Magnetoencephalography biomarkers for assessing myelin content and neuronal function in acute optic neuritis

The visual pathway is an important model system for remyelination and neuroprotection trials in multiple sclerosis, due to its accessibility and the availability of validated methods including visual evoked potential and optical coherence tomography. However, visual evoked potentials are sometimes undetectable and demonstrate limited reliability after acute optic neuritis. This study aims to investigate novel magnetoencephalography markers for assessing myelin content and neuronal dysfunction in the early phase of optic neuritis and describes their inter-run reproducibility ('over a single visit') and association with short-term visual outcomes. Patients with unilateral acute optic neuritis were recruited and underwent ophthalmological assessments, brain MRI and magnetoencephalography. Magnetoencephalography data were acquired during visual stimulation with an alternating checkerboard pattern. We used source localization to reconstruct brain activity in the primary visual cortex (V1) and analysed it in the temporal and frequency domains. In the temporal domain, we focused on M100 latency-the magnetic counterpart of P100 latency. In the frequency domain, we assessed the spectral richness of the steady-state evoked field response by harmonic count, which reflects the diversity of frequency components present in the brain signal. Thirty-two patients were included at a median of 54 days [interquartile range = (37.5-78)] post-symptom onset of optic neuritis. Among patients with optic neuritis, visual evoked field recordings were detectable in 77% of cases, compared with 66% for visual evoked potential recordings. M100 latency demonstrated an excellent inter-run reproducibility for both fellow and affected eyes [intra-class correlation coefficient (ICC) >0.8, mean absolute inter-run difference of 2.99 ± 6.53 and 3.76 ± 7.53 ms, respectively]. By comparison, the reproducibility of P100 latency was good for fellow eye (ICC = 0.7, mean absolute inter-run difference of 3.9 ± 6.2 ms) but moderate for affected eye (ICC = 0.6, mean absolute inter-run difference of 9.1 ± 21.8 ms). In the frequency domain, the harmonic count correlated strongly with ganglion cell layer volume (r = 0.68, P = 0.0001), likely reflecting functional consequences of neuronal loss. Measures reflecting demyelination (P100 and M100 latencies) correlated with measures of neuronal damage (ganglion cell layer volume and harmonic count) from both conventional and magnetoencephalography assessments. Visual impairment was associated with neuronal damage (parameter estimates: β = 0.49, P = 0.017 for ganglion cell layer volume, β = 0.57, P = 0.003 for harmonic count) but not with demyelination measures. Our results highlight magnetoencephalography as a reproducible and comprehensive tool to study both myelin content and neuronal dysfunction shortly after optic neuritis and suggest that, at this early stage, neuronal damage is already the main driver of visual outcome.