Fiber-Specific Measures of White Matter Microstructure and Macrostructure Are Associated With Internalizing and Externalizing Symptoms in Children Born Very Preterm and Full-term

Courtney P. Gilchrist, Claire E. Kelly, Angela Cumberland, Thijs Dhollander, Karli Treyvaud, Katherine Lee, Jeanie L.Y. Cheong, Lex W. Doyle, Terrie E. Inder, Deanne K. Thompson, Mary Tolcos, Peter J. Anderson

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5 Citations (Scopus)


Background: Tensor-based investigations suggest that delayed or disrupted white matter development may relate to adverse behavioral outcomes in individuals born very preterm (VP); however, metrics derived from such models lack specificity. Here, we applied a fixel-based analysis framework to examine white matter microstructural and macrostructural correlates of concurrent internalizing and externalizing problems in VP and full-term (FT) children at 7 and 13 years. Methods: Diffusion imaging data were collected in a longitudinal cohort of VP and FT individuals (130 VP and 29 FT at 7 years, 125 VP and 44 FT at 13 years). Fixel-based measures of fiber density, fiber-bundle cross-section, and fiber density and cross-section were extracted from 21 white matter tracts previously implicated in psychopathology. Internalizing and externalizing symptoms were assessed using the Strengths and Difficulties Questionnaire parent report at 7 and 13 years. Results: At age 7 years, widespread reductions in fiber-bundle cross-section and fiber density and cross-section and tract-specific reductions in fiber density were related to more internalizing and externalizing symptoms irrespective of birth group. At age 13 years, fixel-based measures were not related to internalizing symptoms, while tract-specific reductions in fiber density, fiber-bundle cross-section, and fiber density and cross-section measures were related to more externalizing symptoms in the FT group only. Conclusions: Age-specific neurobiological markers of internalizing and externalizing problems identified in this study extend previous tensor-based findings to inform pathophysiological models of behavior problems and provide the foundation for investigations into novel preventative and therapeutic interventions to mitigate risk in VP and other high-risk infant populations.

Original languageEnglish
Pages (from-to)575-585
Number of pages11
JournalBiological Psychiatry
Issue number6
Publication statusPublished - 15 Mar 2023


  • Adolescence
  • Childhood
  • Fixel-based analysis
  • Magnetic resonance imaging
  • Premature birth
  • Psychopathology

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