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.

Introduction: Transcutaneous electrical stimulation of the cymba concha targets the auricular branch of the vagus nerve (taVNS) to activate the cholinergic anti-inflammatory pathway.This non-invasive form of nerve stimulation is an investigational therapy to treat immune mediated inflammatory diseases (IMIDs) with effectiveness reported in short term clinical trials with small sample sizes.Long-term taVNS for this purpose is not well reported.We review a case of successful longterm use in a child with Crohn's disease.Case Report: Patient SS presented at age 4 years old in 2013 with abdominal pain and bloody stools.Crohn's disease involving the duodenum and colon was found.She was treated with mesalamine (2013-2014) unsuccessfully, then azathioprine (2014-2017) leading to a clinical and biochemical remission.Due to patient concerns about long term risk of immunomodulatory medication, azathioprine was discontinued.She returned to clinical care in 2019 with abdominal pain, fecal calprotectin 333 ug/g and colonoscopy finding active Crohn's disease of her duodenum and right colon.She enrolled in a 16-week clinical trial using taVNS.The TENS 7000 stimulation device was used with parameters of a normal pulse wave, 20 Hz frequency, and 300 s pulse width for 5 minutes twice daily.At the end of 16 weeks, her abdominal pain resolved with overall no symptoms reported.Her fecal calprotectin normalized to 59 ug/g.She then continued taVNS as her sole long term Crohn's disease maintenance therapy.In the first year, adherence to the taVNS stimulation varied between zero, once, or twice daily use.After 1 year of taVNS, her symptoms remained resolved, however her calprotectin increased to previous levels 388 ug/g.Repeat endoscopy found mildly active duodenitis and much improved but not resolved macroscopic disease in the right colon compared to colonoscopy before taVNS therapy was initiated.In 2021, given active disease persisting, ustekinumab (Interleukin 12/23 antagonist) was initiated and taVNS use was increased to a consistent 5 minutes twice daily with adherence.Two years later in 2023, with durable clinical remission achieved, reevaluation of her disease activity identified a completely normalized fecal calprotectin 14 ug/g and complete mucosal healing (endoscopic and histologic healing) of her duodenum and colon.She continues this combination of ustekinumab and taVNS with excellent growth, nutritional status, and clinical remission of her Crohn's disease to date.Discussion: Transcutaneous electrical neurostimulation of the auricular cymba concha is being investigated for treatment of intestinal IMIDs such as Crohn's disease and ulcerative colitis.Its excellent safety profile allows taVNS to be considered as a potential monotherapy or in combination with a conventional pharmacological therapy as we report here.A limitation of taVNS as compared to an implanted device is the potential for non-adherence, which can impact therapy success.Its mechanistic effect through vagus nerve mediated anti-inflammatory signaling and potentially other neural circuits requires further investigation.*The subject/proxies described in the abstract gave consent permissions for this case report.

Bioelectronic Medicine relies on wearable or implantable electronic devices interfacing with the nervous system and other active tissues, offering innovative therapeutic solutions. However, the long-term reliability and stability of these devices remain critical challenges that must be addressed for widespread clinical adoption. Advances in materials science, device engineering, power management, and biocompatibility are essential to ensure sustained functionality in dynamic biological environments. This perspective highlights key factors affecting the durability, reliability and stability of Bioelectronic Medicine technologies, explores current solutions and emerging approaches, and outlines the necessary steps to achieve robust, long-lasting bioelectronic therapeutics. The personal view expressed in this article is aimed to provide structured, accessible insights that support teaching and learning, and is envisioned to help motivate other investigators to develop further strategies for achieving clinically-relevant ultra-stable bioelectronics.

