Neuromodulation: Technology at the Neural Interface

ObjectiveMajor depressive disorder (MDD) is a debilitating condition that inflicts significant personal and economic burdens and affects around 8% of the US population. Approximately 30% of patients with MDD do not respond to conventional antidepressant and psychotherapeutic treatments. Current treatment options for refractory MDD include transcranial magnetic stimulation (TMS) and invasive surgical procedures such as surgical ablation, vagus nerve stimulation, and deep brain stimulation. In this context, therapeutic ultrasound emerges as a promising alternative for treating refractory MDD, which has the unique advantage of combining non-invasiveness with selective targeting. Over the past 10 years, there has been a growth in focused ultrasound research, leading to an exponential increase in interest in the technology. To support the future development of ultrasound for treating MDD, we conducted a systematic review following Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. Materials and MethodsWe identified 86 relevant studies from 1975 through June 2025. Our inclusion criteria were peer-reviewed prospective cohort studies, case-control studies, and randomized controlled trials that report ultrasound efficacy for treating depression in humans or depressive-like behaviors in animal models (PROSPERO registration number: CRD42024626093). 23 studies met all inclusion criteria. We summarized ultrasonic techniques for treating depression and their efficacy. ResultsTwo focused ultrasound (FUS) techniques used to treat depression include magnetic resonance-guided focused ultrasound (MRgFUS) for capsulotomy and low-intensity focused ultrasound (LIFUS) neuromodulation. MRgFUS capsulotomy results in permanent lesioning, whereas LIFUS is non-lesional and thought to have temporary effects. In human trials, the response rate ([≥]50% improvement in depression score from baseline) for MRgFUS capsulotomy and LIFUS neuromodulation were 53.85% and 69.2%, respectively. The odds ratio for LIFUS was 2.8. In addition, LIFUS neuromodulation had a large effect (|Cohens d| > 0.8) on reducing standard depression scale scores in humans or resolving depressive-like behaviors in rodents. The certainty of evidence is moderate for human trials and low for rodent models. MRgFUS capsulotomy had inconsistent lesioning success and a limited response rate, while LIFUS neuromodulation lacked systematic exploration of the parameter space and clear delineation of the underlying mechanisms. Future work should refine patient selection for MRgFUS capsulotomy and optimize the parameters for individualized functional targeting. ConclusionsLIFUS neuromodulation achieved a large reduction in depressive behaviors in both rodent models and human trials. We conclude that LIFUS neuromodulation is a promising, noninvasive option for treating refractory MDD.

ObjectiveTo evaluate configuration- and sex-related differences in pudendal somatosensory evoked potential (SEP) waveform characteristics, tolerability, response stability, and test-retest reliability in healthy adults. MethodsPudendal SEPs were recorded from forty-two able-bodied adults (20 females, 22 males) across multiple electrode configurations that varied in anode-cathode placement for both sexes, and in laterality (unilateral and bilateral) for females only. Tibial SEPs were also recorded as a reference control. Peak-to-peak amplitudes were compared across configurations and between sexes and nerves using linear mixed-effects models. SEP latency was summarized descriptively. Tolerability (self-reported 1-10 Likert scale) was analyzed with cumulative link mixed models. Peak-to-peak amplitude stability was computed from exponential fits of cumulative averages and compared across configurations and nerves. Test-retest reliability for SEP latency and peak-to-peak amplitudes was assessed using intraclass correlation coefficients and Bland-Altman analyses. ResultsElectrode configuration had no effect on peak-to-peak amplitude in females or males, and no sex-based amplitude differences were observed. Tolerability varied significantly by configuration, where the configuration with the clitoral cathode and bilateral anodes was rated least tolerable in females, and the configuration with the anode on the glans and the cathode on the proximal shaft was least tolerable in males. Tibial nerve stimulation was consistently rated as more tolerable than pudendal, with a larger difference observed in females. On average, pudendal SEP amplitudes stabilized at 282 stimuli in females and 324 in males, with no differences across configurations nor compared to tibial SEPs. Test-retest analyses showed no systematic bias and revealed moderate-to-good reliability, with latency measures demonstrating greater reproducibility than peak-to-peak amplitudes. ConclusionsPudendal SEP amplitudes and response stability were robust to electrode configuration, but tolerability differed across configurations, highlighting the need to consider electrode placement when designing protocols to improve participant comfort. Test-retest analyses demonstrated moderate-to-good reproducibility, particularly for latency measures, supporting the reliability of pudendal SEPs for longitudinal or repeated assessments. SignificanceThese findings establish the feasibility and reliability of pudendal SEPs in healthy adults and provide guidance for optimizing stimulation locations in future research.

