Electrical Stimulation Research Articles

Stress-induced impairment of parasympathetic NO-mediated inhibition of sympathetic vasoconstriction in submucosal arteriole of rat rectum.

In the gastrointestinal tract, nitrergic inhibition of the arteriolar contractility has not been demonstrated. Here, we explored whether neurally-released nitric oxide (NO) inhibits sympathetic vasoconstrictions in the rat rectal arterioles. Changes in sympathetic vasoconstrictions and their nitrergic modulation in rats exposed to water avoidance stress (WAS, 10days, 1h per day) were also examined. In rectal submucosal preparations, changes in arteriolar diameter were monitored using video microscopy. In control or sham-treated rats, electrical field stimulation (EFS)-induced sympathetic vasoconstrictions were increased by the neuronal nitric oxide synthase (nNOS) inhibitor L-NPA (1μM) and diminished by the cyclic guanosine monophosphate-specific phosphodiesterase 5 (PDE5) inhibitor tadalafil (10nM). In phenylephrine-constricted, guanethidine-treated arterioles, EFS-induced vasodilatations were inhibited by the calcitonin gene-related peptide (CGRP) receptor antagonist BIBN-4096 (1μM) but not L-NPA. Perivascular nNOS-immunoreactive nitrergic fibres co-expressing the parasympathetic marker vesicular acetylcholine transporter (VAChT) were intermingled with tyrosine hydroxylase (TH)-immunoreactive sympathetic fibres expressing soluble guanylate cyclase (sGC), a receptor for NO. In WAS rats in which augmented sympathetic vasoconstrictions were developed, L-NPA failed to further increase the vasoconstrictions, while tadalafil-induced inhibition of the vasoconstrictions was attenuated. Phenylephrine- or α,β-methylene ATP-induced vasoconstrictions and acetylcholine-induced vasodilatations were unaltered by WAS. Thus, in arterioles of the rat rectal submucosa, NO released from parasympathetic nerves appears to inhibit sympathetic vasoconstrictions presumably by reducing sympathetic transmitter release. In WAS rats, sympathetic vasoconstrictions are augmented at least partly due to the diminished pre-junctional nitrergic inhibition of transmitter release without changing α-adrenoceptor or P2X-purinoctor mediated vasoconstriction and endothelium-dependent vasodilatation.

Reduction in motor error by presenting subthreshold somatosensory information during visuomotor tracking tasks.

Weak sensory noise acts on the nervous system and promotes sensory and motor functions. This phenomenon is called stochastic resonance and is expected to be applied for improving biological functions. This study investigated the effect of electrical stimulation on grip force adjustment ability. The coefficient of variation and absolute motor error in grip force was measured during a visuomotor tracking task under different intensities of somatosensory noise. Depending on the style of force exertion, the grip movement used in the visuomotor tracking task consisted of force generation (FG), force relaxation (FR), and constant contraction (Constant) phases. The subthreshold condition resulted in significantly lower coefficient of variation in the Constant phase and motor errors in the FG and Constant phases than the no-noise condition. However, the differences among the other conditions were insignificant. Additionally, we examined the correlation between the motor error in the condition without electrical stimulation and the change in motor error induced by subthreshold electrical stimulation. Significant negative correlations were observed in all FG, FR, and Constant phases. These results indicated that somatosensory noise had a strong effect on subjects with large motor errors and enhanced the grip force adjustment ability. By contrast, subjects with small motor errors had weak improvement in motor control. Although the effect of subthreshold noise varies depending on the individual differences, stochastic resonance is effective in improving motor control ability.

