Low pressure voiding induced by stimulation and 1 kHz post-stimulation block of the pudendal nerves in cats

Chen, Jialiang; Jian, Jianan; Wang, Jicheng; Shen, Zhijun; Shen, Bing; Wang, William Yang; Beckel, Jonathan M.; Groat, William C. de; Chermansky, Christopher; Tai, Changfeng

doi:10.1016/j.expneurol.2021.113860

Cited by 6 publications

(8 citation statements)

References 22 publications

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“…This study investigated the responses to high‐frequency electrical stimulation by applying high‐frequency potential alternation directly across the neuronal membrane using the voltage clamp technique. Although this method is useful to study membrane current and ion channel gating properties in response to high‐frequency membrane potential alternation, HFBS in clinical applications to block nerve conduction is always applied extracellularly but not directly across the neural membrane (Apovian et al, 2017; Chen et al, 2021; Soin et al, 2015). Since kHz stimulation is also successful when applied to the spinal cord to treat chronic back pain (Al‐Kaisy et al, 2018; Hagedorn et al, 2020), investigation of neuronal response to extracellular application of HFBS using the patch clamp technique will certainly provide information to better understand the possible mechanisms of HFBS in the central nervous system where effects on neuronal perikarya and synaptic transmission as well as effects on axons are likely to be important.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, this nerve block method has been used clinically to treat obesity by blocking the vagus nerve (Apovian et al, 2017 ) or to treat post‐amputation limb pain by blocking the sciatic nerve (Soin et al, 2015 ). HFBS was also investigated in animal studies to block the pudendal nerve for potential treatment of urinary dysfunction after spinal cord injury (Chen et al, 2021 ). Despite the long history of HFBS‐induced nerve conduction block and its recent success in clinical application, the mechanism of action is still unknown.…”

Section: Introductionmentioning

confidence: 99%

“…nerve for potential treatment of urinary dysfunction after spinal cord injury (Chen et al, 2021). Despite the long history of HFBS-induced nerve conduction block and its recent success in clinical application, the mechanism of action is still unknown.…”

mentioning

confidence: 99%

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Effect of high‐frequency membrane potential alternation between depolarization and hyperpolarization on dorsal root ganglion neurons of rats

Shen

Beckel

Groat

et al. 2023

Physiological Reports

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The purpose of this study was to determine how sensory neurons respond to high‐frequency membrane potential alternation between depolarization and hyperpolarization. Membrane currents were recorded from dissociated dorsal root ganglion (DRG) neurons of adult rats using the whole cell patch clamp technique in voltage clamp mode. Stepwise depolarization of the membrane was applied first to determine the threshold membrane potential for inducing an action potential (AP) current. Then, membrane potential alternation between depolarization (to +20 mV) and hyperpolarization (to −110 mV) was applied to the neuron for 10 s at different frequencies (10 Hz to 1 kHz). The tested DRG neurons had APs of either a long duration (>10 ms) or a short duration (<10 ms). Membrane potential alternation at ≥500 Hz completely disrupted the AP generation, disabled the ion channel gating function, and produced membrane current alternating symmetrically across zero. Replacing extracellular sodium with potassium increased the amplitude of the membrane current response and caused the membrane current to be larger during hyperpolarization than during depolarization. These results support the hypothesis that high‐frequency biphasic stimulation blocks axonal conduction by driving the potassium channel open constantly. Understanding neural membrane response to high‐frequency membrane potential alternation is important to reveal the possible mechanisms underlying axonal conduction block induced by high‐frequency biphasic stimulation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effect of high‐frequency membrane potential alternation between depolarization and hyperpolarization on dorsal root ganglion neurons of rats

Shen

Beckel

Groat

et al. 2023

Physiological Reports

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“…In addition, we briefly describe a drug combination therapy, neostigmine plus glycopyrrolate, that has clinical data and which also uses drug repositioning for inducing defecation in spinal injured individuals (Korsten et al, 2005;. Finally, we mention preclinical studies exploring the use of a pudendal and sacral nerve neuromodulation devices to induce urination (Chen et al, 2021) and defecation in spinal injured individuals (Wang et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Recent Developments in On-Demand Voiding Therapies

