Brainstem neurochemical profiles after hospitalisation for COVID-19: a 7T MR spectroscopy study

Carina Graf¹Betty Raman²Anne Eileen Manktelow³Doris A Chatfield¹William Clarke⁴Catarina Rua^1,5,6Virginia Newcombe^1,7Victoria Lupson¹Stephen Sawcer⁸Joanne Outtrim⁷Karen D Ersche^10,9Lin Qiu¹¹Martyn Ezra¹¹Rory McDonald¹¹Stuart Clare¹¹Mark Philip Cassar²Stefan Neubauer²Edward Bullmore⁹David Krishna Menon⁷James Rowe^12,13,8Kyle Pattinson¹¹Chris Rodgers^1*

• ¹Wolfson Brain Imaging Centre, Department of Clinical Neuroscience, School of Clinical Medicine, University of Cambridge, Cambridge, England, United Kingdom
• ²Division of Cardiovascular Medicine, Radcliffe Department of Medicine, Medical Sciences Division, University of Oxford, Oxford, England, United Kingdom
• ³Division of Anaesthesia, Addenbrooke's Hospital, Cambridge University Hospitals, Cambridge, United Kingdom
• ⁴Wellcome Centre For Integrative Neuroimaging, Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, Oxford, England, United Kingdom
• ⁵Invicro LLC, REALM IDx, Inc, Burlington Danes Building, Imperial College London, Hammersmith Hospital, London, United Kingdom
• ⁶Cambridge Centre for Parkinson-plus, University of Cambridge, Cambridge, United Kingdom
• ⁷Department of Medicine, School of Clinical Medicine, University of Cambridge, Cambridge, England, United Kingdom
• ⁸Department of Clinical Neuroscience, School of Clinical Medicine, University of Cambridge, Cambridge, England, United Kingdom
• ⁹Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Cambridge, England, United Kingdom
• ¹⁰Department of Addictive Behaviour and Addiction Medicine, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Baden-Württemberg, Germany
• ¹¹Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, Oxford, England, United Kingdom
• ¹²Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
• ¹³MRC Cognition and Brain Sciences Unit, School of Clinical Medicine, University of Cambridge, Cambridge, England, United Kingdom

BACKGROUND Somatic, cognitive, and mental health issues have been identified in three-quarters of people five months after hospitalization for severe acute SARS-CoV-2 (COVID-19) infection. The underlying neuroanatomical basis of these symptoms remains unclear, but recent studies suggest a role for altered brainstem physiology. We aimed to test the hypothesis that brainstem neurochemical profiles differed in patients who had been hospitalised for COVID-19 compared to matched controls using 7T MR spectroscopy (MRS). METHODS This prospective case-control study recruited 34 individuals who were hospitalized for COVID-19 and 15 healthy controls with no history of COVID-19 infection from two major UK hospitals before vaccines were available. Participants underwent 7T sLASER 1H-MRS at the ponto-medullary junction. Water referenced metabolite concentrations were compared between patients and controls, and correlated with infection severity, as measured by maximum C-reactive protein (CRPmax) assay during in-patient admission. Linear mixed modelling was used with 0.05 significance level. RESULTS Spectral quality was high/acceptable in 44/49 participants according to MRS Consensus criteria. The magnitude of inflammation during patient admission (i.e. CRPmax) correlated positively with myo-inositol concentration (β=0.005, p=0.035) as did patient-reported symptoms (β=-0.564, p=0.023). However, metabolite concentrations were not significantly different between patients and controls. CONCLUSIONS We show feasibility to assess brainstem neurochemical profiles by 7T 1H-MRS in a multi-centre study. Technical limitations of one site’s 7T MRI led to variable repetition times, which limited our statistic power and should be avoided in future studies. Our findings suggest a need for further investigation of the role of neuroinflammation in post-acute COVID-19.