Neuromodulation: Technology at the Neural Interface

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.

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.

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: Pressure pain threshold (PPT) is commonly assessed using pressure algometry. Self-administered algometry could reduce examiner involvement and may facilitate repeated assessment outside specialist settings. Objective: To examine the concurrent agreement of a previously described syringe-based pneumatic algometer with a commercially available comparator during self-administered PPT measurement in healthy adults. Methods: Thirty healthy volunteers completed researcher-administered and self-administered pain threshold measurements utilizing an AMF-500 device and the syringe-based pneumatic algometer. Results: During self-administration, measurements from the two devices were strongly correlated (r = 0.82, p < 0.05); the mean paired difference was 6.01 N (95% CI, -0.58 to 12.59 N). Self-administered test values were lower than researcher-administered test values in the fixed-order comparison (p = 0.0029). Conclusion: According to our findings the proposed device is a valid tool for autoalgometry and may potentially be introduced as an element of routine self-assessment of PPT.

Objective. Intermittent theta burst stimulation (iTBS) is a repetitive transcranial magnetic stimulation (rTMS) protocol used in clinical settings to alleviate symptoms of psychiatric disorders. Although the pulse parameters currently used in iTBS have remained unchanged since the first treatments, recent controllable TMS devices allow for the personalization of pulse shape and duration, opening the possibility of testing the efficacy of other pulse parameters in modulating corticospinal excitability (CSE). Methods. In a repeated-measures design, changes in CSE were induced by the administration of iTBS over the left primary motor cortex under three different conditions: long bidirectional pulse (L-Bi), long quasi-unidirectional pulse (L-QU), and a control short quasi-unidirectional pulse (S-QU). We assessed TMS-induced motor evoked potentials before and up to 70 minutes after iTBS. We hypothesized that L-QU pulses would induce greater facilitation than other conditions. Results. A mixed linear model showed that all conditions induced increased MEPs compared to baseline. However, the L-Bi pulse led to a larger and more sustained MEP increase than both unidirectional pulses, while the S-QU pulse appeared less effective in modulating CSE. We observed large within- and between-subject variability in responsiveness to the iTBS protocols. Conclusion. These results suggest that L-Bi pulses in iTBS protocols are more potent than unidirectional pulses in inducing CSE changes in the cortex of healthy adults. The individual variability in response to iTBS and the potential clinical relevance of these findings are discussed.

Background: Temporary 60-day percutaneous peripheral nerve stimulation (PNS) can relieve pain in refractory occipital neuralgia (ON), but whether it alters acute healthcare utilization relative to the natural trajectory of the disease is unknown, because prior studies have lacked a concurrent comparator. Methods: We performed a secondary analysis of prospectively collected data from a tertiary interventional pain center. Adults with medically refractory ON (primary diagnosis occipital neuralgia, ICD-10-CM M54.81) who underwent 60-day occipital PNS (n = 42) were compared with concurrent patients who were clinically eligible for PNS but were denied insurance authorization and continued optimized non-PNS management (usual care; n = 63). Headache-related emergency department (ED) encounters - index (occipital neuralgia) and non-index (other headache/facial-pain diagnoses) - were ascertained over the 12 months before and after the treatment window via the electronic record and the statewide health information exchange. Patients were 1:1 propensity-matched on a priori confounders (age, sex, baseline total headache-related ED utilization, HIT-6, and baseline headache-medication use). The primary analysis was a difference-in-differences (DiD) comparison of the change in headache-related ED utilization, reported as the additive difference (Hodges-Lehmann estimate, distribution-free 95% CI) and, alongside, as a multiplicative rate ratio (RR). Results: Thirty-six matched pairs were well balanced. Baseline headache-related ED utilization was nearly identical between matched groups (6.3 vs. 6.2 visits/year). Over the following year, PNS patients' utilization fell to 2.5 while usual-care patients' rose to 6.9. The DiD was 5.0 fewer headache-related ED visits per patient (95% CI 3.0-6.0; p < 0.001), corresponding to a rate ratio of 0.36 (95% CI 0.27-0.48; p < 0.001). Results were consistent in the full sample, in covariate-adjusted models, and after excluding controls denied for incomplete conservative-therapy trials. The effect was driven by non-index headache visits. Conclusions: Relative to a concurrent, matched usual-care cohort whose headache related ED utilization rose over time, 60-day occipital PNS was associated with a substantial reduction in acute-care use, strengthening the case for a role of PNS on healthcare utilization in refractory ON.

