Mechanistic underpinnings of trigeminal nerve stimulation as a therapeutic approach to TBI

Project Summary/Abstract Traumatic brain injury (TBI) is a leading cause of death and disability, and is associated with elevated risk of chronic health conditions including dementia. Cerebral edema is a particularly deleterious complication of TBI which greatly increases risk of death, but current clinical approaches for edema management do not lead to signif- icant improvements in patient outcomes. Recent translational studies of TBI in mice demonstrate that trigeminal nerve stimulation (TNS) offers a low-risk, noninvasive therapeutic approach that reduces edema and improves functional outcomes. However, stimulation parameters vary widely across studies, and the mechanisms of edema reduction are not well-understood. The research proposed herein seeks to utilize both mouse experiments and realistic numerical simulations to probe stimulation parameter sensitivity and obtain a mechanistic understanding of how nerve stimulation leads to edema reduction. Such insights are necessary for rapid and effective trans- lation of TNS-based therapies, and indeed, results from this research will help inform upcoming TNS studies in humans. The central hypothesis of this proposal is that TNS improves functional outcomes after TBI by enhanc- ing extracellular fluid transport through the glymphatic system (a pathway in which cerebrospinal fluid exchanges with interstitial fluid in the brain). Four lines of evidence support this hypothesis: (1) a recent Nature publica- tion demonstrates that restoring disrupted glymphatic transport following TBI removes excess fluid and cortical debris, sharply reducing neuroinflammation and improving functional outcomes; (2) glymphatic flow is driven by arterial pulsations, and prior TNS studies use pulsed stimulation that enhances arterial pulsatility; (3) prior work shows that stimulation of the vagus nerve enhances glymphatic transport; and (4) multiple studies show analo- gous sensory (e.g., whisker) stimulation alters cortical blood flow and enhances glymphatic transport. Specific Aim 1 will test the central hypothesis by measuring brain-wide glymphatic influx due to variable TNS parameters (stimulation frequency, intensity, duty cycle) and will yield a near-optimal parameter set corresponding to maxi- mum glymphatic transport. Specific Aim 2 will provide the first high-resolution, in vivo quantification of changes in arterial diameter and glymphatic transport during TNS. This will be achieved using two-photon microscopy while TNS is administered with near-optimal parameters. Specific Aim 3 will leverage an existing, versatile simulation of the murine glymphatic system to causally establish the extent to which increased arterial pulsatility enhances glymphatic transport. Results from this study will: (1) conclusively demonstrate whether TNS ameliorates acute post-TBI edema via enhanced glymphatic transport, (2) yield a set of near-optimal TNS parameters, (3) directly quantify TNS-induced alterations to blood/glymphatic flow, and (4) quantify the extent to which increased glym- phatic transport due to sensory/nerve stimulation may be attributed to increased arterial pulsatility. Importantly, this study will have direct translational value: research results will help guide upcoming human studies in which TNS will be administered to humans using a noninvasive, wearable device with potential for commercialization.