1.ObjectivesImplanted cervical vagus nerve stimulation (VNS) is used to treat refractory epilepsy, depression, stroke sequelae and rheumatoid arthritis. The therapeutic efficacy of VNS is limited by stimulation- induced side effects, including hoarseness, coughing, and voice alteration. We quantified VNS-evoked laryngeal muscle activation (EMG; indicating side effects) and changes in heart rate (HR; proxy for activation of therapeutic fibers) in participants undergoing VNS implant surgery. MethodsWe recruited adult participants (7F/3M) with treatment-resistant epilepsy who were receiving a new VNS implant ("acute") or replacement of an implanted VNS pulse generator ("chronic"). During these procedures, we delivered VNS across pulsewidths (50, 250, and 1000 {micro}s/phase) and stimulation amplitudes (0.05-28 mA) while recording laryngeal EMG and HR. ResultsThe median stimulation amplitudes to evoke 50% of maximal laryngeal EMG response were 1.32, 0.49, and 0.34 mA for pulsewidths of 50, 250, and 1000 {micro}s/phase, respectively; thresholds were comparable between EMG electrodes placed endotracheally and subcutaneously. The median stimulation amplitudes to cause a 10% decrease in HR were 13.39 and 3.53 mA at 50 and 250 {micro}s/phase, respectively--i.e., ~6 to 63x higher than the 50% EMG thresholds. We did not observe a difference in EMG or HR responses between sexes, acute/chronic, or stimulation polarities. For each subject in the chronic implant group, clinician- selected stimulation amplitudes were higher than the 50% EMG thresholds and lower than the 10% HR thresholds. ConclusionsThresholds to evoke bradycardia were ~2x higher than clinician-selected stimulation amplitudes. This indicates that the target fibers of VNS for epilepsy may be larger diameter than those projecting to the heart. Alternatively, the therapeutic effect in refractory epilepsy may be evoked with less fiber activation than is required to produce bradycardia.

ObjectiveInadequate pain control during early zoster-associated pain (ZAP) can lead to postherpetic neuralgia (PHN), and traditional treatments have limitations. This retrospective analysis compares the analgesic effects of burst (BurstSCS) versus traditional tonic (TonicSCS) spinal cord stimulation in early ZAP patients, using retrospective data. It also evaluates differences in psychological state and sleep quality. The findings offer insights into the multidimensional effects of these SCS modalities for future research. MethodsRetrospective analysis included 40 consecutive early ZAP patients undergoing SCS trial (From March 1, 2023 to March 1, 2025). Groups: BurstSCS (n=20) vs. TonicSCS (n=20) based on documented treatment selection. Outcomes assessed at baseline, 14, and 30 days: visual analog scale (VAS), Pittsburgh Sleep Quality Index (PSQI), Pain Vigilance and Awareness Questionnaire (PVAQ). Intergroup comparisons used independent t-tests (significant at P<0.05). ResultsAt 14 days, BurstSCS achieved greater pain reduction (VAS: 1.95 {+/-} 0.76 vs 2.65 {+/-} 0.75; *P*=0.006) and better secondary outcomes:PSQI: 7.00 {+/-} 2.08 vs 8.90 {+/-} 1.89,PVAQ: 15.55 {+/-} 2.80 vs 22.20{+/-}2.42,(all *P*<0.05). At 30 days, VAS was comparable (1.40{+/-}1.23 vs 1.80{+/-}0.95) but BurstSCS maintained lower PSQI (4.90{+/-}1.33 vs 5.85{+/-}1.60) and PVAQ (9.00{+/-}1.56 vs 18.50{+/-}2.16) (*P*<0.05). ConclusionsBurstSCS provided superior early pain reduction (>70% VAS decrease at 14 days) and sustained improvements in sleep quality and pain vigilance in early ZAP patients. These findings support its potential for multidimensional symptom management, warranting validation through prospective trials. KEYWORDS:Spinal cord stimulation; Neuralgia, Postherpetic; Retrospective studies; Pain management.

ObjectivesTranscutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive neuromodulation technique that has shown potential to enhance cognitive function, including working memory. This study investigated the acute effects of both electrical (E-taVNS) and ultrasound (U-taVNS) modalities on working memory using a 3-back task in healthy young adults. We hypothesized that active taVNS would enhance working memory performance relative to sham, and that both stimulation modalities would engage similar neuromodulatory mechanisms. Materials and MethodsFifty-nine participants underwent a single-blind, sham-controlled, within-subject design study, with working memory performance assessed using a 3-back task before and after stimulation. Primary performance measures included correct rejection rate, error false alarm, and sensitivity (d'). Statistical analyses compared pre- and post-stimulation performance across modalities. ResultsE-taVNS significantly enhanced working memory performance through an increase in correct rejection rate and sensitivity (measured by d), alongside a reduction in error of false alarm. U-taVNS showed a similar directional trend across performance measures, although these effects did not reach statistical significance. Baseline anxiety levels significantly predicted individual responsiveness to taVNS. In terms of tolerability, a higher proportion of participants receiving E-taVNS reported skin irritation compared to those receiving U-taVNS. ConclusionsE-taVNS can acutely enhance working memory performance, while U-taVNS may offer a comparable, better tolerated alternative. Our findings highlight the potential of taVNS to support memory function, while showing the importance of further research to clarify modality-specific effects and optimize stimulation parameters.