Background: Response to Comprehensive Behavioral Intervention for Tics (CBIT), the first-line treatment for tic disorders, is suboptimal. We conducted Phase 1 of a two-phase, milestone-driven trial to determine if augmenting CBIT with repetitive transcranial magnetic stimulation (TMS) to supplementary motor area (SMA) could safely engage targeted sensorimotor circuitry and improve tic controllability. Methods: In a 3-arm, double-blind, sham-controlled randomized trial (NCT04578912), 50 youth (ages 12-21) with moderate-to-severe tics received 10 sessions of either 1Hz rTMS, continuous theta burst stimulation (cTBS), or sham stimulation to the SMA, immediately followed by CBIT. Primary outcomes were safety, feasibility, and neural target engagement (fMRI SMA activation and resting-state functional connectivity [RSFC]). Secondary outcomes included change in tic controllability, tic frequency at rest, and urges. Results: The CBIT+TMS intervention was safe and feasible (96% completion). Treatment-related adverse events were mild-to-moderate and occurred more frequently in the 1Hz rTMS group (27% of sessions) vs. cTBS (14.7%) and sham (11.3%). While task-based SMA activation remained unchanged, cTBS demonstrated robust neural target engagement, reducing SMA-primary motor cortex (M1) RSFC and putamen-M1 RSFC. Conversely, 1Hz rTMS blunted the cortico-striatal connectivity reductions observed in the sham group. All groups exhibited significant reductions in tic frequency and improved controllability. Premonitory urges increased in the 1Hz rTMS group but decreased in sham and cTBS. Conclusions: SMA-directed cTBS is a safe, feasible augmentation that may amplify the neural effects of CBIT on sensorimotor circuitry. Findings identify cTBS as the preferred stimulation regimen for future efficacy testing. Clinical Trial Registration: ClinicalTrials.gov; Identifier: NCT04578912.

Electrocutaneous stimulation provides a means to warn workers of potential hazards. Our previous parameter studies were conducted at rest or under controlled external influences such as vibration, temperature, and humidity, whereas actual work tasks have not yet been addressed. As a step towards greater practical applicability, we conducted two studies in which a circumferential electrocutaneous warning signal was applied to the upper right arm while participants performed a reading task, screw-driving, and polishing. In study 1 (n = 32), the pulse interval was adjusted individually to evoke a vibrating sensation, and the intolerance threshold was determined. In study 2 (n = 29), a fixed pulse interval of 36 ms was applied to all participants, the warning threshold was determined in addition to the intolerance threshold, and muscle twitches were documented both by participant report and by an independent observer. Study 1 demonstrated that electrocutaneous warning during work tasks is feasible, with a median intolerance threshold higher during polishing (16.5 mA) than during reading or screw-driving (14 mA each). In study 2, the fixed parameter setting elicited the intended pulsating or vibrating sensation at rest in 89 % of the participants in both presentations. The median warning threshold was 8 mA and did not differ between the three work tasks, whereas the intolerance threshold was lower during reading (18 mA) than during screw-driving and polishing (20 mA each). Muscle twitches were largely absent at the warning threshold and became frequent towards the intolerance threshold, with a ventral dominance of their location in both studies. An individual parametrization is therefore not required for the majority of users when a binary warning is to be conveyed, and operating the system slightly above the warning threshold provides a usable amplitude range while minimizing muscle twitches. Future work will focus on electrode optimization and on the objective measurement of motor responses.

