Effects of Oral Contraceptive Pills on Brain Networks: A Conceptual Replication and Extension

Neuroimaging studies have reported that oral contraceptive pills (OCPs) alter brain connectivity, but findings have varied widely and are often derived from observational designs. Here, we used a randomized, double-blind, placebo-controlled crossover design to test for conceptual replication of three prior studies and to explore broader network-level effects of OCPs. Replication analyses largely did not confirm previously reported seed-based connectivity changes in edges containing amygdala, putamen, or dorsal anterior cingulate nodes (ps > 0.05). In the absence of a clear replication, we pursued exploratory analyses using functional connectome fingerprinting, a multivariate, data-driven method that allows parsimonious interrogation of connectivity changes simultaneously across the whole by detecting whole-brain connectivity patterns that distinguish individuals from one another. This approach revealed network-level changes during OCP use, especially within subcortical, executive, and somatomotor circuits. OCPs also increased between-subject similarity in functional connectomes (I_other, p_FWE < 0.001), suggesting a loss of individual idiosyncrasy while using OCPs. Intraclass correlations indicated that idiosyncrasy was significantly lowered in the default mode, executive, limbic, salience, somatomotor, and subcortical networks (all p_FWE < 0.05). Finally, changes in functional connectivity were significantly associated with increases in negative affect, with 13 connectivity edges showing significant (p < 0.001) correlations with DRSP symptom scores. These findings suggest that OCPs induce widespread and individually meaningful alterations to brain network organization, which may underlie mood-related side effects and should be considered in future neuroimaging research involving hormonal contraceptive users.