Afferent Stimulation Research Articles

A Wearable Multichannel Electrical Stimulator for Tremor Suppression

Abstract Pathological wrist and finger tremors can be mitigated by out-of-phase stimulation of the sensory nerves in the flexor and extensor muscles. This study endeavors to develop a portable, multichannel electrical stimulator designed to deliver high-frequency, low-intensity, biphasic charge-balanced current pulses within a practical load range to effectively suppress wrist and finger tremors. The circuit architecture integrates an Arduino Nanomicrocontroller, a four-channel digital potentiometer, and four Howland current pumps. The Howland current pump, employing an operational amplifier, generates bipolar currents by accepting bipolar voltages, whereas the digital potentiometer offers programmable bipolar voltages via its wiper terminals. Experimental results indicate that the pulse frequency can be adjusted between 50 Hz and 200 Hz, and the current level can be modulated within a range of −10 mA to +10 mA, with load resistance spanning 100 Ω to 1.3 kΩ. This portable and multichannel device is effective in delivering high-frequency, low-intensity sensory nerve stimulation through programmable biphasic charge-balanced current pulses. The proposed stimulator has the potential to enable adaptive muscle activation, thereby initiating, promoting, and generating movements, and facilitating interactive in-home neurorehabilitation for disabled patients. The portability and programmability of this device make it a promising tool for personalized tremor management and rehabilitation, enhancing the quality of life for individuals with motor impairments.

Neuromodulators in Acute and Chronic Cough in Children: An Update From the Literature

Cough is one of the most common reasons leading to pediatric consultations, negatively impacting the quality of life of patients and caregivers. It is defined as a sudden and forceful expulsion of air from the lungs through the mouth, typically triggered by irritation or the stimulation of sensory nerves in the respiratory tract. This reflex is controlled by a neural pathway that includes sensory receptors, afferent nerves, the brainstem’s cough center, efferent nerves, and the muscles involved in coughing. Based on its duration, cough in children may be classified as acute, lasting less than four weeks, and chronic, persisting for more than four weeks. Neuromodulators have shown promise in reducing the frequency and severity of cough by modulating the neural pathways involved in the cough reflex, although they require careful monitoring and patient selection to optimize the outcomes. This review aims to examine the rationale for using neuromodulators in the management of cough in children.

Amelioration of social impairments in autism: Possible role of vagal afferent stimulation in modification of the prefrontal-amygdala connectivity

Impairment in social interactions is a prominent feature of autism spectrum disorder (ASD). The present hypothesis explains the possible role of vagal afferent stimulation in the modification of prefrontal-amygdala connectivity in the amelioration of social impairments in ASD. Currently, there is no definitive treatment for ASD. However, there is documented evidence showing that interventions that increase vagal tone lead to the improvement of autism-related social symptoms. However, the exact mechanism that explains the correlation between the elevation of vagal tone and the amelioration of autism-related symptoms has not been elucidated. In the present hypothesis, it is proposed that the increase in vagal tone affects the nucleus tractus solitarius (NTS) in the brainstem. The NTS has strong connections with other brainstem nuclei, such as the locus coeruleus and dorsal raphe nucleus. The aforementioned nuclei are the main sources of norepinephrine and serotonin, with extensive projections to various brain areas, especially the prefrontal cortex (PFC) and amygdala. PFC-amygdala functional connectivity plays an important role in social behavior and emotion regulation. Therefore, visceral stimulation, which subsequently increases the vagal tone, possibly leads to the improvement of autistic social deficits through the enhancement of PFC-amygdala functional connectivity. Further investigations are needed to evaluate the function of the mentioned neural pathways during visceral stimulation in individuals with ASD.

Intracerebroventricular insulin injection acutely normalizes the augmented exercise pressor reflex in male rats with type 2 diabetes mellitus.

