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ABSTRACT ObjectiveThis study aimed to investigate the potential role of cesium chloride (CsCl), ivabradine (IVA), and isoproterenol (ISO) on the sensory transmission of bladder afferents to graded urinary bladder distension (UBD). We specifically selected these drugs to target the hyperpolarization‐activated cyclic nucleotide‐gated (HCN) cation channels to determine their role in afferent encoding. MethodsThe bladders of C57BL/6 female mice were harvested with attached pelvic nerves in continuity, and the stimulus–response function (SRF) of bladder afferents to stepped bladder distension (20, 40, 60, 80 cmH₂O) was recorded by single‐fiber recordings. Their changes in SRF to bath application of CsCl, IVA, and ISO were then evaluated. The presence of HCN on bladder afferent endings was assessed through immunohistological staining on bladder sections from mice with genetically labeled bladder afferents. ResultsIVA and ISO did not significantly reduce afferent responses to UBD, whereas CsCl increased afferent responses. Bladder afferents in the pelvic nerve pathway were categorized into low‐firing (LF, < 10 Hz) and high‐firing (HF, > 10 Hz) groups. SRF in both the LF and HF groups showed similar trends with no significant changes in response to IVA and ISO. CsCl increased SRF only in the HF group but not in the LF group. Immunohistological staining revealed that HCN1 does not extensively co‐localize with afferent endings, showing only sporadic presence. ConclusionOur targeted pharmacological studies with single‐fiber recordings and immunohistological staining collectively suggest that HCN channels do not play a significant role in bladder afferent sensory transmission. 

Background.Safe sensory-selective local anesthetics would be a major advance in the management of acute and chronic pain. Here we describe the sensory-selective local anesthetic properties and the toxicity profile of a known metabolite of amino-amide local anesthetics,2',6'-pipecolylxylidine (PPX). Methods.PPX was synthesized and made into its hydrochloride salt. PPX or ropivacaine (ROP) were injected at the sciatic nerve or intrathecally in rats, who then underwent modified hotplate (sensory) testing and weight-bearing (motor) testing. Rats injected with PPX or ROP were assessed for clinical toxicity endpoints. Conduction blockade was studied with single-unit recordings in mice. Biocompatibility was assessed histologically. Results.In male rats, sciatic sensory and motor block from 15 mM ROP lasted ~150 min; sensory nerve block from 30 mM PPX lasted 67.4 ± 17.4 min without motor block. Addition of chemical permeation enhancers to 30 mM PPX abolished sensory selectivity. Intrathecal 15 mM ROP produced sensory and motor block lasting ~15 min; sensory block from 30 mM PPX lasted 24.8 ± 8.7 min without motor block; repeated injection caused continuous sensory-selective block. In female rats, sciatic nerve blocks with ROP were similar to blocks in males, while blocks with PPX were sensory-selective but higher PPX concentrations were required. Ex vivo, 1.5 mM ROP caused reversible block of Aδ and C-fibers; 15 mM PPX blocked Aδ- but not C-fibers. Systemic 39.0 ± 1.8 mg/kg ROP caused severe clinical toxicity; 75.3 ± 3.2 mg/kg PPX caused none. Tissue reaction to PPX was benign, comparable to that of ROP. Conclusions.PPX provides sensory-selective local and neuraxial anesthesia with a good safety profile. The sensory selectivity may be attributable to the particular hydrophilic-hydrophobic balance of PPX. 

