The overall goal of the proposed R03 study is to elucidate the neuroanatomical substrates and neurophysiological mechanisms underlying response inhibition through the integration of brain imaging methods with high spatial and temporal resolution (fMRI and ERPs, respectively). This NIDA I/START award will foster the applicant's entry to the area of brain imaging in addiction research by allowing him to generate preliminary data that can be used to facilitate more extensive use of imaging methodologies in his research program linking genetics and cognitive neuroscience in order to understand the determinants and consequences of addiction. Converging evidence from epidemiologic, genetic, and cognitive neuroscience research on addiction suggests that there is a common genetic liability to a range of addictive behaviors and comorbid externalizing psychopathology reflected in the highly heritable latent trait of """"""""behavioral disinhibition"""""""". However, specific neural substrates and mechanisms mediating genetic influences on inhibitory self-regulation of behavior remain poorly understood. The applicant's past and ongoing twin studies have demonstrated strong genetic influences on frontally localized components of event-related brain potentials (ERPs) associated with conflict detection and response inhibition in a Go/No-Go task. However, due to the limited spatial resolution and other limitations of the ERP method, the contribution of specific neural structures and circuits to these heritable differences remains unclear, which limits the interpretation of results and impedes further research progress. To address this problem, we propose a combined functional magnetic resonance (fMRI) and ERP assessment of 30 MZ and DZ twin pairs. We hypothesize that the highly heritable frontal ERP components (N2 and P3a) will show significant correlations with BOLD responses in a network of regions implicated in conflict detection and response inhibition by previous studies, most notably the anterior cingulate cortex. We further expect that BOLD responses will show significant MZ but not DZ twin correlations. In addition, we will conduct exploratory analyses of the association between a functional polymorphism in the catecholamine-O-methyltransferase (COMT) gene and BOLD/ERP activations related to response inhibition. These preliminary data will allow us to combine the strengths of ERP and fMRI in order to further elucidate the neural substrates of response inhibition, provide a neuroanatomical validation for ERP endophenotypes, and support the development of a future R01 project using """"""""genomic imaging"""""""" approach to understand the neurogenetic architecture of addiction vulnerability. In summary, this award will allow the applicant to incorporate brain imaging methods for the first time in his research program focused on the etiology and consequences of substance use disorders.
STAEMENT: The costs of substance use disorders to society are enormous. Impaired impulse control has been implicated as a major predisposing risk factor for addiction. A better understanding of the genetic and neurobiological underpinnings of this major risk factor can facilitate the development of more effective prevention, early intervention, and treatment strategies.
| Mulligan, Richard C; Kristjansson, Sean D; Reiersen, Angela M et al. (2014) Neural correlates of inhibitory control and functional genetic variation in the dopamine D4 receptor gene. Neuropsychologia 62:306-18 |
