Neural Basis of Emotion Regulation in Pediatric Post-traumatic Stress Disorder

描述（由申请人提供）：这个职业发展奖项的目标是为候选人提供额外的知识和技能，以实施和分析与事件相关的fMRI和大脑连接。这些知识和技能将用于探索有和没有创伤暴露的健康青少年情绪调节的神经基础，及其在青少年创伤后应激障碍（PTSD）中的功能障碍。创伤后应激障碍对年轻人和他们的家庭来说是一种使人衰弱的疾病，通常与其他焦虑症和抑郁症并存。与童年创伤相关的成人PTSD会增加抑郁、焦虑、药物滥用和自杀的风险。儿童创伤后应激障碍的治疗主要局限于心理治疗，其效果适中，即使这种治疗方法是可行的，但仍有许多年轻人患有持续性疾病。虽然证据有限，但药物对儿童创伤后应激障碍的疗效甚微。鉴于这些因素，了解创伤后应激障碍如何改变神经发育轨迹是非常重要的，目的是建立生物学上知情的早期干预措施，以避免童年和成年后的负面结果。儿童创伤后应激障碍以异常的情绪调节为临床和行为特征，但很少有研究探讨这种疾病中情绪调节的神经基础。成人创伤后应激障碍的脑功能研究提供了一个可测试的边缘和前额叶变化模型，这可能是情绪调节受损的基础。这包括扁桃体和背前扣带皮层（dACC）的激活增加，后者会促进恐惧反应。与此同时，通常抑制恐惧和焦虑反应的腹内侧前额叶皮层（vmPFC）的活动受损。青春期是前额皮质发育的一个特别敏感的时期，与创伤后应激障碍相关的前额叶边缘失衡的可能性更大。例如，这可以通过前额叶皮层中与年龄相关的活动减少来反映出来。相比之下，健康的创伤暴露青少年可能表现出更大的与年龄相关的腹侧前额叶恢复。成功的治疗，反过来，对青年创伤后应激障碍可能涉及代偿或弹性机制，看到健康的创伤暴露的青年。然而，这些模型在很大程度上仍未经检验。本研究计划将研究有创伤和无创伤的健康青年以及创伤后应激障碍青年的内隐情绪调节的功能神经相关性，重点研究杏仁核和前额叶皮质区域。这项研究将首先关注与健康青年相比的基线（治疗前）大脑差异，并进行为期一年的纵向随访作为探索性目标。每组将招募40名年龄在12- 18岁之间的青年。将采用经过验证的fMRI范例和行为测量。功能磁共振成像任务包括两个互补的范式，分别使用情绪面孔和情绪图片来探索内隐情绪调节。在Aim 1中，我们预测健康的年轻人在情绪调节过程中会同时参与杏仁核和前额叶区域，并且前额叶-杏仁核的连通性会随着年龄的增长而增加。健康的创伤暴露青年会表现出更大的杏仁核激活，但更大的vmPFC激活和代偿连接。在Aim 2中，我们预测儿童创伤后应激障碍和健康的创伤青年，与健康的非创伤青年相比，将显示出增加的杏仁核和dACC激活。然而，儿童创伤后应激障碍将通过情绪调节过程中vmPFC激活和连接受损与两组对照组区分开来。这将反映在创伤后应激障碍中vmPFC功能与年龄相关的增加减少上。探索性分析将检验健康和创伤后应激障碍青少年杏仁核和前额叶功能的纵向变化，以及创伤后应激障碍症状变化与大脑功能变化的关系。候选人是一名儿科精神病学家和情感神经科学家，长期对压力引起的大脑和行为变化感兴趣。他的临床专业包括

DESCRIPTION (provided by applicant): The goal of this career development award is to provide the candidate with additional knowledge and skills in the implementation and analysis of event-related fMRI and brain connectivity. This knowledge and skill set will be used to explore the neural basis of emotion regulation in healthy adolescents with and without trauma exposure, and its dysfunction in adolescent post-traumatic stress disorder (PTSD). PTSD is a debilitating illness for youth and their families, and is often comorbid with other anxiety disorders and depression. Adult PTSD related to childhood trauma carries additional risk for depression, anxiety, substance abuse, and suicide. Treatment of pediatric PTSD is largely limited to psychotherapy, which shows moderate effect sizes, leaving many youth with persistent illness even when such treatment is accessible. While evidence is limited, medications have shown little benefit for pediatric PTSD. In light of these factors, it is of great importance to understad how PTSD may alter neurodevelopmental trajectories, with the aim of instituting biologically informed, early interventions that may avert negative outcomes in childhood and subsequent adulthood. Pediatric PTSD is characterized clinically and behaviorally by abnormal emotion regulation, but few studies have examined the neural basis of emotion regulation in this illness. Functional brain studies in adult PTSD offer a testable model of limbic and prefrontal changes that that may underlie impaired emotion regulation. This includes increased activation of the amygdala and the dorsal anterior cingulate (dACC) cortex, which promote fear responses. At the same time, there is impaired engagement of the ventromedial prefrontal cortex (vmPFC), which normally suppresses fear and anxiety responses. Adolescence is a particularly sensitive period of prefrontal cortical development, with the potential for even greater prefrontal-limbic imbalance associated with PTSD. This could be reflected, for example, by diminished age-related activity in the prefrontal cortex. In contrast, healthy trauma-exposed adolescents may show even greater age-related ventral prefrontal