The most common neuroradiological changes described in hospitalized patients severely affected by the severe acute respiratory syndrome coronavirus (SARS-CoV-2) are cerebral microhemorrhages, encephalopathy, and white matter hyperintensities. Previous autopsy studies reported brainstem involvement with tissue neurodegeneration and inflammatory responses. In this study, the authors from the United Kingdom used a more advanced magnetic resonance imaging (MRI) technique, quantitative susceptibility mapping (QSM), to investigate abnormalities in the brainstem subregions in COVID survivors several months after acute COVID-19 hospitalization. They also used a voxel-by-voxel approach to localize the brainstem clusters of atrophy and determine whether brainstem QSM abnormalities correlate with clinical measures, laboratory results, and recovery.
QSM effectively detects cerebral microbleeds, increased iron deposition in the basal ganglia and midbrain, and chronic inflammation in multiple sclerosis. Since high-resolution, ultra-high field (≥7 T) QSM detects microstructural alterations with greater sensitivity, it could identify more subtle abnormalities and neuroanatomical changes after COVID infection. In their preliminary analysis, the same group of researchers showed that brain stem QSM was abnormal in post-hospitalized COVID survivors. They hypothesized that a brainstem insult caused by COVID-19 impairs autonomic function and contributes to persistent clinical symptoms.
It was suggested that brain stem abnormalities are involved in the pathophysiological mechanism of long COVID or post-acute COVID syndrome (PACS). A recent resting-state functional magnetic resonance imaging (fMRI) study found changes in the functional connectome of the brainstem, limbic system, olfactory system, thalamus, and cerebellum in participants with long COVID syndrome seven months after acute COVID-19. https://discovermednews.com/changes-in-brain-functional-connectome-in-post-covid-syndrome/  In addition, a PET study with a novel radiopharmaceutical agent [18F]F-AraG, showing elevated T-cell activation, demonstrated that vaccinated COVID convalescents, including those with and without long COVID symptoms, had higher [18F]F-AraG uptake in the brainstem (pons), thoracic spinal cord, cauda equina, lumbar and iliac crest, bone marrow, and many other anatomical regions than pre-pandemic controls. https://discovermednews.com/elevated-t-cell-activation-vaccinated-covid-convalescents-2-years-after-infection/
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Brainstem
About the study
In this study, the researchers used 7 T QSM to investigate abnormalities in the brainstem subregions, including midbrain, pons, medulla, and superior cerebellar peduncle (SCP), defined a priori as regions of interest (ROIs). The study enrolled post-hospitalization COVID patients and healthy controls. Inclusion criteria for COVID patients were: evidence of COVID-19 infection confirmed by polymerase chain reaction (PCR) of respiratory samples for SARS-CoV-2, no pre-COVID history of neurological or psychiatric disorders, and no contradictions to 7 T MRI. The healthy controls consisted of individuals scanned before the COVID-19 pandemic and those scanned during the pandemic, who were asymptomatic and had no history of positive PCR for SARS-CoV-2.
Laboratory analysis included peak C-reactive protein (CRP) levels, D-dimer levels, and the lowest platelet count during hospital stay. At follow-up, functional recovery was assessed using the modified Rankin Scale, and mental health was assessed using the anxiety (the Generalized Anxiety Disorder-7 ) and depression (the Patient Health Questionnaire-9) questionnaires.
Results
The study included 30 post-hospitalization COVID patients and 51 healthy controls. Age did not differ between the two groups (57 ± 12 years in the post-hospitalization COVID group and 53 ± 15 years in the control group), but there were more men in the control group than in the COVID group (34 vs. 18). The median time from hospital admission to the MRI scan in the post-hospitalization COVID group was 199 days (93–548 days).
The analysis focused on changes in the subregions of the brainstem (midbrain, pons, medulla, and SCP) and a voxel-by-voxel analysis to provide higher anatomical resolution. Voxel-wise analysis showed that the post-hospitalization COVID group had increased QSM abnormalities in the medulla, pons, and midbrain regions compared with healthy controls. Specifically, two significant clusters in the inferior medullary reticular formation nuclei, the raphe obscurus, and pallidus displayed significant magnetic resonance susceptibility abnormalities. The locations of these clusters partially overlap with brainstem regions associated with respiratory function and body homeostasis. Neurons in the medullar reticular formation are responsible for the central control of the respiratory cycle, and neurons in the raphe pallidus and obscurus are central chemoreceptors responsible for the full ventilatory response to hypercapnia.
Importantly, worse acute disease severity, the highest CRP levels, and worse functional recovery were found in patients with increased tissue abnormalities in the inferior medullary reticular formation nuclei, the raphe obscurus, and pallidus. In turn, patients with a more favorable functional outcome, shorter hospital stays, or lower ratings of acute disease severity had decreased susceptibility in the medullary clusters.
Conclusion
This study used non-invasive ultra-high-field 7 T MRI and demonstrated imaging evidence of pathophysiological changes and microstructural abnormalities in the brainstem of post-hospitalization COVID patients. Since several regions of the medulla oblongata, pons, and midbrain showed increased QSM abnormalities at a median of 6.5 months after hospitalization, these results suggest that these regions were still affected over months after acute infection with SARS-CoV-2. These changes were more evident in patients with longer hospital stays, higher COVID severity, more prominent inflammatory responses, and worse functional outcomes.Â
Because ultra-high-field 7 T QSM was sensitive to observed pathological changes in the brainstem that are not detected at standard clinical field strengths, the researchers suggested that this approach may be a valuable tool for investigating the long-term effects of COVID-19 on the brain.
This article was published in Brain.
Journal Reference
Rua C, Raman B, Rodgers CT et al. Quantitative susceptibility mapping at 7 T in COVID-19: brainstem effects and outcome associations, Brain, 2024: 00; 1–10. https://doi.org/10.1093/brain/awae215
