TEST-RETEST RELIABILITY OF PUTATIVE FMRI ENDOPHENOTYPES FOR SUBSTANCE ABUSE RISK

 描述（由申请人提供）：本探索性发育研究的总体目标是鉴定具有显著重测可靠性和家族相似性的反应抑制神经影像学标志物，这是纳入成瘾风险内表型大规模遗传研究的重要标准。遗传因素在成瘾性疾病易感性中的作用已被充分证实，然而，调节这些遗传影响的神经生物学机制却知之甚少。越来越多的证据表明，成瘾的风险可以通过行为抑制性自我调节的缺陷来介导。功能磁共振成像（fMRI）是研究抑制性控制的脑机制和通路的重要工具。然而，一个关键的障碍，遗传学研究的神经机制的抑制控制是缺乏知识的可靠性fMRI表型。重测信度的证据是遗传学研究的重要前提，因为只有稳定的、类似性状的个体差异才是可遗传的，而重测信度可以看作是遗传力的上限。由于足够有力的遗传学研究需要大样本，因此需要大量的时间和资源投入，因此此类研究的成像表型的选择应基于其可靠性的可靠证据。然而，很少有研究，检查重测信度的大脑激活反应抑制任务产生不确定的结果。拟议的研究将填补这一空白的知识，通过长期的重测信度的区域和网络水平的大脑激活在三个反应抑制任务的系统调查。此外，拟议中的研究将提供初步证据的fMRI表型的家族传播，并检查各种因素影响重测信度。本研究的主要目的是：1）评价反应抑制相关脑区激活的长期重测信度; 2）研究实验设计、预处理参数、练习效果和数据分析方法对重测信度的影响; 3）利用同卵双生子（MZ）对内相关性评价家族因素对功能磁共振成像测量的影响。总之，这些信息将使我们能够确定候选的fMRI表型适合于更大规模的遗传学研究。 研究反应抑制的神经基础。由于反应抑制也被认为是其他精神病理学（如ADHD）的关键结构，因此该提议将对临床神经科学领域产生更广泛的影响。

 DESCRIPTION (provided by applicant): 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.