Volumetric Prefrontal Cortex Alterations in Patients With Alcohol Dependence and the Involvement of Self‐Control

Background: Aspects of self-control such as sensation seeking and impaired impulse control have been implicated in alcohol dependence (ALC). Conversely, sensation seeking has been ascribed a possible protective role in stress-related psychopathologies. We therefore examined gray matter (GM) morphology in individuals with ALC, focusing on differences in prefrontal regions that have been associated with self-control. Additionally, we accounted for differences in lifetime alcohol intake regarding self-control measures and cortical structures in ALC patients. Methods: With voxel-based morphometry (VBM) focusing on prefrontal a priori defined regions of interest, we assessed a group of 62 detoxified ALC patients and 62 healthy controls (HC). ALC patients were subsequently divided into high (n = 9) and low consumers (n = 53). Self-control was assessed by use of the Barratt Impulsiveness Scale and the Sensation Seeking Scale. Results: Compared to HC, ALC had significantly less GM volume in bilateral middle frontal gyrus (MFG) and right medial prefrontal cortex as well as in the right anterior cingulate. High-consuming ALC showed smaller GM in right orbitofrontal cortex as well as lower sensation seeking scores than low consumers. In low-consuming ALC, right MFG-GM was positively associated with magnitude of sensation seeking; particularly, larger MFG-GM correlated with greater thrill and adventure seeking. Conclusion: Thus, our findings (i) indicate deficient GM volume in prefrontal areas related to self-control and (ii) might accentuate the phenotypic divergence of ALC patients and emphasize the importance of the development of individual treatment options

Epigenome-wide association study of alcohol consumption in N = 8161 individuals and relevance to alcohol use disorder pathophysiology:identification of the cystine/glutamate transporter SLC7A11 as a top target

Alcohol misuse is common in many societies worldwide and is associated with extensive morbidity and mortality, often leading to alcohol use disorders (AUD) and alcohol-related end-organ damage. The underlying mechanisms contributing to the development of AUD are largely unknown; however, growing evidence suggests that alcohol consumption is strongly associated with alterations in DNA methylation. Identification of alcohol-associated methylomic variation might provide novel insights into pathophysiology and novel treatment targets for AUD. Here we performed the largest single-cohort epigenome-wide association study (EWAS) of alcohol consumption to date (N = 8161) and cross-validated findings in AUD populations with relevant endophenotypes, as well as alcohol-related animal models. Results showed 2504 CpGs significantly associated with alcohol consumption (Bonferroni p value < 6.8 × 10(−8)) with the five leading probes located in SLC7A11 (p = 7.75 × 10(−108)), JDP2 (p = 1.44 × 10(−56)), GAS5 (p = 2.71 × 10(−47)), TRA2B (p = 3.54 × 10(−42)), and SLC43A1 (p = 1.18 × 10(−40)). Genes annotated to associated CpG sites are implicated in liver and brain function, the cellular response to alcohol and alcohol-associated diseases, including hypertension and Alzheimer’s disease. Two-sample Mendelian randomization confirmed the causal relationship of consumption on AUD risk (inverse variance weighted (IVW) p = 5.37 × 10(−09)). A methylation-based predictor of alcohol consumption was able to discriminate AUD cases in two independent cohorts (p = 6.32 × 10(−38) and p = 5.41 × 10(−14)). The top EWAS probe cg06690548, located in the cystine/glutamate transporter SLC7A11, was replicated in an independent cohort of AUD and control participants (N = 615) and showed strong hypomethylation in AUD (p < 10(−17)). Decreased CpG methylation at this probe was consistently associated with clinical measures including increased heavy drinking days (p < 10(−4)), increased liver function enzymes (GGT (p = 1.03 × 10(−21)), ALT (p = 1.29 × 10(−6)), and AST (p = 1.97 × 10(−8))) in individuals with AUD. Postmortem brain analyses documented increased SLC7A11 expression in the frontal cortex of individuals with AUD and animal models showed marked increased expression in liver, suggesting a mechanism by which alcohol leads to hypomethylation-induced overexpression of SLC7A11. Taken together, our EWAS discovery sample and subsequent validation of the top probe in AUD suggest a strong role of abnormal glutamate signaling mediated by methylomic variation in SLC7A11. Our data are intriguing given the prominent role of glutamate signaling in brain and liver and might provide an important target for therapeutic intervention

