Neural Signature of Fear Overgeneralization in Trauma Exposed Adults

 描述（由申请人提供）：暴露于严重创伤的人群，如退伍军人，灾难幸存者和袭击受害者，具有一系列创伤相关精神病理学的高风险。超过三分之一的接触者可能会出现严重的致残性精神病理学，包括创伤后应激障碍（PTSD）、广泛性焦虑症（GAD）、恐慌症（PD）和重度抑郁症。然而，努力推进创伤相关异常的神经机制的知识已经受到几乎只关注PTSD的诊断分类方法的阻碍，忽视了识别跨焦虑，情绪和创伤相关障碍的共享域/结构的神经机制的关键需求，这些机制可以可靠地测量并作为新治疗的生理靶点。条件性恐惧过度泛化，其中有缺陷的区别学习危险线索类似的安全刺激，最近已被提出作为一个潜在的内表型，跨越诊断界限，包括患者与创伤后应激障碍，广泛性焦虑症和PD。在动物和健康人身上都已经阐明了恐惧过度概括的神经回路，这表明海马体和恐惧网络区域的功能缺陷。为了进一步识别创伤相关精神病理学的神经特征（可能作为一种新型的神经科学治疗靶点），并与RDoC强调的基于神经的跨疾病功能域一致，当前的4年R 01应用将使用fMRI范式评估有和无创伤暴露的受试者（N=120）的恐惧过度泛化。将评估80名充分确定的严重创伤暴露成人和40名匹配的非创伤暴露健康成人。在功能磁共振成像过程中，逐渐增加大小的环将在视觉上呈现，极端大小的环作为条件危险提示（CS+;与电击配对）和条件安全提示（CS-）。中间大小的环充当“泛化刺激”（GS），并在CS+和CS-之间创建连续的大小。在这个连续体中，用图形表示的条件性恐惧反应被称为泛化梯度，已经被可靠地证明具有反映泛化程度的陡度（或斜率）。对于皮肤电导响应（SCR），不太陡的斜率指示更大的泛化。将通过以下范例生成单独的泛化梯度：a）局部fMRI激活; B）SCR;和3）自我报告的休克风险。将应用机器学习方法来识别过度概括的基于fMRI的神经特征，并测试其与创伤相关诊断中的功能障碍和症状严重程度的关联。如果成功的话，这项研究的发现将显著推进内表型的表征，这将作为病理学的客观测量和专门针对过度泛化受损机制及其神经特征的干预措施的新靶点。

 DESCRIPTION (provided by applicant): Populations exposed to severe trauma such as war veterans, disaster survivors, and assault victims are at high risk for a range of trauma related psychopathology. Over one third of the exposed individuals are likely to develop significant and disabling psychopathology including posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), panic disorder (PD), and major depression. However, efforts to advance knowledge on neural mechanisms of trauma related abnormalities have been hampered by a diagnostic categorical approach that has been focused almost solely on PTSD, neglecting a critical need to identify neural mechanisms of shared domains/constructs across anxiety, mood, and trauma-related disorders, which can be reliably measured and serve as physiological targets for novel treatments. Conditioned fear overgeneralization, in which there is deficiency in distinguishing learned danger cues from resembling safe stimuli, has been recently proposed as a potential endophenotype that crosses diagnostic boundaries including patients with PTSD, GAD and PD. The neural circuitry of fear overgeneralization has been elucidated in both animals and healthy humans, suggesting deficient functioning of the hippocampus and fear network regions. To advance identification of a neural signature of trauma related psychopathology that can potentially serve as a novel, neuroscience informed treatment target, and consistent with the RDoC emphasis on neurally-based domains of function across disorders, the current 4-year R01 application will use an fMRI paradigm for assessing fear overgeneralization among subjects with and without exposure to trauma (N=120). Eighty adults with well-ascertained, severe exposure to trauma and 40 matched non-trauma exposed healthy adults will be assessed. Rings of gradually increasing size will be visually presented during fMRI, with extreme sizes serving as conditioned danger cues (CS+; paired with electric shock) and conditioned safety cues (CS-). The rings of intermediary size serve as `generalization stimuli' (GS) and create a continuum-of-size between CS+ and CS-. Graphically represented conditioned-fear responses across this continuum, known as generalization gradients, have been reliably shown to have a steepness (or slope) that reflects the degree of generalization. For skin conductance response (SCR), a less steep slope indicates greater generalization. Separate generalization gradients will be generated by the paradigm for: a) regional fMRI activations; b) SCR; and 3) self-reported risk of shock. Machine-learning methodology will be applied to identify an fMRI-based neural signature of overgeneralization and test its associations with functional impairment and symptom severity across trauma- associated diagnoses. If successful, findings from this study will significantly advance the characterization of an endophenotype that will serve as an objective measure of pathology and a novel target for interventions specifically designed to target the impaired mechanism of overgeneralization and its neural signature.