Efficacy Of Nerve Stimulation Research Articles

Serotonin and vasovagal syncope.

The goal of this manuscript was to review the biological and clinical evidence that serotonin neurotransmission might play an important role in the physiology and treatment of vasovagal syncope. The authors reviewed PubMed and handsearches of secondary sources for papers related to the Bezold-Jarisch reflex and serotonin, the plausible involvement of the Bezold-Jarisch reflex in vasovagal syncope, and three lines of clinical evidence involving serotonin and the syncope. The Bezold-Jarisch reflex was first described following the infusion of veratrum alkaloids into animals in the 19th century. The reflex is triggered by serotonin stimulation chemoreceptors and mechanoreceptors in the the left ventricle. The afferent component of the reflex is carried by unmyelinated type C vagal nerve fibers, which results in parasympathetic efferent stimulation that causes bradycardia. The similarity of the combination of hypotension and bradycardia in the Bezold-Jarisch reflex and in vasovagal syncope led to the suggestion that the reflex was the cause of the syndrome. Three lines of evidence implicate the serotonin 5HT3 receptors in the heart in the reflex. There is genetic and physiologic evidence for the serotonin 5HT1A and 5HT3 receptors and the serotonin reuptake transporter (SERT). Acute blockade of SERT induces vasovagal syncope in humans undergoing head-up tilt table testing, and SERT inhibition reduces hypotension and bradycardia during spinal anaesthesia. Finally, three randomized clinical trials of SERT inhibitors uniformly reported that they significantly reduce the likelihood of vasovagal syncope recurrences. Multiple lines of evidence implicate serotonin neurotransmission in the cause of vasovagal syncope.

A predictive model combining connectomics and entropy biomarkers to discriminate long-term vagus nerve stimulation efficacy for pediatric patients with drug-resistant epilepsy.

To predict the vagus nerve stimulation (VNS) efficacy for pediatric drug-resistant epilepsy (DRE) patients, we aim to identify preimplantation biomarkers through clinical features and electroencephalogram (EEG) signals and thus establish a predictive model from a multi-modal feature set with high prediction accuracy. Sixty-five pediatric DRE patients implanted with VNS were included and followed up. We explored the topological network and entropy features of preimplantation EEG signals to identify the biomarkers for VNS efficacy. A Support Vector Machine (SVM) integrated these biomarkers to distinguish the efficacy groups. The proportion of VNS responders was 58.5% (38/65) at the last follow-up. In the analysis of parieto-occipital α band activity, higher synchronization level and nodal efficiency were found in responders. The central-frontal θ band activity showed significantly lower entropy in responders. The prediction model reached an accuracy of 81.5%, a precision of 80.1%, and an AUC (area under the receiver operating characteristic curve) of 0.838. Our results revealed that, compared to nonresponders, VNS responders had a more efficient α band brain network, especially in the parieto-occipital region, and less spectral complexity of θ brain activities in the central-frontal region. We established a predictive model integrating both preimplantation clinical and EEG features and exhibited great potential for discriminating the VNS responders. This study contributed to the understanding of the VNS mechanism and improved the performance of the current predictive model.

Метод викликаних потенціалів як перспективний напрямок дослідження ноцицепції у наркотизованих тварин

The sensation of pain is a pathogenetic link in a wide range of diseases, and the study of nociception as its component is an important area of physiology and medicine. However, modern requirements for research conducted using laboratory animals require the search for new approaches to studying nociception and analgesia with minimizing the suffering of subjects in ethological testing and maximizing the transition to instrumental testing. We proposed the use of a standard formalin model of pain in combination with the recording of changes in somatosensory cortex potentials caused by electrical stimulation of efferents at the level of the forelimb. It was found that after subcutaneous injection of 0.30 ml of 4% formalin, the amplitude of evoked potentials increased. Under the conditions of the proposed testing design, both dosedependent and time-dependent effects of the formalin model of pain were observed in an anesthetized animal. The peculiarity of the obtained results was that the fixed somatosensory potentials of the brain in the S1 forelimb region showed sensitivity to the administration of a nociceptive agent in those areas of the body that topographically did not belong to the cortical representation of the forelimbs. This probably indicates the potential universality of this test approach. Thus, it was shown that evoked potentials in the forelimb representation of the primary somatosensory cortex demonstrate a clearly fixed response to painful stimulation in the formalin model of pain and can be used in studies of nociceptive and analgesic effects as a partial alternative to standard ethological testing.