The exercise pressor reflex (EPR) is exaggerated in type 2 diabetes mellitus (T2DM), but the underlying central nervous system aberrations have not been fully delineated. Stimulation of muscle afferents within working skeletal muscle activates the EPR, by sending information to neurons in the brainstem, where it is integrated and results in reflexively increased mean arterial pressure (MAP) and sympathetic nerve activity. Brain insulin is known to regulate neural activity within the brainstem. We hypothesize that brain insulin injection in T2DM rats attenuates the augmented EPR, and that T2DM is associated with decreased brain insulin. Using male Sprague-Dawley rats, T2DM and control rats were generated via an induction protocol with two low doses of streptozotocin (35 and 25mg/kg, i.p.) in combination with a 14-23-week high-fat diet or saline injections and a low-fat diet, respectively. After decerebration, MAP and renal sympathetic nerve activity (RSNA) were evaluated during EPR stimulation, evoked by electrically induced muscle contraction via ventral root stimulation, before and after (1 and 2h post) intracerebroventricular (i.c.v.) insulin microinjections (500mU, 50nl). i.c.v. insulin decreased peak MAP (ΔMAP Pre (36±14mmHg) vs. 1h (21±14mmHg) vs. 2h (11±6mmHg), P<0.05) and RSNA (ΔRSNA Pre (107.5±40%), vs. 1h (75.4±46%) vs. 2h (51±35%), P<0.05) responses in T2DM, but not controls. In T2DM rats, cerebrospinal fluid insulin was decreased (0.41±0.19 vs. 0.11±0.05ng/ml, control (n=14) vs. T2DM (n=4), P<0.01). The results demonstrated that insulin injections into the brain normalized the augmented EPR in brain hypoinsulinaemic T2DM rats, indicating that the EPR can be regulated by brain insulin. KEY POINTS: The reflexive increase in blood pressure and sympathetic nerve activity mediated by the autonomic nervous system during muscle contractions is also known as the exercise pressor reflex. The exercise pressor reflex is dangerously augmented in type 2 diabetes, in both rats and humans. In type 2 diabetic rats both cerebrospinal fluid insulin and phosphoinositide 3-kinase signalling within cardiovascular brainstem neurons decrease in parallel. Brain insulin injections decrease the magnitude of the reflexive pressor and sympathetic responses to hindlimb muscle contraction in type 2 diabetic rats. Partial correction of low insulin within the central nervous system in type 2 diabetes may treat aberrant exercise pressor reflex function.

Emergent epileptiform activity in spinal sensory circuits drives ectopic bursting in afferent axons and sensory dysfunction after cord injury.

Spinal cord injury leads to hyperexcitability and dysfunction in spinal sensory processing. As hyperexcitable circuits can become epileptiform, we explored whether such activity emerges in a thoracic spinal cord injury (SCI) contusion model of neuropathic pain. Recordings from spinal sensory axons in multiple below-lesion segmental dorsal roots demonstrated that SCI facilitated the emergence of spontaneous ectopic burst spiking in afferent axons, which were correlated across multiple adjacent dorsal roots. Burst frequency correlated with behavioral mechanosensitivity. The same bursting events were recruited by afferent stimulation, and timing interactions with ongoing spontaneous bursts revealed that recruitment was limited by a prolonged post-burst refractory period. Ectopic bursting in afferent axons was driven by GABAA receptor activation, presumably by conversion of subthreshold GABAergic interneuronal presynaptic axoaxonic inhibitory actions to suprathreshold spiking. Collectively, the emergence of stereotyped bursting circuitry with hypersynchrony, sensory input activation, post-burst refractory period, and reorganization of connectivity represent defining features of an epileptiform network. Indeed, these same features were reproduced in naive animals with the convulsant 4-aminopyridine (fampridine). We conclude that spinal cord injury promotes the emergence of epileptiform activity in spinal sensory networks that promote profound corruption of sensory signaling. This includes hyperexcitability and bursting by ectopic spiking in afferent axons that propagate bidirectionally by reentrant central and peripheral projections as well as sensory circuit hypoexcitability during the burst refractory period. More broadly, the work links circuit hyperexcitability to epileptiform circuit emergence, further strengthening it as a conceptual basis to understand features of sensory dysfunction and neuropathic pain.

Effects of auricular stimulation on weight- and obesity-related parameters: a systematic review and meta-analysis of randomized controlled clinical trials.

Over the last three decades, the number of randomized controlled trials (RCTs) using stimulation of auricular vagal sensory nerves by means of electrical stimulation, auricular acupuncture, or acupressure to support weight loss has increased markedly. This systematic review focuses on the effects of auricular stimulation (AS) on anthropometric parameters and obesity-related blood chemistry. The following databases were searched until November 2021: MEDLINE (PubMed), EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), ISI Web of Science, and Scopus Database. Data collection and analysis were conducted by two reviewers independently. Quality and risk assessment of included studies was performed using the risk of bias tool of the Cochrane Handbook, and the meta-analysis of the effect of the most frequently assessed biomarkers was conducted using the statistical software RevMan. The full texts of 1,274 studies were screened; 22 contained data on obesity-related outcomes, and 15 trials with 1,333 patients were included in the meta-analysis. The overall quality of the included trials was moderate. AS significantly reduced body mass index (BMI) (mean difference (MD) = -0.38 BMI points, 95% CI (-0.55 to -0.22), p < 0.0001), weight (MD = -0.66 kg, 95% CI (-1.12 to -0.20), p = 0.005), waist circumference (MD = -1.44 cm, 95% CI (-2.69 to -0.20), p = 0.02), leptin, insulin, and HOMA insulin resistance compared to controls. No significant reduction was found in body fat, hip circumference, ratio of waist/hip circumference, cholesterol, LDL, triglycerides, adiponectin, ghrelin, and glucose levels. The AS was safe throughout the trials, with only minor adverse reactions. The study results suggest that a reduction of weight and BMI can be achieved by AS in obese patients; however, the size of the effect does not appear to be of clinical relevance. The effects might be underestimated due to active sham trials. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021231885.

