Short-term Dorsal Genital Nerve Stimulation Increases Subjective Arousal in Women With and Without Spinal Cord Injury: A Preliminary Investigation.

OBJECTIVES: Female sexual dysfunction (FSD) affects an estimated 40% of women. Unfortunately, FSD is understudied, leading to limited treatment options for FSD. Neuromodulation has shown some success in alleviating FSD symptoms. We developed a pilot study to investigate the short-term effect of electrical stimulation of the dorsal genital nerve and tibial nerve on sexual arousal in healthy women, women with FSD, and women with spinal cord injury (SCI) and FSD. MATERIALS AND METHODS: This study comprises a randomized crossover design in three groups: women with SCI, women with non-neurogenic FSD, and women without FSD or SCI. The primary outcome measure was change in vaginal pulse amplitude (VPA) from baseline. Secondary outcome measures were changes in subjective arousal, heart rate, and mean arterial pressure from baseline. Participants attended one or two study sessions where they received either transcutaneous dorsal genital nerve stimulation (DGNS) or tibial nerve stimulation (TNS). At each session, a vaginal photoplethysmography sensor was used to measure VPA. Participants also rated their level of subjective arousal and were asked to report any pelvic sensations. RESULTS: We found that subjective arousal increased significantly from before to after stimulation in DGNS study sessions across all women. TNS had no effect on subjective arousal. There were significant differences in VPA between baseline and stimulation, baseline and recovery, and stimulation and recovery periods among participants, but there were no trends across groups or stimulation type. Two participants with complete SCIs experienced genital sensations. CONCLUSIONS: To our knowledge, this is the first study to measure sexual arousal in response to short-term neuromodulation in women. This study indicates that short-term DGNS but not TNS can increase subjective arousal, but the effect of stimulation on genital arousal is inconclusive. This study provides further support for DGNS as a treatment for FSD.

Multiformity of extracellular microelectrode recordings from Aδ neurons in the dorsal root ganglia: a computational modeling study.

Microelectrodes serve as a fundamental tool in electrophysiology research throughout the nervous system, providing a means of exploring neural function with a high resolution of neural firing information. We constructed a hybrid computational model using the finite element method and multicompartment cable models to explore factors that contribute to extracellular voltage waveforms that are produced by sensory pseudounipolar neurons, specifically smaller A-type neurons, and that are recorded by microelectrodes in dorsal root ganglia. The finite element method model included a dorsal root ganglion, surrounding tissues, and a planar microelectrode array. We built a multicompartment neuron model with multiple trajectories of the glomerular initial segment found in many A-type sensory neurons. Our model replicated both the somatic intracellular voltage profile of Aδ low-threshold mechanoreceptor neurons and the unique extracellular voltage waveform shapes that are observed in experimental settings. Results from this model indicated that tortuous glomerular initial segment geometries can introduce distinct multiphasic properties into a neuron's recorded waveform. Our model also demonstrated how recording location relative to specific microanatomical components of these neurons, and recording distance from these components, can contribute to additional changes in the multiphasic characteristics and peak-to-peak voltage amplitude of the waveform. This knowledge may provide context for research employing microelectrode recordings of pseudounipolar neurons in sensory ganglia, including functional mapping and closed-loop neuromodulation. Furthermore, our simulations gave insight into the neurophysiology of pseudounipolar neurons by demonstrating how the glomerular initial segment aids in increasing the resistance of the stem axon and mitigating rebounding somatic action potentials.NEW & NOTEWORTHY We built a computational model of sensory neurons in the dorsal root ganglia to investigate factors that influence the extracellular waveforms recorded by microelectrodes. Our model demonstrates how the unique structure of these neurons can lead to diverse and often multiphasic waveform profiles depending on the location of the recording contact relative to microanatomical neural components. Our model also provides insight into the neurophysiological function of axon glomeruli that are often present in these neurons.

Immediate and Long-Term Effects of Tibial Nerve Stimulation on the Sexual Behavior of Female Rats.

