Activation Of Nerve Fibers Research Articles

Activation of mouse skin mast cells and cutaneous afferent C-fiber subtypes by bee venom

In mammals, many Hymenopteran stings are characterized by pain, redness, and swelling − three manifestations consistent with nociceptive nerve fiber activation. The effect of a Western honeybee (Apis mellifera) venom on the activation of sensory C-fibers in mouse skin was studied using an innervated isolated mouse skin preparation that allows for intra-arterial delivery of chemicals to the nerve terminals in the skin. Our data show that honeybee venom stimulated mouse cutaneous nociceptive-like C-fibers, with an intensity (action potential discharge frequency) similar to that seen with a maximally-effective concentration of capsaicin. The venom had a stronger effect on chloroquine-sensitive C-fibers compared to chloroquine-insensitive C-fibers, an effect that was recapitulated with a wasp (Vespula spp.) venom. Blocking TRPV1 and TRPA1 channels did not influence the honeybee venom-induced C-fiber activation. The effect of the venoms on chloroquine-sensitive and −insensitive subpopulation of C-fiber terminals was mimicked by melittin but not apamin; two of peptide venom components. Chloroquine-sensitive C-fibers are stimulated as a consequence of mast cell activation. Melittin degranulated mast cells in mouse skin by a non-IgE and non-MrgprB2 mechanism, and this may explain the stronger activation of the chloroquine-sensitive C-fibers.

First-in-human microelectrode recordings from the vagus nerve during clinical vagus nerve stimulation.

Vagus nerve stimulation (VNS) is an effective treatment for people with drug-resistant epilepsy. However, its mechanisms of action are poorly understood, including which nerve fibers are activated in humans during VNS in typical clinical settings and which are required for clinical efficacy. In particular, there have been no intraneural recordings of vagus nerve fiber activation in awake humans undergoing chronic VNS. In this study, for the first time, we report recordings from the vagus nerve in this setting. The recordings were performed using a sterile tungsten microelectrode inserted percutaneously into the cervical vagus nerve under ultrasound guidance. The clinical VNS systems were used to deliver stimulation while activity in the vagus nerve was recorded. In addition to activating myelinated axons at low currents, we provide evidence that VNS can also activate unmyelinated C fibers in the vagus nerve at currents <1 mA. These results add to our understanding of how VNS exerts its beneficial effects in drug-resistant epilepsy. Here we describe for the first time, electrical recordings from the vagus nerve in awake drug-resistant epilepsy patients with an implanted vagus nerve stimulation (VNS) device. We found that the VNS device was able to activate both myelinated and unmyelinated fibers within the vagus nerve, whichcontributes to our understanding of how VNS works in the context of drug-resistant epilepsy.

Novel KIF26A variants associated with pediatric intestinal pseudo-obstruction (PIPO) and brain developmental defects.

Pediatric intestinal pseudo-obstruction (PIPO) is a rare congenital disorder of the enteric nervous system with distal colon aganglionosis potentially leading to intestinal obstruction. Recently, biallelic variants in KIF26A, encoding a crucial motor protein for the migration and differentiation of enteric neural crest cells, have been associated with a neurodevelopmental condition featuring cortical defects and PIPO-like features, though in absence of aganglionosis. So far, only 10 patients have been reported. In this study, we investigated three subjects with congenital hydrocephalus, neurodevelopmental impairment, and intestinal obstruction megacolon syndrome. Brain MRI revealed malformations within cortical dysplasia spectrum, including polymicrogyria and heterotopia. Pathology study of the intestine revealed aganglionosis and elevated acetylcholinesterase activity in parasympathetic nerve fibers. Through trio-exome sequencing (ES), we detected four novel biallelic KIF26A variants, including two missense changes (#1) and two distinct homozygous truncating variants in (#2 and #3). All variants are rare and predicted to be deleterious according to in silico tools. To characterize the impact of the missense variants, we performed 3D protein modeling using Alphafold3 and YASARA. Mutants exhibited increased energy scores compared to wild-type protein, supporting a significant structural destabilization of the protein. Our study expands the genotype and phenotype spectrum of the emerging KIF26A-related disorder.

