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We recently showed that vestibular stimulation can produce a long-lasting alleviation of motor features in Parkinson's disease. Here we investigated whether components of the motor related cortical response that are commonly compromised in Parkinson's - the Bereitschaftspotential and mu-rhythm event-related desynchronization - are modulated by concurrent, low frequency galvanic vestibular stimulation (GVS) during repetitive limb movement amongst 17 individuals with idiopathic Parkinson's disease. Relative to sham, GVS was favourably associated with higher amplitudes during the late and movement phases of the Bereitschaftspotential and with a more pronounced decrease in spectral power within the mu-rhythm range during finger-tapping. These data increase understanding of how GVS interacts with the preparation and execution of voluntary movement and give added impetus to explore its therapeutic effects on Parkinsonian motor features., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Novel stimulation methods are needed to overcome the limitations of contemporary cochlear implants. Optogenetics is a technique that confers light sensitivity to neurons via the genetic introduction of light-sensitive ion channels. By controlling neural activity with light, auditory neurons can be activated with higher spatial precision. Understanding the behaviour of opsins at high stimulation rates is an important step towards their translation. To elucidate this, we compared the temporal characteristics of auditory nerve and inferior colliculus responses to optogenetic, electrical, and combined optogenetic-electrical stimulation in virally transduced mice expressing one of two channelrhodopsins, ChR2-H134R or ChIEF, at stimulation rates up to 400 pulses per second (pps). At 100 pps, optogenetic responses in ChIEF mice demonstrated higher fidelity, less change in latency, and greater response stability compared to responses in ChR2-H134R mice, but not at higher rates. Combined stimulation improved the response characteristics in both cohorts at 400 pps, although there was no consistent facilitation of electrical responses. Despite these results, day-long stimulation (up to 13 h) led to severe and non-recoverable deterioration of the optogenetic responses. The results of this study have significant implications for the translation of optogenetic-only and combined stimulation techniques for hearing loss., (© 2024. The Author(s).)

Objective. In neural electrical stimulation, safe stimulation guidelines are essential to deliver efficient treatment while avoiding neural damage and electrode degradation. The widely used Shannon's limit, k , gives conditions on the stimulation parameters to avoid neural damage, however, underlying damage mechanisms are not fully understood. Moreover, the translation from bench testing to in vivo experiments still presents some challenges, including the increased polarisation observed, which may influence charge-injection mechanisms. In this work, we studied the influence on damage mechanisms of two electrolyte parameters that are different in vivo compared to usual bench tests: solution pH and electrolyte gelation. Approach. The potential of a platinum macroelectrode was monitored in a three-electrode setup during current-controlled biphasic charge-balanced cathodic-first pulse trains. Maximum anodic and cathodic potential excursions during pulse trains were projected on cyclic voltammograms to infer possible electrochemical reactions. Main results. In unbuffered saline of pH ranging from 1 to 12, the maximum anodic potential was systematically located in the oxide formation region, while the cathodic potential was located the molecular oxygen and oxide reduction region when k approached Shannon's damage limit, independent of solution pH. The results support the hypothesis that Shannon's limit corresponds to the beginning of platinum dissolution following repeated cycles of platinum oxidation and reduction, for which the cathodic excursion is a key tipping point. Despite similar potential excursions between solution and gel electrolytes, we found a joint influence of pH and gelation on the cathodic potential alone, while we observed no effect on the anodic potential. We hypothesise that gelation creates a positive feedback loop exacerbating the effects of pH ; however, the extent of that influence needs to be examined further. Significance. This work supports the hypothesis of charge injection mechanisms associated with stimulation-induced damage at platinum electrodes. The validity of a major hypothesis explaining stimulation-induced damage was tested and supported on a range of electrolytes representing potential electrode environments, calling for further characterisation of platinum dissolution during electrical stimulation in various testing conditions., (Creative Commons Attribution license.)

Background and Aims: The spleen serves as an important relay organ that releases cardioprotective factor(s) upon vagal activation during remote ischaemic conditioning (RIC) in rats and pigs. The translation of these findings to humans was attempted., Methods: Remote ischaemic conditioning or electrical auricular tragus stimulation (ATS) were performed in 10 healthy young volunteers, 10 volunteers with splenectomy, and 20 matched controls. Venous blood samples were taken before and after RIC/ATS or placebo, and a plasma dialysate was infused into isolated perfused rat hearts subjected to global ischaemia/reperfusion., Results: Neither left nor right RIC or ATS altered heart rate and heart rate variability in the study cohorts. With the plasma dialysate prepared before RIC or ATS, respectively, infarct size (% ventricular mass) in the recipient rat heart was 36 ± 6% (left RIC), 34 ± 3% (right RIC) or 31 ± 5% (left ATS), 35 ± 5% (right ATS), and decreased with the plasma dialysate from healthy volunteers after RIC or ATS to 20 ± 4% (left RIC), 23 ± 6% (right RIC) or to 19 ± 4% (left ATS), 26 ± 9% (right ATS); infarct size was still reduced with plasma dialysate 4 days after ATS and 9 days after RIC. In a subgroup of six healthy volunteers, such infarct size reduction was abrogated by intravenous atropine. Infarct size reduction by RIC or ATS was also abrogated in 10 volunteers with splenectomy, but not in their 20 matched controls., Conclusions: In humans, vagal innervation and the spleen as a relay organ are decisive for the cardioprotective signal transduction of RIC and ATS., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Abstract: In humans and animals, high-frequency electrocutaneous stimulation (HFS) induces an "early long-term potentiation-like" sensitisation, where synaptic plasticity is underpinned by an ill-defined interaction between peripheral input and central modulatory processes. The relative contributions of these processes to the initial pain or nociceptive response likely differ from those that underpin development of the heightened response. To investigate the impact of HFS-induced hyperalgesia on pain and nociception in perception and neural terms, respectively, and to explore the impact of descending inhibitory pathway activation on the development of HFS-induced hyperalgesia, we performed parallel studies utilising identical stimuli to apply HFS concurrent to (1) a conditioned pain modulation paradigm during psychophysical testing in healthy humans or (2) a diffuse noxious inhibitory controls paradigm during in vivo electrophysiological recording of spinal neurones in healthy anaesthetised rats. High-frequency electrocutaneous stimulation alone induced enhanced perceptual responses to pinprick stimuli in cutaneous areas secondary to the area of electrical stimulation in humans and increased the excitability of spinal neurones which exhibited stimulus intensity-dependent coded responses to pinprick stimulation in a manner that tracked with human psychophysics, supporting their translational validity. Application of a distant noxious conditioning stimulus during HFS did not alter perceived primary or secondary hyperalgesia in humans or the development of primary or secondary neuronal hyperexcitability in rats compared with HFS alone, suggesting that, upon HFS-response initiation in a healthy nervous system, excitatory signalling escapes inhibitory control. Therefore, in this model, dampening facilitatory mechanisms rather than augmenting top-down inhibitions could prevent pain development., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Muscle sympathetic nerve responses to sudden sensory stimuli have been elucidated in several studies on young healthy men, showing reproducible interindividual differences ranging from varying degrees of inhibition to no significant change, with very few subjects showing significant excitation. These individual response patterns have been shown to predict the neural response to mental stress and coupled blood pressure responses. The aim of this study was to investigate whether premenopausal healthy women show similar neural and blood pressure responses. Muscle sympathetic nerve recordings from the peroneal nerve were performed in 34 healthy women (mean age 27 ± 8 yr) during sudden sensory stimuli (electrical stimuli to a finger) and 3 min of mental stress (forced arithmetics). After sensory stimuli, 18 women showed varying degrees of inhibition of muscle sympathetic nerve activity (burst amplitude mean reduction 60%, range 34-100%). The remaining 16 showed no inhibition (mean 5%, range -31 to 28%; one subject exhibiting excitation). During 3 min of mental stress, the normalized change in burst incidence for muscle sympathetic nerve activity correlated with the percentage change of muscle sympathetic nerve activity induced by the sensory stimulation protocol (r = 0.64, P = 0.0042). In contrast to men, the neural responses did not predict changes in blood pressure. Thus, premenopausal females show a similar range of individual differences in defense-related muscle sympathetic neural responses as men, but no associated differences in blood pressure responses. Whether these patterns are unchanged after menopause remains to be investigated. NEW & NOTEWORTHY Muscle sympathetic neural responses to sudden sensory stimuli in premenopausal women showed interindividual differences and the distribution of sympathetic responses was similar to that previously found in men. Despite this similarity, the associated differences in transient blood pressure responses seen in men were not found in women. The increased risk of developing hypertension in postmenopausal women warrants an investigation of whether these response patterns are altered after menopause.

