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、发病率和死亡率的主要原因。的高遗传率 BD使患有BD的父母的子女患BD和其他精神疾病的风险增加 如抑郁症、多动症和焦虑症。通过识别在结构和功能上的异常 BD患者的情绪和情绪调节过程中重要的神经回路异常， 对BD高危青年的神经影像研究可能确定BD的病理生理过程的生物标志物 目前未受影响的个体可用于BD的早期诊断和治疗。因为没有 迄今为止在自然空间进行的多模式或纵向神经成像研究在健康青年中存在遗传风险 发展中的BD，白质与这些神经回路中的功能异常之间的关系， 以及它们与可能早于BD发病的症状的关系尚不清楚。的目标是 因此，该建议将扩散张量成像(DTI)和功能磁共振成像相结合 (FMRI)通过检查脑白质结构和 BD中支持情绪调节过程的神经回路功能异常。这将会实现的 通过对30名双相父母的健康子女和30名儿童健康子女的横断面比较 健康父母，以及对双相父母子女的纵向分析(随访：1.5-2 年)，研究情绪调节回路中与BD风险有关的结构-功能关系。 第一个目的是阐明前额叶皮质白质结构和功能之间的关系。 皮质下神经回路与高危青年BD的病理生理学有关。功能连接 分析和最小绝对收缩和选择运算符(套索)回归分析将用于 确定在情绪调节回路中重要的白质束结构之间的关系 (胼胝体、前扣带束、钩状束和上纵束)和 情绪调节回路中重要的神经区内活动和神经区之间的功能连接 (杏仁核、背外侧和腹外侧前额叶皮质，以及前扣带回皮质) 情绪加工任务。第二个目标是确定结构和功能之间的关系 这一回路的异常和在BD发展之前的症状，即焦虑，会影响不稳定， 抑郁症和躁狂症。第三个目标是探索白质纵向变化之间的关系 BD高危青年的结构、活动、功能连通性和症状严重程度。这是世界上第一次 文献，使用这些多模式神经成像方法对BD高危青年进行横断面研究 纵向上将提供对发展轨迹的更全面的理解 高危青年易患BD。这最终将提高早期诊断的准确性和 为患有BD和有发生BD风险的个体提供治疗干预的神经靶点。

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.