personalised TMS; Pain; M1; CON; SCAN

Home-based 2 mA transcranial direct current stimulation (tDCS) was recently approved by the US Food and Drug Administration for depression, but tDCS amplitude has been limited largely by skin tolerance, and higher-intensity, accelerated dosing may be more efficacious or faster-acting. Using a novel high-capacity tDCS (HC-tDCS) stimulator and hydrogel electrodes, we evaluated the safety, tolerability and feasibility of accelerated HC-tDCS (20-minute bifrontal 6 mA sessions, twice daily for five days) in 20 patients with major depressive disorder. A Safety Review Committee reviewed data from the first three participants, who completed a within-day escalation to 6 mA, before the remaining 17 were enrolled. Retention and adherence were 100% (203 of 203 sessions), and 19/20 tolerated the full 6 mA amplitude without dose reduction. There were no serious adverse events. The most common symptoms were fatigue (49% of sessions), burning (46%) and tingling (43%) at the electrode, and difficulty concentrating (40%). Electrode-site erythema occurred in all participants, with no severe reaction or skin breakdown. At 1 week, 7 of 20 reported a residual skin change, mostly peeling or redness, none painful; at 1 month, hyperpigmentation at the electrode site persisted in 2 participants, both Black. At the end of the five-day course, PHQ-9 scores decreased from 15.8 to 7.2 (Hedges g = 1.62); 50% of participants responded, 45% remitted, and improvement was maintained at 1-month follow-up. Accelerated HC-tDCS was feasible, well tolerated, and warrants a sham-controlled trial.

Low-intensity focused ultrasound (LI-FUS) clinical trials exploit either the neural activity modulating, or the blood-brain barrier opening, capacity of this stimulation modality. However, LI-FUS currently is applied only transcranially which means that it is conducive only for episodic and intermittent stimulation, although, clinical data shows that in numerous neurological and psychiatric applications, chronic and continuous stimulation is required for long-term, stable therapeutic effect. The paper presents experimental data on a novel and innovative approach describing an implantable, epidural focus ultrasound (eFUS) device, designed for continuous, chronic and multi-site steerable neuromodulation. The miniaturized eFUS device consists of a two-dimensional piezoelectric transducer array directly integrated onto a custom ASIC, specifically engineered for proof-of-principle neuromodulation studies in the rat brain. The system generates electronically steerable focused ultrasound with software-defined focal coordinates, sufficient to stimulate neuronal activity in deep brain structures. In vitro acoustic characterization confirmed accurate beam steering and focusing, while in vivo validation demonstrated reliable stimulation of a deep subcortical target with measurable physiological effects. eFUS-mediated targeting of the ventral tegmental area in awake and freely moving rats produced increase in dopamine release in the nucleus accumbens as confirmed using fiber photometry recordings. Post-mortem histological analysis of the target regions showed the absence of inflammatory markers, although the epidural placement of the eFUS device was associated with mild tissue damage. Overall, the study provides in vitro data demonstrating the energy efficiency, and steerability of the technology, and in vivo physiological evidence of neuromodulatory ability of a deep, subcortical brain structure.

Auditory confounds have proven to be a major hurdle in the elucidation of veridical neuromodulation effects with transcranial ultrasound stimulation (TUS). Auditory noise masks are an essential method to reduce the audibility of TUS and have shown promise in several studies. Here we describe a novel approach for design, calibration, and psychometric validation of auditory noise masks to reduce the perceptibility of TUS. White noise masks and spectrum-tuned masks matched to a TUS protocol that generates highly salient auditory costimulation (487.5 Hz pulse repetition frequency, 10% duty cycle, 68 W/cm2 pulse-peak average intensity, 500 kHz acoustic frequency) were generated, and dB(A) levels were calibrated with an artificial ear. The masker levels needed to reduce TUS detection performance in a two-interval forced choice task were determined with an adaptive QUEST+ staircase in 20 neurotypical participants. Detection performance of this highly salient TUS protocol was driven to near chance performance (<55%) in 17/20 participants with white-noise and 18/20 participants with spectrum-tuned noise. However, high masker levels approaching safety limits were needed to render TUS inaudible for the majority of participants, indicating the need for formal masker calibration for these TUS settings. Additionally, against expectation the spectrum-tuned masker did not significantly outperform the white-noise masker, suggesting that perceptibility of TUS auditory costimulation does not lawfully follow the sound expected from its pulse envelope and the known spectrum of human hearing.