Low-intensity focused ultrasound (LIFU) is a non-invasive neuromodulation technique with a favorable safety profile in healthy volunteers. Participant-experienced symptoms however remain inconsistently measured, and prospective benchmarks are lacking. Here, we prospectively characterized symptoms associated with LIFU neuromodulation across eight studies using a standardized Report of Symptoms (ROS). We compiled 629 sessions (472 LIFU, 157 sham) in 106 healthy adults (28.1 +/- 9.8 years) across eight cortical and subcortical targets (500 kHz; extracranial ISPPA 3.9-33.3 W/cm2; mechanical index 0.5-1.4). The ROS rated 17 symptom domains from 0 (absent) to 3 (severe) before and after each session. New-onset incidence, symptom severity, and total symptom burden were compared between LIFU and sham. The same instrument was applied in 35 patients with chronic pain. Symptom profiles after LIFU were indistinguishable from sham across all 17 domains. Total symptom burden averaged approximately one domain per session and did not increase after LIFU (0.94 to 1.03; p = 0.120). Post-intervention burden was predicted by baseline burden (beta = 0.347, p < 0.001) but not by stimulation condition (p = 0.222). New-onset symptoms did not increase across up to 27 LIFU sessions (OR = 0.99, p = 0.73) and were weakly, non-significantly related to acoustic intensity (rho = 0.37). Across a prospective, sham-controlled dataset, LIFU added no measurable symptom burden and was well tolerated in healthy adults, with comparable tolerability in patients. These findings establish a benchmark for the safety of human LIFU neuromodulation and a foundation for its therapeutic translation.

BackgroundTranscranial focused ultrasound (tFUS) is a promising noninvasive technique for modulating deep brain structures, but the optimal and safe intensity range for neuromodulation remains unclear. Current FDA intensity limits, designed for diagnostic use rather than therapy, may limit the potential effectiveness of tFUS. ObjectiveThis study aimed to evaluate the safety and preliminary efficacy of escalating tFUS intensities targeting the right amygdala in healthy volunteers, including intensity levels exceeding current FDA diagnostic ultrasound limits. MethodsTen healthy adults (mean age = 19.5 {+/-} 1.4 years; 70% female) participated in a within-subject, repeated-measures design. Each received four randomized tFUS stimulation conditions (ISPTA.3 = 0.72-10.08 W/cm{superscript 2}) using the BX Pulsar 1002 system. Structural MRI was performed before each stimulation to monitor safety. Affective modulation was assessed pre- and post-stimulation via the International Affective Picture Set (IAPS) task, measuring changes in valence and arousal ratings. Acoustic modeling was conducted using BabelBrain to estimate intracranial energy deposition. ResultsNo adverse events or MRI-detectable structural changes (e.g., edema, hemorrhage, or microstructural abnormalities) occurred under any stimulation condition. Behavioral analyses revealed no significant overall effects of intensity on affective measures. Comparisons between excitatory and inhibitory paradigms showed no significant differences. ConclusionstFUS of the right amygdala at intensities up to 10.08 W/cm{superscript 2} ISPTA.3--over 14 times the FDA diagnostic limit--was well tolerated and produced no structural or subjective adverse effects. These findings support the safety of higher-intensity tFUS and justify further investigation in larger and clinical populations to explore potential dose-response effects on emotion regulation.

Even mild SARS-CoV-2 infection can lead to post-COVID syndrome, 70% of such patients have post-COVID fatigue (pCF). Many physiological abnormalities observed in pCF could be explained by reduced vagus nerve activity. The vagus nerve, central to metabolic and inflammatory homeostasis, can be activated non-invasively by transcutaneous auricular vagus nerve stimulation (taVNS). Can taVNS improve symptoms in pCF? Data were collected from a randomized study including 114 individuals with pCF. They completed 16 weeks of daily home-based active, sham, or placebo taVNS. Data on subjective fatigue, captured by a Visual Analogue Scale (VAS), and objective measures of cortical excitability, muscle fatigue and autonomic function were collected. In participants meeting minimum adherence ([&ge;]1 h/day on [&ge;]50% of days), VAS and peripheral fatigue improved significantly after 8 weeks of active (but not sham or placebo) taVNS (11.9 {+/-} 17.8 points improvement, p=0.003, N=24). These results support taVNS as a potential therapy for pCF.