Stochastic electrical stimulation of the thoracic or cervical regions with surface electrodes facilitates swallow in rats.

Aspiration pneumonia, a leading cause of mortality, poses an urgent challenge in contemporary society. Neuromuscular electrical stimulation (NMES) has been commonly used in dysphagia rehabilitation. However, given that NMES at motor threshold targets only specific muscles, it carries a potential risk of further compromising functions related to swallowing, respiration, and airway protection. Considering that the swallow motor pattern is orchestrated by the entire swallow pattern generator (the neural mechanism governing a sequence of swallow actions), a rehabilitation approach that centrally facilitates the entire circuit through sensory nerve stimulation is desirable. In this context, we propose a novel stimulation method using surface electrodes placed on the back to promote swallowing. The efficacy of the proposed method in promoting swallowing was evaluated by electrically stimulating sensory nerves in the back or neck. Probabilistic stimulus was applied to either the back or neck of male and female rats. Swallows were evoked by an oral water stimulus, and electromyographic (EMG) activity of the mylohyoid, thyroarytenoid, and thyropharyngeus muscles served as the primary outcome measure. Gaussian frequency stimulation applied to the skin surface of the thoracic back elicited significant increases in EMG amplitude of all three swallow-related muscles. Neck stimulation elicited a significant increase in EMG amplitude of the thyroarytenoid during swallow, but not the mylohyoid or thyropharyngeus muscles. While the targeted thoracic spinal segments T9-T10 have been investigated for enhancing respiration, the promotion of swallowing through back stimulation has not been previously studied. Furthermore, this study introduces a new probabilistic stimulus based on Gaussian distribution. Probabilistic stimuli have been reported to excel in nerve stimulation in previous research. The results demonstrate that back stimulation effectively facilitated swallow more than neck stimulation and suggest potential applications for swallowing rehabilitation.

Transcutaneous neuromodulation versus oxybutynin for neurogenic detrusor overactivity in persons with spinal cord injury: A randomized, investigator blinded, parallel group, non-inferiority controlled trial

Study design This study is a randomized, investigator-blinded, controlled trial with a non-inferiority design. Objective To investigate the effectiveness of neuromodulation by transcutaneous electrical stimulation of the somatic afferent nerves of the foot in neurogenic detrusor overactivity (NDO) in persons with spinal cord injury (SCI) and compare its effectiveness with oral oxybutynin. Setting The study was conducted in a rehabilitation in-patient ward of a tertiary care hospital. Methods Twenty-nine persons with SCI with NDO, either sex, aged 18 years and above were randomized into two groups, one group receiving oral oxybutynin (5 mg thrice a day for two weeks) and the other transcutaneous electrical stimulation (5 Hz, 200 µs pulse, biphasic, amplitude up to 60 mA, 30 min/day for two weeks). Bladder capacity was evaluated by clinical bladder evaluation (i.e. bladder capacity measured by adding leak volume, voiding volume if any, and post-void residue using a catheter) and cystometric bladder capacity by one-channel cystometry. Maximum cystometric pressure was evaluated by one-channel water cystometry. Data were analyzed with Fisher's Exact, t-test, and Wilcoxon rank sum tests. Results Bladder capacity improved significantly in the oxybutynin and neuromodulation groups as measured by one-channel water cystometry (136 ml vs. 120.57 ml) and clinical evaluation (138.93 ml vs. 112 ml). The increase in the neuromodulation group achieved the pre-decided non-inferiority margin of 30 ml over the oxybutynin group when measured by one-channel water cystometry but not by clinical evaluation. Maximum cystometric pressure did not significantly improve in either group when compared with the baseline. Conclusion Transcutaneous neuromodulation and oxybutynin effectively increased bladder capacity in persons with SCI with NDO. Neuromodulation by once-a-day transcutaneous electrical stimulation was non-inferior to thrice-a-day oxybutynin when evaluated by one-channel water cystometry. Trial registration: Clinical Trials Registry India identifier: CTRI/2018/05/013735.

Astrocyte D1/D5 Dopamine Receptors Govern Non-Hebbian Long-Term Potentiation at Sensory Synapses onto Lamina I Spinoparabrachial Neurons.