Метод викликаних потенціалів як перспективний напрямок дослідження ноцицепції у наркотизованих тварин

The sensation of pain is a pathogenetic link in a wide range of diseases, and the study of nociception as its component is an important area of physiology and medicine. However, modern requirements for research conducted using laboratory animals require the search for new approaches to studying nociception and analgesia with minimizing the suffering of subjects in ethological testing and maximizing the transition to instrumental testing. We proposed the use of a standard formalin model of pain in combination with the recording of changes in somatosensory cortex potentials caused by electrical stimulation of efferents at the level of the forelimb. It was found that after subcutaneous injection of 0.30 ml of 4% formalin, the amplitude of evoked potentials increased. Under the conditions of the proposed testing design, both dosedependent and time-dependent effects of the formalin model of pain were observed in an anesthetized animal. The peculiarity of the obtained results was that the fixed somatosensory potentials of the brain in the S1 forelimb region showed sensitivity to the administration of a nociceptive agent in those areas of the body that topographically did not belong to the cortical representation of the forelimbs. This probably indicates the potential universality of this test approach. Thus, it was shown that evoked potentials in the forelimb representation of the primary somatosensory cortex demonstrate a clearly fixed response to painful stimulation in the formalin model of pain and can be used in studies of nociceptive and analgesic effects as a partial alternative to standard ethological testing.

Transcriptional response of the heart to vagus nerve stimulation.

Heart failure is a major clinical problem, with treatments involving medication, devices, and emerging neuromodulation therapies such as vagus nerve stimulation (VNS). Considering the ongoing interest in using VNS to treat cardiovascular disease it is important to understand the genetic and molecular changes developing in the heart in response to this form of autonomic neuromodulation. This experimental animal (rat) study investigated the immediate transcriptional response of the ventricular myocardium to selective stimulation of vagal efferent activity using an optogenetic approach. Vagal preganglionic neurons in the dorsal motor nucleus of the vagus nerve were genetically targeted to express light-sensitive chimeric channelrhodopsin variant ChIEF, and stimulated using light. RNA sequencing of left ventricular myocardium identified 294 differentially expressed genes (DEGs, false discovery rate <0.05). Qiagen Ingenuity Pathway Analysis (IPA) highlighted 118 canonical pathways that were significantly modulated by vagal activity, of which 14 had a z-score of ≥2/≤-2, including EIF-2, IL-2, Integrin, and NFAT-regulated cardiac hypertrophy. IPA revealed the effect of efferent vagus stimulation on protein synthesis, autophagy, fibrosis, autonomic signalling, inflammation, and hypertrophy. IPA further predicted that the identified DEGs were the targets of 50 upstream regulators, including transcription factors (e.g., MYC, NRF1) and microRNAs (e.g., miR-335-3p, miR-338-3p). These data demonstrate that the vagus nerve has a major impact on myocardial expression of genes involved in regulation of key biological pathways. The transcriptional response of the ventricular myocardium induced by stimulation of vagal efferents is consistent with the beneficial effect of maintained/increased vagal activity on the heart.

The Vagus Nerve Regulates Immunometabolic Homeostasis in the Ovine Fetus near Term: The Impact on Terminal Ileum.

