Neuromodulation: Technology at the Neural Interface

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.

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.

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

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.

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.

The subgenual anterior cingulate cortex (sgACC) is a key node in treatment-resistant depression (TRD), but precise non-invasive neuromodulation of this target is challenging. Preclinical studies of non-ablative stereotactic radiosurgery (SRS) have shown neuromodulatory ("radiomodulation") effects. In this single-center, double-masked, randomized, dose-seeking pilot trial, nine adults with TRD were randomly assigned to bilateral sgACC radiomodulation at a dose of either 15, 20, or 25 Gy per hemispheric target. Primary endpoints were safety and feasibility; the efficacy endpoint was week-4 change in the Montgomery-Asberg Depression Rating Scale (MADRS). Both primary endpoints were met: the only treatment-related adverse event was transient grade 1 dizziness, with no structural MRI abnormality through week 12. Mean MADRS fell from 33.0 to 17.0 (48.5% reduction); 67% responded and 44% remitted, with benefit sustained to week 12. Resting-state fMRI revealed regional connectivity changes correlating with clinical improvement, with tractography showing streamline counts differing by response status. These first-in-human findings support a larger randomized controlled trial of sgACC radiomodulation for TRD. ClinicalTrial.gov registration: NCT07274917.

Background: Pain relief is the principal patient-centered goal of surgery for symptomatic lumbar synovial facet cysts, yet comparative reviews have often emphasized cyst recurrence. Whether adding fusion improves postoperative pain or reduces later surgery remains uncertain. Objective: To compare decompression alone with decompression plus fusion, with postoperative back- and leg-pain outcomes as the primary domain. Methods: PubMed, Embase, Scopus, Web of Science, and the Cochrane Library were searched from inception to 2 June 2026. Comparative cohorts and case series with at least five patients were eligible. Twenty-two studies were re-extracted for VAS/NRS scores, change scores, and persistent or recurrent pain. Random-effects restricted maximum likelihood models with Hartung-Knapp inference were used; clinically distinct pain outcomes were analyzed separately. Results: Twenty-two studies (16 cohorts, 6 case series; 51,899 participants) were included. Two studies provided compatible final VAS data. Fusion did not improve postoperative back pain (MD -0.04, 95% CI -0.17 to 0.10; I2=0%) or leg pain (MD -0.03, 95% CI -0.28 to 0.21; I2=0%). Postoperative back pain (RR 0.58, 95% CI 0.14-2.30) and leg/radicular symptoms (RR 0.75, 95% CI 0.42-1.32) were also not significantly reduced. Fusion decreased confirmed cyst recurrence (RR 0.29, 95% CI 0.15-0.57) but not reoperation or subsequent lumbar surgery (RR 0.80, 95% CI 0.42-1.50). Conclusion: Current comparative evidence does not demonstrate superior postoperative pain control with routine fusion. Fusion reduces cyst recurrence without clearly reducing reoperation, supporting selective use when instability is present or anticipated.

Background: Vertebroplasty and balloon kyphoplasty are used for symptomatic vertebral hemangiomas, although comparative evidence is limited. We summarized pain relief, cement leakage, and recurrence after vertebral augmentation and assessed whether direct comparison of the two techniques was feasible. Methods: Five databases were searched from inception to January 2, 2026, with an update on July 5, 2026. Because only one small cohort directly compared vertebroplasty with kyphoplasty, outcomes were pooled as single-arm proportions or, for early pain change, as a mean difference using random-effects models. Prespecified subgroup, sensitivity, small-study effect, and influence analyses were performed. Results: Forty-four studies were included: 33 case series, 10 cohort studies, and one randomized trial. Kyphoplasty-specific evidence comprised one dedicated series and one comparative cohort. Any cement leakage occurred in 10.5% of patients (14 studies; 95% CI 5.7-18.4%), while trim-and-fill gave an exploratory adjusted estimate of 20.4%. Early pain reduction averaged 5.13 points on a 0-10 scale (8 studies; 95% CI 4.48-5.77; I2=89.4%). Complete or near-complete pain relief occurred in 79.4% of patients (10 studies), and recurrence, progression, or retreatment occurred in 3.9% (13 studies). Symptomatic cement leakage was uncommon at 0.4%. Conclusion: The available literature, which is mainly retrospective and vertebroplasty-based, supports substantial pain relief with infrequent symptomatic complications. Kyphoplasty data remain insufficient for a reliable technique comparison. Prospective studies with standardized clinical and imaging outcomes are needed.