BackgroundTranscranial direct current stimulation (tDCS) is one of the most widely used noninvasive neuromodulation methods. Despite its popularity, some recent studies highlighted issues about the reproducibility of earlier reported tDCS results. Until recently, it was assumed that tDCS elicits its neuromodulatory effects by increasing cortical excitability through direct polarization of cortical neurons. However, recent studies have shown that the electric field that reaches the cortex is relatively weak, whereas the electric field in the scalp underneath the stimulation electrodes is sufficiently strong to stimulate peripheral nerves, thereby potentially indirectly affecting cortical excitability and plasticity. ObjectiveIn this study, we aimed to replicate the effect of anodal tDCS in enhancing motor sequence learning and investigate if the effect is caused by the polarization of cortical neurons, or more indirectly through stimulation of peripheral nerve in the scalp, or a combination of both mechanisms. MethodsIn a double-blind, pre-registered study including 99 healthy young adults, we investigated the effect of 1mA anodal tDCS over the left primary motor cortex (M1) on motor sequence learning in three serial reaction time task (SRTT) sessions using a between-subjects design. In addition to the standard sham condition, we introduced an additional control condition in which the peripheral input was blocked using the BL10 topical anesthetic gel to investigate the potential contribution of peripheral nerve stimulation in mediating tDCS effects in motor sequence learning. ResultsOur results provided evidence of motor sequence learning in all three stimulation conditions (p<0.0001). However, no significant differences were observed among the three stimulation conditions (p = 0.94). ConclusionWe were unable to replicate previous findings indicating significant beneficial effects of tDCS on motor sequence learning. Consequently, we were unable to address our main research question of whether tDCS effects are driven by the resulting electric field in the cortex or by stimulation of peripheral nerves in the scalp. This non-replication of one of the presumably most reliable tDCS effects in a much larger sample size than the original studies, among the findings of comparable studies reporting similar outcomes, should prompt a renewed discussion regarding the efficacy of tDCS as a neuromodulation technique, particularly given the earlier reported concerns about its reproducibility and reliability.

Tourette syndrome (TS) and chronic tic disorder (CTD) are neurological disorders of childhood onset characterised by the occurrence of tics; repetitive, purposeless, movements or vocalisations of short duration which can occur many times throughout a day. Currently, effective treatment for tic disorders is an area of considerable unmet clinical need. We aimed to evaluate the efficacy of a home-administered neuromodulation treatment for tics involving the delivery of rhythmic pulse trains of median nerve stimulation (MNS) delivered via a wearable watch-like device worn at the wrist. We conducted a UK-wide parallel double-blind sham-controlled trial for the reduction of tics in individuals with tic disorder. The device was programmed to deliver rhythmic (10Hz) trains of low-intensity (1-19 mA) electrical stimulation to the median nerve for a pre-determined duration each day, and was intended to be used by each participant in their home once each day, 5 days each week, for a period of 4 weeks. Between 18th March 2022 and 26th September 2022 135 participants (45 per group) were initially allocated, using stratified randomisation, to one of the following groups; active stimulation; sham stimulation; or a to waitlist (i.e., treatment as usual) control group. Recruited participants were individuals with confirmed or suspected TS/CTD aged 12 years of age or upward with moderate to severe tics. Researchers involved in the collection or processing of measurement outcomes and assessing the outcomes, as well as participants in the active and sham groups and their legal guardians were all blind to the group allocation. The primary outcome measure used to assess the offline or treatment effect of stimulation was the Yale Global Tic Severity Scale - Total Tic Severity Score (YGTSS-TTSS) assessed at the conclusion of 4-weeks of stimulation. The primary outcome measure used to assess the online effects of stimulation was tic frequency, measured as the number of tics per minute (TPM) observed, based upon blind analysis of daily video recordings obtained while stimulation was delivered. The results demonstrated that after 4-weeks stimulation, tic severity (YGTSS-TTSS) had reduced by 7.1 points (35% reduction) for the active stimulation group compared to 2.13/2.11points for the sham stimulation and waitlist control groups. The reduction in YGTSS-TTSS for the active stimulation group was substantially larger, clinically meaningful (effect size = 0.5), and statistically significant (p = 0.02) compared to both the sham stimulation and waitlist control groups, which did not differ from one another (effect-size = -0.03). Furthermore, blind analyses of video recordings demonstrated that tic frequency (tics per minute) reduced substantially (-15.6 TPM) during active stimulation compared to sham stimulation (-7.7 TPM). This difference represents a statistically significant (p < 0.03) and clinically meaningful reduction in tic frequency (> 25% reduction: effect-size = 0.3). These findings indicate that home-administered rhythmic MNS delivered through a wearable wrist-worn device has potential as an effective community-based treatment for tic disorders.

