A Multi-Modal Investigation of Neurophysiological Deficits in PTSD

项目摘要 创伤后应激障碍（PTSD）是一种以神经回路改变为特征的衰弱性疾病 潜在的威胁和情绪处理。女性创伤后应激障碍（PTSD）的发病率是男性的两倍，而且月经周期 阶段与性别差异有关，但PTSD的神经回路在女性中的特征很差。 一致的发现是，PTSD与背侧前扣带回静息态活动增加有关 皮质（dACC）和腹内侧前额叶皮质（vmPFC）活动减少，反映了夸大的 情绪反应和情绪调节减弱。PTSD也与减少 在θ频率范围内（4-7 Hz）的功能连接性。dACC似乎是θ范围的发生器 大脑活动，这与创伤后应激障碍有关;然而，没有先前的研究探讨了基于θ的休息 陈述dACC和vmPFC活性，或PTSD中基于θ的dACC-vmPFC连接。此外，没有先前的研究 根据月经周期的不同阶段对女性的这些影响进行了研究。除了休息状态赤字，恐惧 条件反射研究表明，PTSD与晚期正电位（LPP）振幅增加有关 对恐惧刺激的反应，反映了夸张的情绪编码。虽然有公认的影响， 月经周期阶段对LPP的影响，没有先前的研究已经在患有PTSD的女性中测试了这些影响。 这种神经回路的特征和月经周期阶段的调节作用代表了关键的差距 女性患创伤后应激障碍的风险更大 为了解决这些未满足的需求，我们将通过测试对PTSD大脑回路采取多模式方法， 有和没有创伤后应激障碍的创伤暴露女性的静息状态和事件相关神经生理缺陷。 我们将使用高密度EEG来探测dACC和vmPFC的基于θ的静息状态活动，以及 PTSD中的dACC-vmPFC功能连接。然后，我们将通过测量LPP来探测事件相关的缺陷 以及恐惧条件反射过程中的潜在皮层来源。最后，我们将收集雌二醇和孕酮， 确定月经周期阶段，并测试其对这些现象的调节作用。申请人将学习 使用最先进的生理方法，如标准化的低分辨率电磁 断层扫描（sLORETA）、功率包络连接分析、ERP和源定位，以及血清 激素测定。利用高密度脑电图的时间分辨率，这项研究将提供一个更细致入微， 对PTSD女性恐惧回路缺陷的机械理解我们的总体目标与 NIMH战略计划的目标1：“定义复杂行为的机制”。具体而言是 该提案将进一步阐明女性创伤后应激障碍的神经生理回路和机制。通过 利用先进的EEG技术，这项研究将最终有助于改善PTSD 通过提高我们的理解和告知个性化的方法（例如，刺激 vmPFC调节dACC活性，基于月经周期阶段调整方法）。

Project Summary Posttraumatic stress disorder (PTSD) is a debilitating condition characterized by altered neural circuitry underlying threat and emotion processing. PTSD is twice as prevalent in women than men, and menstrual cycle phase has been implicated in sex differences, but the neural circuitry of PTSD is poorly characterized in women. A consistent finding is that PTSD is associated with increased resting state activity of dorsal anterior cingulate cortex (dACC) and decreased activity of ventromedial prefrontal cortex (vmPFC), reflecting exaggerated emotional responding and dampened emotion regulation, respectively. PTSD is also associated with decreased functional connectivity in the theta frequency range (4-7 Hz). The dACC appears to be a generator of theta range brain activity, which has been implicated in PTSD; however, no prior research has probed theta-based resting state dACC and vmPFC activity, or theta-based dACC-vmPFC connectivity in PTSD. Further, no prior research has examined these effects in women based on menstrual cycle phase. In addition to resting state deficits, fear conditioning studies have shown that PTSD is associated with increased late positive potential (LPP) amplitudes in response to fearful stimuli, reflecting exaggerated emotional encoding. While there are well-established effects of menstrual cycle phase on the LPP, no prior research has tested these effects in women with PTSD. Characterization of this neural circuitry and the moderating role of menstrual cycle phase represent critical gaps in understanding how women experience greater risk for PTSD. To address these unmet needs, we will take a multi-modal approach to PTSD brain circuitry by testing resting state and event-related neurophysiological deficits in trauma-exposed women with and without PTSD. We will use high-density EEG to probe theta-based resting state activity of the dACC and vmPFC, as well as dACC-vmPFC functional connectivity in PTSD. We will then probe event-related deficits by measuring the LPP and its underlying cortical sources during fear conditioning. Finally, we will collect estradiol and progesterone to determine menstrual cycle phase and test its moderating effects on these phenomena. The applicant will learn to use state-of-the-art physiological methods such as standardized Low Resolution Electromagnetic Tomography (sLORETA), power envelope connectivity analyses, ERPs with source localization, and serum hormone assays. Using the temporal resolution of high-density EEG, this study will provide a more nuanced and mechanistic understanding of fear circuitry deficits in women with PTSD. Our overall goal is directly in line with Objective 1 of the NIMH’s Strategic Plan: “Define the Mechanisms of Complex Behaviors.” Specifically, the proposal will further elucidate the neurophysiological circuits and mechanisms underlying PTSD in women. By leveraging advanced EEG techniques, this study will ultimately contribute to the improvement of PTSD treatments by improving our understanding and informing individualized approaches (e.g., stimulation of the vmPFC to regulate dACC activity, adjusting approaches based on menstrual cycle phase).