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.
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. 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. 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. 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.
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.
Abstract 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 κ = 0.77 ). For daytime MWT trials, agreement was moderate (Cohen’s κ = 0.50 ), 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 ( n = 24 )—averaging across trials as in standard clinical practice—agreement was good (ICC = 0.71, r = 0.75 , MAD = 5.1 min). Among the 37 of 126 trials where both devices detected sleep (approximately 30 n = 16 healthy controls), total sleep time ( r = 0.94 , ICC = 0.85), sleep efficiency ( r = 0.94 ), and wake after sleep onset ( r = 0.93 ) 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.
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. 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. 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. 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. https://clinicaltrials.gov , identifiers (NCT06381102 and NCT06614933).
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. 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. 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. 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.
Background Electrical stimulation of the cervical vagus nerve reduces traumatic blood loss in models of soft tissue injury. This pathway, termed the neural tourniquet, can be accessed with a transcutaneous auricular neurostimulation (tAN) targeting vagus and trigeminal nerve branches on and around the ear. The cymba concha is the most targeted dermatome to activate the auricular branch of the vagus nerve (ABVN); however due to variable ear anatomy, participants can report electrode discomfort leading to reduced treatment compliance and device usability. This study examined a novel electrode configuration to improve hemostasis during menstruation and device usability. Methods This open-label pilot trial (NCT06814028) sought to determine whether the use of tAN reduced menstrual blood loss in women with heavy menstrual bleeding (HMB).The device included a novel electrode configuration through which the auricular branch of the vagus nerve (ABVN) was targeted posterior to the auricle, near the mastoid process. Participants with a history of heavy menstrual bleeding gave informed consent to participate in an IRB-approved, decentralized clinical trial. Participants were followed for three consecutive menstrual cycles, during which estimated daily blood loss using a validated pictorial blood loss assessment chart (PBAC) and menstrual symptoms were recorded at the end of each menstruation. During the first menstruation, baseline PBAC and menstrual symptom scores were measured without the use of tAN. During the second menstruation, participants selfadministered two 1-h sessions of tAN daily throughout menstruation; during the third menstruation, participants selfadministered one 2-h session of tAN daily throughout menstruation. The PBAC was also used to calculate the duration of each menstruation, defined by the use of menstrual products. Student's paired T-test was used to compare mean outcome scores to baseline. Results Use of the novel electrode design to deliver tAN was associated with lower PBAC scores and reduced duration of menstruation as compared with baseline. Notably, device usability surveys of participants revealed high device satisfaction scores, including comfort of the novel electrode configuration. Conclusions These pilot results suggest that stimulating the ABVN posterior to the auricle is effective, safe and feasible for reducing menstrual blood loss in women with HMB.
Bioelectronic medicine (BEM) is an emerging scientific field that aims to revolutionize the way we understand and treat disease by using electrical impulses for diagnosis and therapy. It is an interdisciplinary endeavour that draws on advances in microelectronics, information technology, materials science, and medicine, and it holds strong promise for addressing currently unmet medical needs. At its core, BEM seeks to develop implantable devices capable of modulating neuronal circuits and biological functions in a precise, targeted, and adaptable manner. Neural interfaces play a pivotal role within this therapeutic paradigm, as they must safely probe and interact with the nervous system while maintaining long‑term stability and biocompatibility. This editorial introduces the papers published in our collection “Neural Interfaces for Bioelectronic Medicine”. The included works present the clinical landscape of neuromodulation, examine mechanisms of device failure and reliability, introduce electrode technologies with improved biocompatibility and selectivity, and explore the therapeutic potential of alternative neuromodulation strategies, such as ultrasound and magnetoelectric nanoparticle‑based approaches, supported by computational models. Together, these contributions highlight both the opportunities and the challenges that must be addressed for bioelectronic medicine to fully flourish. They also identify the key technological advancements that will shape the future of neural interfaces and enable the next generation of bioelectronic therapies. We hope you enjoy this collection as much as we did.