Thor,

Marson,

Katofiasc

et al. 2024

J Pharmacol Exp Ther

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One cannot survive without regularly urinating and defecating. People with neurological injury (spinal cord injury, traumatic brain injury, stroke) or disease (multiple sclerosis, Parkinson's disease, spina bifida) and many elderly are unable to voluntarily initiate voiding. The great majority of them require bladder catheters to void urine and "manual bowel programs" with digital rectal stimulation and manual extraction to void stool. Catheterassociated urinary tract infections frequently require hospitalization, while manual bowel programs are time-consuming (1-2 hours), stigmatizing, and cause rectal pain and discomfort.Laxatives and enemas produce defecation, but onset and duration are unpredictable, prolonged, and difficult to control, which can produce involuntary defecation and fecal incontinence. Patients with spinal cord injury (SCI) consider recovery of bladder and bowel function a higher priority than recovery of walking. Bladder and bowel dysfunction are a top reason for institutionalization of elderly. Surveys indicate that convenience, rapid onset and short duration, reliability and predictability, and efficient voiding are priorities of SCI individuals.Despite the severe, unmet, medical need; there is no literature regarding on-demand, rapidonset, short-duration, drug-induced, voiding therapies. This article provides in depth discussion of recent discovery and development of two candidates for on-demand voiding therapies. The first, DTI-117, a neurokinin 2 receptor agonist, induces both urination and defecation after systemic administration. The second, DTI-301, is a TRPV1 receptor agonist that induces defecation after intrarectal administration. The review also presents clinical studies of a combination drug therapy administered via iontophoresis and preclinical studies of neuromodulation devices that induce urination and defecation.

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“…Axonal conduction block by high-frequency (kHz) biphasic stimulation (HFBS) has been known for 80 years [1]. Recently it has been successfully applied in clinical applications to treat obesity and amputation limb pain [2,3] or in preclinical study to restore bladder function after chronic spinal cord injury [4]. However, currently the mechanism of action is still unclear.…”

Section: Introductionmentioning

confidence: 99%

Intracellular sodium concentration and membrane potential oscillation in axonal conduction block induced by high-frequency biphasic stimulation

Zhong¹,

Zhang²,

Beckel³

et al. 2022

J. Neural Eng.

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Objective. A new axonal conduction model was used to analyze the interaction between intracellular sodium concentration and membrane potential oscillation in axonal conduction block induced by high-frequency (kHz) biphasic stimulation (HFBS). Approach. The model includes intracellular and extracellular sodium and potassium concentrations and ion pumps. First, the HFBS (1 kHz, 5.4 mA) was applied for a duration (59.4 seconds) long enough to produce an axonal conduction block after terminating the stimulation, i.e., a post-stimulation block. Then, the intensity of HFBS was reduced to a lower level for 4 seconds to determine if the axonal conduction block could be maintained. Main results. The block duration was shortened from 1363 ms to 5 ms as the reduced HFBS intensity was increased from 0 mA to 4.1 mA. The block was maintained for the entire tested period (4000 ms) if the reduced intensity was above 4.2 mA. At the low intensity (<4.2 mA) the membrane potential oscillation disrupted the post-stimulation block caused by the increased intracellular sodium concentration, while at the high intensity (>4.2 mA) the membrane potential oscillation was strong enough to maintain the block and further increased the intracellular sodium concentration. Significance. This study indicates a possibility to develop a new nerve block method to reduce the HFBS intensity, which can extend the battery life for an implantable nerve stimulator in clinical applications to block pain of peripheral origin.

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Low pressure voiding induced by stimulation and 1 kHz post-stimulation block of the pudendal nerves in cats

Cited by 6 publications

References 22 publications

Effect of high‐frequency membrane potential alternation between depolarization and hyperpolarization on dorsal root ganglion neurons of rats

Effect of high‐frequency membrane potential alternation between depolarization and hyperpolarization on dorsal root ganglion neurons of rats

Recent Developments in On-Demand Voiding Therapies

Intracellular sodium concentration and membrane potential oscillation in axonal conduction block induced by high-frequency biphasic stimulation

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