Mild White Matter Changes in Un-Medicated Obsessive-Compulsive Disorder Patients and Their Unaffected Siblings

Abstract

Objective: Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disorder with moderate genetic influences and white matter abnormalities in frontal-striatal and limbic regions. Inconsistencies in reported white matter results from diffusion tensor imaging (DTI) studies can be explained, at least partly, by medication use and between-group differences in disease profile and stage. We used a family design aiming to establish whether white matter abnormalities, if present in un-medicated OCD patients, also exist in their unaffected siblings.Method: Forty-four OCD patients, un-medicated for at least the past 4 weeks, 15 of their unaffected siblings, and 37 healthy controls (HC) underwent DTI using a 3-Tesla MRI-scanner. Data analysis was done using tract-based spatial statistics (TBSS). Fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD) values were compared within seven skeletonised regions of interest (ROIs), i.e., corpus callosum, bilateral cingulum bundle, bilateral inferior longitudinal fasciculus/ frontal-occipital fasciculus (ILF/FOF) and bilateral superior longitudinal fasciculus (SLF).Results: Un-medicated OCD patients, compared with HC, had significantly lower FA in the left cingulum bundle. FA was trend-significantly lower in all other ROIs, except for the corpus callosum. Significant three-group differences in FA (and in RD at trend-significant level) were observed in the left cingulum bundle, with the unaffected siblings representing an intermediate group between OCD patients and HC.Conclusions: OCD patients showed lower FA in the left cingulum bundle, partly driven by trend-significantly higher values in RD. Since the unaffected siblings were found to be an intermediate group between OCD patients and HC, this white matter alteration may be considered an endophenotype for OCD.

White matter microstructure and connectivity in patients with obsessive‐compulsive disorder and their unaffected siblings

“…The sibling group showed intermediate FA and RD values between OCD and HC groups in the cingulum and forceps minor which are spatially in line with previous studies reporting intermediate FA values in the medial frontal regions 22 and intermediate FA and RD values in cingulum 12 in unaffected siblings of OCD patients. Furthermore, the sibling group also showed intermediate streamline numbers in all edges with significantly lower streamline counts in patients with OCD compared to HCs.…”

“…Consistent with previous studies, 12,14,19,20 FA differences were mainly due to increases in RD values in both OCD and sibling groups suggesting myelin‐related WM alterations. In line with this hypothesis, a recent longitudinal study in healthy adolescents and young adults reported increased compulsivity is tied to slower myelination in fronto‐striatal regions 72 .…”

“…The second study used a whole‐brain approach and found reduced FA in the arcuate fibers near the superior parietal lobule and anterior limb of internal capsule in siblings compared to controls 23 . A subsequent region‐of‐interest (ROI) analysis revealed lower FA and increased RD in the left cingulum bundle in siblings compared to controls 12 . While these studies provide the first evidence of WM alterations in relatives of individuals with OCD, the voxel‐wise or brain regional approach can limit the extent to which the findings can be interpreted in terms of whole‐brain networks.…”

“…To differentiate myelin‐related pathology from axonal damage, the component measures from which FA is derived can be studied: an increase in radial diffusivity (RD) may signify increased space between fibers suggesting demyelination or dysmyelination, 5 whereas a decrease in axial diffusivity (AD) may suggest axonal injury 6 . Although results are mixed, most previous dMRI studies have reported lower FA in patients with OCD as compared to healthy controls, most consistently in the cingulum bundle 7‐13 and corpus callosum 8,10,11,14‐18 . A small number of previous dMRI studies have also investigated RD and AD in OCD patients, which report higher RD values in the forceps major, 19 corpus callosum 14,20 and in widespread WM, 21 as well as no between‐group difference in AD, suggesting that decreased myelination rather than axonal degeneration may underlie WM pathology in OCD.…”

Altered frontal interhemispheric and fronto‐limbic structural connectivity in unmedicated adults with obsessive‐compulsive disorder

“…Alternatively, that subgroup analysis was insufficiently powered to detect group differences. Findings from previous TBSS studies of unmedicated OCD participants are discrepant, with one showing reduced FA in anterior corpus callosum (Nakamae et al, 2011) (i.e., forceps minor) and the other showing reduced FA in the left cingulum (Fan et al, 2016). Over half of the OCD participants included in the latter study also met criteria for one or more comorbid current axis 1 disorder, suggesting that further study of white matter microstructure in a larger sample of unmedicated OCD participants free of psychiatric comorbidities is warranted.…”