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.

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.

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.

Transcutaneous Electrical Nerve Stimulation to Improve Female Sexual Dysfunction Symptoms: A Pilot Study.

OBJECTIVES: To perform a pilot study using transcutaneous electrical nerve stimulation (TENS) on the dorsal genital nerve and the posterior tibial nerve for improving symptoms of female sexual dysfunction (FSD) in women without bladder problems. We hypothesize that this therapy will be effective at improving genital arousal deficits. MATERIALS AND METHODS: Nine women with general FSD completed the study. Subjects received 12 sessions of transcutaneous dorsal genital nerve stimulation (DGNS; n = 6) or posterior tibial nerve stimulation (PTNS; n = 3). Stimulation was delivered for 30 min at 20 Hz. Sexual functioning was evaluated with the female sexual functioning index (FSFI), and surveys were also given on general health, urological functioning, and the Patients' Global Impression of Change (PGIC) after treatment. Surveys were given before treatment (baseline), after 6 and 12 weeks of treatment, and 6 weeks after the completion of stimulation sessions. RESULTS: The average total FSFI score across all subjects significantly increased from 15.3 ± 4.8 at baseline to 20.3 ± 7.8 after six sessions, 21.7 ± 7.5 after 12 sessions, and 21.3 ± 7.1 at study completion (p < 0.05 for all time points). Increases were observed in both DGNS and PTNS subjects. Significant FSFI increases were seen in the subdomains of lubrication, arousal, and orgasm, each of which is related to genital arousal. Bladder and general health surveys did not change across the study. PGIC had a significant increase. CONCLUSIONS: This study provides evidence that transcutaneous stimulation of peripheral nerves has the potential to be a valuable therapeutic tool for women with FSD.

Tibial Nerve Stimulation to Drive Genital Sexual Arousal in an Anesthetized Female Rat.

BACKGROUND: There is clinical evidence that percutaneous tibial nerve stimulation can positively benefit women with female sexual interest/arousal disorder, yet no studies have explored the potential mechanisms further. AIM: To investigate the effect of tibial nerve stimulation on vaginal blood perfusion (VBP) in an anesthetized rat model. METHODS: 16 ketamine-anesthetized rats were surgically implanted with a nerve cuff electrode on 1 tibial nerve. The tibial nerve was stimulated for 30 minutes continuously or non-continuously at a frequency of 10 to 25 Hz. OUTCOMES: VBP was measured with laser Doppler flowmetry and analyzed using a wavelet transform of time-frequency representations with a focus on the neurogenic energy range (0.076-0.200 Hz). RESULTS: 25 of 33 (75.8%) stimulation periods had at least a 500% increase in laser Doppler flowmetry neurogenic energy compared with baseline. This increase was most common within 20 to 35 minutes after the start of stimulation. There was no statistically significant difference for frequency used or estrous cycle stage. CLINICAL TRANSLATION: The results of this study provide further support for percutaneous tibial nerve stimulation as an alternative treatment option for women with genital arousal aspects of female sexual interest/arousal disorder. STRENGTHS AND LIMITATIONS: This study successfully demonstrates the ability of tibial nerve stimulation to increase VBP. However, further studies to determine parameter optimization and to illuminate neural mechanisms are needed. Further studies also are necessary to determine effects of repeated stimulation sessions. CONCLUSION: Long-duration tibial stimulation was successful at driving increases in the neurogenic component of VBP, providing evidence that tibial nerve stimulation could be used to treat genital arousal aspects of female sexual interest/arousal disorder by improving pelvic blood flow. Zimmerman LL, Rice IC, Berger MB, Bruns TM. Tibial Nerve Stimulation to Drive Genital Sexual Arousal in an Anesthetized Female Rat. J Sex Med 2018;15:296-303.

Time-Frequency Analysis of Increases in Vaginal Blood Perfusion Elicited by Long-Duration Pudendal Neuromodulation in Anesthetized Rats.

OBJECTIVES: Female sexual dysfunction (FSD) affects a significant portion of the population. Although treatment options for FSD are limited, neuromodulation for bladder dysfunction has improved sexual function in some women. A few studies have investigated peripheral neuromodulation for eliciting changes in vaginal blood flow, as a proxy for modulating genital sexual arousal, however results are generally transient. Our central hypothesis is that repeated or extended-duration pudendal nerve stimulation can elicit maintained vaginal blood flow increases. MATERIALS AND METHODS: Under ketamine anesthesia, the pudendal nerve of 14 female rats was stimulated at varying frequencies (1-100 Hz) and durations (0.15-60 min). Vaginal blood perfusion was measured with a laser Doppler flowmetry probe. Changes in blood perfusion were determined through raw signal analysis and increases in the energy of neurogenic (0.076-0.200 Hz) and myogenic (0.200-0.740 Hz) frequency bands through wavelet analysis. Additionally, a convolution model was developed for a carry-over stimulation effect. RESULTS: Each experiment had significant increases in vaginal blood perfusion due to pudendal nerve stimulation. In addition, there were large concurrent increases in neurogenic and myogenic frequency-band energy in 11/14 experiments, with an average maximal response at 31.3 min after stimulation initiation. An effective stimulation model with a 30-min carry-over effect had a stronger correlation to blood perfusion than the stimulation period itself. CONCLUSIONS: Repeated or extended-duration pudendal nerve stimulation can elicit maintained increases in vaginal blood perfusion. This work indicates the potential for pudendal neuromodulation as a method for increasing genital arousal as a potential treatment for FSD.