Neural Signature of Fear Overgeneralization in Trauma Exposed Adults

 描述(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，都是一系列与创伤相关的精神病理学的高危人群。超过三分之一的接触者可能会患上严重的致残精神病理学，包括创伤后应激障碍(PTSD)、广泛性焦虑症(GAD)、惊恐障碍(PD)和严重抑郁症。然而，几乎只关注创伤后应激障碍的诊断分类方法阻碍了人们对创伤相关异常神经机制的了解，忽视了识别跨焦虑、情绪和创伤相关障碍的共同领域/结构的神经机制的迫切需要，这些神经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，即在区分习得的危险线索和相似的安全刺激方面存在缺陷，最近被认为是一种跨越诊断界限的潜在内表型，包括PTSD、GAD和PD患者。在动物和健康人类中，恐惧过度泛化的神经回路都已被阐明，这表明海马体和恐惧网络区域功能不足。为了进一步识别创伤相关精神病理学的神经特征，这种神经特征可能作为一种新的、神经科学知情的治疗目标，并与RDoC强调的基于神经的跨障碍功能领域保持一致，目前为期4年的R01应用程序将使用fMRI范式来评估有和没有暴露于创伤的受试者的恐惧过度泛化(N=120)。将评估80名明确、严重暴露于创伤的成年人和40名匹配的非创伤暴露的健康成年人。在功能磁共振成像过程中，逐渐增大的环将在视觉上呈现，极大的环作为条件危险提示(CS+；与电击配对)和条件安全提示(CS-)。中等大小的环起到“泛化刺激”(GS)的作用，并在CS+和CS-之间创建大小连续的连续体。在这个连续体中用图形表示的条件性恐惧反应被称为概化梯度，已经被可靠地证明具有反映概化程度的陡度(或斜率)。对于皮肤电导响应(SCR)，斜率越小，泛化程度越大。该范式将产生不同的概括梯度：a)区域性功能磁共振激活；b)SCR；以及3)自我报告的休克风险。将应用机器学习方法来识别基于fMRI的过度泛化的神经特征，并测试其与创伤相关诊断中的功能损害和症状严重程度的相关性。如果成功，这项研究的发现将大大推进内表型的表征，这将作为病理的客观衡量标准，并成为专门针对过度泛化的受损机制及其神经特征而设计的干预的新靶点。

 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.