Developmental trajectory of anxiety, avoidance, and arousal in girls with the FMR1 full mutation

焦虑、回避和觉醒（AAA）的症状会对一个人的一天产生显著的负面影响- 今天的功能和生活质量。这对女孩和妇女来说尤其如此，她们的死亡率是女孩和妇女的两倍多。 与男性相比，更有可能被诊断为焦虑症。拟议项目涉及 AAA的发病机制，三个负价RDoC系统，在特定的遗传风险的背景下， FMR 1完全突变的女孩（即脆性X综合征，FXS）。人们普遍认识到， AAA症状是FXS女孩和妇女的一个重要和临床上重要的问题。最近 调查报告表明，56%的FXS女孩接受了焦虑症的治疗。女性 在研究中代表性不足的FXS患者有更多样化的症状， 智商高于FXS男性，这使得女性在翻译中发挥特别重要的作用。 了解AAA表型的复杂性。 使用FXS作为人体模型系统，我们关于AAA症状的知识库中的关键空白将 被解决。该项目将采用加速纵向设计来跟踪60年内的症状发展 8-15岁的FXS女孩，以及线性混合模型来估计与年龄相关的变化。的 负效价RDoC系统的发展将与关键神经系统一起跟踪， 考虑到可能导致临床表现的遗传、激素和环境因素， AAA症状这种多模态方法将有助于基因-大脑-行为的综合分析 AAA症状背后的相互作用。我们的设计将使我们能够测试关于 AAA症状的过程和检查中介因素，如HPA轴调节。结合传统 大脑连接的功能和结构指标将使我们能够探测已知的前额叶边缘回路， 在AAA症状中起关键作用。利用灵活的光学神经成像（功能性近红外 光谱，fNIRS），我们将检查前额叶皮层对焦虑的反应，在自然的社会 相互作用以产生体内真实的时间焦虑反应的生态有效评估。 这里提出的项目建立在过去资助期内大量研究的基础上，重点是基因， FXS女性的环境-大脑-行为关联。关于FXS的新知识的结合 在过去的几年里， 提供了一个理想的基础，新的假设可以在新的赠款期内进行测试。绘制 AAA症状发展的轨迹，并检查与神经生物学，生理学，激素， 基因和环境将推进关于FXS中AAA发病机制的科学知识基础。 这些结果将通过确定干预和预防措施的关键窗口来推进临床实践 这些策略将是最有效的，并有助于在FXS内推进精准医疗方法。 1

Symptoms of anxiety, avoidance and arousal (‘AAA’) can significantly, and negatively, impact on one’s day- to-day functioning and quality of life. This is especially true for girls and women who are more than twice as likely to be diagnosed with an anxiety disorder when compared to men. The proposed project addresses the pathogenesis of AAA, three of the negative valance RDoC systems, in the context of a specific genetic risk for such symptoms in girls with the FMR1 full mutation (i.e. fragile X syndrome, FXS). It is broadly recognized that AAA symptoms are an important and clinically significant problem for girls and women with FXS. Recent survey reports indicate that 56% of girls with FXS have received treatment for an anxiety disorder. Females with FXS, who are underrepresented in research studies, have a more diverse range of symptoms and overall higher IQ than males with FXS, which allows females to play a particularly important translational role in understanding the complexities of the AAA phenotype. Using FXS as a human model system, critical gaps in our knowledge base regarding AAA symptoms will be addressed. This project will employ an accelerated longitudinal design to track symptom development in 60 girls with FXS from ages 8-15 years, and linear mixed modeling to estimate change associated with age. The development of negative valence RDoC systems will be tracked in tandem with key neural systems while considering genetic, hormonal, and environmental factors that may contribute to the clinical presentation of AAA symptoms. This multimodal approach will facilitate comprehensive analysis of gene-brain-behavior interactions that underlie AAA symptoms. Our design will allow us to test novel hypotheses regarding the course of AAA symptoms and examine mediating factors such as HPA axis regulation. Combining traditional functional and structural metrics of brain connectivity will allow us probe the prefrontal-limbic circuitry known to have a key role in AAA symptoms. Utilizing flexible, optical neuroimaging (functional near infrared spectroscopy, fNIRS), we will examine prefrontal cortical responses to anxiety during naturalistic social interactions to yield ecologically valid assessments of real time anxiety response in vivo. The project proposed here builds on substantial research in the past grant period focused on gene- environment-brain-behavior associations in females with FXS. The combination of new knowledge about FXS that has become available in the past several years and new methods for interrogating these associations provides an ideal foundation from which new hypotheses can be tested in the new grant period. Plotting the trajectory of AAA symptom development and examining key linkages with neurobiology, physiology, hormones, genes and environment will advance the scientific knowledge base regarding the pathogenesis of AAA in FXS. These results will advance clinical practice by identifying critical windows when interventions and preventative strategies will be most effective and help to advance a precision medicine approach within FXS. 1