Crosstalk across barriers: choroid plexus volume affects white matter integrity in bipolar depression

Choroid plexus (CP) is a physiological barrier, producing cerebrospinal fluid (CSF), neurotrophic, and inflammatory factors. It’s involved in the neuro-immune axis, facilitating the interplay between central and peripheral inflammation, allowing trafficking of immune cells. Coherently, CP enlargement has been found in pathological conditions characterized by inflammatory signature, including mood disorders. More specifically, CP volume was correlated with the amounts of white matter (WM) lesions in multiple sclerosis, and it was correlated with central microglia activation in major depressive disorder, suggesting an increasing trafficking across parenchyma and periphery. It becomes crucial to understand the possible role of CP enlargement in WM integrity disruption in bipolar disorder (BD) in order to better elucidate ongoing immune mechanisms fostering the psychopathology. Methods: We studied 70 BD depressed patients and 50 age- and sex-matched healthy controls (HCs). We assessed differences in the left and right CP volume between the two groups in the context of the Generalized Linear Model (GLMZ) accounting for total intracranial volume (ICV). Diffusion Weighted Images (DWI) were acquired on a 3-Tesla scanner for the BD sample, while T1-weighted images for both samples. CP was segmented and volume was extracted using FreeSurfer 6.0. Diffusion Tensor images (DTI) correction, analysis, and tensor calculations were carried out with FSL 6.0. Next, using Tract-Based Spatial Statistics individual tract invariant skeletons for each participant were obtained. The skeletons were then fed into voxel-wise nonparametric permutation-based cross- subject statistics, as implemented in Randomise FSL’s tool. We tested for linear effects of left and right CP volume on Fractional Anisotropy (FA), Mean (MD), Axial (AD), and Radial Diffusivity (RD) across the WM skeleton with general linear models (GLM), accounting for the effects of age, sex, ICV, and lithium treatment. Threshold-free cluster enhancement (TFCE) was used. Results: Statistical analyses revealed that BD patients had significantly greater bilateral CP volume compared with HCs (Left: LR χ21⁄4 12.434, p<0.001; Right: LR χ21⁄4 8.232, p1⁄40.004). DTI regressions highlighted a significant negative association of both left and right CP volume with FA (Left: p1⁄40.004; Right: p1⁄40.002), and a positive one with AD (Left: p<0.001; Right: p<0.001), RD (Left: p1⁄40.004; Right: p1⁄40.004), and MD (Left: p1⁄40.006, Right: p1⁄40.005) in BD. Significant findings included a widespread pattern of WM tracts encompassing: corpus callosum, bilateral corona radiata (anterior, superior, and posterior), bilateral cingulate gyrus, bilateral superior longitudinal fasciculus, bilateral superior and inferior fronto-occipital fasciculi, fornix, bilateral anterior and posterior limbs of internal capsule, and bilateral posterior thalamic radiation. Conclusion: This is the first finding pointing out the effect of CP enlargement on WM alterations in patients with BD. A widespread pattern of negative association with FA associated with positive ones with RD, MD, and AD may indicate a general WM sufferance in condition of greater CP volume and immune system alterations. In particular, these results could clarify the role of immune system cross-talk between central and peripheral inflammation, supporting the hypothesis of a heightened trafficking of immune mediators that may underlie an inflammation-resolving mechanism in the central nervous system.