Endophenotyping with fMRI: Genetic modulation and treatment response

Coordinator:    Prof. Dr. Andreas Heinz                                                               
Institution: Klinik für Psychiatrie und Psychotherapie, Charité-Universitätsmedizin Berlin
Alcohol use disorders are up to 50% genetically driven and related to high relapse rates. To develop new therapeutic approaches, it is essential to extend our understanding of the genetic and biological underlying mechanisms. Therefore, we examine the influence of relevant genetic variations, which may increase the risk of developing alcohol dependence. We use functional magnetic resonance tomography to image specific brain processes, which are affected by chronic alcohol abuse, in 200 alcohol-dependent and 240 healthy individuals.
So far, we identified brain mechanisms, which indicated a decreased relapse risk in recently detoxified alcohol-dependent patients: less brain atrophy (Beck et al. 2012; Charlet et al. 2013), increased connectivity between the neural reward system and the amygdala when alcoholic beverages were shown (Beck et al. 2012), increased activity in emotion-associated brain areas towards negative facial expressions (Charlet et al. 2013), and compensatory neural activation during high task demand (Charlet et al. 2013). These findings may represent resilience factors against relapse in alcohol-dependent individuals: a) an enhanced “warning signal” towards aversive aspects of alcohol (Beck et al. 2012), b) increased emotional control in social stressful situations (Charlet et al. 2013), and c) engagement of intact neural resources to master challenging tasks (Charlet et al. 2013).
Further, we investigated alcohol-associated “cue reactivity”, which involves immediate reactions in alcohol-dependent patients. Thus, we found brain areas, which were associated with automatic attentional biases towards alcohol cues (Vollstädt-Klein et al. 2012) and with successful treatment processes (Vollstädt-Klein et al. 2011). We also developed a paradigm for testing temptation resistance in alcohol-dependent patients, which engages cortical control areas that act on the neural reward system (Wimmer et al. 2012).
Concerning the identification of specific risk genes, we observed that individual variations of the GATA4-gene were associated with the relapse risk of alcohol-dependent patients (Kiefer et al. 2010), which was mediated by functional alterations of the amygdala, an important emotion-related brain region.
In future analyses we plan to investigate how risk genes modulate the observed brain mechanisms. This could help to develop new, more effective therapeutic interventions for the treatment of alcohol use disorders.
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