The overall goal of this exploratory-developmental study is to identify neuroimaging markers of response inhibition with significant test-retest reliability and familial resemblance, important criteria for inclusion in a larger-scale genetic stdy of endophenotypes for addiction risk. The role of genetic factors in predisposition to addictive disorders is well documented, however, neurobiological mechanisms mediating these genetic influences are poorly understood. Converging evidence suggests that risk for addictions can be mediated by deficits in inhibitory self-regulation of behavior. Functional magnetic resonance imaging (fMRI) is an important tool for investigation of brain mechanisms and pathways underlying inhibitory control. However, a critical barrier to genetic studies of the neural mechanisms of inhibitory control is the dearth of knowledge about reliability of fMRI phenotypes. Evidence for test-retest reliability is an important prerequisite for genetic studies because only stable, trait-like individual differences can be heritable, and test-retest reliability can be viewd as the upper boundary for heritability. Since adequately powered genetic studies require large samples and thus substantial investment of time and resources, selection of imaging phenotypes for such studies should be based on solid evidence for their reliability. However, very few studies that examined test-retest reliability of brain activation in response inhibition tasks yielded inconclusive results. The proposed study will fill this gap in knowledge through a systematic investigation of long-term test-retest reliability of regional and network-level brain activation in three response inhibition tasks. Furthermore, the proposed study will provide preliminary evidence for familial transmission of fMRI phenotypes and examine a variety of factors affecting test-retest reliability. The following Specific Aims will be pursued: 1) To asses long-term test-retest reliability of regional brain activations related to response inhibition, 2) o examine the effect of experimental design, preprocessing parameters, practice effects, and data analytical approaches on test-retest reliability, and 3) To assess familial influences on fMRI measures using intrapair correlations between monozygotic (MZ) twins. Taken together, this information will allow us to identify candidate fMRI phenotypes suitable for a larger scale genetic study of the neural underpinnings of response inhibition. Since response inhibition has also been implicated as a key construct in other psychopathology (e.g. ADHD), the proposed will have a broader impact on the clinical neuroscience field.
Important role of genetic factors in predisposition to addictive disorders is well documented, and recent studies suggest that these genetic influences might be mediated by abnormalities in the frontal lobes of the brain responsible for inhibitory self-control Therefore, to better understand the mechanisms of addiction, it is important to investigate genetic influences on frontal brain function. However, the first step towards this goal is to identify stable individual characteristics of brain function related to inhibitory control of behavor, which is the purpose of this exploratory-developmental study.
