Wednesday, January 15, 2025
1/15/2025
ABSTRACT Posttraumatic stress disorder (PTSD) is a common and highly disabling psychiatric disorder. Pathological fear is at the core of PTSD, and accordingly, neural accounts of PTSD have emphasized dysfunctions of the fear system (primarily, the amygdala-prefrontal-cortex fear circuit). Motivated by recent expansion of the fear circuit into the sensory cortex and growing recognition of rich sensory anomalies in PTSD, we have proposed a neurosensory account of PTSD, integrating basic sensory cortical pathophysiology with amygdala-prefrontal-cortex dysfunctions into a tripartite Sensory-Prefrontal-cortex-Amygdala (SPA) pathology of PTSD. Specifically, we propose that PTSD involves sensory cortical disinhibition that exacerbates amygdala-prefrontal-cortex dysfunctions, which in turn impairs top-down regulation, resulting in a vicious cycle of SPA pathology. The current project seeks to elucidate three specific mechanisms in this account: (Aim 1) Intrinsic (tonic) sensory cortical disinhibition that maintains SPA pathology in PTSD (by sustaining intrinsic amygdala- prefrontal-cortex dysfunctions with excessive spontaneous sensory afferents); (Aim 2) Novelty-related (phasic) sensory cortical disinhibition that drives SPA pathology in PTSD (by heightening sensory cortical reactivity to novel cues, resulting in excessive sensory output that drives amygdala-prefrontal-cortex dysfunctional response to novelty); and (Aim 3) Threat-related sensory cortical disinhibition that exacerbates SPA pathology and threat biases in PTSD (by heightening sensory cortical reactivity to threat stimuli and synergizing with biased sensory cortical encoding of threat, resulting in excessive, threat-laden sensory output that exacerbates amygdala-prefrontal-cortex dysfunctional response to threat). This project will leverage our fully-developed cutting-edge methodology of simultaneous EEG-fMRI combined with non-invasive neuromodulation (specifically, transcranial alternating current stimulation/tACS to enhance sensory cortical inhibition), thereby permitting integrative spatial and temporal assays and causal inferences. This mechanistic investigation has the potential to break new theoretical ground by revealing a tripartite SPA pathology of PTSD. Clinically, identification of sensory cortical disinhibition as a fundamental mechanism that is malleable (via neuromodulation) would open a new line of mechanism- based treatments for PTSD.
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