Date of Award

2019

Embargo Period

8-1-2024

Document Type

Dissertation - MUSC Only

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

DeAnna L. Adkins

Second Advisor

Heather Boger

Third Advisor

Colleen Hanlon

Fourth Advisor

Antonieta Lavin

Fifth Advisor

Michelle Woodbury

Abstract

Stroke is currently the fifth leading cause of death and a leading cause of disability within the United States (American Heart Association: “About Stroke” 2019). Motor impairments are one of the more debilitating and persistent functional deficits that exist due to stroke and are not fully reversed by physical rehabilitation (RT) alone (Hatem, 2016). A promising treatment approach is to combine physical rehabilitation with electrical or magnetic stimulation of motor cortex. In adult rats, we and others have found that high-frequency (50Hz – 100Hz) excitatory cortical stimulation (ECS) over the peri-lesion motor cortex following a focal, moderate stroke delivered concurrently during motor rehabilitative training (RT), improves functional motor recovery better than RT alone (Liew, S.L. et al., 2014, Adkins, D.L., 2008, 2015, Kleim et al., 2003, Zhou et al., 2010, Teskey et al., 2003; Boychuck et al., 2016, Plow, 2009; and O’Bryant et al., 2016). While these studies are compelling, they were conducted using young adult animals (~3-4 months old) with moderate motor impairments. However, stroke is most common in individuals over 65, and stroke severity is quite heterogeneous, resulting in both moderate and severe motor impairments. The goal of these studies was to investigate whether inhibitory stimulation during RT is an effective tool in ameliorating functional deficits as a result of stroke; and to determine if improvements in recovery correlated with changes in BDNF/TrkB functioning. In the following studies, we investigated whether inhibitory CS (ICS) over the non-infarcted motor cortex combined with RT or ECS+RT over the infarcted motor cortex would enhance motor recovery compared to RT alone, in young adult rats that are either moderately or severely impaired and in middle aged rats. The specific goal of this research was to determine if the mechanisms of action of brain stimulation were dependent upon BDNF and its downstream signaling pathways. We hypothesized that inhibitory stimulation with rehabilitation is an effective tool in ameliorating functional deficits as a result of stroke, and that these improvements in recovery may correlate with changes in BDNF/TrkB functioning. These studies suggest that the effectiveness of either excitatory or inhibitory stimulation given concurrently with rehabilitation is dependent on injury severity. Previous studies have found that ECS+RT did not enhance motor recovery compared to RT alone in animals that were severely impaired (presenting post-operative impairments that are greater than 30%) (Adkins, Hsu, and Jones, 2008). The research revealed that ECS+RT was most effective in animals with moderate impairments, which negatively correlated with contralesional BDNF changes. We also found that ICS+RT resulted in the greatest improvements in forelimb recovery in animals that were more severely impaired (severely impaired young and aged animals). We also discovered that these different stimulation protocols also resulted in varying changes in BDNF concentration levels after ischemic injury and 21 days of treatment. Therefore, we performed a BDNF/TrkB signaling inhibition to determine if the ICS and ECS are dependent on BDNF/TrkB signaling. These studies revealed that recovery of function was slightly attenuated in animals that received ECS+RT treatment. Overall, these studies indicate a relationship between intervention effectiveness, impairment after stroke, and elevations in BDNF.

Rights

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