Exploring the multiple-hit hypothesis of preterm white matter damage using diffusion MRI

Abstract

BackgroundPreterm infants are at high risk of diffuse white matter injury and adverse neurodevelopmental outcome. The multiple hit hypothesis suggests that the risk of white matter injury increases with cumulative exposure to multiple perinatal risk factors. Our aim was to test this hypothesis in a large cohort of preterm infants using diffusion weighted magnetic resonance imaging (dMRI).MethodsWe studied 491 infants (52% male) without focal destructive brain lesions born at < 34 weeks, who underwent structural and dMRI at a specialist Neonatal Imaging Centre. The median (range) gestational age (GA) at birth was 30+ 1 (23+ 2–33+ 5) weeks and median postmenstrual age at scan was 42+ 1 (38–45) weeks. dMRI data were analyzed using tract based spatial statistics and the relationship between dMRI measures in white matter and individual perinatal risk factors was assessed. We tested the hypothesis that increased exposure to perinatal risk factors was associated with lower fractional anisotropy (FA), and higher radial, axial and mean diffusivity (RD, AD, MD) in white matter. Neurodevelopmental performance was investigated using the Bayley Scales of Infant and Toddler Development, Third Edition (BSITD-III) in a subset of 381 infants at 20 months corrected age. We tested the hypothesis that lower FA and higher RD, AD and MD in white matter were associated with poorer neurodevelopmental performance.ResultsIdentified risk factors for diffuse white matter injury were lower GA at birth, fetal growth restriction, increased number of days requiring ventilation and parenteral nutrition, necrotizing enterocolitis and male sex. Clinical chorioamnionitis and patent ductus arteriosus were not associated with white matter injury. Multivariate analysis demonstrated that fetal growth restriction, increased number of days requiring ventilation and parenteral nutrition were independently associated with lower FA values. Exposure to cumulative risk factors was associated with reduced white matter FA and FA values at term equivalent age were associated with subsequent neurodevelopmental performance.ConclusionThis study suggests multiple perinatal risk factors have an independent association with diffuse white matter injury at term equivalent age and exposure to multiple perinatal risk factors exacerbates dMRI defined, clinically significant white matter injury. Our findings support the multiple hit hypothesis for preterm white matter injury.

ADHD symptoms and their neurodevelopmental correlates in children born very preterm

“…This was assessed using markers of general infant health: number of days of parenteral nutrition (reflecting gut failure) and number of days spent on invasive ventilation via an endotracheal tube (reflecting respiratory failure). In a larger sample of infants the current study participants were drawn from, these two risk factors were independently associated with lower fractional anisotropy values throughout the white matter at term equivalent age, reflecting alterations in brain development [52]. However, the current results did not find significant differences in ADHD symptomatology between groups with differing severity of brain lesions, unlike previous findings in 11 years old children who were born extremely preterm [5].…”

“…In summary, this study shows that already during preschool age very preterm children are at increased risk of sub-threshold ADHD symptoms, especially the inattentive type. Inattentive ADHD symptoms were associated with intellectual functioning at time of assessment, and with perinatal clinical risk, supporting the hypothesis of a possible neurobiological origin of ADHD, via alteration of white matter microstructural properties [52] that can affect brain maturational processes resulting in topological alterations of large-scale brain networks [64] that are not detectable with conventional MRI. In light of these findings, further investigation of early inattentive symptoms may support the development of effective interventions and provide new models for understanding the neurofunctional trajectories leading to ADHD in children born very preterm.…”

The fetus at the tipping point: modifying the outcome of fetal asphyxia

“…A recent MRI study in preterm infants demonstrated that a synergy between prenatal and postnatal insults, such as intrauterine growth restriction and prolonged mechanical ventilation had a cumulative effect on white matter injury, as shown by lower white matter fractional anisotropy at term equivalent age, and impaired neurodevelopmental outcomes at 20 months corrected age (Barnett et al . ). In the section below we discuss how exposure to inflammation, antenatal treatments (e.g.…”

Sex differences in brain connectivity and male vulnerability in very preterm children

“…Diffusion tensor imaging (DTI) studies also reported sex differences in the preterm population, which includes lower regional and mean fractional anisotropy (FA) and higher medium diffusivity in boys indicating less organized white matter microstructure (Constable et al, 2008;Liu et al, 2011;Thompson et al, 2018). Similarly, other studies have reported male sex to be associated with reduced corpus callosum microstructural growth trajectory during first 6 months of life as well as being a risk factor for diffuse white matter injury (Barnett et al, 2017;Teli et al, 2018).…”