Development of Tonic and Phasic Neural Systems Mediating Affect and Anxiety

描述（由申请人提供）：儿童期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较高，使其成为与整个生命周期相关的公共卫生问题。迄今为止，描述焦虑症病理生理学特征的工作主要集中在焦虑症状的一个领域——对潜在威胁线索的超敏反应，例如情绪化的面孔或负面图像（例如阶段性反应），而其他关键焦虑症状的生物标志物，例如持续的过度警觉和觉醒（例如强直反应），仍然相对未经探索。该研究计划的目标是：1）描绘涉及威胁处理和警惕性的阶段性和强直性过程的大脑系统的典型发育，2）为它们在代表广泛性焦虑症的强直性焦虑表型特征中的不同作用提供初步证据； 3) 测试其对家族病例风险的预测价值。拟议的工作将首先使用功能神经影像学和心理生理学来表征大脑网络的功能特性，这些网络在横截面、典型的发育样本（K 期）中介导焦虑的强直和阶段性症状。然后，将在患有儿科广泛性焦虑症 (GAD) 的个体样本中识别出异常的神经和行为特征，GAD 是一种以慢性忧虑和警惕（K 期）为特征的临床综合征。使用这些样本，我们将评估基于家族史（R 期）患焦虑症风险较高的儿童样本中是否也存在明显的广泛性焦虑症（GAD）生物行为标志物。为了实现这些目标，候选人将在发育和临床神经科学教育以及先进的神经影像技术（包括静息态连接、扩散张量连接和网络建模方法）的支持下，接受儿科和临床人群测试方面的广泛培训。这项工作和培训将为候选人准备建立一个能够进行发育、临床和高级神经影像研究的独立实验室。无论观察到的结果如何，这项工作将作为未来 R01 资助申请的自然先驱，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评估针对强直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症风险预测标记的最终目标迈进，这将有助于早期识别和预防。 公共卫生相关性：儿童期焦虑症影响多达十分之一的儿童，并导致整个一生患精神疾病的风险增加。这项工作的目标是通过描述威胁偏见和警惕性发展过程中的神经生物学机制，扩大我们对对不同焦虑症状至关重要的大脑系统的理解。预计介导这些症状的大脑网络在焦虑症的病理生理学中发挥独特的作用，并将评估其在根据家族史识别焦虑症高风险个体方面的预测价值。最终，这项工作应该提供焦虑症风险的生物学有效行为标记，这将有助于早期识别，并为优化个性化治疗的临床试验提供新的结果测量。

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.