Functional & Structural Connectivity in Alcohol Use Disorder

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1. Functional Connectivity a. Longitudinal alterations in functional connectivity of AUD subjects - The addiction neurocircuitry model describes the role of several brain circuits (drug reward, negative emotionality, and craving/executive control) in alcohol use and subsequent development of alcohol use disorder (AUD). Human studies examining longitudinal change using resting-state functional magnetic resonance imaging (rs-fMRI) are needed to understand how functional changes to these circuits are caused by or contribute to continued AUD. In order to characterize how intrinsic functional connectivity changes with sustained AUD, we analyzed rs-fMRI data from individuals with (n = 18; treatment seeking and non-treatment seeking) and without (n = 21) AUD collected on multiple visits as part of various research studies at the NIAAA intramural program from 2012-2020. Results of the seed correlation analysis showed that individuals with AUD had an increase in functional connectivity over time between emotionality and craving neurocircuits, and a decrease between executive control and reward networks. Posthoc investigations of AUD severity and alcohol consumption between scans revealed an additive effect of these AUD features in many of the circuits, such that more alcohol consumption or more severe AUD was associated with more pronounced changes to synchronicity. These findings suggest an increased concordance of networks underlying emotionality and compulsions towards drinking while also a reduction in network connectivity, consistent with the addiction neurocircuitry model. Further, they suggest a compounding effect of continued heavy drinking on these vulnerabilities in neurocircuitry. More longitudinal research is necessary to understand the trajectories of individuals with AUD not adequately represented in this study, as well as whether this can inform effective harm reduction strategies (Fede et al. 2022). b. Trauma Timing Load (TTL) and functional connectivity - Timing and type of trauma have been shown to impact on the development, function and connectivity of brain circuits implicated in emotion processing, top-down inhibitory control, and cognitive functions. Dysfunctions in these processes and their underlying brain circuits are commonly observed in patients with alcohol use disorder (AUD). Furthermore, the high comorbidity between AUD and PTSD suggests that trauma exposure during adulthood also plays a critical role in increasing the risk and severity of AUD. Building on this body of evidence, the goal of this study is to investigate whether timing of trauma (childhood vs. adulthood) differentially affect the behavioral and circuit-level phenotype of individuals with AUD. Our preliminary data analysis indicates that the effect of alcohol use disorder is far more impressive than that of abuse on alteration of resting state connectivity in regions associated with abuse experiences. The analysis of data in this study continues to further confirm these effects. c. PAG functional connectivity - The Periaqueductal gray (PAG) is a region widely implicated in pain, depression, negative emotionality, and sleep studies, most of which are also comorbidities associated with substance use disorders (SUDs) (Le, et al. 2020; George, et al. 2019). Despite the apparent prominent involvement of PAG in behavioral psychiatric disorders there have been limited neuroimaging studies investigating the modulatory role that this region plays in SUD maintenance and relapse. In collaboration with Dr. Spagnolo, we have conducted a preliminary study of the association between AUD and functional PAG connectivity. In this analysis we have found that there are alterations in salience network connectivity between left and right rostral prefrontal cortex (RPFC), left RPFC and anterior cingulate (ACC), left supramarginal gyrus and right RPFC, ACC and left anterior insula (AIns), and between the right and left AIns. This project has been on hold due to other priorities. We will summarize the results from this study in the near future. d. Glucagon Like Peptide-1 Receptor (GLP-1R) gene variants and brain functional connectivity - A study of the association between alcohol use severity and GLP-1R gene variants, and the functional connectivity of human brain was conducted in collaboration between CNIRC and Dr. Leggio's Clinical Psychoneuroendocrinology group and Neuropsychopharmacology Section. In this study we found there was a significant interaction effect between one of the GLP-1R variants and network connectivity of the anterior salience network, the dorsal default mode network, and the basal ganglia network. We also found that high versus low AUDIT scores were associated with stronger within-network connectivity in some of these networks (Farokhnia, Fede, et al., 2022) e. Alcohol use severity and resting state - In another collaboration, we contributed to the study of association between alcohol use disorder and brain functional connectivity. This study, conducted by Dr. Volkow's Laboratory of Neuroimaging (LNI), was focused on greater vulnerability of women than men to the adverse effects of alcohol on mood and sleep. This study concluded that both men and women participants with alcohol use disorder had greater sleep and mood problems than healthy control, with sex by alcohol use effect varying by severity. The results of this study also suggested that changes in resting state functional connectivity may account for sleep and mood impairments in females with alcohol use disorder (Zhang et al., 2022).