Sex-related Differences in Stress Reactivity and Cingulum White Matter

Abstract

The prefrontal cortex and limbic system are important components of the neural circuit that underlies stress and anxiety. These brain regions are connected by white matter tracts that support neural communication including the cingulum, uncinate fasciculus, and the fornix/stria-terminalis. Determining the relationship between stress reactivity and these white matter tracts may provide new insight into factors that underlie stress susceptibility and resilience. Therefore, the present study investigated sex differences in the relationship between stress reactivity and generalized fractional anisotropy (GFA) of the white matter tracts that link the prefrontal cortex and limbic system. Diffusion weighted images were collected and deterministic tractography was completed in 104 young adults (55 men, 49 women; mean age = 18.87 SEM = 0.08). Participants also completed self-report questionnaires (e.g., Trait Anxiety) and donated saliva (later assayed for cortisol) before, during, and after the Trier Social Stress Test. Results revealed that stress reactivity (area under the curve increase in cortisol) and GFA of the cingulum bundle varied by sex. Specifically, men demonstrated greater cortisol reactivity and greater GFA within the cingulum than women. Further, an interaction between sex, stress reactivity, and cingulum GFA was observed in which men demonstrated a positive relationship while women demonstrated a negative relationship between GFA and cortisol reactivity. Finally, trait anxiety was positively associated with the GFA of the fornix/stria terminalis - the white matter pathways that connect the hippocampus/amygdala to the hypothalamus. These findings advance our understanding of factors that underlie individual differences in stress reactivity.

Keywords: DTI; anxiety; cingulum; cortisol; sex; stress.

Conflict of interest statement

Disclosure Statement

In the interest of full disclosure DAG is Founder and Chief Scientific and Strategy Advisor at Salimetrics LLC and SalivaBio LLC and these relationships are managed by the policies of the committees on conflict of interest at the Johns Hopkins University School of Medicine and the University of California at Irvine. All authors have approved the final manuscript.

Copyright © 2021 IBRO. Published by Elsevier Ltd. All rights reserved.

Figures

Figure 1.

Cortisol reactivity differed between men and women. A) There was a significant sex by time interaction (p<0.05) such that men demonstrated a greater cortisol response at post-stress and recovery than women. Error bars reflect standard error of the mean. B) Area under the curve increase (AUCi) in cortisol was greater for men than women. Boxes represent the 1st and 3rd quartiles and whiskers represent 1.5 times the interquartile range. **p<0.005 *p<0.05

Figure 2.

Relationship between trait anxiety and the fornix/stria terminalis. Tract color represents generalized fractional anisotropy (GFA). Trait anxiety increased as the GFA of the left fornix/stria terminalis increased (FDR p<0.05). Lines on either side of the fitted line represent the 95% individual prediction interval.

Figure 3.

Sex differences in the bilateral cingulum. Tract color represents generalized fractional anisotropy (GFA). GFA of tracts within the cingulum bundle differed between sexes. Men had significantly greater GFA within the left and right cingulum than women (FDR p<0.05). Boxes represent the 1st and 3rd quartiles and whiskers represent 1.5 times the interquartile range. *Indicates p<0.01.

Figure 4.

Sex and cingulum Generalized Fractional Anisotropy (GFA). A) An interaction was observed between sex, cortisol area under the curve with respect to increase (AUCi), and right cingulum GFA (p<0.05). B) While a similar pattern was observed between sex and left cingulum GFA, this relationship did not meet statistical significance (p>0.05).