Neuro-microcirculatory interrelationships in patients with kyphoscoliosis associated with neurological deficits

Background: The use of laser Doppler flowmetry with spectral wavelet analysis of blood flow fluctuations allows us to assess the functional state of thin unmyelinated nerve fibers and objectify the dynamics of recovery processes in patients with kyphoscoliotic spinal deformities associated with spinal cord compression. AIM: To study the features of neuromicrocirculatory relationships in patients with kyphoscoliosis associated with neurological deficits before and after surgical treatment. MATERIALS AND METHODS: 20 patients with spinal deformities associated with neurological deficits of varying severity were examined using the LDF method and operated on. Patients were examined before surgery, 1–2 weeks after surgery following regression of acute postoperative pain syndrome, 3–6 months, 6–12 months, and more than a year after surgery. The scope of the study included a general examination with a detailed assessment of the neurological status, radiation diagnostics (postural radiographs of the spine, computed tomography and magnetic resonance imaging of the spine with assessment of spinal canal stenosis). Patients with severe kyphoscoliotic deformities underwent CT myelography followed by the design of individual full-size 3D plastic models of the spine and myeloradicular structures. LDF with wavelet analysis was carried out at all periods of the survey. A perfusion study with determination of the average microcirculation was carried out at the level of the pad of the distal phalanx of the big toe using a two-channel LAKK-02 device with a semiconductor laser (sensing in the red Raman and infrared IR channels). The obtained LDF results were processed by spectral amplitude-frequency wavelet analysis to characterize microcirculation regulation factors in the ranges of sympathetic adrenergic regulation (0.02–0.046 Hz), sensory peptidergic influences (0.047–0.069 Hz), myogenic oscillations (0.07–0.145 Hz). RESULTS: After surgery, the activity of trophotropic sensory peptidergic nerve fibers, the values of perfusion of the microcirculatory channel increased and was maintained starting from the early postoperative period. Ergotropic sympathetic adrenergic activity was significantly decreased in the period of 6-12 months after surgery. Maximum mobilization of trophotropic neurogenic mechanisms of sanogenesis was observed in the period of 6-12 months after surgery. CONCLUSION: The obtained data indicate a significant participation of thin nerve fibers in the recovery processes after decompressive surgeries in the spinal canal zone and the creation of anatomical conditions for neurophysiological repair at the spinal cord level. The use of the LDF method with spectral wavelet analysis of blood flow fluctuations makes it possible to objectify the dynamics of thin unmyelinated nerve fibers and recovery processes in patients with kyphoscoliotic deformities of the spine associated with spinal cord compression.

Subminute thermal damage to cell types present in the skin

Introduction Psoriasis is characterized by an increase in the proliferation of keratinocytes and nerve fiber activity, contributing to the typical skin lesions. Pulsed Dye Laser (PDL) treatment is effective for the treatment of psoriatic lesions but its mechanism remains unclear. One hypothesis is that PDL causes thermal damage by the diffusion of heat to neighboring structures in lesional skin. There is limited information on the thermal sensitivity of these neighboring skin cells when exposed to hyperthermia for durations lasting less than a minute. Our study aimed to investigate the cell-specific responses to heat using sub-minute exposure times and moderate to ablative hyperthermia. Materials and Methods Cultured human endothelial cells, smooth muscle cells, neuronal cells, and keratinocytes were exposed to various time (2–20 sec) and temperature (45–70 °C) combinations. Cell viability was assessed by measuring intracellular ATP content 24 h after thermal exposure and this data was used to calculate fit parameters for the Arrhenius model and CEM43 calculations. Results Our results show significant differences in cell survival between cell types (p < 0.0001). Especially within the range of 50–60 °C, survival of neuronal cells and keratinocytes was significantly less than that of endothelial and smooth muscle cells. No statistically significant difference was found in the lethal dose (LT50) of thermal energy between neuronal cells and keratinocytes. However, CEM43 calculations showed significant differences between all four cell types. Conclusion The results imply that there is a cell-type-dependent sensitivity to thermal damage which suggests that neuronal cells and keratinocytes are particularly susceptible to diffusing heat from laser treatment. Damage to these cells may aid in modulating the neuro-inflammatory pathways in psoriasis. These data provide insight into the potential mechanisms of PDL therapy for psoriasis and advance our understanding of how thermal effects may play a role in its effectiveness.

