White matter microstructure correlates of general and specific second-order factors of psychopathology

Abstract

Increasing data indicate that prevalent forms of psychopathology can be organized into second-order dimensions based on their correlations, including a general factor of psychopathology that explains the common variance among all disorders and specific second-order externalizing and internalizing factors. Nevertheless, most existing studies on the neural correlates of psychopathology employ case-control designs that treat diagnoses as independent categories, ignoring the highly correlated nature of psychopathology. Thus, for instance, although perturbations in white matter microstructure have been identified across a range of mental disorders, nearly all such studies used case-control designs, leaving it unclear whether observed relations reflect disorder-specific characteristics or transdiagnostic associations. Using a representative sample of 410 young adult twins oversampled for psychopathology risk, we tested the hypothesis that some previously observed relations between white matter microstructure properties in major tracts and specific disorders are related to second-order factors of psychopathology. We examined fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD). White matter correlates of all second-order factors were identified after controlling for multiple statistical tests, including the general factor (FA in the body of the corpus callosum), specific internalizing (AD in the fornix), and specific externalizing (AD in the splenium of the corpus callosum, sagittal stratum, anterior corona radiata, and internal capsule). These findings suggest that some features of white matter within specific tracts may be transdiagnostically associated multiple forms of psychopathology through second-order factors of psychopathology rather with than individual mental disorders.

Longitudinal Associations Between White Matter Microstructure and Psychiatric Symptoms in Adolescence

“…Our findings partly contrast prior literature 3,16 . We propose several explanations for our results.…”

“…have not yet occurred or are less prominent in children at a given age. Cross-sectional studies have generally shown that higher psychiatric symptoms are associated with lower FA and higher MD [15][16][17] . However, our understanding of the longitudinal relation between neuro-and behavioral development is limited by a dearth of well-powered longitudinal studies with repeated measurements 18 and by the overlooking of how brain and behavior relate to each other over time.…”

White matter microstructure and the clinical risk for psychosis: A diffusion tensor imaging study of individuals with basic symptoms and at ultra-high risk

“…This may be an early marker of transdiagnostic relevance, as suggested by a review indicating that WM pathology, especially that affecting the corpus callosum, is shared across several neuropsychiatric disorders ( Sagarwala and Nasrallah, 2020 ); this conclusion was also supported by a recent mega-analysis ( Koshiyama et al, 2020 ), making the corpus callosum a promising structural candidate underlying a high-order psychopathology “ p ” factor ( Caspi and Moffitt, 2018 ). Another study using a latent factor approach further demonstrated that the properties of the corpus callosum are related to general psychopathology, while second-order factors are reflected in abnormalities of more specific WM tracts ( Hinton et al, 2019 ). Compromised WM integrity in the splenium may represent not only a biomarker, but also a therapeutic target.…”

Prenatal Depression Exposure Alters White Matter Integrity and Neurodevelopment in Early Childhood

“…We observed differences in FA, MD and RD in PDE compared to controls in this region, a difference in RD suggesting altered myelination. Given the importance of the sagittal stratum in terms of connections, alteration of white matter integrity in this tract bundle may have widespread implications for effective integration of numerous functions including emotional processing, regulation of mental distress, sensory and motor function (Hinton et al 2019;Juttukonda et al 2019;Patel et al 2018;Poletti et al 2020). One prior study in neonates found sex-by-symptom interaction effects for FA in the sagittal stratum for a composite of prenatal depression and anxiety (Dean et al 2018).…”