Computational modelling of nerve stimulation and recording with peripheral visceral neural interfaces

Objective: Neuromodulation of visceral nerves is being intensively studied for treating a wide range of conditions, but effective translation requires increasing the efficacy and predictability of neural interface performance. Here we use computational models of rat visceral nerve to predict how neuroanatomical variability could affect both electrical stimulation and recording with an experimental planar neural interface. Approach: We developed a hybrid computational pipeline, Visceral Nerve Ensemble Recording & Stimulation (ViNERS), to couple finite-element modelling of extracellular electrical fields with biophysical simulations of individual axons. Anatomical properties of fascicles and axons in rat pelvic and vagus nerves were measured or obtained from public datasets. To validate ViNERS, we simulated pelvic nerve stimulation and recording with an experimental four-electrode planar array. Main results: Axon diameters measured from pelvic nerve were used to model a population of myelinated and unmyelinated axons and simulate recordings of electrically evoked single-unit field potentials (SUFPs). Across visceral nerve fascicles of increasing size, our simulations predicted an increase in stimulation threshold and a decrease in SUFP amplitude. Simulated threshold changes were dominated by changes in perineurium thickness, which correlates with fascicle diameter. We also demonstrated that ViNERS could simulate recordings of electrically-evoked compound action potentials (ECAPs) that were qualitatively similar to pelvic nerve recording made with the array used for simulation. Significance: We introduce ViNERS as a new open-source computational tool for modelling large-scale stimulation and recording from visceral nerves. ViNERS predicts how neuroanatomical variation in rat pelvic nerve affects stimulation and recording with an experimental planar electrode array. We show ViNERS can simulate ECAPS that capture features of our recordings, but our results suggest the underlying NEURON models need to be further refined and specifically adapted to accurately simulate visceral nerve axons.

The Frequency-Dependence of Pre- and Postganglionic Nerve Stimulation of Pig and Rat Bladder

Purpose: The urinary bladder generates phasic contractions via action potentials generated in pre- and then postganglionic neurons. Whilst the frequency-dependence of postganglionic neurons to generate contractions has been quantified, the dynamic range of preganglionic neurons is less clear and if intramural ganglia exert frequency-dependent modulation of transmission between pre- and postganglionic neurons. The phosphodiesterase type 5 inhibitor sildenafil reduces neurotransmitter release from postganglionic fibres to detrusor smooth muscle and an additional question was if there was also a preganglionic action. This study aimed to compare the frequency range of bladder contractile activation by pre- and postganglionic stimulation in pig and rat bladders and if sildenafil exerted additional preganglionic actions.Methods: An arterially-perfused ex vivo pig bladder preparation was used for preganglionic (pelvic nerve) and mixed pre-and postganglionic (direct bladder wall) stimulation at 36°C and postganglionic mediated contractions achieved by field-stimulation of in vitro isolated detrusor strips. With rats, pelvic nerve stimulation was carried out in vivo and postganglionic stimulation also with isolated detrusor strips.Results: All contractions were abolished by 2% lignocaine indicating they are nerve-mediated. Stimulation targets were verified with hexamethonium that completely abolished pelvic nerve responses by had no effect on detrusor strips; responses to mixed bladder wall stimulation were partially reduced. The frequency-dependence of contractile activation was similar whether by pre- or postganglionic stimulation in both pigs and rats. Sildenafil reduced contractions to preganglionic stimulation significantly more than to postganglionic stimulation. Mixed pre- and postganglionic stimulation were reduced by an intermediate extent.Conclusions: Intramural ganglia offer no frequency-dependent modulation under the experimental conditions used here and the sildenafil data are consistent with multiple sites of action underlying generation of bladder contractions. A translational aspect of these findings is discussed in terms of setting stimulation parameters for neuromodulation protocols.

