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Date of Award
Doctor of Philosophy (PhD)
Stroke is a significant health problem in the United States and the world. Even with rehabilitation intervention, about 30% of people who have had a stroke have persistent disability and do not return to their prior level of function. Recovery from neurological injury requires that the nervous system reorganize in structure and function, a process called neuroplasticity. Neuroplasticity occurs through changes in genes, synapses, neurons, and neuronal networks and is the basis of learning. One promising method to improve outcomes is to combine interventions, such that the first intervention primes the nervous system and establishes an optimal environment to support neuroplasticity and learning, and the second intervention is some form of behavioral training that guides neuroplasticity. In this dissertation, we pursued combinational therapies with two different primers, one of which was exogenous and the other which was endogenous. To evaluate the effects of these primers on learning, we used a highly controlled experimental paradigm which involved motor and cognitive behavioral training on well-established laboratory tasks.
The first primer that we tested was an exogenous pharmaceutical agent. Pharmaceutical agents have long been used as an easy and effective means of influencing the nervous system to augment the effects of other treatments. The agent used for a number of the recent combination therapy studies in the psychology and psychiatry literature is d-cycloserine (DCS). DCS acts at the N-methyl-D-aspartate (NMDA) receptor to boost long-term potentiation and has been found to promote learning and enhance the efficacy of cognitive behavioral therapies for a number of psychological and psychiatric conditions. Despite the promise shown with DCS in other realms, the potential of DCS to act as a primer to promote human learning in the motor domain had not yet been tested.
The second primer intended to influence neuroplasticity and learning was endogenous and involved activating the bodys innate cellular and molecular mechanism. Applying brief bouts of ischemia and reperfusion to a remote organ or tissue has been shown to initiate cellular cascades leading to cardiac and neurologic tissue protection, reducing damage from subsequent ischemic challenges. This phenomenon, called remote ischemic conditioning, has been demonstrated in animal models as well as in humans and the protective effects are present whether it is done before, during, or after ischemic challenge. Given the multifactorial, epigenetic basis of remote ischemic conditioning-induced tissue protection, we postulated that remote ischemic conditioning might also induce some of the mechanisms responsible for neuroplasticity and therefore facilitate learning. The next critical step was to investigate whether remote limb ischemic conditioning (RLIC), a form of remote ischemic conditioning in which brief bouts of limb ischemia are produced through blood pressure cuff inflation, could be employed to elicit neuroplasticity and improve learning. With a homogenous group of young adults, we first completed a proof-of-concept study testing the effects of RLIC at the standard high dose of blood pressure cuff inflation to 200 mmHg. As we moved the RLIC protocol down the translational pathway toward clinical implementation, we then tested RLIC at the lower, potentially more tolerable, dose of blood pressure cuff inflation to 20 mmHg above a persons systolic blood pressure and probed for blood biomarkers of RLIC.
The results of this dissertation show that while DCS does not have an effect on learning, RLIC robustly enhances behavioral training and facilitates learning in neurologically-intact young adults. Moreover, RLIC with blood pressure cuff inflation pressures of 20 mmHg above a persons systolic blood pressure are as effective as RLIC at the higher dose. Ultimately, RLIC may serve as a clinically-feasible primer to enhance learning during neurorehabilitation and have a profound impact on recovery after stroke or other neurological injury.
Chair and Committee
Catherine E. Lang
Gammon M. Earhart, Jin-Moo Lee, Eric J. Lenze, Gretchen A. Meyer,
Cherry-Allen, Kendra Michelle, "Exogenous and Endogenous Priming to Enhance Learning" (2016). Arts & Sciences Electronic Theses and Dissertations. 735.
Available for download on Friday, May 15, 2116