Functional dissection of prenatal drug effects on baby brain and behavioral development

Abstract

Prenatal drug exposure (PDE) is known to affect fetal brain development with documented long‐term consequences. Most studies of PDE effects on the brain are based on animal models. In this study, based on a large sample of 133 human neonates and leveraging a novel linear mixed‐effect model designed for intersubject variability analyses, we studied the effects of six prenatally exposed drugs (i.e., nicotine, alcohol, selective serotonin reuptake inhibitor, marijuana, cocaine, and opioids) on neonatal whole‐brain functional organization and compared them with five other critical nondrug variables (i.e., gestational age at birth/scan, sex, birth weight, and maternal depression). The behavioral implications were also examined. Magnitude‐wise, through summing across individual drug effects, our results highlighted ~5% of whole‐brain functional connections (FCs) affected by PDE, which was highly comparable with the combined effects of the five nond rug variables. Spatially, the detected PDE effects featured drug‐specific patterns with a common bias in higher‐order brain regions/networks. Regarding brain–behavioral relationships, the detected connections showing significant drug effects also demonstrated significant correlations with 3‐month behavioral outcomes. Further mediation analyses supported a mediation role of the detected brain FCs between PDE status and cognitive/language outcomes. Our findings of widespread, and spatially biased PDE effect patterns coupled with significant behavioral implications may hopefully stimulate more human‐based studies into effects of PDE on long‐term developmental outcomes.

Prenatal antidepressant exposure and sex differences in neonatal corpus callosum microstructure

“…Neuroimaging shortly after birth can provide critical insight into potential brain changes associated with prenatal exposures. In recent years, magnetic resonance imaging (MRI) and electroencephalography (EEG) studies on humans infants following prenatal SSRI exposure provide evidence of microstructural (Jha et al., 2016; Lugo‐Candelas et al., 2018; Podrebarac et al., 2017), electrocortical (Grieve et al., 2019; Videman et al., 2017) and functional (Rotem‐Kohavi et al., 2018, 2019; Salzwedel et al., 2016, 2020) alterations, though studies remain limited, methodologically varied, and some contain heterogeneous cohort characteristics with potentially confounding factors (e.g., prematurity, poly‐drug exposure). While prenatal exposures to maternal depression, anxiety and/or stress have been widely reported to impact early brain development, particularly in limbic regions (El Marroun et al., 2018; Lautarescu et al., 2020; Posner et al., 2016; Qiu et al., 2013, 2015; Rifkin‐Graboi et al., 2013, 2015; Scheinost et al., 2016), SSRI‐related effects beyond those related to maternal mood disturbances point to disrupted development impacting diverse brain regions and functions.…”

“…observed altered functional connectivity in infants with prenatal poly‐drug exposure, with SSRIs exhibiting the largest single‐drug effect in frontal and visual regions. Importantly, they report a posthoc sex‐drug interaction, suggesting that differential effects of prenatal drug exposure may exist in male and female infants (Salzwedel et al., 2020). Sex‐specific brain outcomes have been reported for other prenatal drug exposures, such as alcohol and opiates (Terasaki et al., 2016); however, it remains unknown as to whether prenatal SSRI exposure has sex‐specific effects on early brain development.…”

Global Brain Functional Network Connectivity in Infants With Prenatal Opioid Exposure

“…Maternal depression and anxiety have also been associated with altered white matter microstructure in infants, especially decreased neuritic density and increased mean, radial and axial diffusivity in specific brain regions ( 62 ). SSRIs used to treat depression are also shown to be associated with the relationship between infant brain functional connectivity and early infant behavior ( 57 ); however, none of the women in our study were on SSRIs during pregnancy. We did not identify any significant effects of polysubstance use on altered infant brain functional connectivity in our cohort of prenatal opioid exposed infants, which may partly be explained by the differential “signatures” of altered infant brain functional connectivity of different prenatal substance exposures ( 57 , 58 ).…”

“…Brain resting state functional networks exist in infants and have recently been shown to be altered in the presence of prenatal exposure to substances ( 27 , 28 , 57 ). However, prenatal substance exposure has also shown to be associated with alterations in multiple other brain regions, both intra-network and inter-network, outside of these canonical resting state functional networks ( 57 ). Our study focused on a network-free model of global brain functional connectivity, rather than predefined networks.…”

“…This suggests a role of the interplay between maternal opioid use and psychological disorders on the developing infant brain. Brain resting state functional networks exist in infants and have recently been shown to be altered in the presence of prenatal exposure to substances (27,28,57). However, prenatal substance exposure has also shown to be associated with alterations in multiple other brain regions, both intra-network and inter-network, outside of these canonical resting state functional networks (57).…”