Bioelectronic medicine最新文献

The NIH Common Fund's SPARC (Stimulating Peripheral Activity to Relieve Conditions) program was launched in 2015 to catalyze bioelectronic medicine by advancing foundational knowledge of the autonomic nervous system (ANS) and enabling clinical translation of novel bioelectronic medicines. While the program officially ended in 2025, activities related to the program are still ongoing through no-cost extensions, data sharing, and derivative efforts. We provide here an overview of the major outcomes of SPARC under its four focus areas: Anatomical and Functional Mapping, Technology Development, Translational Research, and Data/Modeling Infrastructure. In the Anatomical and Functional Mapping focus areas, teams generated cross-species, cross-organ ANS connectivity datasets, detailed nerve anatomy, along with detailed maps and connectivity resources to support query, visualization, and hypothesis-generation. Under the Technology Development focus area, teams developed new tools for recording and stimulating autonomic pathways and built computational pipelines for realistic neuromodulation simulations. Within the Translational Research, teams conducted pre-clinical and clinical proof-of-concept studies and used prize-driven efforts to accelerate clinically ready neuromodulation solutions. Data/Modeling Infrastructure teams built a durable open-science ecosystem enabling FAIR sharing, exploration, and reuse of SPARC datasets, models, and workflows by the broader community. Together, SPARC's integrated approach has lowered barriers to precision neuromodulation research and established reusable resources to sustain the field beyond the program.

Background: Virtual Reality (VR) has previously been found to provide both an effective and enjoyable learning environment for users to develop a wide range of skills. However, despite uptake in fields such as medicine and veterinary medicine, there is little research into the use of VR for diagnostics training with Orthoptists.

Methods: This study compared students' experiences of a collaborative VR learning environment with the Strabismus desktop computer simulation for practicing the diagnosis of ocular deviations and limitations. The VR system provided stereoscopic depth and natural controller-based interaction, enabling students to practice diagnostic procedures with greater spatial realism than 2D simulators. Thirty one first year and twenty one second year Orthoptics students from the University of Liverpool were tasked with diagnosing simulated patients in both learning environments. After completing their diagnoses, students' user experience, sense of presence, comfort with patient proximity, and their thoughts on the use of VR in higher education (SHEQ) were measured.

Results: Students reported higher hedonic user experience scores for VR, whereas pragmatic user experience scores were higher for the desktop simulation. SHEQ responses indicated a general preference for VR as a learning tool. However, there were no significant differences in sense of presence, or comfort with proximity to patient scores.

Conclusions: This study shows how commodity VR hardware can be adapted for specialist healthcare training. Although VR did not demonstrate advantages across all measured outcomes, students generally perceived it positively and preferred it over using 2D displays as a learning tool within higher education. These findings suggest that VR may have potential as a supplementary educational resource for Orthoptics training. However, further research is required to determine whether these positive perceptions translate into real world improvements in learning, diagnostic performance, and clinical practice.

The National Institutes of Health (NIH) Common Fund supports bold scientific programs that catalyze discovery across all biomedical and behavioral research to address high priority challenges for the NIH as a whole and make a broader impact in the scientific community. In 2015, the NIH Common Fund established the Stimulating Peripheral Activity to Relieve Conditions (SPARC) program. This program's overall goal was to accelerate the development of neuromodulation, a field of study that uses bioelectronic devices to deliver electrical current to nervous system tissues to produce therapeutic effects in patients. Because the nervous system impacts all bodily functions, neuromodulation therapies have the potential to treat a variety of health conditions by regulating nerves that innervate affected bodily tissues and organs, with high specificity and few side effects. The SPARC program aimed to capitalize on recent advances in technology to deliver detailed, integrated functional and anatomical neural circuit maps for organs and to provide the necessary scientific foundation for clinical translation of more effective and advanced neuromodulation devices and stimulation protocols. Here we outline the SPARC program's contribution to the field of neuromodulation over the past ten years, laying a comprehensive foundation of knowledge to inspire future research and accelerate translation. We discuss the reasoning behind the formation of the program, its structure, and outcomes.