Accurate hippocampal electric field (E-field) prediction is important for individualized electroconvulsive therapy (ECT) dosing and emerging deep-brain stimulation approaches such as temporal interference. Because hippocampal fields are far weaker than those beneath the stimulation electrodes, they are highly sensitive to tissue interfaces, conductivity contrasts, and numerical discretization, so numerical error can rival the physical uncertainties of anatomy and conductivity. We investigate this numerical component of hippocampal dosimetry using individualized head models from eleven ECT patients. Identical head40 segmentations, comprising 40 tissue compartments including the bilateral hippocampi, were simulated with three independent numerical methods: a charge-based boundary-element fast multipole method (BEM-FMM), a voxel-based hexahedral finite-element solver, and a conformal tetrahedral finite-element solver. For each, resolution was increased systematically and convergence assessed from the average hippocampal E-field magnitude. At the highest attainable resolutions, the three methods agreed closely, differing by 6%-7% in the left hippocampus and 9%-12% in the right. At default or coarse resolutions, however, they disagreed by 28.8% on average and up to 50.3% in the right hippocampus. Numerical convergence should therefore be established before differences are attributed to anatomical or conductivity uncertainty, and independent-solver agreement provides a practical basis for reliable hippocampal dosimetry.

Background: Depression symptoms following traumatic brain injury (TBI) are common and strongly associated with adverse overall outcomes in military service members, veterans, and civilians. Cognitive behavioral therapy for depression (CBT-D) is considered a first-line treatment for depression symptoms in many contexts. However, costs associated with CBT-D can be substantial, and there are insufficient numbers of providers trained to perform CBT-D. In contradistinction, digital therapeutic interventions such as smartphone apps have virtually unlimited availability and low per-patient costs. However, evidence for efficacy of digital interventions providing CBT-D in the context of TBI is limited. The aims of this study were to design, develop, and test a novel smartphone app to provide CBT-D intended for military service members with depression symptoms and history of mild TBI. Results: We designed a novel smartphone app featuring digital avatar coaches to provide CBT-D intended for military service members with depression symptoms and history of mild TBI. Key features and goals of the 12 weekly CBT lessons included stigma minimization, personal engagement, and 1-2 hours per week of personal challenge homework assignments. We performed a randomized controlled trial initially involving military service members and veterans. Inclusion criteria were later relaxed to allow for civilian participation due to practical constraints . The control group received an app providing educational lessons about concussions and depression which did not include the therapeutic components of CBT. There was no difference between the groups randomized to CBT-D (n=19) vs. educational app control (n=23) in self-reported depression symptoms. Nevertheless, there was a statistically significant benefit of the CBT-D intervention in self-reported insomnia severity at the 16-week follow-up (four weeks post intervention) assessment (Cohens D=0.45, p=0.0064). There were also statistically significant positive correlations (r= 0.46 to 0.76, p=0.046 to 0.001) between changes over time in depression symptoms and changes over time in both insomnia and PTSD symptoms in the CBT-D group. There were no such correlations in the control group. Participants reported higher therapeutic alliance (p=0.0001) and overall mobile application user rating (p=0.036) for the CBT-D app than for the control education app. More favorable therapeutic alliance and mobile application user ratings correlated significantly with greater improvements in depression symptoms in the CBT-D group (r=0.53 to 0.66, p=0.02 to 0.002). However, dropout was substantial (40/59 in the CBT-D group and 31/54 in the control group) and results may not be fully representative of the population at risk. Conclusions: There remains a major unmet need for widely available, low-cost, effective interventions for depression symptoms in the context of mild TBI. The challenges of designing and rigorously assessing the effects such interventions remain formidable. However, the lessons learned from this study and indications of benefit in a highly relevant secondary outcome measure (insomnia) suggest that remote app-based interventions remain therapeutically viable. Trial Registration: clinicaltrials.gov NCT05147506, submitted 20 July 2021, posted 7 December 2021.

