Abstract
Altered functional connectivity has been reported in infants with prenatal exposure to opioids, which significantly interrupts and influences endogenous neurotransmitter/receptor signaling during fetal programming. Better birth outcomes and long-term developmental outcomes are associated with medication for opioid use disorder (MOUD) during pregnancy, but the neural mechanisms underlying these benefits are largely unknown. We aimed to characterize effects of prenatal opioid/other drug exposure (PODE) and the neural basis for MOUD’s reported beneficial effects by examining neonatal brain functional organization. A cohort of 109 human newborns (42 PODE, 39 with prenatal exposure to drugs excluding opioids (PDE), 28 drug-free controls; males and females) underwent resting-state fMRI at 2 weeks of age. To examine neural effects of MOUD, PODE infants were separated into subgroups based on whether mothers received MOUD (n=31) or no treatment (n=11). A novel heatmap analysis was designed to characterize PODE-associated functional connectivity alterations and MOUD-related effects, and permutation testing identified regions of interest with significant effects. PODE neonates showed alterations beyond those associated with PDE, particularly in reward-related frontal-sensory connectivity. MOUD was associated with a significant reduction of PODE-related alterations in key regions of endogenous opioid pathways including limbic and frontal connections. However, significant residual effects in limbic and subcortical circuitry were observed. These findings confirm altered brain functional organization associated with PODE. Importantly, widespread normalization effects associated with MOUD reveal, for the first time, the potential brain basis of MOUD’s beneficial effects on the developing brain and underscore the importance of this treatment intervention for better developmental outcomes.
Significance Statement:
This is the first study to reveal the potential neural mechanisms underlying the beneficial effects on the neonate brain associated with medication for opioid use disorder (MOUD) during pregnancy. We identified both normalization and residual effects of MOUD on brain functional architecture by directly comparing neonates prenatally exposed to opioids with MOUD and those exposed to opioids but without MOUD. Our findings confirm altered brain functional organization associated with prenatal opioid exposure and demonstrate that although significant residual effects remain in reward circuitry, MOUD confers significant normalization effects on functional connectivity of regions associated with socioemotional development and reward processing. Taken together, our results highlight the importance of MOUD intervention for better neurodevelopmental outcomes.
Footnotes
The authors declare no financial conflicts of interest for this work.
W.G. and K.G. designed the study. K.G. conducted subject recruitment and data acquisition. J.L. conducted image processing and data analysis. J.L. and W.G. wrote the manuscript and K.G. provided input and additional feedback. This work was supported by the National Institutes of Health (R01DA042988, R01DA043678 to W.G. and K.G.; R34DA050255 to W.G.) and by Cedars–Sinai Precision Medicine Initiative Award and institutional support (to W.G.). The authors declare no competing financial interests. The authors thank the families who generously gave their time to participate in this study.
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