THE FUNCTIONAL NEUROANATOMY OF RESPONSE INHIBITION: INTEGRATING ERP AND FMRI DATA

描述（由申请人提供）：拟议R03研究的总体目标是通过整合高空间和时间分辨率的脑成像方法（分别为fMRI和erp）来阐明反应抑制的神经解剖学基础和神经生理学机制。NIDA I/START奖将鼓励申请人进入成瘾研究中的脑成像领域，允许他生成初步数据，这些数据可用于促进在他的研究项目中更广泛地使用成像方法，将遗传学和认知神经科学联系起来，以了解成瘾的决定因素和后果。来自流行病学、遗传学和认知神经科学成瘾研究的证据表明，一系列成瘾行为和共病的外化精神病理具有共同的遗传倾向，反映在“行为去抑制”这一高度遗传的潜在特征中。然而，特定的神经基质和机制介导的抑制自我调节行为的遗传影响仍然知之甚少。申请人过去和正在进行的双胞胎研究表明，遗传对与Go/No-Go任务中的冲突检测和反应抑制相关的事件相关脑电位（ERPs）的前额定位成分有很强的影响。然而，由于ERP方法的空间分辨率和其他限制，特定的神经结构和电路对这些遗传差异的贡献尚不清楚，这限制了结果的解释并阻碍了进一步的研究进展。为了解决这个问题，我们提出了一个联合功能磁共振（fMRI）和ERP评估30对MZ和DZ双胞胎。我们假设高度遗传的额叶ERP成分（N2和P3a）将在先前研究中涉及冲突检测和反应抑制的区域网络中显示出与BOLD反应显著相关，尤其是前扣带皮层。我们进一步预计BOLD响应将显示显著的MZ而不是DZ双胞胎相关性。此外，我们将探索性分析儿茶酚胺- o -甲基转移酶（COMT）基因的功能多态性与与反应抑制相关的BOLD/ERP激活之间的关系。这些初步数据将使我们能够结合ERP和fMRI的优势，以进一步阐明反应抑制的神经基质，为ERP内表型提供神经解剖学验证，并支持未来R01项目的发展，利用“基因组成像”方法来了解成瘾易感性的神经遗传学结构。总之，该奖项将允许申请人首次将脑成像方法纳入其专注于物质使用障碍的病因和后果的研究项目中。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE 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.