Identification of an intrusive-hypervigilant phenotype of posttraumatic stress symptoms with unique stress peptide and amygdala functional connectivity profiles

Posttraumatic stress disorder (PTSD) is a highly heterogeneous psychiatric disorder, complicating efforts to identify consistent biological markers and develop targeted treatments for individuals exposed to trauma. Recent research has identified a distinct intrusive-hypervigilant (IH) phenotype, which is characterized by heightened intrusive reexperiencing and hypervigilance symptoms along with elevated levels of pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide involved in stress response via amygdala signaling. In an independent sample of 172 symptomatic trauma-exposed adults, we replicated this IH phenotype using latent profile analysis of Clinician-Administered PTSD Scale for DSM-5 symptom severity ratings and expanded its biological characterization using resting-state functional magnetic resonance imaging (rs-fMRI). Consistent with prior work, the identified IH group demonstrated more severe intrusive reexperiencing and hypervigilance symptoms and higher PACAP levels compared to groups with generally High or Low symptom severity. Additionally, the IH phenotype exhibited stronger functional connectivity of the centromedial, but not basolateral, amygdala with regions in the occipital cortex, precuneus, and medial prefrontal cortex - areas primarily within the Default Mode and Visual Networks. Meta-analytic decoding linked these regions to mental imagery, memory processing, fear, and threat perception. These findings support the existence of an IH phenotype of posttraumatic stress that may exhibit a distinct biological profile, characterized by exaggerated interactions between memory, threat, and arousal systems that may be mediated by PACAP and its effects of amygdala connectivity. This phenotype may serve as a promising target for precision psychiatry approaches, including pharmacological and neurotherapeutic interventions that modulate PACAP signaling and amygdala connectivity.