Ion channels in EEG: isolating channel dysfunction in NMDA receptor antibody encephalitis

• Published in: Brain (London, England : 1878) Vol. 141; no. 6; pp. 1691 - 1702
• Main Authors: Symmonds, Mkael, Moran, Catherine H, Leite, M Isabel, Buckley, Camilla, Irani, Sarosh R, Stephan, Klaas Enno, Friston, Karl J, Moran, Rosalyn J
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.06.2018
• Subjects: Adolescent; Adult; Aged; Anti-N-Methyl-D-Aspartate Receptor Encephalitis - immunology; Anti-N-Methyl-D-Aspartate Receptor Encephalitis - pathology; Anti-N-Methyl-D-Aspartate Receptor Encephalitis - physiopathology; Autoantibodies - metabolism; Brain - pathology; Brain - physiopathology; Brain Mapping; Electroencephalography; Female; Humans; Male; Middle Aged; Models, Neurological; Neural Pathways - physiopathology; Nonlinear Dynamics; Original; Receptors, N-Methyl-D-Aspartate - immunology; Young Adult; NMDA receptor antibody encephalitis; encephalopathy; dynamic causal modelling; EEG
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/awy107

See Roberts and Breakspear (doi:10.1093/brain/awy136) for a scientific commentary on this article. Patients with anti-NMDA-receptor encephalitis display diverse early symptoms and no clear imaging marker of the disease is currently available. Symmonds et al. report that using EEG alone, it is possible to identify the common underlying abnormality in NMDA receptor function, facilitating early diagnosis and potentially improving patient outcomes. Abstract Neurological and psychiatric practice frequently lack diagnostic probes that can assess mechanisms of neuronal communication non-invasively in humans. In N-methyl-d-aspartate (NMDA) receptor antibody encephalitis, functional molecular assays are particularly important given the presence of NMDA antibodies in healthy populations, the multifarious symptomology and the lack of radiological signs. Recent advances in biophysical modelling techniques suggest that inferring cellular-level properties of neural circuits from macroscopic measures of brain activity is possible. Here, we estimated receptor function from EEG in patients with NMDA receptor antibody encephalitis (n = 29) as well as from encephalopathic and neurological patient controls (n = 36). We show that the autoimmune patients exhibit distinct fronto-parietal network changes from which ion channel estimates can be obtained using a microcircuit model. Specifically, a dynamic causal model of EEG data applied to spontaneous brain responses identifies a selective deficit in signalling at NMDA receptors in patients with NMDA receptor antibody encephalitis but not at other ionotropic receptors. Moreover, though these changes are observed across brain regions, these effects predominate at the NMDA receptors of excitatory neurons rather than at inhibitory interneurons. Given that EEG is a ubiquitously available clinical method, our findings suggest a unique re-purposing of EEG data as an assay of brain network dysfunction at the molecular level.