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.

Modulation of TNF Release by the Innate Fear Odorant 2-Methylthiazoline Requires TRPA1-Mediated Signaling

The innate fear odorant 2-Methylthiazoline (2-MT) elicits highly robust innate fear and defensive behaviors, such as freezing, hypothermia and bradycardia via activation of transient receptor potential ankyrin 1 (TRPA1) channels. Activation of TRPA1-expressing vagus nerve fibers also regulates IL-1β induced hypothermia and reflex anti-inflammatory responses. However, it is unclear whether 2-MT can trigger an anti-inflammatory response via TRPA1 activation. Here, we demonstrate that 2-MT attenuates endotoxin-induced tumor necrosis factor (TNF) production in wild-type mice in TRPA1-dependent manner. Exposure to 2-MT induces a significant reduction in serum TNF in wild-type mice injected with endotoxin as compared to vehicle control mice (vehicle control vs. 2-MT; 1,123 ± 32.3 pg/mL vs. 714.1 ± 58.2 pg/mL; * p=0.02). However, 2-MT exposure fails to suppress endotoxin-induced TNF-release in TrpA1-knock out mice (vehicle control vs. 2-MT; 1,123 ± 32.3 vs. 948.7 ± 99.2 pg/mL; ns p=0.89). A single exposure to 2-MT during endotoxin injection also protects animals from lethal endotoxemia and significantly improves survival as compared to vehicle-exposed endotoxemic controls (vehicle control vs. single 2-MT Odor; 26.7% vs. 66.7% survival 120 hours post LPS injection). In addition, significant improvement in disease activity is observed in mice exposed to 2-MT odorant (vehicle control vs. single 2-MT Odor; disease activity: 0.5 ± 0.2 a.u. vs. 0.3 ± 0.1 a.u., * p=0.01). Collectively, these data characterize the anti-inflammatory effcacy of 2-MT and demonstrate that the modulation of TNF release by 2-MT requires TRPA1-mediated signaling. This work is supported in part by grants from NIH, NIGMS, 1R35 GM118182 to KJT and 1R01AR083159-01 to SSC. 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.

Retraction Note: Genetic manipulation of autonomic nerve fiber innervation and activity and its effect on breast cancer progression.

Retraction Note: Genetic manipulation of autonomic nerve fiber innervation and activity and its effect on breast cancer progression.

Development of a feline model for preclinical research of a new translabyrinthine auditory nerve implant.

Cochlear implants are among the most successful neural prosthetic devices to date but exhibit poor frequency selectivity and the inability to consistently activate apical (low frequency) spiral ganglion neurons. These issues can limit hearing performance in many cochlear implant patients, especially for understanding speech in noisy environments and in perceiving or appreciating more complex inputs such as music and multiple talkers. For cochlear implants, electrical current must pass through the bony wall of the cochlea, leading to widespread activation of auditory nerve fibers. Cochlear implants also cannot be implanted in some individuals with an obstruction or severe malformations of the cochlea. Alternatively, intraneural stimulation delivered via an auditory nerve implant could provide direct contact with neural fibers and thus reduce unwanted current spread. More confined current during stimulation can increase selectivity of frequency fiber activation. Furthermore, devices such as the Utah Slanted Electrode Array can provide access to the full cross section of the auditory nerve, including low frequency fibers that are difficult to reach using a cochlear implant. However, further scientific and preclinical research of these Utah Slanted Electrode Array devices is limited by the lack of a chronic large animal model for the auditory nerve implant, especially one that leverages an appropriate surgical approach relevant for human translation. This paper presents a newly developed transbullar translabyrinthine surgical approach for implanting the auditory nerve implant into the cat auditory nerve. In our first of a series of studies, we demonstrate a surgical approach in non-recovery experiments that enables implantation of the auditory nerve implant into the auditory nerve, without damaging the device and enabling effective activation of the auditory nerve fibers, as measured by electrode impedances and electrically evoked auditory brainstem responses. These positive results motivate performing future chronic cat studies to assess the long-term stability and function of these auditory nerve implant devices, as well as development of novel stimulation strategies that can be translated to human patients.

