Quantitative susceptibility mapping at 7 Tesla in COVID-19: mechanistic and outcome associations

Post mortem studies have shown that patients dying from severe SARS-CoV-2 infection frequently have pathological changes in their central nervous system, particularly in the brainstem. Many of these changes are proposed to result from para-infectious and/or post-infection immune responses. Clinical symptoms such as fatigue, breathlessness, and chest pain are frequently reported in post-hospitalized COVID-19 patients. We propose that these symptoms are in part due to damage to key neuromodulatory brainstem nuclei. While brainstem involvement has been demonstrated in the acute phase of the illness, the evidence of long-term brainstem change on magnetic resonance imaging (MRI) is inconclusive. We therefore used ultra-high field (7T) quantitative susceptibility mapping (QSM) to test the hypothesis that brainstem abnormalities persist in post-COVID patients and that these are associated with persistence of key symptoms. We used 7T QSM data from 30 patients, scanned 93-548 days after hospital admission for COVID-19 and compared them to 51 age-matched controls without prior history of COVID-19 infection. We correlated the patients' QSM signals with disease severity (duration of hospital admission and COVID-19 severity scale), inflammatory response during the acute illness (C-reactive protein, D-Dimer and platelet levels), functional recovery (modified Rankin scale; mRS), depression (PHQ-9) and anxiety (GAD-7). In COVID-19 survivors the MR susceptibility increased in the medulla, pons and midbrain regions of the brainstem. Specifically, there was increased susceptibility in the inferior medullary reticular formation and the raphe pallidus and obscurus. In these regions, patients with higher tissue susceptibility had worse acute disease severity, higher acute inflammatory markers, and significantly worse functional recovery. Using non-invasive ultra-high field 7T MRI, we show evidence of brainstem pathophysiological changes associated with inflammatory processes in post-hospitalized COVID-19 survivors. This study contributes to understanding the mechanisms of long-term effects of COVID-19 and recovery. ### Competing Interest Statement Dr. Pattinson is named as co-inventor on a provisional U.K. patent application titled "Use of cerebral nitric oxide donors in the assessment of the extent of brain dysfunction following injury". Dr Pattinson is named as co-inventors on a provisional U.K. patent titled "Discordant sensory stimulus in VR based exercise" UK Patent office application: 2204698.1 filing date 31/3/2022. ### Funding Statement This work was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. JBR was supported by the Wellcome Trust (103838; 220258) and Medical Research Council (M C\_UU\_00030/14). VFJN was supported by an Academy of Medical Sciences / The Health Foundation Clinician Scientist Fellowship. ETB was supported by an NIHR Senior Investigator award. BR, MC, SN are supported by NIHR Oxford BRC and BHF Oxford CRE. WTC was supported by funding from Wellcome Trust [225924/Z/22/Z]. CTR was supported by funding from Wellcome Trust [098436/Z/12/B]. For the purpose of open access, the authors have applied a CC-BY public copyright licence to any Author Accepted Manuscript version arising from this submission. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the following ethics committees: Cambridgeshire Research Ethics Committee HBREC.2016.13.am3, East of England Research Ethics Committee 17/EE/0025 , Norfolk Research Ethics Committee EE/0395, and North West Preston Research Ethics Committee 20/NW/0235. All participants provided informed consent in accordance with the Declaration of Helsinki. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes We can provide average QSM χ extracted values from the brainstem and subregions upon reasonable request.