The inflammatory foreign body response that follows cochlear implantation produces intracochlear fibrosis, neo-ossification, and elevated electrode impedances that can compromise implant performance. Dexamethasone-eluting cochlear implants reduce this response, but the durability of their anti-inflammatory effect over long implantation intervals has not been established. Using a murine model of chronic cochlear implantation in CX3CR1+/eGFP Thy1+/eYFP dual-reporter mice, we compared dexamethasone-eluting and standard mouse cochlear implants at 224 and 336 days post-implantation. Density of CX3CR1+ macrophages, MHCII+CX3CR1+ antigen-presenting macrophages, -SMA+ fibrosis, and neo-ossification were quantified in the scala tympani, Rosenthal canal, and lateral wall of the basal turn. Standard implants produced persistent macrophage and antigen-presenting macrophage infiltration, accompanied by an -SMA+ fibrotic response and neo-ossification. Dexamethasone-eluting implants suppressed macrophage infiltration in all three regions out to 336 days and reduced fibrosis at 224 days. In the subset of cochleae with electrode array translocation, dexamethasone-eluting implants attenuated macrophage infiltration and confined the fibrotic and osseous response to the site of translocation, whereas standard implants produced a widespread response. A reduction in immune cell density was also observed in the contralateral, unimplanted cochleae of animals implanted with dexamethasone-eluting implants, suggesting a wider component to the drug's effect. Dexamethasone-eluting cochlear implants therefore provide sustained, long-term suppression of the cochlear foreign body response in mice, supporting their continued translation toward clinical application. This effect was associated with continued low-level dexamethasone elution out to 336 days post-implantation; further work is needed to assess the durability of this effect at the conclusion of drug elution.

Objective: To evaluate the clinical efficacy of non-invasive electrical pulsed radiofrequency (PRF) stimulation on diagnostic thresholds and subjective pain in chronic, pedal diabetic peripheral neuropathy (DPN). Methods: A randomized, single-blind, placebo-controlled trial (ClinicalTrials.gov: NCT07725419) enrolled 92 patients with pedal DPN naive to PRF and scoring [&ge;] 4/10 on the Douleur Neuropathique 4 (DN4) test. Participants received either active PRF stimulation (n = 46) or a non-stimulating placebo (n = 46) applied bilaterally to the sciatic nerve in the popliteal fossa for 10 minutes per limb, once weekly for three weeks. The primary outcome was clinical neuropathic resolution (DN4 < 4). Secondary outcomes included subjective pain tracking via the Brief Pain Inventory-Short Form (BPI-SF) Worst Pain scale over a 6-month follow-up window. Missing data were handled via Non-Responder Imputation (NRI). Longitudinal continuous trajectories were modeled using Linear Mixed-Effects Models (LMMs) adjusted for age, gender, and baseline medication use. Results: In the Intention-to-Treat population (N = 92), a significant diagnostic responder effect occurred at 3 months, with 39.1% of active patients dropping below the diagnostic threshold for neuropathy (DN4 < 4) versus 19.6% of placebo controls (p = 0.039). For subjective pain, 47.7% of active patients achieved a Minimally Clinically Important Difference ([&ge;] 3-point reduction) in BPI Worst Pain at 1 month compared to 19.4% of placebo controls (p = 0.008). Multivariable logistic regression identified active treatment as a significant independent predictor of clinical response (Adjusted OR = 4.86; 95% CI: 1.56 to 17.53; p = 0.010). Continuous LMM tracking confirmed a statistically significant treatment-by-timepoint interaction for BPI Worst Pain at 1 month (p = 0.046). Conclusion: A brief, three-week course of non-invasive PRF stimulation serves as a safe, effective, non-pharmacological adjunct that aids in managing the diagnostic presentation of neuropathic pain and mitigates worst pain experiences in patients suffering from pedal DPN.

