Author ORCID Identifier


Defense Date


Document Type


Degree Name

Doctor of Philosophy


Physical Therapy

First Advisor

Edmund Acevedo, Ph.D., FACSM.

Second Advisor

Carrie L. Peterson, Ph.D.

Third Advisor

James Thomas, PT, Ph.D.

Fourth Advisor

D'Arcy P Mays Ph.D.


Chronic pain (CP) is a significant contributor to disability and disease burden globally. In 2019, approximately 50.2 million adults (20.4% of the US population) experienced chronic pain, contributing to $560-635 billion in direct medical costs. In addition, the worldwide prevalence of diabetes mellitus has reached epidemic proportions and is set to increase to 629 million by 2045. Almost 50% of patients with diabetes present with diabetic neuropathy (DN), and one in five patients with diabetes presents with painful DN (pDN) which is the most common cause of neuropathic pain (NP) in the US. Symptomatic treatment is the mainstay of management for pDN due to the paucity of disease-modifying therapies targeting the irreversible nerve damage from DN. Noninvasive brain stimulation using transcranial magnetic stimulation (TMS) has been utilized as a therapeutic tool in patients with neuropsychiatric disorders, and has only been used in CP patients for research purposes. Previous studies have consistently reported the analgesic

effects of high frequency repetitive TMS (HF-rTMS) via stimulation of the primary motor cortex (M1) in patients with NP. Another cortical target that has been studied using rTMS is the Dorsolateral Prefrontal Cortex (DLPFC). More recently, rTMS paradigms such as theta burst stimulation (TBS) have been developed that require less stimulation time (1-4 minutes) and lower stimulation intensities than conventional HF-rTMS protocols. TBS can be provided using either the intermittent or continuous paradigms. A prolonged form of continuous TBS (pcTBS) produces facilitatory and analgesic effects similar to HF-rTMS. No study has examined the analgesic effects of pcTBS targeted at the M1 and DLPFC brain regions in pDN patients, and concomitantly evaluated neural mechanisms of pain perception. Therefore, the central aim of this dissertation is to examine the effectiveness of pcTBS as an intervention in pDN patients by targeting the M1 and DLPFC regions of the brain, and to investigate the neural mechanisms that may explain the changes in pain perception. Therefore, Study 1 (Chapter 3) examined the efficacy of pcTBS targeted at the M1 and DLPFC brain regions as an intervention in pDN patients with a single session, prospective, single-blind, sham-controlled, randomized clinical trial. Study 2 (Chapter 4) investigated the neural mechanisms that could potentially explain the effects of pcTBS targeted at the M1 and DLPFC brain regions on pain perception in patients with pDN; (a) psychophysical mechanisms that comprise of the descending and ascending endogenous pain modulatory systems (b) neurophysiological mechanisms of corticospinal excitability, and (c) intracortical inhibition measures linked to GABA activity. The main findings from this dissertation are that pcTBS targeted at M1 or DLPFC may constitute an effective analgesic treatment for pDN and neurophysiological mechanisms related to corticospinal excitability and neurochemical mechanisms linked to intracortical inhibition may explain the analgesic response to pcTBS stimulation at the M1 and DLPFC brain regions in patients with pDN. Chapter 2 presents a review of the literature on brain derived neurotrophic factor (BDNF), focusing on its role as a biomarker, its mechanism of action in NP, and a critical analysis of the quantification of BDNF in serum and plasma.


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