Higher limbic and basal ganglia volumes in surviving COVID-negative patients and the relations to fatigue

Abstract

Background: Among systemic abnormalities caused by the novel coronavirus, little is known about the critical attack on the central nervous system (CNS). Few studies have shown cerebrovascular pathologies that indicate CNS involvement in acute patients. However, replication studies are necessary to verify if these effects persist in COVID-19 survivors more conclusively. Furthermore, recent studies indicate fatigue is highly prevalent among 'long-COVID' patients. How morphometry in each group relate to work-related fatigue need to be investigated.

Method: COVID survivors were MRI scanned two weeks after hospital discharge. We hypothesized, these survivors will demonstrate altered gray matter volume (GMV) and experience higher fatigue levels when compared to healthy controls, leading to stronger correlation of GMV with fatigue. Voxel-based morphometry was performed on T1-weighted MRI images between 46 survivors and 30 controls. Unpaired two-sample t-test and multiple linear regression were performed to observe group differences and correlation of fatigue with GMV.

Results: The COVID group experienced significantly higher fatigue levels and GMV of this group was significantly higher within the Limbic System and Basal Ganglia when compared to healthy controls. Moreover, while a significant positive correlation was observed across the whole group between GMV and self-reported fatigue, COVID subjects showed stronger effects within the Posterior Cingulate, Precuneus and Superior Parietal Lobule.

Conclusion: Brain regions with GMV alterations in our analysis align with both single case acute patient reports and current group level neuroimaging findings. We also newly report a stronger positive correlation of GMV with fatigue among COVID survivors within brain regions associated with fatigue, indicating a link between structural abnormality and brain function in this cohort.

Keywords: Basal ganglia; COVID-19; Fatigue; Limbic; VBM.

Fig. 1

VBM demonstrating significantly higher gray matter volume in COVID-19 subjects compared to HC. Two significant clusters were observed, comprising of several deep brain structures: Right – Hc, Am, Ent, PHG, VDC and Left – Hc, VDC, Pu, Pd, Am, PP, AIns, PIns. The clusters surviving FWE correction, consisted of 1000 and 1968 voxels, with exact corrected p-values of p = 0.017 and 0.023 at MNI coordinates: [34 -4 -24] and [-28 -16 -10], respectively. The orthogonal slices on the left show the difference maps along with a cut-to-depth volume rendered image to better visualize the spatial extent of the anatomical locations comprising the cluster. The multi-slice image on the right shows finer slices (Z-slice gap≥5) to highlight and assess the structural regions with significantly higher GMV. The cluster extends from inferior to superior Z-slices spanning from Hc to AIns, Pu, and PIns regions, respectively. Some of the relevant brain regions with significant differences have been pointed within the figure with purple arrows. The colorbar represents t-score values from the group level contrast. Keys: Hc = Hippocampus, Am = Amygdala, Ent = Entorhinal Area, PHG = Parahippocampal Gyrus, VDC = Ventral Diencephalon, Pu = Putamen, Pd = Pallidum, PP = Planum Polare, AIns = Anterior Insula and PIns = Posterior Insula. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2

VBM demonstrating significantly positive correlation with fatigue scores across the whole group. The significant cluster (top-left) consisting of 3547 voxels (k_E= 3547), comprised of: Left – PCC, PRC, SPL and Right - PRC with peak t-score of 4.74 and exact corrected p-value of p_FWE = 0.019 at MNI coordinates: [-16 -54 48]. The axial slices (bottom) show the spatial extent of the same cluster over finer slices. The scatter plot (top-right) with the linear regression line shows significant positive correlation of GMV with self-reported fatigue score across the whole group (ρ = 0.34, p = 0.016, r²= 0.11). Please note, the ρ represents Spearman's rank-order correlation coefficient. The light pink colored dots represent the COVID subjects, and the cyan dots represent the HCs. The COVID group clearly demonstrates higher effects than the HC group. Please note, the GMV in the x-axis represents the residuals plus the mean GMV of the cluster across subjects added back after linear regression. Keys: PCC = Posterior Cingulate Cortex, PRC = Precuneus, SPL = Superior Parietal Lobule. The linear plot (blue) represents the least squares regression line (best fit), and the shaded gray area represents the 95% confidence interval. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)