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

Mkael Symmonds,M Isabel Leite,Karl J Friston,Sarosh R Irani,Klaas Enno Stephan,Catherine H Moran,Rosalyn J Moran,Camilla Buckley

doi:10.1093/brain/awy107

Abstract

See Roberts and Breakspear (doi:10.1093/brain/awy136) for a scientific commentary on this article.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.

Highlights

N-Methyl-D-aspartate receptor (NMDAR) antibody encephalitis, first described in 2007, is an autoimmune disorder with diverse psychiatric and neurological features, most commonly psychosis, disorientation, amnesia, seizures and a complex movement disorder (Dalmau et al, 2011)
The data in the current study comprised resting state, eyes open, recordings acquired in one sitting, from 29 patients with NMDAR-antibody encephalitis (Supplementary Table 1), 18 encephalopathic controls and 18 neurological patient control participants (Supplementary Table 3)
The patients with NMDAR-antibody encephalitis had behavioural changes ranging from subtle encephalopathic features to gross obtundation or unresponsiveness, which were graded using the West Haven encephalopathy scale (Supplementary Table 5)

Summary

Introduction

N-Methyl-D-aspartate receptor (NMDAR) antibody encephalitis, first described in 2007, is an autoimmune disorder with diverse psychiatric and neurological features, most commonly psychosis, disorientation, amnesia, seizures and a complex movement disorder (Dalmau et al, 2011). A non-invasive measure of NMDAR function could facilitate early diagnosis and treatment, and provide the ability to track therapeutic response with a specific biomarker of disease activity. The ability to non-invasively assay synaptic ion channel function in clinical settings would translate our growing molecular understandings of psychiatric and neurological diseases into novel tools for clinical practice (Lisman, 2012; Friston et al, 2016a). If successful, such assays would allow for detecting ion channel disruptions across a wide class of illnesses, not limited to those with an immunological aetiology

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