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.

For completeness of disclosure: SLR has been employed by Mass General Brigham/McLean Hospital; paid as secretary of Society of Biological Psychiatry, and for Board service to Mindpath Health/Community Psychiatry and National Association of Behavioral Healthcare; served as volunteer member of the Board for Anxiety & Depression Association of America, and The National Network of Depression Centers; received royalties from Oxford University Press, American Psychiatric Publishing Inc, and Springer Publishing; received research funding from NIMH. WAC is a member of the NPP Editorial Board. Within the past 3 years, WAC has served as a consultant for Psy Therapeutics and has had sponsored research agreements with Cerevel Therapeutics and Delix Therapeutics. KJR has performed scientific consultation for Bioxcel, Bionomics, Acer, and Jazz Pharma; serves on Scientific Advisory Boards for Sage, Boehringer Ingelheim, Senseye, and the Brain Research Foundation. He has received sponsored research support from Alto Neuroscience. None of these relationships are related to the current manuscript. The remaining authors have no disclosures.

This work was supported by NIH awards P50-MH115874 (to WAC, KJR; Project 4: IMR, SLR). Additionally, IMR was supported by NIH awards R01-MH120400 and R01-MH125852, KJC was supported by NIH award K23-MH137459, and SEH and VM were supported by NIH award R01-MH97988.

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