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Access Type
WSU Access
Date of Award
January 2025
Degree Type
Dissertation
Degree Name
Ph.D.
Department
Psychiatry and Behavioral Neurosciences
First Advisor
Mark K. Greenwald
Abstract
Stress exposure may lead to negative physical and psychological responses. Stress can be particularly problematic for people trying to recover from opioid use disorder (OUD) because it impairs executive function and increases craving and likelihood of relapse. Research shows that acute stressors increase drug-seeking behavior; however, the mechanisms by which stress impacts behavior are not fully understood. Moreover, there are no FDA-approved medications to reduce effects of stress on cognitive function, and current OUD treatments do not effectively address stress. Neuromodulation with repetitive transcranial magnetic stimulation (rTMS) is a promising tool for developing a deeper understanding of mechanisms relating stress to drug-related outcomes. The Competing Neurobehavioral Decisions System theory posits that persons with SUDs may have hyperactive limbic reward circuitry and hypoactive executive control circuitry. This theory supports using rTMS to target limbic reward (via mPFC) or executive control (via dlPFC) circuitry to modulate drug-seeking. Although the theoretical framework indicates both dlPFC and mPFC could serve as potential targets, we chose the mPFC because it is associated with the hyperactive limbic activity that is theorized to be associated with stress-induced dysfunction; furthermore, the majority of research thus far has focused on the dlPFC so there are minimal data looking at effects of NIBS of the mPFC. We examined the effects of a psychological stressor in conjunction with inhibitory (1Hz) mPFC vs. sham rTMS in participants with OUD in treatment with either methadone or buprenorphine. The central aim is to investigate how inhibition of theoretically overactive limbic circuits via inhibitory rTMS of the mPFC would alter stress-induced executive dysfunction, emotion dysregulation, and drug-seeking. We aimed to address this knowledge gap through guided imagery stressors paired with 10 sessions of active mPFC rTMS vs. sham (within subjects). Stress-induced dysfunction was indexed with carefully selected cognitive (e.g., executive function), affective (e.g., emotional arousal), and behavioral (e.g., opioid seeking) measures pre- and post-rTMS. To confirm changes are associated with altered neural activity in the targeted regions, we measured event-related potentials (ERPs) during key tasks. We hypothesized that stressors would increase executive dysfunction, emotion dysregulation, and drug-seeking, and we theorize that rTMS mPFC inhibition will decrease limbic activation, which in turn could translate to changes in craving and drug-seeking. Sample size was limited for these initial analyses, so discussion is focused on effect sizes and predicted outcomes rather than statistical significance. Initial results indicated that psychological stress resulted in impaired executive functioning, increased anxiety, decreased mood, and increased drug motivation and craving in people with OUD. These findings were also associated with an increase in objective cardiovascular and salivary markers of sympathetic nervous system activation. Initial results also indicated that inhibitory rTMS of the mPFC as associated with a decrease in stress-induced executive dysfunction, negative mood, and drug motivation and craving. Conversely, it appears as though rTMS negatively impacts anxiety, resulting in an increase in anxiety symptoms immediately post stressor after active rTMS only. Physiological measures suggest that rTMS preferentially impacted noradrenergic activity, contrary to expectations, and it may have increased noradrenergic tone in response to stressor. It is possible that these physiological symptoms of NE activity might have played a role in the apparent increase in subjective anxiety post-active rTMS. Our findings provide important insights into the ways key neural networks contribute to drug-seeking and other associated dysfunctions in people with SUDs. Furthermore, they suggest that at least some of the mechanisms by which the mPFC affects EF, emotional arousal, and drug motivation are distinct from those affected by the stress response. The differential effects of active rTMS on sympathetic activation and drug motivation highlight the complex activity of the mPFC and the importance of considering each neural region within the context of the whole brain. This is not the first study to highlight potential divergent effects within the mPFC; it underscores the importance of developing clear rTMS protocols based on understood mechanisms, and it highlights the risks of imprecise targeting methodology. The results of this and similar studies can provide key insights into future interventions for people with SUDs.
Recommended Citation
Moses, Tabitha Emily Howard, "Using Neuromodulation To Investigate Potential Treatment Pathways Associated With Stress And Substance Use In Opioid Use Disorder" (2025). Wayne State University Dissertations. 4242.
https://digitalcommons.wayne.edu/oa_dissertations/4242