Deep brain stimulation (DBS) is a well-established therapy for various neurological disorders. Clinical outcomes of DBS depend on electrode placement and stimulation programming, with growing evidence suggesting that targeting specific sites and networks can improve therapeutic efficacy. This targeting can be facilitated using high-accuracy, multi-modal biophysical models. In this article, we present the open-source platform OSS-DBS v2 that enables researchers and clinicians to build such biophys- ical models. Building upon previous work, the new version combines automated volume conductor generation, accurate and efficient electric field modelling and stimulation-driven neural simulations. OSS-DBS v2 provides an extensive library of intracranial electrodes, which can be modelled simul- taneously to test complex stimulation paradigms. Its application programming interface facilitates integration of external data workflows, such as impedance measurements. Furthermore, an integration with the Lead-DBS toolbox offered a straightforward graphical user interface for stimulation volume and pathway activation modelling, further complemented by an optimization framework. OSS-DBS v2 relies entirely on open-source software, supports all major operating systems and is designed for efficient execution on consumer-grade hardware.

Reward operates as a cycle in which a stimulus produces a pleasure response, and the degree of pleasure experienced reinforces the behaviours that lead back to it. Music provides a useful model for examining this cycle because it is intrinsically pleasurable, can be learned, and engages reward-related frontostriatal circuitry that overlaps with circuitry involved in primary and secondary rewards, such as food, sex, and money. Transcranial magnetic stimulation (TMS), a non-invasive stimulation method, has been shown to produce bidirectional effects on music-evoked pleasure by increasing or decreasing activity in cortical regions, such as the left dorsolateral prefrontal cortex (DLPFC), that are functionally connected to subcortical regions, including the striatum. Here, we further characterize the reward cycle by incorporating TMS into a paradigm that combines musical pleasure ratings with an early musical skill acquisition task. In a within-subjects, counterbalanced crossover design, 23 participants with 2-10 years of musical experience received intermittent TBS (iTBS; excitatory) and continuous TBS (cTBS; inhibitory) over the left DLPFC in separate sessions. Participants rated the pleasantness of short piano melodies before stimulation (T0), immediately afterwards (T1), and 24 hours later (T2). After stimulation, they learned to play the melodies, and pitch and rhythm accuracy were assessed during three performance phases, namely acquisition, immediately after acquisition, and 24 hours later. Liking did not differ between conditions at T1; however, the increase in liking from baseline (T0) to T2 was significantly larger following iTBS than cTBS, a divergence that emerged across the 24-hour interval spanning both learning and sleep. Pitch and rhythm accuracy did not differ between conditions at any phase, despite improvement across trials in both. These results indicate that TMS to the left DLPFC can produce delayed, condition-dependent shifts in musical liking without a parallel change in early skill acquisition.

Deep brain stimulation (DBS) of the mesencephalic locomotor region (MLR) has been explored to treat gait disturbances. However, clinical outcomes of MLR-DBS have been disappointing overall, with only modest benefits in some individuals and unwanted effects, including anxiety, reported in others. Preclinical studies in several species, by contrast, show that MLR-DBS can improve locomotor and gait deficits, although defensive behaviours in response to stimulation have also been reported in some species. To investigate this discrepancy, we examined frequency- and amplitude-dependent effects of MLR-DBS in healthy rats, combining semi-supervised and unsupervised behavioural analyses. High-frequency, high-amplitude DBS (80-130 Hz), but not low-frequency stimulation (20-60 Hz), elicited hyperlocomotion intermixed with acute defensive-like behaviours. Low-frequency stimulation instead promoted phases of immobility. Consistently, only high-frequency DBS induced region-specific c-Fos expression in the MLR. Complex behaviours, including hyperlocomotion, rearing, tail rattling, and periods of immobility, were most pronounced in animals with the DBS electrode tip localized to the cuneiform nucleus (CnF) of the MLR. Using AAV tracer constructs for bright labelling of CaMKII-positive neurons and their axons, we identified prominent ascending projections from the CnF to the thalamus, substantia nigra pars compacta, zona incerta, hypothalamus, subthalamic nucleus, and central amygdala (CeA). Retrograde tracing confirmed the CnF-to-CeA projection independently. These findings show that the MLR is anatomically connected to higher-order centres linking motor and defensive networks, with DBS frequency and amplitude critically shaping behavioural outcomes that extend beyond locomotion.

