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

项目总结/摘要 该职业发展奖的目标是为候选人提供更多的知识和技能， 事件相关功能磁共振成像和大脑连接的实现和分析。这些知识和技能将 用于探索有创伤和无创伤的健康青少年情绪调节的神经基础 暴露，以及青少年创伤后应激障碍（PTSD）的功能障碍。创伤后应激障碍是一种 这种疾病对青年及其家庭来说是一种严重的疾病，并且经常与其他焦虑症和抑郁症共病。成人 与童年创伤有关的PTSD会带来抑郁、焦虑、药物滥用和自杀的额外风险。 儿童创伤后应激障碍的治疗在很大程度上局限于心理治疗，其效果中等， 许多青年即使在可以获得治疗的情况下，仍然患有顽固性疾病。虽然证据有限， 药物治疗对儿童创伤后应激障碍没有什么好处。鉴于这些因素， 了解PTSD如何改变神经发育轨迹，目的是从生物学上建立 知情的早期干预措施，可以避免儿童期和随后的成年期的负面结果。 儿童创伤后应激障碍的临床和行为特征是异常的情绪调节，但很少有研究 已经研究了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 提供了一个边缘系统和前额叶变化的可测试模型，这些变化可能是情绪调节受损的基础。 这包括杏仁核和背侧前扣带皮层（dACC）的激活增加， 促进恐惧反应。与此同时，腹内侧前额叶皮层的参与受损， （vmPFC），通常抑制恐惧和焦虑反应。青春期是一个特别敏感的 前额叶皮层发育时期，有可能导致更严重的前额叶-边缘系统失衡 与创伤后应激障碍有关这可能反映在，例如，减少与年龄相关的活动，在前额叶皮层 皮层相比之下，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 招聘反过来，对患有PTSD的年轻人的成功治疗可能会使他们获得补偿或恢复能力。 在健康的创伤暴露青年中观察到的机制。然而，这些模型在很大程度上仍未得到检验。 这项研究计划将探讨内隐情绪调节的功能神经相关因素， 健康的青少年，有和没有创伤暴露，和青年与创伤后应激障碍，重点是杏仁核， 前额叶皮质区这项研究将集中在最初的基线（治疗前）大脑的差异 与健康青年相比，以一年的纵向随访作为探索性目标。40个12岁的年轻人 18、每个人都会被招募。将采用经验证的功能磁共振成像范例和行为测量。 功能磁共振成像任务包括两个互补的范式来探索内隐情绪调节，使用情绪 面部表情和情感图片。在目标1中，我们预测健康的年轻人会同时使用杏仁核和杏仁核， 前额叶-杏仁核的连通性会随着 年龄健康的创伤暴露青年将表现出更大的杏仁核激活，但更大的vmPFC激活， 连接补偿。在目标2中，我们预测儿童PTSD和健康的创伤青年，与 健康的无创伤青年，将显示杏仁核和dACC激活增加。然而，儿童创伤后应激障碍将 通过在情绪过程中受损的vmPFC激活和连接与两个对照组区分开来 调控这将反映在PTSD中与年龄相关的vmPFC功能增加减少。 探索性分析将检查健康和肥胖儿童杏仁核和前额叶功能的纵向变化， PTSD青少年，以及PTSD症状的变化如何与大脑功能随时间的变化相关。 候选人是一名儿科精神病学家和情感神经学家，长期对压力感兴趣- 引起大脑和行为的变化。他的临床专业包括使用创伤集中的认知 行为疗法来治疗受创伤的年轻人这位候选人已经对情绪进行了初步的功能磁共振成像研究， 在创伤，年轻的成年人群体的监管，在块设计任务的分析经验。 在奖励期间，立即的职业发展目标包括进行fMRI的额外培训， 青年，分析事件相关的功能磁共振成像和功能/有效的连接，并在临床试验的培训， 未来R 01 fMRI治疗研究。这些技能和知识的获得将使候选人成为 一位独立的儿童创伤后应激障碍情感神经科学研究者。长期职业目标包括 发展专门知识，描绘创伤恢复与创伤的神经发育轨迹， 与儿童创伤后应激障碍有关的脆弱的情绪调节，以及探索治疗方法的开创性研究- 在儿童创伤后应激障碍中引起情绪调节回路的变化。拟议的培训方案和 研究将在威斯康星大学麦迪逊分校进行，这是一个领先的机构， 情绪的神经科学研究，具有最先进的神经成像设施和杰出的教师。 其中包括Richard Davidson博士（导师）和Ned Kalin博士（共同导师），他们都是 研究健康和精神病理学中情绪调节的神经回路。十字架- 因此，学科研究计划允许逐步进入情感神经科学的职业生涯， 小儿创伤后应激障碍

Project Summary/Abstract 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 understand 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) brain 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 clinical 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.