BackgroundThe integration of virtual reality (VR) and non-invasive brain stimulation (NIBS), particularly transcranial magnetic stimulation (TMS), represents a promising approach for closed-loop neuromodulation. Yet the concurrent application remains limited, partly due to insufficient characterization of hardware compatibility of head-mounted displays with standard TMS coil placement protocols. ObjectiveTo systematically quantify the coil-to-scalp distance constraints imposed by VR headsets across cortical targets and coil orientations and to determine feasible intensity compensation ranges based on stimulator output parameters. MethodsNeuronavigated coil positioning was performed on five anatomically realistic 3D-printed head models across 26 scalp positions in eight coil orientations based on the 10-10 EEG system and dorsolateral prefrontal cortex (DLPFC) using two VR headsets of notably different form factors (Meta Quest 2 and Bigscreen Beyond). The deviations of coil positions from intended targets were registered and quantified as coil-to-scalp distance displacement. Individual electric field (E-field) simulations were conducted in SimNIBS at the F3 position across 4-40 mm coil-to-scalp distance to characterize field decay and assess the limits of intensity compensation. ResultsBoth in the directed DLPFC targeting and in systematic scalp positions evaluation, the Meta Quest 2 headset substantially increased coil-to-scalp distance over prefrontal regions, exceeding the compensable range across all metrics. The Bigscreen Beyond headset produced significantly smaller coil-to-scalp distance displacement in prefrontal regions, remaining within feasible E-field intensity compensation limits. Single-pulse and iTBS protocols did not induce functional interference with the hardware under realistic targeting conditions. ConclusionVR headset geometry is the primary determinant of concurrent VR-TMS feasibility. The findings define practical quantitative hardware design requirements and boundaries for future integrated VR-TMS systems and provide a practical framework for optimizing existing VR-TMS protocols.

Although non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) has demonstrated a therapeutic-relevant potential by enhancing mood recovery and fear extinction, its influence on neural dynamics during naturalistic, sustained fear processing remains unclear. In this study, we employed a randomized, sham-controlled, parallel-group design involving 63 participants (taVNS: n = 33; sham: n = 30) who provided continuous subjective fear ratings (1170 timepoints) while watching a 10-minute fear-inducing video, with simultaneous fNIRS recordings. We employed: (1) a convolutional neural network (CNN) to decode fear ratings from frontal activations, (2) validation of stimulus-evoked activity comparing fNIRS with fMRI signal, (3) dynamic conditional correlation analysis to assess taVNS-induced connectivity changes, and (4) moderation analysis to examine anxiety state effects. Behaviorally, taVNS significantly attenuated fear responses during four threat phases by content analysis: T1 (ghost appearance), T2 (escape sequence), T3 (sudden threat emergence) and T4 (suicide scene). Neurally, taVNS suppressed medial prefrontal cortex (mPFC) activation during escape (T2) and disrupted the typical fear coupling between fear experience and brain activity. Furthermore, taVNS enhanced intra-mPFC functional connectivity, suggesting a potential neural basis for modulating subjective threat appraisal. Additionally, state anxiety significantly moderated brain-behavior relationships. These findings demonstrate that taVNS attenuates fear responses through modulation of mPFC engagement and strengthening frontal network integration. Our results highlight taVNS as a promising neuromodulatory intervention for fear-related disorders (e.g., anxiety disorder), particularly as an early adjunct to exposure-based therapies, warranting further clinical validation.

