Cortical neurophysiology changes in asymptomatic MND genetic variant carrier groups

<h3></h3> Presymptomatic biomarkers in motor neuron disease (amyotrophic lateral sclerosis, ALS), would facilitate preventative interventions. Carriers of highly penetrant genetic variants linked to ALS offer the opportunity to study changes many years before the onset of symptoms. Magnetoencephalography (MEG), non-invasively measuring micro-magnetic fields from cortical activity, is uniquely sensitive to dynamic brain networks that may reflect sub-clinical declining brain health. People living with ALS (n=61) underwent resting-state MEG recordings and compared with asymptomatic carriers of the pathological expansion in <i>C9orf72</i> (n=16), or pathological variants in <i>SOD1</i> (n=12), and healthy controls (n=84). Regional oscillatory power, connectivity, and spectral shape were extracted. Dynamic network modelling identified five functional networks, whose activity and pairwise co-activation were analysed. The reduced beta frequency power seen in ALS patients was also present in asymptomatic <i>C9orf72</i> expansion carriers, but not in <i>SOD1</i> carriers. Significant alterations in spectral shape measures and temporal network co-activation were seen in all patient groups. A random forest classifier separated asymptomatic gene carriers from healthy controls (receiver operating characteristic (ROC) area-under-curve of 0.90). Easily detectable neurophysiological changes in asymptomatic gene carrier populations using MEG reveals motor system changes that might form the basis for outcome measures in future preventative therapeutic trials.