Prenatal Stress Exposure Modulates Resting State Functional Connectivity by Sex in Midlife

Kyoko Konishi, PhD

Massachusetts General Hospital
Prenatal Stress Exposure Modulates Resting State Functional Connectivity by Sex in Midlife

Scientific Abstract

Background: Brain development, beginning in utero, has implications for brain aging with significant sex-dependent outcomes. The default mode network (DMN), which primarily includes medial prefrontal cortex (mPFC), posterior cingulate cortex (PCC), angular gyrus (AG), and hippocampus (HIPP), is a brain network vulnerable to the effects of aging in early midlife. Here, we investigate the impact of prenatal stress on the intrinsic functional connectivity of the DMN in early midlife, and the sex differences therein.

Methods: 212 middle-aged adults (ages 45–55; 106F:106M) were recruited from the New England Family Study (NEFS) cohort. NEFS is a unique prenatal cohort that has been followed since birth for >50 years. Subjects were siblings discordant for prenatal stress exposure (preeclampsia and fetal growth restriction), such that one sibling was exposed and the other was not. Reproductive history and serologic evaluation were used to determine women’s reproductive staging. Subjects underwent a resting state fMRI scan and data were analyzed using ROI-to-ROI-based functional connectivity analyses.

Results: We found overall sex differences in resting state functional connectivity within the DMN, specifically in midlife adults exposed to prenatal stress. In the exposed group, women had higher functional connectivity between anterior–posterior regions of the DMN (mPFC-RAG: t=2.35, p=0.04; mPFC-LAG: t=1.94, p=0.05) and within posterior regions of the network (RAG- LAG: t=2.12, p=0.04) compared to men. In “prenatally exposed” women, DMN functional connectivity decreased across the menopausal transition (pre>post: mPFC-LAG: t=3.02, p=0.02) and was related to declining levels of estradiol (r=0.42, p=0.004). Overall, no significant differences were observed in the unexposed group by sex or menopausal status.

Conclusion: Findings demonstrate that prenatal stress exposure is associated with sex differences in the intrinsic functional connectivity in the brain 50+ years later. Further, results suggest that menopause may present a critical period of accelerated brain aging in women and that prenatal stress exposure may increase vulnerability to these changes.

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Kyoko Konishi, PhD, Justine E. Cohen, PhD, Emily G. Jacobs, PhD, Anne Remington, MA, Harlyn Aizley, EdM, Susan Whitfield-Gabrieli, PhD, Jill M. Goldstein, PhD