BackgroundAccording to the Office for National Statistics, an estimated 2.3% of people in the UK suffer from post-COVID Fatigue (pCF) following acute COVID-19 infection. Feedback from those with pCF has highlighted the devastating impact it has on their lives and the need for novel therapeutic options. Fatigue encompasses not only the perception of increased physical effort and extreme tiredness but also cognitive/mental fatigue. As part of a previous study (Baker et al., 2023), we recently showed that fatigue in pCF correlates with dysregulation in specific components of the central, peripheral and autonomic nervous systems. The vagus nerve is a major component of the autonomic nervous system and plays an important role both in metabolic homeostasis and in inflammatory modulation. Transcutaneous auricular vagus nerve stimulation (taVNS) offers an easy and reliable approach to activating the vagus nerve non-invasively and can be self-administered safely at home. This study will probe the mechanisms of pCF in adults by testing whether taVNS self-administered using a transcutaneous electrical nerve stimulation (TENS) device can reduce symptoms of fatigue and normalise changes in the peripheral and central nervous system that are hypothesized to mediate fatigue. DesignThis will be a single-site, single-blind, sham-controlled, randomized, interventional trial in 96 people with pCF. Participants will be randomized to one of three groups, one active and two control interventions, which they will self-administer for 8 weeks. After 8 weeks everyone will crossover to the active intervention for another 8 weeks of taVNS. Ongoing levels of fatigue will be assessed using visual analogue scales and a battery of relevant questionnaires. All participants will undergo extensive electrophysiological testing at week 0, week 8 and week 16. Ambulatory data (heart rate variability, activity levels) will be collected using wearable technology. DiscussionThis study will establish whether vagus nerve dysfunction is important mechanistically in pCF and whether boosting vagus nerve activity by taVNS can not only improve symptoms of fatigue in pCF but normalise biological and behavioural correlates of fatigue in otherwise healthy members of the public with pCF. Trial registrationThis trial is prospectively registered at www.isrctn.com/ISRCTN18015802. Registered May 12, 2022.

BackgroundAlthough heterogeneity of treatment effects (HTE) is commonly observed in clinical trials, it has received little attention in studies on transcranial direct current stimulation (tDCS). This study aimed to identify the presence of HTE in tDCS treatment among participants with symptomatic knee osteoarthritis (KOA) and to explore participant characteristics associated with this heterogeneity. MethodsThis exploratory secondary analysis of a randomized clinical trial included 120 participants with symptomatic KOA who received 15 daily sessions of home-based 2-mA active or sham tDCS (20 minutes per session) over three weeks. First, we used a multi-trajectory latent class growth analysis to identify distinct subgroups based on the longitudinal trajectories of KOA pain and symptoms from baseline to three months postintervention, capturing differential responses to tDCS. We then performed bivariate analyses to examine associations between trajectory groups and baseline demographic, clinical, and quantitative sensory testing characteristics. ResultsIn the active tDCS group, two distinct trajectories emerged: "low initial symptoms with significant improvement" (high responders; n = 28) and "high initial symptoms with minimal improvement" (low responders; n = 32). Compared to high responders, low responders had a higher body mass index (p = .040), lower educational attainment (p = .013), and greater pain catastrophizing (p < .000). Low responders also exhibited lower pressure pain thresholds at both the medial knee (p = .009) and trapezius (p = .002), higher punctate mechanical pain at both the patella (p = .013) and hand (p = .016), lower conditioned pain modulation at 30 seconds (p = .008) and 60 seconds (p < .000), and higher cold pain intensity (p = .003) at baseline. No notable HTE was observed in the sham tDCS group. ConclusionParticipants exhibited varying responses to active tDCS. The characteristics associated with HTE may inform the development of personalized stimulation protocols. Further research is needed to investigate potential HTE in the sham tDCS group and refine strategies to address placebo-related effects.

