Prevailing neurobiological models of posttraumatic stress disorder (PTSD) have focused on dysfunctions of a prefrontal-cortex-amygdala-hippocampal circuit in the top-down regulation of threat detection and emotion regulation. Nevertheless, evidence is accruing for a pathology in broad, low-level sensory hyperactivity that accounts for the unique sensory features of posttraumatic stress symptoms (PTSS). We have thus proposed a "sensory model" of PTSD, centered on deficient sensory gating and broad sensory hyperactivity. The neurophysiology of the model rests on "sensory disinhibition", whereby disinhibited sensory processing allows for unfiltered sensory input to inundate the prefrontal cortex, even at rest, and the consequent prefrontal dysfunction further fuel sensory disinhibition, resulting in a vicious cycle to perpetuate PTSD pathology. Combining neuroimaging (functional magnetic resonance imaging/fMRI and electroencephalogram/EEG) and non-invasive brain stimulation, this dissertation conducted a series of five studies to test this sensory model and develop an intervention to enhance sensory inhibition. Study 1 (Chapter 2) revealed that resting-state (intrinsic) alpha (8-12 Hz) oscillations, a key neural process involved in sensory cortical inhibition and sensory gating, were deficient among patients with PTSD, the degree of which varied with PTSD symptom severity. These findings indicate intrinsic sensory disinhibition in PTSD. Study 2 (Chapter 3) replicated the initial findings in a sample of combat-exposed Veterans, particularly highlighting an association between alpha deficiency and symptoms of intrusive re-experiencing of trauma. Importantly, akin to our sensory model, it demonstrated that sensory disinhibition could contribute to intrusive reexperiencing through the activation of trauma memory via sensory cues. Study 3 (Chapter 4) isolated PTSD-related alpha deficits in the visual cortex and the default mode network (DMN), a key large-scale intrinsic neural network, as well as communication between the visual and the DMN. These findings thus elucidate a visual-cortex-DMN circuit dysfunction, highlighting that sensory disinhibition can underlie large-scale neural dysregulation in PTSD. Identification of this sensory pathology, which is closely associated with alpha deficiency, motivated Studies 4 and 5 to develop a novel intervention for this pathology by augmenting alpha oscillations. Study 4 (Chapter 5) applied alpha-frequency transcranial alternating current stimulation (i.e., α-tACS) over four consecutive days and demonstrated lasting and reliable alpha enhancement, which was further accompanied by reduction in anxious arousal and sensory aversion. Study 5 (Chapter 6), combining simultaneous EEG-fMRI recordings with α-tACS, not only replicated the efficacy of α-tACS in alpha enhancement but also demonstrated DMN upregulation via α-tACS. Importantly, this DMN upregulation was mediated by alpha enhancement. Together, this series of studies provide converging evidence for the sensory disinhibition model of PTSD and identify a novel mechanism-based intervention that could be used to treat PTSD and related disorders.
