Effective Connectivity During Threat Processing in Internalizing Psychopathology and Alcohol Use Disorder

Heightened reactivity to uncertain threats (U-threats) has emerged as a transdiagnostic marker of internalizing psychopathologies (IPs) as evidenced by increased startle responses. A developing theory and recent research also suggest that heightened reactivity to U-threats may be an important individual difference factor that facilitates excessive drinking as a means of avoidance-based coping and characterizes individuals with current and past alcohol use disorder (AUD). Previous studies have used fMRI to identify the neural correlates of heightened responses to U-threat and consistently observed increased activation in the anterior insula (AIC), anteromedial (AM) thalamus and dorsal anterior cingulate cortex (dACC); however, no study to date that we are aware of has examined directional information flow between these regions, which was the primary aim of our study. Specifically, the current study aimed to understand how these three regions function as a network during anticipation of U-threat (and predictable threat/P-threat) in IP and AUD. Towards this goal, functional magnetic resonance imaging (fMRI) and dynamic causal modeling (DCM) were used to study inter-regional effective connectivities (ECs) and U- (and P-) threat-related modulations thereof within this network in two study samples. The first included a heterogeneous, transdiagnostic IP sample and a group of healthy controls (without any psychopathology). The second included groups of individuals with and without AUD diagnosis within the past two years who were otherwise matched on the rates of IPs. Within each study sample, parametric empirical Bayesian (PEB) modeling was used to conduct between-group differences in modulatory changes of ECs during U-threat and P-threat trials. In addition, we conducted exploratory analyses to determine whether any of the observed modulatory changes of ECs were associated with individual differences in anxiety and depressive symptoms (Study 1) or average weekly alcohol consumption in the past month (Study 2). Two main findings emerged: (Study 1) During U-threat trials, the right AM thalamus was more inhibited by the right AIC in individuals with IP relative to healthy controls; this directional influence was more prominent among participants who endorsed greater depressive, but not anxiety, symptoms; (Study 2) During U-threat trials, compared to the control group, the right AIC was more excited by the right AM thalamus in the AUD group; this directional influence was stronger among individuals who on average consumed more drinks per week. As expected, we found no group differences in modulatory changes of ECs during P-threat trials in either study sample. To our knowledge, this is the first study to examine directional interactions between key frontolimbic regions during anticipation of U-threat (and P-threat) and demonstrate the importance of top-down and bottom-up thalamic-insular projections during U-threat processing in IP and AUD, respectively. Prospective studies are warranted to examine causal pathways and establish temporal precedence.