Supplement

Transcranial magnetic stimulation: Pro

Richard K OlneyALS Center, University of California, San Francisco

ALS and other motor neuron disorders 2002 (suppl 1), S111© 2002 ALS and other motor neuron disorders. All rights reserved. ISSN 1466-0822 S111

Following Merton and Morton’s description of electricalstimulation of human motor cortex in 1980, Barker andcolleagues �rst described transcranial magnetic stimulation(TMS) of the human motor cortex with recording of motorresponses in 1985.1 Subsequently, various techniques uti-lizing TMS have been developed to assess upper motorneuron and cortical abnormalities in ALS. These varioustechniques focus on the in�uence of upper motor neuronseither on the discharge characteristics of single motor unitsor on the compound response of a muscle or group ofmuscles. Those electrophysiological techniques that proveto estimate quantitatively and reproducibly the number ofsurviving upper motor neurons and correlate with the clin-ical course of ALS would be quite useful in clinical trials asa surrogate marker or a secondary endpoint.

The in�uence of corticomotoneurons on single volun-tarily activated lower motor neurons may be studied withTMS by analysing peristimulus time histograms. Thesetypes of studies have provided insight into the disturbedinteractions of corticomotoneurons with the lower motorneuron pool, but only limited information is availableregarding longitudinal changes in these measures and thecorrelation between these electrophysiological changesand clinical changes in ALS,2 so that their potential role inclinical trials remains to be clari�ed.

Single-pulse TMS studies that measure central motorconduction time and MEP (motor-evoked potential)amplitude are easy to perform and well tolerated bypatients. However, central motor conduction time has lowdiagnostic sensitivity and speci�city in ALS and changesare not known to correlate reliably with disease progres-sion. Motor-evoked potential amplitude tends to correlatewith disease progression, but is variable and affected by

progressive loss of upper and lower motor neurons. Arecently described triple stimulation technique, in whichthe �rst stimulation is TMS, holds greater promise as a sur-rogate measure that is proportional to the number of sur-viving upper motor neurons.3 Through a peripheral doublecollision technique, the effects of lower motor neuron lossare largely subtracted from the response. The triple stimu-lation technique is three times more sensitive at detectingabnormality in limbs of ALS patients than simple TMS.4

However, longitudinal studies are necessary to demon-strate that decreasing MEP amplitude ratio with the triplestimulation technique correlates well with clinical progres-sion in ALS.

Changes in cortical excitability have also been studiedin ALS, using corticomotor threshold, cortical silentperiod, and paired TMS with various protocols. In general,ALS patients have a loss of inhibition early and decreasedexcitability late in the course of disease. With paired TMS,many, but not all, patients with ALS have a loss of intra-cortical inhibition that may be restored in some withcertain drug therapies.5,6 The identi�cation of subsets ofALS patients with different pathophysiologies or differentphysiological responses to treatment may be useful forprospective or retrospective strati�cation of patients fordata analysis.

In conclusion, no TMS technique seems suitable as asurrogate or endpoint measure in a clinical trial based oncurrently available data. However, TMS has potential usesin clinical trials to quantify the degree of upper motorneuron loss or to recognize subsets of ALS patients whohave more or less desirable responses to speci�c drug treat-ments.

References

1. Barker AT, Jalinous R, Freeston IL. Non-invasive magneticstimulation of human motor cortex. Lancet 1985; 1:1106–1107.

2. Weber M, Eisen A, Nakajima M. Corticomotoneuronal activ-ity in ALS: changes in the peristimulus time histogram overtime. Clin Neurophysiol 2000; 111: 169–177.

3. Magistris MR, Rösler KM, Truffert A, Myers JP. Transcranialstimulation excites virtually all motor neurons supplying thetarget muscle. A demonstration and a method improving thestudy of motor evoked potentials [see comments]. Brain1998; 121: 437–450.

4. Rösler KM, Truffert A, Hess CW, Magistris MR. Quanti�ca-tion of upper motor neuron loss in amyotrophic lateralsclerosis. Clin Neurophysiol 2000; 111: 2208–2218.

5. Caramia MD, Palmieri MG, Desiato MT et al. Pharmacologicreversal of cortical hyperexcitability in patients with ALS.Neurology 2000; 54: 58–64.

6. Stefan K, Kunesch E, Benecke R, Classen J. Effects of riluzoleon cortical excitability in patients with amyotrophic lateralsclerosis. Ann Neurol 2001; 49: 536–539.

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