Imbalance in cortical inhibition-excitation networks underlies als

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Abstract

Objectives

Recent cellular work in TDP-43 models of ALS convincingly demonstrated the importance of somatostatin interneuronal circuits in mediating corticomotoneuronal hyperexcitability, previously indirectly measured by short interval intracortical inhibition (SICI). Somatostatin interneurons reside in layers 2–3 of the primary motor cortex, with their output projecting directly onto and modulating pyramidal tract neurons. These circuits can be non-invasively interrogated using TMS. As such, the present study developed a novel threshold tracking TMS technique of this excitatory output, termed short interval intracortical facilitation (or SICF), and postulated that it would be increased in ALS patients when compared with healthy controls.

Methods

Threshold tracking TMS techniques assessed the function of somatostatin excitatory interneurons in 15 ALS patients. Short interval intracortical facilitation was measured by setting the subthreshold conditioning stimulus to 95% of resting motor with interstimulus intervals (ISI) between 1-5 ms. The TMS findings were compared with a cohort of 25 healthy controls.

Results

Short interval intracortical facilitation was significantly increased in ALS patients when compared with controls with Z=2.291 and p<0.05 (mean SICF Ave ALS=−17.23% (+/−2.68) and controls=−10.39% (+/−1.52)). The rise in short interval intracortical facilitation was accompanied by a reduction of SICI (mean ALS SICI Ave=3.13% (+/-1.45) and Controls=13.23% (+/-1.37)) with Z=4.302 and p<0.05.

Conclusions

The present study has established that cortical hyperexcitabilty in ALS is mediated through a combination of reduced inhibition (implying dysfunction of inhibitory circuits) combined with increased activity of the excitatory cortical networks. Strategies aimed at modulating the imbalance in cortical inhibition-excitation axis may prove therapeutically useful.

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