Impaired pharyngeal sensing of negative pressure (NP) can lead to a blunted response of the upper airway dilator muscles and contribute to the development of obstructive sleep apnea (OSA). This response is modulated by the nerve fibers in the internal branch of the superior laryngeal nerve (iSLN), mediating negative pressure sensation. Artificial excitation of these fibers could be a potential treatment target for OSA. To evaluate this, electrostimulation of the iSLN was performed in a porcine-isolated upper airway model. Artificial obstructions were induced by varying the levels of negative pressure, and the ability of the animal to resolve these obstructions was evaluated. The pressure at which the animal was still able to resolve the obstruction was quantified as "Resolvable Pressure." Thereby, the effects on pharyngeal patency ( n = 35) and the duration of the therapeutic effect outlasting the stimulation ( n = 6) were quantified. Electrostimulation before the introduction of an artificial obstruction improved the median resolvable pressure from -28.3 cmH 2 O [IQR: -45.9; -26.1] to -92.6 cmH 2 O [IQR: -105.1; -78.6]. The median therapeutic effect was found to outlast the last stimulation burst applied by 163 s when five stimulation bursts were applied in short succession [IQR: 58; 231], 58 s when two were applied [IQR: 7; 65], and 6 s when one was applied [IQR: 0; 51]. Stimulation of the iSLN increased electromyography (EMG) in the genioglossus (GG). The proposed treatment concept can improve pharyngeal patency in the model. Transfer of the results to clinical application could enable the development of a new neuromodulation therapy for OSA. NEW & NOTEWORTHY Electrostimulation before the introduction of an artificial obstruction to induce artificial sleep apnea in the pig model improves the response of the upper airway to negative pressure (NP). The electrostimulation creates a sustained therapeutic effect that outlasts the initial electrostimulation. The use of this therapy in clinical practice has the potential to treat obstructive sleep apnea (OSA).

The restoration of adequate function and sensation in nerves following an injury is often insufficient. Electrical stimulation (ES) applied during nerve repair can promote axon regeneration, which may enhance the likelihood of successful functional recovery. However, increasing operation time and complexity are associated with limited clinical use of ES. This study aims to better assess whether short-duration ES types (voltage mode vs. current mode) are able to produce enhanced regenerative activity following peripheral nerve repair in rat models. Wistar rats were randomly divided into 3 groups: no ES (control), 30-minute ES with a current pulse, and 30-minute ES with a voltage pulse. All groups underwent sciatic nerve transection and repair using a silicone tube to bridge the 6-mm gap between the stumps. In the 2 groups other than the control, ES was applied after the surgical repair. Outcomes were evaluated using electrophysiology, histology, and serial walking track analysis. Biweekly walking tracks test over 12 weeks revealed that subjects that underwent ES experienced more rapid functional improvement than subjects that underwent repair alone. Electrophysiological analysis of the newly intratubular sciatic nerve at week 12 revealed strong motor function recovery in rats that underwent 30-minute ES. Histologic analysis of the sciatic nerve and its tibial branch at 12 weeks demonstrated robust axon regrowth in all groups. Both types of short-duration ES applied during nerve repair can promote axon regrowth and enhance the chances of successful functional recovery., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Tissue stimulations greatly affect cell growth, phenotype, and function, and they play an important role in modeling tissue physiology. With the goal of understanding the cellular mechanisms underlying the response of tissues to external stimulations, in vitro models of tissue stimulation have been developed in hopes of recapitulating in vivo tissue function., Methods: Herein we review the efforts to create and validate tissue stimulators responsive to electrical or mechanical stimulation including tensile, compression, torsion, and shear., Results: Engineered tissue platforms have been designed to allow tissues to be subjected to selected types of mechanical stimulation from simple uniaxial to humanoid robotic stain through equal-biaxial strain. Similarly, electrical stimulators have been developed to apply selected electrical signal shapes, amplitudes, and load cycles to tissues, lending to usage in stem cell-derived tissue development, tissue maturation, and tissue functional regeneration. Some stimulators also allow for the observation of tissue morphology in real-time while cells undergo stimulation. Discussion on the challenges and limitations of tissue simulator development is provided., Conclusions: Despite advances in the development of useful tissue stimulators, opportunities for improvement remain to better reproduce physiological functions by accounting for complex loading cycles, electrical and mechanical induction coupled with biological stimuli, and changes in strain affected by applied inputs., (© 2024 International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

The aim of this study was to determine whether brushing rams before and during electroejaculation (EE) reduces their stress response and improves the characteristics of the ejaculate. A single person brushed each ram for 5 min daily, for 15 days, in an individual pen. Semen was collected from five rams brushed before and during EE by the same brusher, while the other five were electroejaculated without being brushed. The treatments were exchanged three days later, so semen was collected from all the rams with both treatments. Brushing increased mass motility (P = 0.05), and curvilinear (P = 0.001), linear (P = 0.02), and average path (P = 0.01) velocities of sperm, as well as the average amplitude of lateral displacement of the sperm head (P = 0.05), and tended to increase sperm concentration (P = 0.09). Brushing tended to reduce the cortisol concentration (P = 0.06) and the duration of head movements when 2 V pulse series V was applied (P = 0.1). Brushing increased creatine kinase concentration (P = 0.04) and tended to increase rectal (P = 0.06) and maximum eye surface temperatures (P = 0.1), total time, and number of electrical pulses administered (P = 0.07 for both variables), as well as the sum of pulses per voltage applied during EE (P = 0.06). In rams accustomed to being brushed by the same person, brushing them before and during EE improved semen quality, with slight changes in the stress responses., Competing Interests: Declaration of Competing Interest Authors have no conflict of interest, (Copyright © 2024 Elsevier B.V. All rights reserved.)

Electrical stimulation (ES) has a remarkable capacity to regulate neuronal differentiation and neurogenesis in the treatment of various neurological diseases. However, wired devices connected to the stimulating electrode and the mechanical mismatch between conventional rigid electrodes and soft tissues restrict their motion and cause possible infections, thereby limiting their clinical utility. An approach integrating the advantages of wireless techniques and soft hydrogels provides new insights into ES-induced nerve regeneration. Herein, a flexible and implantable wireless ES-responsive electrode based on an annular gelatin methacrylate-polyaniline (Gel/Pani) hydrogel is fabricated and used as a secondary coil to achieve wireless ES via electromagnetic induction in the presence of a primary coil. The Gel/Pani hydrogels exhibit favorable biocompatibility, biodegradability, conductivity, and compression resistance. The annular electrode of the Gel/Pani conductive hydrogel (AECH) supports neural stem cell growth, while the applied wireless ES facilitates neuronal differentiation and the formation of functional neural networks in vitro. Furthermore, AECH is implanted in vivo in rats with ischemic stroke and the results reveal that AECH-mediated wireless ES significantly ameliorates brain impairment and neurological function by activating endogenous neurogenesis. This novel flexible hydrogel system addresses wireless stimulation and implantable technical challenges, holding great potential for the treatment of neurodegenerative diseases., (© 2024 Wiley‐VCH GmbH.)

Background:  We previously reported that normalization of motor evoked potential (MEP) monitoring amplitude by compound muscle action potential (CMAP) after peripheral nerve stimulation prevented the expression of anesthetic fade (AF), suggesting that AF might be due to reduced synaptic transfer in the neuromuscular junction., Methods:  We calculated the time at which AF began for each of craniotomy and spinal cord surgery, and examined whether AF was avoided by CMAP after peripheral nerve stimulation normalization in each. Similar studies were also made with respect to the upper and lower limb muscles., Results:  AF was observed in surgery lasting 160 minutes for craniotomy and 260 minutes or more for spinal surgery, and 195 minutes in the upper limb muscles and 135 minutes in the lower limb muscles. In all the series, AF could be avoided by CMAP after peripheral nerve stimulation normalization., Conclusion:  AF of MEP occurred in both craniotomy and spinal cord surgery, and it was also corrected by CMAP after peripheral nerve stimulation. AF is considered to be mainly due to a decrease in synaptic transfer of the neuromuscular junction due to the accumulation of propofol because of the avoidance by CMAP normalization. However, it may be partially due to a decrease in the excitability of pyramidal tracts and α-motor neurons, because AF occurred earlier in the lower limb muscles than in the upper limb muscles., Competing Interests: None declared., (Thieme. All rights reserved.)