Importance: Upper extremity impairment is a leading cause of post-stroke disability, yet clinically approved neuromodulation therapies are currently limited by the risks and costs of surgical implantation. There is an unmet need for non-invasive brain stimulation. Objective: To evaluate the feasibility, safety, and preliminary clinical efficacy of a novel form of non-invasive brain stimulation, kilohertz transcranial magnetic perturbation (kTMP), for upper limb motor recovery after stroke. Design: A single-center, open-label trial was conducted between September 2025 and April 2026 and comprised a 4-week standard-of-care baseline period, 4 weeks of active treatment with kTMP combined with motor training, and a 4-week follow-up. Setting: Academic research center. Participants: Seven individuals with chronic stroke and upper extremity motor deficits. Intervention: Four weeks of kTMP (3 sessions/week), a brain stimulation approach using magnetic induction to generate subthreshold electric fields, paired with motor tasks. Main Outcomes: Change in Fugl-Meyer Assessment for Upper Extremity (FMA-UE) scores across study periods (standard-of-care baseline, active treatment, follow up). Secondary outcomes included measures of movement smoothness (Spectral Arc Length, SPARC) and fragmentation (mean velocity peak count), and intervention tolerability ratings. Results: Across 7 participants (mean [SD] age, 57.4 [8.7] years; 4 males; mean [SD] time poststroke, 3.5 [2.1] years). No device-related adverse events occurred, and the intervention was well-tolerated (participants rated sensation intensity at an average of less than 0.5 on a 0-10 scale). FMA-UE scores remained stable during the baseline period (mean change, +0.14 points; 95% CI, -1.21 to 1.50; adjusted P = .98), increased significantly following the kTMP-intervention (mean change, +7.00 points; 95% CI, 5.31 to 8.69; adjusted P = .047), and were sustained at the 4-week follow-up (mean change, -1.33 points; 95% CI, -2.42 to -.25 points; adjusted P = .13). Movement smoothness improved significantly within 1 week of kTMP onset (mean change, 1.48 points; 95% CI, .49 to 2.47; adjusted P = .03); movement fragmentation showed a similar but nonsignificant trend. Conclusions and Relevance: This pilot trial provides preliminary evidence that kTMP combined with motor tasks is safe, feasible, and may support upper extremity recovery. These pilot data warrant large, randomized controlled trials to evaluate efficacy in support of poststroke motor recovery. Trial Registration: ClinicalTrials.gov Identifier: NCT06317194

Non-pharmacological adjuncts are needed for chronic non-cancer pain in patients receiving long-term opioid therapy. Music listening may reduce pain, but most previous trials have used passive controls, limiting attribution of effects specifically to music. In this open-label, parallel- group, proof-of-concept randomized controlled trial, adults with chronic non-cancer pain receiving long-term opioid therapy were randomized 1:1 to four weeks of daily home-based music or audiobook listening. Analgesic outcomes included pain intensity, responder rates, quantity of pain relief, and multidimensional pain assessment; secondary outcomes included mood, quality of life, global impression of change, and safety. Of 70 participants entering the run-in period, 56 were randomized (28 per group). Adjusting for baseline pain intensity in a linear mixed-effects model, the between-group difference at end of treatment was -1.26 NRS points (95% CI -1.98 to -0.55; p<0.001; d=-0.70), favoring music. A [&ge;]30% pain-reduction criterion was met by 21.4% of participants in the music group and none in the audiobook group (p=0.023). An exploratory between-group difference in pain intensity favoring music was also observed at follow-up. Other analgesic and secondary outcomes showed no significant between-group differences, although exploratory within-group improvements in mood and health-related quality of life were observed with music. Both groups reported overall improvement in global perceived change, with ratings numerically favoring music. No intervention-related harms were observed. These findings support an analgesic benefit of music beyond the structured listening experience shared with the active comparator. Daily self-administered music listening may represent a feasible, low-cost adjunct for chronic non-cancer pain in patients receiving long-term opioid therapy.

Background: Individuals receiving buprenorphine treatment for opioid use disorder (OUD) remain at high risk for treatment discontinuation and return to opioid use. Transcranial magnetic stimulation (TMS) has shown efficacy in reducing craving and substance use in other substance use disorders, but its application in OUD remains limited and the neural mechanism underlying its therapeutic effects is poorly understood. Determining the feasibility and generalizability of TMS in patients receiving buprenorphine - the most commonly prescribed medication for OUD - is therefore critical. This protocol aims to address these issues in a clinical trial of weekly TMS sessions for OUD. Methods: We will enroll up to 120 individuals with OUD taking buprenorphine in a randomized, single-blind, sham-controlled trial of left dorsolateral prefrontal cortex (DLPFC)-targeted intermittent theta burst stimulation (iTBS). Participants will receive active or sham iTBS weekly (2 sessions of 1800 pulses each applied once per week x 8 weeks, 16 sessions total) with pre- and post-iTBS assessments (10, 12, 20 weeks) of craving, opioid use, and treatment retention. A subset of individuals will undergo optional pre- and post-iTBS neuroimaging. The study will be conducted at an academic medical center and a private outpatient TMS clinic. Aims: Our primary aim is to determine whether 16 sessions of active iTBS applied to the left DLPFC results in reduced craving and opioid use, and higher treatment retention, relative to sham. In a secondary aim, we will also examine whether iTBS-related changes in craving are associated with changes in functional connectivity between the left DLPFC and both the dorsal striatum and anterior cingulate cortex. Discussion: By evaluating the feasibility and efficacy of a weekly TMS protocol that aligns with routine care and focuses on patients maintained on buprenorphine, this study addresses key limitations of prior TMS research in OUD. Furthermore, the inclusion of neuroimaging will help characterize the neural mechanisms underlying TMS-related changes in craving. Trial registration: This clinical trial is registered at ClinicalTrials.Gov; ID NCT07457489; date of registration: 03/02/2026.