Phantom limb pain (PLP) is common after amputation, yet why poor sleep becomes pain in only some individuals is unknown. We hypothesized that a regulatory response is interpretable only against the reserve sustaining it, and thus we tested whether autonomic capacity relative to demand moderates the sleep-pain relationship in 121 amputee adults. Sleep was assessed with the Pittsburgh Sleep Quality Index; PLP, residual limb pain (RLP), and phantom limb sensation (PLS) on 0-10 scales. Heart rate variability was summarized as autonomic reserve (log-transformed SDNN, RMSSD, total and high-frequency power) and autonomic drive (normalized low-frequency power). Poorer sleep was associated with greater PLP and RLP, but not PLS. No single HRV index moderated these associations, but the sleep x reserve x drive interaction did for PLP (b =-0.51, p = 0.026). Poor sleep predicted pain most strongly under high drive with reduced reserve. PLP vulnerability reflects autonomic capacity relative to demand, instead of any single HRV marker alone.

Neurofeedback shows promise as a clinical intervention, but its effectiveness is hindered by variability of response across individuals. One factor influencing neurofeedback success may be endogenous brain states, particularly the baseline power within target frequency bands. Transcranial alternating current stimulation (tACS) provides a potential mechanism to modulate these baseline frequency bands. This study explored whether tACS could effectively enhance participants' ability to gain neurofeedback control by increasing lateralised posterior alpha activity prior to engagement in a covert spatial attention-based neurofeedback task. Participants completed three counterbalanced sessions: 1) alpha tACS and active neurofeedback, 2) alpha tACS and sham neurofeedback, 3) gamma (40Hz) tACS and active neurofeedback. Neurofeedback performance was assessed via lateralised posterior alpha power shifts and Posner task reaction times. We identified no difference in reaction times or lateralised alpha power shifts across conditions. While participants reliably demonstrated lateralised posterior alpha patterns, consistent with the covert spatial attention neurofeedback protocol, no advantage of active neurofeedback over sham was observed. The lack of significant effects underscores the need for further rigorous tACS studies to identify the parameters essential for successful neural entrainment, and to evaluate its potential in enhancing neurofeedback efficacy.

Closed-loop brain stimulation offers a promising approach for modulating neural oscillations, but the mechanisms of phase-dependent neuromodulation remain poorly understood. We developed a real-time MEG-based closed-loop system delivering median nerve stimulation using a phase-modulated Poisson process. Sixteen healthy participants (11 female, 5 male) underwent open-loop characterization followed by closed-loop testing of eight phase-offset conditions (0 degrees-315 degrees), each paired with a statistically matched replay control. Closed-loop stimulation induced robust phase-dependent modulation (14.21 +/- 8.24%) versus replay (7.03 +/- 2.95%; p = 0.0003), with consistent phase specificity across participants (circular mean: 70.2 degrees, referenced to each individual's dominant frequency). At the group level, alpha oscillations (8-12 Hz) showed bidirectional modulation (mean boost: +21.0 +/- 19.9% at 0 degrees-135 degrees; mean suppression: -13.3 +/- 10.8% at 180 degrees-315 degrees), while beta oscillations (13-30 Hz) showed predominantly unidirectional suppression (-9.3 +/- 9.6%). Successful fixed-frequency targeting required alignment with each individual's natural peak. Misalignment led to different phase shifts producing power at different frequencies, a phenomenon we term phase-frequency coupling. Dynamic frequency tracking (8-30 Hz) automatically identified and targeted each individual's natural peak, achieving robust bidirectional modulation without prior knowledge of peak location. These findings demonstrate that real-time phase-locked peripheral nerve stimulation selectively modulates sensorimotor oscillations beyond statistically matched open-loop stimulation. The distinct phase-excitability relationships of alpha and beta oscillations, together with the importance of aligning stimulation with individual natural peaks, establish principled guidelines for personalized closed-loop neuromodulation.

