MRI-based structural development of the human newborn hypothalamus

BACKGROUND: Preclinical evidence suggests that intrauterine exposures can impact hypothalamic structure at birth and future disease risk, yet early human data are limited. Because the hypothalamus regulates critical early life processes including sleep, growth, stress regulation, and metabolic control, characterizing its structural maturation and how it relates to developmental conditions and exposures is essential for understanding links to later health. METHODS: We measured hypothalamic volumes from T1-weighted MRI scans in the dHCP study (631 newborns; 699 observations). To characterize normative development, we examined associations with postmenstrual age (PMA, sum of gestational and chronological age) at scan and sex. Given the wide range of gestational age (GA) at birth in this sample, we also tested GA as a key intrauterine influence. In addition, we evaluated cigarette smoking during pregnancy, a perinatal risk factor with biological plausibility (e.g., effects on growth and neuroendocrine function). Finally, we tested whether these associations persisted in an independent adolescent cohort from the ABCD study (11,207 adolescents; 16,934 observations). RESULTS: Absolute hypothalamus volume increased with PMA (+5.5 %/week, t = 39.9, p < 10⁻¹⁰), but not after adjusting for brain volume (t = 1.2, p = 0.24). Males showed larger absolute (+3.3 %, t = 3.2, p = 0.002) but smaller relative volumes (t = -2.8, p = 0.005). Lower GA was linked to larger relative volume (t = -6.5, p < 10⁻⁹), with sex moderation (t = -2.4, p = 0.019). Smoking during pregnancy was associated with smaller newborn hypothalamus volume (t = -2.05, p = 0.04; dose dependence t = -2.4, p = 0.03). In adolescents, maternal smoking, but not categorical preterm birth, was linked to reduced hypothalamus volume (t = -2.8, p = 0.005). CONCLUSIONS: Early-life hypothalamic volume reflects both normative growth and vulnerability to intrauterine exposures, with smoking-related differences persisting into adolescence.