Document Type


Date of Award

Summer 8-31-2019

Degree Name

Doctor of Philosophy in Biomedical Engineering - (Ph.D.)


Biomedical Engineering

First Advisor

Sergei Adamovich

Second Advisor

Antje Ihlefeld

Third Advisor

Alma S. Merians

Fourth Advisor

Mesut Sahin

Fifth Advisor

Gerard G. Fluet


An essential feature of the brain is its capacity to undergo long-lasting morphological or functional changes in response to experiences or trauma. Advances in noninvasive brain stimulation techniques have led to increased interest in understanding neural mechanisms of neuroplasticity at the network level. Paired associative stimulation (PAS) is one of the most commonly used applications for noninvasive brain stimulation because of its clinical potential as an adjuvant rehabilitative intervention. However, the optimal method for incorporating PAS into rehabilitative activities remains unknown. This dissertation explores different approaches to combining PAS with movement and investigates the enhancement of the specificity of conventional PAS-induced effects.

A fundamental aspect in combining PAS and voluntary movement is the timing of stimuli with respect to muscle activation onset. Therefore, this dissertation first focuses on determining the effect of PAS on the primary motor cortex (M1) excitability when the stimuli are delivered during preparation or execution of a voluntary finger extension in a reaction time setup. The results of this investigation show that applying PAS during voluntary contraction or at rest increases the corticospinal excitability (CSE), while PAS delivered during movement preparation decreases CSE. This suggests that the direction of PAS-induced plasticity is dependent on the order of stimulation and the phase of the movement.

Next, combining PAS with the movement of the stimulated limb may further increase the enhancement of CSE. However, individuals with moderate to severe motor function impairment due to stroke may not be able to engage in the necessary repetitive voluntary movements of the paretic limb. The objective of this study is to investigate the feasibility of contralaterally coordinated PAS applied to the resting hand’s extensors during fast extension of the contralateral hand in healthy individuals. PAS delivered during the muscle contraction of the left hand, and PAS delivered at rest both increase the CSE. Delivering PAS during the preparation phase of the left-hand movement leads to a decrease in the CSE. Thus, PAS-induced bidirectional plasticity effects that are dependent on the phase of the movement of the opposite hand.

Additionally, given the noted topographical specificity of the somatosensory cortex and reported muscle-specific PAS-induced changes, this dissertation also evaluates the feasibility of enhancing the specificity of PAS-induced effects through a simultaneous application of facilitatory PAS to hand extensor muscles and inhibitory PAS to flexor muscles while at rest in healthy individuals. The simultaneous application of PAS, targeting the hand extensor muscle with facilitatory PAS and hand flexor muscle with inhibitory PAS leads to a consistent and significant increase in CSE of the extensor muscle.

Finally, in a pilot study, two scenarios combining PAS with dynamic hand movements in a reaction time paradigm are explored in people with stroke. PAS of the ipsilesional M1 is combined with a voluntary activation of finger extensors of the paretic limb or during a nonparetic finger extension. This is done to evaluate the feasibility of combining PAS with voluntary movement in chronic stroke patients. Although there were no notable changes in the CSE, recruited stroke patients are able to tolerate and perform a motor task with both their affected and less affected hand while PAS is applied.



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