Glucosensing elements are widely distributed throughout the body and relay information about circulating glucose levels to the brain via the vagus nerve. However, while anatomical wiring has been established, little is known about the physiological role of the vagus nerve in glucosensing. The contribution of the vagus nerve to inflammation in the fetus is poorly understood. Increased glucose levels and inflammation act synergistically when causing organ injury, but their interplay remains incompletely understood. We hypothesized that vagotomy (Vx) will trigger a rise in systemic glucose levels and this will be enhanced during systemic and organ-specific inflammation. Efferent vagus nerve stimulation (VNS) should reverse this phenotype. Near-term fetal sheep (n = 57) were surgically prepared using vascular catheters and ECG electrodes as the control and treatment groups (lipopolysaccharide (LPS), Vx + LPS, Vx + LPS + selective efferent VNS). The experiment was started 72 h postoperatively to allow for post-surgical recovery. Inflammation was induced with LPS bolus intravenously (LPS group, 400 ng/fetus/day for 2 days; n = 23). For the Vx + LPS group (n = 11), a bilateral cervical vagotomy was performed during surgery; of these n = 5 received double the LPS dose, LPS800. The Vx + LPS + efferent VNS group (n = 8) received cervical VNS probes bilaterally distal from Vx in eight animals. Efferent VNS was administered for 20 min on days 1 and 2 +/10 min around the LPS bolus. Fetal arterial blood samples were drawn on each postoperative day of recovery (-72 h, -48 h, and -24 h) as well as at the baseline and seven selected time points (3-54 h) to profile inflammation (ELISA IL-6, pg/mL), insulin (ELISA), blood gas, and metabolism (glucose). At 54 h post-LPS, a necropsy was performed, and the terminal ileum macrophages' CD11c (M1 phenotype) immunofluorescence was quantified to detect inflammation. The results are reported for p < 0.05 and for Spearman R2 > 0.1. The results are presented as the median (IQR). Across the treatment groups, blood gas and cardiovascular changes indicated mild septicemia. At 3 h in the LPS group, IL-6 peaked. That peak was decreased in the Vx + LPS400 group and doubled in the Vx + LPS800 group. The efferent VNS sped up the reduction in the inflammatory response profile over 54 h. The M1 macrophage activity was increased in the LPS and Vx + LPS800 groups only. The glucose and insulin concentrations in the Vx + LPS group were, respectively, 1.3-fold (throughout the experiment) and 2.3-fold higher vs. control (at 3 h). The efferent VNS normalized the glucose concentrations. The complete withdrawal of vagal innervation resulted in a 72-h delayed onset of a sustained increase in glucose for at least 54 h and intermittent hyperinsulinemia. Under the conditions of moderate fetal inflammation, this was related to higher levels of gut inflammation. The efferent VNS reduced the systemic inflammatory response as well as restored both the concentrations of glucose and the degree of terminal ileum inflammation, but not the insulin concentrations. Supporting our hypothesis, these findings revealed a novel regulatory, hormetic, role of the vagus nerve in the immunometabolic response to endotoxin in near-term fetuses.

Temporary and highly variable recovery of neuromuscular dysfunction by electrical stimulation in the follow-up of acute critical illness neuromyopathy: a pilot study

BackgroundIn sepsis-associated critical illness neuromyopathy (CIPNM) serial electrical stimulation of motor nerves induces a short-lived temporary recovery of compound muscle action potentials (CMAPs) termed facilitation phenomenon (FP). This technique is different from other stimulation techniques published. The identification of FP suggests a major functional component in acute CIPNM.MethodsFrom our previous study cohort of 18 intensive care unit patients with sepsis associated CIPNM showing profound muscle weakness and low or missing CMAPs on nerve conduction studies, six patients with different severity could be followed. In a pilot sub-study we analyzed the variability of FP during follow up. Over up to 6 weeks we performed 2–6 nerve conduction studies with our novel stimulation paradigm. Motor nerves were stimulated at 0.2–0.5 Hz with 60–100 mA at 0.2–0.5 ms duration, and CMAP responses were recorded. Standard motor nerve conduction velocities (NCV) could be done when utilizing facilitated CMAPs. Needle electromyography was checked once for spontaneous activity to discover potential denervation and muscle fiber degeneration. Serum electrolytes were checked before any examination and corrected if abnormal.ResultsIn all six patients a striking variability in the magnitude and pattern of FP could be observed at each examination in the same and in different motor nerves over time. With the first stimulus most CMAPs were below 0.1 mV or absent. With slow serial pulses CMAPs could gradually recover with normal shape and near normal amplitudes. With facilitated CMAPs NCV measurements revealed low normal values. With improvement of muscle weakness subsequent tests revealed larger first CMAP amplitudes and smaller magnitudes of FP. Needle EMG showed occasional spontaneous activity in the tibialis anterior muscle.ConclusionIn this pilot study striking variability and magnitude of FP during follow-up was a reproducible feature indicating major fluctuations of neuromuscular excitability that may improve during follow-up. FP can be assessed by generally available electrophysiological techniques, even before patients could be tested for muscle strength. Large scale prospective studies of the facilitation phenomenon in CIPNM with or without sepsis are needed to define diagnostic specificity and to better understand the still enigmatic pathophysiology.Trial registration: This trial was registered at the Leipzig University Medical Center in 2021 after approval by the Ethics Committee.

