Related Experiment Video
Updated: Feb 17, 2026
Advanced Diffusion Imaging in The Hippocampus of Rats with Mild Traumatic Brain Injury
Published on: August 14, 2019
Exploring the multiple-hit hypothesis of preterm white matter damage using diffusion MRI
Madeleine L Barnett1, Nora Tusor1, Gareth Ball1
1Centre for the Developing Brain, Division of Imaging Sciences & Biomedical Engineering, King's College London, London SE1 7EH, UK.
Insights
Multiple perinatal risk factors increase the risk of white matter injury in preterm infants. Cumulative exposure to these factors exacerbates this injury, supporting the multiple hit hypothesis.
Area of Science:
- Neonatal neuroscience
- Perinatal medicine
- Neuroimaging
Background:
- Preterm infants face high risks of diffuse white matter injury and poor neurodevelopmental outcomes.
- The multiple hit hypothesis posits that cumulative perinatal risk factors amplify white matter injury risk.
- Diffusion weighted magnetic resonance imaging (dMRI) is crucial for assessing white matter integrity.
Purpose of the Study:
- To test the multiple hit hypothesis in a large cohort of preterm infants.
- To investigate the association between dMRI measures and perinatal risk factors.
- To determine if white matter integrity at term equivalent age predicts neurodevelopmental performance.
Main Methods:
- 491 preterm infants (<34 weeks GA) without focal brain lesions underwent structural and dMRI.
- Tract-based spatial statistics analyzed dMRI data, assessing fractional anisotropy (FA) and diffusivity measures (RD, AD, MD).
- Neurodevelopment was evaluated using the Bayley Scales of Infant and Toddler Development (BSITD-III) in a subset of infants.
Main Results:
- Lower gestational age, fetal growth restriction, prolonged ventilation/parenteral nutrition, necrotizing enterocolitis, and male sex were risk factors for white matter injury.
- Fetal growth restriction, extended ventilation, and parenteral nutrition were independently linked to lower FA.
- Cumulative risk factor exposure correlated with reduced white matter FA, which predicted neurodevelopmental outcomes.
Conclusions:
- Multiple perinatal risk factors are independently associated with diffuse white matter injury in preterm infants.
- Cumulative exposure to these factors worsens dMRI-defined white matter injury.
- Findings support the multiple hit hypothesis for preterm white matter injury.
Background:
Preterm 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).
Methods:
We 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.
Results:
Identified 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.
Conclusion:
This 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.
