A Multi-Modal Investigation of Neurophysiological Deficits in PTSD

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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).