Threat-induced cortisol is positively associated with white matter microarchitecture in infant rhesus monkeys

Cortisol is a stress hormone that mediates key physiological responses to threatening situations and modulates neural systems. However, its impact on brain structure in early-life, particularly white matter (WM) microarchitecture, remains poorly understood. In a longitudinal study of infant macaques, we use diffusion tensor imaging and quantitative relaxometry to characterize the early-life link between threat-induced cortisol and WM microarchitecture. 35 rhesus macaques were imaged with DTI and the MPnRAGE sequence on a 3T-scanner at 3, 7, 13, 25, and 53 weeks old to compute FA and qR1 (higher values~increased WM-microstructure) and MD and RD (higher values~decreased WM-microstructure). At each timepoint, subjects underwent 30 min of the no-eye-contact paradigm (NEC), in which they were exposed to an indirect threat, the profile of a human intruder. Plasma cortisol was measured after each NEC. Linear mixed-effects models assessed within-subject relations between cortisol and each WM metric in 18 WM ROIs, controlling for age-at-scan and sex. On a within-subject level (p<0.05-corrected), cortisol was positively associated with FA in 15/18 ROIs (mean-R2=0.08) and qR1 in 18/18 ROIs (mean-R2=0.12). Cortisol was negatively associated with MD in 11/18 ROIs (mean-R2=0.11) and RD in 14/18 ROIs (mean-R2=0.11). Threat-induced cortisol predicts WM microarchitecture, as measured by multimodal imaging, across the infant macaque brain. Interestingly, cortisol relates most widely to qR1 and RD, metrics thought to be relatively sensitive markers of myelin. These findings warrant further study into cortisol’s role in very early WM development and neuroplasticity, particularly as it may relate to myelination processes.