recruitment. Successful treatment, in turn, for youth with PTSD may engage compensatory or resilient mechanisms seen in healthy trauma-exposed youth. However, these models remain largely untested. The proposed research plan will examine the functional neural correlates of implicit emotion regulation in healthy youth with and without trauma exposure, and youth with PTSD, with an emphasis on amygdala and prefrontal cortical regions. This research will focus on initially on baseline (pre-treatment) brai differences compared to healthy youth, with a longitudinal one-year follow up as an exploratory aim. Forty youth, ages 12- 18, will be recruited for each group. Validated fMRI paradigms and behavioral measures will be employed. The fMRI tasks include two complementary paradigms to explore implicit emotion regulation, using emotional faces and emotional pictures, respectively. In Aim 1, we predict that healthy youth will engage both amygdala and prefrontal areas during emotion regulation, and that prefrontal-amygdala connectivity will increase with age. Healthy trauma-exposed youth will show greater amygdala activation, but greater vmPFC activation and connectivity in compensation. In Aim 2, we predict that pediatric PTSD and healthy trauma youth, compared to healthy non-trauma youth, will show increased amygdala and dACC activation. However pediatric PTSD will be differentiated from both comparison groups by impaired vmPFC activation and connectivity during emotion regulation. This will be reflected by diminished age-associated increases in vmPFC function in PTSD. Exploratory analyses will examine longitudinal changes in amygdala and prefrontal function in healthy and PTSD adolescents, and how PTSD symptom changes correlate with brain function change over time. The candidate is a pediatric psychiatrist and affective neuroscientist, with a long-standing interest in stress- induced changes in brain and behavior. His clinical specialization includes the use of trauma-focused cognitive behavioral therapy to treat traumatized youth. The candidate has conducted initial fMRI studies of emotion regulation in a traumatized, young adult population, with experience in the analysis of block design tasks. Immediate career development goals during the award period include additional training in conducting fMRI in youth, analysis of event related fMRI and functional/effective connectivity, and training in clinicl trials for a future R01 fMRI treatment study. Acquisition of these skills and knowledge will allow the candidate to become an independent investigator in the affective neuroscience of pediatric PTSD. Long-term career goals include the development of expertise in delineating neurodevelopmental trajectories of trauma-resilient vs. trauma- vulnerable emotion regulation as related to pediatric PTSD, and pioneering research exploring treatment- induced changes in emotion regulation circuitry in pediatric PTSD. The proposed program of training and research will be conducted at the University of Wisconsin-Madison, which is a leading institution in the neuroscientific study of emotion, featuring state-of-the art neuroimaging facilities and distinguished faculty. These include Drs. Richard Davidson (mentor) and Ned Kalin (co-mentor), both of whom are pioneers in the study of the neural circuitry underlying emotion regulation in health and psychopathology. This cross- disciplinary research plan therefore allows for a stepwise approach to a career in the affective neuroscience of pediatric PTSD.