Functional Connectivity Disruption in Neonates with Prenatal Marijuana Exposure

Abstract

Prenatal marijuana exposure (PME) is linked to neurobehavioral and cognitive impairments; however, findings in childhood and adolescence are inconsistent. Type-1 cannabinoid receptors (CB1R) modulate fetal neurodevelopment, mediating PME effects on growth of functional circuitry sub-serving behaviors critical for academic and social success. The purpose of this study was to investigate the effects of prenatal marijuana on development of early brain functional circuitry prior to prolonged postnatal environmental influences. We measured resting state functional connectivity during unsedated sleep in infants at 2-6 weeks (+MJ: 20 with PME in combination with nicotine, alcohol, opiates, and/or selective serotonin reuptake inhibitors; -MJ: 23 exposed to the same other drugs without marijuana, CTR: 20 drug-free controls). Connectivity of subcortical seed regions with high fetal CB1R expression was examined. Marijuana-specific differences were observed in insula and three striatal connections: anterior insula-cerebellum, right caudate-cerebellum, right caudate-right fusiform gyrus/inferior occipital, left caudate-cerebellum. +MJ neonates had hypo-connectivity in all clusters compared with -MJ and CTR groups. Altered striatal connectivity to areas involved in visual spatial and motor learning, attention, and in fine-tuning of motor outputs involved in movement and language production may contribute to neurobehavioral deficits reported in this at-risk group. Disrupted anterior insula connectivity may contribute to altered integration of interoceptive signals with salience estimates, motivation, decision-making, and later drug use. Compared with CTRs, both +MJ and -MJ groups demonstrated hyper-connectivity of left amygdala seed with orbital frontal cortex and hypo-connectivity of posterior thalamus seed with hippocampus, suggesting vulnerability to multiple drugs in these circuits.

Keywords: caudate; cerebellum; functional connectivity; insula; neonatal; prenatal marijuana; resting state.

Figure 1

Neonatal functional connectivity and prenatal marijuana exposure. Functional connectivity for different seed regions (top to bottom) and infant groups (left to right): marijuana positive (+MJ) with or without in utero exposure to alcohol, nicotine, SSRIs, and opiates; infants with in utero exposure to some combination of the aforesaid drugs minus marijuana (−MJ); and age-matched drug-free controls (CTR). Data threshold set using the combined approach: α = 0.05: voxel-wise p ≤ 0.01, cluster size = 32 voxels. Pseudo-coloring (see color bar at bottom) is based on Fisher’s Z-transformation of the temporal correlation between each voxel and the seed region. Data visualized in the axial view on a subset of high-resolution T1-weighted reference images.

Figure 2

Localization of group-level (+MJ, −MJ, CTR) functional connectivity differences at the cluster level and comparisons by group. (A) Clusters depicted on the high-resolution anatomical reference images. Clusters were detected using the combined threshold approach controlling for gestational age, birth weight, scan age, gender, and scanner (α < 0.05): multivariate group-wise difference (+MJ, −MJ, CTR) p ≤ 0.01, minimum number of voxels = 32, nearest neighbor clustering (NN) = 3. (B) Comparisons of functional connectivity within cluster by neonatal group. (*) indicates significant (p ≤ 0.05 Dunn–Sidak corrected) pair-wise differences between groups while accounting for participant characteristics. Data plotted as mean ± SEM.