OBJECTIVESNoninvasive brain stimulation continues to grow as an effective, low-risk way of improving the symptoms of brain conditions. Transcranial direct current stimulation (tDCS) is particularly well-tolerated, with benefits including low cost and potential portability. Nevertheless, continued study of perceptual and cognitive side effects is warranted, given the complexity of functional brain organization. This paper describes the results of a brief battery of tablet-based tasks used in a recent pilot study of auditory-cortex tDCS in people with chronic tinnitus. METHODSVolunteers with chronic tinnitus (n=20) completed two hearing tasks (pure-tone thresholds, Words In Noise) and two cognitive tasks (Flanker, Dimension Change Card Sort) from the NIH Toolbox. Volunteers were randomized to active or sham 4x1 Ag/AgCl tDCS of auditory cortex, and tasks were completed immediately before and after the first tDCS session, and after the fifth/final tDCS session. Statistics included linear mixed-effects models for change in task performance over time. RESULTSBefore tDCS, performance on both auditory tasks was highly correlated with clinical audiometry, supporting the external validity of these measures (r2>0.89 for all). Although overall auditory task performance did not change after active or sham tDCS, detection of right-ear Words in Noise stimuli modestly improved after five active tDCS sessions (t(34)=-2.07, p=0.05). On cognitive tasks, reaction times were quicker after sham tDCS, reflecting expected practice effects (e.g., t(88)=3.22, p=0.002 after 5 sessions on Flanker task). However, reaction times did not improve over repeated sessions in the active group, suggesting that tDCS interfered with learning these practice effects. CONCLUSIONSRepeated sessions of auditory-cortex tDCS does not appear to adversely affect hearing or cognition, but may modestly improve hearing in noisy environments and interfere with some types of motor learning. Low-burden cognitive/perceptual test batteries could be a powerful way to identify adverse effects and new treatment targets in brain stimulation research.

AimWe investigated the heterogeneity of treatment effects in transcranial direct current stimulation (tDCS) with mindfulness-based meditation (MBM) and within each individual study group (tDCS alone, MBM alone, and sham) among individuals with symptomatic knee osteoarthritis. We also explored participant characteristics underlying this heterogeneity. MethodsThis secondary analysis drew on a double-blind, randomized, sham-controlled, phase II, parallel-group trial in which 200 participants were assigned to one of four groups: (1) active tDCS + active MBM, (2) active tDCS + sham MBM, (3) sham tDCS + active MBM, or (4) sham tDCS + sham MBM. Participants received ten 20-minute tDCS sessions (active or sham) administered concurrently with MBM (active or sham). Latent class growth analysis was used to identify subgroups with distinct treatment response trajectories (responders vs. non-responders) based on changes in clinical pain (Numeric Rating Scale) from baseline to post-intervention. Generalized linear models were then applied to determine baseline factors associated with participants response classification, including demographic, clinical, and psychological characteristics; quantitative sensory testing battery; and pain-related cortical hemodynamic activity measured using functional near-infrared spectroscopy (fNIRS) in response to punctate and thermal stimuli. ResultsResponders in the active tDCS + active MBM and active tDCS + sham MBM groups demonstrated greater improvements in clinical pain from baseline to post-intervention than non-responders (p < 0.001). In the active tDCS + active MBM group, greater cortical activation in the fNIRS channel S06-D06 of the left somatosensory cortex in response to punctate stimuli, identifying as white, and lower conditioned pain modulation (reflecting less efficient endogenous pain modulation), were significantly associated with being responders (p < 0.05). In the active tDCS + sham MBM group, younger age and lower heat pain tolerance at the knee were significantly associated with being responders (p < 0.05). No clear response patterns were observed in the remaining groups. ConclusionFactors underlying heterogeneity of treatment effects, including somatosensory cortical activation and pain modulatory profiles, may provide preliminary insights to inform the development of personalized neuromodulation (stimulation) protocols.

Structured AbstractO_ST_ABSObjectiveC_ST_ABSThe therapeutic effect of magnetic resonance-guided focused ultrasound is limited to patients with a low skull density ratio (SDR). We explored the skull conditions associated with successful treatment among low-SDR patients, and, to compensate for the small sample size, performed analyses using all cases irrespective of SDR. This is the first report to examine the significance of regional skull conditions. MethodsWe retrospectively analyzed 171 consecutive cases. Descriptive statistics for the entire skull, and averages for 10 regions, were obtained for variables including the SDR, skull thickness, and ultrasound incident angle (IA; smaller = more vertical). The 1,024 ultrasonic transducer elements were divided into 10 regions predefined by ExAblate4000. Symptoms were evaluated by Clinical Rating Scale for Tremor for essential tremor and Unified Parkinsons Disease Rating Scale tremor score for Parkinsons tremor. Successful treatment was defined as <half preoperative symptom score at 6 months postoperatively. First, univariate analysis of cases with SDR < 0.40 was conducted to explore candidates for skull conditions associated with successful treatment. Subsequently, for all cases regardless of SDR, several multiple regression models were built to predict the maximum temperature rise, and their performance was compared. ResultsOf the cases, 26 had SDR < 0.40, and 15 were successful. Among the cases with SDR < 0.40, IA of the parietal region on the sonication side and SDR of the bilateral temporal region tended to be smaller in the success group (not statistically significant). The maximum temperature was more accurately predicted when IA of the parietal region on the sonication side was included in the model (Akaike information criterion, 777 [from 757]). Furthermore, replacing SDR with SDR excluding the bilateral temporal region enhanced predictions (Akaike information criterion, 777 [from 767]). ConclusionsEven if SDR is low, treatment success may be more attainable if the IA in the parietal region on the sonication side is smaller, or if the SDR excluding the bilateral temporal regions is large.