Abstract TMP111: Selective Activation of Peritoneal TRPV1-Containing Vagal Afferents Promotes Sustained Mild Hypothermia and Neuroprotection Following Stroke

Intro: Mild hypothermia has been clinically effective at improving outcomes in cardiac arrest patients for decades. Similarly, mild hypothermia has been shown to neuroprotective in experimental stroke models. Unfortunately, hypothermia protocols in awake subjects are hampered by inconsistent temperature management due to incomplete suppression of cold defense mechanisms (e.g. shiver response). To address a need for better strategies for cooling conscious subjects, we sought to promote mild hypothermia by pharmacological activation of heat-sensing nerve fibers in the thermoregulatory system. We hypothesize that selective activation of TRPV1-containing vagal afferents in the peritoneal cavity can promote sustained hypothermia and protection following stroke. Methods: Aged (18-20 mo) and young (11 weeks) C57BL6 mice of both sexes were given a capsinoid mixture consisting of capsiate and dihydrocapsiate. Mice from both the aged and young cohorts underwent permanent distal middle cerebral artery occlusion (pdMCAO) or sham before recovering for 2hrs in warming cages to maintain normal body temperatures during post-stroke recovery. At 2 hours after stroke, mice were given capsinoids or vehicle (4 IP injections, 90 min interval) to produce 6 hours of mild hypothermia (or normothermic control). After 3 days brains were collected for histological analysis. Results: Capsinoids are particularly suited for region selective activation of TRPV1 targets, as they are degraded by ubiquitous esterases, and thus limited in biodistribution to distant targets. This regionally restricted activation was demonstrated through induction of mild hypothermia with IP capsinoid administration, but not with oral or subcutaneous delivery. We demonstrated that the hypothermic effect is TRPV1 dependent and that IP capsinoid delivery increases activity of the cervical vagus (hook electrode). We applied this capsinoid-mediated hypothermia approach to the pdMCAO model and demonstrated a significant reduction of brain infarct at 3 days post-stroke in both young and aged mice of both sexes. Conclusion: Selective activation of TRPV1-containing peritoneal vagal afferents is sufficient to promote sustained mild hypothermia and protection following ischemic stroke.

Investigation of the functioning of a neurohybrid system based on the FitzHugh–Nagumo radio generator and mouse hippocampal neurons

