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

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.