Aim: Neonatal hypoxic-ischemic encephalopathy (HIE) injures the infant brain during the basic formation of the developing functional connectome. This study aimed to investigate long-term changes in the functional connectivity (FC) networks of the adolescent brain following neonatal HIE treated with therapeutic hypothermia (TH). Method: This prospective, population-based cohort study included all infants (n=66) with TH-treated neonatal HIE in Stockholm during 2007-2009 and a control group (n=43) of children with normal neonatal course. Assessment with resting-state functional magnetic resonance imaging (fMRI) was performed at Karolinska Institutet, Stockholm at age 9-12 years. Results: fMRI data met quality criteria for 35 children in the HIE-cohort (mean [SD] age at MRI: 11.2 [0.74] years, 46% male) and 30 children in the control group (mean [SD] age at MRI: 10.1 [0.78] years, 53% male). Clinical neurologic symptoms were present in 40% of children in the HIE-cohort. Non-parametric statistical analysis failed to detect any significant (p<0.001) alterations of FC networks in the HIE-cohort, nor between children in the HIE-cohort with or without neurological sequelae. Interpretation: HT-treated HIE could not be associated with persistent alteration of the functional connectome. This indicates a notable resilience of the functional architecture of the brain against this type of early brain injury.

The authors have declared no competing interest.

This study was funded by Stiftelsen Promobilia (F20501), Stiftlesen Sunnerdahls Handikappfond (F18/20), Drottning Silvias Jubileumsfond, Lilla Barnets Fond, Jerringfonden, Stiftelsen Kempe-Carlgrenska Fonden, HKH Kronprinsessan Lovisas Forening for Barnasjukvard, Norrbacka-Eugeniastiftelsen (866/20), Neurofonden (F2020-0009) and grants provided by Region Stockholm (ALF project and Centre for innovative medicine).

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Regional Ethical Review Board in Stockholm, Sweden, gave ethical approval for this work (2009/735-31/4, 2010(850-31/1, 2012/617-32, 2016/1921-32, 2019-01447, 2020-03318).

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