Temporal interference stimulation (TIS) is a new form of transcranial electrical stimulation (tES) that has been proposed as a method for targeted, non-invasive stimulation of deep brain structures. While TIS holds promise for a variety of clinical and non-clinical applications, little data is yet available regarding its effects in humans. To inform the design and approval of experiments involving TIS, researchers require quantitative guidance regarding exposure limits and other safety concerns. To this end, we sought to delineate a safe range of exposure parameters (voltages and currents applied via external scalp electrodes) for TIS in humans through comparisons with well-established but related brain stimulation modalities. Specifically, we surveyed the literature for adverse events (AEs) associated with transcranial alternating/direct current stimulation (tACS/tDCS), deep brain stimulation (DBS), and TIS to establish known boundaries for safe operating conditions. Drawing on the biophysical mechanisms associated with the identified AEs, we determined appropriate exposure metrics for each stimulation modality. Using these metrics, we conducted an in silico comparison of various exposure scenarios for tACS, DBS, and TIS using multiphysics simulations in an anatomically detailed head model with realistic current strengths. By matching stimulation scenarios in terms of biophysical impact, we inferred the frequency-dependent TIS stimulation parameters that resulted in exposure magnitudes known to be safe for tACS and DBS. Based on the results of our simulations and existing knowledge regarding tES and DBS safety, we propose frequency-dependent thresholds below which TIS voltages and currents are unlikely to pose a risk to humans. Safety-related data from ongoing and future human studies are required to verify and refine the thresholds proposed here.

BackgroundDirectional deep-brain stimulation (DBS) requires knowledge of lead orientation to maximize benefit and minimize side effects. While CT-based software is widely used, its accuracy may decrease with the use of oblique leads. Rotational fluoroscopy using the Iron Sight method offers an alternative; however, its reliability in clinical practice has not been fully established. ObjectiveTo assess the reliability of the Iron Sight method for postoperative lead orientation and compare it with CT-based software (Brainlab Elements). MethodsWe prospectively analyzed 70 directional leads implanted at our center (2022-2024). Orientation was measured on postoperative rotational fluoroscopy by two independent observers and compared with postoperative CT analyzed in Brainlab Elements. The agreement was evaluated using established reliability statistics. ResultsObservers using the Iron Sight method produced highly consistent measurements, differing on average by <1{degrees} and rarely more than {+/-}7{degrees}. Compared with CT-based analysis, the Iron Sight method showed good agreement, with differences typically within {+/-}15{degrees}. These margins correspond to <1.5 mm displacement around the lead -- well within clinically acceptable limits for programming. ConclusionRotational fluoroscopy, combined with the Iron Sight method, provides clinicians with a reliable and reproducible tool to confirm lead orientation. It may be especially valuable when CT-based software is unavailable, inconclusive, or requires corroboration.

Background: Deep brain stimulation (DBS) is a widely used therapy for neurologic and psychiatric disorders. Conventional DBS delivers highly regular stimulation patterns that suppress pathological activity but can induce stimulation-related side effects, limiting the therapeutic window. Introducing controlled temporal variability through stochastic pulse timing may represent an alternative programming dimension to improve tolerability while preserving clinical benefit. Methods: An adult in their 60's with bilateral Vim DBS underwent evaluation of tonic, pink-noise, and white-noise stimulation patterns delivered through his chronically implanted Boston Scientific Genus system using the Chronos research platform. We assessed tremor and stimulation-induced side effects using accelerometry, spiral drawing tasks, standardized speech recordings, and patient-reported paresthesias. Results: Pink noise stimulation preserved meaningful tremor suppression while improving tolerability compared with conventional tonic 130 Hz stimulation. Under tonic stimulation, dysarthria and paresthesias were prominent at 2.0 mA, narrowing the usable therapeutic window. In contrast, pink noise maintained tremor control across the same amplitude range with reduced side-effect burden. White noise stimulation demonstrated intermediate effects, providing improved tolerability relative to tonic stimulation but less tremor suppression than pink noise. Findings were consistent across accelerometry and functional drawing tasks. Conclusion: This study provides first-in-human evidence that temporally structured stochastic pulse timing can preserve therapeutic benefit while expanding the tolerable stimulation range relative to tonic DBS. These findings suggest that temporal structure represents a clinically meaningful programming dimension that may broaden the DBS therapeutic window using software based updates to existing hardware. Further evaluation in larger cohorts is warranted