Objective: This study aimed at investigating the effect of median nerve stimulation on ipsilateral cortical potentials evoked by contralateral median nerve electrical stimulation., Methods: We recorded somatosensory-evoked potentials (SEPs) from the left parietal cortex in 15 right-handed, healthy subjects. We administered bilateral median nerve stimulation, with the ipsilateral stimulation preceding the stimulation on the contralateral by intervals of 5, 10, 20, or 40 ms. We adjusted these intervals based on each individual's N20 latency. As a measure of S1 excitability, the amplitude of the N20 and the area of the High Frequency Oscillation (HFO) burst were analyzed for each condition., Results: The results revealed significant inhibition of N20 amplitude by ipsilateral median nerve stimulation at interstimulus intervals (ISIs) between 5 and 40 ms. Late HFO burst was suppressed at short ISIs of 5 and 10 ms, pointing to a transcallosal inhibitory effect on S1 intracortical circuits., Conclusions: Findings suggest interhemispheric interaction between the primary somatosensory areas, supporting the existence of transcallosal transfer of tactile information., Significance: This study provides valuable insights into the interhemispheric connections between primary sensory areas and underscore the potential role of interhemispheric interactions in somatosensory processing., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Purpose: Despite its susceptibility to muscle fatigue, combined neuromuscular electrical stimulation (NMES) and blood flow restriction (BFR) are effective regimens for managing muscle atrophy when traditional resistance exercises are not feasible. This study investigated the potential of low-level laser therapy (LLLT) in reducing muscle fatigue after the application of combined NMES and BFR., Methods: Thirty-six healthy adults were divided into control and LLLT groups. The LLLT group received 60 J of 850-nm wavelength LLLT before a training program of combined NMES and BFR of the nondominant extensor carpi radialis longus (ECRL). The control group followed the same protocol but received sham laser therapy. Assessments included maximal voluntary contraction, ECRL mechanical properties, and isometric force tracking for wrist extension., Results: The LLLT group exhibited a smaller normalized difference in maximal voluntary contraction decrement (-4.01 ± 4.88%) than the control group (-23.85 ± 7.12%) ( P < 0.001). The LLLT group demonstrated a smaller decrease in muscle stiffness of the ECRL compared with the control group, characterized by the smaller normalized changes in frequency ( P = 0.002), stiffness ( P = 0.002), and relaxation measures ( P = 0.011) of mechanical oscillation waves. Unlike the control group, the LLLT group exhibited a smaller posttest increase in force fluctuations during force tracking ( P = 0.014), linked to the predominant recruitment of low-threshold MU ( P < 0.001) without fatigue-related increases in the discharge variability of high-threshold MU ( P > 0.05)., Conclusions: LLLT preexposure reduces fatigue after combined NMES and BFR, preserving force generation, muscle stiffness, and force scaling. The functional benefits are achieved through fatigue-resistant activation strategies of motor unit recruitment and rate coding., (Copyright © 2024 by the American College of Sports Medicine.)

Identification of seizure sources in the brain is of paramount importance, particularly for drug-resistant epilepsy patients who may require surgical operation. Interictal epileptiform discharges (IEDs), which may or may not be frequent, are known to originate from seizure networks. Delayed responses (DRs) to brain electrical stimulation have been recently discovered. If DRs and IEDs come from the same location and the DRs can be accurately localized, there will be a significant step in identification of the seizure sources. The solution to this important question has been investigated in this paper. For this, we have exploited the morphology of these spike-type events, as well as the variability in their temporal locations, to develop new constraints for an adaptive Bayesian beamformer that outperforms the conventional and recently proposed beamformers even for identifying correlated sources. This beamformer is applied to an array (a.k.a mat) of cortical EEG electrodes. The developed approach has been tested on 300 data segments from five epileptic patients included in this study, which clinically represent a large population of candidates for surgical treatment. As the significant outcome of applying this beamformer, it is very likely (if not certain) that for an epileptic subject, the IEDs and DRs originate from the same location in the brain. This paves the way for a quick identification of the source(s) of seizure in the brain.

The human vestibular system is adversely affected by the aging process. Recent evidence indicates that vestibular information and cognitive functions are related, suggesting that age-related vestibular loss may contribute to cognitive impairment. In this study, we aimed to investigate the effects of repetitive, home-based galvanic vestibular stimulation (GVS) on cognitive functions in healthy older adults. Twenty-one participants (age = 64.66 ± 2.97 years, 12 females) were randomly allocated to either a home-based GVS or an active control group. The GVS intervention lasted 20 min per session, five times a week, for two weeks (10 sessions). Cognitive functions were assessed before and after the intervention using the Stroop Test, Trail Making Test A&B, and Dual-Task (digit recall and paper-pencil tracking test). Our findings revealed a significant group-by-time interaction effect for the tracking accuracy (F(1,18) = 7.713, p = 0.012, η p 2  = 0.30), with only the home-based GVS group showing significant improvement (t = -2.544, p = 0.029). The proposed home-based GVS protocol offers a promising non-pharmacological avenue for enhancing visuospatial ability in healthy older adults. Further research is needed to investigate the effects of different GVS protocols on various cognitive functions, particularly in older individuals with different health conditions., Competing Interests: Declaration of competing interest The authors report there are no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Peripheral neuromodulation has emerged as a powerful modality for controlling physiological functions and treating a variety of medical conditions including chronic pain and organ dysfunction. The underlying complexity of the nonlinear responses to electrical stimulation make it challenging to design precise and effective neuromodulation protocols. Computational models have thus become indispensable in advancing our understanding and control of neural responses to electrical stimulation. However, existing approaches suffer from computational bottlenecks, rendering them unsuitable for real-time applications, large-scale parameter sweeps, or sophisticated optimization. In this work, we introduce an approach for massively parallel estimation and optimization of neural fiber responses to electrical stimulation using machine learning techniques. By leveraging advances in high-performance computing and parallel programming, we present a surrogate fiber model that generates spatiotemporal responses to a wide variety of cuff-based electrical peripheral nerve stimulation protocols. We used our surrogate fiber model to design stimulation parameters for selective stimulation of pig and human vagus nerves. Our approach yields a several-orders-of-magnitude improvement in computational efficiency while retaining generality and high predictive accuracy, demonstrating its robustness and potential to enhance the design and optimization of peripheral neuromodulation therapies., (© 2024. The Author(s).)

Background: Galvanic Vestibular Stimulation (GVS) is a non-invasive electrical stimulation technique that is typically used to probe the vestibular system. When using direct current or very low frequency sine, GVS causes postural sway or perception of illusory (virtual) motions. GVS is commonly delivered using two electrodes placed at the mastoids, however, placements involving additional electrodes / locations have been employed. Our objective was to systematically evaluate all known GVS electrode placements, compare induced current flow, and how it relates to the archetypal sway and virtual motions. The ultimate goal is to help users in having a better understanding of the effects of different placements., Methods: We simulated seven GVS electrode placements with same total injected current using an ultra-high resolution model. Induced electric field (EF) patterns at the cortical and the level of vestibular organs (left and right) were determined. A range of current flow metrics including potential factors such as inter-electrode separation, percentage of current entering the cranial cavity, and symmetricity were calculated. Finally, we relate current flow to reported GVS motions., Results: As expected, current flow patterns are electrode placement specific. Placements with two electrodes generally result in higher EF magnitude. Placements with four electrodes result in lower percentage of current entering the cranial cavity. Symmetric placements do not result in similar EF values in the left and the right organs respectively- highlighting inherent anatomical asymmetry of the human head. Asymmetric placements were found to induce as much as ~3-fold higher EF in one organ over the other. The percentage of current entering the cranial cavity varies between ~15% and ~40% depending on the placement., Conclusions: We expect our study to advance understanding of GVS and provide insight on probable mechanism of action of a certain electrode placement choice. The dataset generated across several metrics will support hypothesis testing relating empirical outcomes to current flow patterns. Further, the differences in current flow will guide stimulation strategy (what placement and how much scalp current to use) and facilitate a quantitatively informed rational / optimal decision., Competing Interests: DQT, CT, SI, YV, and AD are employees of Soterix Medical. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Truong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Individuals with motor dysfunction caused by damage to the central nervous system are unable to transmit voluntary movement commands to their muscles, resulting in a reduced ability to control their limbs. However, traditional rehabilitation methods have problems such as long treatment cycles and high labor costs. Functional electrical stimulation (FES) based on brain-computer interface (BCI) connects the patient's intentions with muscle contraction, and helps to promote the reconstruction of nerve function by recognizing nerve signals and stimulating the moving muscle group with electrical impulses to produce muscle convulsions or limb movements. It is an effective treatment for sequelae of neurological diseases such as stroke and spinal cord injury. This article reviewed the current research status of BCI-based FES from three aspects: BCI paradigms, FES parameters and rehabilitation efficacy, and looked forward to the future development trend of this technology, in order to improve the understanding of BCI-based FES.