BackgroundPreclinical and early clinical evidence demonstrates that electrical stimulation (ES) applied for one hour following surgical nerve intervention enhances axonal regeneration and functional outcomes. Wide clinical implementation however, has been hindered by a lack of suitably designed stimulators. The aim of this pilot study was to investigate sensory recovery, safety, tolerability, and RCT feasibility for the use of a novel single-use stimulator to deliver ES therapy in an acute nerve transection cohort.MethodsPatients with complete transection of a proper digital nerve were included in the trial. An investigational version of PeriPulseTM was used with intraoperative electrode implantation and 1-hour ES therapy delivered postoperatively. Patient tolerance was assessed during stimulation and visual-analogue pain scores were collected at the first post-operative visit. At 3- and 6-months post-op, sensory recovery and quality of life were assessed using 2-point discrimination, monofilament tests, and the Disability of Arm, Shoulder, and Hand (DASH) questionnaire, respectively.ResultsA total of 10 patients were enrolled. Intraoperative electrode placement did not impact operating room time, taking less than 5 minutes to implement. There were no related adverse events. Participants reported tolerable stimulation during ES therapy with no reports of pain. At the first post-operative visit patients had a mean visual-analogue pain score of 0.6 (range 0 - 1.9). Pressure threshold detection significantly improved between baseline, 3 months and 6 months. A greater proportion of ES treated patients (87.5%) had improved hand pressure thresholds (diminished light touch or diminished protective sensation) at 6 months compared to a historical comparator group. DASH scores improved over the timeline. Participants treated with ES therapy experienced minimal postoperative functional disability.ConclusionsThe use of the PeriPulseTM prototype for the delivery of perioperative ES therapy was safe, well-tolerated, and usable. Sensory recovery was demonstrated and a larger RCT is feasible.Trial Registration NCT04732936; 2021 - 01 - 29

Temporal interference (TI) is a method of non-invasive brain stimulation using transcutaneous electrodes which allows the targeting and modulation of deeper brain structures, not normally associated with non-invasive simulation, while avoiding unwanted stimulation of shallower cortical structures. The properties of TI have been previously demonstrated, however, the problem of decoupling stimulation focality from stimulation intensity has not yet been well addressed. In this paper, we provide a possible novel solution, multipolar TI (mTI), which allows increased independent control over both the size of the stimulated region and the stimulation intensity. The mTI method uses multiple carrier frequencies to create multiple overlapping amplitude-modulated envelopes, rather than using one envelope as in standard TI. The study presents an explanation of the concept of mTI along with experimental data gathered from Rhesus macaques and mice. We improved the focality at depth in anesthetized mice and monkeys, and using the new focality in awake monkeys, evoked targeted activity at depth in the superior colliculus. The mTI method could be an interesting and potentially useful new tool alongside other forms of non-invasive brain stimulation. Teaser Multipolar Temporal Interference Stimulation can produce a more focal brain stimulation at depth compared to Temporal Interference.

BackgroundCurrent inflammatory bowel disease (IBD) treatments often fail to achieve lasting remission and have adverse effects. Vagus nerve stimulation (VNS) offers a promising therapy due to its anti-inflammatory effects. Its invasive nature, however, has led to the development of non-invasive methods like transcutaneous auricular VNS (taVNS). This study assesses taVNS’s impact on acute colitis progression, inflammatory, anti-inflammatory, and apoptosis-related markers.MethodsMale C57BL/6 mice (11–12 weeks) were used for dextran sulfate sodium (DSS)- and dinitrobenzene sulfonic acid (DNBS)-induced colitis studies. The administration of taVNS or no stimulation (anesthesia without stimulation) for 10 min per mouse began one day before colitis induction and continued daily until sacrifice. Ulcerative colitis (UC)-like colitis was induced by administering 5% DSS in drinking water for 5 days, after which the mice were sacrificed. Crohn’s disease (CD)-like colitis was induced through a single intrarectal injection of DNBS/ethanol, with the mice sacrificed after 3 days. Disease activity index (DAI), macroscopic evaluations, and histological damage were assessed. Colon, spleen, and blood samples were analyzed via qRT-PCR and ELISA. One-way or two-way ANOVA with Bonferroni and Šídák tests were applied.ResultstaVNS improved DAI, macroscopic, and histological scores in DSS colitis mice, but only partially mitigated weight loss and DAI in DNBS colitis mice. In DSS colitis, taVNS locally decreased colonic inflammation by downregulating pro-inflammatory markers (IL-1β, TNF-α, Mip1β, MMP 9, MMP 2, and Nos2) at the mRNA level and upregulating anti-inflammatory TGF-β in non-colitic conditions at both mRNA and protein levels and IL-10 mRNA levels in both non-colitic and colitic conditions. Systemically, taVNS decreased splenic TNF-α in non-colitic mice and increased serum levels of TGF-β in colitic mice and splenic levels in non-colitic and colitic mice. Effects were absent in DNBS-induced colitis. Additionally, taVNS decreased pro-apoptotic markers (Bax, Bak1, and caspase 8) in non-colitic and colitic conditions and increased the pro-survival molecule Bad in non-colitic mice.ConclusionsThis study demonstrates that taVNS has model-dependent local and systemic effects, reducing inflammation and apoptosis in UC-like colitis while offering protective benefits in non-colitic conditions. These findings encourage further research into underlying mechanisms and developing adjunct therapies for UC.

