Urinary incontinence (UI) significantly impacts approximately 30% of the world?s population. The most prevalent condition, overactive bladder (OAB), affects 15% of adults and often manifests with other urinary dysfunctions causing urine leakage. OAB has an enormous US economic burden of $83 billion, in part from increased nursing home use due to UI. Incontinence profoundly impacts dignified, independent living, contributes to urinary tract infections, pressure ulcer sepsis and fall risk, and is a leading factor in functional decline among the elderly. As a result, UI is a major factor in clinical depression and contributes to social isolation . The risk factors for OAB (aging, obesity, diabetes, menopause, enlarged prostate) are disproportionately experienced by Veterans, and UI associates with military service and post-traumatic stress disorder in both male and female Veterans. Therefore UI (and OAB in particular) will continue to affect older Veterans disproportionately. Of the limited treatments for refractory OAB, percutaneous tibial nerve stimulation (PTNS) is likely the cheapest and safest. This project will demonstrate the feasibility of using ultrasonic nerve stimulation (UNS) as a novel alternative to PTNS. The rapidly decreasing cost for ultrasonic equipment is driving investigation of UNS to deliver targeted energy to the nerve without breaking the skin or causing discomfort from surface stimulation. UNS has many potential rehabilitation uses, i.e. for the treatment of neuropathic or amputee pain, or for locations that are difficult to access surgically. These treatments are all opportunities for future research. However, beginning with OAB is an excellent option for initial translation because the tibial nerve is superficial, PTNS is an established therapy, and because there are designated safe limits for ultrasound exposure. At this stage of research, our first goal is to generate the needed evidence to compete for funding to translate UNS to Veterans with OAB. Wearable tibial neurostimulation that is easy to use in the home would greatly expand access to these rehabilitation treatments for Veterans who have limited mobility, income, or live in rural locales. Critically, prior studies have demonstrated that low-intensity tibial UNS modulates bladder function and that peripheral UNS occurs with ultrasonic intensities below FDA safety limits. However, the UNS energy thresholds to produce compound action potentials (CAP) in the tibial and sciatic nerves have not been determined in the context of UI. Further, all prior UNS research has used bulky transducers which are not usable outside of laboratory settings. This work will address two feasibility challenges for future funding and translation: 1) identifying the minimum UNS intensity needed to noninvasively modulate CAPs and inhibit bladder contractions and 2) showing that thin, flexible, beam-formed arrays can produce ultrasonic intensities up to FDA safety limits at human anatomical scales. These data will be generated in two Specific Aims (SA). SA1 will determine the nerve activation and bladder inhibition power thresholds using ultrasonic nerve stimulation in an established rat model of bladder reflex contractions. Commercial fixed-focus transducers and an anesthetized animal model must be used in this aim because wearable devices for UNS are not yet available. Primary outcomes in this aim are i) sciatic CAP amplitude, ii) gastrocnemius electromyogram (EMG) amplitudes, and iii) bladder contraction rates. Outcomes from variable-intensity low-frequency UNS and high-frequency UNS will be compared to conventional electrical tibial nerve stimulation. SA2 will develop a wearable flexible ultrasonic neuromodulation array and demonstrate that flexible ultrasound arrays can generate mechanical index (MI) in the estimated neuromodulation range. In SA2a we will design array geometries and acoustic lens profiles using computer simulations and validate pressure levels with a water bath hydrophone. In SA2b we will fabricate flexible arrays with direct-printed acoustic fillers and lenses, and substrate-printed curvature sensors. Beam steering patterns will be iterated to produce a focal region smaller than 0.1 cm3 and MI between 0.5?1.9, within the estimated neuromodulation range and below FDA safety limits.

Public Health Relevance

Incontinence associates with military service and post-traumatic stress disorder in both male and female Veterans. Overactive bladder (OAB) incontinence is disproportionately experienced by Veterans and women, is correlated to depression among Veterans, and women are increasing as a proportion of the Veteran population. Urinary incontinence will continue to affect Veterans disproportionately as the Veteran population ages. This project will demonstrate the use of low intensity, focused ultrasonic neuromodulation (UNS) for noninvasive treatment of OAB through tibial nerve stimulation. The effect of UNS on neural and bladder activity will be compared to electrical stimulation of the tibial nerve. UNS from a wearable cuff could offer at-home OAB treatment which would greatly expand access to treatment for Veterans who have limited mobility, income, or live in rural locales. Future work could use the UNS technology platform to stimulate new nerve targets for drug- free treatment of other challenging conditions such as peripheral neuropathic pain of trunk or limbs.

National Institute of Health (NIH)
Veterans Affairs (VA)
Veterans Administration (I21)
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Rehabilitation Research and Development SPiRE Program (RRDS)
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Louis Stokes Cleveland VA Medical Center
United States
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