Interventional neurorehabilitation for glioma patients: a systematic review

Abstract Background Harnessing the neuroplastic potential of the human brain is being increasingly recognized as an important neuro-oncological paradigm to facilitate safe resection of brain tumors while preserving neurological function and quality of life. Interventional neurorehabilitation, employing both invasive and non-invasive neuromodulation techniques, represents an important emerging therapeutic strategy to induce or enhance neural plasticity to promote functional recovery in brain tumor patients. This study aimed to conduct a comprehensive review of interventional neurorehabilitation techniques for glioma patients. Methods In accordance with PRISMA guidelines, searches of Medline, Embase, Web of Science, APA PsycINFO, and Cochrane were undertaken from database inception to November 28th 2023. Studies reporting on neuromodulation applied to glioma patients were included. Results Seven studies reporting findings from 118 patients met the inclusion criteria. Three neuromodulation techniques were identified and included transcranial magnetic stimulation (TMS) reported in 5 out of 7 (71.4%) studies; transcranial direct current stimulation (tDCS), and continuous cortical electrical stimulation (cCES) using grid electrodes, reported in one study each. All studies applying non-invasive stimulation to ameliorate postoperative deficits demonstrated an improvement on at least one outcome measure. The two studies applying tDCS and cCES to induce plasticity reported evidence of functional reorganization. Conclusion There is emerging evidence of benefits of neuromodulation to improve postoperative outcome in glioma patients. In the current literature, non-invasive stimulation has shown to have a favorable safety profile. Large-scale double-blind sham-controlled trials are warranted to further investigate the effectiveness of these interventions for modulating different cognitive networks in patients undergoing glioma surgery.

A screening for cerebral deoxygenation during VT ablations in patients with structural heart disease.

Patients undergoing ventricular tachycardia (VT) ablation often present with structural heart disease (SHD) and reduced ejection fraction. Inducing VT by programmed electrical stimulation (PES) puts these patients at risk for hemodynamic instability and cerebral hypoperfusion. The present study screens for cerebral oxygen desaturation phases (ODPs) in patients undergoing VT ablation. Forty-seven patients (age 61 ± 14years, 72% males) underwent ablation of sustained VT with simultaneous neuromonitoring using near-infrared spectroscopy (NIRS). Analysis of NIRS signal identified ODPs in 29 patients (62%). ODPs were associated with a higher prevalence of ischemic heart disease (IHD) (45% vs. 11%, p = 0.024), previous VT episodes (n = 16 vs. 4, p = 0.018), and VTs inducible by PES (n = 2.4 vs. 1.2, p = 0.004). Patients with ODPs were more likely to be admitted to intensive care unit (ICU) (78% vs. 33%, p = 0.005) and had more in-hospital VT recurrences (24% vs. 0%, p = 0.034). No differences were observed in VT recurrencerates after hospital discharge (41.4% vs. 44.4%, p = 0.60) and left ventricularejection fraction (34% vs. 38%, p = 0.567). IHD (OR: 32.837, p = 0.006), ICU admission (OR: 14.112, p = 0.013), and the number of VTs inducible at PES (OR: 2.705, p = 0.015) were independently associated with ODPs. This study registers episodes of cerebral hypoperfusion in 62% of patients undergoing VT ablation and identifies IHD and the number of VTs inducible at PES as possible risk factors for these episodes.

Blocking Aδ- and C-fiber neural transmission by sub-kilohertz peripheral nerve stimulation

IntroductionWe recently showed that sub-kilohertz electrical stimulation of the afferent somata in the dorsal root ganglia (DRG) reversibly blocks afferent transmission. Here, we further investigated whether similar conduction block can be achieved by stimulating the nerve trunk with electrical peripheral nerve stimulation (ePNS).MethodsWe explored the mechanisms and parameters of conduction block by ePNS via ex vivo single-fiber recordings from two somatic (sciatic and saphenous) and one autonomic (vagal) nerves harvested from mice. Action potentials were evoked on one end of the nerve and recorded on the other end from teased nerve filaments, i.e., single-fiber recordings. ePNS was delivered in the middle of the nerve trunk using a glass suction electrode at frequencies of 5, 10, 50, 100, 500, and 1000 Hz.ResultsSuprathreshold ePNS reversibly blocks axonal neural transmission of both thinly myelinated Aδ-fiber axons and unmyelinated C-fiber axons. ePNS leads to a progressive decrease in conduction velocity (CV) until transmission blockage, suggesting activity-dependent conduction slowing. The blocking efficiency is dependent on the axonal conduction velocity, with Aδ-fibers efficiently blocked by 50–1000 Hz stimulation and C-fibers blocked by 10–50 Hz. The corresponding NEURON simulation of action potential transmission indicates that the disrupted transmembrane sodium and potassium concentration gradients underly the transmission block by the ePNS.DiscussionThe current study provides direct evidence of reversible Aδ- and C-fiber transmission blockage by low-frequency (<100 Hz) electrical stimulation of the nerve trunk, a previously overlooked mechanism that can be harnessed to enhance the therapeutic effect of ePNS in treating neurological disorders.

