Multimodal MRI demonstrates task-related cortical hyper-activation and neuro- chemical alteration in amyotrophic lateral sclerosis

Abstract

BackgroundThere is a paucity of reliable markers of disease activity and progression in ALS. Better biomarkers would also reduce clinical trial duration and cost by providing more sensitive measures of target engagement. Cortical hyperexcitability with transcranial magnetic stimulation, while promising, has not yet been clinically translatable. Multimodal correlation of cortical hyperexcitability could yield more robust composite biomarkers.MethodsThis project applies multimodal non-invasive neuroimaging (MRI, MEG) and neurophysiol- ogy (TMS) to explore cortical hyperexcitability in ALS. 11 affected ALS patients, 9 age matched healthy controls and 13 asymptomatic relatives at-risk of inheriting the disease-causing C9orf72 hexanucleotide repeat expansion were studied. MRI findings are reported here (diffusion-tensor imaging [DTI], functional MRI and MR spectroscopy).ResultsRight cortical activation with contralateral finger movement was significantly increased in patients (p = 0.04), while right cortical de-activation with ipsilateral movement was lost (p = 0.01). N-acetyl-aspar- tate (p=0.04) and glutamate (p = 0.01) are significantly reduced in patients. At-risk relatives occupy an intermediate profile.DiscussionBilateral motor cortex hyperexcitability was found in ALS. Asymmetry in task-related activa- tion is consistent with previously reported loss of cortical inhibition in early ALS. Integration of multimodal imaging and neurophysiological data could explain variable phenotype and disease mechanisms in ALS.eedmond@gmail.com