OBJECTIVES: There are limited treatment options for female sexual dysfunction (FSD). Percutaneous tibial nerve stimulation (PTNS) has shown improvements in FSD symptoms in neuromodulation clinical studies, but the direct effects on sexual function are not understood. This study evaluated the immediate and long-term effects of PTNS on sexual motivation and receptivity in a rat model of menopausal women. Our primary hypothesis was that long-term PTNS would yield greater changes in sexual behavior than short-term stimulation. MATERIALS AND METHODS: In two experiments, after receiving treatment, we placed ovariectomized female rats in an operant chamber in which the female controls access to a male by nose poking. We used five treatment conditions, which were with or without PTNS and no, partial, or full hormone priming. In experiment 1, we rotated rats through each condition twice with behavioral testing immediately following treatment for ten weeks. In experiment 2, we committed rats to one condition for six weeks and tracked sexual behavior over time. We quantified sexual motivation and sexual receptivity with standard measures. RESULTS: No primary comparisons were significant in this study. In experiment 1, we observed increased sexual motivation but not receptivity immediately following PTNS with partial hormone priming, as compared with priming without PTNS (linear mixed effect models; initial latency [p = 0.34], inter-interval latency [p = 0.77], nose poke frequency [p = 0.084]; eight rats). In experiment 2, we observed trends of increased sexual receptivity (linear correlation for weekly group means; mounts [p = 0.094 for trendline], intromissions [p = 0.073], lordosis quotient [p = 0.58], percent time spent with a male [p = 0.39], decreased percent time alone [p = 0.024]; four rats per condition), and some sexual motivation metrics (linear correlation for weekly group means; nose pokes per interval [p = 0.050], nose poke frequency [p = 0.039], decreased initial latency [p = 0.11]; four rats per condition) when PTNS was applied long-term with partial hormone priming, as compared with hormone-primed rats without stimulation. CONCLUSIONS: PTNS combined with hormone priming shows potential for increasing sexual motivation in the short-term and sexual receptivity in the long-term in rats. Further studies are needed to examine variability in rat behavior and to investigate PTNS as a treatment for FSD in menopausal women.

Acute dorsal genital nerve stimulation increases subjective arousal in women with and without spinal cord injury: a preliminary investigation.

Introduction: Female sexual dysfunction (FSD) impacts an estimated 40% of women. Unfortunately, female sexual function is understudied, leading to limited treatment options for FSD. Neuromodulation has demonstrated some success in improving FSD symptoms. We developed a pilot study to investigate the short-term effect of electrical stimulation of the dorsal genital nerve and tibial nerve on sexual arousal in healthy women, women with FSD, and women with spinal cord injury (SCI) and FSD. Methods: This study consists of a randomized crossover design in three groups: women with SCI, women with non-neurogenic FSD, and women without FSD or SCI. The primary outcome measure was change in vaginal pulse amplitude (VPA) from baseline. Secondary outcome measures were changes in subjective arousal, heart rate, and mean arterial pressure from baseline. Participants attended one or two study sessions where they received either transcutaneous dorsal genital nerve stimulation (DGNS) or tibial nerve stimulation (TNS). At each session, a vaginal photoplethysmography sensor was used to measure VPA. Participants also rated their level of subjective arousal and were asked to report any pelvic sensations. Results: We found that subjective arousal increased significantly from before to after stimulation in DGNS study sessions across all women. TNS had no effect on subjective arousal. There were significant differences in VPA between baseline and stimulation, baseline and recovery, and stimulation and recovery periods among participants, but there were no trends across groups or stimulation type. Two participants with complete SCIs experienced genital sensations. Discussion: This is the first study to measure sexual arousal in response to acute neuromodulation in women. This study demonstrates that acute DGNS, but not TNS, can increase subjective arousal, but the effect of stimulation on genital arousal is inconclusive. This study provides further support for DGNS as a treatment for female sexual dysfunction.

Pudendal, but not tibial, nerve stimulation modulates vulvar blood perfusion in anesthetized rodents.

INTRODUCTION AND HYPOTHESIS: Preclinical studies have shown that neuromodulation can increase vaginal blood perfusion, but the effect on vulvar blood perfusion is unknown. We hypothesized that pudendal and tibial nerve stimulation could evoke an increase in vulvar blood perfusion. METHODS: We used female Sprague-Dawley rats for non-survival procedures under urethane anesthesia. We measured perineal blood perfusion in response to 20-minute periods of pudendal and tibial nerve stimulation using laser speckle contrast imaging (LSCI). After a thoracic-level spinalization and a rest period, we repeated each stimulation trial. We calculated average blood perfusion before, during, and after stimulation for three perineal regions (vulva, anus, and inner thigh), for each nerve target and spinal cord condition. RESULTS: We observed a significant increase in vulvar, anal, and inner thigh blood perfusion during pudendal nerve stimulation in spinally intact and spinalized rats. Tibial nerve stimulation had no effect on perineal blood perfusion for both spinally intact and spinalized rats. CONCLUSIONS: This is the first study to examine vulvar hemodynamics with LSCI in response to nerve stimulation. This study demonstrates that pudendal nerve stimulation modulates vulvar blood perfusion, indicating the potential of pudendal neuromodulation to improve genital blood flow as a treatment for women with sexual dysfunction. This study provides further support for neuromodulation as a treatment for women with sexual arousal disorders. Studies in unanesthetized animal models of genital arousal disorders are needed to obtain further insights into the mechanisms of neural control over genital hemodynamics.

