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，导致明显的社会障碍。这些人成年后患情绪和焦虑症的风险也很高，这是一个与整个寿命相关的公共卫生问题。到目前为止，对焦虑症的病理生理学特征的研究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(例如，相位反应)的高敏感性，而其他焦虑关键症状的生物标记物，如持续的高度警惕和觉醒(例如，紧张反应)，仍然相对未被探索。这项研究的目标是：1)描绘参与威胁处理和警觉的阶段性和紧张性过程的大脑系统的典型发育；2)为它们在表现广泛性焦虑症的紧张性焦虑表型中的不同作用提供初步证据；以及3)测试它们在家族性病例中对风险的预测价值。这项拟议的工作将首先使用功能神经成像和心理生理学来表征大脑网络的功能特性，这些网络在横截面的典型发育中的样本(K期)中调节焦虑的紧张性和相性症状。然后，将在患有儿童广泛性焦虑障碍(GAD)的个体样本中识别出异常的神经和行为特征，GAD是一种以慢性恐惧和警惕(K期)为标志的临床综合征。使用这些样本，我们将评估GAD的生物行为标记物是否也明显存在于基于家族史(R期)的焦虑症高危儿童样本中。为了实现这些目标，应聘者将接受广泛的儿科和临床人群测试培训，并辅之以发展和临床神经科学教育，以及先进的神经成像技术，包括静息状态连接、扩散张量连接和网络建模方法。这项工作和培训将为候选人建立一个独立的实验室做好准备，该实验室能够进行开发、临床和高级神经成像研究。不管观察到的结果如何，这项工作将成为未来R01资金申请的自然先驱，以纵向跟踪高危个体和/或在临床研究中利用已确定的生物标记物来评估针对补药系统及其相关的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的预测性标记物的最终目标前进，这将有助于早期识别和预防。 公共卫生相关性：儿童焦虑症影响多达十分之一的儿童，并在一生中增加患精神疾病的风险。这项工作的目的是通过表征威胁、偏见和警觉在发育过程中的神经生物学机制，扩大我们对大脑系统的理解，这些系统对不同的焦虑症状至关重要。据预测，介导这些症状的大脑网络将在焦虑症的病理生理学中发挥独特的作用，并将根据家族史评估其在识别焦虑症高风险个体方面的预测价值。最终，这项工作应该为焦虑症的风险提供生物学上有效的行为标记物，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衡量标准。

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.