Abstract Background Current imaging assessment for pancreatic cancer resectability demonstrates problematic inter-observer variability, with only fair-to-moderate agreement among experienced raters. Virtual reality technology offers stereoscopic three-dimensional visualization that may improve diagnostic accuracy and agreement. However, optimal visualization strategies for clinical adoption remain unclear. Methods Ten hepatopancreatobiliary surgeons from two high-volume centers were randomized 1:1 to assess twelve contrast-enhanced CT cases using either VR volumetric rendering or CSI. Primary outcomes included inter-rater agreement, diagnostic accuracy against expert reference standard, assessment time, and surgeon confidence. Statistical analysis employed Fleiss’ κ for inter-rater agreement and two-sided Mann–Whitney U tests on surgeon-level summary measures for between-group comparisons. Results CSI display on 2D screens achieved substantial inter-rater agreement for resectability assessment (κ = 0.609) while VR demonstrated only slight agreement (κ = 0.127). Diagnostic accuracy was superior with CSI (84.7% vs. 79.7%), with the most pronounced difference in resectability determination (83.3% vs. 58.3%, p = 0.033). VR users reported significantly lower confidence (4.85 ± 1.15 vs. 6.32 ± 0.77, p = 0.028). Assessment times were comparable between groups (median 313.5 s vs. 327.5 s, p = 1.00). Conclusions In this preliminary investigation, our VR visualization strategy demonstrated lower diagnostic accuracy and inter-rater agreement than CSI. However, prior studies suggest that VR systems employing alternative, hybrid visualization approaches may improve inter-rater agreement, indicating that visualization strategy, rather than VR technology per se, is the primary determinant of utility. Trial registration DRKS00033932 (German Clinical Trials Register), registered prospectively.
Wireless telemetry from fully implanted, millimeter-scale neuromodulation devices is constrained by tight power budgets, inefficient antennas, and in-body attenuation. Standard protocols (e.g., BLE) offer mature ecosystems but exhibit throughput shortfalls and reduced robustness under non-ideal operating conditions. This study introduces the Neural Real-Time Telemetry Protocol (NRTP), a 2.4 GHz, half-duplex protocol designed to address the unmet need for reliable, real-time neural telemetry from miniaturized implants using off-the-shelf hardware, without custom electronics or ASICs. NRTP was implemented on commercial 2.4 GHz hardware with static-length packets, immediate acknowledgments, bounded retransmissions, and single RF channel operation. We evaluated three mitigation strategies—retries, sample-level interleaving, and data overlapping—individually and in combination, and defined a quantitative evaluation metric that prioritizes data quality and power draw. Using identical hardware for NRTP and BLE, we performed controlled sweeps of received signal strength, tested multiple payload lengths and timing configurations, and measured throughput, data loss, and current draw. NRTP sustained zero data loss down to -75 dBm, whereas BLE performance degraded below -55 dBm due to throughput shortfalls under interference and deferred unlimited retries. Interleaving converted contiguous gaps into half-rate segments, delaying score decline at lower received signal strength; overlapping improved robustness but its doubled packet rate requirement was power-prohibitive for implant constraints. Across variants, NRTP delivered higher scores and lower variability over a wider operational range than BLE; BLE’s greater scores at high signal strength were driven by lower current consumption but fell off earlier with attenuation. The observed link-margin advantage for NRTP (up to 23 dB at first loss; 11 dB at 0.5
Peripheral nerve interfaces play a central role in bioelectronic medicine. Since the early foundational experiments of Luigi Galvani in the 1770s, there have been over 250 years of development in electrical neuromodulation. Even so, current clinical approaches to interface with peripheral nerves are limited. Bioelectronic interfaces for small, branched nerves are of increasing interest to unlock new therapies and minimize off-target effects. This is facilitated by our growing understanding of peripheral nervous system physiology and advances in new materials and technologies. Therefore, this review examines historical and recent developments in FDA-approved peripheral nerve interfaces and investigational interfaces with an emphasis on approaches to target smaller nerves. Unmet needs in small nerve peripheral nerve interfaces are highlighted, followed by an examination of new strategies being pursued to address them. To conclude, ongoing challenges are summarized, revealing opportunities and prospects for future advancements.