Currently, in the treatment of neurodegenerative diseases that are difficult to respond to drug therapy, electrical stimulation of the brain is performed through invasive intervention in damaged structures of the nervous tissue. The development and development of invasive technologies of closed-loop neural interfaces have made it possible to achieve great success in restoring neural connections, since they have finer and more precise stimulation settings that respond to changes in the physiological state, which is important in the process of restoring the functions of the nervous tissue. Advances in these areas open up prospects for the treatment of a wide range of diseases of the motor system and neurodegenerative diseases of the brain. In this study, a neurohybrid closed system was used, consisting of a FitzHugh-Nagumo radio generator and live surviving slices of the mouse brain hippocampus. For the preparation of surviving slices of the hippocampus, sexually mature males aged 2-3 months of the C57BL/6 mouse line were used. For the preparation and incubation of slices of the hippocampus, a solution of artificial cerebrospinal fluid (ACSF) was used, composition in (mM): 126 NaCl; 3.5 KCl; 1.2 KH2PO4; 26 NaHCO3; 1.3 MgCl * 6H2O; 2 CaCl2 * 6H2O; 10 D-glucose at constant carbogen saturation (95% O2 and 5% CO2). Registration of the electrical activity of brain neurons was carried out using optical and electrophysiological methods. In experiments on pairing a neuron-like FitzHugh-Nagumo generator and biological nerve cells in a closed circuit, an effect was obtained when the activity of brain nerve cells switched the generator to a self-oscillating mode. The evoked oscillations in the neuron-like generator provided an effective stimulus for the activation of nerve fibers in the perforant pathway of the hippocampus. As a result, it was possible to fix a decrease in the frequency of the generator impulses, which was provoked by the responses of living neurons to the incoming stimulus from the neuron-like generator. These results show the ability of live neural networks to control an artificial signal by adjusting its parameters by changing their own activity and confirm the efficiency of using closed loop systems when combining live and artificial neurons. The present study requires further experiments to create more physiological conditions for the functioning of the proposed neurohybrid system. In addition, this neurohybrid system will be improved and have adaptive properties through the use of memristive devices. Advances in this direction will help solve the urgent problem of restoring lost brain functions at the cellular and network levels.

The neural control of movement: a century of in vivo motor unit recordings is the legacy of Adrian and Bronk.

In two papers dated 1928 to 1929 in The Journal of Physiology, Edgar Adrian and Detlev Bronk described recordings from motor nerve and muscle fibres. The recordings from motor nerve fibres required progressive dissection of the nerve until a few fibres remained, from which isolated single fibre activity could be detected. The muscle fibre recordings were performed in humans during voluntary contractions with an intramuscular electrode - the concentric needle electrode - that they describe for the first time in the second paper. They recognised that muscle fibres would respond to each impulse sent by the innervating motor neurone and that therefore muscle fibre recordings provided information on the times of activation of the motor nerve fibres which were as accurate as a direct record from the nerve. These observations and the description of the concentric needle electrode opened the era of motor unit recordings in humans, which have continued for almost a century and have provided a comprehensive view of the neural control of movement at the motor unit level. Despite important advances in technology, many of the principles of motor unit behaviour that would be investigated in the subsequent decades were canvassed in the two papers by Adrian and Bronk. For example, they described the concomitant motor neurones' recruitment and rate coding for force modulation, synchronisation of motor unit discharges, and the dependence of discharge rate on motor unit recruitment threshold. Here, we summarise their observations and discuss the impact of their work. We highlight the advent of the concentric needle, and its subsequent influence on motor control research.

Towards a more accurate quasi-static approximation of the electric potential for neurostimulation with kilohertz-frequency sources * *This work has been partially supported by ANID Millennium Science Initiative Program through Millennium Nucleus for Applied Control and Inverse Problems NCN19-161.

Objective. Our goal was to determine the conditions for which a more precise calculation of the electric potential than the quasi-static approximation may be needed in models of electrical neurostimulation, particularly for signals with kilohertz-frequency components. Approach. We conducted a comprehensive quantitative study of the differences in nerve fiber activation and conduction block when using the quasi-static and Helmholtz approximations for the electric potential in a model of electrical neurostimulation. Main results. We first show that the potentials generated by sources of unbalanced pulses exhibit different transients as compared to those of charge-balanced pulses, and this is disregarded by the quasi-static assumption. Secondly, relative errors for current-distance curves were below 3%, while for strength-duration curves these ranged between 1%–17%, but could be improved to less than 3% across the range of pulse duration by providing a corrected quasi-static conductivity. Third, we extended our analysis to trains of pulses and reported a ‘congruence area’ below 700 Hz, where the fidelity of fiber responses is maximal for supra-threshold stimulation. Further examination of waveforms and polarities revealed similar fidelities in the congruence area, but significant differences were observed beyond this area. However, the spike-train distance revealed differences in activation patterns when comparing the response generated by each model. Finally, in simulations of conduction-block, we found that block thresholds exhibited errors above 20% for repetition rates above 10 kHz. Yet, employing a corrected value of the conductivity improved the agreement between models, with errors no greater than 8%. Significance. Our results emphasize that the quasi-static approximation cannot be naively extended to electrical stimulation with high-frequency components, and notable differences can be observed in activation patterns. As well, we introduce a methodology to obtain more precise model responses using the quasi-static approach, retaining its simplicity, which can be a valuable resource in computational neuroengineering.