Theta-burst stimulation (TBS), a patterned brain stimulation technique that mimics rhythmic bursts of 3-8 Hz endogenous brain rhythms, has emerged as a promising therapeutic approach for treating a wide range of brain disorders, though the neural mechanism of TBS action remains poorly understood. We investigated the neural effects of TBS using intracranial EEG (iEEG) in 10 pre-surgical epilepsy participants undergoing intracranial monitoring. Here we show that individual bursts of direct electrical TBS at 29 frontal and temporal sites evoked strong neural responses spanning broad cortical regions. These responses exhibited dynamic local field potential voltage changes over the course of stimulation presentations, including either increasing or decreasing responses, suggestive of short-term plasticity. Stronger stimulation augmented the mean TBS response amplitude and spread with more recording sites demonstrating short-term plasticity. TBS responses were stimulation site-specific with stronger TBS responses observed in regions with strong baseline stimulation effective (cortico-cortical evoked potentials) and functional (low frequency phase locking) connectivity. Further, we could use these measures to predict stable and varying (e.g. short-term plasticity) TBS response locations. Future work may integrate pre-treatment connectivity alongside other biophysical factors to personalize stimulation parameters, thereby optimizing induction of neuroplasticity within disease-relevant brain networks., (© 2024. The Author(s).)

Objective . Previous preclinical and clinical studies have demonstrated that pudendal nerve is a promising target for restoring bladder control. The spatial proximity between the pudendal nerve and its accompanying blood vessels in the pudendal canal provides an opportunity for endovascular neurostimulation, which is a less invasive approach compared to conventional chronically implanted electrodes. In this study, we investigated the feasibility of excitatory stimulation and kilohertz-frequency block of the compound pudendal nerve in sheep using a stent-mounted electrode array. Approach . In a set of acute animal experiments, a commercially available hexapolar electrode catheter was introduced in the unilateral internal pudendal artery to deliver bipolar electrical stimulation of the adjacent compound pudendal nerve. The catheter electrode was replaced with a custom-made stent-mounted electrode array and the stimulation sessions were repeated. Global electromyogram activity of the pelvic floor and related sphincter muscles was recorded with a monopolar electrode placed within the urethra concurrently. Main results . We demonstrated the feasibility of endovascular stimulation of the pudendal nerve with both electrode types. The threshold current of endovascular stimulation was influenced by electrode-nerve distance and electrode orientation. Increasing the axial inter-electrode distance significantly decreased threshold current. Endovascular kilohertz-frequency nerve block was possible with the electrode catheter. Significance . The present study demonstrated that endovascular stimulation of the pudendal nerve with the stent-mounted electrode array may be a promising less invasive alternative to conventional implantable electrodes, which has important clinical implications in the treatment of urinary incontinence. Endovascular blocking of pudendal nerve may provide an alternative solution to the bladder-sphincter dyssynergia problem in bladder management for people with spinal cord injury., (Creative Commons Attribution license.)

Objective. In recent years, the robot assisted (RA) rehabilitation training has been widely used to counteract defects of the manual one provided by physiotherapists. However, since the proprioception feedback provided by the robotic assistance or the manual methods is relatively weak for the paralyzed patients, their rehabilitation efficiency is still limited. In this study, a dynamic electrical stimulation (DES) based proprioception enhancement and the associated quantitative analysis methods have been proposed to overcome the limitation mentioned above. Approach. Firstly, the DES based proprioception enhancement method was proposed for the RA neural rehabilitation. In the method, the relationship between the surface electromyogram (sEMG) envelope of the specified muscle and the associated joint angles was constructed, and the electrical stimulation (ES) pulses for the certain joint angles were designed by consideration of the corresponding sEMG envelope, based on which the ES can be dynamically regulated during the rehabilitation training. Secondly, power spectral density, source estimation, and event-related desynchronization of electroencephalogram, were combinedly used to quantitatively analyze the proprioception from multiple perspectives, based on which more comprehensive and reliable analysis results can be obtained. Thirdly, four modes of rehabilitation training tasks, namely active, RA, DES-RA, and ES-only training, were designed for the comparison experiment and validation of the proposed DES based proprioception enhancement method. Main results. The results indicated that the activation of the sensorimotor cortex was significantly enhanced when the DES was added, and the cortex activation for the DES-RA training was similar to that for the active training. Meanwhile, relatively consistent results from the multiple perspectives were obtained, which validates the effectiveness and robustness of the proposed proprioception analysis method. Significance. The proposed methods have the potential to be applied in the practical rehabilitation training to improve the rehabilitation efficiency., (© 2024 IOP Publishing Ltd.)

Objective: Solute transport in the brain is essential for maintaining cerebral homeostasis. Recent studies have shown that neuronal activity enhances the transport of cerebrospinal fluid solutes, but its impact on interstitial solute transport has not been established. In this study, we investigated whether neuronal activity affects the transport of interstitial solutes., Methods: Fluorescent Texas Red ovalbumin was injected intracortically into the unilateral sensorimotor area of the Sprague-Dawley rats. Regional neuronal activity around the injection site was elicited by transdermal electrical stimulation of a corresponding forelimb for 90 min ( n  = 6). The control group of rats ( n  = 6) did not receive any electrical stimulation. Subsequently, the spatial distributions of the tracer over the cortical surface and from the brain sections were imaged and compared between two groups. The ovalbumin fluorescence from the cervical lymph nodes was also compared between the groups to evaluate the effect of neuronal activity on solute clearance from the brain., Results: Tracer distribution over the brain surface/sections revealed a significantly higher uptake of ovalbumin in the hemisphere ipsilateral to the injection among the stimulated animals compared to the unstimulated group. This difference, however, was not seen in the hemisphere contralateral to injection. A trace amount of ovalbumin in the lymph nodes was equivalent between the groups, which indicated a considerable time needed for interstitial solutes to be drained from the brain., Conclusion: The results suggest that neuronal activity enhances interstitial solute transport, calling for further examination of ultimate routes and mechanisms for brain solute clearance., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Electric fields affect the activity of neurons and brain circuits, yet how this happens at the cellular level remains enigmatic. Lack of understanding of how to stimulate the brain to promote or suppress specific activity significantly limits basic research and clinical applications. Here, we study how electric fields impact subthreshold and spiking properties of major cortical neuronal classes. We find that neurons in the rodent and human cortex exhibit strong, cell-class-dependent entrainment that depends on stimulation frequency. Excitatory pyramidal neurons, with their slower spike rate, entrain to both slow and fast electric fields, while inhibitory classes like Pvalb and Sst (with their fast spiking) predominantly phase-lock to fast fields. We show that this spike-field entrainment is the result of two effects: non-specific membrane polarization occurring across classes and class-specific excitability properties. Importantly, these properties are present across cortical areas and species. These findings allow for the design of selective and class-specific neuromodulation., Competing Interests: Declaration of interests S.Y.L. has previously consulted for Starfish Neuroscience, Inc. C.A.A. and S.Y.L. are listed as inventors on a patent application related to this work. C.K. is a board member of and has a financial interest in Intrinsic Powers, Inc., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective . Normal function of the vestibular system can be disturbed using a noninvasive technique called electrical vestibular stimulation (EVS), which alters a person's sense of balance and causes false sensations of movement. EVS has been widely used to study the function of the vestibular system, and it has recently gained interest as a therapeutic tool to improve postural stability and help those suffering from vestibular dysfunction. Yet, understanding of how EVS stimulates the vestibular system, the current intensity needed to produce an effect and the frequencies at which it occurs have remained unclear. Approach . The effect of EVS on postural sway was examined in five participants using sinusoidal alternating current with time-varying amplitude from 0 to 1.5 mA and frequency from 0.1 to 10 Hz for three electrode configurations. Dosimetry of the current flow inside the head was conducted using anatomically realistic computational models created individually for each subject based on magnetic resonance imaging data. An estimate for the minimal field strength capable of affecting the vestibular system was calculated with the finite element method. Main results . Bipolar EVS at frequencies up to 10 Hz caused harmonic full-body swaying, and the frequency of the sway was the same as that of the stimulation current. The size of the sway was amplified by increasing the current intensity. Dosimetry modeling indicated that, for 0.2 mA current, the average electric field strength in the vestibular system was approximately 10-30 mV m -1 , depending on the electrode montage. The size of the measured postural sway was proportional to the montage-specific electric field strength in the vestibular system. Significance . The results provide insight to EVS's working mechanisms and improve its potential as a tool to study the sense of balance., (Creative Commons Attribution license.)