Vagal-immune interactions are increasingly recognized to play a role in the pathogenesis of diseases associated with immune dysfunction. To study the direct effects of altered vagal activity on adaptive immune function and antibody production, we modeled a state of elevated vagal activation by delivering chronic vagus nerve stimulation (VNS) in immunized mice. We delivered VNS for 14 days before and 14 days after immunization with an antigen, using 2 schedules: Twice Daily VNS, to model intermittently elevated vagal activity, and Continuous Burst VNS, to model chronically elevated vagal activity. We found that Continuous Burst VNS is associated with increased heart rate variability (HRV) on the first week of treatment, remodeling of cellular splenic compartments, as well as weight loss. Such changes are not seen with Twice Daily VNS. High-affinity antibody production is reduced with both Continuous Burst and Twice Daily VNS, compared to no VNS. Total IgG antibody titers are reduced in Continuous Burst VNS, even prior to immunization, likely an effect of weight loss. In conclusion, both continuously and intermittently elevated vagal tone limits the antibody response. Nonselective, whole nerve VNS produces multiple effects that may confound interpretation of specific immune effects at higher stimulation doses.

Background: Transcutaneous cervical electrical stimulation (TCES) offers a noninvasive approach to modulate the autonomic nervous system (ANS), but optimal stimulation parameters remain undefined. This pilot study aimed to identify optimal TCES parameters by evaluating autonomic and neural responses across varying frequencies, current intensities, electrode montages, and durations, using heart rate variability (HRV) and electroencephalography (EEG) alpha-band power as biomarkers of parasympathetic activity.

Methods: Twenty healthy adults completed four testing sessions, each examining one stimulation parameter. Autonomic data were collected including electrocardiography, non-invasive blood pressure, pupillometry, photoplethysmography, and dry-electrode EEG. Four frequencies (10, 25, 40, 150 Hz), three current intensities (sub-sensation threshold, sensation threshold, supra-sensation threshold), three electrode montages (bilateral, left-only, right-only), and two durations (4, 20 min) were tested. Root mean square of successive differences (RMSSD) and global EEG alpha-band power were primary outcomes. Parameters were sequentially optimized across visits based on individual RMSSD responses.

Results: No single frequency produced a significantly higher RMSSD or alpha-band power response. However, each participant exhibited a personalized preferred frequency yielding a mean 41% RMSSD increase in visit 1. This individualized frequency was selected for further visits varying current intensity and electrode montage. Supra-sensation threshold intensity was most effective, with 60% of participants responding strongest at this level. Left-sided stimulation resulted in a decrease in both RMSSD and alpha-band power, while right-sided and bilateral montages resulted in similar increases for these biomarkers. Due to decreasing cardiac vagal response in successive sessions, the preferred frequency was reevaluated before testing duration. The mean RMSSD response increased 54% upon recalibration in visit 4, though the preferred frequency shifted in 75% of participants. Autonomic vitals did not significantly modulate more with longer stimulation duration; pulse rate variability during 20-min stimulation revealed oscillatory autonomic dynamics with peak parasympathetic responses emerging around 4 min.

Conclusions: TCES can modulate cardiac vagal and cortical responses as measured by RMSSD and EEG alpha-band power, respectively, and a personalized, biomarker-guided approach to TCES parameter optimization is essential for future clinical applications targeting autonomic dysfunction.

Trial registration: This study was registered with Clinicaltrials.gov, identifier NCT04100486, on September 16, 2019.

High mobility group box 1 protein (HMGB1) is a central mediator of inflammation and pain, but efforts to neutralize it therapeutically have had limited clinical success. This gap suggests that the essential problem is not simply the abundance of extracellular HMGB1, but its accessibility: its availability to assemble into pathogenic complexes, engage receptors such as the receptor for advanced glycation end products (RAGE), enter cells, and deliver inflammatory cargo to the cytosol. Here, a perspective is advanced that integrates HMGB1 biology with the inflammatory reflex and the cholinergic anti-inflammatory pathway. In this framework, HMGB1 promotes inflammatory entry and amplification, whereas acetylcholine, acting through the vagus nerve and alpha7 nicotinic acetylcholine receptors, limits HMGB1 release and uptake of HMGB1-containing complexes. Vagus nerve stimulation therefore emerges as a bioelectronic strategy to restrict upstream access of danger signals to intracellular inflammatory pathways, in addition to suppressing downstream cytokine signaling. This formulation does not alter the established biology of HMGB1; rather, it places existing observations into a unifying model with direct relevance to inflammation and pain.

