Abstract
Objectives Cortical hyperexcitability through cortical GABA-ergic interneuronal dysfunction is a key step in ALS pathogenesis. This work combines Transcranial Magnetic Stimulation (TMS) with EEG to directly capture the responses of cortical interneurons within Transcranial Evoked Potentials (TEP) in the emerging field of TMSEEG. Earlier work demonstrated the P60 amplitude of the TEP is reduced through activation of GABA-ergic inhibitory circuits. We hypothesized inhibitory modulation of the P60 potential of the TEP would be reduced in ALS patients.
Methods TEP were studied in 15 ALS patients and 17 age-matched controls (HC). TMS responses were studied under two conditions – a single pulse delivered at 110% of Resting Motor Threshold (RMT), and inhibitory paired pulse paradigm with a 70%RMT conditioner delivered 3ms before a 110%RMTtest-pulse. Recordings were processed offline with an established signal processing protocol.
Results There was a significant reduction in TEP P60 inhibition for ALS patients (-16.1%±9.3) compared to controls (-43.5%±10.5,P=0.032) when examined within the inhibitory paradigm. Changes in ALS P60 inhibition were correlated with the rate of disease progression, denoted by both the rate of monthly decline in the ALSFRS-R since symptom onset (R2=0.31,P=0.048), and the rate of increase in upper motor neurone features, expressed as the UMN Score, (R2=0.3195,P=0.035).
Conclusions Data from TMS-EEG directly demonstrate dysfunction of cortical inhibitory circuits is present in ALS patients at an early clinical stage. Dysfunction of GABA-ergic circuits appears to be proportional to disease disability and the rate of disease progression. Interventions aimed at modulating these cortical circuits may prove therapeutically useful.