The consequences of short-term disuse are well known, but effective countermeasures remain elusive. This study investigated the effects of neuromuscular electrical stimulation (NMES) during 5 days of bed rest on retaining lower limb muscle mass and muscle function in healthy young and old participants. One leg received NMES of the quadriceps muscle (3 × 30min/day) (NMES), and the other served as a control (CON). Isometric quadriceps strength (MVC), rate of force development (RFD), lower limb lean mass, and muscle thickness were assessed pre-and post-intervention. Muscle thickness remained unaltered with NMES in young and increased in old following bed rest, while it decreased in CON legs. In old participants, mid-thigh lean mass (MTLM) was preserved with NMES while decreased in CON legs. In the young, only a tendency to change with bed rest was detected for MTLM. MVC and early-phase RFD decreased in young and old, irrespective of NMES. In contrast, late-phase RFD was retained in young participants with NMES, while it decreased in young CON legs, and in the old, irrespective of NMES. NMES during short-term bed rest preserved muscle thickness but not maximal muscle strength. While young and old adults demonstrated similar adaptive responses in preventing the loss of skeletal muscle thickness, RFD was retained in the young only., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Conventional electrophysiological methods, i.e. nerve conduction studies and electromyography are suitable methods for the diagnosis of neuromuscular disorders, however, they provide limited information about muscle fibre membrane properties and underlying disease mechanisms. Muscle excitability testing is a technique that provides in vivo information about muscle fibre membrane properties such as membrane potential and ion channel function. Since the 1960s, various methodologies have been suggested to examine muscle membrane properties but technical difficulties have limited its use. In 2009, an automated, fast and simple application, the so-called multi-fibre muscle velocity recovery cycles (MVRC) has accelerated the use of muscle excitability testing. Later, frequency ramp and repetitive stimulation protocols have been developed. Though this method has been used mainly in research for revealing disease mechanisms across a broad range of neuromuscular disorders, it may have additional diagnostic uses; value has been shown particularly in muscle channelopathies. This review will provide a description of the state-of-the art of methodological and clinical studies for muscle excitability testing., (Copyright © 2024 International Federation of Clinical Neurophysiology. All rights reserved.)

Background: Neuromuscular electrical stimulation (NMES) can generate muscle contractions and elicit excitability of neural circuits. However, the optimal stimulation frequency for effective neuromodulation remains unclear., Methods: Eleven able-bodied individuals participated in our study to examine the effects of: (1) low-frequency NMES at 25 Hz, (2) high-frequency NMES at 100 Hz; and (3) mixed-frequency NMES at 25 and 100 Hz switched every second. NMES was delivered to the right tibialis anterior (TA) muscle for 1 min in each condition. The order of interventions was pseudorandomized between participants with a washout of at least 15 min between conditions. Spinal reflexes were elicited using single-pulse transcutaneous spinal cord stimulation applied over the lumbar enlargement to evoke responses in multiple lower-limb muscles bilaterally and maximum motor responses (M max ) were elicited in the TA muscle by stimulating the common peroneal nerve to assess fatigue at the baseline and immediately, 5, 10, and 15 min after each intervention., Results: Our results showed that spinal reflexes were significantly inhibited immediately after the mixed-frequency NMES, and for at least 15 min in follow-up. Low-frequency NMES inhibited spinal reflexes 5 min after the intervention, and also persisted for at least 10 min. These effects were present only in the stimulated TA muscle, while other contralateral and ipsilateral muscles were unaffected. M max responses were not affected by any intervention., Conclusions: Our results indicate that even a short-duration (1 min) NMES intervention using low- and mixed-frequency NMES could inhibit spinal reflex excitability of the TA muscle without inducing fatigue., (© 2024 The Authors. Artificial Organs published by International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Background: Neuroprostheses are used to electrically stimulate the brain, modulate neural activity and restore sensory and motor function following injury or disease, such as blindness, paralysis, and other movement and psychiatric disorders. Recordings are often made simultaneously with stimulation, allowing the monitoring of neural signals and closed-loop control of devices. However, stimulation-evoked artifacts may obscure neural activity, particularly when stimulation and recording sites are nearby. Several methods have been developed to remove stimulation artifacts, but it remains challenging to validate and compare these methods because the 'ground-truth' of the neuronal signals may be contaminated by artifacts., New Method: Here, we delivered stimulation to the visual cortex via a high-channel-count prosthesis while recording neuronal activity and stimulation artifacts. We quantified the waveforms and temporal properties of stimulation artifacts from the cortical visual prosthesis (CVP) and used them to build a dataset, in which we simulated the neuronal activity and the stimulation artifacts. We illustrate how to use the simulated data to evaluate the performance of six software-based artifact removal methods (Template subtraction, Linear interpolation, Polynomial fitting, Exponential fitting, SALPA and ERAASR) in a CVP application scenario., Results: We here focused on stimulation artifacts caused by electrical stimulation through a high-channel-count cortical prosthesis device. We find that the Polynomial fitting and Exponential fitting methods outperform the other methods in recovering spikes and multi-unit activity. Linear interpolation and Template subtraction recovered the local-field potentials., Conclusion: Polynomial fitting and Exponential fitting provided a good trade-off between the quality of the recovery of spikes and multi-unit activity (MUA) and the computational complexity for a cortical prosthesis., Competing Interests: Declaration of Competing Interest F W declares no conflict of interests. P R and X C are co-founders and shareholders of a neurotechnology start-up, Phosphoenix BV (Netherlands) (https://phosphoenix.nl)., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The vagus nerve plays an important role in neuroimmune interactions and in the regulation of inflammation. A major source of efferent vagus nerve fibers that contribute to the regulation of inflammation is the brainstem dorsal motor nucleus of the vagus (DMN), as recently shown using optogenetics. In contrast to optogenetics, electrical neuromodulation has broad therapeutic implications. However, the anti-inflammatory effectiveness of electrical stimulation of the DMN (eDMNS) and the possible heart rate (HR) alterations associated with this approach have not been investigated. Here, we examined the effects of eDMNS on HR and cytokine levels in mice administered with lipopolysaccharide (LPS, endotoxin) and in mice subjected to cecal ligation and puncture (CLP) sepsis., Methods: Anesthetized male 8-10-week-old C57BL/6 mice on a stereotaxic frame were subjected to eDMNS using a concentric bipolar electrode inserted into the left or right DMN or sham stimulation. eDMNS (500, 250 or 50 μA at 30 Hz, for 1 min) was performed and HR recorded. In endotoxemia experiments, sham or eDMNS utilizing 250 μA or 50 μA was performed for 5 mins and was followed by LPS (0.5 mg/kg) i.p. administration. eDMNS was also applied in mice with cervical unilateral vagotomy or sham operation. In CLP experiments sham or left eDMNS was performed immediately post CLP. Cytokines and corticosterone were analyzed 90 mins after LPS administration or 24 h after CLP. CLP survival was monitored for 14 days., Results: Either left or right eDMNS at 500 μA and 250 μA decreased HR, compared with baseline pre-stimulation. This effect was not observed at 50 μA. Left side eDMNS at 50 μA, compared with sham stimulation, significantly decreased serum and splenic levels of the pro-inflammatory cytokine TNF and increased serum levels of the anti-inflammatory cytokine IL-10 during endotoxemia. The anti-inflammatory effect of eDMNS was abrogated in mice with unilateral vagotomy and was not associated with serum corticosterone alterations. Right side eDMNS in endotoxemic mice suppressed serum TNF and increased serum IL-10 levels but had no effects on splenic cytokines. In mice with CLP, left side eDMNS suppressed serum IL-6, as well as splenic IL-6 and increased splenic IL-10 and significantly improved the survival rate of CLP mice., Conclusions: For the first time we show that a regimen of eDMNS which does not cause bradycardia alleviates LPS-induced inflammation. These eDMNS anti-inflammatory effects require an intact vagus nerve and are not associated with corticosteroid alterations. eDMNS also decreases inflammation and improves survival in a model of polymicrobial sepsis. These findings are of interest for further studies exploring bioelectronic anti-inflammatory approaches targeting the brainstem DMN., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [VAP, SSC, and KJT have co-authored patents broadly related to the content of this paper. They have assigned their rights to the Feinstein Institutes for Medical Research. KJT also declares that he is a consultant to SetPoint Medical. RD is a member of the Scientific Advisory Board of GoodCap Pharma, Toronto, Ontario, Canada for work not related to the present study]., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective . The cochlear implant (CI) belongs to the most successful neuro-prostheses. Traditionally, the stimulating electrode arrays are inserted into the scala tympani (ST), the lower cochlear cavity, which enables simple surgical access. However, often deep insertion is blocked, e.g. by ossification, and the auditory nerve fibers (ANFs) of lower frequency regions cannot be stimulated causing severe restrictions in speech understanding. As an alternative, the CI can be inserted into the scala vestibuli (SV), the other upper cochlear cavity. Approach . In this computational study, the excitability of 25 ANFs are compared for stimulation with ST and SV implants. We employed a 3-dimensional realistic human cochlear model with lateral wall electrodes based on a μ -CT dataset and manually traced fibers. A finite element approach in combination with a compartment model of a spiral ganglion cell was used to simulate monophasic stimulation with anodic (ANO) and cathodic (CAT) pulses of 50 μ s. Main results . ANO thresholds are lower in ST (mean/std = μ / σ = 189/55 μ A) stimulation compared to SV ( μ / σ = 323/119 μ A) stimulation. Contrary, CAT thresholds are higher for the ST array ( μ / σ = 165/42 μ A) compared to the SV array ( μ / σ = 122/46 μ A). The threshold amplitude depends on the specific fiber-electrode spatial relationship, such as lateral distance from the cochlear axis, the angle between electrode and target ANF, and the curvature of the peripheral process. For CAT stimulation the SV electrodes show a higher selectivity leading to less cross-stimulation of additional fibers from different cochlear areas. Significance . We present a first simulation study with a human cochlear model that investigates an additional CI placement into the SV and its impact on the excitation behavior. Results predict comparable outcomes to ST electrodes which confirms that SV implantation might be an alternative for patients with a highly obstructed ST., (Creative Commons Attribution license.)

