Neural correlates of instrumental responding in the context of alcohol-related cues index disorder severity and relapse risk

Daniel J. Schad, Maria Garbusow, Eva Friedel, Christian Sommer, Miriam Sebold, Claudia Hägele, Nadine Bernhardt, Stephan Nebe, Sören Kuitunen-Paul, Shuyan Liu, Uta Eichmann, Anne Beck, Hans-Ulrich Wittchen, Henrik Walter, Philipp Sterzer, Ulrich S. Zimmermann, Michael N. Smolka, Florian Schlagenhauf, Quentin J. M. Huys, Andreas Heinz, Michael A. Rapp

The influence of Pavlovian conditioned stimuli on ongoing behavior may contribute to explaining how alcohol cues stimulate drug seeking and intake. Using a Pavlovian-instrumental transfer task, we investigated the effects of alcohol-related cues on approach behavior (i.e., instrumental response behavior) and its neural correlates, and related both to the relapse after detoxification in alcohol-dependent patients. Thirty-one recently detoxified alcohol-dependent patients and 24 healthy controls underwent instrumental training, where approach or non-approach towards initially neutral stimuli was reinforced by monetary incentives. Approach behavior was tested during extinction with either alcohol-related or neutral stimuli (as Pavlovian cues) presented in the background during functional magnetic resonance imaging (fMRI). Patients were subsequently followed up for 6 months. We observed that alcohol-related background stimuli inhibited the approach behavior in detoxified alcohol-dependent patients (t = - 3.86, p < .001), but not in healthy controls (t = - 0.92, p = .36). This behavioral inhibition was associated with neural activation in the nucleus accumbens (NAcc) (t(30) = 2.06, p < .05). Interestingly, both the effects were only present in subsequent abstainers, but not relapsers and in those with mild but not severe dependence. Our data show that alcohol-related cues can acquire inhibitory behavioral features typical of aversive stimuli despite being accompanied by a stronger NAcc activation, suggesting salience attribution. The fact that these findings are restricted to abstinence and milder illness suggests that they may be potential resilience factors. LeAD study, http://www.lead-studie.de , NCT01679145.