A new parameter to discriminate amyotrophic lateral sclerosis patients from healthy participants by motor cortical excitability changes

Abstract

Introduction We sought a combination of abnormalities to define a more sensitive measure of cortical excitability in amyotrophic lateral sclerosis (ALS). Methods The automatic threshold tracking method was employed to assess the resting motor threshold, intracortical facilitation (ICF), short‐interval intracortical inhibition (SICI), and short‐interval intracortical faciilitation (SICF) in patients and controls. Results SICF at interstimulus intervals (ISI) between 1 and 1.8 ms and 2 and 3 ms as well as average SICI and SICI at ISIs of 1 and 2.5 ms were significantly reduced in ALS. The SICI curve was altered, displaying a solitary peak. Discriminant analysis revealed that the combination of SICI 2.5 ms and the mean SICF between 1 and 1.8 ms ISIs was the most sensitive parameter to distinguish patients with ALS from healthy participants. Discussion Along with the reduced SICI and its altered shape, connectivity between motor cortical circuits is changed in ALS. Combination with SICF increases the diagnostic utility of SICI in ALS.

Synaptic Transmission and Motoneuron Excitability Defects in Amyotrophic Lateral Sclerosis

“…TMS studies in humans have also demonstrated ICF (111)(112)(113)(114)122), and Vucic et al reported that the measured reduction in SICI represented degeneration of inhibitory cortical circuits combined with hyperexcitation of highthreshold excitatory pathways (123). More recent work has shown that reduced and altered SICI affects motor cortical circuits in ALS; the study also showed that combining two parameters, short-interval ICF and SICI, increases the utility of SICI for identifying patients with ALS (124). Overall, these results demonstrate that in ALS the imbalance between excitatory and inhibitory circuits in the M1 cortex is based on a combination of increased excitability and decreased inhibition (125).…”

Exciting Complexity: The Role of Motor Circuit Elements in ALS Pathophysiology

“…For the assessment of motor cortex excitability it is coupled with the measurement of motor evoked potentials (MEP), recorded from a contralateral innervated muscle (e.g., abductor pollicis brevis muscle) (Vucic et al, 2013). Threshold-tracking TMS: The electromagnetic stimulus intensity required to maintain a target MEP response of 200 µV (motor threshold) is measured, reflecting the excitability of UMN (Fisher et al, 2002;Vucic et al, 2018;Cengiz and Kuruoglu, 2020). Resting motor threshold (RMT): The lowest electromagnetic stimulus intensity required to produce an MEP of at least 50 µV at rest (Rothwell et al, 1999;Rosso and Lamy, 2018).…”

“…Short-interval intracortical inhibition (SICI): Inhibition of the MEP response upon a conditioning stimulus applied at a short latency (7−10 ms) prior to the actual stimulation. It compares the MEP amplitude with and without a preceding subthreshold conditioning stimulus (Wagle-Shukla et al, 2009;Cengiz and Kuruoglu, 2020). Cortical silent-period (CSP) duration: Assessment of the duration a voluntary muscle contraction (as measured be EMG) is interrupted by a previous TMS stimulation (typically 100−300 ms upon TMS stimulation).…”

“…The approach is based on the application of a local time-varying magnetic field of increasing intensities to gauge the intensity needed to depolarize neurons beyond their firing threshold (Barker et al, 1985;Hess and Ludin, 1988;Hallett, 1996;Oliveri et al, 2000, Oliviero et al, 2011. Although the mechanisms underlying the TMS-triggered depolarization of pyramidal neurons (PN) are still incompletely understood, it is a widely used approach to investigate the excitability of neuronal populations (Kim et al, 2005), such as UMN in humans (Ziemann et al, 1997;Siciliano et al, 1999;Zanette et al, 2002;Turner et al, 2005b;Vucic et al, 2008;Menon et al, 2015Menon et al, , 2017Shibuya et al, 2017;Van den Bos et al, 2018;Cengiz et al, 2019;Cengiz and Kuruoglu, 2020). To verify the activation of UMN [or corticospinal excitability; (Cortes et al, 2012)], the motor evoked potential (MEP) of the innervated muscle is recorded (e.g., the abductor pollicis brevis muscle) (Vucic and Kiernan, 2006;Van den Bos et al, 2018).…”

“…The intensity of the test stimulus, necessary to evoke a defined MEP response, is lower compared to an unconditioned stimulus (Ziemann et al, 1998;Vucic et al, 2008; Box 2). Employing variations of those TMS stimulation protocols studies have identified a reduction in the threshold needed to generate a MEP (Zanette et al, 2002;Menon et al, 2015Menon et al, , 2017, as well as a reduction in the intracortical inhibition (Ziemann et al, 1997;Zanette et al, 2002;Turner et al, 2005a,b;Vucic et al, 2008Menon et al, 2015Menon et al, , 2017Shibuya et al, 2017;Van den Bos et al, 2018;Cengiz et al, 2019;Cengiz and Kuruoglu, 2020) and an increase in the intracortical facilitation (Zanette et al, 2002;Vucic et al, 2008;Menon et al, 2017;Van den Bos et al, 2018), thereby establishing that M1 E/I imbalance in ALS is based on a combination of increased excitability and decreased inhibition ( Table 1). Ziemann et al, 1997) 65.3 years threshold-tracking TMS compromised inhibition: MEP onset latency ↑, CSP duration ↑/↓, early stages: CSP duration ↑, later stages: CSP duration ↓ (Siciliano et al, 1999) 61.4 years single pulse and paired-pulse threshold tracking TMS inhibition ↓: MEP amplitude ↔, RMT ↔, ICF ↔, ICI ↓, CSP duration ↓ (Zanette et al, 2002) 56.3 years microarray, RT-qPCR of post-mortem tissue various transcriptional alterations, including NMDA and AMPA receptors (Aronica et al, 2015) 62 Petri et al, 2003) 59.5 years 3-T proton magnetic resonance spectroscopy excitatory & inhibitory NT imbalance: GABA ↓, Glu ↓ (in Riluzole-treated group) (Foerster et al, 2013) 60 AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; asymp., asymptomatic; CMAP, compound muscle action potential; CSP, cortical-silent period; fALS, familial ALS; GABA, γ -aminobutyric acid; GABA A , γ -aminobutyric acid receptor subtype A; Glu, glutamate; hom, homozygous; SOD1, superoxide dismutase 1; ICF, intracortical facilitation; ISH, in situ hybridization; ISI, interstimulus interval; LAI, long latency afferent inhibit...…”