Recent work demonstrated that activation of spinal D1 and D5 dopamine receptors (D1/D5Rs) facilitates non-Hebbian long-term potentiation (LTP) at primary afferent synapses onto spinal projection neurons. However, the cellular localization of the D1/D5Rs driving non-Hebbian LTP in spinal nociceptive circuits remains unknown, and it is also unclear whether D1/D5R signaling must occur concurrently with sensory input in order to promote non-Hebbian LTP at these synapses. Here we investigate these issues using cell-type-selective knockdown of D1Rs or D5Rs from lamina I spinoparabrachial neurons, dorsal root ganglion (DRG) neurons, or astrocytes in adult mice of either sex using Cre recombinase-based genetic strategies. The LTP evoked by low-frequency stimulation of primary afferents in the presence of the selective D1/D5R agonist SKF82958 persisted following the knockdown of D1R or D5R in spinoparabrachial neurons, suggesting that postsynaptic D1/D5R signaling was dispensable for non-Hebbian plasticity at sensory synapses onto these key output neurons of the superficial dorsal horn (SDH). Similarly, the knockdown of D1Rs or D5Rs in DRG neurons failed to influence SKF82958-enabled LTP in lamina I projection neurons. In contrast, SKF82958-induced LTP was suppressed by the knockdown of D1R or D5R in spinal astrocytes. Furthermore, the data indicate that the activation of D1R/D5Rs in spinal astrocytes can either retroactively or proactively drive non-Hebbian LTP in spinoparabrachial neurons. Collectively, these results suggest that dopaminergic signaling in astrocytes can strongly promote activity-dependent LTP in the SDH, which is predicted to significantly enhance the amplification of ascending nociceptive transmission from the spinal cord to the brain.

Effects of transcutaneous auricular vagus nerve stimulation (tVNS) on balance in patient with chronic lower back pain

Background. tVNS is a technique of electrical stimulation of vagus nerve afferents that is used as a therapy for chronic pain. This study aims to analyze the effect of adding tVNS to exercise therapy on dynamic balance in chronic LBP patients measured by Maximized Reach Distance (%MAXD) and composite score of Modified Star Excursion Balance Test (MSEBT). Method. The method is an experimental study with a pretest-posttest randomized control group study. 22 people with mechanical chronic LBP aged 16-55 years who were randomly allocated into an exercise group (control group) and an exercise plus tVNS group (intervention group). MSEBT dynamic balance was measured before and after intervention. Results. In the intervention group the average MSEBT anterior right and left leg before (74.57±14.72;73.53±15.0) after (86.45±15.98; 86.98±15.9), posteromedial right and left before (88.23±16.76; 75.15±15.04) after (99.65±14.56, 92.19±11.91), right and left posterolateral before (76.66±13.89, 78.02±13.44) after (84.00±17.25, 84.30±13.90) there was a significant difference (p &lt;0.05). Comparing anterior ΔMSEBT, right composite score and left posteromedial posterolateral ΔMSEBT between groups, there was a significant difference (p &lt;0.05), not significant in right posteromedial posterolateral ΔMSEBT. Conclusion. The addition of tVNS to exercise therapy after 2 weeks on dynamic balance with MSEBT assessment showed a significant improvement in the intervention group. The results were better in the intervention group than in the control group. Further research is still needed to investigate the potential of adding tVNS to chronic LBP.

Sensorimotor Integration in Chronic Low Back Pain

Objective: Chronic low back pain (CLBP) impacts on spine movement. Altered sensorimotor integration can be involved. Afferents from the lumbo-pelvic area might be processed differently in CLBP and impact on descending motor control. This study aimed to determine whether afferents influence the corticomotor control of paravertebral muscles in CLBP. Fourteen individuals with CLBP (11 females) and 13 pain-free controls (8 females) were tested with transcranial magnetic stimulation (TMS) to measure the motor-evoked potential [MEP] amplitude of paravertebral muscles. Noxious and non-noxious electrical stimulation, and magnetic stimulation in the lumbo-sacral area were used as afferent stimuli and triggered 20 to 200 ms prior to TMS. EMG modulation elicited by afferent stimulation alone was measured to control net motoneuron excitability. MEP/EMG ratio was used as a measure of corticospinal excitability with control of net motoneuron excitability. MEP/EMG ratio was larger at 60, 80 and 100-ms intervals in CLBP compared to controls, and afferent stimulations alone reduced EMG amplitude greater in CLBP than controls at 100 ms. Our results suggest alteration in sensorimotor integration in CLBP highlighted by a greater facilitation of the descending corticospinal input to paravertebral muscles. Our results can help to optimise interventions by better targeting mechanisms.

Effects of intrarenal pelvic infusion of tumour necrosis factor-α and interleukin 1-β on reno-renal reflexes in anaesthetised rats.

