fMRI study of cognition, motivation, decision-making, reward, risk, aversion, negative emotion, arousal, craving, impulsivity, and stress in alcohol use disorder

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1. Study of cognitive functions a. We have assessed the potential interaction of cognitive and motor processes in alcohol use disorder is currently using the inhibitory interference of response task (IIRT) developed in CNIRC. Analysis of the fMRI data using this task for approximately 30 participants is on the way and in final stages. b. We have completed a study of the neural correlates of decision making when making choices about whether to give money to charitable causes. Previous studies find that charitable decision making is associated with integration of value computing (from the ventral striatum) with social cognitive processing (such as in the insula and temporoparietal junction) through the ventromedial prefrontal cortex (vmPFC; e.g., Hare et al., 2010; Izuma et al., 2010; Tusche et al., 2016). The above mentioned regions have also been implicated in AUD and our goal was whether such an fMRI task would provide further granularity in the decision making process of AUD patients as a biomarker. Twenty-nine participants subjectively rated ten charities on their value, effectiveness, and the subjects personal chance of donating. Participants then completed an fMRI task requiring them to decide to donate to certain charities given the probability of the donation helping, their personal preference for the charity, and whether the donation came at cost to themselves. Probability of a donation being helpful and how much the subject favored a charity moderated PCC and left IFG engagement. Interestingly, reward neurocircuitry did not demonstrate similar sensitivity to these variations. There was a main effect of charitable giving scenarios (see Table 3 / Figure 2). In contrast 1 (Giving Self + Foundation > Neutral Feedback), there was extensive engagement of regions across the brain including right fusiform gyrus, left supramarginal gyrus, frontal eye fields, bilateral thalamus, posterior cingulate (PCC), caudate/putamen, bilateral anterior insula/IFG, and bilateral hippocampus. There was greater deactivation in the superior temporal sulcus. The PCC was also found in contrast 2 (Giving Self + Foundation > Neutral Scenario). Decisions to donate to charity compared to choosing not to donate to charity was associated with greater engagement of right IFG, left visual association area (V3), right supplementary motor area (SMA), and right superior parietal lobule (SPL) regions. There were also effects of charity characteristics on neural underpinnings of charitable giving. Contrast 5 (Giving Self + Foundation; 100% > Giving Self + Foundation; 30%) showed engagement of the PCC. Contrast 7 (Giving Favorite > Giving Least Favorite) was associated with greater engagement of left IFG and reduced deactivation of the PCC. Our secondary interest in utilizing this task as an AUD biomarker, there were no significant differences compared to healthy controls when controlled for multiple comparisons at the whole brain level. (Fede et al., manuscript in preparation) 2. fMRI Studies of Stress a. In a collaborative study with Dr. Lohoffs CGET we have implemented an fMRI fear extinction task. The primary goal of this study is to evaluate the role and interaction of (epi)genetic factors, early life stress (ELS) exposure, and alcohol use disorder (AUD) on neuronal mechanisms of fear conditioning and extinction. This cross-sectional, case-control study found significantly reduced amygdala activation during fear conditioning and fear renewal in individuals with alcohol dependence compared to healthy controls. Decreased amygdala activation during fear conditioning was significantly associated with alcohol dependence-related clinical measures, including alcohol dependence severity, depressive symptoms, trait anxiety, and perceived stress. (Muench et al., 2019) b. Epigenomic study. We also collaborated with Dr. Lohoffs Lab in their DNA methylation epigenome-wide association study (EWAS). This study identified novel epigenetic probs relevant to AUD such as Growth Arrest Specific 5 gene (GAS5). Endophenotypic analyses using peripheral cortisol levels and neuroimaging paradigms showed that methylomic variation in GAS5 network related probes were associated with stress phenotypes. During a fear acquisition functional MRI a significant associations were observed in the left amygdala, and both left and right insula with DNA methylation variation potentially associated with AUD. The results in this study suggested that DNA methylation changes in response to alcohol exposure may mediate altered brain activity patterns through alteration of HPA axis activity and stress sensitivity. There was also an association of hippocampal volume with this AUD related epigenetic variation. (Lohoff, et al., 2020)