Posttraumatic headache: pain related evoked potentials (PREP) and conditioned pain modulation (CPM) to assess the pain modulatory function

Posttraumatic headache (PTH) is common following traumatic brain injury and impacts quality of life. We investigated descending pain modulation as one possible mechanism for PTH and correlated it to clinical measures. Pain-related evoked potentials (PREP) were recorded in 26 PTH-patients and 20 controls after electrical stimulation at the right hand and forehead with concentric surface electrodes. Conditioned pain modulation (CPM) was assessed using painful cutaneous electric stimulation (PCES) on the right hand as test stimulus and immersion of the left hand into 10 °C-cold water bath as conditioning stimulus based on changes in pain intensity and in amplitudes of PCES-evoked potentials. All participants completed questionnaires assessing depression, anxiety, and pain catastrophising. PTH-patients reported significantly higher pain ratings during PREP-recording in both areas despite similar stimulus intensity at pain threshold. N1P1-amplitudes during PREP and CPM-assessment were lower in patients in both areas, but statistically significant only on the hand. Both, PREP-N1-latencies and CPM-effects (based on the N1P1-amplitudes and pain ratings) were similar in both groups. Patients showed significantly higher ratings for anxiety and depression, which did not correlate with the CPM-effect. Our results indicate generalized hyperalgesia for electrical stimuli in both hand and face in PTH. The lacking correlation between pain ratings and EEG parameters indicates different mechanisms of pain perception and nociception.

Electrical stimulation for brighter persistent luminescence

An immature understanding of the mechanisms of persistent luminescence (PersL) has hindered the development of new persistent luminescent materials (PersLMs) with increased brightness. In this regard, in-situ direct current (DC) electric field measurements were conducted on a layered structure composed of the SrAl2O4:Eu2+,Dy3+ phosphor, and an electrode. In this study, the photoluminescence (PL) and afterglow properties were investigated with respect to voltage by analyzing the current signal and thermoluminescence (TL) spectroscopy. The intensity of PersL increased due to a novel phenomenon known as “external electric field stimulated enhancement of initial brightness of afterglow”. This dynamic process was illustrated via the use of a rate equation approach, where the electrons trapped by the ultra-shallow trap at 0.022 eV could be transferred through the conduction band during long afterglow. The afterglow intensity could reach 0.538 cd m−2 at a 6 V electric voltage. The design of an electric field stimulation technique enables the enhancement of the intensity of PersLMs and provides a new perspective for exploring the fundamental mechanics of certain established PersLMs.

Electrospun PAN/PANI/CNT scaffolds and electrical pulses: a pathway to stem cell-derived nerve regeneration

Biocompatible polymer-based scaffolds hold great promise for neural repair, especially when they are coupled with electrostimulation to induce neural differentiation. In this study, a combination of polyacrylonitrile/polyaniline (PAN/PANI) and Carbon Nanotubes (CNTs) were used to fabricate three different biomimetic electrospun scaffolds (samples 1, 2 and 3 containing 0.26 wt%, 1 wt% and 2 wt% of CNTs, respectively). These scaffolds underwent thorough characterization for assessing electroconductivity, tensile strength, wettability, degradability, swelling, XRD, and FTIR data. Notably, scanning electron microscopy (SEM) images revealed a three-dimensional scaffold morphology with aligned fibers ranging from 60 nm to 292 nm in diameter. To comprehensively investigate the impact of electrical stimulation on the nervous differentiation of the stem cells seeded on these scaffolds, cell morphology and adhesion were assessed based on SEM images. Additionally, scaffold biocompatibility was studied through MTT assay. Importantly, Real-Time PCR results indicated the expression of neural markers—Nestin, β-tubulin III, and MAP2—by the cells cultured on these samples. In comparison with the control group, samples 1 and 2 exhibited significant increases in Nestin marker expression, indicating early stages of neuronal differentiation, while β-tubulin III expression was significantly reduced and MAP2 expression remained statistically unchanged. In contrast, sample 3 did not display a statistically significant upturn in Nestin maker expression, while showcasing remarkable increases in the expression of both MAP2 and β-tubulin III, as markers of the end stages of differentiation, leading to postmitotic neurons. These results could be attributed to the higher electroconductivity of S3 compared to other samples. Our findings highlight the biomimetic potential of the prepared scaffolds for neural repair, illustrating their effectiveness in guiding stem cell differentiation toward a neural lineage.