Background: Although opioids are frequently prescribed for refractory chronic neuropathic pain, few data are available on baseline factors that may identify individuals more likely to respond and inform individually tailored practice. Methods: This was a post hoc, exploratory analysis of individual-level data from a placebo-controlled trial of methadone for chronic neuropathic pain (NCT05235191). Baseline clinical, psychological, psychophysical and radiological variables were tested for association with 30% or more pain reduction in the methadone group. The correlation between expectation of improvement and pain reduction was examined in both groups. Results: Of the 81 participants completing the 8-week follow-up, 28 (70%) on methadone and 14 (34.1%) on placebo achieved 30% or more pain reduction. In the methadone group, responders had higher baseline expectation of improvement (median 100 [80-100] vs. 55 [50-81]; p=0.004), which correlated moderately with percentage pain reduction (rs=0.508; p<0.001). Neither finding was observed in the placebo group (p=0.211 and p=0.161, respectively), although the correlation did not differ significantly between groups (p for interaction=0.728). Other clinical, sociodemographic, psychological and psychophysical variables were not associated with response. In the subsample with peripheral neuropathic pain and structural MRI (n=37), lower left precentral cortex volume was associated with response to methadone (p=0.041), and lower right paracentral volume with response to placebo (p=0.003). Conclusions: Baseline expectation may influence treatment outcomes, supporting its inclusion as a covariate to improve the precision of treatment effect estimates in trials, and its use in clinical practice to help tailor treatment to individual patients. These exploratory findings require confirmation in larger studies.

Rhythmic visual stimulation offers a non-invasive means of modulating oscillatory brain activity, but conventional flicker may induce considerable visual discomfort. We developed an individualized Gabor flicker stimulation designed to balance neural entrainment and tolerability. In Experiment 1, thirty-four participants passively viewed Plain and Gabor flickers presented at their individual alpha frequency (IAF), IAF - 2 Hz, or IAF + 2 Hz, and at threshold-adjusted or full intensity. Steady-state visual evoked potential signal-to-noise ratio (SNR) was highest at IAF and increased with intensity. Plain and Gabor flickers produced comparable overall SNR, but Gabor flicker was rated as substantially more comfortable and less mentally fatiguing, with stimulation at IAF providing the most favorable balance between neural entrainment and tolerability. In Experiment 2, the optimized stimulation parameters were applied during a retro-cue working memory task using individualized theta and alpha frequency flickers. Stimulation increased SNR and inter-trial phase coherence relative to a non rhythmic Natural condition. No behavioral benefit was observed in the full sample. However, an exploratory subgroup analysis indicated higher accuracy with theta stimulation of cued representations and alpha stimulation of uncued representations than in the Natural condition among participants who showed limited baseline retro-cue benefits. These findings show that individualized Gabor flicker can provide robust and well-tolerated neural entrainment during passive viewing and working memory retention, although its behavioral effects may vary across individuals according to their cognitive performance.

Background Spinal manipulation therapy (SMT) is widely used for low back pain (LBP), yet comparative effectiveness findings across trials remain inconsistent. One potential explanation is incomplete separation of treatment-specific effects from natural recovery and placebo response, which may differ between acute and chronic presentations. Methods We conducted a Bayesian hierarchical analysis of 120 randomized controlled trials (298 arms; 19,059 patients) evaluating SMT, exercise, medical management, physical modalities, self-care, and control conditions. Natural history (NH) trajectories were derived from independent observational cohorts and incorporated as external model components. Treatment effects were estimated as deviations from NH, and sham-corrected effects as deviations from control conditions. Results In acute LBP, NH trajectories predicted substantial improvement by 26 weeks. Estimated treatment effects relative to NH were negative across all categories, and sham-corrected effects were near zero, with credible intervals overlapping zero. In chronic LBP, NH trajectories predicted more gradual improvement. Control conditions exceeded NH, consistent with a substantial placebo response. Exercise and SMT demonstrated positive sham-corrected effects with credible intervals excluding zero; however, estimated magnitudes were modest and did not consistently exceed commonly cited thresholds for clinical importance. Higher study quality was associated with smaller estimated effects in chronic trials. Conclusions Modeling natural history as a structural component of treatment response alters estimates of comparative effectiveness in LBP. Improvements observed in acute LBP appear largely consistent with underlying recovery processes, whereas in chronic LBP, contextual and placebo-related effects contribute substantially to observed outcomes. Explicit separation of these components may help reconcile inconsistencies in the literature and inform interpretation of treatment effects.