Structural-functional relationships: a multimodal neuroimaging approach to the study of children and adolescents genetically at risk for bipolar disorder

项目摘要 双相情感障碍（BD）是世界范围内导致残疾、发病和死亡的主要原因。遗传力高， BD使BD父母的后代患BD和其他精神疾病的风险增加 比如抑郁症多动症和焦虑症通过识别结构和功能的异常， 对于BD患者的情绪和情绪调节过程异常重要的神经回路， 对有BD风险的青年进行神经影像学研究，可以确定BD病理生理过程的生物标志物， 尚未受影响的个体，其可用于BD的早期诊断和治疗。由于没有 迄今为止，在有遗传风险的健康青年中进行的多模式或纵向神经影像学研究 发展中的BD，这些神经回路中的白色物质和功能异常之间的关系， 以及它们与可能早于BD发作的症状的关系尚未阐明。的目标 因此，该建议将联合收割机扩散张量成像（DTI）和功能磁共振成像结合起来 （功能磁共振成像）通过检查白色物质结构， BD患者支持情绪调节过程的神经回路功能异常。这将是完成 通过对双相父母的30名健康后代和双相父母的30名健康后代的横断面比较， 健康的父母，以及通过纵向分析的后代的双相父母（随访：1.5-2 年），研究与BD风险有关的情绪调节回路的结构-功能关系。 目的一是阐明前额叶皮层白色物质结构与功能的关系 和皮质下神经回路牵连的病理生理学BD在高危青年。功能连接 分析和最小绝对收缩和选择算子（LASSO）回归分析将用于 识别在情绪调节回路中重要的白色物质束结构之间的关系 （胼胝体、前扣带束、钩束和上级纵束）和 在情绪调节回路中重要的神经区域内的活动和神经区域之间的功能连接 （杏仁核，背外侧和腹外侧前额叶皮层，前扣带皮层）在面部 情绪处理任务第二个目标是确定结构和功能之间的关系 该回路的异常和BD发展之前的症状，即焦虑，影响不稳定性， 抑郁症和躁狂症。第三个目的是探索白色物质纵向变化之间的关系 BD高危青年的结构、活动、功能连接和症状严重程度。上首次 文献，使用这些多模式神经影像学方法研究青年在风险的BD都横截面 纵向将提供对发展轨迹的更全面的理解 易患BD的高危青少年。这将最终导致早期诊断准确性的提高， 为患有BD和有发展BD风险的个体的治疗干预提供神经靶点。

Project Summary Bipolar Disorder (BD) is a leading cause of disability, morbidity, and mortality worldwide. The high heritability of BD places offspring of parents with BD at an increased risk for developing BD and other psychiatric disorders such as Depression, ADHD, and Anxiety Disorders. By identifying abnormalities in the structure and function of neural circuitries important for emotion and emotional regulation processes aberrant in individuals with BD, neuroimaging studies of youth at risk for BD may identify biomarkers of pathophysiological processes of BD in as yet unaffected individuals which may be used for earlier diagnosis and treatment of BD. Since there are no multimodal or longitudinal neuroimaging studies in native space to date in healthy youth genetically at risk for developing BD, the relationships between white matter and functional abnormalities in these neural circuitries, and their relationships with symptoms that may predate BD onset, have yet to be elucidated. The objective of this proposal is thus to combine diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) to identify neuroimaging biomarkers of risk for future BD by examining the white matter structure and function of neural circuitry supporting emotional regulation processes aberrant in BD. This will be accomplished both through a cross-sectional comparison of 30 healthy offspring of bipolar parents and 30 healthy offspring of healthy parents, as well as through a longitudinal analysis of the offspring of bipolar parents (follow-up: 1.5-2 years), to study structural-functional relationships in emotional regulation circuitries implicated in risk for BD. The first aim is to elucidate the relationships between white matter structure and function in prefrontal cortical and subcortical neural circuitry implicated in the pathophysiology of BD in at-risk youth. Functional connectivity analyses and Least Absolute Shrinkage and Selection Operator (LASSO) regression analyses will be used to identify relationships between the structure of white matter tracts important in emotion regulation circuitry (corpus callosum, anterior cingulum bundle, uncinate fasciculus, and superior longitudinal fasciculus) and activity within and functional connectivity between neural regions important in emotional regulation circuitry (amygdala, dorsolateral and ventrolateral prefrontal cortex, and anterior cingulate cortex) during a facial emotion processing task. The second aim is to determine relationships between structural and functional abnormalities in this circuitry and symptoms that predate the development of BD, namely anxiety, affect lability, depression, and mania. The third aim is to explore relationships among longitudinal changes in white matter structure, activity, functional connectivity, and symptom severity in BD at-risk youth. For the first time in the literature, using these multimodal neuroimaging methods to study youth at risk for BD both cross-sectionally and longitudinally will provide a more comprehensive understanding of the developmental trajectories predisposing to BD in at-risk youth. This will ultimately lead to improvements in earlier diagnostic accuracy and provide neural targets for therapeutic interventions in individuals suffering from, and at risk for developing, BD.