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Chapter 3 The triple stimulation technique to study corticospinal conduction
Transcranial Magnetic Stimulation and Transcranial Direct Current Stimulation (Supplements to Clinical Neurophysiology. Vol. 56) Editors: W. Paulus. F. Tergau, M.A. Nitsche, I.e. Rothwell, U. Ziemann. M. Hallett © 2003 Elsevier Science B.V. All rights reserved
24
Chapter 3
The triple stimulation technique to study corticospinal conduction M.R. Magistris-" and K.M. Resler" Departments of Neurology, University Hospitals of "Geneva and bBeme (Switzerland)
1. Introduction Motor evoked potentials (MEPs) are presently widely used to study the physiology of corticospinal conduction in healthy subjects and in patients with diseases of the central nervous system (cf. review in Mills, 2000). Main parameters studied by "conventional" MEPs are the central motor conduction time (CMCT) and the size of the MEP (amplitude, duration and area); other parameters of interest (such as stimulation thresholds, silent period, etc.) will not be considered in this chapter. Measurement of the CMCT is of interest since it can disclose slowings of central conduction that could otherwise remain subclinical (Beer et al., 1995). The evaluation of the size of the MEP should allow assessing deficits of corticospinal conduction causing the handicap of a patient, because theoretically the size of a MEP should be related to the number of conducting corticospinal motor neurons. However, this relation is obscured by some particular characteristics of MEPs, making the
* Correspondence to: Prof. Michel R. Magistris, Unite d'Electroneuromyographie et des Affections Neuromusculaires, Clinique de Neurologie, Hepitaux Universitairesde Geneve,CH-1211 Geneva 14,Switzerland. Tel: (+4122) 37 28 348; Fax (+4122) 37 28 350; E-mail: [email protected]
interpretation of MEP size measurements difficult. First, the size of a MEP is reduced (as compared to the peripheral response), and it varies from subject to subject and from one stimulus to the next (Hess et al., 1987). The magnitude of this reduction of amplitude, varies among subjects and is unpredictable (Magistris et al., 1998; Resler et al., 2002). Second, the MEP is influenced by the excitability of the corticospinal pathway, which is variable and can be facilitated by a number of mechanisms (Hess et al., 1986; Andersen et al., 1999). In particular, voluntary "background" contraction of the target muscle facilitates the MEP, reducing its threshold, shortening its latency and - most notably - increasing its size. The relation between MEP size and background contraction force is not linear and differs between muscles (Hess et al., 1987; Kischka et aI., 1993; Resler et al., 2002). Finally, a MEP includes responses of spinal motor neurons discharging more than once in response to the transcranial stimulus. Probably, the number of such multiple spinal motor neuron discharges differs between subjects, may be facilitated by voluntary contraction, and may be affected by diseases (Naka and Mills, 2000), yet their contribution to the MEP size of a given subject or patient is not known. For these reasons, conventional MEPs do not allow for an accurate assessment of corticospinal deficits.
25 The triple stimulation technique (TST) was first developed to measure conduction blocks at the peripheral nerve level (Roth and Magistris, 1989). It has been adapted for the use with transcranial brain stimulation (Magistris et al., 1998). It resolves the above mentioned difficulties of conventional MEPs. We shall describe the technique and discuss its yield and limitations in the study of corticospinal conduction.
2. Methods The TST has been described in detail in several publications (Magistris et al., 1998, 1999; Rosier et al., 1999, 2000; BUhler et aI., 2001). In short, three sequential stimuli are given with appropriate delays (Fig. 1). Two collisions of the evoked action potentials can occur. The first stimulus is the transcranial
brain stimulus. It is followed by two supramaximal stimuli of the nerve supplying the target muscle. distal then proximal. Two different TST protocols were developed, one for the study of a small hand muscle (abductor digiti minimi; ADM), and one for a foot muscle (abductor hallucis; AH). The peripheral stimuli in the TST-ADM procedure are applied over the ulnar nerve at the wrist, and over the brachial plexus (Magistris et al., 1998). Those for the TSTAH are given over the tibial nerve at the internal malleolus, and to the sciatic nerve at the gluteal fold (BUhler et al., 2001). For the latter, a monopolar needle electrode is used, which is brought into the nerve's proximity to reduce the current needed to reach supramaximal stimulation (Yap and Hirota, 1967). The descending action potentials evoked by the transcranial stimulus collide with the action
T8Tt88t
TM8
W
T8Tcontroi
Plex.