Objective: To describe the self-reported effects of incobotulinumtoxinA treatments on migraine-like headache in participants who experienced traumatic brain injury versus Anomalous Health Incidents. Background: Persistent headache attributed to traumatic injury to the head has been widely recognized as among the most common sequelae of concussion/mild traumatic brain injury. Such persistent headaches often have migraine-like characteristics and are typically treated similarly to idiopathic migraine. Patients who have experienced Anomalous Health Incidents have also commonly reported migraine-like headaches, but to our knowledge, no reports describing treatment for persistent headaches attributed to Anomalous Health Incidents have been published. Methods: We describe the self-reported effects of incobotulinumtoxinA treatments on headache with migraine-like characteristics in 19 participants with traumatic brain injury and 11 who had experienced Anomalous Health Incidents from a single center. Results: Self-reported benefits from incobotulinumtoxinA treatments were generally similar and statistically indistinguishable between groups. The Headache Impact Test-6 score decreased by a mean of 12 points in the traumatic brain injury group and 9.5 points in the Anomalous Health Incidents group from baseline to peak efficacy (p = 0.43), with concomitant reductions in work/school hours lost (62% vs. 50%) and family/leisure hours lost (75% vs. 33%). Furthermore, reductions in headache frequency (67% for the traumatic brain injury group vs. 57% for the Anomalous Health Incidents group), headache severity (36% vs. 23%), headache duration (37% vs. 50%), nausea/vomiting (50% vs. 25%), photophobia (34% vs. 29%), phonophobia (30% vs. 37%), visual aura (50% vs. 29%), vestibular aura (50% vs. 33%), and other aura (21% vs. 25%) from baseline to peak efficacy were similar in both groups. Likewise, time from treatment to response (6.5 vs. 7 days), duration of response (10.2 vs. 9.1 weeks), adverse effects (3/19 for the traumatic brain injury group, 3/11 for the Anomalous Health Incidents group), and improved efficacy of concomitant abortive treatments (30% vs. 50% for pain, 50% vs. 55% for aura) did not differ between groups. Osmophobia and cogniphobia, when present, did not improve on average in either group. Notably, the mean duration of response was less than 12 weeks in both groups, with only 3 participants with traumatic brain injury and 1 participant who had experienced Anomalous Health Incidents reporting benefit beyond the typical 12-week incobotulinumtoxinA treatment interval. Conclusion: Overall, these findings provisionally indicate that at least some patients who have experienced Anomalous Health Incidents may subjectively benefit from incobotulinumtoxinA treatment for persistent migraine-like headaches similarly to patients with traumatic brain injury. Limitations include the open-label, single-center, primarily retrospective design; small sample size; and limited representativeness. Further prospective controlled studies are needed to determine whether these groups truly respond similarly to incobotulinumtoxinA and other standard treatments.

Background: Transcranial low-intensity focused ultrasound (LIFU) neuromodulation can alter human task performance depending on target and acoustic configurations. However, single behavioral endpoints cannot locate effects within multistep tasks, and predefined target labels ignore acoustic variations. Objective: To determine whether thalamic LIFU affects visual categorization or subsequent subjective report latency and whether the effects vary with target, acoustic parameter, and beam location. Methods: Sixty healthy adults were randomized to 70% or 5% duty cycle (DC70 or DC5) and received sonication on four left thalamic targets with matched pulse repetition frequency (10 Hz) and temporal-average intensity (0.72 W/cm2). Behavioral models tested target-by-DC interactions in categorization (RT1) and subjective report (RT2) latencies. Spatial analyses correlated focal spot coordinates and voxel-wise intensity from 179 acoustic simulations to baseline-adjusted RT2. Results: The target-by-DC interaction was detected for RT2 but not RT1. At the ventroposterior thalamic target, adjusted RT2 was 55.9 ms longer under DC70 than DC5. More anterior focal spots shortened RT2 under DC70 but increased RT2 under DC5. Correlation between intensity and adjusted RT2 significantly differed between DC70 and DC5 in 18.8% of thalamic voxels. These voxels formed an anterior mediodorsal-motor set and a posterior pulvinar-dominant set. Conclusions: The latency of reporting conscious visual experience, but not categorization latency, was affected by thalamic LIFU. This effect varied jointly with anterior-posterior target engagement and acoustic configuration. Analyzing sequential reaction times separately and treating field variation as an anatomical variable revealed associations not fully captured by a single endpoint or predefined target labels.

