Development of Tonic and Phasic Neural Systems Mediating Affect and Anxiety

描述（由申请人提供）：儿童焦虑症影响大约十分之一的儿童，导致明显的社交障碍。这些人在成年后患情绪和焦虑症的风险也更高，这是一个与整个生命周期相关的公共卫生问题。迄今为止，表征焦虑障碍病理生理学的工作主要集中在焦虑症状的一个领域——对潜在威胁的线索（如情绪面孔或负面图像）的过度敏感（例如，相位反应），而其他关键焦虑症状的生物标记，如持续的高度警觉和觉醒（例如，强直反应），仍然相对未被探索。本研究项目的目标是：1)描述与威胁处理和警觉性相关的相位和强直过程的典型脑系统发育；2)为它们在代表广泛性焦虑障碍的强直焦虑表型特征中的不同作用提供初步证据；3)测试它们对家族病例风险的预测价值。建议的工作将首先使用功能性神经影像学和心理生理学来表征大脑网络的功能特性，这些网络在横断面中介导焦虑的强直性和阶段性症状，典型的发展样本（K期）。然后，将在儿童广泛性焦虑障碍（GAD）患者样本中识别异常的神经和行为特征，GAD是一种以慢性忧虑和警觉性（K期）为特征的临床综合征。利用这些样本，我们将评估广泛性焦虑症的生物行为标志物是否在基于家族史（R期）的高风险儿童样本中也很明显。为了实现这些目标，候选人将接受广泛的儿科和临床人群测试培训，并接受发育和临床神经科学教育，以及先进的神经成像技术，包括静息状态连通性，扩散张量连通性和网络建模方法。这项工作和培训将为候选人准备一个独立的实验室，能够进行发育、临床和高级神经影像学研究。无论观察到的结果如何，这项工作将作为未来R01基金应用的自然先驱，用于纵向跟踪高风险个体和/或在临床研究中利用已识别的生物标志物来评估针对紧张系统及其相关慢性焦虑症状的新疗法。这项工作正在朝着确定焦虑障碍风险的预测标记的最终目标前进，这将有助于早期识别和预防。

DESCRIPTION (provided by applicant): Childhood anxiety disorders affect approximately one in ten children resulting in marked social impairment. These individuals also carry a heightened risk for mood and anxiety disorders in adulthood, rendering this a public health issue relevant to the entire lifespan. Work to date characterizing the pathophysiology of anxiety disorders has focused on one sphere of anxious symptoms- hypersensitivity to cues of potential threat such as emotional faces or negative images (e.g., phasic responses), while biological markers for other key symptoms of anxiety, such as sustained hypervigilance and arousal (e.g., tonic responses), remain relatively unexplored. The objectives of this program of research are: 1) to delineate the typical development of brain systems involved in phasic and tonic processes that map onto threat processing and vigilance, 2) to provide preliminary evidence for their differential roles in representing tonic anxious phenotypes characteristic of generalized anxiety disorder; and 3) to test their predictive merit for risk in familial cases. The proposed work will first use functional neuroimaging and psychophysiology to characterize the functional properties of brain networks that mediate tonic and phasic symptoms of anxiety in a cross-sectional, typically developing sample (K phase). Then, deviant neural and behavioral signatures will be identified in a sample of individuals with pediatric Generalized Anxiety Disorder (GAD), a clinical syndrome marked by chronic apprehension and vigilance (K phase). Using these samples, we will assess whether biobehavioral markers of GAD are also evident in a sample of children at heightened risk for developing anxiety disorders based on family history (R phase). To accomplish these objectives, the candidate will receive extensive training in testing pediatric and clinical populations bolstered by education in developmental and clinical neuroscience, and advanced neuroimaging techniques including resting-state connectivity, diffusion tensor connectivity and network modeling methodologies. This work and training will prepare the candidate for initiating an independent laboratory capable of developmental, clinical and advanced neuroimaging research. Irrespective of the observed findings, this work will serve as a natural precursor to future R01 funding applications to track high-risk individuals longitudinally and/or utilize identified biomarkers in clinical research evaluating new therapies targeting the tonic system and its associated chronic anxious symptomatology. This work is progressing toward the ultimate goal of identifying predictive markers of risk for anxiety disorders that will facilitate early identification and prevention. PUBLIC HEALTH RELEVANCE: Childhood anxiety disorders affect as many as one in ten children and confer a heightened risk for psychiatric disorders throughout the lifespan. The objective of work is expand our understanding of brain systems critical to different symptoms of anxiety by characterizing the neurobiological mechanisms of threat biases and vigilance across development. Brain networks that mediate these symptoms are predicted to play distinctive roles in the pathophysiology of anxiety disorders and will be evaluated for their predictive merit in identifying individuals at heightened risk for anxiety disorders based on family history. Ultimately, this work should provide biologically valid behavioral markers of risk for anxiety disorders that will facilitate early identification as well as new outcome measures for clinical trials for optimizing personalized treatment.