Reno-renal reflexes are disturbed in cardiovascular and hypertensive conditions when elevated levels of pro-inflammatory mediators/cytokines are present within the kidney. We hypothesised that exogenously administered inflammatory cytokines tumour necrosis factor alpha (TNF-α) and interleukin (IL)-1β modulate the renal sympatho-excitatory response to chemical stimulation of renal pelvic sensory nerves. In anaesthetised rats, intrarenal pelvic infusions of vehicle [0.9% sodium chloride (NaCl)], TNF-α (500 and 1000 ng/kg) and IL-1β (1000 ng/kg) were maintained for 30 min before chemical activation of renal pelvic sensory receptors was performed using randomized intrarenal pelvic infusions of hypertonic NaCl, potassium chloride (KCl), bradykinin, adenosine and capsaicin. The increase in renal sympathetic nerve activity (RSNA) in response to intrarenal pelvic hypertonic NaCl was enhanced during intrapelvic TNF-α (1000 ng/kg) and IL-1β infusions by almost 800% above vehicle with minimal changes in mean arterial pressure (MAP) and heart rate (HR). Similarly, the RSNA response to intrarenal pelvic adenosine in the presence of TNF-α (500 ng/kg), but not IL-1β, was almost 200% above vehicle but neither MAP nor HR were changed. There was a blunted sympatho-excitatory response to intrapelvic bradykinin in the presence of TNF-α (1000 ng/kg), but not IL-1β, by almost 80% below vehicle, again without effect on either MAP or HR. The renal sympatho-excitatory response to renal pelvic chemoreceptor stimulation is modulated by exogenous TNF-α and IL-1β. This suggests that inflammatory mediators within the kidney can play a significant role in modulating the renal afferent nerve-mediated sympatho-excitatory response.

Pathological Turbulence of the Heart Rhythm and Activation of the Antinociceptive System as Predictors of the Complicated Course of Silent Myocardial Ischemia in Patients with Post Infarction Cardiosclerosis According to the Data of Long-term Observation

To date, the issues of evaluating the course of silent myocardial ischemia (SMI) after a myocardial infarction (MI) taking into account risk factors (RF), evaluating the pathological turbulence of the heart rhythm, the state of activation of the body’s antinociceptive system, which necessitates an in-depth study of this pathology, remain unresolved, as well as new differentiated approaches to the treatment and rehabilitation of the modern category of patients. The objective: to analyze the features of the SMI course in patients with post-infarction cardiosclerosis depending on the RF. Identification of the interdependence between the degree of activation of the sympathoadrenal system and the features of the SMI course in patients with post-infarction cardiosclerosis, as well as the prognostic value for assessing the severity of the course of the disease. Materials and methods. The research was performed on the basis of the Ivano-Frankivsk Regional Clinical Cardiology Center (Ukraine). 154 patients with a silent form of coronary artery disease, which occurred in people with post-infarction cardiosclerosis, were examined. The diagnostic criteria were: episodes of SMI verified with the help of HM ECG and a test with dosed physical load. Results. Significant deviation of the ST segment which was detected during Holter monitoring of the ECG (HM ECG) in patients with SMI episodes does not mean that the absence of pain sensations in the presence of efferent nociceptive stimulation is a sign of the absence of ischemia and does not indicate an easier course of SMI compared to clinically manifest forms of CHD. The average concentration of β-endorphins in patients with lipid metabolism disorders was 4.01±0.02 ng/ml, in the presence of diabetes mellitus this indicator was equal to 4.68±0.03 ng/ml (р&lt;0.01), and in persons with concomitant arterial hypertension it was 4.91±0.02 ng/ml (р&lt;0.05). In subjects with two or more RFs, the similar indicator was the highest and amounted to 5.73±0.03 ng/ml (р&lt;0.01). The point-biserial correlation coefficient was equal to 0.61 (р&lt;0.05), which indicates a sufficiently high probability of the influence of the processes of activation of the antinociceptive system on the risk of myocardial infarction and unstable angina. Conclusions. It has been proven that the presence of postinfarction cardiosclerosis, type 2 diabetes mellitus, dyslipidemia, and arterial hypertension should be considered as factors that increase the risk of complications of coronary artery disease in patients with SMI. In the painless form of CHD, there is a probable increase in β-endorphins in the blood, which indicates the presence of pronounced afferent nociceptive stimulation, the intensity of which depends on the degree of myocardial ischemia. It has been proven that an increase of β-endorphins levels is associated with an increase in the risk of a complicated course of coronary heart disease in patients with silent myocardial ischemia. The presence in patients with SMI of myocardial ischemia, pathological turbulence of the heart rhythm, and activation of the antinociceptive system are extremely important for understanding the main links of the course of SMI and make it possible to base the approach to the therapy of such patients on a differentiated system algorithm that takes into account the discrepancy between the clinical manifestations of the disease and its real impact on coronary perfusion and the condition of the vascular wall.

