Int. J. Environ. Res. Public Health 2009, 6 2022 demonstrates a relative decline in alcoholics’ performance as task demands become more complex. Notably, we have already shown that abstinent alcoholics are impaired in the simpler delay discrimination reversal task when compared to a normal group [11]. In this earlier study, alcoholics did acquire some level of differential responding during both discrimination and reversal learning, but it was impaired compared to normal controls. Thus, the evidence of some differential learning in a delay paradigm when compared to a control group, coupled with the current results showing no differential learning in a trace paradigm, clearly demonstrates that as task difficulty increases and learning demands are more complex (e.g., a silent trace interval is introduced), abstinent alcoholics’ ability to reverse a previously learned discrimination is eliminated. The ability to reverse a learned discrimination has been linked by both animal and human studies to forebrain structures, in particular the hippocampal system [15,17] and prefrontal cortex [18]. The reversal impairment following prefrontal lesions and thalamic mediodorsal nucleus lesions in non- human animals involved slowed acquisition of reversal contingencies. Rabbits were able to acquire the reversed discrimination but more slowly than normal animals [16,40]. The selective impairment in reversal learning in abstinent alcoholics is therefore in line with the animal literature [18,41]. Given alcohol’s documented neurotoxic predisposition for cerebellar and frontal brain regions, the current study also lends support for the notion that a cerebellar-thalamic-prefrontal cortex module controls eyeblink associative learning during nonoptimal conditions or more complex tasks such as reversal learning [42,43]. However, it is possible that alcohol may exert a neurotoxic effect on the hippocampal system as well, which could explain these findings at least in part. Interestingly, the nature of the reversal learning impairment observed in abstinent alcoholics appears to be different than that associated with hippocampal system damage. The abstinent alcoholics’ reversal deficit appeared to be due to an inability to produce a normal percentage of conditioned responses during CS+ trials rather than a deficit in inhibiting responses to new CS- (i.e., extinguishing the old CS+) as seen with hippocampal damage. Alcoholics appear to have a selective impairment in the ability to flexibly manipulate previously learned associations. In particular, they are impaired in producing a positive response to a previously acquired neutral or inhibited response. We therefore conclude, similarly to a recent study in our laboratory [11], that frontal system damage, as seen in alcoholics, disrupts the ability to differentially respond at a high rate to a stimulus previously responded to at a low rate. The frontal system dysfunction related to chronic alcoholism may have behavioral consequences related to alcoholic relapse. Frontal system dysfunction may further perpetuate alcoholics’ inability to maintain abstinence because the previously learned behavioral patterns, such as drinking triggers and maladaptive coping mechanisms, are so pervasive that they interfere with the individuals’ ability to flexibly learn new patterns of behavior. This idea is similar to Hyman’s hypothesis [44] that addiction represents “a pathological usurpation of neural processes that normally serve reward-related learning.” (p. 565) and may help provide a framework of understanding what happens in alcoholics’ resistant to treatment. Correlations and post-hoc analyses revealed significant differences in some measures of basic learning acquisition between individuals grouped according to severity of alcohol dependence. Individuals meeting criteria for alcohol dependence on the DIS performed worse than those meeting criteria for abuse. Specifically, individuals meeting criteria for alcohol dependence were unable to