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COVID-19 is associated with neurological complications including stroke, delirium and encephalitis. Furthermore, a post-viral syndrome dominated by neuropsychiatric symptoms is common, and is seemingly unrelated to COVID-19 severity. The true frequency and underlying mechanisms of neurological injury are unknown, but exaggerated host inflammatory responses appear to be a key driver of COVID-19 severity. We investigated the dynamics of, and relationship between, serum markers of brain injury [neurofilament light (NfL), glial fibrillary acidic protein (GFAP) and total tau] and markers of dysregulated host response (autoantibody production and cytokine profiles) in 175 patients admitted with COVID-19 and 45 patients with influenza. During hospitalization, sera from patients with COVID-19 demonstrated elevations of NfL and GFAP in a severity-dependent manner, with evidence of ongoing active brain injury at follow-up 4 months later. These biomarkers were associated with elevations of pro-inflammatory cytokines and the presence of autoantibodies to a large number of different antigens. Autoantibodies were commonly seen against lung surfactant proteins but also brain proteins such as myelin associated glycoprotein. Commensurate findings were seen in the influenza cohort. A distinct process characterized by elevation of serum total tau was seen in patients at follow-up, which appeared to be independent of initial disease severity and was not associated with dysregulated immune responses unlike NfL and GFAP. These results demonstrate that brain injury is a common consequence of both COVID-19 and influenza, and is therefore likely to be a feature of severe viral infection more broadly. The brain injury occurs in the context of dysregulation of both innate and adaptive immune responses, with no single pathogenic mechanism clearly responsible.

BACKGROUND: An improved understanding of the trajectory of recovery after mild traumatic brain injury is important to be able to understand individual patient outcomes, for longitudinal patient care and to aid the design of clinical trials. OBJECTIVE: To explore changes in health, well-being and cognition over the 2 years following mTBI using latent growth curve (LGC) modelling. METHODS: Sixty-one adults with mTBI presenting to a UK Major Trauma Centre completed comprehensive longitudinal assessment at up to five time points after injury: 2 weeks, 3 months, 6 months, 1 year and 2 years. RESULTS: Persisting problems were seen with neurological symptoms, cognitive issues and poor quality of life measures including 28% reporting incomplete recovery on the Glasgow Outcome Score Extended at 2 years. Harmful drinking, depression, psychological distress, disability, episodic memory and working memory did not improve significantly over the 2 years following injury. For other measures, including the Rivermead Post-Concussion Symptoms and Quality of Life after Brain Injury (QOLIBRI), LGC analysis revealed significant improvement over time with recovery tending to plateau at 3-6 months. INTERPRETATION: Significant impairment may persist as late as 2 years after mTBI despite some recovery over time. Longitudinal analyses which make use of all available data indicate that recovery from mTBI occurs over a longer timescale than is commonly believed. These findings point to the need for long-term management of mTBI targeting individuals with persisting impairment.

A central question in neuroscience is how consciousness arises from the dynamic interplay of brain structure and function. Here we decompose functional MRI signals from pathological and pharmacologically-induced perturbations of consciousness into distributed patterns of structure-function dependence across scales: the harmonic modes of the human structural connectome. `We show that structure-function coupling is a generalisable indicator of consciousness that is under bi-directional neuromodulatory control. We find increased structure-function coupling across scales during loss of consciousness, whether due to anaesthesia or brain injury, capable of discriminating between behaviourally indistinguishable sub-categories of brain-injured patients, tracking the presence of covert consciousness. The opposite harmonic signature characterises the altered state induced by LSD or ketamine, reflecting psychedelic-induced decoupling of brain function from structure and correlating with physiological and subjective scores. Overall, connectome harmonic decomposition reveals how neuromodulation and the network architecture of the human connectome jointly shape consciousness and distributed functional activation across scales., AIL, JV and PAMM would like to thank Lena Dorfschmidt for co-organising OxBridge BrainHack 2019, where this work began. We also thank all volunteers and patients who provided data. This work was supported by grants from The Wellcome Trust Research Training Fellowship (grant no. 083660/Z/07/Z), Raymond and Beverly Sackler Studentship, and the Cambridge Commonwealth Trust [RA]; the UK Medical Research Council (U.1055.01.002.00001.01) [JDP]; The James S. McDonnell Foundation [JDP]; the Canadian Institute for Advanced Research (CIFAR; grant RCZB/072 RG93193) [to DKM and EAS]; The National Institute for Health Research (NIHR, UK), Cambridge Biomedical Research Centre and NIHR Senior Investigator Awards [JDP and DKM]; The British Oxygen Professorship of the Royal College of Anaesthetists [DKM]; The Stephen Erskine Fellowship, Queens’ College, University of Cambridge [EAS]; The Evelyn Trust, Cambridge and the EoE CLAHRC fellowship [JA]; The Gates Cambridge Trust [AIL]; The Cambridge International Trust and the Howard Sidney Sussex Studentship [MMC]; The Oon Khye Beng Ch'Hia Tsio Studentship for Research in Preventive Medicine, Downing College, University of Cambridge [IP]; The Wellcome Trust (grant no. 210920/Z/18/Z) [PAMM]; The European Research Council Consolidator Grant CAREGIVING (615539) [MLK and SA]; The Center for Music in the Brain, funded by the Danish National Research Foundation (DNRF117) [MLK, SA and JV]; The Centre for Eudaimonia and Human Flourishing, funded by the Pettit and Carlsberg Foundations [MLK]; The Imperial College President’s Scholarship [LR]; The Alex Mosley Charitable Trust [RLCH]; The ketamine study was funded by the Bernard Wolfe Health Neuroscience Fund and the Wellcome Trust. The original LSD study received support from a Crowd Funding Campaign and the Beckley Foundation, as part of the Beckley-Imperial Research Programme. The research was also supported by the NIHR Brain Injury Healthcare Technology Co-operative based at Cambridge University Hospitals NHS Foundation Trust and University of Cambridge. Data used to obtain the human connectome were provided by the Human Connectome Project, WU-Minn Consortium (Principal Investigators: David Van Essen and Kamil Ugurbil; 1U54MH091657) funded by the 16 NIH Institutes and Centers that support the NIH Blueprint for Neuroscience Research; and by the McDonnell Center for Systems Neuroscience at Washington University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.