677 - The Newborn Connectome in Antenatal Opioid Exposure

Publication Number: 2660.677

Josepheen De Asis-Cruz, Children's National Health System, Bethesda, MD, United States; Yao Wu, Children's National Hospital, Washington, DC, United States; Dae-young Kim, Children's National Hospital, Halethorpe, MD, United States; Kushal Kapse, Developing Brain Institute, Washington, DC, United States; Stephanie L. Merhar, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States; Carla M. Bann, RTI International, Apex, NC, United States; Jamie E. Newman, RTI International, Research Triangle Park, NC, United States; Nicole Mack, RTI International, Chicago, IL, United States; Sara DeMauro, Children's Hospital of Philadelphia, Philadelphia, PA, United States; Namasivayam Ambalavanan, University of Alabama School of Medicine, Birmingham, AL, United States; Scott A. Lorch, The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, United States; Deanne Wilson-Costello, Case Western Reserve University School of Medicine, Cleveland, OH, United States; Brenda Poindexter, Children's Healthcare of Atlanta, Atlanta, GA, United States; Myriam Peralta-Carcelen, University of Alabama at Birmingham, Birmingham, AL, United States; Jonathan M. Davis, Tufts University School of Medicine, Boston, MA, United States; Catherine Limperopoulos, Children's National Health System, Washington DC, DC, United States

Background: Antenatal opioid exposure increases the risk of neurodevelopmental disorders in children. The few studies in exposed neonates using advanced neuroimaging have shown widespread disruptions in regional functional connectivity (FC), providing clues to the neural basis of later impairments. However, these studies provide limited insights into information flow within developing networks. To address this knowledge gap, we leveraged a large sample of opioid-exposed neonates and age-matched controls (total N=258) to investigate the impact of opioids on the neonatal connectome.

Objective: To compare global, intermediate, and local network organization in healthy, term (Ctrl; n=90) and opioid-exposed (Exp; n=158) neonates using graph theory.

Design/Methods: Resting state functional MRI data were preprocessed using a previously validated pipeline. FC was measured from 93 whole-brain regions of interest. Network metrics were calculated using the Brain Connectivity Toolbox, including global, intermediate, and nodal metrics providing a comprehensive characterization of brain network organization. See Table 1 for a description of the metrics.

Results: Demographic data are presented in Table 2. Both groups demonstrated efficient small world topology (index>1), indicating preserved overall balanced network integration and segregation in opioid-exposed neonates (Figure 1A). Exposed neonates' networks also exhibited rich-club architecture (coefficient>1), but the range of degrees (k) at which the rich club was observed in opioid-exposed neonates was narrower (Ctrl=2-25 vs Exp=2-23), suggesting reduced density of connections between important rich-club nodes (hubs) in opioid-exposed neonates (Figure 1B). At the nodal level, degree and closeness centrality of the top third influential nodes were higher in opioid-exposed neonates, compared to controls (Figure 1C). Hubs common to both cohorts included bilateral superior frontal gyri, mid- and orbital frontal cortices. Lastly, we demonstrated reduced resilience of brain networks in opioid-exposed neonates (Figure 1D).

Conclusion(s): Our findings of intact global topology, increased centrality of specific nodes, and reduced resilience to network perturbation in brain networks of exposed neonates help bridge the gap between observed regional FC disruptions and broader dysfunction in information flow. This offers novel insights into potential neural substrates that predict later neurodevelopmental deficits in opioid-exposed children. Additional studies are needed to evaluate the prognostic, diagnostic and surveillance potential of these imaging findings.

Table 1. Description of global, intermediate, and nodal metrics.


Table 2. Characteristics of unexposed and opioid-exposed newborns.
Categorical data are presented as numbers of participants, with percentages in parentheses; continuous data are presented as means, with standard deviations in parentheses; ordinal categorical data are presented as medians, with (e.g., Apgar) IQRs in parentheses. Continuous variables were compared using a two-sample independent t-tests; ranked data (e.g., Apgar scores) were compared using Wilcoxon rank-sum tests; categorical data were compared using chi-square goodness-of-fit tests.

Figure 2. Altered resting state network topology in opioid-exposed neonates.
Figure 1. (A) Opioid-exposed neonates' resting state networks exhibit small world topology. Like unexposed neonates, opioid-exposed neonates clustering coefficient (C) and characteristic path length (L) greater than random networks' C and L. In addition, small world index ≥ 1. (B) Rich club organization is preserved in opioid-exposed neonates (rich club coefficient, φnorm > 1), but for a narrower range of degree (k) values. Blue = unexposed range; red = opioid-exposed range. (C) Network hubs in opioid-exposed neonates exhibit higher degree and closeness centrality. While node rankings were similar, the degree and closeness of the most influential nodes (ranked in the top third) were higher in opioid-exposed (red) compared to unexposed neonates (blue). (D) Networks of opioid-exposed neonates are less resilient to perturbation compared to unexposed neonates. Response to targeted removal of degree hubs on the largest connected cluster (left) and global efficiency (right) is shown.