Eric M. Chin, Kennedy Krieger Institute, Baltimore, MD, United States; Yuma Kitase, Johns Hopkins school of Medicine, Baltimore, MD, United States; Nethra Madurai, Johns Hopkins Hospital, Lutherville-Timonium, MD, United States; Shenandoah Robinson, Johns Hopkins Children's Center, Baltimore, MD, United States; Lauren Jantzie, Johns Hopkins University School of Medicine, Baltimore, MD, United States
Assistant Professor of Neurology and Pediatrics Kennedy Krieger Institute Kennedy Krieger Institute Baltimore, Maryland, United States
Background: The opioid epidemic is an ongoing public health crisis, and children born following prenatal opioid exposure (POE) have increased risk of long-term cognitive and behavioral sequelae. Studies have identified reduced gray matter volume and abnormal white matter microstructure, but impacts on whole-brain functional brain connectivity (FC) have not been reported. Using an established rat model of POE, we have previously reported hyperactivity and impaired executive function in juvenile and adult rats analogous to persistent neurocognitive symptoms described in humans with POE. Objective: To define effects of POE on whole brain FC and white matter injury in adult animals
Design/Methods: Pregnant Sprague-Dawley rat dams received continuous methadone (12 mg/kg/day) vs. saline infusion (CTRL) for 28 days via osmotic mini-pumps. At young adult age (P60), rats underwent in vivo MRI on a 11.7T scanner and a volumetric head coil. Whole brain imaging ([0.4mm]3 resolution) included diffusion tensor imaging (DTI; 30 directions@b=1000) and fMRI (TR=1s x 15min).
DTI metrics were examined in manually-defined corpus callosum and external capsule regions of interest (ROIs), and group differences were examined using non-parametric rank sum tests corrected for 2 comparisons/metric.
fMRI FC was examined amongst 46 atlas-defined gray matter regions of interest (ROIs). Inter-ROI edge identity (46*45/2 edges) and group identity (POE vs. CTRL) were examined within an ANOVA to define brain-wide group differences in FC magnitude as well as edge-specific differences. Results: FA was decreased in POE [n=10] than in CTRL [n=10] in both white matter ROIs (p< 0.05) as was axial diffusivity in the external capsule (p=0.02). Notably, brainwide FC was lower in POE (p< 10-6; 10% of variance explained by group). Decreases in cortical-cortical and cortico-basal ganglia circuitry were particularly prominent with large effect sizes (Glass’s Δ >1).
Conclusion(s): POE reduces brainwide functional connectivity as well as microstructural integrity of major white matter tracts. Altered neural circuitry, dysregulated network refinement, and diffuse network dysfunction have been implicated in executive function deficits that are common in children with POE. FC may serve as a translatable biomarker in children with POE.
