The single positive correlation was found between the anterior thalamic radiation, which connects the anterior and dorsomedial thalamic nuclei with the prefrontal cortex, and

BOLD activity throughout the amygdala, prefrontal cortex, and parahippocampal gyrus. Involvement of the amygdala is particularly interesting because it receives direct input from the olfactory bulb, which presumably would be a primary sensory substrate for the alcohol taste cue. Frank and Claus (2006) put forward a model of striato-orbitofrontal interaction in which the orbitofrontal cortex receives input from the amygdala about reinforcement value of outcomes associated with sensory cues. The orbitofrontal cortex, which in turn projects Inhibitors,research,lifescience,medical to the basal ganglia, encodes and maintains in working memory information about reward to enable adaptive, differential Inhibitors,research,lifescience,medical Verteporfin responding (Frank and Claus 2006). The positive correlation invites speculation that repeated experiences with alcohol selectively strengthens the influence of subcortical outputs to prefrontal cortex and limbic structures through enhanced white matter connectivity, possibly increasing the relative influence of subcortical

pathways over subsequent reward-seeking behavior. Again, given that the anterior thalamic radiation is a bidirectional tract, the direction and order of effects remain unknown. Although white matter damage has Inhibitors,research,lifescience,medical been established as a hallmark injury of AUD, causal mechanisms are still under investigation. In animal Inhibitors,research,lifescience,medical models of alcohol dependence, the presence of alcohol in the brain triggers stimulation of proinflammatory

cascades leading to cell death or dysfunction and inhibition of neurogenesis in adult neural stem cells in the olfactory bulb and hippocampus (Crews and Nixon 2009). Pinpointing mechanisms of alcohol-induced brain damage in vivo in humans presents a challenge, but our findings support the notion that Inhibitors,research,lifescience,medical long-term heavy drinking contributes to decreased white matter integrity. Alcohol-related white matter damage is likely to be one constituent of the AUD cycle in which heavy drinking contributes to impaired cognition and emotion regulation, leading to further problematic drinking (Crews 1999). A potential clinical implication is that those with long-standing AUD, and therefore greater damage Adenylyl cyclase to white matter substrates, may have more difficulty applying cognitive or emotional-regulation strategies in the context of AUD intervention. A strength of this study is its use of multimodal imaging methods to explore functional correlates of white matter integrity in problem drinking. Further strengths are the size of the sample and the variability in participants’ drinking histories. A major limitation is the inherent inability of cross-sectional design to establish causal relations between white matter profiles and cue reactivity. Whether greater cue reactivity preceded or followed heavy drinking remains a topic for further investigation.