Objectives To explore the acceptability and tolerability of cranial electrotherapy stimulation (CES) using Alpha-Stim AID as a potential intervention for anxiety associated with breathlessness in people with advanced chronic respiratory disease. Methods A multicentre, mixed-methods, non-randomised interventional feasibility study with a parallel usual-care control group. Participants were adults with chronic respiratory disease and significant anxiety and breathlessness symptoms (assessed via Integrated Palliative Outcome Scale) receiving care from hospice services. The intervention groups used Alpha-Stim AID for eight weeks either at a fixed or personalised dose, followed by a four-week follow-up period. This feasibility study was not powered to assess clinical efficacy. Results 12.5% of screened patients at the primary site were eligible, and 29 unique participants were recruited. Three participants withdrew from the study (10.3%), none of which were attributable to CES. Most adverse events were mild, with headache reported frequently across control and intervention groups. Outcome measure completion was high, with data missingness below 6.4%. Numerical rating scales of anxiety and breathlessness fluctuated daily and remained broadly static, whereas GAD-7 scores assessing anxiety improved over time across all groups. This feasibility study was not powered to assess clinical efficacy. Conclusion CES using Alpha-Stim AID was deliverable within hospice services and was generally acceptable and tolerable among participants who enrolled. Our findings support further evaluation which should involve a fully-powered randomised controlled trial against a sham device to determine whether CES provides clinically meaningful improvements in anxiety for this patient population.

Background: Substance use is common among individuals with depression. Transcranial magnetic stimulation (TMS) is an effective treatment for depression, but current clinical guidelines have discouraged TMS treatment for individuals with depression and co-occurring substance use given concerns for limited efficacy. However, limited data exists on whether substance use affects response to TMS. Methods: Using electronic health record data from patients who received a standard course of TMS for major depressive disorder at an academic medical center, we investigated associations between substance use frequency and response to TMS, defined as change in Patient Health Questionnaire-9 (PHQ-9) scores. Substance use frequency was extracted for alcohol, cannabis, nicotine, stimulants, benzodiazepines, opioids, inhalants, psychedelics, and other drugs. We performed ANCOVA and multiple regression analyses to predict change in PHQ-9 score based on substance use frequency, controlling for pre-TMS PHQ-9 score, age, sex, and number of TMS sessions received. Results: We extracted data from 219 TMS courses. Alcohol was the substance used most commonly (34.2%), followed by prescription benzodiazepines (28.3%), and prescription stimulants (21.0%). Across all substance categories, substance use was not associated with change in PHQ-9 score (all p > 0.05, Cohens d=0.00 to 0.30). In multiple regression models to compare individual levels of substance use frequency (e.g., daily use vs. no use), level of substance use was not associated with change in PHQ-9 score (all p > 0.05). The range of plausible effects of substance use frequency on PHQ-9 change was generally below the minimal clinically important difference for PHQ-9, suggesting substance use was unlikely to have a meaningful clinical effect on antidepressant response to TMS. Conclusions: Low to moderate substance use does not have a clinically significant effect on antidepressant response to TMS. Low-level substance use should not exclude individuals with depression from receiving TMS.

Gaps remain in the evidence base for postoperative management following forefoot surgery. A recent randomized controlled trial (ClinicalTrials.gov NCT04927234) demonstrated improved outcomes with intermittent one Hertz (Hz) neuromuscular electrical stimulation (NMES) of the common peroneal nerve. This sub-analysis evaluates its effect in patients undergoing forefoot surgery. Forty-two patients undergoing forefoot procedures were included; 26 received NMES plus standard of care (SOC) and 16 received SOC alone. Wound healing was assessed at 14 days. Edema was measured using the figure-of-eight (FO8) method. Patient-reported outcomes were assessed using the Manchester-Oxford Foot Questionnaire (MOXFQ). At 14 days, complete wound healing occurred in 77% of patients receiving NMES plus SOC compared with 40% in the SOC group (p<0.05). Edema reduction was significantly greater in the NMES group, with a 74% relative reduction compared with SOC (p=0.02). Intermittent one Hz NMES of the common peroneal nerve was associated with improved wound healing and reduced postoperative edema following forefoot surgery.