Transcriptional response of the heart to vagus nerve stimulation.

Heart failure is a major clinical problem, with treatments involving medication, devices, and emerging neuromodulation therapies such as vagus nerve stimulation (VNS). Considering the ongoing interest in using VNS to treat cardiovascular disease, it is important to understand the genetic and molecular changes developing in the heart in response to this form of autonomic neuromodulation. This experimental animal (rat) study investigated the immediate transcriptional response of the ventricular myocardium to selective stimulation of vagal efferent activity using an optogenetic approach. Vagal preganglionic neurons in the dorsal motor nucleus of the vagus nerve were genetically targeted to express light-sensitive chimeric channelrhodopsin variant ChIEF and stimulated using light. RNA sequencing of the left ventricular myocardium identified 294 differentially expressed genes (false discovery rate < 0.05). Qiagen Ingenuity Pathway Analysis (IPA) highlighted 118 canonical pathways that were significantly modulated by vagal activity, of which 14 had a z score of ≥2/≤-2, including EIF-2, IL-2, integrin, and NFAT-regulated cardiac hypertrophy. IPA revealed the effect of efferent vagus stimulation on protein synthesis, autophagy, fibrosis, autonomic signaling, inflammation, and hypertrophy. IPA further predicted that the identified differentially expressed genes were the targets of 50 upstream regulators, including transcription factors (e.g., MYC and NRF1) and microRNAs (e.g., miR-335-3p and miR-338-3p). These data demonstrate that the vagus nerve has a major impact on the myocardial expression of genes involved in the regulation of key biological pathways. The transcriptional response of the ventricular myocardium induced by stimulation of vagal efferents is consistent with the beneficial effect of maintained/increased vagal activity on the heart.NEW & NOTEWORTHY This experimental animal study investigated the immediate transcriptional response of the ventricular myocardium to selective stimulation of vagal efferent activity. Vagal stimulation induced significant transcriptional changes in the heart involving the pathways controlling autonomic signaling, inflammation, fibrosis, and hypertrophy. This study provides the first direct evidence that myocardial gene expression is modulated by the activity of the autonomic nervous system.

Voluntary muscle activation in people with Multiple Sclerosis is reduced across a wide range of forces following maximal effort fatiguing contractions.

Although Multiple Sclerosis (MS) is frequently associated with motor impairment, little is known about how muscle activation is affected with MS. The aim of this study was to use transcranial magnetic stimulation (TMS) and motor nerve stimulation to investigate voluntary muscle activation in people with MS across a range of contraction forces. Ten people with MS (39 ± 7 years) and 10 healthy controls (40 ± 5 years) performed elbow flexions at target contraction forces of 25%, 50%, 75%, 90%, and 100% maximal voluntary contraction (MVC) while electromyography (EMG) of the biceps brachii was recorded. Sustained elbow flexion MVCs were then performed until force declined to 60% of baseline MVC, where the target contraction forces were again examined but after the sustained MVC. Following the sustained MVC there was a reduction in biceps EMG amplitude (P < 0.01) and motor cortical voluntary activation (P < 0.01) for the MS group across all contraction intensities. There was also an increase in the rate of torque development for motor nerve resting twitches in the MS group following the sustained MVC (P = 0.03). Despite the MS group reporting higher Fatigue Severity Scale scores (P < 0.01), disease duration was a better predictor of muscle activation for the MS group (r = -0.757, P = 0.01). These findings indicate that voluntary muscle activation is compromised in people with MS following maximal effort contractions, which may be associated with disease duration rather than self-reports of fatigue.

Enhanced suppression of otoacoustic emissions by contralateral stimulation in Parkinson's disease.

