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The recent Coronavirus Disease 2019 (COVID-19) has affected all aspects of life around the world. Neuroimaging evidence suggests the novel coronavirus can attack the central nervous system (CNS), causing cerebro-vascular abnormalities in the brain. This can lead to focal changes in cerebral blood flow and metabolic oxygen consumption rate in the brain. However, the extent and spatial locations of brain alterations in COVID-19 survivors are largely unknown. In this study, we have assessed brain functional connectivity (FC) using resting-state functional MRI (RS-fMRI) in 38 (25 males) COVID patients two weeks after hospital discharge, when PCR negative and 31 (24 males) healthy subjects. FC was estimated using independent component analysis (ICA) and dual regression. The COVID group demonstrated significantly enhanced FC in regions from the Occipital and Parietal Lobes, comparing to the HC group. On the other hand, the COVID group exhibited significantly reduced FC in several vermal layers of the cerebellum. More importantly, we noticed negative correlation of FC with self-reported fatigue within regions from the Parietal lobe, which are known to be associated with fatigue. Keywords: COVID, Functional Connectivity, ICA, Fatigue, RS-fMRI

Functional connectivity (FC) and resting-state network (RSN) analyses using functional magnetic resonance imaging (fMRI) have evolved into a growing field of research and have provided useful biomarkers for the assessment of brain function in neurological disorders. However, the underlying mechanisms of the blood oxygen level-dependant (BOLD) signal are not fully resolved due to its inherent complexity. In contrast, [ 18 F]fluorodeoxyglucose positron emission tomography ([ 18 F]FDG-PET) has been shown to provide a more direct measure of local synaptic activity and may have additional value for the readout and interpretation of brain connectivity. We performed an RSN analysis from simultaneously acquired PET/fMRI data on a single-subject level to directly compare fMRI and [ 18 F]FDG-PET-derived networks during the resting state. Simultaneous [ 18 F]FDG-PET/fMRI scans were performed in 30 rats. Pairwise correlation analysis, as well as independent component analysis (ICA), were used to compare the readouts of both methods. We identified three RSNs with a high degree of similarity between PET and fMRI-derived readouts: the default-mode-like network (DMN), the basal ganglia network and the cerebellar-midbrain network. Overall, [ 18 F]FDG connectivity indicated increased integration between different, often distant, brain areas compared to the results indicated by the more segregated fMRI-derived FC. Additionally, several networks exclusive to either modality were observed using ICA. These networks included mainly bilateral cortical networks of a limited spatial extent for fMRI and more spatially widespread networks for [ 18 F]FDG-PET, often involving several subcortical areas. This is the first study using simultaneous PET/fMRI to report RSNs subject-wise from dynamic [ 18 F]FDG tracer delivery and BOLD fluctuations with both independent component analysis (ICA) and pairwise correlation analysis in small animals. Our findings support previous studies, which show a close link between local synaptic glucose consumption and BOLD-fMRI-derived FC. However, several brain regions were exclusively attributed to either [ 18 F]FDG or BOLD-derived networks underlining the complementarity of this hybrid imaging approach, which may contribute to the understanding of brain functional organization and could be of interest for future clinical applications.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused a global pandemic. Among several systemic abnormalities, little is known about the critical attack on the central nervous system (CNS). Several patient reports with multiple pathologies – ischemic strokes, mild infarcts, encephalitis, cerebro-vascular abnormalities, cerebral inflammation, and loss of consciousness, indicate CNS involvement. However, due to limited neuroimaging studies, conclusive group level effects are scarce in the literature and replication studies are necessary to verify if these effects persist in surviving acute-COVID patients. Furthermore, recent reports indicate fatigue is highly prevalent among slowly recovering patients. How early structural changes relate to fatigue need to be investigated. Our goal was to address this by scanning COVID subjects two weeks after hospital discharge. We hypothesized these surviving patients will demonstrate altered gray matter volume (GMV) when compared to healthy controls and further demonstrate correlation of GMV with fatigue. Voxel-based morphometry was applied to T1-weighted MRI images between 46 patients with COVID and 32 healthy controls. Significantly higher GMV in the Limbic System and Basal Ganglia regions were observed in surviving COVID-19 patients when compared to healthy controls. Moreover, within the patient group, there was a significant positive correlation between GMV and self-reported fatigue scores during work, within the ventral Basal Ganglia and Ventromedial Prefrontal Cortex regions. Therefore, our results align with both single case acute patient reports and current group level neuroimaging findings. Finally, we newly report a positive correlation of GMV with fatigue in COVID survivors.

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