Non-invasive brain stimulation (NIBS) has become an important tool for investigating brain function and exploring therapeutic intervention in neurodevelopmental disorders (NDDs). Nevertheless, relevant studies are scattered across different NDDs, stimulation modalities, target regions, and experimental designs, which makes systematic exploration and comparative analysis challenging. Therefore, we present NANHA, a manually curated, harmonized and freely accessible resource of published NIBS studies in NDDs. The database was constructed using systematic PubMed searches covering 22 NDDs and five NIBS modalities. NANHA captures participant characteristics, study design, stimulation purpose and parameters, targeted brain regions, behavioral, cognitive, and neurophysiological outcomes, safety information, and follow-up assessments, whenever available. The NANHA web platform (https://cb.imsc.res.in/nanha/) provides searchable and downloadable records, advanced filtering options, and interactive visualizations to support data exploration. Overall, NANHA is a standardized resource for evidence synthesis, comparative analyses, identification of research gaps, and the development of disease-specific stimulation protocols for NDDs.

Background: Deep brain stimulation of the medial forebrain bundle (mfb DBS) is a promising intervention for psychiatric disorders, but the neurochemical mechanisms underlying its effects remain incompletely understood. Methods: In adult Sprague Dawley rats, fiber photometry was used to monitor mfb-DBS evoked dopamine (DA) and noradrenaline (NA)-signaling in the nucleus accumbens (NAc) and prefrontal cortex (PFC), following different stimulation patterns, laterality conditions, and prolonged stimulation paradigms. Ultrasonic vocalizations (USVs) were recorded in parallel as a behavioral measure. Results: Bilateral stimulation robustly increased catecholaminergic signals relative to sham in both NAc and PFC. The magnitude and temporal profile of these responses depended more on stimulation pattern rather than on laterality, with long pulse-width generally evoking the largest responses and laterality producing no significant differences across the four recording groups. During 10 min bilateral stimulation, catecholaminergic signals increased rapidly and remained elevated throughout stimulation, with the clearest sustained effect observed in NAc DA. mfb DBS also increased USV calls and peak frequencies, whereas these behavioral changes showed no consistent region-specific correlation with catecholaminergic signal magnitude. Conclusions: mfb DBS recruits catecholaminergic signaling in a parameter-dependent and region specific manner and increases positive-affective USV output. These findings identify temporal patterning as an important determinant of downstream circuit engagement, whereas the relationship between acute USV responses and regional catecholamine signaling appears more complex.

Transcranial ultrasound stimulation (TUS) is an emerging tool to non-invasively modulate neural activity in deep brain areas. A key need in accelerating TUS into cognitive neuroscience and neuropsychiatry is to better understand how different sonication parameters relate to neuromodulatory effects. Here we assess the role of pulse repetition frequency (PRF), a key TUS parameter thought to determine the relative contribution of molecular displacement and acoustic radiation force effects on neural tissue using the human subcortical visual pathway as a testbed. We combined frequency-tagged steady-state visual evoked potential (SSVEP) measures of contrast-response with contrast increment detection psychophysics as neural and behavioral readouts of visual pathway function. We used structural MRIs and acoustic simulations to target the lateral geniculate nucleus (LGN). Concurrent with visual stimulus presentation, the left LGN or a more superficial control site were stimulated with a neuronavigated depth-steerable 4-element TUS transducer at a range of PRFs with 68 W/cm2 free-water ISPPA, and a 10% duty cycle. An effective white-noise auditory mask blinded participants to stimulation conditions. Recordings from 25 neurotypical participants failed to detect any impact of TUS on SSVEP response amplitude, SSVEP response latency, or perceptual behavior. Analysis of simulations generated from the measured transducer positions grant reasonably high confidence that the LGN was within the TUS focus in most participants, with no correlation between targeting accuracy and changes in activity during TUS. Our results provide a cautionary note about the effect size of neuronavigated TUS for online causal manipulations in cognitive and clinical neuroscience.