Well-Established and Traditional Use of Vegetal Extracts as an Approach to the "Deep Roots" of Cough.

Cough is a common presenting symptom for patients in a primary care setting and significantly impacts a patient's quality of life. Cough involves a complex reflex arc beginning with the stimulation of sensory nerves that function as cough receptors that stimulate the cough center in the brain. This "cough center" functions to receive these impulses and produce a cough by activating efferent nervous pathways to the diaphragm and laryngeal, thoracic, and abdominal musculature. Drugs that suppress the neural activity of cough are non-specific as those treatments are not directed toward pathogenic causes such as inflammation and oxidative stress. Moreover, they block a reflex called the watchdog of the lung and have a defense mechanism. Acute respiratory infections of the upper and lower airways most commonly cause acute cough. In contrast, the most common causes of chronic cough are upper airway cough syndrome, asthma, and gastroesophageal reflux disease, all associated with an inflammatory reaction at the level of the cough receptors. The use of natural compounds or herbal drugs such as carob syrup, dry blackcurrant extract, dry extract of caraway fruit, dry extract of ginger rhizome, dry extract of marshmallow root, and dry extract of ivy leaves, to name a few, not only have anti-inflammatory and antioxidant activity, but also act as antimicrobials, bronchial muscle relaxants, and increase gastric motility and empty. For these reasons, these natural substances are widely used to control cough at its deep roots (i.e., contrasting its causes and not inhibiting the arch reflex). With this approach, the lung watchdog is not put to sleep, as with peripheral or central inhibition of the cough reflex, and by contrasting the causes, we may control cough that viruses use at self-advantage to increase transmission.

Selective intrafascicular stimulation of myelinated and unmyelinated nerve fibers through a longitudinal electrode: A computational study

Carbon nanotube (CNT) fiber electrodes have demonstrated exceptional spatial selectivity and sustained reliability in the context of intrafascicular electrical stimulation, as evidenced through rigorous animal experimentation. A significant presence of unmyelinated C fibers, known to induce uncomfortable somatosensory experiences, exists within peripheral nerves. This presence poses a considerable challenge to the excitation of myelinated Aβ fibers, which are crucial for tactile sensation. To achieve nuanced tactile sensory feedback utilizing CNT fiber electrodes, the selective stimulation of Aβ sensory afferents emerges as a critical factor.In confronting this challenge, the present investigation sought to refine and apply a rat sciatic-nerve model leveraging the capabilities of the COMSOL-NEURON framework. This approach enables a systematic evaluation of the influence exerted by stimulation parameters and electrode geometry on the activation dynamics of both myelinated Aβ and unmyelinated C fibers. The findings advocate for the utilization of current pulses featuring a pulse width of 600 μs, alongside the deployment of CNT fibers characterized by a diminutive diameter of 10 μm, with an exclusively exposed cross-sectional area, to facilitate reduced activation current thresholds. Comparative analysis under monopolar and bipolar electrical stimulation conditions revealed proximate activation thresholds, albeit with bipolar stimulation exhibiting superior fiber selectivity relative to its monopolar counterpart. Concerning pulse waveform characteristics, the adoption of an anodic-first biphasic stimulation modality is favored, taking into account the dual criteria of activation threshold and fiber selectivity optimization. Consequently, this investigation furnishes an efficacious stimulation paradigm for the selective activation of touch-related nerve fibers, alongside provisioning a comprehensive theoretical foundation for the realization of natural tactile feedback within the domain of prosthetic hand applications.

Chronic Vagotomy Blunts Cardiorespiratory Reflex Responses Through Pre- and Postsynaptic Effects in the Brainstem Nucleus Tractus Solitarii (nTS)

