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Principal Investigator: John Harvey Kindred
Organization: RALPH H JOHNSON VA MEDICAL CENTER
Fiscal Year: 2024
Funding agency: Veterans Affairs
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.
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