Dopamine depletion affects several aspects of hearing function. Previous work [Wu, Yi, Manca, Javaid, Lauer, and Glowatzki, eLife 9, e52419 (2020)] demonstrated the role of dopamine in reducing the firing rates of inner ear cells, which is thought to decrease synaptic excitotoxicity. Thus, a lack of dopamine could indirectly increase acoustic stimulation of medial olivocochlear efferents. To investigate that, here we studied contralateral suppression of distortion product otoacoustic emissions in a population of Parkinsonian patients, compared to an age-matched control group, both audiometrically tested. To rule out activation of the acoustic reflex, middle ear impedance was monitored during testing. The results show significantly stronger contralateral suppression in the patient group.

Investigating the safety and efficacy of nerve stimulation for management of groin pain after surgical herniorrhaphy: a systematic review and meta-analysis.

Chronic post-operative inguinal pain (CPIP) following inguinal hernia repair has been a major sequela affecting 4000-48000 patients annually. Optimal management of CPIP has been a challenge, and pharmacological management particularly with opioids has shown unsatisfactory results. The main objective of this systematic review is to investigate the safety and efficacy of neuromodulation as an alternative intervention for the management of post-operative inguinal pain. A literature search was conducted by three reviewers to identify all relevant studies on the use of neuromodulatory interventions for treating post-operative inguinal pain. Data on study characteristics, neuromodulatory modalities, and patient's clinical data such as pre/post-interventional pain scores and analgesic requirements were extracted and reported. A total of 389 patients with 357 (95.9%) males and 15 (4.1%) females were evaluated. The mean age of study participants was 47.9 ± 10.4 years. There were 187 (48.1%) and 202 (51.9%) patients allocated to the control and trial groups, respectively. The most common neuromodulation modality was TENS (4, 36.4%), followed by SCS (3, 27.3%), PNS (3, 27.3%), and acupuncture-assisted (2, 18.2%). The overall mean follow-up duration of the entire cohort was 3.8 months. The mean difference between pre-operative and post-operative VAS scores in the trial groups was 4.65 (95% Confidence Interval [CI], 2.97, 6.33), which was statistically significant (P value < 0.05). Patient-reported outcome measures showed significant responsiveness toward their treatments. Nerve stimulation, in its many forms, is a safe and feasible option for the management of post-operative inguinal pain.

Dopamine release in the nucleus accumbens promotes REM sleep and cataplexy

Patients with the sleep disorder narcolepsy suffer from excessive daytime sleepiness, disrupted nighttime sleep, and cataplexy-the abrupt loss of postural muscle tone during wakefulness, often triggered by strong emotion. The dopamine (DA) system is implicated in both sleep-wake states and cataplexy, but little is known about the function of DA release in the striatum and sleep disorders. Recording DA release in the ventral striatum revealed orexin-independent changes across sleep-wake states as well as striking increases in DA release in the ventral, but not dorsal, striatum prior to cataplexy onset. Tonic low-frequency stimulation of ventral tegmental efferents in the ventral striatum suppressed both cataplexy and rapid eye movement (REM) sleep, while phasic high-frequency stimulation increased cataplexy propensity and decreased the latency to REM sleep. Together, our findings demonstrate a functional role of DA release in the striatum in regulating cataplexy and REM sleep.

A multiscale predictive digital twin for neurocardiac modulation.

Cardiac function is tightly regulated by the autonomic nervous system (ANS). Activation of the sympathetic nervous system increases cardiac output by increasing heart rate and stroke volume, while parasympathetic nerve stimulation instantly slows heart rate. Importantly, imbalance in autonomic control of the heart has been implicated in the development of arrhythmias and heart failure. Understanding of the mechanisms and effects of autonomic stimulation is a major challenge because synapses in different regions of the heart result in multiple changes to heart function. For example, nerve synapses on the sinoatrial node (SAN) impact pacemaking, while synapses on contractile cells alter contraction and arrhythmia vulnerability. Here, we present a multiscale neurocardiac modelling and simulator tool that predicts the effect of efferent stimulation of the sympathetic and parasympathetic branches of the ANS on the cardiac SAN and ventricular myocardium. The model includes a layered representation of the ANS and reproduces firing properties measured experimentally. Model parameters are derived from experiments and atomistic simulations. The model is a first prototype of a digital twin that is applied to make predictions across all system scales, from subcellular signalling to pacemaker frequency to tissue level responses. We predict conditions under which autonomic imbalance induces proarrhythmia and can be modified to prevent or inhibit arrhythmia. In summary, the multiscale model constitutes a predictive digital twin framework to test and guide high-throughput prediction of novel neuromodulatory therapy. KEY POINTS: A multi-layered model representation of the autonomic nervous system that includes sympathetic and parasympathetic branches, each with sparse random intralayer connectivity, synaptic dynamics and conductance based integrate-and-fire neurons generates firing patterns in close agreement with experiment. A key feature of the neurocardiac computational model is the connection between the autonomic nervous system and both pacemaker and contractile cells, where modification to pacemaker frequency drives initiation of electrical signals in the contractile cells. We utilized atomic-scale molecular dynamics simulations to predict the association and dissociation rates of noradrenaline with the β-adrenergic receptor. Multiscale predictions demonstrate how autonomic imbalance may increase proclivity to arrhythmias or be used to terminate arrhythmias. The model serves as a first step towards a digital twin for predicting neuromodulation to prevent or reduce disease.

