Transcranial magnetic stimulation: pro.

1Subsequently, various techniques utilizing TMS have been developed to assess upper motor neuron and cortical abnormalities in ALS. These various techniques focus on the ineuence of upper motor neurons either on the discharge characteristics of single motor units or on the compound response of a muscle or group of muscles. Those electrophysiological techniques that prove to estimate quantitatively and reproducibly the number of surviving upper motor neurons and correlate with the clinical course of ALS would be quite useful in clinical trials as a surrogate marker or a secondary endpoint. The ineuence of corticomotoneurons on single voluntarily activated lower motor neurons may be studied with TMS by analysing peristimulus time histograms. These types of studies have provided insight into the disturbed interactions of corticomotoneurons with the lower motor neuron pool, but only limited information is available regarding longitudinal changes in these measures and the correlation between these electrophysiological changes and clinical changes in ALS, 2 so that their potential role in clinical trials remains to be clarieed. Single-pulse TMS studies that measure central motor conduction time and MEP (motor-evoked potential) amplitude are easy to perform and well tolerated by patients. However, central motor conduction time has low diagnostic sensitivity and speciecity in ALS and changes are not known to correlate reliably with disease progression. Motor-evoked potential amplitude tends to correlate with disease progression, but is variable and affected by progressive loss of upper and lower motor neurons. A recently described triple stimulation technique, in which the erst stimulation is TMS, holds greater promise as a surrogate measure that is proportional to the number of surviving upper motor neurons. 3 Through a peripheral double collision technique, the effects of lower motor neuron loss are largely subtracted from the response. The triple stimulation technique is three times more sensitive at detecting abnormality in limbs of ALS patients than simple TMS. 4 However, longitudinal studies are necessary to demonstrate that decreasing MEP amplitude ratio with the triple stimulation technique correlates well with clinical progression in ALS. Changes in cortical excitability have also been studied in ALS, using corticomotor threshold, cortical silent period, and paired TMS with various protocols. In general, ALS patients have a loss of inhibition early and decreased excitability late in the course of disease. With paired TMS, many, but not all, patients with ALS have a loss of intracortical inhibition that may be restored in some with certain drug therapies. 5,6 The identiecation of subsets of ALS patients with different pathophysiologies or different physiological responses to treatment may be useful for prospective or retrospective stratiecation of patients for data analysis. In conclusion, no TMS technique seems suitable as a surrogate or endpoint measure in a clinical trial based on currently available data. However, TMS has potential uses in clinical trials to quantify the degree of upper motor neuron loss or to recognize subsets of ALS patients who have more or less desirable responses to speciec drug treatments.