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One problematic and undertreated consequence of spinal cord injury (SCI) is urinary dysfunction. Treatment is usually conservative, involving regulation of fluid intake and scheduled bladder emptying through intermittent catheterization. These interventions provide symptomatic relief but are associated with recurrent urinary tract infections and increased risk of kidney disease. Neuromodulation has been used to counteract aberrant signals, such as bladder overactivity, but has yet to address other symptoms, such as urethral sphincter tonic activity or poor bladder compliance. Combining rehabilitation with vagus nerve stimulation (VNS), which is known to engage neuromodulatory nuclei to promote synaptic neuroplasticity and recovery, has emerged as a potential therapy to restore function after neurological injury including SCI. Our perspective is that a congruent strategy of pairing VNS with bladder function after incomplete SCI can promote neuroplastic changes in spared neural pathways to strengthen neural control of bladder function.

Metabolic stress during major surgery increases insulin resistance and causes post-operative hyperglycemia (POHG), which may in turn contribute to post-operative morbidity and mortality. Intensive insulin therapy for POHG is often ineffective and may even worsen patient outcomes. Non-invasive focused ultrasound stimulation (FUS) of glucose-sensing abdominal neurons improves glucose metabolism in animal models of diabetes, but its potential role in treating POHG remains unknown. In this study, we explored whether FUS of the superior mesenteric plexus (SMP) alters insulin sensitivity and post-operative fasting blood glucose (FBG) in a swine model of surgical stress-induced POHG. In each of 3 anesthetized animals, FUS targeting the porta hepatis (PH) of the liver or the SMP was delivered and insulin sensitivity was assessed in each case. In another series of experiments, 4 animals received SMP-FUS and 3 sham stimulation, after which surgical stress was induced via small bowel resection. In the 7 surgically operated animals, insulin sensitivity was measured before and after SMP-FUS (or sham), and fasting blood glucose (FBG) was measured before and 16 h after surgery. In all animals, insulin sensitivity was assessed using the hyperinsulinemic-euglycemic clamp (HEC) method. Results: SMP-FUS elicits a greater increase in insulin sensitivity than PH-FUS. On the day of surgery, SMP-FUS increases insulin sensitivity, compared to sham treatment. The day after surgery, surgically operated animals develop mild hyperglycemia. SMP-FUS-treated animals have higher FBG than sham-FUS-treated animals. No clear relationship is observed between FUS-induced changes in insulin sensitivity and next-day FBG. Conclusion: While SMP-FUS improves insulin sensitivity during surgery, it may exacerbate POHG.

Breast cancer (BC) is still the most diagnosed cancer for females with an increased focus on immunotherapy as a promising precise treatment. Selecting appropriate patients and monitoring patient treatments are crucial to ensure higher response rates with low adverse events. Various biomarkers were proposed to predict immunotherapy response, including tumor mutation burden, immune cell, and tumor microenvironment expression. However, traditional methods for evaluating immunotherapy are invasive and inaccurate, and their assessments could be biased due to the variability in quantification techniques. Artificial intelligence (AI) has emerged as a powerful technology that addresses these challenges, handling heterogeneous data to identify complex patterns and offering accurate and non-invasive solutions. In this paper, we review emerging AI-based models for immunotherapy prediction in BC using diverse biomarkers. We first discussed the application of AI models for each biomarker, highlighting both direct prediction of immunotherapy response and prognosis, as well as indirect approaches via the identification of immune subtypes or specific predictive biomarkers. Then, we investigated the integration of all biomarkers in multi-modal AI approaches for a precise and personalized prediction of immunotherapy response. We have also addressed the implication of integrating AI in the healthcare ecosystem with other new technologies, including nanodevices, and wearable technologies. We further elucidated the role of AI and healthcare providers with this convergence of personalized medicine and demonstrated its role in enhancing population health management and supporting personalized patient care.

Background: Epilepsia partialis continua (EPC) is a medication-resistant form of focal status epilepticus (SE), causing significant morbidity. This case series explored whether continuous theta burst stimulation (cTBS) could reduce seizure activity in patients with EPC.

Methods: Three patients with motor EPC (2M/1F) underwent an accelerated cTBS protocol over four consecutive days (five 40-s trains/day, 5Hz bursts, 3 pulses at 50Hz/burst). Stimulation targeted the epileptogenic zone using a figure-of-eight coil at 80% of the resting motor threshold. Electroencephalography (EEG) was conducted before and after each session. Seizure frequency, intensity, adverse events (AEs), seizure diaries, and follow-up data were assessed.

Results: cTBS did not interrupt EPC in any patient. One patient reported a 17% reduction in seizure frequency. Another noted mild improvement in shoulder jerks, and a third reported reduced arm tension, though without clinical confirmation. EEG showed no significant changes. One patient experienced seizures during stimulation, and another reported worsening of pre-existing headaches.

Conclusion: In this small case series, a four-day accelerated cTBS protocol did not yield clinically meaningful seizure control in EPC. Further research is needed to evaluate TMS and TBS in SE and EPC, where a significant treatment gap remains.

Background: Previous efforts to translate vagus nerve stimulation (VNS) therapies from preclinical studies to human clinical applications (e.g., for stroke, heart failure, and inflammatory diseases) did not account for individual- or species-specific differences in nerve responses when selecting stimulation parameters. Lack of explicit consideration for producing equivalent nerve responses could contribute to clinical outcomes not replicating promising results from preclinical animal studies.