BackgroundGlioblastoma (GBM) presents as an aggressive brain cancer, notorious for its recurrence and resistance to conventional treatments. This study aimed to assess the efficacy of the EMulate Therapeutics Voyager®, a non-invasive, non-thermal, non-ionizing, battery-operated, portable experimental medical device, in treating GBM. Using ultra-low radiofrequency energy (ulRFE) to modulate intracellular activity, previous preliminary results in patients have been encouraging. Now, with a focus on murine models, our investigation seeks to elucidate the device's mechanistic impacts, further optimizing its therapeutic potential and understanding its limitations.MethodsThe device employs a silicone over molded coil to deliver oscillating magnetic fields, which are believed to interact with and disrupt cellular targets. These fields are derived from the magnetic fluctuations of solvated molecules. Xenograft and syngeneic murine models were chosen for the study. Mice were injected with U-87 MG or GL261 glioma cells in their flanks and were subsequently treated with one of two ulRFE cognates: A1A, inspired by paclitaxel, or A2, based on murine siRNA targeting CTLA4 + PD1. A separate group of untreated mice was maintained as controls.ResultsMice that underwent treatments with either A1A or A2 exhibited significantly reduced tumor sizes when compared to the untreated cohort.ConclusionThe EMulate Therapeutics Voyager® demonstrates promising potential in inhibiting glioma cells in vivo through its unique ulRFE technology and should be further studied in terms of biological effects in vitro and in vivo.

Reference Tharu, et al. Neuromodulation for recovery of trunk and sitting functions following spinal cord injury: a comprehensive review of the literature.

BackgroundVagus nerve stimulation (VNS) is a FDA approved therapy regularly used to treat a variety of neurological disorders that impact the central nervous system (CNS) including epilepsy and stroke. Putatively, the therapeutic efficacy of VNS results from its action on neuromodulatory centers via projections of the vagus nerve to the solitary tract nucleus. Currently, there is not an established large animal model that facilitates detailed mechanistic studies exploring how VNS impacts the function of the CNS, especially during complex behaviors requiring motor action and decision making.MethodsWe describe the anatomical organization, surgical methodology to implant VNS electrodes on the left gagus nerve and characterization of target engagement/neural interface properties in a non-human primate (NHP) model of VNS that permits chronic stimulation over long periods of time. Furthermore, we describe the results of pilot experiments in a small number of NHPs to demonstrate how this preparation might be used in an animal model capable of performing complex motor and decision making tasks.ResultsVNS electrode impedance remained constant over months suggesting a stable interface. VNS elicited robust activation of the vagus nerve which resulted in decreases of respiration rate and/or partial pressure of carbon dioxide in expired air, but not changes in heart rate in both awake and anesthetized NHPs.ConclusionsWe anticipate that this preparation will be very useful to study the mechanisms underlying the effects of VNS for the treatment of conditions such as epilepsy and depression, for which VNS is extensively used, as well as for the study of the neurobiological basis underlying higher order functions such as learning and memory.