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<p>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 (Cohen’s d’s = 0.61-6.93) and hypervigilance symptoms (d’s = 0.57-0.88) and higher PACAP levels compared to groups with generally High (<i>d</i> = 0.35) or Low (<i>d</i> = 0.44) symptom severity. Additionally, the IH phenotype exhibited stronger functional connectivity of the centromedial, but not basolateral, amygdala with regions in the occipital cortex (d’s = 0.78-0.95), precuneus (d’s = 1.20-1.21), and medial prefrontal cortex (d’s = 0.81-1.18)—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 on 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月8日

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  • Kevin J. Clancy,
  • Caitlin Ravichandran,
  • Sydney A. Jobson,
  • Victor May,
  • Sayamwong E. Hammack,
  • William A. Carlezon Jr,
  • Kerry J. Ressler,
  • Scott L. Rauch,
  • Isabelle M. Rosso

摘要

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 (Cohen’s d’s = 0.61-6.93) and hypervigilance symptoms (d’s = 0.57-0.88) and higher PACAP levels compared to groups with generally High (d = 0.35) or Low (d = 0.44) symptom severity. Additionally, the IH phenotype exhibited stronger functional connectivity of the centromedial, but not basolateral, amygdala with regions in the occipital cortex (d’s = 0.78-0.95), precuneus (d’s = 1.20-1.21), and medial prefrontal cortex (d’s = 0.81-1.18)—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 on 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.