Detrusor Pressure Estimation from Single-Channel Urodynamics.

Urodynamics is the current gold-standard for diagnosing lower urinary tract dysfunction, but uses non-physiologically fast, retrograde cystometric filling to obtain a brief snapshot of bladder function. Ambulatory urodynamics allows physicians to evaluate bladder function during natural filling over longer periods of time, but artifacts generated from patient movement necessitate the use of an abdominal pressure sensor, which makes long-term monitoring and feedback for closed-loop treatment impractical. In this paper, we analyze the characteristics of single-channel bladder pressure signals from human and feline datasets, and present an algorithm designed to estimate detrusor pressure, which is useful for diagnosis and treatment. We utilize multiresolution analysis techniques to maximize the attenuation of probable abdominal pressure components in the vesical pressure signal. Results indicate a strong correlation, averaging 0.895 ± 0.121 (N = 40) and 0.812 ± 0.113 (N = 16) between the estimated detrusor pressure obtained by the proposed method and recorded urodynamic data from human and feline subjects, respectively. Clinical Relevance- This work establishes that signal pro-cessing techniques may be applied to vesical pressure alone to accurately reconstruct pressures generated independently by the detrusor muscle. This is relevant for emerging sensors that measure vesical pressure alone or for data analysis of bladder pressure in ambulatory subjects which contains significant abdominal pressure artifacts.

Ultraflexible and Stretchable Intrafascicular Peripheral Nerve Recording Device with Axon-Dimension, Cuff-Less Microneedle Electrode Array.

Peripheral nerve mapping tools with higher spatial resolution are needed to advance systems neuroscience, and potentially provide a closed-loop biomarker in neuromodulation applications. Two critical challenges of microscale neural interfaces are 1) how to apply them to small peripheral nerves, and 2) how to minimize chronic reactivity. A flexible microneedle nerve array (MINA) is developed, which is the first high-density penetrating electrode array made with axon-sized silicon microneedles embedded in low-modulus thin silicone. The design, fabrication, acute recording, and chronic reactivity to an implanted MINA, are presented. Distinctive units are identified in the rat peroneal nerve. The authors also demonstrate a long-term, cuff-free, and suture-free fixation manner using rose bengal as a light-activated adhesive for two time-points. The tissue response is investigated at 1-week and 6-week time-points, including two sham groups and two MINA-implanted groups. These conditions are quantified in the left vagus nerve of rats using histomorphometry. Micro computed tomography (micro-CT) is added to visualize and quantify tissue encapsulation around the implant. MINA demonstrates a reduction in encapsulation thickness over previously quantified interfascicular methods. Future challenges include techniques for precise insertion of the microneedle electrodes and demonstrating long-term recording.

Closed-loop sacral neuromodulation for bladder function using dorsal root ganglia sensory feedback in an anesthetized feline model.

Overactive bladder patients suffer from a frequent, uncontrollable urge to urinate, which can lead to a poor quality of life. We aim to improve open-loop sacral neuromodulation therapy by developing a conditional stimulation paradigm using neural recordings from dorsal root ganglia (DRG) as sensory feedback. Experiments were performed in 5 anesthetized felines. We implemented a Kalman filter-based algorithm to estimate the bladder pressure in real-time using sacral-level DRG neural recordings and initiated sacral root electrical stimulation when the algorithm detected an increase in bladder pressure. Closed-loop neuromodulation was performed during continuous cystometry and compared to bladder fills with continuous and no stimulation. Overall, closed-loop stimulation increased bladder capacity by 13.8% over no stimulation (p < 0.001) and reduced stimulation time versus continuous stimulation by 57.7%. High-confidence bladder single units had a reduced sensitivity during stimulation, with lower linear trendline fits and higher pressure thresholds for firing observed during stimulation trials. This study demonstrates the utility of decoding bladder pressure from neural activity for closed-loop control of sacral neuromodulation. An underlying mechanism for sacral neuromodulation may be a reduction in bladder sensory neuron activity during stimulation. Real-time validation during behavioral studies is necessary prior to clinical translation of closed-loop sacral neuromodulation.

