Glial activation and metabolite contributions to 'brain fog' post-acute sequelae of COVID-19 (PASC)

Project summary The COVID-19 pandemic has left potentially millions of individuals with ongoing symptoms months after initial infection by SARS-CoV-2, a syndrome called post-acute sequalae of COVID-19, or PASC. A common and often-debilitating core symptom of PASC is colloquially known as "brain fog," which involves disruption in cognitive control or the ability to maintain focus and attention especially in the presence of distraction. Our project is based in the fact that the key cognitive control hub, the anterior midcingulate cortex (aMCC), is also uniquely sensitive to systemic inflammation, which several studies have reported in PASC. By using dual MR-PET neuroimaging during a cognitive control task, we will operationalize and objectively measure the brain fog symptom, and test the potential contribution of microglial activation and metabolite concentrations to this symptom. The multi-source interference task (MSIT) is a well-validated cognitive control task that reliably activates the aMCC when administered during fMRI. We will recruit 11 individuals with World Health Organization defined PASC who also fulfill at least one criterion from each cluster of the myalgic encephalomyelitis International Consensus Criteria, and 11 COVID-recovered healthy matched controls. All participants will complete the MSIT task during MRI-PET (magnetic resonance imaging - positron emission tomography) neuroimaging. Functional MRI will be conducted during performance of the MSIT task. We expect the fMRI blood oxygen level-dependent (BOLD) response to be larger and more intense in PASC than control aMCC. At an individual level, we will locate the voxel within aMCC that is most activated (peak voxel) during MSIT, and we will use this region of interest (ROI) to extract data from the other neuroimaging modalities acquired by the MR-PET scanner. Using the [11C]PBR28 radioligand, we expect to find increased microglial activation within the aMCC ROI in PASC versus controls. Furthermore, using a whole-brain magnetic resonance spectroscopy (MRS) sequence, we expect to find increased concentration of inflammation-linked chemical metabolites within that same ROI. By using these complimentary techniques, we will create an objective measure of brain fog, and will create a more detailed mechanistic understanding of its cause.