33 - Cyclohexanone Impairs Functional and Anatomical Brain Connectivity Following Perinatal Exposure

Monday, May 1, 2023

9:30 AM – 11:30 AM ET

Poster Number: 33
Publication Number: 33.435

Yuma Kitase, Johns Hopkins school of Medicine, Baltimore, MD, United States; Eric M. Chin, Kennedy Krieger Institute, Baltimore, MD, United States; Shenandoah Robinson, Johns Hopkins Children's Center, Baltimore, MD, United States; David Graham, Johns Hopkins University School of Medicine, Germantown, MD, United States; Allen D. Everett, Johns Hopkins University School of Medic, Glenwood, MD, United States; Lauren Jantzie, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Presenting Author(s)

Yuma Kitase, MD, PhD (he/him/his)

Postdoctoral Research fellow
Johns Hopkins school of Medicine
Baltimore, Maryland, United States

Background: Cyclohexanone (CXO) is ubiquitous in an ICU environment. It is an organic solvent sealer for IV bags and stopcocks that seeps from plastic tubing into infused medical fluids, including total parenteral nutrition (TPN). Previously, we showed circulating CXO levels were independently associated with impaired neurodevelopment after neonatal cardiac surgery, although the mechanism for this is unknown.

Objective: To test that neonatal rats exposed to clinically relevant CXO levels would significantly alter white matter microstructure and diminish functional brain connectivity.

Design/Methods: Cyclohexanone concentrations were determined from 25 independent IV bags of TPN from the NICU with a median concentration of 10.1 ug/mL (6.8-12.4 ug/mL). On postnatal day 7 (P7, term) rats of both sexes were randomly allocated to receive CXO (0.7ul/g ip body weight/day based on the above concentrations, n=7) or saline (CTRL, n=6) q12 h for 7 days (P15, infant). In vivo diffusion tensor imaging and functional MRI occurred at P21 (Adolescent). BOLD-fMRI and T2-weighted images were non-linearly aligned to the Waxholm v4 atlas. Functional connectivity was examined amongst 46 gray matter regions of interest (ROIs). Inter-ROI edge identity and group identity were included in a Type III ANOVA to distinguish connectivity patterns, brain-wide differences in connectivity magnitude, and differences between groups in specific connections.

Results:

CXO exposure disrupted integrity of major white matter tracts. Fractional anisotropy was reduced in the corpus callosum (p< 0.001) and capsular white matter (p< 0.05), concomitant with increased radial diffusivity (p< 0.01). CXO strikingly decreased global network connectivity and network topology, particularly for cortical and basal ganglia (p< 10^-6). Brain wide functional connectivity was lower in CXO than in CTRL (group main effect: p< 10^-6). Decreases in cortical-cortical and cortico-basal ganglia circuitry were particularly prominent with large effect sizes (Glass’s Δ >1).

Conclusion(s): Seven days of CXO exposure, equivalent to NICU exposure from a standard TPN solution, has profound effects on white matter integrity and functional brain connectivity persisting into adolescence. CXO decreased connectivity across cortical and deep gray networks. Network dysfunction has been implicated in executive function deficits in children after cardiac surgery, and may be key to CXO-induced impairments in neurodevelopment. Additional studies are urgently needed to address mechanism of this injury, avenues for neurorepair and to reduce CXO in medical environments.