Stimulation parameters for directional vagus nerve stimulation

BackgroundAutonomic nerve stimulation is used as a treatment for a growing number of diseases. We have previously demonstrated that application of efferent vagus nerve stimulation (eVNS) has promising glucose lowering effects in a rat model of type 2 diabetes. This paradigm combines high frequency pulsatile stimulation to block nerve activation in the afferent direction with low frequency stimulation to activate the efferent nerve section. In this study we explored the effects of the parameters for nerve blocking on the ability to inhibit nerve activation in the afferent direction. The overarching aim is to establish a blocking stimulation strategy that could be applied using commercially available implantable pulse generators used in the clinic.MethodsMale rats (n = 20) had the anterior abdominal vagus nerve implanted with a multi-electrode cuff. Evoked compound action potentials (ECAP) were recorded at the proximal end of the electrode cuff. The efficacy of high frequency stimulation to block the afferent ECAP was assessed by changes in the threshold and saturation level of the response. Blocking frequency and duty cycle of the blocking pulses were varied while maintaining a constant 4 mA current amplitude.ResultsDuring application of blocking at lower frequencies (≤ 4 kHz), the ECAP threshold increased (ANOVA, p < 0.001) and saturation level decreased (p < 0.001). Application of higher duty cycles (> 70%) led to an increase in evoked neural response threshold (p < 0.001) and a decrease in saturation level (p < 0.001). During the application of a constant pulse width and frequency (1 or 1.6 kHz, > 70% duty cycle), the charge delivered per pulse had a significant influence on the magnitude of the block (ANOVA, p = 0.003), and was focal (< 2 mm range).ConclusionsThis study has determined the range of frequencies, duty cycles and currents of high frequency stimulation that generate an efficacious, focal axonal block of a predominantly C-fiber tract. These findings could have potential application for the treatment of type 2 diabetes.

Sympathetic modulation of hindlimb muscle contractility is altered in aged rats

It has recently been demonstrated that reflex excitation of muscle sympathetic nerves triggered by muscle contraction contributes to the maintenance of tetanic force (TF) in rat hindlimb muscles. We hypothesized that this feedback mechanism between the contraction of hindlimb muscles and the lumbar sympathetic nerves declines during aging. In this study, we examined the contribution of sympathetic nerves on skeletal muscle contractility in young adult (4–9 months old, n = 11) and aged (32–36 months old, n = 11) male and female rats. The tibial nerve was electrically stimulated to measure the TF of the triceps surae muscles resulting from motor nerve activation before and after cutting or stimulating (at 5–20 Hz) the lumbar sympathetic trunk (LST). The TF amplitude decreased by cutting the LST in the young and aged groups; however, the magnitude of the decrease in TF following transection of the LST in the aged rats (6.2%) was significantly (P = 0.02) smaller compared with that in the young rats (12.9%). The TF amplitude was increased by LST stimulation at ≥ 5 Hz in the young and ≥ 10 Hz in the aged groups. The overall TF response to LST stimulation was not significantly different between the two groups; however, an increase in muscle tonus resulting from LST stimulation, independent of motor nerve stimulation, was significantly (P = 0.03) greater in aged compared with young rats. The sympathetic contribution to support motor nerve-induced muscle contraction declined, whereas sympathetic-mediated muscle tonus, independent of motor nerve activity, was augmented in aged rats. These changes in sympathetic modulation of hindlimb muscle contractility may underlie the reduction of skeletal muscle strength during voluntary contraction and rigidity of motion during senescence.