Methods: We used models of VNS built with ASCENT (Musselman, PLoS Comput Biol 17:e1009285, 2021) to quantify nerve responses across species and simulate translation of VNS therapies via either recycling or linear scaling of stimulation parameters. For humans (n = 9) and pigs (n = 12), we used previously validated computational models with the standard clinical helical cuff electrode on individual-specific nerve morphologies (Musselman, J Neural Eng 20:acda64, 2023b). We also modeled rat VNS (n = 9) with the Micro-Leads Neuro bipolar cuff. We calculated thresholds for fiber activation (A-, B-, and C-fibers) with biphasic rectangular pulses (0.13, 0.25, 0.5 ms). We defined "K" as the ratio of activation thresholds between a pair of individuals. We used a mixed model ANOVA on the natural logarithm of K to test for differences in inter-species Ks across fiber types and pulse widths. Lastly, using the same nerve morphologies and application-specific device design (cuff and waveform), we developed models to predict nerve responses in chronic human and rat VNS studies for treatment of stroke, inflammation, and heart failure.

Results: Depending on the individual and species, the activation amplitude required to produce a given nerve response varied widely. Thus, applying the same VNS parameters across individuals within a species produced a large range of nerve responses. Further, applying the same or linearly scaled stimulation amplitudes across species also produced highly variable responses. Ks were greater for B fibers than A fibers (p < 0.0001) and decreased with longer pulse widths (p < 0.0001 between consecutive pairs).

Conclusions: The results highlight the need for systematic approaches to select stimulation parameters that account for individual- and species-specific differences in nerve responses to stimulation. Such parameter tuning may lead to higher response rates and greater therapeutic benefits from VNS therapies.

Over a third of the global population is affected by obesity, fatty liver disease (Metabolic Dysfunction-Associated Steatotic Liver Disease, MASLD), and its severe form, MASH (Metabolic Dysfunction-Associated Steatohepatitis), which can ultimately progress to hepatocellular carcinoma (HCC). Recent advancements include therapeutics such as glucagon-like peptide 1 (GLP-1) agonists and neural/vagal modulation strategies for these disorders. Among the many pathways regulating these conditions, emerging insights into transforming growth factor-β (TGF-β) signaling highlight potential future targets through its role in pathophysiological processes such as adipogenesis, inflammation, and fibrosis. Vagus nerve innervation in the gastrointestinal tract is involved in satiety regulation and energy homeostasis, and vagus nerve stimulation has been applied in weight loss and diabetes. This review explores clinical trials in obesity, novel therapeutic targets, and the role of TGF-β signaling and vagus nerve modulation in obesity-related liver diseases and HCC.

Background: Preclinical 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.

Methods: Patients with complete transection of a proper digital nerve were included in the trial. An investigational version of PeriPulse^TM 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.

Results: A 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.

Conclusions: The use of the PeriPulse^TM 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.

Low intensity, trans-spinal focused ultrasound (tsFUS) is a noninvasive neuromodulation approach that has been shown to modulate spinal circuit excitability in healthy rats. Here, we evaluated the potential of tsFUS for alleviating neuropathic pain by testing it in a chronic constriction injury (CCI) model. Male rats underwent CCI of the left sciatic nerve and then received tsFUS (2 kHz pulse repetition frequency; 40% duty cycle) or sham stimulation, targeted at spinal segment level L5 for 3 min daily over three days. As expected, CCI causes significant reduction of von Frey Threshold (vFT), a measure of mechanical sensitivity. We found that tsFUS treatment is associated with increased vFT compared to sham; this increase persists beyond the duration of treatment, through days 4 to 23 post-CCI. In spinal cords of tsFUS-treated animals, counts of spinal microglia (Iba1 + cells) and of activated, pro-inflammatory microglia (Iba1 + /CD86 + cells), are reduced compared to sham-treated animals. This reduction in microglia counts is limited to the insonified side of the spinal cord, ipsilateral to CCI. These findings suggest that tsFUS may be a promising approach for treatment of neuropathic pain at early stages, possibly by attenuating the development of microglial-driven inflammation.

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.

Implanted neural interfaces are electronic devices that stimulate or record from neurons with the purpose of improving the quality of life of people who suffer from neural injury or disease. Devices have been designed to interact with neurons throughout the body to treat a growing variety of conditions. The development and use of implanted neural interfaces is increasing steadily and has shown great success, with implants lasting for years to decades and improving the health and quality of life of many patient populations. Despite these successes, implanted neural interfaces face a multitude of challenges to remain effective for the lifetime of their users. The devices are comprised of several electronic and mechanical components that each may be susceptible to failure. Furthermore, implanted neural interfaces, like any foreign body, will evoke an immune response. The immune response will differ for implants in the central nervous system and peripheral nervous system, as well as over time, ultimately resulting in encapsulation of the device. This review describes the challenges faced by developers of neural interface systems, particularly devices already in use in humans. The mechanical and technological failure modes of each component of an implant system is described. The acute and chronic reactions to devices in the peripheral and central nervous system and how they affect system performance are depicted. Further, physical challenges such as micro and macro movements are reviewed. The clinical implications of device failures are summarized and a guide for determining the severity of complication was developed and provided. Common methods to diagnose and examine mechanical, technological, and biological failure modes at various stages of development and testing are outlined, with an emphasis on chronic in vivo characterization of implant systems. Finally, this review concludes with an overview of some of the innovative solutions developed to reduce or resolve the challenges faced by implanted neural interface systems.