Background Cervical spondylotic myelopathy (CSM) is the most common cause of nontraumatic spinal cord dysfunction in adults. For mild disease, guidelines recommend shared decision-making between surgery and structured rehabilitation on the basis of clinical equipoise, yet no comparative effectiveness study has reported outcomes in this population. Whether a randomized trial is feasible is unknown. Methods We conducted two cross-sectional surveys between December 2025 and July 2026: one of patients with surgeon-confirmed CSM recruited from academic outpatient spine clinics, and one of practicing neurosurgical and orthopedic spine surgeons. Respondents rated willingness to participate in (1) a randomized trial of early surgery versus observation and (2) a prospective observational study in which treatment was patient-selected. Responses of likely or very likely were classified as willing. Groups were compared using Fisher exact tests, designs within respondents using exact McNemar tests, and predictors using univariable logistic regression. Results Fifty-four patients and 52 surgeons completed the surveys. Patients were markedly less willing than surgeons to accept randomization (15 of 54, 27.8% versus 44 of 52, 84.6%; p < 0.001). Both groups accepted the observational design (39 of 54, 72.2% versus 51 of 52, 98.1%; p < 0.001), and 26 of 39 patients unwilling to be randomized were willing to enroll in an observational study (p < 0.001). Willingness to be randomized did not differ across mJOA severity (mild 30.4%, moderate 25.0%, severe 27.3%; p = 0.93). Among patients declining randomization, 85.2% cited a wish to retain control over treatment, whereas fear of surgery was cited by one respondent. Forty-five surgeons (86.5%) considered both surgery and observation reasonable, and preference was divided (46.2% favoring early surgery, 48.1% favoring initial observation). Conclusions Surgeons report equipoise and high willingness to randomize, but most patients would decline random allocation, citing a wish to retain treatment choice rather than fear or distrust. A prospective observational study appears the more feasible route to comparative evidence in mild CSM. Feasibility assessments restricted to clinicians may substantially overestimate attainable accrual.

Objective: To evaluate long-term neurological, mental, and menstrual health outcomes using a mixed-methods approach among women approximately 2 years after concussion compared with non-head-injured controls. Setting: Participants were recruited from [University X] sites, including the Concussion Clinic, Emergency Departments, Student Health Clinic, and [University X] + Me registry (April 2023 to September 2025). Follow-up occurred October to November 2025. Participants: Eligible participants were assigned female at birth, aged 18 to 45 years, not using hormonal birth control, and, for the concussion group, diagnosed within 7 days of injury. Of 45 concussion patients and 29 controls recruited, 11 concussion patients (mean age 30.4 +/- 8.4 years) and 16 controls (31.3 +/- 7.4 years) completed follow-up. Main Measures: Post-concussion symptoms were assessed using the Rivermead Post-Concussion Symptoms Questionnaire (RPQ), depression using the Patient Health Questionnaire-9 (PHQ-9), and anxiety using the Generalized Anxiety Disorder-7 (GAD-7). Menstrual health was assessed using study-specific measures. Qualitative data captured perceived impacts on daily life, with recurring themes summarized using word clouds. Results: At follow-up, concussion patients reported significantly greater symptom burden (RPQ: 31.6 +/- 13.5 vs 9.4 +/- 9.8; p=0.0002; Hedges g=1.90), depression (PHQ-9: 9.5 +/- 6.5 vs 2.3 +/- 2.2; p=0.0005; g=1.60), and anxiety (GAD-7: 9.8 +/- 6.8 vs 2.8 +/- 3.0; p=0.0057; g=1.42). Qualitative findings highlighted persistent headaches, sleep difficulties, reduced interest, and effects on relationships and daily functioning. Conclusions: This study demonstrates significant long-term differences in symptom burden among women with concussions compared to controls. Findings highlight the importance of understanding real-world impacts to improve long-term care.