Tibial nerve stimulation increases vaginal blood perfusion and bone mineral density and yield load in ovariectomized rat menopause model.

INTRODUCTION AND HYPOTHESIS: Human menopause transition and post-menopausal syndrome, driven by reduced ovarian activity and estrogen levels, are associated with an increased risk for symptoms including but not limited to sexual dysfunction, metabolic disease, and osteoporosis. Current treatments are limited in efficacy and may have adverse consequences, so investigation for additional treatment options is necessary. Previous studies have demonstrated that percutaneous tibial nerve stimulation (PTNS) and electro-acupuncture near the tibial nerve are minimally invasive treatments that increase vaginal blood perfusion or serum estrogen in the rat model. We hypothesized that PTNS would protect against harmful reproductive and systemic changes associated with menopause. METHODS: We examined the effects of twice-weekly PTNS (0.2 ms pulse width, 20 Hz, 2× motor threshold) under ketamine-xylazine anesthesia in ovariectomized (OVX) female Sprague-Dawley rats on menopause-associated physiological parameters including serum estradiol, body weight, blood glucose, bone health, and vaginal blood perfusion. Rats were split into three groups (n = 10 per group): (1) intact control (no stimulation), (2) OVX control (no stimulation), and (3) OVX stimulation (treatment group). RESULTS: PTNS did not affect serum estradiol levels, body weight, or blood glucose. PTNS transiently increased vaginal blood perfusion during stimulation for up to 5 weeks after OVX and increased areal bone mineral density and yield load of the right femur (side of stimulation) compared to the unstimulated OVX control. CONCLUSIONS: PTNS may ameliorate some symptoms associated with menopause. Additional studies to elucidate the full potential of PTNS on menopause-associated symptoms under different experimental conditions are warranted.

Sharpened and Mechanically Durable Carbon Fiber Electrode Arrays for Neural Recording.

Bioelectric medicine treatments target disorders of the nervous system unresponsive to pharmacological methods. While current stimulation paradigms effectively treat many disorders, the underlying mechanisms are relatively unknown, and current neuroscience recording electrodes are often limited in their specificity to gross averages across many neurons or axons. Here, we develop a novel, durable carbon fiber electrode array adaptable to many neural structures for precise neural recording. Carbon fibers ( [Formula: see text] diameter) were sharpened using a reproducible blowtorchmethod that uses the reflection of fibers against the surface of a water bath. The arrays were developed by partially embedding carbon fibers in medical-grade silicone to improve durability. We recorded acute spontaneous electrophysiology from the rat cervical vagus nerve (CVN), feline dorsal root ganglia (DRG), and rat brain. Blowtorching resulted in fibers of 72.3 ± 33.5-degree tip angle with [Formula: see text] exposed carbon. Observable neural clusters were recorded using sharpened carbon fiber electrodes fromrat CVN ( [Formula: see text]), feline DRG ( [Formula: see text]), and rat brain ( [Formula: see text]). Recordings from the feline DRG included physiologically relevant signals from increased bladder pressure and cutaneous brushing. These results suggest that this carbon fiber array is a uniquely durable and adaptable neural recordingdevice. In the future, this device may be useful as a bioelectric medicine tool for diagnosis and closed-loop neural control of therapeutic treatments and monitoring systems.

High-density neural recordings from feline sacral dorsal root ganglia with thin-film array.

Objective. Dorsal root ganglia (DRG) are promising sites for recording sensory activity. Current technologies for DRG recording are stiff and typically do not have sufficient site density for high-fidelity neural data techniques.Approach. In acute experiments, we demonstrate single-unit neural recordings in sacral DRG of anesthetized felines using a 4.5µm thick, high-density flexible polyimide microelectrode array with 60 sites and 30-40µm site spacing. We delivered arrays into DRG with ultrananocrystalline diamond shuttles designed for high stiffness affording a smaller footprint. We recorded neural activity during sensory activation, including cutaneous brushing and bladder filling, as well as during electrical stimulation of the pudendal nerve and anal sphincter. We used specialized neural signal analysis software to sort densely packed neural signals.Main results. We successfully delivered arrays in five of six experiments and recorded single-unit sensory activity in four experiments. The median neural signal amplitude was 55µV peak-to-peak and the maximum unique units recorded at one array position was 260, with 157 driven by sensory or electrical stimulation. In one experiment, we used the neural analysis software to track eight sorted single units as the array was retracted ∼500µm.Significance. This study is the first demonstration of ultrathin, flexible, high-density electronics delivered into DRG, with capabilities for recording and tracking sensory information that are a significant improvement over conventional DRG interfaces.

