Utility of threshold tracking transcranial magnetic stimulation in ALS

Abstract

Upper motor neuron [UMN] and lower motor neuron [LMN] dysfunction, in the absence of sensory features, is a pathognomonic feature of amyotrophic lateral sclerosis [ALS]. Although the precise mechanisms have yet to be elucidated, one leading hypothesis is that UMN precede LMN dysfunction, which is induced by anterograde glutamatergic excitotoxicity. Transcranial magnetic stimulation (TMS) is a neurophysiological tool that provides a non-invasive and painless assessment of cortical function. Threshold tracking methodologies have been recently adopted for TMS, whereby changes in threshold rather than motor evoked potential (MEP) amplitude serve as outcome measures. This technique is reliable and provides a rapid assessment of cortical function in ALS. Utilisng the threshold tracking TMS technique, cortical hyperexcitability was demonstrated as an early feature in sporadic ALS preceding the onset of LMN dysfunction and possibly contributing to disease spread. Separately, cortical hyperexcitability was reported to precede the clinical onset of familial ALS. Of further relevance, the threshold tracking TMS technique was proven to reliably distinguish ALS from mimicking disorders, even in the presence of a comparable degree of LMN dysfunction, suggesting a diagnostic utility of TMS. Taken in total, threshold tracking TMS has provided support for a cortical involvement at the earliest detectable stages of ALS, underscoring the utility of the technique for probing the underlying pathophysiology. The present review will discuss the physiological processes underlying TMS parameters, while further evaluating the pathophysiological and diagnostic utility of threshold tracking TMS in ALS.

Keywords: Amyotrophic lateral sclerosis; Cortical hyperexcitability; Threshold tracking TMS.

Fig. 1

(A) The tracking target of 0.2 mV ( ± 20%) lies in the steepest portion of the stimulus response curve (green color), such that a large variation in motor evoked potential (MEP) amplitude translates to a small variation in transcranial magnetic stimulation (TMS) intensity. (B) When the MEP amplitude is larger than the tracking target (a) the TMS intensity is reduced on subsequent stimulus, while when MEP is smaller (b) the TMS intensity is increased. (C) SICI is mediated by inhibitory GABAergic interneurons located within the primary motor cortex, mostly layers 2 and 3, projecting onto pyramidal cells. (D) Short interval intracortical inhibition (SICI) is reflected by conditioned-test stimulus intensity being greater than zero, while the converse is true for intracortical facilitation (ICF). In amyotrophic lateral sclerosis (ALS) there is a significant reduction in SICI and an increase in ICF, indicative of cortical hyperexcitability. (E) Treatment with the anti-glutamatergic agent riluzole partially normalizes SICI in ALS patients.