Brain functional connectivity-based prediction of vagus nerve stimulation efficacy in pediatric pharmacoresistant epilepsy.

Although vagus nerve stimulation (VNS) is a common and widely used therapy for pharmacoresistant epilepsy, the reported efficacy of VNS in pediatric patients varies, so it is unclear which children will respond to VNS therapy. This study aimed to identify functional brain network features associated with VNS action to distinguish VNS responders from nonresponders using scalp electroencephalogram (EEG) data. Twenty-three children were included in this study, 16 in the discovery cohort and 7 in the test cohort. Using partial correlation value as a measure of whole-brain functional connectivity, we identified the differential edges between responders and nonresponders. Results derived from this were used as input to generate a support vector machine-learning classifier to predict VNS outcomes. The postcentral gyrus in the left and right parietal lobe regions was identified as the most significant differential brain region between VNS responders and nonresponders (p < 0.001). The resultant classifier demonstrated a mean AUC value of 0.88, a mean sensitivity rate of 91.4%, and a mean specificity rate of 84.3% on fivefold cross-validation in the discovery cohort. In the testing cohort, our study demonstrated an AUC value of 0.91, a sensitivity rate of 86.6%, and a specificity rate of 79.3%. Furthermore, for prediction accuracy, our model can achieve 81.4% accuracy at the epoch level and 100% accuracy at the patient level. This study provides the first treatment response prediction model for VNS using scalp EEG data with ictal recordings and offers new insights into its mechanism of action. Our results suggest that brain functional connectivity features can help predict therapeutic response to VNS therapy. With further validation, our model could facilitate the selection of targeted pediatric patients and help avoid risky and costly procedures for patients who are unlikely to benefit from VNS therapy.

A portable, programmable, multichannel stimulator with high compliance voltage for noninvasive neural stimulation of motor and sensory nerves in humans

Most neural stimulators do not have a high enough compliance voltage to pass current through the skin. The few stimulators that meet the high compliance voltage necessary for transcutaneous stimulation are typically large benchtop units that are not portable, and the stimulation waveforms cannot be readily customized. To address this, we present the design and validation of a portable, programmable, multichannel, noninvasive neural stimulator that can generate three custom bipolar waveforms at ± 150 V with microsecond temporal resolution. The design is low-cost, open-source, and validated on the benchtop and with a healthy population to demonstrate its functionality for sensory and motor stimulation. Sensory stimulation included electrocutaneous stimulation targeting cutaneous mechanoreceptors at the surface of the skin and transcutaneous nerve stimulation targeting the median nerve at the wrist. Both electrocutaneous stimulation on the hand and transcutaneous stimulation at the wrist can elicit isolated tactile percepts on the hand but changes in pulse frequency are more discriminable for electrocutaneous stimulation. Also, neuromuscular electrical stimulation of the flexor digiti profundus is evoked by applying electrical stimulation directly above the muscle in the forearm and to the median and ulnar nerves in the upper arm. Muscle and nerve stimulation evoked similar grip forces and force rise times, but nerve stimulation had a significantly slower fatigue rate. The development and validation of this noninvasive stimulator and direct comparison of common sensory and motor stimulation targets in a human population constitute an important step towards more widespread use and accessibility of neural stimulation for education and research.

Abstract WP58: Corticomotor Input Integrity To The Dorsi-plantarflexors And Motor Control In Chronic Stroke