Unlocking opioid neuropeptide dynamics with genetically encoded biosensors.

Neuropeptides are ubiquitous in the nervous system. Research into neuropeptides has been limited by a lack of experimental tools that allow for the precise dissection of their complex and diverse dynamics in a circuit-specific manner. Opioid peptides modulate pain, reward and aversion and as such have high clinical relevance. To illuminate the spatiotemporal dynamics of endogenous opioid signaling in the brain, we developed a class of genetically encoded fluorescence sensors based on kappa, delta and mu opioid receptors: κLight, δLight and µLight, respectively. We characterized the pharmacological profiles of these sensors in mammalian cells and in dissociated neurons. We used κLight to identify electrical stimulation parameters that trigger endogenous opioid release and the spatiotemporal scale of dynorphin volume transmission in brain slices. Using in vivo fiber photometry in mice, we demonstrated the utility of these sensors in detecting optogenetically driven opioid release and observed differential opioid release dynamics in response to fearful and rewarding conditions.

Prognostic efficiency of diagnostic blockade as a method of modeling the result of selective neurotomy of the motor branches of the median nerve in patients with cerebral palsy

BACKGROUND: A feature of the disease course in patients with spastic cerebral palsy is a combination of motor neurological disorders with contractures in extremity joints. Neurosurgical methods are currently the main treatment for correcting the pathological tone of the “spastic hand.” However, the decreased tone does not affect secondary (fixed) contractures; therefore, the effectiveness of this type of treatment is extremely dependent on the accurate selection of a certain category of patients. Presumably, diagnostic blockade of the median nerve can create a reversible model for planned neurosurgical treatment. The inclusion of this technique as a standard for examining a patient with spastic cerebral palsy before invasive tone-lowering treatment can radically promote treatment effectiveness. AIM: This study aimed to assess the prognostic effectiveness of diagnostic blockade as a method of modeling the result of selective neurotomy of the motor branches of the median nerve in patients with cerebral palsy. MATERIALS AND METHODS: A longitudinal prospective study enrolled 39 children (aged 5–18 years) with spastic cerebral palsy. Before neurosurgical treatment, each patient underwent a diagnostic n. medianus under electrical stimulation and ultrasound control. After a diagnostic blockade, only patients who had a good functional and goniometric response were selected for the study, which served as an indication for selective neurotomy of the median nerve, and orthopedic treatment was performed in children with a negative event. Patients referred for neurotomy underwent a standardized examination before treatment during the diagnostic blockade and after neurosurgical treatment. The examination included the assessment of the amplitude of passive and active movements in the joints of the upper extremities, muscle tone, and functional capabilities of the upper extremities and dynamometry. RESULTS: In comparison with the initial data, a significant increase in the amplitude of passive and active hand extension, passive and active abduction of the first finger, and upper limb functional capabilities according to the MACS classification and the Miller scale was determined both after the diagnostic blockade and after selective neurotomy of the motor branches of the median nerve. CONCLUSIONS: Based on the results of the study, the effect of the diagnostic blockade and neurosurgical treatment outcomes are unidirectional, which allows the use of blockade as a method for modeling the possible result in clinically complex cases of spastic hand. The use of diagnostic blockade in clinical practice makes it possible to adequately assess the severity of fixed contractures and reduce the pathological hypertonicity of the target muscles. Diagnostic blockade allows for the collection of sufficient information to make an objective decision about which type of treatment is most preferable for each patient – neurosurgical, orthopedic, or sequential use of both methods.