Introduction/aims: Previous studies have suggested that treatments targeting the neuromuscular junction (NMJ) may play a role in the treatment of amyotrophic lateral sclerosis (ALS). However, factors impacting repetitive nerve stimulation (RNS), a technique to evaluate NMJ function, have yet to be fully elucidated. We aimed to identify independent factors contributing to the decremental response of the accessory nerve and evaluated its value in ALS clinical practice., Methods: A total of 626 patients who were diagnosed with ALS and underwent 3 Hz RNS tests on the accessory nerve were enrolled. Data on their clinical and electrophysiological indicators were divided into a training set (collected from June 2016 to December 2022) and a test set (collected from January to August 2023). Stepwise regression was used in independent variable selection and model building., Results: Forty-two percent of patients had a decrement larger than 10% and 24% had a decrement larger than 15%. Onset age, sex, onset site, forced vital capacity (FVC) and motor unit potential (MUP) duration were independent factors contributing to the results of the RNS test. MUP duration had the greatest impact on decremental response, followed by FVC and onset age. The decremental response in females was larger than in males. Upper limb onset was found to contribute more to the decrement than lower limb or bulbar onset., Discussion: In patients with ALS, NMJ safety factor is reduced during re-innervation. Decremental response is affected by multiple factors, which needs to be considered in clinical trials targeting the NMJ in these patients., (© 2024 The Author(s). Muscle & Nerve published by Wiley Periodicals LLC.)

Objective: This study investigated the neurologic symptoms and stimulus intensities in the stimulation of deep structures and subcortical fibers with the depth electrodes., Methods: Seventeen patients with drug-refractory epilepsy who underwent functional brain mapping with the depth electrodes were enrolled. The 50 Hz electrical stimulation was applied, and the diffusion tensor image was used to identify subcortical fibers. The responsible structures and stimulus intensities for the induced neurologic symptoms were evaluated., Results: Neurologic symptoms were induced in 11 of 17 patients. The opercular stimulation elicited the neurologic symptoms in 6 patients at the median threshold of 4.0 mA (visceral/face/hand sensory, hand/throat motor, negative motor and auditory symptoms). The insular stimulation induced the neurologic symptoms in 4 patients at the median threshold of 4.0 mA (auditory, negative motor, and sensory symptoms). The stimulation of subcortical fibers was induced in 5 of 9 patients at the median threshold of 4.5 mA. The thresholds of depth electrodes were significantly lower than those of subdural electrodes in 8 patients who used both subdural and depth electrodes and induced symptoms with both electrodes., Conclusions: The stimulation of depth electrodes can identify the function of deep structures and subcortical fibers with lower intensities than subdural electrodes., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction/aims: Paired-pulse stimulation provides clinically useful information regarding sensory inhibition. When supraorbital nerve stimulation is repeated within a short interval, the response to the second stimulation is reduced to varying degrees. This magnitude of change in stimulation response can be monitored by electromyogram (EMG) or by mechanomyogram (MMG) as in this report. MMG has some advantages such as being less time consuming and lacking stimulus artifact. We compared the use of MMG and EMG to validate MMG as an effective method of assessing blink reflex paired-pulse inhibition., Methods: Eight volunteers participated. Participants received electrical stimulation to the supraorbital nerve of each side. A paired-pulse paradigm was employed, varying the conditioning-test interval between 5 and 800 ms. The R1 component of the induced blink reflex was simultaneously recorded by EMG using a pair of electrodes placed on the lower eyelid and by MMG using an accelerometer placed between the electrodes., Results: The correlation coefficient of the R1 amplitude between MMG and EMG of the grand-averaged waveforms was 0.99. The average participant r value was .91 (range .76-.99). Similar analyses were performed for the amplitude variation of the second response relative to the first response. Results correlated well, yielding r values of .97 and .86 for the grand-averaged waveform and the average for each subject., Discussion: The present results demonstrate that MMG could be an alternative to EMG in assessing paired-pulse inhibition of the electrical blink reflex R1 component., (© 2024 The Author(s). Muscle & Nerve published by Wiley Periodicals LLC.)

Objective: Intraoperative mapping of the nervous system is used to identify "eloquent" cortical areas. In this technical report, we describe a novel way of mapping the somatosensory cortex so that injury to those critical pathways can be avoided., Methods: An 8-year-old female with drug resistant epilepsy presented for resection of a right posterior parietal focal cortical dysplasia. Left median nerve stimulation was used to record somatosensory evoked potentials (SEPs) directly from the somatosensory cortex with a strip electrode. A handheld monopolar electrode was also used to record both the median and tibial SEP. Total intravenous anesthesia with propofol and remifentanil was used., Results: SEP recordings were obtained from a 4-contact strip electrode placed across the central sulcus. A phase reversal was identified and the most likely post central gyrus was noted. With the strip electrode left in place, a monopolar handheld electrode was used to record the median nerve SEPs from different locations on the postcentral gyrus. The tibial nerve was also stimulated to record where the highest amplitude tibial nerve SEP was present. This map was used delineate functionally "eloquent" areas to avoid during surgery. During resection, the median nerve SEP was recorded from the strip electrode continuously. No significant change in the SEP was noted, and the patient awoke without any sensory deficits., Conclusions: Sensory mapping of the cortex is possible with a handheld monopolar electrode. This technique is easy to perform and can help reduce neurological morbidity., (Published by Elsevier Inc.)

The early (≤50 ms) rate of torque development (RTD) is dependent upon the speed of neuromuscular activation; however, few studies have evaluated the determinants of rate of velocity development (RVD), which may be load-dependent. The purpose here was to explore the relationship between stimulation frequency with the early and late (≥100 ms) phase isometric RTD and isotonic RVD. The knee extensors of 16 (five female) young recreationally active participants were stimulated using 14 frequencies from 1 to 100 Hz during isometric and isotonic ("unloaded" and 7.5% of the isometric maximal voluntary contraction [MVC]) contractions. Isometric RTD and isotonic RVD were evaluated for the early (0-50 ms) and late (0-100 ms) phases from torque and velocity onset, respectively. Sigmoid functions were fit and bilinear regressions were used to examine the slopes of the steep portion of the curve and the plateau frequency. RTD- and RVD-frequency relationships were well described by a sigmoid function (all r 2  > 0.96). Compared with the late phase, early isometric RTD, and unloaded RVD displayed lower slopes (all P ≤ 0.001) and higher plateau frequencies (all P < 0.001). In contrast, early and late RVD of a moderately loaded isotonic contraction did not display different slopes ( P = 0.055) or plateau frequencies ( P = 0.690). Early isometric RTD and unloaded isotonic RVD are more dependent on changes in stimulation frequency compared with late phases. However, RVD for a moderately loaded isotonic contraction displayed similar responses for the early and late phases. Therefore, a high frequency of activation is critical for early torque and velocity generation but dependent upon the load for isotonic contractions. NEW & NOTEWORTHY We show that during an "unloaded" isotonic contraction, the early phase rate of velocity development is more dependent upon a high electrical activation frequency compared with the late phase, similar to isometric torque. However, early and late phase rates of velocity development of moderately loaded isotonic contractions display similar responses. These results indicate that the determinants of isotonic shortening function are dependent on the externally applied load, highlighting the importance of task-specificity of contraction.

