https://orcid.org/0000-0003-0381-917X
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Mehdi A J van den Bos, Parvathi Menon, Nathan Pavey, Mana Higashihara, Matthew C Kiernan, Steve Vucic, Direct interrogation of cortical interneuron circuits in amyotrophic lateral sclerosis, Brain, Volume 148, Issue 4, April 2025, Pages 1169–1179, https://doi.org/10.1093/brain/awae317
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Abstract
Cortical hyperexcitability is a key pathogenic feature of amyotrophic lateral sclerosis (ALS), believed to be mediated through complex interplay of cortical interneurons. To date, there has been no technological approach to facilitate the direct capture of cortical interneuron function.
Through combination of transcranial magnetic stimulation (TMS) with advanced EEG, the present study examined GABAergic dysfunction in ALS by recording focused cortical output whilst applying TMS over the primary motor cortex contralateral to the site of symptom onset. Using both a single-pulse and a novel inhibitory paired-pulse paradigm, TMS-EEG studies were undertaken on 21 ALS patients and results compared with healthy controls. TMS responses captured by EEG form a discrete waveform known as the transcranial evoked potential (TEP), with positive (P) or upward deflections occurring at 30 (P30), 60 (P60) and 190 ms (P190) after TMS stimulus. Negative (N) or downward deflections occur at 44 (N44), 100 (N100) and 280 ms (N280) after TMS stimulus. The single-pulse TEPs recorded in ALS patients demonstrated novel differences suggestive of cortical GABAergic dysfunction. When compared with controls, the N100 component was significantly reduced (P < 0.05), whereas the P190 component increased (P < 0.05) in ALS patients. Additionally, the N44 component was correlated with muscle weakness (r = −0.501, P < 0.05). These findings were supported by reduced paired-pulse inhibition of TEP components in ALS patients (P60, P < 0.01; N100, P < 0.005), consistent with dysfunction of cortical interneuronal GABAA-ergic circuits. Furthermore, the reduction in short-interval intracortical inhibition, as reflected by changes in paired-pulse inhibition of the N100 component, was associated with longer disease duration in ALS patients (r = −0.698, P < 0.001).
In conclusion, intensive and focused interrogation of the motor cortex using novel TMS-EEG combined technologies has established localized dysfunction of GABAergic circuits, supporting the notion that cortical hyperexcitability is mediated by cortical disinhibition in ALS. Dysfunction of GABAergic circuits was correlated with greater clinical disability and disease duration, implying pathophysiological significance.