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

Abstract Silicone‐based devices have the potential to achieve an ideal interface with nervous tissue but suffer from scalability, primarily due to the mechanical mismatch between established electronic materials and soft elastomer substrates. This study presents a novel approach using conventional electrode materials through multifunctional nanomesh to achieve reliable elastic microelectrodes directly on polydimethylsiloxane (PDMS) silicone with an unprecedented cellular resolution. This engineered nanomesh features an in‐plane nanoscale mesh pattern, physically embodied by a stack of three thin‐film materials by design, namely Parylene‐C for mechanical buffering, gold (Au) for electrical conduction, and Poly(3,4‐ethylenedioxythiophene)‐poly(styrenesulfonate) (PEDOT:PSS) for improved electrochemical interfacing. Nanomesh elastic neuroelectronics are validated using single‐unit recording from the small and curvilinear epidural surface of mouse dorsal root ganglia (DRG) with device self‐conformed and superior recording quality compared to plastic control devices requiring manual pressing is demonstrated. Electrode scaling studies from in vivo epidural recording further revealed the need for cellular resolution for high‐fidelity recording of single‐unit activities and compound action potentials. In addition to creating a minimally invasive device to effectively interface with DRG sensory afferents at a single‐cell resolution, this study establishes nanomeshing as a practical pathway to leverage traditional electrode materials for a new class of elastic neuroelectronics. 

Wearable devices for continuous health monitoring in humans are constantly evolving, yet the signal quality may be improved by optimizing electrode placement. While the commonly used locations to measure electrodermal activity (EDA) are at the fingers or the wrist, alternative locations, such as the torso, need to be considered when applying an integrated multimodal approach of concurrently recording multiple bio-signals, such as the monitoring of visceral pain symptoms like those related to irritable bowel syndrome (IBS). This study aims to quantitatively determine the EDA signal quality at four torso locations (mid-chest, upper abdomen, lower back, and mid-back) in comparison to EDA signals recorded from the fingers. Concurrent EDA signals from five body locations were collected from twenty healthy participants as they completed a Stroop Task and a Cold Pressor task that elicited salient autonomic responses. Mean skin conductance (meanSCL), non-specific skin conductance responses (NS.SCRs), and sympathetic response (TVSymp) were derived from the torso EDA signals and compared with signals from the fingers. Notably, TVSymp recorded from the mid-chest location showed significant changes between baseline and Stroop phase, consistent with the TVSymp recorded from the fingers. A high correlation (0.77–0.83) was also identified between TVSymp recorded from the fingers and three torso locations: mid-chest, upper abdomen, and lower back locations. While the fingertips remain the optimal site for EDA measurement, the mid-chest exhibited the strongest potential as an alternative recording site, with the upper abdomen and lower back also demonstrating promising results. These findings suggest that torso-based EDA measurements have the potential to provide reliable measurement of sympathetic neural activities and may be incorporated into a wearable belt system for multimodal monitoring. 

Functional understanding of visceral afferents is important for developing the new treatment to visceral hypersensitivity and pain. The sparse distribution of visceral afferents in dorsal root ganglia (DRGs) has challenged conventional electrophysiological recordings. Alternatively, Ca 2+ indicators like GCaMP6f allow functional characterization by optical recordings. Here we report a turnkey microscopy system that enables simultaneous Ca 2+ imaging at two parallel focal planes from intact DRG. By using consumer-grade optical components, the microscopy system is cost-effective and can be made broadly available without loss of capacity. It records low-intensity fluorescent signals at a wide field of view (1.9 × 1.3 mm) to cover a whole mouse DRG, with a high pixel resolution of 0.7 micron/pixel, a fast frame rate of 50 frames/sec, and the capability of remote focusing without perturbing the sample. The wide scanning range (100 mm) of the motorized sample stage allows convenient recordings of multiple DRGs in thoracic, lumbar, and sacral vertebrae. As a demonstration, we characterized mechanical neural encoding of visceral afferents innervating distal colon and rectum (colorectum) in GCaMP6f mice driven by VGLUT2 promotor. A post-processing routine is developed for conducting unsupervised detection of visceral afferent responses from GCaMP6f recordings, which also compensates the motion artifacts caused by mechanical stimulation of the colorectum. The reported system offers a cost-effective solution for high-throughput recordings of visceral afferent activities from a large volume of DRG tissues. We anticipate a wide application of this microscopy system to expedite our functional understanding of visceral innervations.