Resting State Functional MRI Connectivity Association with Consciousness, Mortality, Longitudinal and Two-Year Outcomes in Neonatal Acute Brain Injury

Background An accurate and comprehensive test of integrated brain network function is needed for neonates during the acute brain injury period to inform on morbidity. In our first term neonatal acute brain injury (ABI) study we demonstrated resting state functional MRI (RS) acquired within 31 days of life, results in disrupted connectivity of the resting state fMRI networks, incrementally associated with consciousness, mortality, cognitive and motor development, and ongoing concern for seizures at 6 months post-gestation. In this retrospective cohort study, we evaluate extended 2-year outcomes in the same patients. Methods Study subjects included the same 40 consecutive neonates from our prior study, with resting state functional MRI acquired within 31 days after suspected brain insult from March 2018 to July 2019. Acute-period exam and test results were assigned ordinal scores based on severity as documented by respective treating specialists. Analyses (Fisher exact, Wilcox Sum-Rank test ordinal/multinomial logistic regression) examined association of resting state networks with demographics, presentation, neurological exam, electroencephalogram, anatomical MRI, magnetic resonance spectroscopy, passive task functional MRI, and outcomes of NICU and all mortality, outpatient development measured by exam and the Pediatric Cerebral Performance Category Scale (PCPC), motor development and tone, and ongoing concern for seizure at up to 42 months of age. All statistical tests were 2-sided, with statistical significance and CI adjusted using a Bonferroni correction to account for multiple test comparisons for each network and other modality. Results Subjects had a mean (standard deviation) gestational age of 37.8 (2.6) weeks, follow-up median age follow-up median age (interquartile range) 30.5 (23.6, 36.7) months, 68% were male, with a diagnosis of hypoxic ischemic encephalopathy (60%). Of the 40 patients, three died prior to discharge, and another four between 6-42 months, and 5 were lost to follow-up. Of the followed, findings at birth included mild distress (46%), moderately abnormal neurological exam (34%), and consciousness characterized as awake but irritable (37%). Significant associations after multiple testing corrections were detected for resting state networks: basal ganglia with PCPC (odds ratio [OR], 9.54; 99.4% confidence interval [CI], 1.89-48.1; P = 0.0003), NICU mortality (OR, 57.5; 99% CI, 1.35->999; P = 0.006), outpatient mortality (OR, 65.7; 99% CI 1.47->999; P = 0.005), and motor tone/weakness (OR, 17.8; 99% CI, 2.2-143; P = 0.0004); language/frontoparietal network with developmental delay (OR, 3.64; 99% CI, 1.02-13.05; P = 0.009), PCPC (OR, 3.98; 99% CI, 1.09-14.45; P = 0.006), and all mortality (OR, 9.2; 99% CI, 0.91-92.6; P = 0.01; default mode network with developmental delay (OR, 4.14; 99% CI, 1.19-14.43; P = 0.003); PCPC (OR, 4.1; 99% CI, 1.2-14.2; P = 0.004), NICU mortality (OR, 20.41; 99% CI, 0.89-468; P = 0.01), and motor tone/weakness (OR, 3.35; 99% CI, 1.01-11.12; P = 0.009); and seizure onset zone with concern for seizures (OR, 4.02; 99% CI, 1.0-16.15; P = 0.01). Of the other acute phase tests, only anatomical MRI was showed association with and outcome, concern for seizure (OR, 2.40; 99% CI, 0.94-6.13; P = 0.01). Conclusions This study provides level 3 evidence (OCEBM Levels of Evidence Working Group) demonstrating that in neonatal acute brain injury, the degree of abnormality of resting state networks is associated with mortality, ongoing concern for seizure and 2 year outcomes. These findings suggest RS is feasible and safe to implement in a busy tertiary neonatal ICU and the findings are of at least equivalent value to other standard of care diagnostics. Highlights ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The PCH IRB approved this retrospective follow-up analysis (PCH IRB-20-331) and waived consent for this study. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript * LTFU : lost to follow up ABI : acute brain injury DOC : disorders of consciousness EEG : electroencephalogram fMRI : functional magnetic resonance imaging RSN : resting state network(s) DMN : default mode network FP : frontoparietal network Lang/FP : language/frontoparietal network HIE : hypoxic ischemic encephalopathy a-MRI : anatomical MRI RS : resting state functional magnetic resonance imaging MRS : magnetic resonance spectroscopy cv-EEG : continuous video EEG ICA : independent component analysis BOLD : blood oxygenation level dependent signal DRE : drug resistant epilepsy FE : Fisher exact OR : odds ratio CI : confidence intervals OLR : ordinal logistic regression analyses MLR : multinomial logistic regression models CC : correlation coefficient TBI : traumatic brain injury RS-SOZ : seizure onset zone networks PCPC : Pediatric Cerebral Performance Category Scale BG : basal ganglia resting state network DWI : diffusion-weighted imaging IC : \---|\---|- TR : repetition time DRE : drug resistant epilepsy WLST : withdrawal of life sustaining therapies non-RSN : atypical neuronal networks NICU : neonatal intensive care unit