BackgroundPersistent Spinal Pain Syndrome (PSPS) type II represents a challenging clinical entity with limited therapeutic options. Various spinal cord stimulation (SCS) modalities have emerged as potential treatments, but their comparative effectiveness remains unclear. ObjectiveOur goal in this paper is to systematically evaluate and compare the efficacy of different SCS modalities in patients with PSPS type II through meta-analysis of available randomized controlled trials. Evidence ReviewWe conducted a systematic review following PRISMA guidelines, searching major databases for randomized controlled trials evaluating SCS modalities in PSPS type II patients until the end of May 2025(search updated on October 3rd). Primary outcomes included pain intensity (VAS) and functional disability (ODI) at 6 and 12 months. Subgroup analyses compared tonic versus burst stimulation and high-frequency versus low-frequency SCS. FindingsNine randomized controlled trials were included, encompassing 565 patients across different SCS modalities. For the primary outcome of clinically meaningful pain relief ([&ge;]50% reduction), pooled analysis demonstrated that 45% (95% CI: 18-75%, I{superscript 2} = 92.2%) of patients achieved this threshold for back pain and 55% (95% CI: 45-65%, I{superscript 2} = 0%) for leg pain. Subgroup analysis revealed significant differences in back pain responder rates by stimulation modality: High-frequency SCS demonstrated responder rates of 92% (95% CI: 79-98%) versus 28% (95% CI: 13-49%) for conventional frequencies (p < 0.001). For leg pain, no significant difference was observed between tonic (51%, 95% CI: 37-65%) and burst stimulation (60%, 95% CI: 45-74%, p = 0.36) and mean VAS scores demonstrated significantly lower pain with high-frequency SCS (13.30, 95% CI: 8.82-17.78) compared to conventional frequency (28.42, 95% CI: 24.02-32.88, p<0.0001). For back pain, mean VAS scores decreased from a baseline of 73.03 to 41.67 (95% CI: 36.12-47.22, I{superscript 2}=22.8%) at 6 months and remained stable at 35.66 (95% CI: 25.39-45.93, I{superscript 2}=75.0%) at 12 months. Leg pain showed more pronounced improvement, with VAS scores declining from a baseline of 61.81 to 23.75 (95% CI: 17.69-29.81, I{superscript 2}=78.8%) at 6 months and 29.16 (95% CI: 24.81-33.52, I{superscript 2}=0%) at 12 months). Meta-regression identified longer pain duration and older age as positive predictors of response, while higher baseline leg pain predicted lower responder rates. Serious adverse events occurred in 10%, with a 16% revision surgery rate. Only two studies demonstrated a low risk of bias across all domains. ConclusionsCurrent evidence demonstrates that various SCS modalities provide clinically meaningful pain relief in PSPS type II patients, with approximately half achieving [&ge;]50% pain reduction. High-frequency SCS shows significantly superior responder rates for back pain compared to conventional tonic stimulation, while burst stimulation yields significantly superior reductions in continuous pain intensity metrics. However, the limited number of studies, substantial heterogeneity, and lack of head-to-head comparisons prevent definitive recommendations regarding optimal stimulation parameters. Future large-scale randomized trials with standardized protocols and responder-based outcomes are needed to establish evidence-based treatment algorithms for PSPS type II patients.

Transcranial Magnetic Stimulation (TMS) involves pulsed magnetic fields that pass through the scalp to stimulate the brain, with incidental stimulation to superficial nerves and muscles. From a research perspective, the tactile sensations can be a problematic confound, particularly when stimulation approaches an unpleasant or painful level. Additionally, tactile sensations contribute to difficult challenges in establishing an appropriate sham control condition. Clinically, some patients find stimulation uncomfortable or intolerable. Clinicians need data on adjustments to stimulation parameters to improve tolerability and efficacy. The primary objective of this study was to characterize the tolerability of TMS by location (over modified Beam F3 prefrontal, THREE-D prefrontal, right orbitofrontal, medial prefrontal, motor, and parietal cortical targets, as well as the knee) and by frequency (1 Hz, 10 Hz, or iTBS), with increasing levels of stimulation intensity. We also characterized sensory thresholds and qualitative aspects of stimulation across locations and frequencies. For location, sites distal to the facial nerves and muscle (Knee, P3, M1, mPFC) were more tolerable, followed by Beam F3, with the THREE-D and AF8 locations as least tolerable. For frequency, we found that 1 Hz was significantly more tolerable than 10 Hz and iTBS. iTBS was more annoying than 10 Hz but only marginally different in tolerability. TMS researchers and clinicians should understand the impact of sensation based on location and frequency, with increasing stimulation intensity. This is a single-session study in generally healthy individuals, and there is a need for additional data to further inform research and clinical practice.