The long-term goal of this proposed career development award (CDA-2) is to accelerate my training and development so that I can establish an independent line of research unraveling the causes and consequences of fatigue and to develop effective evidence-based therapies for fatigue in Veterans with neurological conditions. Before my collegiate studies, I served nine years on active duty in the United States Marine Corps and received an Honorable Discharge upon the expiration of my service contract. I completed my Ph.D. in Human Bioenergetics at Colorado State University in 2017. Upon graduation, I began a post-doctoral position at the Medical University of South Carolina working with Dr. Mark G. Bowden, PT, Ph.D. Shortly after starting my post- doc position, I acquired a WOC appointment at the Ralph H. Johnson VA Medical Center and was awarded a VA Rehabilitation Research and Development Career Development Award – 1 that began in Oct 2019. Since the beginning of my research journey, I have published 22 peer-reviewed manuscripts, 12 as the first author. My most recent publications have centered on measuring the neurophysiological state of the nervous system and relating that state to post-stroke disability. These most recent manuscripts are based on data collected at the laboratories at Ralph H. Johnson before my arrival and the co-authors include several of the members of this proposal’s mentorship team. Upon completing my CDA-1 (end date Sep 30, 2021), I have focused my attention on the neurophysiological biomarkers of post-stroke fatigue. This CDA-2 proposal will provide me with the opportunity to learn new neurophysiological assessment methods and advance my knowledge and ability to apply neuromodulatory treatments. These skills will provide me the foundation to build an independent VA- backed research program focusing on reducing the impact of fatigue in Veterans with an array of neurological conditions. The assembled mentorship team is composed of experts in post-stroke rehabilitation, neuromodulation, neuroimaging, and clinical assessment. Up to 92% of people post-stroke experience fatigue. Fatigue negatively affects physical and mental performance leading to a lower quality of life. Fatigue is also present in many other neurological populations within the Veteran community, such as traumatic brain injury, multiple sclerosis, and the newly coined phenomenon of Long-COVID. Advances in the knowledge and understanding of post-stroke fatigue are likely to lead to advances in other clinical populations within the Veteran community. The first aim is to test the effects of a well-established neuromodulatory therapy, repetitive transcranial magnetic stimulation (rTMS), on reducing the severity of post-stroke fatigue. This aim is predicated on theoretical principles obtained from the study of other neuro-psychiatric/-cognitive disorders and therapeutic attempts to reduce fatigue in other neurological illnesses. Participating Veterans will receive high-frequency rTMS to the frontal lobe, either the left prefrontal dorsolateral cortex or bilaterally to the motor cortices. These locations have been implicated in fatigue in other neurological conditions. I expect to show rTMS can be used to reduce post-stroke fatigue severity. However, the effectiveness and location of treatment may partially be dependent on individual characteristics. The second aim of the study is based on the skills and knowledge developed in the CDA-1, I plan on identifying additional neurophysiological biomarkers of fatigue. In this project, I will assess glutamatergic activity/signaling of the upper and lower extremity sensorimotor network of Veterans with and without post-stroke fatigue. I expect to show that the fatigued group will show glutamatergic dysfunction, measured by greater asymmetries in intracortical facilitation and the facilitatory response to paired associative stimulation, compared to the non-fatigued group. Identification of glutamate and related metabolites as a pathophysiological contributor to post-stroke fatigue may help in the development of new therapeutic approaches for post-stroke fatigue and fatigue in other neurological conditions.

Fatigue affects up to 92% of individuals post-stroke and contributes to decreased physical and cognitive function leading to a reduced quality of life. There are currently no effective evidence-based treatments for post-stroke fatigue partially due to the unknown pathophysiology of fatigue. While the exact mechanisms/pathophysiology of post-stroke fatigue are unknown, changes in the structure and function of the nervous system likely play prominent roles. Since post-stroke fatigue originates within the central nervous system, neuromodulatory therapies may prove to be an effective treatment option. This proposal will explore the utility of using repetitive transcranial magnetic stimulation to treat post-stroke fatigue and attempt to further elucidate the biomarkers and pathophysiology of post-stroke fatigue. Fatigue is not unique to stroke and is common a common sequela of many neurological conditions. Gaining a better understanding of post-stroke fatigue may provide greater insights into fatigue in other conditions, e.g. traumatic brain injury, multiple sclerosis, and Long-COVID.