Multimodal imaging of hippocampal-cortical networks and mechanisms of trauma-related intrusions

总结 侵入性创伤回忆是创伤后应激障碍（PTSD）的标志性症状，表现为 闪回噩梦以及对创伤回忆的反应这些症状令人痛苦，致残， 他们预测更严重的病程，超过总的症状严重程度。临床描述强调了 在“此时此地”重新体验创伤的感官知觉方面。已经提出 这些心理机制代表了海马体之间整合的丧失，海马体介导了 上下文绑定和中线顶枕皮层，支持感官知觉的阐述。 然而，没有研究调查已经测试海马电路的成像测量是否与 这些入侵的关键机械特征。大多数创伤后应激障碍的研究都是用仪器来评估入侵 容易受到回顾性回忆偏差的影响，并且不能评估入侵的心理特征 可能对神经变异最敏感。此外，先前的研究没有解析创伤机制， 相关的海马表型，如创伤（威胁）暴露的慢性化，这缓和了 海马缺陷的严重程度。最后，大多数创伤后应激障碍成像研究认为海马体是一个单一的 结构，而证据表明前海马（aHPC）和后海马（pHPC）具有可分离的 功能和连通性，以及PTSD中的差异参与。这项研究将利用多个 一系列证据表明，入侵的关键心理机制可能是通过改变 pHPC代谢和与顶枕皮质的连接。我们将利用生态瞬间 评估日常生活中的侵入特征（基线后两周内 成像）。我们将检验pHPC功能连接性、解剖学连接性和神经功能的成像测量的假设。 连通性和神经化学预测感官知觉生动性和入侵的上下文质量 症状，尤其是随着创伤（威胁）暴露的慢性化。最后，我们将进行多变量 建模以识别最能预测EMA评估变量的神经成像指标组合。这 该项目是创新的入侵和创伤暴露的机械尺寸的联合检查， 根据其预测的神经生物学相关性进行选择。这也将是第一个应用多模式的研究 PTSD患者aHPC和pHPC网络的分离成像，并检查这些海马指标 与真实世界中创伤后应激障碍症状的联系总的来说，我们的研究策略与NIMH一致 研究领域标准（RDOC）关于识别神经生物学相关的行为维度 （侵入性记忆）及其与环境影响（创伤，威胁暴露）的相互作用。一个主要 与侵入和创伤机制相关的分离神经生物标志物的含义是， 识别有助于用新的感知或认知训练程序进行靶向治疗的神经终点， 或靶向神经调节。

SUMMARY Intrusive trauma recollections are hallmark symptoms of posttraumatic stress disorder (PTSD), manifesting as flashbacks, nightmares, and reactivity to trauma reminders. These symptoms are distressing, disabling, and they predict worse illness course, above-and-beyond total symptom severity. Clinical descriptions highlight the re-experiencing of sensory-perceptual aspects of the trauma in the “here-and-now”. It has been proposed that these psychological mechanisms represent a loss of integration between the hippocampus, which mediates contextual binding, and midline parieto-occipital cortices, which support sensory-perceptual elaboration. However, no research investigations have tested whether imaging measures of hippocampus circuitry relate to these key mechanistic features of intrusions. Most PTSD studies have assessed intrusions using instruments that are vulnerable to retrospective recall bias and that do not assess psychological characteristics of intrusions that may be most sensitive to neural variation. In addition, prior studies have not parsed trauma mechanisms relevant to hippocampus phenotypes, such as chronicity of trauma (threat) exposure, which moderates the severity of hippocampus deficits. Finally, most PTSD imaging studies considered the hippocampus as a unitary structure, whereas evidence shows that anterior (aHPC) and posterior hippocampus (pHPC) have dissociable functions and connectivity, as well as differential involvement in PTSD. The proposed study will leverage multiple lines of evidence suggesting that key psychological mechanisms of intrusions may be mediated by alterations in pHPC metabolism and connectivity with parieto-occipital cortices. We will use ecological momentary assessment (EMA) to assess intrusion characteristics in daily life (over a two-week period following the baseline imaging). We will test hypotheses that imaging measures of pHPC functional connectivity, anatomical connectivity, and neurochemistry predict sensory-perceptual vividness and out-of-context quality of intrusion symptoms, more so with increasing chronicity of trauma (threat) exposure. Finally, we will conduct multivariate modeling to identify combinations of neuroimaging metrics that best predict EMA-assessed variables. This project is innovative for its joint examination of mechanistic dimensions of intrusions and trauma exposure, both selected based on their predicted neurobiological relevance. This also will be the first study to apply multimodal imaging for the dissociation of aHPC and pHPC networks in PTSD, and to examine these hippocampus metrics in relation to real-world symptoms of PTSD. Overall our research strategy is consistent with that of the NIMH Research Domain Criteria (RDOC) with regards to identifying neurobiologically-relevant dimensions of behavior (intrusive memory) and their interactions with environmental influences (trauma, threat exposure). A major implication of segregating neural biomarkers in relation to intrusion and trauma mechanisms is the potential for identifying neural endpoints conducive to targeted treatment with novel perceptual or cognitive training programs, or targeted neuromodulation.