Table 1

Summary of identified studies using non-invasive brain stimulation techniques in ALS with the aim of prolonged neuromodulation62–68 70–73

Transcranial magnetic stimulation
Study	Trial design	Subjects	Site	Protocol	Schedule	Sham	Riluzole	Inclusion criteria	Exclusion criteria	Outcome measures	Findings
Di Lazzaro et al 66	Pilot	4 ALS	Bilateral motor cortex	1 Hz or 20 Hz	Variable	None	2 taking	Definite ALS	Not stated	Norris Scale, MRC	Well tolerated. Trend to slower progression in 1 Hz.
Angelucci et al 67	Cross-sectional	4 ALS 10 healthy	Bilateral motor cortex	1 Hz or 20 Hz	8 days	None	Not stated	Definite ALS	Not stated	Serum BDNF	20 Hz rTMS transiently reduces BDNF in ALS. 1 Hz reduces BDNF in controls but not ALS.
Zanette et al 68	RCT	10 ALS 5 active 5 sham	Bilateral motor cortex	5 Hz	5 days per week/2 weeks	Sham coil	All	Probable/Definite ALS	Not stated	ALSFRS-R, MRC, grip strength, fatigue, QoL	No effect on ALSFRS-R and MRC. Improved grip strength and QoL at 1 week, not significant at 2 weeks.
Di Lazzaro et al 62	RCT	20 ALS 10 active 10 sham	Bilateral motor cortex	cTBS	5 days per month/12 months	Sham coil	All	Probable/Definite ALS, age >18	TMS risk, severe medical condition	ALSFRS-R, MRC, AMT, CMCT	Active rTMS reduced rate of ALSFRS-R decline at 6 months, but insignificant at 12 months. No effect on AMT/CMCT.
Di Lazzaro et al 63	Pilot	1 ALS	Bilateral motor cortex	cTBS	5 days per month/26 months	None	All	Definite ALS	Not stated	ALSFRS-R, MEP, CMCT	Well tolerated. Both patients deteriorated.
Munneke et al 64	Cross-sectional	10 ALS 10 healthy	Left motor cortex	cTBS	5 days	None	All	Probable/Definite ALS, spinal onset within 6–36 months	Familial ALS, TMS risk	CMAP, MEP, RMT, SICI, ICF	rTMS reduces MEP amplitude and resting motor threshold in both patients with ALS and controls.
Di Lazzaro et al 65	Open-label	3 ALS	Bilateral motor cortex	cTBS	5 days per month/6 months	None	All	Completed 2009 trial	TMS risk, comorbidity	ALSFRS-R, respiratory failure, tracheostomy	Trend towards reduced rate of ALSFRS-R decline with rTMS.
Ceccanti et al 70	Cross-sectional	24 ALS	Non-dominant motor cortex	0.3 Hz	2 days	None	Pre/Post riluzole	Probable/Definite ALS	Not stated	MEP, RMT, median nerve sensory threshold	Paired associative stimulation increases MEP amplitude in both patients with ALS and controls. Effect significantly reduced postriluzole.

Transcranial direct current stimulation
Study	Trial design	Subjects	Electrode montage	Protocol	Schedule	Sham	Riluzole	Inclusion criteria	Exclusion criteria	Outcome measures	Findings
Quartarone et al 71	Cross-sectional	8 ALS 8 healthy	L motor cortex, R frontal	1 mA anodal/cathodal	2×7 min 1 week apart	None	1 taking	Definite ALS	MEP not elicited	MEP, RMT, AMT, SICI, ICF	After-effects of both anodal and cathodal tDCS seen in controls but not in ALS.
Munneke et al 72	Cross-sectional	10 ALS 10 healthy	L motor cortex, R frontal	1 mA cathodal	3× (7,11 or 15 min) 1 week apart	None	All	Probable ALS	Not stated	MEP, motor threshold, SICI, ICF	tDCS reduces MEP amplitude in controls but not ALS.
Madhavan et al 73	Pilot	1 ALS	L motor cortex, R frontal	2 mA anodal/cathodal/sham	12×20 min over 4 weeks	30 s ramp	Not stated	Not stated	Not stated	Muscle strength, ALSFRS-R, MEP	No significant effects. MEP could not be evoked before or after stimulation.

ALS, amyotrophic lateral sclerosis; ALSFRS-R, ALS Functional Rating Scale (revised); AMT, active motor threshold; BDNF, brain-derived neurotrophic factor; CMAP, compound motor action potential; CMCT, central motor conduction time; ICF, intracortical facilitation; L, left; MEP, motor evoked potential; MRC, Medical Research Council Power Scale; QoL, quality of life; R, right; RCT, randomised controlled trial; RMT, resting motor threshold; SICI, short-interval cortical inhibition; cTBS, continuous theta burst stimulation; rTMS, repetitive transcranial magnetic stimulation; tDCS, transcranial direct current stimulation.