Preterm infants with isolated cerebellar hemorrhage show bilateral cortical alterations at term equivalent age

Abstract

the cerebellum is connected to numerous regions of the contralateral side of the cerebrum. Motor and cognitive deficits following neonatal cerebellar hemorrhages (CbH) in extremely preterm neonates may be related to remote cortical alterations, following disrupted cerebello-cerebral connectivity as was previously shown within six CbH infants. In this retrospective case series study, we used MRI and advanced surface-based analyses to reconstruct gray matter (GM) changes in cortical thickness and cortical surface area in extremely preterm neonates (median age = 26; range: 24.9-26.7 gestational weeks) with large isolated unilateral CbH (N = 5 patients). Each CbH infant was matched with their own preterm infant cohort (range: 20-36 infants) based on sex and gestational age at birth. On a macro level, our data revealed that the contralateral cerebral hemisphere of CbH neonates did not show less cortical thickness or cortical surface area than their ipsilateral cerebral hemisphere at term. None of the cases differed from their matched cohort groups in average cortical thickness or average cortical surface area in the ipsilateral or contralateral cerebral hemisphere. On a micro (i.e. vertex) level, we established high variability in significant local cortical GM alteration patterns across case-cohort groups, in which the cases showed thicker or bigger volume in some regions, among which the caudal middle frontal gyrus, insula and parahippocampal gyrus, and thinner or less volume in other regions, among which the cuneus, precuneus and supratentorial gyrus. This study highlights that cerebellar injury during postnatal stages may have widespread bilateral influence on the early maturation of cerebral cortical regions, which implicate complex cerebello-cerebral interactions to be present at term birth. The cerebellum is fundamental for cognitive and coordinated motor function, varying from sensorimotor mapping to language regulation (as reviewed by Caligiore et al.) 1. Pioneering work in both animal and human studies has established that the cerebellum collaborates with the cerebral cortex and sends output to, and receives input from, contralateral cortical areas via enclosed-loops 2-5 , In human these projection areas include multiple higher-order cerebral regions, such as the dorsolateral prefrontal cortex, the parietal and superior temporal lobes 6-8. Cerebello-cerebral loops are thought to be anatomically separated and involved in distinct functional processes 1,9. Many of these efferent and afferent connections have been identified as early as term-equivalent age (TEA) in preterm infants 10-12. Cerebellar hemorrhage (CbH) is a common neonatal complication with an ultrasound-detected incidence of 7.6% in extremely preterm infants (gestational age at birth <28 weeks) 13. In general the most immature and the sickest children are at a higher risk for developing CbH 14,15 , The actual incidence, however, may be higher as it has likely been underdiagnosed clinically. A recent review demonstrates that between 43% and 75% of t...

Maturation of Purkinje cell firing properties relies on granule cell neurogenesis

“…The loss of just a few precursors has exponential effects on the number of granule cells that integrate into the cerebellar circuit (Corrales et al, 2004(Corrales et al, , 2006. Our findings contribute to understanding how early changes in cerebellar volume become correlated with downstream circuit dysfunction and the resulting neurological disorders observed in premature infants (Dijkshoorn et al, 2020).…”

“…Abnormal cerebellar development instigates motor diseases and neurodevelopmental disorders including ataxia, dystonia, tremor, and autism. These conditions are highly prevalent in premature infants and in newborns with cerebellar hemorrhage (Dijkshoorn et al, 2020;Limperopoulos et al, 2007;Steggerda et al, 2009;Zayek et al, 2012), who ultimately attain a smaller cerebellar size compared to children born full-term (Limperopoulos et al, 2005;Volpe, 2009). During the third trimester of human development, which corresponds to the first two postnatal weeks in mice (Sathyanesan et al, 2019), the cerebellum increases five-fold in size due to the rapid proliferation of granule cell precursors and the integration of granule cells into the cerebellar circuit (Chang et al, 2000).…”

Cerebellum and Prematurity: A Complex Interplay Between Disruptive and Dysmaturational Events

“…Nowadays, numerous studies have clearly established the cerebellar connections with the contralateral cerebral cortices and particularly with the dorsolateral prefrontal cortex, the parietal and superior temporal lobes ( Dijkshoorn et al, 2020 ). An interruption of this well-formed circuit between areas of the CNS may determine a diaschisis, meaning a functional impairment of the region linked to the one subject of a structural lesion ( Catsman-Berrevoets, 2017 ).…”

“…Cerebellar hemorrhage is a well-known complication of premature birth with a higher risk of incidence in children born before 28 weeks of gestational age and a birthweight inferior to 750 g. This is even truer in premature newborns with worse adaptation to extrauterine life ( Volpe, 2009 ; Dijkshoorn et al, 2020 ). Other noteworthy risk factors include preeclampsia, traumatic delivery, sepsis, prolonged mechanical ventilation, patent ductus arteriosus, and hemodynamically significant hypotension ( Boswinkel et al, 2019 ; Gano and Barkovich, 2019 ; Garfinkle et al, 2020 ).…”

Maturation of Purkinje cell firing properties relies on neurogenesis of excitatory neurons

“…Abnormal cerebellar development instigates motor diseases and neurodevelopmental disorders including ataxia, dystonia, tremor, and autism. These conditions have a high incidence in premature infants as well as in newborns with cerebellar hemorrhage ( Dijkshoorn et al, 2020 ; Limperopoulos et al, 2007 ; Steggerda et al, 2009 ; Zayek et al, 2012 ). The affected children ultimately attain a smaller cerebellar size compared to children born full-term ( Limperopoulos et al, 2005 ; Volpe, 2009 ), and they have altered functional connectivity between the cerebellum and the neocortex ( Herzmann et al, 2019 ; Hortensius et al, 2018 ).…”