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Neonatal encephalopathy prediction of poor outcome with diffusion-weighted imaging connectome and fixel-based analysis



Better biomarkers of eventual outcome are needed for neonatal encephalopathy. To identify the most potent neonatal imaging marker associated with 2-year outcomes, we retrospectively performed diffusion-weighted imaging connectome (DWIC) and fixel-based analysis (FBA) on magnetic resonance imaging (MRI) obtained in the first 4 weeks of life in term neonatal encephalopathy newborns.


Diffusion tractography was available in 15 out of 24 babies with MRI, five each with normal, abnormal motor outcome, or death. All 15 except one underwent hypothermia as initial treatment. In abnormal motor and death groups, DWIC found 19 white matter pathways with severely disrupted fiber orientation distributions.


Using random forest classification, these disruptions predicted the follow-up outcomes with 89–99% accuracy. These pathways showed reduced integrity in abnormal motor and death vs. normal tone groups (p < 10−6). Using ranked supervised multi-view canonical correlation and depicting just three of the five dimensions of the analysis, the abnormal motor and death were clearly differentiated from each other and the normal tone group.


This study suggests that a machine-learning model for prediction using early DWIC and FBA could be a possible way of developing biomarkers in large MRI datasets having clinical outcomes.


  • Early connectome and FBA of clinically acquired DWI provide a new noninvasive imaging tool to predict the long-term motor outcomes after birth, based on the severity of white matter injury.

  • Disrupted white matter connectivity as a novel neonatal marker achieves high accuracy of 89–99% to predict 2-year motor outcomes using conventional machine-learning classification.

  • The proposed neonatal marker may allow better prognostication that is important to elucidate neural repair mechanisms and evaluate treatment modalities in neonatal encephalopathy.

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Fig. 1: Fiber orientation distribution (FOD) function as a potential biomarker of white matter injury.
Fig. 2: Schematic of the DWIC analysis to construct the connectome graph, G = (Ω, S), of an individual infant.
Fig. 3: To the naked eye, three groups of 2-year outcomes can be differentiated by comparing the shapes of FOD functions in the somatosensory motor system.
Fig. 4: Trend for differentiating three groups of 2-year outcomes by comparing five DWIC markers that were measured from neural pathways of interest.
Fig. 5: Using α < 0.05, significant alterations of FOD functions underlying early hypoxic injuries were found in subcortical regions of abnormal motor and death groups, including thalamus, posterior limb of internal capsule, and cerebellar peduncle.
Fig. 6: Prediction of the eventual outcome made easier by ranked SMVCCA showing a figure plotting three of the five fused dimensions, which provided the most significant discrimination for three groups (Fig. 4a)


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We thank the families who took part in the study, our colleagues in the Neonatal Intensive Care Unit, and the Developmental Assessment Clinic at Children’s Hospital of Michigan. S.T. and J.-W.J. have been funded through NS114972 and NS117146 (S.T., P.I.) from NINDS, NIH.

Author information




J.-W.J.—study conception and design, data acquisition, data analysis and interpretation, statistical analysis, drafting manuscript and revision, final approval of the manuscript. M.-H.L.—data analysis and interpretation, statistical analysis, final approval of the manuscript. N.F.—drafting manuscript and revision, final approval of the manuscript. S.D.—drafting manuscript and revision, final approval of the manuscript. S.M.—drafting manuscript and revision, final approval of the manuscript. S.A.—manuscript revision, final approval of the manuscript. R.B.C.—manuscript revision, final approval of the manuscript. S.T.—study conception and design, data analysis and interpretation, drafting manuscript and revision, final approval of the manuscript.

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Correspondence to Jeong-Won Jeong.

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The authors declare no competing interests.

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The present study was approved by the University’s Institutional Review Board, and a waiver of written informed consent was obtained to perform the analysis of existing data in the clinical archive.

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Jeong, JW., Lee, MH., Fernandes, N. et al. Neonatal encephalopathy prediction of poor outcome with diffusion-weighted imaging connectome and fixel-based analysis. Pediatr Res (2021).

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