Objectives Functional abnormalities of motor and extra-motor cortical regions are an intrinsic feature of amyotrophic lateral sclerosis (ALS). Connectomics is a novel field utilising whole brain network analysis, providing an in depth understanding of cortical networks. The present study utilised a multimodality approach encompassing connectome network and brain volume analysis, combined with clinical functional measures and cortical excitability studies to gather novel insights in ALS pathogenesis.

Methods Resting state functional MRI was used to map functional connectomes in 20 ALS patients and 20 age-matched controls. Connectomes were analysed to assess functional connectivity networks using network based statistics (NBS) and whole brain functional topology, using graph theoretical approaches. Grey matter (GM) volumes, functional disability and cortical excitability was assessed, to provide a context to interpret the functional connectomic differences.

Results NBS analysis disclosed increased functional connectivity within the frontal, temporal, parietal and subcortical regions. Topologically, ALS patients showed increased segregation of regions as measured by clustering coefficient (p<0.05), nodal degree (representing local connectedness) was reduced in the frontal and increased in the occipital regions. Changes in functional connectivity were accompanied by reduced GM volumes in the frontal, temporal, cerebellar, subcortical and prefrontal regions. Features of cortical hyperexcitability were evident and negatively correlated with functional connectivity in the precentral gyrus (p<0.01). Separately, connectivity changes in the frontal regions were negatively associated with functional disability (p<0.05).

Conclusions Novel MRI techniques of functional connectivity highlight region specific abnormalities in ALS patients. Furthermore these changes correlate with a functional neurophysiological parameter which has previously been shown to be an early marker of cortical dysfunction. These techniques may aid in evaluating the complex pathophysiological processes underlying ALS.