Plexus
-- -wrist
test 1
test 2
-- -teat 3
teat 4
wrist
~-- control 1 control 2 control 3 control 4
Fig. I. Triple stimulation technique (TST) principle. The motor tract is simplified to three spinal motor neurons; horizontal lines represent the muscle fibres of the three motor units. Black arrows depict action potentials that cause a trace deflection, open arrows those that do not. (test I) A submaximaltranscranial stimulus excites two spinal motor neurons out of three (large open arrows). (test 2) On 2/3 neurons, TMS induced action potentials descend. Desynchronisation of the two action potentials has occurred (possibly at spinal cell level). After a delay, a maximal stimulus is applied to the peripheral nerve at the wrist. It gives rise to a first negative deflection of the recording trace. The antidromic action potentials collide with the descending action potentials on motor neurons I and 2. The action potential on neuron 3 continues to ascend. (test 3) after a second delay a maximal stimulus is applied at the brachial plexus (Plex.), On motor neuron 3, the descending action potential collides with the ascending action potential. (test 4) A synchronised response from the two motor neurons that were initially excited by the transcranial stimulus is recorded as the second deflection of the TST test trace. (control I) A maximal stimulus is applied at Erb's point. (control 2) after a delay, a maximal stimulus applied at the wrist is recorded as the first deflection of the TST control trace. (control 3) after a delay a maximal stimulus is applied at Erb's point. (control 4) a synchronised response from the three motor neurons is recorded as the second deflection of the TST control trace. The test response is quantified as the ratio of TST test (test 4): TST control (control 4).
26 potentials evoked by the second, distal stimulus, which is given after a first delay (Fig. 1). After a second delay, the third stimulus, proximal, evokes the response that will be studied. This is the response of those motor units which were initially excited by the transcranial stimulus. However, whereas the descending activity evoked by the brain stimulus was desynchronised, the activity of the same motor units is now synchronised by the collisions, in the same manner as it would in response to a single proximal nerve stimulus (Fig. 1). The response is compared to that of a control curve, obtained by a triple stimulation procedure performed on the peripheral nerve (where the first transcranial stimulus is replaced by a stimulus applied at the proximal site, Fig. 1). The size ratio of the TST test and TST control curves was termed "TST amplitude ratio" or ''TST area ratio"; it is an estimate of the proportion of the motor neuron pool of the target muscle that was driven to discharge by the transcranial stimulus. The TST procedure, which originally required additional external stimulators, has recently been simplified by a dedicated software package for the Nicolet Viking apparatus (Judex Datasystemer AlS, Lyngvej 8, DK-9000 Aalborg, and Nicolet, Madison, WI, USA). Using this software, the two stimulators of the
EMG machine are sequentially triggered at preselected intervals, to provide the stimulations needed during both TST test and TST control procedures. For transcranial stimulation, a standard magnetic stimulator is used, and choice of coils and coil placements are the same as for conventional MEPs. A high voltage electrical stimulator (Digitimer, Welwyn Garden City, UK) may replace the magnetic stimulator when direct stimulation of the pyramidal axon hillock is required. Table 2 details the TST procedures.
3. Results 3.1. Neurophysiological aspects The three stimuli of the TST couple central and peripheral conductions through the two collisions (Fig. 1). This results in a "resynchronisation" of the action potentials evoked by the transcranial stimulus. Moreover, the influence of multiple discharges of spinal neurons is avoided. Indeed, the collision affects only the first descending action potential descending on a given peripheral axon, whereas any following action potentials (i.e. the multiple discharges) escape collision. The latter are recorded between the two main deflections of the TST curve.
