Theoretical models of alcohol use disorder (AUD) argue that dysfunction in frontal lobe-mediated neural circuitry contributes to executive function deficits that are hallmark neurocognitive features of the disorder. Empirical support for these models is extensive, with prior studies reporting pronounced deficits in cortical thickness and white matter integrity in the frontal lobes and associated regions. However, considerably less is known about the impact of AUD on myelinated neurons localized in deeper cortical layers (i.e., intracortical myelin; ICM). These ICM fibers play a crucial role in speeding and synchronizing of neural signals throughout cortex, thereby helping to support optimal cognitive functioning. We hypothesize that ICM deficits directly contribute to executive function impairment in AUD. Importantly, standard techniques for quantifying cortical thickness via magnetic resonance imaging (MRI) lack neurobiological specificity with respect to the disruption of un-myelinated vs. myelinated cortical tissue in AUD. However, recent methodological advances in structural MRI have enabled in vivo estimation of ICM thickness. The proposed study will utilize a recently-developed T1- weighted pulse sequence that yields high intracortical contrast to examine deficits in ICM as a novel neural marker of AUD. The study has three aims: 1) to compare ICM thickness between individuals with AUD and matched controls; 2) to examine associations between ICM and clinical indicators of alcohol misuse (drinking quantity/frequency and AUD severity) and three domains of executive functioning (response inhibition, delay discounting, working memory) and processing speed; and 3) to explore sex differences in ICM. As the first investigation of ICM in AUD, this study will provide proof-of-concept of whether deficits in ICM are present in comparison with control individuals as well as contextualize variation in ICM within relevant clinical and neurocognitive indices of AUD. If successful, the study will also provide preliminary data for a future longitudinal R01 study investigating the predictive utility of ICM and its recovery over the course of AUD treatment. In sum, we believe that the ICM imaging approach is a distinct methodological innovation that has considerable potential to increase our ability to disentangle subtle differences in cortical morphology that may serve as novel neural markers of AUD in future clinical and research applications.

Public Health Relevance

Alcohol use disorder is a major public health problem that is associated with numerous brain abnormalities. This study will use a new neuroimaging technique to investigate differences in a specific type of brain tissue called intracortical myelin in people with AUD and healthy controls. The study will also examine associations between intracortical myelin and clinical and cognitive markers of AUD severity, and sex differences between males and females. The study has high potential to improve understanding of brain deficits in AUD, and to lay the foundation for future applications to improve diagnosis and treatment.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Exploratory/Developmental Grants (R21)
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National Institute on Alcohol Abuse and Alcoholism Initial Review Group (AA)
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Matochik, John A
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Mcmaster University
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L8 4K1