Enhancing the selective electrical activation of human vagal nerve fibers: a comparative computational modeling study with validation in a rat sciatic model

Objective. Vagus nerve stimulation (VNS) is an emerging treatment option for a myriad of medical disorders, where the method of delivering electrical pulses can vary depending on the clinical indication. In this study, we investigated the relative effectiveness of electrically activating the cervical vagus nerve among three different approaches: nerve cuff electrode stimulation (NCES), transcutaneous electrical nerve stimulation (TENS), and enhanced TENS (eTENS). The objectives were to characterize factors that influenced nerve activation and to compare the nerve recruitment properties as a function of nerve fiber diameter. Methods. The Finite Element Model, based on data from the Visible Human Project, was implemented in COMSOL. The three simulation types were compared under a range of vertical and horizontal displacements relative to the location of the vagus nerve. Monopolar anodic stimulation was examined, along with latency and activation of different fiber sizes. Nerve activation was determined via the activating function and McIntyre-Richardson-Grill models, and activation thresholds were validated in an in-vivo rodent model. Results. While NCES produced the lowest activation thresholds, eTENS generally performed superior to TENS under the range of conditions and fiber diameters, producing activation thresholds up to three times lower than TENS. eTENS also preserved its enhancement when surface electrodes were displaced away from the nerve. Anodic stimulation revealed an inhibitory region that removed eTENS benefits. eTENS also outperformed TENS by up to four times when targeting smaller diameter nerve fibers, scaling similar to a cuff electrode. In latency and activation of smaller diameter nerve fibers, eTENS results resembled those of NCES more than a TENS electrode. Activation threshold ratios were consistent in in-vivo validation. Significance. Our findings expand upon previously identified mechanisms for eTENS and further demonstrate how eTENS emulates a nerve cuff electrode to achieve lower activation thresholds. This work further characterizes considerations required for VNS under the three stimulation methods.

Peripheral neural synchrony in pediatric cochlear implant users

We recently developed a noninvasive method to quantify neural synchrony in the electrically stimulated cochlear nerve (i.e., peripheral neural synchrony) using an index named the phase locking value (PLV). The PLV is a measurement of trial-to-trial phase coherence in the summated activity of cochlear nerve fibers. Larger PLVs indicate better/stronger peripheral neural synchrony. This tool allows for investigating this important phenomenon in cochlear implant (CI) users for the first time in the literature. The aim of this study was to characterize peripheral neural synchrony in a large group of pediatric CI users with various etiologies. To date, study participants included 17 children with cochlear nerve deficiency, 28 children with Gap Junction Beta-2 mutation, nine children with normal inner ear anatomy and idiopathic hearing loss, three children with enlarged vestibular aqueducts, three children with Mondini malformation and two children with Usher syndrome. All participants use Cochlear™ Nucleus® devices in their test ears. For each implanted ear tested in each participant, peripheral neural synchrony was assessed at the maximum comfortable level and multiple electrode locations across the electrode array. Our preliminary results demonstrated substantial variations in peripheral neural synchrony among pediatric CI users. These variations appear to depend on hearing loss etiologies.

Cochlear aging disrupts the correlation between spontaneous rate- and sound-level coding in auditory nerve fibers.