TABLE 1 NORMAL MEANS AND NORMAL LIMITS FOR EXAMINATION OF TWO MUSCLES USING THE TST ADM
*
AH
**
Mean (SD)
Normal limit
Mean (SD)
Normal limit
TST amplitude ratio TST area ratio
99.1% (2.14) 98.5% (2.48)
~93%
95.0% (4.06) 96.1% (8.30)
~84%
MEP amplitude ratio MEP area ratio
66.1% (12.99) 96.8% (17.95)
~33%
37.2% (9.72) 99.7% (38.45)
~43%
Mean amplitude loss Mean area loss
34.3% 16.2%
TST amplitude variability (CoV) MEP amplitude variability (CoV)
* Magistris et aI.,
1998.
2.6% 8.1%
*** ***
~92%
~52%
57.8% (9.12) 58.9% (11.36)
* *
** BUhler et al., 2000. *** Rosier et aI., 2002. CoY: Coefficient of Variation.
~88%
~21%
27 Nonnalsubjecl
MSpallenl2
MS~llenl1
TSTcontrol
TST llI8l
100"'" 90% lIO%
Cond uct.on deficit: 22%
Conducbon defICit: 54%
(Cent,al conduction time: 7.3 ms)
(Central conduction t,me: 7.1 ms)
Fig. 2. Examples of TST recordings in a normal subject and in two patients with multiple sclerosis. Several recordings are superimposed: The TST control curve (which calibrates the TST test recordings), and TST test curves obtained with increasing stimulus intensity. Note that in the normal subjects, a superposition of the TST test and TST control curves is obtained (TST amplitude ratio = 100%), whereas in the two MS patients, the TST test curve does not reach the TST control curve even with 100% of stimulator output. Thus, the TST demonstrates a conduction deficit in both patients. The central motor conduction time is normal in both patients.
In both target muscles (ADM and AH) and in all healthy subjects studied, the TST amplitude and area ratios were close to 100%, indicating that nearly all target motor units were driven to discharge by the transcranial stimulus (an example is given in Fig. 2). Moreover, the variability of the TST amplitude and area ratios was markedly reduced compared to MEPs (Magistris et al., 1998). These observations demonstrate that size reduction and variability of MEPs are mainly caused by varying synchronisation of the descending action potentials evoked by the transcranial stimulus, and by the associated phase cancellation phenomena (Fig. 3). The mean values of the TST amplitude and area ratio in normal subjects are given along with the respective nonnallimits in Table 1. Comparison of the TST results with those of the conventional MEPs allows an estimate of the degree of size reduction caused by the discharge desynchronisation. For ADM, four previous studies suggested a rather uniform average MEP amplitude loss in healthy subjects and patients, of about one third of the "true" size (Magistris et al., 1998, 1999; Rosler et al., 2000, 2002; Table 1). For AH, the average amplitude loss is greater (approximately
55%), due to the considerably greater degree of discharge desynchronisation (Biihler et al., 2001; Table 1). The size reducing effect of the discharge desynchronisation was not influenced by submaximal stimulation, but differed greatly (and unpredictably) between subjects (Rosler et al., 2(02). An important aspect of the TST is the fact that it does not only resynchronise the motor unit discharges, but that it also suppresses the effects of multiple spinal motor neuron discharges. This effect appeared particularly important for studies involving the AH (Biihler et al., 2(01), where multiple spinal motor neuron discharges sometimes appeared to artificially amplify the MEP responses. One of the reasons for the proneness of AH-MEP to be contaminated by multiple discharges probably relates to the fact that the background contraction needed to obtain discharge of all motor units is higher than in ADM. Multiple spinal motor neuron discharges are markedly facilitated by voluntary background contraction (Naka and Mills, 2000; Magistris, Rosler et al., in preparation). Summarised, the following conclusions can be drawn from the TST studies in healthy subjects:
28 TABLE 2 CLINICAL APPLICATION OF THE TRIPLE STIMULATION TECHNIQUE WITH RECORDING FROM M. ABDUCTOR DIGm MINIMI (ADM); AND MODIFICATION TO USE WITH M. ABDUCTOR HALLUCIS (AB) (1) Muscle recording: (a) Standard recording electrodes, just as for motor nerve conduction studies, belly-tendon technique. (b) Fix fingers by tape around fingers II-V to keep muscle geometry constant. Use sandbag (2.5-5 kg) to hold hand down. (c) Bandpass filters 2 Hz-to kHz.