Objective: To improve recovery of gait after stroke, we need to attain better understanding of lower extremity motor control. Transcranial magnetic stimulation (TMS) allows for evaluation of corticomotor input (CMI) integrity. Our objective was to explore the relationship between CMI to the dorsi-/plantarflexors and measures of motor impairment and gait speed. Methods: Fugl-Meyer for Lower Extremity (FM), gait speed and TMS Motor Evoked Potentials (MEP) were collected for 27 ambulatory chronic stroke survivors. Maximum MEPs (MEP max ) were collected for paretic and non-paretic tibialis anterior (TA) and lateral gastrocnemius muscles (Gastroc) using a cone-shaped TMS coil targeting primary motor cortices. We collected MEPs while seated participants activated their tested muscles to 20% of maximum effort. MEPs were normalized by the maximum compound muscle action potentials obtained by stimulation of the peripheral motor nerves. Symmetry of the corticospinal motor output was calculated as ratio of the normalized paretic and non-paretic MEP max . Analysis included descriptive statistics, paired t-test and Pearson correlation. Non-normally distributed data was log-transformed. Results: Study participants were 65.7±7.5 years old, 5.3±4.4 years after stroke and 81% male. Their mean±SD FM was 24.6±3.7 and gait speed was 0.74±0.38 m/s. For both TA and Gastroc, paretic MEP max were significantly smaller than non-paretic (p=3.8e -18 ). For Gastroc, higher ratio of paretic/non-paretic MEP max correlated with lesser impairment measured with FM (r=0.42, p=0.027). For TA, the correlation was lower and did not reach statistical significance (r=0.33, p=0.088). Gait speed did not have a significant correlation with MEP max . FM moderately correlated with gait speed (r=0.44, p=0.02). Conclusion: Gastroc MEP might be a better biomarker of motor impairment than TA. Thus, CMI to TA and Gastroc may provide different information in elucidating the mechanism of lower limb motor control. Gait speed does not correlate with CMI for dorsi-/plantarflexors which suggests that motor control of ambulation (gait speed) may differ from that of isolated joint movement (FM).

The denervation or activation of renal sympathetic nerve and renal blood flow.

The denervation or activation of the sympathetic nerve in the kidney can affect renal hemodynamics. The sympathetic nervous system regulates the physiological functions of the kidneys. Stimulation of sympathetic efferent nerves affects various parameters related to renal hemodynamics, including sodium excretion, renin secretion, and renal blood flow (RBF). Hence, renal sympathetic fibers may also play an essential role in regulating systemic vascular resistance and controlling blood pressure. In the absence of renal nerves, the hemodynamics response to stimuli is negligible or absent. The effect of renal sympathetic denervation on RBF is dependent on several factors such as interspecies differences, the basic level of nerve activity in the vessels or local density of adrenergic receptor in the vascular bed. The role of renal denervation has been investigated therapeutically in hypertension and related disorders. Hence, the dynamic impact of renal nerves on RBF enables using RBF dynamic criteria as a marker for renal denervation therapy.

Recruitment of inhibitory neuronal pathways regulating dopaminergic activity for the control of cocaine seeking.

Drug seeking is associated with the ventral tegmental area (VTA) dopaminergic (DA) activity. Previously, we have shown that brief optogenetic inhibition of VTA DA neurons with 1s pulses delivered every 9s attenuates cocaine seeking under extinction conditions in rats without producing overt signs of dysphoria or locomotor sedation. Whether recruitment of neuronal pathways inhibiting VTA neuronal activity would suppress drug seeking remains unknown. Here, we asked if optogenetic stimulation of the lateral habenula (LHb) efferents in the rostromedial tegmental nucleus (RMTg) as well as RMTg efferents in VTA would reduce drug seeking. To investigate this, we measured how recruitment of elements of this inhibitory pathway affects cocaine seeking in male rats under extinction conditions. The effectiveness of brief optogenetic manipulations was confirmed electrophysiologically at the level of electrical activity of VTA DA neurons. Real-time conditioned place aversion (RT-CPA) and open field tests were performed to control for potential dysphoric/sedating effects of brief optogenetic stimulation of LHb-RMTg-VTA circuitry. Optogenetic stimulation of either RMTg or LHb inhibited VTA DAergic neuron firing, whereas similar stimulation of RMTg efferents in VTA or LHb efferents in RMTg reduced cocaine seeking under extinction conditions. Moreover, stimulation of LHb-RMTg efferents produced an effect that was maintained 24 h later, during cocaine seeking test without stimulation. This effect was specific, as brief optogenetic stimulation did not affect locomotor activity and was not aversive. Our results indicate that defined inhibitory pathways can be recruited to inhibit cocaine seeking, providing potential new targets for non-pharmacological treatment of drug craving.