White Matter Microstructure in Pediatric Bipolar Disorder and Disruptive Mood Dysregulation Disorder

Abstract

Objective: Disruptive mood dysregulation disorder (DMDD) codifies severe, chronic irritability. Youths with bipolar disorder (BD) also present with irritability, but with an episodic course. To date, it is not clear whether aberrant white matter microstructure-a well-replicated finding in BD-can be observed in DMDD and relates to symptoms of irritability.

Method: We acquired diffusion tensor imaging data from 118 participants (BD = 36, DMDD = 44, healthy volunteers (HV = 38). Images of fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) were processed with tract-based spatial statistics controlling for age and sex. The data were also used to train Gaussian process classifiers to predict diagnostic group.

Results: In BD vs DMDD, FA in the corticospinal tract was reduced. In DMDD vs HV, reductions in FA and AD were confined to the anterior corpus callosum. In BD vs HV, widespread reductions in FA and increased RD were observed. FA in the anterior corpus callosum and corticospinal tract was negatively associated with irritability. The Gaussian process classifier could not discriminate between BD and DMDD, but achieved 68% accuracy in predicting DMDD vs HV and 75% accuracy in predicting BD vs HV.

Conclusion: Aberrant white matter microstructure was associated with both categorical diagnosis and the dimension of irritability. Alterations in DMDD were regionally discrete and related to reduced AD. In BD, we observed widespread increases in RD, supporting the hypothesis of altered myelination in BD. These findings will contribute to the pathophysiological understanding of DMDD and its differentiation from BD.

Clinical trial registration information: Studies of Brain Function and Course of Illness in Pediatric Bipolar Disorder; https://ichgcp.net/clinical-trials-registry/NCT00025935" title="See in ClinicalTrials.gov">NCT00025935; Child & Adolescent Bipolar Disorder Brain Imaging and Treatment Study; https://ichgcp.net/clinical-trials-registry/NCT00006177" title="See in ClinicalTrials.gov">NCT00006177.

Keywords: diffusion tensor imaging; disruptive mood dysregulation disorder; machine learning; pediatric bipolar disorder; tract-based spatial statistics.

Conflict of interest statement

Disclosure: Drs. Linke, Adleman, Sarlls, Towbin, Pine, Leibenluft, Brotman, Mr. Ross, and Mss. Perlstein and Frank have reported no biomedical financial interests or potential conflicts of interest.

Published by Elsevier Inc.

Figures

FIGURE 1. Visualization of Tract-Based Spatial Statistics (TBSS) Analysis

Note:Mean maps of fractional anisotropy (grayscale) and mean fractional anisotropy skeleton (grayscale). Yellow colored voxels represent results of the omnibus F test. (A) Red-colored voxels signify decreased fractional anisotropy (pFWE-corrected < 0.05). (B) Green-colored voxels show areas of reduced axial diffusivity. (C) Blue-colored voxels signify increased radial diffusivity (pFWE-corrected < 0.05). We used the tbss-fill script to improve visualization of the results. NS = not significant. Please note color figures are available online.

FIGURE 2. Associations Between Irritability and Fractional Anisotropy (FA)

Note: (A) Association between irritability and FA in the cluster in the anterior corpus callosum, where we observed FA differences between DMDD and HV as well as BD and HV. (B) Association between irritability and FA in the cluster in the corticospinal tract, where BD showed lower FA compared to HV and DMDD. (C) Association between irritability and FA in the cluster in the posterior corpus callosum, where BD showed lower FA compared to HV and DMDD. ARI = Affective Reactivity Index; BD = bipolar disorder participants; DMDD = disruptive mood dysregulation disorder participants; HV = healthy volunteers. Please note color figures are available online.

FIGURE 3. Depiction of the Predictions Across all Folds, Receiver Operating Characteristic (ROC) Curves, and Model Weights Overlaid on the Mean Fractional Anisotropy (FA) Map

Note: Depiction of the predictions across all folds, receiver operator curves (ROC) curves, and model weights overlaid on the mean FA map for the classification of the following: (A) BD vs HV based on information about FA; (B) DMDD vs HV based on information about AD; and (C) BD vs DMDD based on information about AD obtained with the Gaussian process classifier algorithm, although this result was not significant when correcting for multiple comparisons. Color scale indicates the importance of the voxel location for the classification. High values in regions with positive weights (red) increase the likelihood of being classified as belonging to the group marked with the red circle in the prediction values graph, whereas high values in regions with negative weights (blue) will more likely result in being classified as belonging to the other group. AD = axial diffusivity; BD = bipolar disorder participants; DMDD = disruptive mood dysregulation disorder participants; FA = fractional anisotropy; HV = healthy volunteers. Please note color figures are available online.