Sex Differences in Response Inhibition-Related Neural Predictors of Posttraumatic Stress Disorder in Civilians With Recent Trauma

Abstract

Background: Females are more likely to develop posttraumatic stress disorder (PTSD) than males. Impaired inhibition has been identified as a mechanism for PTSD development, but studies on potential sex differences in this neurobiological mechanism and how it relates to PTSD severity and progression are relatively rare. Here, we examined sex differences in neural activation during response inhibition and PTSD following recent trauma.

Methods: Participants (n = 205, 138 female sex assigned at birth) were recruited from emergency departments within 72 hours of a traumatic event. PTSD symptoms were assessed 2 weeks and 6 months posttrauma. A Go/NoGo task was performed 2 weeks posttrauma in a 3T magnetic resonance imaging scanner to measure neural activity during response inhibition in the ventromedial prefrontal cortex, right inferior frontal gyrus, and bilateral hippocampus. General linear models were used to examine the interaction effect of sex on the relationship between our regions of interest and the whole brain, PTSD symptoms at 6 months, and symptom progression between 2 weeks and 6 months.

Results: Lower response inhibition-related ventromedial prefrontal cortex activation 2 weeks posttrauma predicted more PTSD symptoms at 6 months in females but not in males, while greater response inhibition-related right inferior frontal gyrus activation predicted lower PTSD symptom progression in males but not females. Whole-brain interaction effects were observed in the medial temporal gyrus and left precentral gyrus.

Conclusions: There are sex differences in the relationship between inhibition-related brain activation and PTSD symptom severity and progression. These findings suggest that sex differences should be assessed in future PTSD studies and reveal potential targets for sex-specific interventions.

Keywords: Functional magnetic resonance imaging (fMRI); Posttraumatic stress disorder (PTSD); Response inhibition; Right inferior frontal gyrus (rIFG); Sex differences; Ventromedial prefrontal cortex (vmPFC).

Figure 1:. vmPFC activation predicts PTSD symptoms at 6-months in females.

A) The vmPFC is displayed as a region of interest in red. B) Correlation between vmPFC activation and PTSD symptoms (PCL-5 scores) at 6-months per sex while controlling for age and scanner site. Lower vmPFC activation significantly correlates with more PTSD symptoms at 6-months in females (r=−0.25, p=0.004) but not in males (r=0.06, p=0.65). *Significant correlation p<0.05

Figure 2:. rIFG activation predicts PTSD symptom change over 6 months in males.

A) The rIFG is displayed as a region of interest in blue. B) Correlation between rIFG activation and change in PTSD symptoms (PCL-5 scores 6-months – 2-weeks) over 6-months per sex, while controlling for age and scanner site. Higher rIFG activation significantly correlates with more PTSD symptom improvement in males (r=−0.34, p=0.01), but not in females (r = 0.11, p=0.23). *Significant correlation p<0.05

Figure 3:. Whole brain correlation analyses with PTSD severity

A) The significant cluster for the interaction between sex and PTSD severity at 6-months in the right middle temporal gyrus (rMTG; p<0.005, FWE-corrected cluster threshold, k=194) is extracted and visualized with MRIcron. B) Correlation between rMTG activation (contrast values extracted and averaged for the cluster displayed in A) and PTSD symptoms at 6-months per sex, while controlling for age and scanner site is displayed. Lower rMTG activation correlates with more PTSD symptoms at 6-months in females (correlation with extracted mean: r=−0.30, p<0.001) whereas lower rMTG activation significantly correlates with less PTSD symptoms in males (correlation with extracted mean, r=0.56, p<0.001).

Figure 4:. Whole brain correlation analyses with PTSD progression

A) The significant cluster for the interaction between sex and PTSD progression between 2-weeks and 6-months in the left precentral gyrus (p<0.005, FWE-corrected cluster threshold, k=231) is extracted and visualized with MRIcron. B) Correlation between left precentral gyrus activation (contrast values extracted and averaged for the cluster displayed in A) and PTSD progression between 2-weeks and 6-months per sex, while controlling for age and scanner site is displayed. Less negative precentral gyrus activation correlated with lower PTSD progression (or: more improvement) in males (correlation with extracted mean, r=−0.34, p=0.01), but no association in females was observed.