The Immediate Effect of Dry Needling Electric Muscle Stimulation on the Position of Atlas

Background: cervicogenic headaches are common and are believed to be the cause of dysfunction in the upper cervical spine. The mobility and the position of the atlas have been identified as a cause of upper cervical dysfunction. The mobility of the atlas is entirely under the control of the suboccipital muscles. The oblique capitis inferior muscle has a rotatory effect on the atlas when contracted. This study evaluated the immediate effects of a dry needling electrical stimulation-induced contraction of the left oblique capitis inferior muscle on the position and mobility of the atlas in the atlantoaxial joint. Methods: thirty-one subjects participated in this within-subject repeated measure study design. Each subject underwent a pre-measures neck flexion rotation test, palpation of the atlas position, and measurement of the length of the right oblique capitis inferior muscle with musculoskeletal ultrasound imaging. The pre-measures were repeated after two five-second tetanic contractions of the oblique capitis inferior muscle. Results: post-intervention analysis revealed significant changes in the length of the right oblique capitis inferior muscle. This length change correlated with the palpated positional default position immediately after the intervention. Conclusions: two five-second tetanic contractions of the left oblique capitis inferior muscle immediately affected the position of the atlas in the atlantoaxial joint. In our subjects, 90% displayed a positional default in the left rotation, and this was correlated with a change in the neck flexion rotation test. This study supports the notion that suboccipital muscle tonicity can result in mobility dysfunction and, thus, conditions such as cervicogenic headaches.

Extrusion-based 3D Bioprinting of Bioactive and Piezoelectric Scaffolds for Treating Critical Soft Tissue Wounds.

This study focuses on developing bioactive piezoelectric scaffolds that could deliver bioelectrical cues to potentially treat injuries to soft tissues such as skeletal muscles and promote muscle regeneration. To address the underexplored aspect of bioelectrical cues in skeletal muscle tissue engineering (SMTE), we developed piezoelectric bioinks based on natural bioactive materials such as alginate, gelatin, and chitosan. Extrusion-based 3D bioprinting was utilized to develop scaffolds that mimic muscle stiffness and generate electrical stimulation when subjected to forces. The biocompatibility of these scaffolds was tested with C2C12 muscle cell line. The bioinks demonstrated suitable rheological properties for 3D bioprinting, resulting in high-resolution composite alginate-gelatin-chitosan scaffolds with good structural fidelity. The scaffolds exhibited a 42-60 kPa stiffness, similar to muscles. When a controlled force of 5 N was applied to the scaffolds at a constant frequency of 4 Hz, they generated electrical fields and impulses (charge), indicating their suitability as a standalone scaffold to generate electrical stimulation and instill bioelectrical cues in the wound region. The cell viability and proliferation test results confirm the scaffold's biocompatibility with C2C12s and the benefit of piezoelectricity in promoting muscle cell growth kinetics. Our study indicates that our piezoelectric bioinks and scaffolds offer promise as autonomous electrical stimulation-generating regenerative therapy for SMTE. A novel approach for treating skeletal muscle wounds was introduced by developing a bioactive electroactive scaffold capable of autonomously generating electrical stimulation without stimulators and electrodes. This scaffold offers a unique approach to enhancing skeletal muscle regeneration through bioelectric cues, addressing a major gap in the SMTE, i.e., fibrotic tissue formation due to delayed muscle regeneration. A piezoelectric scaffold was developed, providing a promising solution for promoting skeletal muscle regeneration. This development can potentially address skeletal muscle injuries and offer a unique approach to facilitating skeletal muscle wound healing.

Chronic Electro-Acoustic Stimulation May Interfere With Electric Threshold Recovery After Cochlear Implantation in the Aged Guinea Pig.