Nerve-Sparing Radical Hysterectomy: Kobayashi's Method

After Prof. S. Okabayashi introduced Okabayashi Operation in 1921, several surgeons introduced numerous improvements in Japan. One of them is so-called the Tokyo Method which was improved and revised by Dr. Kyusaku Ogino (1950), Prof. Takashi Kobayashi, University of Tokyo (1961, 1970), and Prof. Shoichi Sakamoto, University of Tokyo (1981). The nerve-sparing radical hysterectomy without sacrificing radicality was introduced in 19611 and improved in 1970 by Prof. Kobayashi.2 The autonomic nerve pathway including hypogastric nerve (sympathetic nerve), pelvic splanchnic nerve (parasympathetic nerve), and pelvic nerve plexus as a junction of the two nerves and the branch of the plexus to the bladder (vesical nerve branch) are preserved except in advanced cases. He divided the process of nerve-sparing surgery into four steps for separating the autonomic nerve pathway from adjacent tissues along the pathway consisting of cardinal, sacrouterine, rectouterine/vaginal, and vesicouterine ligaments. The first step is separation of the cardinal ligament (deep uterine vessels) from the pelvic splanchnic nerve. The second step is separation of the medial side of severed cardinal ligament from the pelvic nerve plexus. The first and second steps are performed in the lateral side of the autonomic nerve system. The third step is separation of sacrouterine and rectouterine/vaginal ligaments from hypogastric nerve and pelvic nerve plexus. The third step is necessary for achieving high radicality, namely, for severing the sacrouterine and rectouterine/vaginal ligaments near the rectum without damage to the pelvic nerve plexus. The fourth step is separation of paravaginal tissues and posterior (deep) layer of the vesicouterine ligament from the vesical nerve branches of the plexus. The third and fourth steps are performed in the medial side of the autonomic nerve system.

Advanced Neural Interface toward Bioelectronic Medicine Enabled by Micro-Patterned Shape Memory Polymer

Recently, methods for the treatment of chronic diseases and disorders through the modulation of peripheral and autonomic nerves have been proposed. To investigate various treatment methods and results, experiments are being conducted on animals such as rabbits and rat. However the diameter of the targeted nerves is small (several hundred μm) and it is difficult to modulate small nerves. Therefore, a neural interface that is stable, easy to implant into small nerves, and is biocompatible is required. Here, to develop an advanced neural interface, a thiol-ene/acrylate-based shape memory polymer (SMP) was fabricated with a double clip design. This micro-patterned design is able to be implanted on a small branch of the sciatic nerve, as well as the parasympathetic pelvic nerve, using the shape memory effect (SME) near body temperature. Additionally, the IrO2 coated neural interface was implanted on the common peroneal nerve in order to perform electrical stimulation and electroneurography (ENG) recording. The results demonstrate that the proposed neural interface can be used for the modulation of the peripheral nerve, including the autonomic nerve, towards bioelectronic medicine.

Review: Pelvic nerves – from anatomy and physiology to clinical applications

A prerequisite for nerve-sparing pelvic surgery is a thorough understanding of the topographic anatomy of the fine and intricate pelvic nerve networks, and their connections to the central nervous system. Insights into the functions of pelvic nerves will help to interpret disease symptoms correctly and improve treatment. In this article, we review the anatomy and physiology of autonomic pelvic nerves, including their topography and putative functions. The aim is to achieve a better understanding of the mechanisms of pelvic pain and functional disorders, as well as improve their diagnosis and treatment. The information will also serve as a basis for counseling patients with chronic illnesses. A profound understanding of pelvic neuroanatomy will permit complex surgery in the pelvis without relevant nerve injury.

Recording of Electrically Evoked Neural Activity and Bladder Pressure Responses in Awake Rats Chronically Implanted With a Pelvic Nerve Array

Bioelectronic medical devices are well established and widely used in the treatment of urological dysfunction. Approved targets include the sacral S3 spinal root and posterior tibial nerve, but an alternate target is the group of pelvic splanchnic nerves, as these contain sacral visceral sensory and autonomic motor pathways that coordinate storage and voiding functions of the bladder. Here, we developed a device suitable for long-term use in an awake rat model to study electrical neuromodulation of the pelvic nerve (homolog of the human pelvic splanchnic nerves). In male Sprague-Dawley rats, custom planar four-electrode arrays were implanted over the distal end of the pelvic nerve, close to the major pelvic ganglion. Electrically evoked compound action potentials (ECAPs) were reliably detected under anesthesia and in chronically implanted, awake rats up to 8 weeks post-surgery. ECAP waveforms showed three peaks, with latencies that suggested electrical stimulation activated several subpopulations of myelinated A-fiber and unmyelinated C-fiber axons. Chronic implantation of the array did not impact on voiding evoked in awake rats by continuous cystometry, where void parameters were comparable to those published in naïve rats. Electrical stimulation with chronically implanted arrays also induced two classes of bladder pressure responses detected by continuous flow cystometry in awake rats: voiding contractions and non-voiding contractions. No evidence of tissue pathology produced by chronically implanted arrays was detected by immunohistochemical visualization of markers for neuronal injury or noxious spinal cord activation. These results demonstrate a rat pelvic nerve electrode array that can be used for preclinical development of closed loop neuromodulation devices targeting the pelvic nerve as a therapy for neuro-urological dysfunction.