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
StudyTrial designSubjectsSiteProtocolScheduleShamRiluzoleInclusion criteriaExclusion criteriaOutcome measuresFindings
Di Lazzaro et al 66 Pilot4 ALSBilateral motor cortex1 Hz or 20 HzVariableNone2 takingDefinite ALSNot statedNorris Scale, MRCWell tolerated. Trend to slower progression in 1 Hz.
Angelucci et al 67 Cross-sectional4 ALS
10 healthy
Bilateral motor cortex1 Hz or 20 Hz8 daysNoneNot statedDefinite ALSNot statedSerum BDNF20 Hz rTMS transiently reduces BDNF in ALS. 1 Hz reduces BDNF in controls but not ALS.
Zanette et al 68 RCT10 ALS
5 active
5 sham
Bilateral motor cortex5 Hz5 days per week/2 weeksSham coilAllProbable/Definite ALSNot statedALSFRS-R, MRC, grip strength, fatigue, QoLNo effect on ALSFRS-R and MRC. Improved grip strength and QoL at 1 week, not significant at 2 weeks.
Di Lazzaro et al 62 RCT20 ALS
10 active
10 sham
Bilateral motor cortexcTBS5 days per month/12 monthsSham coilAllProbable/Definite ALS, age >18TMS risk, severe medical conditionALSFRS-R, MRC, AMT, CMCTActive 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 Pilot1 ALSBilateral motor cortexcTBS5 days per month/26 monthsNoneAllDefinite ALSNot statedALSFRS-R, MEP, CMCTWell tolerated. Both patients deteriorated.
Munneke et al 64 Cross-sectional10 ALS
10 healthy
Left motor cortexcTBS5 daysNoneAllProbable/Definite ALS, spinal onset within 6–36 monthsFamilial ALS, TMS riskCMAP, MEP, RMT, SICI, ICFrTMS reduces MEP amplitude and resting motor threshold in both patients with ALS and controls.
Di Lazzaro et al 65 Open-label3 ALSBilateral motor cortexcTBS5 days per month/6 monthsNoneAllCompleted 2009 trialTMS risk, comorbidityALSFRS-R, respiratory failure, tracheostomyTrend towards reduced rate of ALSFRS-R decline with rTMS.
Ceccanti et al 70 Cross-sectional24 ALSNon-dominant motor cortex0.3 Hz2 daysNonePre/Post riluzoleProbable/Definite ALSNot statedMEP, RMT, median nerve sensory thresholdPaired associative stimulation increases MEP amplitude in both patients with ALS and controls. Effect significantly reduced postriluzole.
 Transcranial direct current stimulation
StudyTrial designSubjectsElectrode montageProtocolScheduleShamRiluzoleInclusion criteriaExclusion criteriaOutcome measuresFindings
Quartarone et al 71 Cross-sectional8 ALS
8 healthy
L motor cortex, R frontal1 mA anodal/cathodal2×7 min 1 week apartNone1 takingDefinite ALSMEP not elicitedMEP, RMT, AMT, SICI, ICFAfter-effects of both anodal and cathodal tDCS seen in controls but not in ALS.
Munneke et al 72 Cross-sectional10 ALS
10 healthy
L motor cortex, R frontal1 mA cathodal3× (7,11 or 15 min) 1 week apartNoneAllProbable ALSNot statedMEP, motor threshold, SICI, ICFtDCS reduces MEP amplitude in controls but not ALS.
Madhavan et al 73 Pilot1 ALSL motor cortex, R frontal2 mA anodal/cathodal/sham12×20 min over 4 weeks30 s rampNot statedNot statedNot statedMuscle strength, ALSFRS-R, MEPNo 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.