Background: Traumatic or surgical hemorrhage causes substantial morbidity and mortality. Electrical vagus nerve stimulation (VNS) reduces traumatic hemorrhage in animal models. VNS targets acetylcholine-producing T lymphocytes in the spleen to increase intracellular calcium within circulating platelets via α7 nicotinic acetylcholine receptors. Elevated calcium levels facilitate platelet activation (priming) after tissue injury to accelerate and increase clot formation that improves hemostasis. Trigeminal nerve stimulation (TNS) also decreases traumatic hemorrhage in mice, but the mechanism remains unknown. Recently, we showed that transcutaneous auricular neurostimulation (tAN; combined auricular VNS and TNS) reduces blood loss and days of menstruation in women with idiopathic or von Willebrand disease related heavy menstrual bleeding. The ability of tAN or transcutaneous auricular VNS (taVNS) to improve platelet function or laboratory hemostasis remains unknown.

Methods: Here we performed a prospective, randomized, double-blind, sham-controlled, single-center, first-in-human exploratory trial to determine the safety and efficacy of taVNS or tAN to prime platelets and augment clot formation. Healthy adult subjects received sham stimulation before taVNS or tAN, followed by serial measurements of platelet and hemostasis markers, including platelet functional analysis, thrombin generation, blood counts, coagulation assays, and thromboelastography. Repeated measures one-way ANOVA followed by Bonferroni's test was used for comparisons between three or more time points. Two-tailed paired T-test was used for comparisons between two time points.

Results: Administration of taVNS or tAN was well tolerated without observable adverse events during the study period. taVNS or tAN primed platelets via collagen- or ADP-mediated signaling pathways, respectively. taVNS accelerated clot initiation, propagation, and stabilization as measured by thromboelastography. There were no differences in systemic or local thrombin generation, circulating white or red blood cell counts, platelet counts, prothrombin time, partial thromboplastin time, or INR assays after administration of taVNS or tAN.

Conclusions: These results provide evidence that taVNS or tAN primes human platelets and taVNS accelerates clotting kinetics as quantified by thromboelastography. taVNS and tAN warrant additional clinical study as therapies for traumatic or surgical hemorrhage and congenital or acquired coagulopathies.

Trial registration: This study is registered with the ClinicalTrials.gov database ( http://clinicaltrials.gov ). The registration number is NCT05977946. The study start is 10-31-2023.

In-ear electroencephalography (EEG) has emerged as a promising alternative to traditional in-laboratory sleep studies, offering greater comfort and practicality. Here we present a novel in-ear EEG system, comparing in-ear recordings against scalp EEG channels acquired concurrently as part of polysomnography (PSG). The study enrolled 16 healthy control participants in a single-visit overnight-plus-daytime design, and 8 participants with central disorders of hypersomnolence (CDH) in a randomized crossover daytime design (medication vs. medication-holiday). For overnight sleep recordings, ear-EEG and scalp EEG sleep staging showed substantial agreement (Cohen's [Formula: see text]). For daytime MWT trials, agreement was moderate (Cohen's [Formula: see text]), reflecting the predominance of wake epochs in this paradigm. For the primary Maintenance of Wakefulness Test (MWT) endpoint of sleep onset latency (SOL), at the per-subject level ([Formula: see text])-averaging across trials as in standard clinical practice-agreement was good (ICC = 0.71, [Formula: see text], MAD = 5.1 min). Among the 37 of 126 trials where both devices detected sleep (approximately 30% of trials), agreement was strong (ICC = 0.82, MAD = 1.9 min), with excellent agreement in healthy controls (ICC = 0.95, MAD = 1.2 min). Overall trial-level agreement across all 126 trials was moderate (ICC = 0.55), reflecting 22 discordant trials in which scalp EEG detected sleep but in-ear EEG did not-predominantly brief, subtle N1 transitions, concentrated in a subset of CDH participants. For overnight sleep architecture ([Formula: see text] healthy controls), total sleep time ([Formula: see text], ICC = 0.85), sleep efficiency ([Formula: see text]), and wake after sleep onset ([Formula: see text]) showed strong agreement, with small systematic biases consistent with reduced N1 detection sensitivity. These findings support the feasibility of in-ear EEG for sleep staging and daytime sleepiness assessment in laboratory settings, and motivate larger confirmatory studies-including home-based longitudinal monitoring-to establish clinical utility, particularly in populations with altered sleep architecture.