Purpose: To determine whether reduced tissue oxygen availability through blood flow restriction (BFR) alone, or in combination with electrically induced muscle contractions, can improve glucose clearance after an acute glucose challenge., Methods: In a randomized crossover design, 21 young participants (females: 12) were allocated to perform 1) electrical muscle stimulation (EMS), 2) BFR, 3) EMS + BFR or 4) no treatment (control). Participants completed each condition immediately preceding a 2 h oral glucose tolerance test (100 g). Primary analyses were performed on the glucose area under the curve (AUC) at time points 0-30, 30-120, and 0-120 min. Secondary analyses were performed on glycemic responses based on biological sex and estimated muscle phenotype., Results: Compared to the control (322±25 mM∙min), the 0-30 min AUC was reduced following EMS (293±22 mM∙min, p = 0.0004), and EMS + BFR (298±36 mM∙min., p = 0.006), whereas BFR in isolation did not differ (306±30 mM∙min, p = 0.1). The 30-120 and 0-120 min glucose AUCs were similar across conditions. Based on effect size from the control conditions, our secondary analysis suggests different 0-30 min glycemic responses after EMS + BFR between females (d z  = 0.206) vs. males (d z  = 1.461) and/or slow (d z  = 0.426) vs. fast (d z  = 1.075) muscle phenotype., Conclusion: Reducing tissue oxygen availability with BFR did not augment the effects of EMS in the overall group; however, we provide preliminary data to suggest possible sex and/or muscle phenotypic responses in glycemic regulation with these modalities., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

To assess the possible interactions between the dorsolateral periaqueductal gray matter (dlPAG) and the different domains of the nucleus ambiguus (nA), we have examined the pattern of double-staining c-Fos/FoxP2 protein immunoreactivity (c-Fos-ir/FoxP2-ir) and tyrosine hydroxylase (TH) throughout the rostrocaudal extent of nA in spontaneously breathing anaesthetised male Sprague-Dawley rats during dlPAG electrical stimulation. Activation of the dlPAG elicited a selective increase in c-Fos-ir with an ipsilateral predominance in the somatas of the loose (p < 0.05) and compact formation (p < 0.01) within the nA and confirmed the expression of FoxP2 bilaterally in all the domains within the nA. A second group of experiments was made to examine the importance of the dlPAG in modulating the laryngeal response evoked after electrical or chemical (glutamate) dlPAG stimulations. Both electrical and chemical stimulations evoked a significant decrease in laryngeal resistance (subglottal pressure) (p < 0.001) accompanied with an increase in respiratory rate together with a pressor and tachycardic response. The results of our study contribute to new data on the role of the mesencephalic neuronal circuits in the control mechanisms of subglottic pressure and laryngeal activity., (© 2024. The Author(s).)

Although stem cell therapy holds promise for the treatment of spinal cord injury (SCI), its practical applications are limited by the low degree of neural differentiation. Electrical stimulation is one of the most effective ways to promote the differentiation of stem cells into neurons, but conventional wired electrical stimulation may cause secondary injuries, inflammation, pain, and infection. Here, based on the high conductivity of graphite and the electromagnetic induction effect, graphite nanosheets with neural stem cells (NSCs) are proposed as an electromagnetic cellularized patch to generate in situ wirelessly pulsed electric signals under a rotating magnetic field for regulating neuronal differentiation of NSCs to treat SCI. The strength and frequency of the induced voltage can be controlled by adjusting the rotation speed of the magnetic field. The generated pulsed electrical signals promote the differentiation of NSCs into functional mature neurons and increase the proportion of neurons from 12.5% to 33.7%. When implanted in the subarachnoid region of the injured spinal cord, the electromagnetic cellularized patch improves the behavioral performance of the hind limbs and the repair of spinal cord tissue in SCI mice. This work opens a new avenue for remote treatment of SCI and other nervous system diseases., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Objective: Somatosensory evoked spikes (SESs) have been reported only in children aged under 14 years and are considered as an age-dependent phenomenon. However, we detected SESs in adult patients with epilepsy using magnetoencephalography (MEG). The present study investigated whether MEG can detect SESs in normal adults., Methods: Spontaneous MEG was recorded during measurement of somatosensory evoked fields (SEFs) for bilateral electrical median nerve stimuli in 30 healthy adults., Results: Bilateral SESs were observed in 10 adults but none in the other 20 subjects. SESs consisted of one or two peaks, and the first peak latency corresponded to that of the second peak (M2) of SEFs. The first SES peak was identical to the M2 in isofield map pattern, as well as location and orientation of the equivalent current dipole (ECD). M2 ECD strength in the 10 subjects with SESs was larger (p <0.0001) than in 20 without SESs., Conclusions: All-or-nothing detection of bilateral SESs by MEG in normal adults must depend on the signal-to-noise issue of symmetrical SEFs and background brain activity., Significance: Our results further confirm the higher sensitivity of MEG compared to scalp EEG for the detection of focal cortical sources tangential to the scalp such as SESs., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objectives: Objective measurements to predict the position of a cochlear electrode during cochlear implantation surgery may serve to improve the surgical technique and postoperative speech outcome. There is evidence that electrically evoked compound action potentials (ECAP) are a suitable approach to provide information about the site of stimulation. This study aims to contribute to the knowledge about the association between the intraoperative intracochlear ECAP characteristics and the site of stimulation., Methods: In a retrospective cohort study, patients undergoing cochlear implant surgery with flexible lateral wall electrode arrays (12 stimulating channels) between 2020 and 2022 were analyzed. The CDL was measured using a CT-based clinical planning software. ECAP were measured for all electrode contacts and associated to the CDL as well as to the site of stimulation in degree., Results: Significant differences among the amplitudes and slopes for the individual stimulated electrode contacts at the stimulation sites of 90°, 180°, 270°, 360°, 450° and 540° were found. The values showed a trend for linearity among the single electrodes., Conclusions: ECAP characteristics correlate with the electrode's position inside the cochlea. In the future, ECAP may be applied to assess the intracochlear position inside the cochlea and support anatomy-based fitting., (© 2024. The Author(s).)

The closed-loop control of pathological brain activity is a challenging task. In this study, we investigated the sensitivity of continuous epileptiform short discharge generation to electrical stimulation applied at different phases between the discharges using an in vitro 4-AP-based model of epilepsy in rat hippocampal slices. As a measure of stimulation effectiveness, we introduced a sensitivity function, which we then measured in experiments and analyzed with different biophysical and abstract mathematical models, namely, (i) the two-order subsystem of our previous Epileptor-2 model, describing short discharge generation governed by synaptic resource dynamics; (ii) a similar model governed by shunting conductance dynamics (Epileptor-2B); (iii) the stochastic leaky integrate-and-fire (LIF)-like model applied for the network; (iv) the LIF model with potassium M-channels (LIF+KM), belonging to Class II of excitability; and (v) the Epileptor-2B model with after-spike depolarization. A semi-analytic method was proposed for calculating the interspike interval (ISI) distribution and the sensitivity function in LIF and LIF+KM models, which provided parametric analysis. Sensitivity was found to increase with phase for all models except the last one. The Epileptor-2B model is favored over other models for subthreshold oscillations in the presence of large noise, based on the comparison of ISI statistics and sensitivity functions with experimental data. This study also emphasizes the stochastic nature of epileptiform discharge generation and the greater effectiveness of closed-loop stimulation in later phases of ISIs.

