Long-term follow-up of dynamic brain changes in patients recovered from COVID-19 without neurological manifestations

Abstract

BACKGROUNDAfter the initial surge in COVID-19 cases, large numbers of patients were discharged from a hospital without assessment of recovery. Now, an increasing number of patients report postacute neurological sequelae, known as "long COVID" - even those without specific neurological manifestations in the acute phase.METHODSDynamic brain changes are crucial for a better understanding and early prevention of "long COVID." Here, we explored the cross-sectional and longitudinal consequences of COVID-19 on the brain in 34 discharged patients without neurological manifestations. Gray matter morphology, cerebral blood flow (CBF), and volumes of white matter tracts were investigated using advanced magnetic resonance imaging techniques to explore dynamic brain changes from 3 to 10 months after discharge.RESULTSOverall, the differences of cortical thickness were dynamic and finally returned to the baseline. For cortical CBF, hypoperfusion in severe cases observed at 3 months tended to recover at 10 months. Subcortical nuclei and white matter differences between groups and within subjects showed various trends, including recoverable and long-term unrecovered differences. After a 10-month recovery period, a reduced volume of nuclei in severe cases was still more extensive and profound than that in mild cases.CONCLUSIONOur study provides objective neuroimaging evidence for the coexistence of recoverable and long-term unrecovered changes in 10-month effects of COVID-19 on the brain. The remaining potential abnormalities still deserve public attention, which is critically important for a better understanding of "long COVID" and early clinical guidance toward complete recovery.FUNDINGNational Natural Science Foundation of China.

Keywords: COVID-19; Neuroimaging; Neuroscience.

Figure 1. Flow diagram of the experimental design.

Five data sets were acquired in follow-up studies. Green color, relative data have been published in our former work (14); blue color, research content focused in this study. BRAVO, brain volume; DTI, diffusion tensor imaging; MG1, mild group at 3 months after discharge; MG2, mild group at 10 months after discharge; NC, normal control; pcASL, pseudocontinuous arterial spin labeling; SG1, severe group at 3 months after discharge; SG2, severe group at 10 months after discharge.

Figure 2. Cortical thickness analyses.

(A–C) There were only significant differences in paired comparisons. L, left; MG1, mild group at 3 months after discharge; MG2, mild group at 10 months after discharge; R, right; SG1, severe group at 3 months after discharge; SG2, severe group at 10 months after discharge.

Figure 3. Cortical CBF analyses.

Compared with NC, SG2 showed extensive lower CBF values in the brain. CBF, cerebral blood flow; L, left; NC, normal control; R, right; SG2, severe group at 10 months after discharge.

Figure 4. Subcortical nuclei with significant volumetric differences between groups.

(A–C) Significant (P < 0.05) volumetric differences in subcortical nuclei were found in MG paired, SG2-MG2, and SG2-NC comparisons. L, left; MG1, mild group at 3 months after discharge; MG2, mild group at 10 months after discharge; NC, normal control; R, right; SG2, severe group at 10 months after discharge.

Figure 5. Subcortical nuclei with significant CBF differences between groups.

(A and B) Both MG2 and SG2 showed significantly reduced CBF than NC in many subcortical nuclei. CBF, cerebral blood flow; L, left; MG2, mild group at 10 months after discharge; NC, normal control; R, right; SG2, severe group at 10 months after discharge.

Figure 6. White matter tracts with significant volumetric differences in paired comparisons.

(A and B) There were significant volumetric differences in tracts between the different recovered periods of MG and SG. AR, acoustic radiation; ATR, anterior thalamic radiation; CST, corticospinal tract; FX, fornix; L, left; MG1, mild group at 3 months after discharge; MG2, mild group at 10 months after discharge; R, right; SG1, severe group at 3 months after discharge; SG2, severe group at 10 months after discharge; SLF1, superior longitudinal fasciculus I; STR, superior thalamic radiation; VOF, vertical occipital fasciculus.

Figure 7. White matter tracts with significant volumetric differences in patients compared with NC.

(A and B) Both MG2 and SG2 showed significantly reduced volumes compared with NC in many white matter tracts. AR, acoustic radiation; CST, corticospinal tract; FAT, frontal aslant tract; FMA, forceps major; FMI, forceps minor; ILF, inferior longitudinal fasciculus; L, left; MDLF, middle longitudinal fasciculus; MG2, mild group at 10 months after discharge; NC, normal control; R, right; SG2, severe group at 10 months after discharge; VOF, vertical occipital fasciculus.