Sensory information from the heart, lungs, and gastrointestinal tract travels to the brain via afferents of the paired vagus nerves, where it is first integrated in the brainstem nTS that critically contributes to cardiorespiratory function. We have shown that reducing input to the nTS by unilaterally transecting the vagus nerve (vagotomy) induces astrocyte reactivity and microglial activation, and reduces sighs in hypoxia. However, the cardiorespiratory effects of vagotomy and contributing mechanisms are not well understood. We hypothesized that chronic vagotomy blunts cardiorespiratory reflex responses to vagal afferent stimulation via reduced nTS neuronal activity. Male Sprague-Dawley rats (6-wk) underwent right cervical vagotomy (or sham surgery) caudal to the nodose ganglion. After 7 days rats were anesthetized, ventilated, and instrumented to record mean arterial pressure (MAP), heart rate (HR), splanchnic sympathetic and phrenic nerve activity (SSNA and PhrNA, respectively), which decreased in response to vagal afferent stimulation in sham animals. Vagotomy blunted these decreases in MAP, SSNA, and PhrNA compared to shams. In rats expressing the calcium indicator GCaMP8m in nTS neurons, vagotomy also reduced neuronal Ca2+ responses to afferent stimulation both in vivo (photometry) and in vitro (live slice imaging). We then hypothesized that these changes were due to altered signaling at the level of the tripartite synapse, where astrocytes enwrap the sensory afferent-nTS soma synapse. We found that there is likely a vagal afferent contribution to the altered reflex responses, as vagotomy reduced presynaptic Ca2+ responses in vagal afferent terminals to solitary tract stimulation in the brainstem slice. Glutamate agonists, which induce similar cardiorespiratory responses as vagal stimulation, were nanoinjected into the nTS to determine if there was a postsynaptic contribution to the blunted responses as well. Responses to glutamate injection were also blunted following vagotomy, indicating that astrocytic glutamate uptake or nTS soma glutamate receptor function may be altered. Blocking astrocytic excitatory amino acid transporters, which remove extracellular glutamate in the nTS induced similar baseline effects and did not restore cardiorespiratory responses to glutamate in vagotomy. However, nanoinjection of NMDA into the nTS to activate ionotropic glutamate receptors mimicked the blunted responses to glutamate following vagotomy, with no difference in responses to AMPA nanoinjection. Likewise, immunohistochemistry and Western blot showed that vagotomy reduced NMDA receptor subunit expression in the nTS. Together these results indicate that chronic vagotomy blunts cardiorespiratory responses to vagal afferent stimulation, likely through reduced presynaptic activation and decreased NMDA receptor expression and function. These studies will help improve our understanding of how afferent input induces neuroplasticity within the nTS, and the resulting impacts on cardiorespiratory function in health and disease. NIH HL132836, HL128454, HL98602, T32OD011126. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

A measure of the blink reflex to parametric variation of mechanical stimulation of the trigeminal nerve.

The primary goal of this study was to develop a parametric model that relates variation in stimulation of the trigeminal nerve to properties of the blink response. We measured blink responses in 17 healthy, adult participants to air puffs directed at the lateral canthus of the eye at five different, log-spaced intensities (3.5-60 PSI). Lid position over time was decomposed into amplitude and velocity components. We found that blink amplitude was systematically related to log stimulus intensity, with the relationship well described by a sigmoidal function. The parameters of the model fit correspond to the slope of the function and the stimulus intensity required to produce half of a maximal blink response (the half-response threshold). There was a reliable increase in the half-response threshold for the contralateral as compared to the ipsilateral blink response. This increase was consistent across participants despite substantial individual differences in the half-response threshold and slope parameters of the overall sensitivity function, suggesting that the laterality effect arises in the neural circuit subsequent to individual differences in sensitivity. Overall, we find that graded mechanical stimulation of the somatosensory trigeminal afferents elicits a graded response that is well described by a simple parametric model. We discuss the application of parametric measurements of the blink response to the detection of group differences in trigeminal sensitivity.

Stimulatory effect of methylglyoxal on capsaicin-sensitive lung vagal afferents in rats: role of TRPA1.

Methylglyoxal (MG), a reactive metabolic byproduct of glycolysis, is a causative of painful diabetic neuropathy. Patients with diabetes are associated with more frequent severe asthma exacerbation. Stimulation of capsaicin-sensitive lung vagal (CSLV) afferents may contribute to the pathogenesis of hyperreactive airway diseases such as asthma. However, the possibility of the stimulatory effect of MG on CSLV afferents and the underlying mechanisms remain unknown. Our results showed that intravenous injection of MG (25 mg/kg, MG25) in anesthetized, spontaneously breathing rats elicited pulmonary chemoreflexes characterized by apnea, bradycardia, and hypotension. The MG-induced apneic response was reproducible and dose dependent. MG25 no longer evoked these reflex responses after perineural capsaicin treatment of both cervical vagi to block C-fibers' conduction, suggesting that the reflexes were mediated through the stimulation of CSLV afferents. Pretreatment with HC030031 [an antagonist of transient receptor potential ankyrin subtype 1 protein (TRPA1)] or AP18 (another TRPA1 antagonist), but not their vehicle, markedly attenuated the apneic response induced by MG25. Consistently, electrophysiological results showed that pretreatment with HC030031 largely attenuated the intense discharge in CSLV afferents induced by injection of MG25 in open-chest and artificially ventilated rats. In isolated CSLV neurons, the perfusion of MG evoked an abrupt and pronounced increase in calcium transients in a concentration-dependent manner. This stimulatory effect on CSLV neurons was also abolished by HC030031 treatment but not by its vehicle. In conclusion, these results suggest that MG exerts a stimulatory effect on CSLV afferents, inducing pulmonary chemoreflexes, and such stimulation is mediated through the TRPA1 activation.NEW & NOTEWORTHY Methylglyoxal (MG) is implicated in the development of painful diabetic neuropathy. A retrospective cohort study revealed an increased incidence of asthma exacerbations in patients with diabetes. This study demonstrated that elevated circulating MG levels stimulate capsaicin-sensitive lung vagal afferents via activation of TRPA1, which in turn triggers respiratory reflexes. These findings provide new information for understanding the pathogenic mechanism of diabetes-associated hyperreactive airway diseases and potential therapy.