The Effect of Clinically Controllable Factors on Neural Activation During Dorsal Root Ganglion Stimulation.

OBJECTIVE: Dorsal root ganglion stimulation (DRGS) is an effective therapy for chronic pain, though its mechanisms of action are unknown. Currently, we do not understand how clinically controllable parameters (e.g., electrode position, stimulus pulse width) affect the direct neural response to DRGS. Therefore, the goal of this study was to utilize a computational modeling approach to characterize how varying clinically controllable parameters changed neural activation profiles during DRGS. MATERIALS AND METHODS: We coupled a finite element model of a human L5 DRG to multicompartment models of primary sensory neurons (i.e., Aα-, Aß-, Aδ-, and C-neurons). We calculated the stimulation amplitudes necessary to elicit one or more action potentials in each neuron, and examined how neural activation profiles were affected by varying clinically controllable parameters. RESULTS: In general, DRGS predominantly activated large myelinated Aα- and Aß-neurons. Shifting the electrode more than 2 mm away from the ganglion abolished most DRGS-induced neural activation. Increasing the stimulus pulse width to 500 µs or greater increased the number of activated Aδ-neurons, while shorter pulse widths typically only activated Aα- and Aß-neurons. Placing a cathode near a nerve root, or an anode near the ganglion body, maximized Aß-mechanoreceptor activation. Guarded active contact configurations did not activate more Aß-mechanoreceptors than conventional bipolar configurations. CONCLUSIONS: Our results suggest that DRGS applied with stimulation parameters within typical clinical ranges predominantly activates Aß-mechanoreceptors. In general, varying clinically controllable parameters affects the number of Aß-mechanoreceptors activated, although longer pulse widths can increase Aδ-neuron activation. Our data support several Neuromodulation Appropriateness Consensus Committee guidelines on the clinical implementation of DRGS.

Bladder pressure encoding by sacral dorsal root ganglion fibres: implications for decoding.

Objective.We aim at characterising the encoding of bladder pressure (intravesical pressure) by a population of sensory fibres. This research is motivated by the possibility to restore bladder function in elderly patients or after spinal cord injury using implanted devices, so called bioelectronic medicines. For these devices, nerve-based estimation of intravesical pressure can enable a personalized and on-demand stimulation paradigm, which has promise of being more effective and efficient. In this context, a better understanding of the encoding strategies employed by the body might in the future be exploited by informed decoding algorithms that enable a precise and robust bladder-pressure estimation.Approach.To this end, we apply information theory to microelectrode-array recordings from the cat sacral dorsal root ganglion while filling the bladder, conduct surrogate data studies to augment the data we have, and finally decode pressure in a simple informed approach.Main results.We find an encoding scheme by different main bladder neuron types that we divide into three response types (slow tonic, phasic, and derivative fibres). We show that an encoding by different bladder neuron types, each represented by multiple cells, offers reliability through within-type redundancy and high information rates through semi-independence of different types. Our subsequent decoding study shows a more robust decoding from mean responses of homogeneous cell pools.Significance.We have here, for the first time, established a link between an information theoretic analysis of the encoding of intravesical pressure by a population of sensory neurons to an informed decoding paradigm. We show that even a simple adapted decoder can exploit the redundancy in the population to be more robust against cell loss. This work thus paves the way towards principled encoding studies in the periphery and towards a new generation of informed peripheral nerve decoders for bioelectronic medicines.

Multi-channel intraneural vagus nerve recordings with a novel high-density carbon fiber microelectrode array.

