Functional brain networks after hypothermia-treated neonatal hypoxic-ischemic encephalopathy

<jats:p>&lt;p dir="ltr"&gt;Background: Neonatal Hypoxic-Ischemic Encephalopathy (HIE) induces brain injury to the immature functional networks that govern brain abilities. Some of these networks, responsible for early-developing abilities such as motor function, have already reached an adult pattern in the newborn's brain. Other networks, responsible for late-maturing, higher-order cognitive functions, are still in a proto-phase of their development.&lt;/p&gt;&lt;p dir="ltr"&gt;Despite the beneficial effects of therapeutic hypothermia (TH) treatment, provided for moderate and severe HIE stages, affected infants still face a high risk of future neuro- logical sequelae. Impairments emerging in toddler and preschool age, such as cerebral palsy (CP) and cognitive delay, have long been recognized as adverse effects of neona- tal HIE and are commonly assessed during clinical follow-up within healthcare services. More recently, late-emerging deficits have been increasingly acknowledged. These in- clude additional rates of motor and visual impairment, as well as higher-order cognitive deficits. This suggests that aberrant, late-maturing cognitive network dynamics are af- fected, influencing both specific mental abilities and their support of primary systems. Additionally, the long-term trajectory of late-emerging cognitive abilities, such as exec- utive functions, remains largely unknown.&lt;/p&gt;&lt;p dir="ltr"&gt;Aim: The studies included in this thesis aimed to investigate the late effects on the func- tional networks of the brain in comparison to typical neurodevelopment.&lt;/p&gt;&lt;p dir="ltr"&gt;In Study I, the global properties of these networks were investigated, and in Studies II and III, their association with early-maturing motor function (Study II) and late-maturing executive functions (Study III) was evaluated, respectively. Additionally, test-based ex- ecutive function performance was evaluated separately in Study III.&lt;/p&gt;&lt;p dir="ltr"&gt;Methods: The studies included in this thesis are all based on a population-based, prospec- tively recruited cohort of children exposed to TH-treated neonatal HIE (n = 66) and a control group of children with normal delivery (n = 43). Both groups were evalu- ated in early adolescence using structured assessments of motor and executive func- tions (EFs). An magnetic resonance imaging (MRI) investigation, including a resting-state functional MRI (fMRI) sequence, was employed for the assessment of functional brain networks. Analysis included direct comparison of the functional networks between the groups (Study I) and brain-behavior analysis for the association with performance-based scores (Studies II and III).&lt;/p&gt;&lt;p dir="ltr"&gt;Results: Direct comparison of the spatio-temporal properties of functional networks did not identify statistically significant group differences (Study I). However, brain-behavior analysis identified differing interactions between multiple functional networks in associa- tion with the tested performance of motor ability and EFs between the groups. These dif-ferences all included aberrant interactions between motor networks and a set of higher- order cognitive networks (Studies II and III). Additionally, EF performance was significantly decreased in the clinical group (Study III).&lt;/p&gt;&lt;p dir="ltr"&gt;Conclusions: On a group level, the basal properties of functional networks after TH- treated neonatal HIE are generally coherent with unexposed children regarding spatio- temporal characteristics. The notion of an aberrant interaction between cognitive and primary brain functions as a cause for additional late-emerging deficits is supported by the aberrant network interactions identified for motor and executive performance. Taken together with the poorer EFs performance, the results of these studies highlight the need for extended clinical follow-up after TH-treated neonatal HIE to continuously assess brain functions at risk at an age when these abilities are sufficiently mature.&lt;/p&gt;&lt;h3 dir="ltr"&gt;List of scientific papers&lt;/h3&gt;&lt;p dir="ltr"&gt;I. &lt;b&gt;Håkansson G,&lt;/b&gt; Robertsson Grossmann K, Ådén U, Blennow M, Fransson P. Functional brain connectivity in early adolescence after hypothermia-treated neona- tal hypoxic-ischemic encephalopathy. Pediatr Res. 2025 Nov;98(5):1827-1834. Epub 2025 Mar 2. &lt;a href="https://doi.org/10.1038/s41390-025-03951-z"&gt;https://doi.org/10.1038/s41390-025-03951-z&lt;br&gt;&lt;/a&gt;&lt;br&gt;&lt;/p&gt;&lt;p dir="ltr"&gt;II. &lt;b&gt;Håkansson G,&lt;/b&gt; Eriksson Westblad M, Örtqvist M, Ådén U, Blennow M, Fransson P. Motor performance and higher associative cortical networks in adolescents with neonatal hypoxic-ischaemic encephalopathy treated with therapeutic hypothermia. Dev Med Child Neurol. 2026 Jan;68(1):99-109. Epub 2025 Jun 22. &lt;a href="https://doi.org/10.1111/dmcn.16371"&gt;https://doi.org/10.1111/dmcn.16371&lt;br&gt;&lt;/a&gt;&lt;br&gt;&lt;/p&gt;&lt;p dir="ltr"&gt;III. &lt;b&gt;Håkansson G,&lt;/b&gt; Blomé S, Thompson WH, Åden U, Thorell L, Blennow M, Fransson P. Executive functions and brain connectivity in adolescents with neonatal hypoxic- ischaemic encephalopathy treated with therapeutic hypothermia. [Submitted]&lt;/p&gt;&lt;p&gt;&lt;br&gt;&lt;/p&gt;</jats:p>