BackgroundPhotobiomodulation (PBM) is an emerging non-invasive light-based brain stimulation technique that can alter cortical oscillations and is currently being pursued for improving cognition and treating neurological and psychiatric conditions. Nearly all human EEG evidence comes from transcranial PBM (tPBM) applied to the forehead, where light must traverse the scalp and thick skull, requiring protocols to compensate with high surface irradiance. Intranasal PBM (iPBM) can reach the anterior skull base at a fraction of that irradiance and has also been shown to modulate cerebrospinal fluid dynamics, yet it has been studied almost exclusively as an adjunct to tPBM, leaving its cortical effects in isolation, and its energy-efficiency relative to the transcranial route, unknown. ObjectiveTo define the spatiotemporal EEG response to pulsed iPBM delivered alone, determine whether stimulation parameters or individual biology moderate it, and compare the energy-efficiency of iPBM and tPBM in the same participants. MethodsHigh-density EEG was collected from forty-six healthy young adults during pulsed iPBM and tPBM spanning a parameter space of varying wavelengths, pulsation frequencies, and irradiances. Percent change in band power from a within-session pre-stimulation baseline was tested with spatiotemporal cluster-based permutation tests. Linear mixed-effects models with backward elimination assessed stimulation and biological moderators (sex, nostril-to-cortex distance). Energy-efficiency, defined as the percent change in band power per J/cm2 of delivered surface energy, was compared between routes within each subject in delivery route-specific cluster regions of interest (ROI) (Wilcoxon signed-rank tests, Benjamini-Hochberg false discovery rate). ResultsiPBM alone produced significant spatiotemporal clusters in theta, beta, and gamma power, with anterior increases and posterior decreases; no delta or alpha clusters survived correction. Beta and gamma effects appeared at stimulation onset and persisted even after stimulation ended, whereas theta effects strengthened after stimulation ended. No predictor survived elimination in any band, time window, or cluster ROI: response magnitude was independent of wavelength, pulsation frequency, irradiance, sex, and nostril-to-cortex distance. Notably, although iPBM delivered roughly twenty times less surface energy than tPBM ([~]0.6-1.1 vs [~]12-24 J/cm2), it produced EEG changes of similar magnitude, and its energy-efficiency exceeded that of tPBM in seven of eight eligible comparisons, with median iPBM-to-tPBM efficiency ratios of 14-32 (all FDR q<0.05) ConclusionsDelivered in isolation, pulsed iPBM elicits a robust cortical EEG signature closely resembling that of tPBM, is insensitive to the stimulation parameters and individual factors tested, and achieves this at a small fraction of the delivered surface energy. As a result, delivery route, not surface irradiance alone, should be treated as a primary variable in PBM dose reporting and protocol design.

Background: Theta burst stimulation (TBS) is an efficient form of repetitive transcranial magnetic stimulation, but tolerability may depend on target and stimulation pattern, limiting translation to accelerated protocols. Objective: To estimate tolerable intensities for intermittent TBS (iTBS) over F3, approximating left dorsolateral prefrontal cortex, and continuous TBS (cTBS) over Fp1, intended to engage more anterior ventral/frontopolar circuitry, in non-treatment-seeking adults with obesity or tobacco use disorder. Methods: In an open-label randomized crossover titration study, 64 adults completed two TBS visits 7 days apart. Each visit included 3 sessions of 600 pulses, beginning at 80% resting motor threshold (RMT) with protocol-permitted escalation or de-escalation. The primary endpoint was participant-level maximum final maintained intensity. Bayesian grouped-binomial logistic regression estimated the intensity tolerated by 70% of participants (ED70), and a prespecified rule selected the highest dose with at least 80% posterior probability of meeting 70% tolerability. Results: Observed tolerability at 80% RMT was 86.4% for iTBS and 51.6% for cTBS. Primary-model ED70 was 105.5% RMT (95% credible interval [CrI], 99.0%-113.9%) for iTBS and 69.2% RMT (95% CrI, 65.0%- 73.4%) for cTBS. The recommended intensity was 100% RMT for iTBS and 60% RMT for cTBS; no cTBS dose at or above 80% RMT met criterion. cTBS produced greater immediate symptom burden, whereas 24-hour symptoms were uncommon. Conclusion: iTBS over F3 supported a future-trial design window of 90%-100% RMT, whereas cTBS over Fp1 showed a tolerability ceiling below 80% RMT. Future cTBS protocols targeting ventral prefrontal circuitry may need to move dorsally to improve tolerability.