Cellular and Extracellular White Matter Abnormalities in Obsessive-Compulsive Disorder: A Diffusion Magnetic Resonance Imaging Study

Abstract

Background: While previous studies have implicated white matter (WM) as a core pathology of obsessive-compulsive disorder (OCD), the underlying neurobiological processes remain elusive. This study used free-water (FW) imaging derived from diffusion magnetic resonance imaging to identify cellular and extracellular WM abnormalities in patients with OCD compared with control subjects. Next, we investigated the association between diffusion measures and clinical variables in patients.

Methods: We collected diffusion-weighted magnetic resonance imaging and clinical data from 83 patients with OCD (56 women/27 men, age 37.7 ± 10.6 years) and 52 control subjects (27 women/25 men, age 32.8 ± 11.5 years). Fractional anisotropy (FA), FA of cellular tissue, and extracellular FW maps were extracted and compared between patients and control subjects using tract-based spatial statistics and voxelwise comparison in FSL Randomise. Next, we correlated these WM measures with clinical variables (age of onset and symptom severity) and compared them between patients with and without comorbidities and patients with and without psychiatric medication.

Results: Patients with OCD demonstrated lower FA (43.4% of the WM skeleton), lower FA of cellular tissue (31% of the WM skeleton), and higher FW (22.5% of the WM skeleton) compared with control subjects. We did not observe significant correlations between diffusion measures and clinical variables. Comorbidities and medication status did not influence diffusion measures.

Conclusions: Our findings of widespread FA, FA of cellular tissue, and FW abnormalities suggest that OCD is associated with microstructural cellular and extracellular abnormalities beyond the corticostriatothalamocortical circuits. Future multimodal longitudinal studies are needed to understand better the influence of essential clinical variables across the illness trajectory.

Keywords: Diffusion MRI; Free-water imaging; Microstructure; Obsessive-compulsive disorder; Tract-based spatial statistics; White matter.

Figure 1:

Frequency of the most prevalent comorbidities in patients with Obsessive-Compulsive Disorder (OCD) More than 75% of all patients with OCD were diagnosed with at least one lifetime or current psychiatric comorbidity. The most common comorbidities were mood disorders, anxiety, and other Obsessive-Compulsive Spectrum disorder

Figure 2:

Voxel-wise group comparison between patients with Obsessive-Compulsive Disorder (OCD) and controls (Cs). Abbreviations: FA = fractional anisotropy, FAt = fractional anisotropy of cellular tissue, FW = free-water. Figure 2 displays the results from voxel-wise non-parametric permutation tests that we performed for the entire white matter skeleton in FSL’s Randomize. We tested data against a null distribution generated with 5000 permutations for each contrast using threshold-free cluster enhancement and family-wise error correction at a significance level of p < 0.05. Images are presented in the radiological convention, with 1 being the most significant. The white matter skeleton is displayed in green on top of an average of the registered FA images. Voxels that demonstrated significant group differences are thickened to increase visibility and are shown in (red to yellow) for FA (row A) and FAt (row B) and blue to dark blue for FW (row C).