TABLE 1.

Summary of excitability changes reported in motor cortex of ALS patients.

ALS type	Age (average)	Method	Finding	References
sALS	63.8 years	paired-pulse TMS	hyperexcitability & inhibition ↓: MEPmax ↓, ICI ↓	(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)
	62.5 years	threshold-tracking TMS	hyperexcitability in cortex (effect more prominent contralateral to site of disease onset) & inhibition ↓: MEP amplitude ↑, RMT ↓, SICI ↓, CSP duration ↓	(Menon et al., 2017)
sALS and fALS (hom SOD1D90A)	57 years (sALS), 53 years (fALS)	single pulse and paired-pulse threshold tracking TMS; [11C]flumazenil PET (GABAA receptor ligand)	inhibition ↓: SICI ↓, [11C]flumazenil binding ↓, neuronal loss/dysfunction ↑	(Turner et al., 2005a, b)
fALS (SOD1, asymp. and symp.)	40 years (asymp.), 58.7 years (symp.)	threshold-tracking TMS	hyperexcitability and inhibition ↓: MEP amplitude ↑, ICF ↑, SICI ↓, stimulus-response curve ↑	(Vucic et al., 2008)
n.s.	67 years	ISH histochemistry on human postmortem M1	inhibition ↓: GABAA α1 subunit mRNA ↓, GABAA β1-subunit mRNA ↑	(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)
	60.2 years	single pulse and paired-pulse threshold tracking TMS	hyperexcitability & inhibition ↓: MEP amplitude ↑, RMT↓, ICF ↑, SICI ↓, CSP duration ↓	(Zanette et al., 2002; Menon et al., 2015)
	63 years	single pulse and paired-pulse threshold tracking TMS	hyperexcitability & inhibition ↓: MEP amplitude ↑, RMT ↔, SICF ↑, SICI ↓, CSP duration ↓	(Van den Bos et al., 2018)
	59.8 years	threshold-tracking TMS	hyperexcitability & inhibition ↓: mean SAI and LAI values ↓, SICI ↓, MEP/CMAP amplitude ratio ↑	(Cengiz et al., 2019)
	61.3 years			(Shibuya et al., 2017)
	57.1 years	threshold-tracking TMS	inhibition ↓: RMT ↔, ICF ↔, SICF ↓ (for ISIs 1−1.8 ms & 2−3 ms), SICF ↔ (for ISI 4−4.6 ms), SICI ↓	(Cengiz and Kuruoğlu, 2020)
fALS	58 years	threshold-tracking TMS	hyperexcitability & inhibition ↓: SICI ↓, ICF ↑	(Vucic and Kiernan, 2009)

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 inhibition; M1, primary motor cortex; MEP, motor evoked potential; MEP_max, maximum motor evoked potential; mRNA, messenger RNA; n.s., not specified; NMDA, N-methyl-D-aspartate; NT, neurotransmitter; PET, positron emission tomography; RT-qPCR, Real-Time quantitative polymerase chain reaction; RMT, resting motor threshold; SAI, short latency afferent inhibition; sALS, sporadic ALS; SICF, short interval intracortical facilitation; SICI, short interval intracortical inhibition; symp., symptomatic; TMS, transcranial magnetic stimulation.