Electro-acoustic stimulation (EAS) combines electric stimulation via a cochlear implant (CI) with residual low-frequency acoustic hearing, with benefits for music appreciation and speech perception in noise. However, many EAS CI users lose residual acoustic hearing, reducing this benefit. The main objectives of this study were to determine whether chronic EAS leads to more hearing loss compared with CI surgery alone in an aged guinea pig model, and to assess the relationship of any hearing loss to histology measures. Conversely, it is also important to understand factors impacting efficacy of electric stimulation. If one contributor to CI-induced hearing loss is damage to the auditory nerve, both acoustic and electric thresholds will be affected. Excitotoxicity from EAS may also affect electric thresholds, while electric stimulation is osteogenic and may increase electrode impedances. Hence, secondary objectives were to assess how electric thresholds are related to the amount of residual hearing loss after CI surgery, and how EAS affects electric thresholds and impedances over time. Two groups of guinea pigs, aged 9 to 21 months, were implanted with a CI in the left ear. Preoperatively, the animals had a range of hearing losses, as expected for an aged cohort. At 4 weeks after surgery, the EAS group (n = 5) received chronic EAS for 8 hours a day, 5 days a week, for 20 weeks via a tether system that allowed for free movement during stimulation. The nonstimulated group (NS; n = 6) received no EAS over the same timeframe. Auditory brainstem responses (ABRs) and electrically evoked ABRs (EABRs) were recorded at 3 to 4 week intervals to assess changes in acoustic and electric thresholds over time. At 24 weeks after surgery, cochlear tissue was harvested for histological evaluation, only analyzing animals without electrode extrusions (n = 4 per ear). Cochlear implantation led to an immediate worsening of ABR thresholds peaking between 3 and 5 weeks after surgery and then recovering and stabilizing by 5 and 8 weeks. Significantly greater ABR threshold shifts were seen in the implanted ears compared with contralateral, non-implanted control ears after surgery. After EAS and termination, no significant additional ABR threshold shifts were seen in the EAS group compared with the NS group. A surprising finding was that NS animals had significantly greater recovery in EABR thresholds over time, with decreases (improvements) of -51.8 ± 33.0 and -39.0 ± 37.3 c.u. at 12 and 24 weeks, respectively, compared with EAS animals with EABR threshold increases (worsening) of +1.0 ± 25.6 and 12.8 ± 44.3 c.u. at 12 and 24 weeks. Impedance changes over time did not differ significantly between groups. After exclusion of cases with electrode extrusion or significant trauma, no significant correlations were seen between ABR and EABR thresholds, or between ABR thresholds with histology measures of inner/outer hair cell counts, synaptic ribbon counts, stria vascularis capillary diameters, or spiral ganglion cell density. The findings do not indicate that EAS significantly disrupts acoustic hearing, although the small sample size limits this interpretation. No evidence of associations between hair cell, synaptic ribbon, spiral ganglion cell, or stria vascularis with hearing loss after cochlear implantation was seen when surgical trauma is minimized. In cases of major trauma, both acoustic thresholds and electric thresholds were elevated, which may explain why CI-only outcomes are often better when trauma and hearing loss are minimized. Surprisingly, chronic EAS (or electric stimulation alone) may negatively impact electric thresholds, possibly by prevention of recovery of the auditory nerve after CI surgery. More research is needed to confirm the potentially negative impact of chronic EAS on electric threshold recovery.

Electric field temporal interference stimulation of neurons in vitro.

