Aberrant cortico-striato-limbic functional connectivity to alcohol cues in co-occurring bipolar disorder and alcohol use disorder

Reward brain circuitry dysfunction is a hypothesized mechanism of bipolar disorder and alcohol use disorder co-occurrence (BD + AUD) that remains largely untested. This neuroimaging study represents the first investigation of functional connectivity in BD + AUD. Following a two-by-two factorial design (N = 90), individuals with BD + AUD (n = 22), AUD alone (n = 20), BD alone (n = 23), and healthy control participants (n = 25) were administered a fMRI alcohol-cue reactivity paradigm. Generalized psychophysiological interaction (PPI) modeling (p < 0.001; p-FDR < 0.05) was performed for regions of interest, including the right dorsal anterior insula, inferior frontal gyrus, and bilateral amygdala and dorsal striatum (i.e., caudate body). Extracted beta weights were explored for bivariate associations with key behavioral correlates (AUD age of onset, alcohol craving and dependence severity, abstinence duration, and impulsivity) (p < 0.05). BD + AUD individuals exhibited cue-modulated hyperconnectivity between the left dorsal striatum and right posterior cingulate cortex (p-FDR = 0.045) versus the AUD and BD groups, who both exhibited hypoconnectivity between these regions versus healthy participants. Additionally, there were main effects of AUD and BD (p-FDR ≤ 0.040) on cue-modulated functional connectivity of the right dAI (↓ middle frontal gyrus [MFG]) and left amygdala (↑ right superior temporal gyrus, anterior cingulate cortex, and MFG), respectively. Select functional connectivity data were associated with trait characteristics of AUD in BD + AUD (r ≥±0.50, p ≤ 0.026) but not AUD. A distinct pattern of cortico-striato-limbic functional connectivity and brain-behavior relationships was found to characterize BD + AUD with implications for treatment development. Namely, leveraging neuromodulation techniques that can effectively normalize the identified circuitry disruptions could represent a novel path for treatment advances in BD + AUD.