Microglial activation and neuroinflammation, important aspects of neurodegeneration and accumulation of amyloid-pathology, is often exacerbated by peripheral inflammation following surgical procedures. Subsequent postoperative delirium is a predictor for long-term cognitive decline and increased rick of Alzheimer’s Disease, and perioperative strategies to reduce inflammatory responses, may be a potential avenue to mitigate postoperative complications. In this issue of Bioelectronic Medicine, Song et al. utilize percutaneous vagus nerve stimulation (pVNS) as a potential novel avenue for the attenuation of neuroinflammation and postoperative cognitive decline, which we have discussed in this commentary.
A single session of vagus nerve stimulation (VNS) has been shown to improve cognition in male rodents, but the influence of sex on the effects of VNS on behavior and synaptic plasticity are poorly understood. The present study investigated cognitive performance and hippocampal (HC) electrophysiology/brain derived neurotrophic factor (BDNF) expression in female healthy adult rats to examine changes in cognition and synaptic plasticity after VNS paired training. A total of 44 female rats were utilized for the cognitive neurobehavior experiments and a total of 68 female rats were utilized for the electrophysiology experiments. Animals were divided into four groups: SHAM in diestrus (SHAM-D), SHAM in estrus (SHAM-E), VNS in diestrus (VNS-D), and VNS in estrus (VNS-E). Electrode wires were surgically implanted around the left cervical vagus nerve (VN) prior to stimulation and experimentation in female Sprague–Dawley rats. A single 30 min session of VNS (100 µs biphasic pulses, 30 Hz, 0.8 mA) was administered after neurobehavior training in a Novel Object Recognition (NOR) and a Passive Avoidance Task (PAT) and testing was performed 24 h after VNS. Electrophysiology recordings for input/output, long-term potentiation, spontaneous spiking, and paired-pulse facilitation (PPF) were collected 90 min after VNS to assess the functional effects of VNS on HC slices. Immunohistochemistry (IHC) was conducted on HC slices collected 48 h after VNS to quantify HC subregion specific changes in BDNF. Stimulated rats exhibited improved performance in the PAT when tested in the diestrus phase. Among all subjects, VNS increased response amplitude and decreased PPF. However, among those in diestrus VNS increased long-term potentiation (LTP) amplitude and frequency of spontaneous spiking, and decreased PPF in the CA1. Among those in estrus, VNS did not change LTP amplitude or PPF, but frequency of spontaneous spiking was increased. VNS and estrous cycle stage additionally influenced the HC expression of BDNF in the CA1 and CA2. These findings suggest that a single session of VNS can increase synaptic plasticity, but that an interaction between estrous cycle phase and VNS influences the effects of VNS in females. This study is among the first to investigate the influence of estrous cycle phase on cognitive neurobehavior and synaptic plasticity outcomes after VNS and contributes to the understanding of VNS-induced cognitive enhancement.
The Sixth Bioelectronic Medicine Summit took place on March 4 and 5, 2025 at the Garden City Hotel in New York, and was co-hosted by the Feinstein Institutes for Medical Research (FIMR), Northwell Health and the University of Minnesota. The Summit brought together speakers and attendees from academia, medicine and industry to discuss the evolving landscape of neuromodulation and bioelectronic therapeutics. This year’s Summit was titled “Neurotechnologies for Individuals and Communities” and emphasized approaches that consider differences between subjects to deliver precision neuromodulation therapies, as well as approaches that expand the therapeutic footprint of neuromodulation to underserved populations and communities. The Summit included sessions covering basic and translational research, device development and commercialization, and emerging clinical applications. This meeting report summarizes the major events from the two days of the Summit, including keynote addresses, scientific sessions, discussion panels, award presentations, and sponsored talks.
