Mapping sex-specific neurodevelopmental alterations in neurite density and morphology in a rat genetic model of psychiatric illness

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ABSTRACT

Neurite orientation dispersion and density imaging (NODDI) is an emerging magnetic resonance (MR) diffusion weighted imaging (DWI) technique that permits non-invasive quantitative assessment of neurite density and morphology. NODDI has improved our ability to image neuronal microstructure over conventional techniques such as diffusion tensor imaging (DTI) and is particularly suited for studies of the developing brain as it can measure and characterize the dynamic changes occurring in dendrite cytoarchitecture that are critical to early brain development. Neurodevelopmental alterations to the diffusion tensor have been reported in psychiatric illness, but it remains unknown whether advanced DWI techniques such as NODDI are able to sensitively and specifically detect neurodevelopmental changes in brain microstructure beyond those provided by DTI. We show, in an extension of our previous work with a Disc1 sv2 rat genetic model of psychiatric illness, the enhanced sensitivity and specificity of NODDI to identify neurodevelopmental and sex-specific changes in brain microstructure that are otherwise difficult to observe with DTI and further corroborate observed changes in brain microstructure to differences in sex-specific systems-level animal behavior. Together, these findings inform the potential application and clinical translational utility of NODDI in studies of brain microstructure in psychiatric illness throughout neurodevelopment and further, the ability of advanced diffusion weighted imaging methods such as NODDI to examine the role of biological sex and its influence on brain microstructure in psychiatric illness.

SIGNIFICANCE STATEMENT This research presents the first demonstration of the ability of NODDI multicompartment diffusion imaging to uncover both neurodevelopmental and sex-specific alterations in brain microstructure in psychiatric illness. We show, in a genetic Disc1 sv2 rat model, sex-specific neurodevelopmental patterns of neural microstructural change with NODDI and corresponding evidence of sex differences in behavioral endophenotypes of anxiety, cognition, and general activity. Together, our results support the potential impact and translational utility of NODDI to identify salient neurodevelopmental and sex-specific changes in brain microstructure in psychiatric illness beyond traditional morphometric and diffusion tensor approaches currently employed.

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