Key result
Higher circulating PACAP levels were significantly associated with increased resting-state functional connectivity between the right amygdala and posterior default mode network regions (r=0.25, p=0.019), particularly in females.
Why the study?
While PACAP influences amygdala reactivity in PTSD, its association with intrinsic amygdala-default mode network connectivity was unknown.
Cross-Sectional (n=89)
No
Effect estimate: r = 0.25
p-value: p=0.019
Circulating PACAP levels are associated with increased intrinsic functional connectivity between the amygdala and posterior DMN in trauma-exposed females, which correlates with anxious arousal symptoms.
PACAP may link to amygdala-DMN dysconnectivity in PTSD; hypothesis-generating and requires replication before any clinical consideration.
The pituitary adenylate cyclase-activating polypeptide (PACAP) system is implicated in posttraumatic stress disorder (PTSD) and related amygdala-mediated arousal and threat reactivity. PTSD is characterized by increased amygdala reactivity to threat and, more recently, aberrant intrinsic connectivity of the amygdala with large-scale resting state networks, specifically the default mode network (DMN). While the influence of PACAP on amygdala reactivity has been described, its association with intrinsic amygdala connectivity remains unknown. To fill this gap, we examined functional connectivity of resting-state functional magnetic resonance imaging (fMRI) in eighty-nine trauma-exposed adults (69 female) screened for PTSD symptoms to examine the association between blood-borne (circulating) PACAP levels and amygdala-DMN connectivity. Higher circulating PACAP levels were associated with increased amygdala connectivity with posterior DMN regions, including the posterior cingulate cortex/precuneus (PCC/Precun) and left angular gyrus (lANG). Consistent with prior work, this effect was seen in female, but not male, participants and the centromedial, but not basolateral, subregions of the amygdala. Clinical association analyses linked amygdala-PCC/Precun connectivity to anxious arousal symptoms, specifically exaggerated startle response. Taken together, our findings converge with previously demonstrated effects of PACAP on amygdala activity in PTSD-related processes and offer novel evidence for an association between PACAP and intrinsic amygdala connectivity patterns in PTSD. Moreover, these data provide preliminary evidence to motivate future work ascertaining the sex- and subregion-specificity of these effects. Such findings may enable novel mechanistic insights into neural circuit dysfunction in PTSD and how the PACAP system confers risk through a disruption of intrinsic resting-state network dynamics.
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Clancy et al. (2023) conducted a cross-sectional in Posttraumatic stress disorder (PTSD) (n=89). Circulating PACAP levels was evaluated on Association between circulating PACAP levels and right amygdala-posterior cingulate cortex/precuneus (rAMYG-PCC/Precun) resting-state functional connectivity (r = 0.25, p=0.019). Higher circulating PACAP levels were significantly associated with increased resting-state functional connectivity between the right amygdala and posterior default mode network regions (r=0.25, p=0.019), particularly in females.
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