The field of cortical sight restoration prostheses is making rapid progress with three clinical trials of visual cortical prostheses underway. However, as yet, we have only limited insight into the perceptual experiences produced by these implants. Here we describe a computational model or 'virtual patient', based on the neurophysiological architecture of V1, which successfully predicts the perceptual experience of participants across a wide range of previously published human cortical stimulation studies describing the location, size, brightness and spatiotemporal shape of electrically induced percepts in humans. Our simulations suggest that, in the foreseeable future the perceptual quality of cortical prosthetic devices is likely to be limited by the neurophysiological organization of visual cortex, rather than engineering constraints., (© 2024. The Author(s).)

We define and explain the quasistatic approximation (QSA) as applied to field modeling for electrical and magnetic stimulation. Neuromodulation analysis pipelines include discrete stages, and QSA is applied specifically when calculating the electric and magnetic fields generated in tissues by a given stimulation dose. QSA simplifies the modeling equations to support tractable analysis, enhanced understanding, and computational efficiency. The application of QSA in neuromodulation is based on four underlying assumptions: (A1) no wave propagation or self-induction in tissue, (A2) linear tissue properties, (A3) purely resistive tissue, and (A4) non-dispersive tissue. As a consequence of these assumptions, each tissue is assigned a fixed conductivity, and the simplified equations (e.g. Laplace's equation) are solved for the spatial distribution of the field, which is separated from the field's temporal waveform. Recognizing that electrical tissue properties may be more complex, we explain how QSA can be embedded in parallel or iterative pipelines to model frequency dependence or nonlinearity of conductivity. We survey the history and validity of QSA across specific applications, such as microstimulation, deep brain stimulation, spinal cord stimulation, transcranial electrical stimulation, and transcranial magnetic stimulation. The precise definition and explanation of QSA in neuromodulation are essential for rigor when using QSA models or testing their limits., (Creative Commons Attribution license.)

Background and Objectives: Muscle atrophy caused by chronic ankle instability (CAI) can incur muscle weakness, altered movement patterns, and increased risk of injury. Previous studies have investigated the effects of rehabilitative exercises and neuromuscular electrical stimulation (NMES) on characteristics in CAI individuals, but few studies have examined their effects on foot and ankle muscle morphology. This study aimed to determine the effects of rehabilitative exercises and NMES on muscle morphology and dynamic balance in individuals with CAI. Materials and Methods: Participants with CAI ( n = 47) were randomly divided into control (CG), rehabilitative exercise (REG), NMES (NG), and rehabilitative exercise and NMES combined (RNG) groups. The six-week intervention program consisting of rehabilitative exercises and NMES was applied to groups excluding CG. Muscle morphology and dynamic balance were evaluated using a portable wireless diagnostic ultrasound device and dynamic balance tests. For statistical analysis, an effect size with 95% confidence interval was calculated to assess mean differences according to intervention. Results: After six weeks, significant increases in morphology and dynamic balance were observed for all muscles except flexor hallucis longus ( p > 0.05) in the intervention groups except for CG. However, no significant changes were observed in the CG ( p > 0.05). Conclusions: These findings suggest that intervention programs may help prevent muscle atrophy and improve balance in CAI individuals.

We investigated sex differences in dopamine (DA) release in the nucleus accumbens (NAc) and dorsolateral striatum (DLS) using a chronic 16-channel carbon fiber electrode and fast-scan cyclic voltammetry (FSCV). Electrical stimulation-induced (ES; 60 Hz) DA release was recorded in the NAc of single- or pair-housed male and female rats. When core (NAcC) and shell (NAcS) were recorded simultaneously, there was greater ES DA release in NAcC of pair-housed females compared with single females and males. Housing did not affect ES NAc DA release in males. In contrast, there was significantly more ES DA release from the DLS of female rats than male rats. This was true prior to and after treatment with methamphetamine. Furthermore, in castrated (CAST) males and ovariectomized (OVX) females, there were no sex differences in ES DA release from the DLS, demonstrating the hormone dependence of this sex difference. However, in the DLS of both intact and gonadectomized rats, DA reuptake was slower in females than that in males. Finally, DA release following ES of the medial forebrain bundle at 60 Hz was studied over 4 weeks. ES DA release increased over time for both CAST males and OVX females, demonstrating sensitization. Using this novel 16-channel chronic FSCV electrode, we found sex differences in the effects of social housing in the NAcS, sex differences in DA release from intact rats in DLS, and sex differences in DA reuptake in DLS of intake and gonadectomized rats, and we report sensitization of ES-induced DA release in DLS in vivo., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Gonzalez et al.)

Electrical brain stimulation has been used in vivo and in vitro to investigate neural circuitry. Historically, stimulation parameters such as amplitude, frequency, and pulse width were varied to investigate their effects on neurotransmitter release and behavior. These experiments have traditionally employed fixed-frequency stimulation patterns, but it has previously been found that neurons are more precisely tuned to variable input. Introducing variability into the interpulse interval of stimulation pulses will inform on how dopaminergic release can be modulated by variability in pulse timing. Here, dopaminergic release in rats is monitored in the nucleus accumbens (NAc), a key dopaminergic center which plays a role in learning and motivation, by fast-scan cyclic voltammetry. Dopaminergic release in the NAc could also be modulated by stimulation region due to differences in connectivity. We targeted two regions for stimulation─the medial forebrain bundle (MFB) and the medial prefrontal cortex (mPFC)─due to their involvement in reward processing and projections to the NAc. Our goal is to investigate how variable interpulse interval stimulation patterns delivered to these regions affect the time course of dopamine release in the NAc. We found that stimulating the MFB with these variable stimulation patterns saw a highly responsive, frequency-driven dopaminergic response. In contrast, variable stimulation patterns applied to the mPFC were not as sensitive to the variable frequency changes. This work will help inform on how stimulation patterns can be tuned specifically to the stimulation region to improve the efficiency of electrical stimulation and control dopamine release.

Accumulation of α-synuclein (α-Syn) has been implicated in proteasome and autophagy dysfunction in Parkinson's disease (PD). High frequency electrical stimulation (HFS) mimicking clinical parameters used for deep brain stimulation (DBS) in vitro or DBS in vivo in preclinical models of PD have been found to reduce levels of α-Syn and, in certain cases, provide possible neuroprotection. However, the mechanisms by which this reduction in α-Syn improves cellular dysfunction associated with α-Syn accumulation remains elusive. Using HFS parameters that recapitulate DBS in vitro, we found that HFS led to a reduction of mutant α-Syn and thereby limited proteasome and autophagy impairments due to α-Syn. Additionally, we observed that HFS modulates via the ATP6V0C subunit of V-ATPase and mitigates α-Syn mediated autophagic dysfunction. This study highlights a role for autophagy in reduction of α-Syn due to HFS which may prove to be a viable approach to decrease pathological protein accumulation in neurodegeneration., (© 2024. The Author(s).)

Electrical stimulation is a key tool in neuroscience, both in brain mapping studies and in many therapeutic applications such as cochlear, vestibular, and retinal neural implants. Due to safety considerations, stimulation is restricted to short biphasic pulses. Despite decades of research and development, neural implants lead to varying restoration of function in patients. In this study, we use computational modeling to provide an explanation for how pulsatile stimulation affects axonal channels and therefore leads to variability in restoration of neural responses. The phenomenological explanation is transformed into equations that predict induced firing rate as a function of pulse rate, pulse amplitude, and spontaneous firing rate. We show that these equations predict simulated responses to pulsatile stimulation with a variety of parameters as well as several features of experimentally recorded primate vestibular afferent responses to pulsatile stimulation. We then discuss the implications of these effects for improving clinical stimulation paradigms and electrical stimulation-based experiments., (© 2024. The Author(s).)

Electrical stimulation of peripheral nerves has been used in various pathological contexts for rehabilitation purposes or to alleviate the symptoms of neuropathologies, thus improving the overall quality of life of patients. However, the development of novel therapeutic strategies is still a challenging issue requiring extensive in vivo experimental campaigns and technical development. To facilitate the design of new stimulation strategies, we provide a fully open source and self-contained software framework for the in silico evaluation of peripheral nerve electrical stimulation. Our modeling approach, developed in the popular and well-established Python language, uses an object-oriented paradigm to map the physiological and electrical context. The framework is designed to facilitate multi-scale analysis, from single fiber stimulation to whole multifascicular nerves. It also allows the simulation of complex strategies such as multiple electrode combinations and waveforms ranging from conventional biphasic pulses to more complex modulated kHz stimuli. In addition, we provide automated support for stimulation strategy optimization and handle the computational backend transparently to the user. Our framework has been extensively tested and validated with several existing results in the literature., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Couppey et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)