Vagotomy blunts cardiorespiratory responses to vagal afferent stimulation via pre- and postsynaptic effects in the nucleus tractus solitarii.

Viscerosensory information travels to the brain via vagal afferents, where it is first integrated within the brainstem nucleus tractus solitarii (nTS), a critical contributor to cardiorespiratory function and site of neuroplasticity. We have shown that decreasing input to the nTS via unilateral vagus nerve transection (vagotomy) induces morphological changes in nTS glia and reduces sighs during hypoxia. The mechanisms behind post-vagotomy changes are not well understood. We hypothesized that chronic vagotomy alters cardiorespiratory responses to vagal afferent stimulation via blunted nTS neuronal activity. Male Sprague-Dawley rats (6weeks old) underwent right cervical vagotomy caudal to the nodose ganglion, or sham surgery. After 1week, rats were anaesthetized, ventilated and instrumented to measure mean arterial pressure (MAP), heart rate (HR), and splanchnic sympathetic and phrenic nerve activity (SSNA and PhrNA, respectively). Vagal afferent stimulation (2-50Hz) decreased cardiorespiratory parameters and increased neuronal Ca2+ measured by in vivo photometry and in vitro slice imaging of nTS GCaMP8m. Vagotomy attenuated both these reflex and neuronal Ca2+ responses compared to shams. Vagotomy also reduced presynaptic Ca2+ responses to stimulation (Cal-520 imaging) in the nTS slice. The decrease in HR, SSNA and PhrNA due to nTS nanoinjection of exogenous glutamate also was tempered following vagotomy. This effect was not restored by blocking excitatory amino acid transporters. However, the blunted responses were mimicked by NMDA, not AMPA, nanoinjection and were associated with reduced NR1 subunits in the nTS. Altogether, these results demonstrate that vagotomy induces multiple changes within the nTS tripartite synapse that influence cardiorespiratory reflex responses to afferent stimulation. KEY POINTS: Multiple mechanisms within the nucleus tractus solitarii (nTS) contribute to functional changes following vagal nerve transection. Vagotomy results in reduced cardiorespiratory reflex responses to vagal afferent stimulation and nTS glutamate nanoinjection. Blunted responses occur via reduced presynaptic Ca2+ activation and attenuated NMDA receptor expression and function, leading to a reduction in nTS neuronal activation. These results provide insight into the control of autonomic and respiratory function, as well as the plasticity that can occur in response to nerve damage and cardiorespiratory disease.

Coherent olfactory bulb gamma oscillations arise from coupling independent columnar oscillators.

Spike timing-based representations of sensory information depend on embedded dynamical frameworks within neuronal networks that establish the rules of local computation and interareal communication. Here, we investigated the dynamical properties of olfactory bulb circuitry in mice of both sexes using microelectrode array recordings from slice and in vivo preparations. Neurochemical activation or optogenetic stimulation of sensory afferents evoked persistent gamma oscillations in the local field potential. These oscillations arose from slower, GABA(A) receptor-independent intracolumnar oscillators coupled by GABA(A)-ergic synapses into a faster, broadly coherent network oscillation. Consistent with the theoretical properties of coupled-oscillator networks, the spatial extent of zero-phase coherence was bounded in slices by the reduced density of lateral interactions. The intact in vivo network, however, exhibited long-range lateral interactions that suffice in simulation to enable zero-phase gamma coherence across the olfactory bulb. The timing of action potentials in a subset of principal neurons was phase-constrained with respect to evoked gamma oscillations. Coupled-oscillator dynamics in olfactory bulb thereby enable a common clock, robust to biological heterogeneities, that is capable of supporting gamma-band spike synchronization and phase coding across the ensemble of activated principal neurons.NEW & NOTEWORTHY Odor stimulation evokes rhythmic gamma oscillations in the field potential of the olfactory bulb, but the dynamical mechanisms governing these oscillations have remained unclear. Establishing these mechanisms is important as they determine the biophysical capacities of the bulbar circuit to, for example, maintain zero-phase coherence across a spatially extended network, or coordinate the timing of action potentials in principal neurons. These properties in turn constrain and suggest hypotheses of sensory coding.