Neurobiological correlates of functional emotion processing and executive functions in alcohol dependence

Zentrale Aspekte der Alkoholabhängigkeit sind eine veränderte Emotionswahrnehmung, –regulation und die verminderte kognitive Fähigkeit zur exekutiven Verhaltenskontrolle. Zurzeit wird auch die Interaktion zwischen genetischen und suchtrelevanten Persönlichkeitsfaktoren und der Hirnfunktion und –struktur verstärkt diskutiert. Ziel der vorliegenden Publikationsdissertation war es, zum erweiterten Verständnis der neurobiologischen Grundlagen der Emotionsverarbeitung und Exekutivfunktionen in der Alkoholab-hängigkeit beizutragen und mögliche Zusammenhänge zum individuellen Rückfallrisiko aufzuzeigen. Dafür wurden alkoholabhängige Patienten und gesunde Erwachsene sowie gesunde Jugendliche mittels funktioneller und struktureller Magnetresonanztomographie prospektiv untersucht. Zusätzlich wurde bei den alkoholabhängigen Patienten das in früheren Studien beschriebene Rückfallrisiko-assoziierte GATA4- rs13273672-Gen bestimmt, um dessen Einfluss auf die funktionelle Alkoholreizverarbeitung und den Therapieverlauf zu prüfen. Dabei konnten protektive Faktoren identifiziert werden, die dem zukünftigem Rückfall entgegenwirken: 1) erhöhte Aktivierung des anterioren cingulären Kortex während der Verarbeitung negativer Emotionen; 2) flexible und kompensatorische Aktivierung neuronaler (präf-rontaler) Ressourcen zur Bewältigung hoher kognitiver Ansprüche; 3) GATA4-Genotyp- abhängige Amygdala-Reaktivität auf Suchtreize; und 4) strukturelle Integrität der Frontalhirnareale, die sowohl mit der Verhaltenssteuerung als auch mit (suchtrelevanter) Impulsivität assoziiert sind. Somit tragen diese Studienergebnisse zu der Identifikation von Resilienzmechnismen in der Alkoholabhängigkeit bei, die Patienten nach der Entgiftung befähigen, auch angesichts schwieriger Situationen abstinent zu bleiben.Central aspects of alcohol dependence are an altered emotion perception and regulation of negative mood as well as a reduced cognitive control of executive functioning. Currently, the interaction between genetic and addiction-associated personality factors on brain function and structure are in the focus of interest. The aim of the present dissertation was to gain further insights into the neurobiological basis of functional emotion processing and executive functions in alcohol dependence and to elucidate their role in increas-ing resilience against relapse. Therefore, we examined detoxified alcohol-dependent patients, healthy adults and adolescents using functional and structural magnetic resonance imaging and associated their clinical development prospectively. Additionally, genotyping of GATA4 rs13273672, which had previ-ously been associated with treatment outcome, was performed to test for potential genotype effects on alcohol-cue induced brain activity and relapse behavior. Our studies revealed protective mechanisms against relapse: 1) increased activation in the anterior cingulate cortex during emotion processing, 2) flex-ible activation of prefrontal resources when mastering high cognitive demands, 3) a GATA4-genotype-dependent high amygdala-reactivity elicited by alcohol cues, and 4) structural integrity of frontal brain areas implicated in reasoning, behavior control and trait impulsiveness. These results help to identify mechanisms contributing to resilience against relapse in alcohol dependence, which enable patients to remain abstinent despite stressful situations