The spiking activity of auditory nerve fibers (ANFs) transmits information about the acoustic environment from the cochlea to the central auditory system. Increasing age leads to degeneration of cochlear tissues, including the sensory hair cells and stria vascularis. Here, we aim to identify the functional effects of such age-related cochlear pathologies of ANFs. Rate-level functions (RLFs) were recorded from single-unit ANFs of young adult (n = 52, 3-12 months) and quiet-aged (n = 24, >36 months) Mongolian gerbils of either sex. RLFs were used to determine sensitivity and spontaneous rates (SRs) and were classified into flat-saturating, sloping-saturating, and straight categories, as previously established. A physiologically based cochlear model, adapted for the gerbil, was used to simulate the effects of cochlear degeneration on ANF physiology. In ANFs tuned to low frequencies (<3.5 kHz), SR was lower in those of aged gerbils, while an age-related loss of low-SR fibers was evident in ANFs tuned to high frequencies. These changes in SR distribution did not affect the typical SR versus sensitivity correlation. The distribution of RLF types among low-SR fibers, however, shifted toward that of high-SR fibers, specifically showing more fast-saturating and fewer sloping-saturating RLFs. A modeled striatal degeneration, which affects the combined inner hair cell and synaptic output, reduced SR but left RLF type unchanged. An additional reduced basilar membrane gain, which decreased sensitivity, explained the changed RLF types. Overall, the data indicated age-related changes in the characteristics of single ANFs that blurred the established relationships between SR and RLF types.NEW & NOTEWORTHY Auditory nerve fibers, which connect the cochlea to the central auditory system, change their encoding of sound level in aged gerbils. In addition to a general shift to higher levels, indicative of decreased sensitivity, level coding was also differentially affected in fibers with low- and high-spontaneous rates. Loss of low-spontaneous rate fibers, combined with a general decrease of spontaneous rate, further blurs the categorization of auditory nerve fiber types in the aged gerbil.

Vagus nerve stimulation using an endovascular electrode array

Objective. Vagus nerve stimulation (VNS), which involves a surgical procedure to place electrodes directly on the vagus nerve (VN), is approved clinically for the treatment of epilepsy, depression, and to facilitate rehabilitation in stroke. VNS at surgically implanted electrodes is often limited by activation of motor nerve fibers near and within the VN that cause neck muscle contraction. In this study we investigated endovascular VNS that may allow activation of the VN at locations where the motor nerve fibers are not localized. Approach. We used endovascular electrodes within the nearby internal jugular vein (IJV) to electrically stimulate the VN while recording VN compound action potentials (CAPs) and neck muscle motor evoked potentials (MEPs) in an acute intraoperative swine experiment. Main Results. We show that the stimulation electrode position within the IJV is critical for efficient activation of the VN. We also demonstrate use of fluoroscopy (cone beam CT mode) and ultrasound to determine the position of the endovascular stimulation electrode with respect to the VN and IJV. At the most effective endovascular stimulation locations tested, thresholds for VN activation were several times higher than direct stimulation of the nerve using a cuff electrode; however, this work demonstrates the feasibility of VNS with endovascular electrodes and provides tools to optimize endovascular electrode positions for VNS. Significance. This work lays the foundation to develop endovascular VNS strategies to stimulate at VN locations that would be otherwise too invasive and at VN locations where structures such as motor nerve fibers do not exist.

Study of Electrical Neural Stimulation Effects Using Extraneural and Intraneural Electrodes

Sensory feedback restoration in upper-limb neuroprosthetics can significantly enhance amputees’ quality of life. Neural interfaces allow the elicitation of sensory information through current stimuli. Stimulation studies can be useful to evaluate the electric potential distribution into the nerve in response to a current stimulus and therefore the activation of fibers. In this paper, hybrid FEM-Neuron computational models are used to study nerve fiber activation in different nerve models that resemble the human median nerve. To conduct a comprehensive study, the variability in fascicular topography and different configurations of active sites of two types of electrodes (intraneural and extraneural) has been considered. Furthermore, the simulation results (in terms of the percentage of fiber activation in nerve fascicles, their location in the nerve section models, and the order of their activation when the stimulus increases) are evaluated according to the sensation intensity perceived by a human amputee in an experimental trial. The obtained results let us infer the effect of using intraneural and extraneural electrodes on the number and position of activated fascicles when the minimum values of electric charges considered in the experimental trial are used, and the dependence of the order of fiber activation into the fascicles on the current stimulus.