Autonomic nerves convey essential neural signals that regulate vital body functions. Recording clearly distinctive physiological neural signals from autonomic nerves will help develop new treatments for restoring regulatory functions. However, this is very challenging due to the small nature of autonomic nerves and the low-amplitude signals from their small axons. We developed a multi-channel, high-density, intraneural carbon fiber microelectrode array (CFMA) with ultra-small electrodes (8-9 µm in diameter, 150-250 µm in length) for recording physiological action potentials from small autonomic nerves. In this study, we inserted CFMA with up to 16 recording carbon fibers in the cervical vagus nerve of 22 isoflurane-anesthetized rats. We recorded action potentials with peak-to-peak amplitudes of 15.1-91.7 µV and signal-to-noise ratios of 2.0-8.3 on multiple carbon fibers per experiment, determined conduction velocities of some vagal signals in the afferent (0.7-4.4 m/s) and efferent (0.7-8.8 m/s) directions, and monitored firing rate changes in breathing and blood glucose modulated conditions. Overall, these experiments demonstrated that CFMA is a novel interface for in-vivo intraneural action potential recordings. This work is considerable progress towards the comprehensive understanding of physiological neural signaling in vital regulatory functions controlled by autonomic nerves.

Anesthetic agents affect urodynamic parameters and anesthetic depth at doses necessary to facilitate preclinical testing in felines.

Urodynamic studies, used to understand bladder function, diagnose bladder disease, and develop treatments for dysfunctions, are ideally performed with awake subjects. However, in small and medium-sized animal models, anesthesia is often required for these procedures and can be a research confounder. This study compared the effects of select survival agents (dexmedetomidine, alfaxalone, and propofol) on urodynamic (Δpressure, bladder capacity, bladder compliance, non-voiding contractions, bladder pressure slopes) and anesthetic (change in heart rate [∆HR], average heart rate [HR], reflexes, induction/recovery times) parameters in repeated cystometrograms across five adult male cats. The urodynamic parameters under isoflurane and α-chloralose were also examined in terminal procedures for four cats. Δpressure was greatest with propofol, bladder capacity was highest with α-chloralose, non-voiding contractions were greatest with α-chloralose. Propofol and dexmedetomidine had the highest bladder pressure slopes during the initial and final portions of the cystometrograms respectively. Cats progressed to a deeper plane of anesthesia (lower HR, smaller ΔHR, decreased reflexes) under dexmedetomidine, compared to propofol and alfaxalone. Time to induction was shortest with propofol, and time to recovery was shortest with dexmedetomidine. These agent-specific differences in urodynamic and anesthetic parameters in cats will facilitate appropriate study-specific anesthetic choices.

Novel diamond shuttle to deliver flexible neural probe with reduced tissue compression.

The ability to deliver flexible biosensors through the toughest membranes of the central and peripheral nervous system is an important challenge in neuroscience and neural engineering. Bioelectronic devices implanted through dura mater and thick epineurium would ideally create minimal compression and acute damage as they reach the neurons of interest. We demonstrate that a three-dimensional diamond shuttle can be easily made with a vertical support to deliver ultra-compliant polymer microelectrodes (4.5-µm thick) through dura mater and thick epineurium. The diamond shuttle has 54% less cross-sectional area than an equivalently stiff silicon shuttle, which we simulated will result in a 37% reduction in blood vessel damage. We also discovered that higher frequency oscillation of the shuttle (200 Hz) significantly reduced tissue compression regardless of the insertion speed, while slow speeds also independently reduced tissue compression. Insertion and recording performance are demonstrated in rat and feline models, but the large design space of these tools are suitable for research in a variety of animal models and nervous system targets.

The rodent vaginal microbiome across the estrous cycle and the effect of genital nerve electrical stimulation.

Treatment options are limited for the approximately 40% of postmenopausal women worldwide who suffer from female sexual dysfunction (FSD). Neural stimulation has shown potential as a treatment for genital arousal FSD, however the mechanisms for its improvement are unknown. One potential cause of some cases of genital arousal FSD are changes to the composition of the vaginal microbiota, which is associated with vulvovaginal atrophy. The primary hypothesis of this study was that neural stimulation may induce healthy changes in the vaginal microbiome, thereby improving genital arousal FSD symptoms. In this study we used healthy rats, which are a common animal model for sexual function, however the rat vaginal microbiome is understudied. Thus this study also sought to examine the composition of the rat vaginal microbiota. Treatment rats (n = 5) received 30 minutes of cutaneous electrical stimulation targeting the genital branch of the pudendal nerve, and Control animals (n = 4) had 30-minute sessions without stimulation. Vaginal lavage samples were taken during a 14-day baseline period including multiple estrous periods and after twice-weekly 30-minute sessions across a six-week trial period. Analysis of 16S rRNA gene sequences was used to characterize the rat vaginal microbiota in baseline samples and determine the effect of stimulation. We found that the rat vaginal microbiota is dominated by Proteobacteria, Firmicutes, and Actinobacteria, which changed in relative abundance during the estrous cycle and in relationship to each other. While the overall stimulation effects were unclear in these healthy rats, some Treatment animals had less alteration in microbiota composition between sequential samples than Control animals, suggesting that stimulation may help stabilize the vaginal microbiome. Future studies may consider additional physiological parameters, in addition to the microbiome composition, to further examine vaginal health and the effects of stimulation.

