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

描述（由申请方提供）：拟议R 03研究的总体目标是通过整合具有高空间和时间分辨率的脑成像方法（分别为fMRI和ERP）阐明反应抑制的神经解剖学基础和神经生理学机制。这个NIDA I/START奖将促进申请人进入成瘾研究中的脑成像领域，使他能够生成初步数据，这些数据可用于促进在他的研究计划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。从流行病学，遗传学和认知神经科学成瘾研究的证据表明，有一个共同的遗传易感性的一系列成瘾行为和共病外化精神病理学反映在高度遗传的潜在特征的“行为去抑制”。然而，具体的神经基板和机制介导的遗传影响抑制性自我调节的行为仍然知之甚少。申请人过去和正在进行的双胞胎研究表明，在Go/No-Go任务中，与冲突检测和反应抑制相关的事件相关脑电位（ERP）的额叶局部成分受到强烈的遗传影响。然而，由于有限的空间分辨率和其他限制的ERP方法，具体的神经结构和电路的贡献，这些遗传差异仍然不清楚，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 MZ和DZ双胞胎对。我们假设，高度遗传的额叶ERP组件（N2和P3 a）将显示显着的相关性与BOLD反应在网络中的冲突检测和反应抑制的区域，最显着的是前扣带皮层。我们进一步预计，BOLD反应将显示显着的MZ，但不是DZ双胞胎相关。此外，我们将进行探索性分析之间的关联在儿茶酚胺-O-甲基转移酶（COMT）基因的功能多态性和BOLD/ERP激活相关的反应抑制。这些初步的数据将使我们能够联合收割机的优势，以进一步阐明反应抑制的神经基板，提供ERP内表型的神经解剖学验证，并支持未来的R 01项目的发展，使用“基因组成像”的方法来了解成瘾脆弱性的神经遗传结构。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计划中。 公共卫生相关声明：物质使用障碍给社会带来的成本是巨大的。冲动控制受损被认为是成瘾的主要诱发风险因素。更好地了解这一主要风险因素的遗传和神经生物学基础，可以促进制定更有效的预防，早期干预和治疗策略。

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.