Electrical stimulation (ES) techniques, such as deep brain and transcranial electrical stimulation, have shown promise in alleviating the symptoms of depression and other neurological disorders in vivo. A new noninvasive ES method called temporal interference stimulation (TIS), possesses great potential as it can be used to steer the stimulation and possibly selectively modulate different brain regions. To study TIS in a controlled environment, we successfully established an in vitro 'TIS on a chip' setup using rat cortical neurons on microelectrode arrays (MEAs) in combination with a current stimulator. We validated the developed TIS system and demonstrated the spatial steerability of the stimulation by direct electric field measurements in the chip setup. We stimulated cultures of rat cortical neurons at 28 days in vitro (DIV) by two-channel stimulation delivering 1) TIS at 653 Hz and 643 Hz, resulting in a 10 Hz frequency envelope, 2) low-frequency stimulation (LFS) at 10 Hz and 3) high-frequency stimulation (HFS) at 653 Hz. Unstimulated cultures were used as control/sham. We observed the differences in the electric field strengths during TIS, HFS, and LFS. Moreover, HFS and LFS had the smallest effects on neuronal activity. Instead, TIS elicited neuronal electrophysiological responses, especially 24 hours after stimulation. Our 'TIS on a chip' approach eludicates the applicability of TIS as a method to modulate neuronal electrophysiological activity. The TIS on a chip approach provides spatially steerable stimuli while mitigating the effects of high stimulus fields near the stimulation electrodes. Thus, the approach opens new avenues for stimulation on a chip applications, allowing the study of neuronal responses to gain insights into the potential clinical applications of TIS in treating various brain disorders.

Pulsatile electrical stimulation creates predictable, correctable disruptions in neural firing

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.

Quasistatic approximation in neuromodulation.

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 neuro-modulation 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.

NRV: An open framework for in silico evaluation of peripheral nerve electrical stimulation strategies.

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.

A robot-based hybrid lower limb system for Assist-As-Needed rehabilitation of stroke patients: Technical evaluation and clinical feasibility

Background:Although early rehabilitation is important following a stroke, severely affected patients have limited options for intensive rehabilitation as they are often bedridden. To create a system for early rehabilitation of lower extremities in these patients, we combined the robotic manipulator ROBERT® with electromyography (EMG)-triggered functional electrical stimulation (FES) and developed a novel user-driven Assist-As-Needed (AAN) control. The method is based on a state machine able to detect user movement capability, assessed by the presence of an EMG-trigger and the movement velocity, and provide different levels of assistance as required by the patient (no support, FES only, and simultaneous FES and mechanical assistance). Methods:To technically validate the system, we tested 10 able-bodied participants who were instructed to perform specific behaviors to test the system states while conducting knee extension and ankle dorsal flexion exercises. The system was also tested on two stroke patients to establish its clinical feasibility. Results:The technical validation showed that the state machine correctly detected the participants’ behavior and activated the target AAN state in more than 96% of the exercise repetitions. The clinical feasibility test showed that the system successfully recognized the patients’ movement capacity and activated assistive states according to their needs providing the minimal level of support required to exercise successfully. Conclusions:The system was technically validated and preliminarily proved clinically feasible. The present study shows that the novel system can be used to deliver exercises with a high number of repetitions while engaging the participants’ residual capabilities through the AAN strategy.

High frequency electrical stimulation reduces α-synuclein levels and α-synuclein-mediated autophagy dysfunction

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.

Electrical Stimulating Redox Membrane Incorporated with PVA/Gelatin Nanofiber for Diabetic Wound Healing.

Chronic wounds adversely affect the quality of life. Although electrical stimulation has been utilized to treat chronic wounds, there are still limitations to practicing it due to the complicated power system. Herein, an electrostimulating membrane incorporated with electrospun nanofiber (M-sheet) to treat diabetic wounds is developed. Through the screen printing method, the various alternate patterns of both Zn and AgCl on a polyurethane substrate, generating redox-mediated electrical fields are introduced. The antibacterial ability of the patterned membrane against both E. coli and S. aureus is confirmed. Furthermore, the poly(vinyl alcohol) (PVA)/gelatin electrospun fiber is incorporated into the patterned membrane to enhance biocompatibility and maintain the wet condition in the wound environment. The M-sheet can improve cell proliferation and migration in vitro and has an immune regulatory effect by inducing the polarization of macrophage to the M2 phenotype. Finally, when applied to a diabetic skin wound model, the M-sheet displays an accelerated wound healing rate and enhances re-epithelialization, collagen synthesis, and angiogenesis. It suggests that the M-sheet is a simple and portable system for the spontaneous generation of electrical stimulation and has great potential to be used in the practical wound and other tissue engineering applications.