Beta-blockade enhances anthracycline control of metastasis in triple-negative breast cancer.

Beta-adrenergic blockade has been associated with improved cancer survival in patients with triple-negative breast cancer (TNBC), but the mechanisms of these effects remain unclear. In clinical epidemiological analyses, we identified a relationship between beta-blocker use and anthracycline chemotherapy in protecting against TNBC progression, disease recurrence, and mortality. We recapitulated the effect of beta-blockade on anthracycline efficacy in xenograft mouse models of TNBC. In metastatic 4T1.2 and MDA-MB-231 mouse models of TNBC, beta-blockade improved the efficacy of the anthracycline doxorubicin by reducing metastatic development. We found that anthracycline chemotherapy alone, in the absence of beta-blockade, increased sympathetic nerve fiber activity and norepinephrine concentration in mammary tumors through the induction of nerve growth factor (NGF) by tumor cells. Moreover, using preclinical models and clinical samples, we found that anthracycline chemotherapy up-regulated β2-adrenoceptor expression and amplified receptor signaling in tumor cells. Neurotoxin inhibition of sympathetic neural signaling in mammary tumors using 6-hydroxydopamine or genetic deletion of NGF or β2-adrenoceptor in tumor cells enhanced the therapeutic effect of anthracycline chemotherapy by reducing metastasis in xenograft mouse models. These findings reveal a neuromodulatory effect of anthracycline chemotherapy that undermines its potential therapeutic impact, which can be overcome by inhibiting β2-adrenergic signaling in the tumor microenvironment. Supplementing anthracycline chemotherapy with adjunctive β2-adrenergic antagonists represents a potential therapeutic strategy for enhancing the clinical management of TNBC.

Abstract WP216: Intraperitoneal Delivery Of Capsinoids (Non-pungent TRPV1 Agonists) Promotes Mild Hypothermia And Improved Long-term Outcome Following Stroke

Intro: Mild hypothermia has been shown to improve outcomes in cardiac arrest and experimental stroke models. Unfortunately, hypothermia protocols in awake subjects are hampered by inconsistent temperature management due to incomplete suppression of cold defense mechanisms (e.g. shiver response). To address a need for better strategies for cooling conscious subjects, we sought to promote mild hypothermia by pharmacological activation of heat-sensing nerve fibers in the thermoregulatory system. We hypothesize that capsinoids - non-pungent agonists of the transient receptor potential vanilloid 1 (TRPV1) channel - activate vagal afferents, triggering thermoregulatory regions of the brain to induce mechanisms of whole-body cooling, protecting the brain and preventing injury progression after a stroke. Methods: C57BL6 male mice of 11wks underwent permanent distal middle cerebral artery occlusion (pdMCAO) or sham. Mice recovered for 2hrs in warming cages to maintain normal body temperatures during post-stroke recovery before being administered capsinoids or vehicle (4 IP injections, 90 min interval) to produce 6 hours of mild hypothermia (or normothermic control). After 1 month, mice underwent functional tests and brains were collected for histological analysis. Results: Capsinoids provided a significant and consistent hypothermia whereas vehicle maintained a baseline temperature (two-way ANOVA, n=7, p=0.0036). Capsinoid-treated mice showed ~50% infarct volume reduction 1 month after stroke, measured by cresyl-violet staining (0.7% ± 0.1% SEM vs 1.5% ± 0.2% SEM, n=7, two-tailed unpaired t-test: p=0.0046). Additionally, a stroke-induced breathing dysfunction (decrease in tidal volume by plethysmography) was significantly restored toward normal in the capsinoid-treated group (7.7e-3 ± 5.6e-4 SEM vs 5.8e-3 ± 2.4e-4 SEM, n=8, one-way ANOVA: p=0.033). Conclusion: Capsinoids delivered to TRPV1-containing visceral afferents promotes reversible mild hypothermia in freely moving conscious mice. Application of this form of cooling in the pdMCAO model provides significant reduction of stroke injury volume and long-term improvement in functional outcome.