Spatial models of cell distribution in human lumbar dorsal root ganglia.

Dorsal root ganglia (DRG), which contain the somata of primary sensory neurons, have increasingly been considered as novel targets for clinical neural interfaces, both for neuroprosthetic and pain applications. Effective use of either neural recording or stimulation technologies requires an appropriate spatial position relative to the target neural element, whether axon or cell body. However, the internal three-dimensional spatial organization of human DRG neural fibers and somata has not been quantitatively described. In this study, we analyzed 202 cross-sectional images across the length of 31 human L4 and L5 DRG from 10 donors. We used a custom semi-automated graphical user interface to identify the locations of neural elements in the images and normalize the output to a consistent spatial reference for direct comparison by spinal level. By applying a recursive partitioning algorithm, we found that the highest density of cell bodies at both spinal levels could be found in the inner 85% of DRG length, the outer-most 25-30% radially, and the dorsal-most 69-76%. While axonal density was fairly homogeneous across the DRG length, there was a distinct low density region in the outer 7-11% radially. These findings are consistent with previous qualitative reports of neural distribution in DRG. The quantitative measurements we provide will enable improved targeting of future neural interface technologies and DRG-focused pharmaceutical therapies, and provide a rigorous anatomical description of the bridge between the central and peripheral nervous systems.

Ultracompliant Carbon Nanotube Direct Bladder Device.

The bladder, stomach, intestines, heart, and lungs all move dynamically to achieve their purpose. A long-term implantable device that can attach onto an organ, sense its movement, and deliver current to modify the organ function would be useful in many therapeutic applications. The bladder, for example, can suffer from incomplete contractions that result in urinary retention with patients requiring catheterization. Those affected may benefit from a combination of a strain sensor and electrical stimulator to better control bladder emptying. The materials and design of such a device made from thin layer carbon nanotube (CNT) and Ecoflex 00-50 are described and demonstrate its function with in vivo feline bladders. During bench-top characterization, the resistive and capacitive sensors exhibit stability throughout 5000 stretching cycles under physiology conditions. In vivo measurements with piezoresistive devices show a high correlation between sensor resistance and volume. Stimulation driven from platinum-silicone composite electrodes successfully induce bladder contraction. A method for reliable connection and packaging of medical grade wire to the CNT device is also presented. This work is an important step toward the translation of low-durometer elastomers, stretchable CNT percolation, and platinum-silicone composite, which are ideal for large-strain bioelectric applications to sense or modulate dynamic organ states.

Real-Time Bladder Pressure Estimation for Closed-Loop Control in a Detrusor Overactivity Model.

Overactive bladder (OAB) patients suffer from a frequent urge to urinate, which can lead to a poor quality of life. Current neurostimulation therapy uses open-loop electrical stimulation to alleviate symptoms. Continuous stimulation facilitates habituation of neural pathways and consumes battery power. Sensory feedback-based closed-loop stimulation may offer greater clinical benefit by driving bladder relaxation only when bladder contractions are detected, leading to increased bladder capacity. Effective delivery of such sensory feedback, particularly in real-time, is necessary to accomplish this goal. We implemented a Kalman filter-based model to estimate bladder pressure in real-time using unsorted neural recordings from sacral-level dorsal root ganglia, achieving a 0.88 ± 0.16 correlation coefficient fit across 35 normal and simulated OAB bladder fills in five experiments. We also demonstrated closed-loop neuromodulation using the estimated pressure to trigger pudendal nerve stimulation, which increased bladder capacity by 40% in two trials. An offline analysis indicated that unsorted neural signals had a similar stability over time as compared to sorted single units, which would require a higher computational load. We believe this paper demonstrates the utility of decoding bladder pressure from neural activity for closed-loop control; however, real-time validation during behavioral studies is necessary prior to clinical translation.