BACKGROUND: Transcutaneous auricular vagus nerve stimulation (taVNS) is a promising noninvasive technique for modulating parasympathetic activity, yet optimal stimulation parameters and comprehensive tolerability profiles remain undefined. Traditional assessments of taVNS tolerability have focused narrowly on safety and adverse events, overlooking participant comfort and subjective experience, which are critical factors for adherence and clinical translation. METHODS: We conducted two randomized crossover trials in healthy adults to evaluate the tolerability of taVNS across different stimulation parameters. Study 1 compared two monophasic duty cycles (30 s on/30 s off vs. 10 s on/10 s off), while study 2 compared monophasic and biphasic waveforms. Tolerability was assessed using questionnaires and semi-structured interviews, with secondary outcomes including heart rate variability (HRV), pain sensitivity, and transcranial magnetic stimulation (TMS) measures of corticospinal excitability and intracortical inhibition/facilitation. RESULTS: Both studies demonstrated high tolerability across all taVNS conditions, with low median ratings for pain and irritation. The most common sensations were tingling, tickling, or pricking, reported by the majority of participants but rated as mild. Qualitative analysis revealed nuanced preferences related to comfort, perceived effectiveness, and ease of adjustment to stimulation. No significant differences in secondary physiological outcomes were observed between conditions, though trends suggested parameter-specific effects on HRV and pain sensitivity. CONCLUSIONS: Our findings highlight that taVNS is well tolerated in healthy adults, regardless of duty cycle application or waveform, when tolerability is defined to include comfort and participant experience. Incorporating these dimensions into tolerability assessments may enhance protocol optimization and support broader adoption of taVNS in clinical practice. Further research in clinical populations is warranted. TRIAL REGISTRATION: https://clinicaltrials.gov , identifiers (NCT06381102 and NCT06614933).

BACKGROUND: The vagus nerve (VN) has anti-inflammatory properties. We have previously reported in a 1-year pilot study that VN stimulation (VNS) improved patients with active Crohn’s disease (CD). In this paper, we present the results of the long-term follow-up of these CD patients (between four and ten years) and raise questions about the use of VNS in inflammatory bowel disease. METHODS: At the end of the pilot study, the 7 patients who ended the pilot study (corresponding to a 1-year active VNS), accepted to continue VNS as well as the 2 patients retrieved from the study, because of an early worsening (at 3 months of VNS) of their disease. Patients were then followed-up twice a year as far as possible with clinical and biological evaluation. Ileo-colonoscopy, as well as intestinal ultrasound evaluation were performed as far as possible. Vagal tone was evaluated by heart rate variability (HRV). The state perceived digestive pain score and the anxiety and depression score were also evaluated. RESULTS: Over a decade-long follow-up of nine CD patients implanted with VNS, sustained clinical benefits were observed despite heterogeneous disease courses and treatment histories. Three patients achieved long-term remission under VNS alone, without any additional therapy at 10 years. Several others initially controlled disease activity with VNS alone for 3–7 years before required biologics or surgery, most often during COVID-19. Clinical, biological, and endoscopic markers generally improved or stabilized, with relapse episodes responding to added standard therapies when needed. Autonomic data showed increased median parasympathetic HRV (HFnu) after implantation, persisting over six years despite interindividual variability. Median anxiety–depression scores decreased below clinical thresholds, and digestive pain shifted from moderate to low within the first year and remained low thereafter. Overall, long-term VNS was feasible, well tolerated, and associated with durable symptom control or remission in this small pilot cohort. CONCLUSIONS: This pilot study should primarily be viewed as a proof-of-concept demonstration that long-term invasive cervical VNS is feasible, safe, and acceptable for CD patients. It also highlights a potential therapeutic signal in a subset of individuals, supporting further investigation.