TY - JOUR
T1 - In utero methadone exposure permanently alters anatomical and functional connectivity
T2 - A preclinical evaluation
AU - Chin, Eric M.
AU - Kitase, Yuma
AU - Madurai, Nethra K.
AU - Robinson, Shenandoah
AU - Jantzie, Lauren L.
N1 - Funding Information:
The authors are grateful for the generous funding provided by the National Institutes of Health/National Institute of Drug Abuse 1U18DA052402 to LLJ and SR, the National Institutes of Health R01HL139492 to LLJ, the Blaustein Pain Research Fund to LLJ, the Johns Hopkins Children’s Innovation fund to LLJ, the Institutional Training Grant for Clinician Scientists in Pediatric Critical Cardiopulmonary Disease (T32HL125239) to NM, and the Johns Hopkins Neurosurgery Pain Research Institute Scholars Program to EMC. Acknowledgments
Publisher Copyright:
2023 Chin, Kitase, Madurai, Robinson and Jantzie.
PY - 2023
Y1 - 2023
N2 - 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. Clinical studies have identified reduced gray matter volume and abnormal white matter microstructure in children with POE but impacts on whole-brain functional brain connectivity (FC) have not been reported. To define effects of POE on whole brain FC and white matter injury in adult animals, we performed quantitative whole-brain structural and functional MRI. We used an established rat model of POE in which we have previously reported impaired executive function in adult rats analogous to persistent neurocognitive symptoms described in humans with POE. Pregnant Sprague-Dawley rat dams received continuous methadone (12 mg/kg/day) vs. saline infusion for 28 days via osmotic mini-pumps, exposing rats to pre- and postnatal opioid until weaning. At young adult age (P60), POE and saline exposed offspring underwent in vivo MRI included diffusion tensor imaging and functional MRI (fMRI). Results indicate that fractional anisotropy (FA) was decreased in adult animals with POE [n = 11] compared to animals that received saline [n = 9] in major white matter tracts, including the corpus callosum (p < 0.001) and external capsule (p < 0.01). This change in FA was concomitant with reduced axial diffusivity in the external capsule (p < 0.01) and increased radial diffusivity in the corpus callosum (p < 0.01). fMRI analyses reveal brainwide FC was diffusely lower in POE (p < 10−6; 10% of variance explained by group). Decreased connectivity in cortical-cortical and cortico-basal ganglia circuitry was particularly prominent with large effect sizes (Glass's Δ > 1). Taken together, these data confirm 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.
AB - 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. Clinical studies have identified reduced gray matter volume and abnormal white matter microstructure in children with POE but impacts on whole-brain functional brain connectivity (FC) have not been reported. To define effects of POE on whole brain FC and white matter injury in adult animals, we performed quantitative whole-brain structural and functional MRI. We used an established rat model of POE in which we have previously reported impaired executive function in adult rats analogous to persistent neurocognitive symptoms described in humans with POE. Pregnant Sprague-Dawley rat dams received continuous methadone (12 mg/kg/day) vs. saline infusion for 28 days via osmotic mini-pumps, exposing rats to pre- and postnatal opioid until weaning. At young adult age (P60), POE and saline exposed offspring underwent in vivo MRI included diffusion tensor imaging and functional MRI (fMRI). Results indicate that fractional anisotropy (FA) was decreased in adult animals with POE [n = 11] compared to animals that received saline [n = 9] in major white matter tracts, including the corpus callosum (p < 0.001) and external capsule (p < 0.01). This change in FA was concomitant with reduced axial diffusivity in the external capsule (p < 0.01) and increased radial diffusivity in the corpus callosum (p < 0.01). fMRI analyses reveal brainwide FC was diffusely lower in POE (p < 10−6; 10% of variance explained by group). Decreased connectivity in cortical-cortical and cortico-basal ganglia circuitry was particularly prominent with large effect sizes (Glass's Δ > 1). Taken together, these data confirm 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.
KW - functional connectivity
KW - methadone
KW - neurodevelopment
KW - prenatal opioid exposure
KW - white matter microstructure
UR - http://www.scopus.com/inward/record.url?scp=85149876238&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85149876238&partnerID=8YFLogxK
U2 - 10.3389/fped.2023.1139378
DO - 10.3389/fped.2023.1139378
M3 - Article
C2 - 36911026
AN - SCOPUS:85149876238
SN - 2296-2360
VL - 11
JO - Frontiers in Pediatrics
JF - Frontiers in Pediatrics
M1 - 1139378
ER -