Delirium and delirium superimposed on dementia (DSD) are common complications affecting patients suffering from ongoing neurodegenerative pathologies. Peripheral surgical trauma can trigger neuroinflammation and ensuing DSD via mechanisms that remain poorly understood. Given the multifactorial therapeutic effects of neuromodulation, including vagal nerve stimulation, we have tested a minimally invasive approach to combat DSD following orthopedic surgery. We performed orthopedic surgery on 5xFAD and CVN-AD mice and tested the efficacy of minimally invasive percutaneous vagus nerve stimulation (pVNS). We applied immunohistochemical, biochemical, and behavioral assays to evaluate the impact of surgery on postoperative delirium on DSD pathology in Alzheimer’s disease-like mice. To confirm the role of systemic factors in neuroinflammation and amyloid-β dyshomeostasis, we conducted experiments using interleukin-6 (IL-6), a cytokine commonly upregulated in postoperative delirium and in vitro co-culture assays for validation. In AD-like mice surgery induced acute changes in amyloid-β; perioperative treatment with pVNS effectively reduced amyloid-β load, plaque sphericity, and neuronal loss. The rescue of these pathological hallmarks led to improved delirium-like behavior, as demonstrated by the 5-choice serial reaction time task on postoperative days 1 and 2. pVNS improved microglial morphology, particularly near amyloid-β plaques. Acute isolation of microglial cells from 5xFAD mice after surgery indicated that pVNS partially enhanced key Disease-Associated Microglia (DAM) markers. The contribution of pro-inflammatory cytokines to amyloid-β aggregation was validated using an in vitro transwell culture model following Cytomix exposure, which also caused endothelial barrier disruption. Finally, we isolated IL-6 as a well-established biomarker of postoperative delirium and described its role in DSD pathology following systemic administration. These findings establish a role for neuromodulation after pVNS in regulating perioperative immunity and advance a new paradigm for perioperative interventions in patients at risk for DSD.
Measuring the weak magnetic fields generated by spontaneous biological activity, such as those produced in the brain or heart, offers complementary information to conventional electrophysiological techniques, as electroencephalography and electrocardiography. Nevertheless, the widespread clinical use of biomagnetic sensing is hindered by the bulky and costly technology currently available, including SQUID-based and optically pumped magnetometers. In recent years magnetoelectric materials have been explored as highly sensitive, room-temperature magnetic field sensors, offering a compelling alternative to conventional approaches. Here, we investigate the feasibility of using resonant magnetoelectric nanoparticles (MENPs) as nanoscale magnetic sensors by exploiting the delta-E effect, in which magnetic-field–induced changes in elastic properties, i.e. Young’s modulus, shift the nanoparticle’s resonance frequency. Using a computational modeling approach, we first developed and characterized a core–shell MENP model. We then identified its natural resonance frequencies in the GHz range, evaluated its sensitivity to external magnetic field variations, and determined the optimal bias static magnetic field and core radius for maximum sensitivity. Finally, we assessed the performance of the optimized nanoparticle in detecting neural-level magnetic fields. Our simulations demonstrate that MENP can achieve a maximum sensitivity of 2.59 Hz/nT for a core diameter of 50 nm under a bias static magnetic field of 1000 Oe. These findings highlight both the feasibility of exploiting the delta-E effect in MENPs and the tunability of their structural parameters, which could be tailored for specific applications. In conclusion, this work set the theoretical groundwork for the development of cutting-edge, wireless and non-invasive nanoscale magnetic sensors for neural interfacing and biomedical signals sensing.
The Utah electrode array (UEA) is a promising microelectrode technology with potential applications to assist patients with sensory loss, spinal cord injuries, and limb loss serving as neural prosthetics and brain-computer interfaces. Performance lifetime of microelectrodes, particularly when used for stimulation, remains one of the challenges for their clinical translation. This study characterizes the stimulation stability of an optimized iridium oxide (IrOx) research metallization for the UEA in comparison to the Blackrock standard practice metallization. The stimulation stability (Stim-Stab) protocol used electrochemical characterization and either 106 or 4 × 106 pulses at 2,100 µA (420 nC/ph) with longitudinal voltage transient measurements and physical characterization to quantify electrode lifetime. Approximately 50