(2) Peripheral nerve stimulation:
(a) Supramaximal stimulation of ulnar nerve at the wrist. (b) Use external stimulator triggered through external timer, or internal stimulator of EMG apparatus with timer software. (c) Silver stimulation electrodes (8 mID diameter), taped over the nerve. (d) To account for volume conduction from brachial plexus by Erb stimulation, the median nerve may be stimulated simultaneously. (e) Apply same facilitation manoeuvre during peripheral stimulation than during transcranial magnetic stimulation (e.g. slight voluntary contraction).
(3) Proximal nerve stimulation:
(a) Brachial plexus stimulation using monopolar cathode at Erb's point (surface 1 cnr') and large remote anode (30 em') taped over internal region of suprascapular fossa. Supramaximal stimulation often requires application of some external pressure on the stimulating cathode. (b) Use external stimulator triggered through external timer, or internal stimulator of EMG apparatus with timer software. (c) Supramaximal stimulation! (is always possible). (d) Apply same facilitation manoeuvre during peripheral stimulation than during transcranial magnetic stimulation (e.g. slight voluntary contraction).
(4) Transcranial magnetic stimulation:
(a) Any magnetic stimulator can be used. (b) Circular coil (or other coils depending on purpose of study, e.g, mapping with figure-of-eight coil). (c) Coil placement as for conventional motor evoked potentials.
(5) Procedure: (a) Patient lays supine. Fingers fixed by tape and hand fixed by sandbag. (b) Supramaximal ulnar nerve stimulation at wrist, during slight voluntary contraction. (c) Supramaximal stimulation at Erb's point, during slight voluntary contraction. (d) Conventional TMS, several stimuli using increasing stimulation intensity and slight voluntary contraction to facilitate the responses. Measurement of shortest latency and largest amplitude of the motor evoked potential (MEP). (e) Calculation of delay I latency of MEP - latency of CMAP wrist (rounded down to nearest ms). (f) Calculation of delay II latency of CMAP Erb - latency of CMAP wrist (rounded down to nearest ms). (g) TST control curve: 3 stimuli are given: Erb - wrist - Erb. Interval between stimuli = delay II. (h) TST test curve: 3 stimuli are given: TMS - wrist - Erb, Interval between stimuli delay I (TMS - wrist) and delay II (wrist - Erb). (i) Several TST test curves are obtained by increasing stimulation intensity of TMS, and applying facilitation manoeuvres, until TST test response size does not increase further. (j) Repeat TST control curve, perform wrist stimulation alone to insure that no change has occurred during the procedure. (k) Evoke F-waves by wrist stimulation, for calculation of central motor conduction time.
=
=
=
6) Measurement:
(a) Compare size of TST test curve with that of TST control curve (see Fig. 2). TST amplitude ratio = TST test: TST control; in normal subjects always near 100%; may be reduced in patients in case of conduction failure. Normal limit for ADM> 93% (Table 1).
29 TABLE 2
CONTINUED «7) Modifications for leg examination: (a) Recording from m. abductor hallucis (AH) (b) Distal nerve stimulation: tibial nerve at ankle. (c) Proximal nerve stimulation: sciatic nerve at gluteal fold, using "near nerve" needle cathode electrode with large surface anode (30 cm-) over ventral thigh. (d) Patient prone; assistant (technician) needed to hold leg. (e) Double cone coil. (t) To facilitate responses: flexion and abduction of big toe.
• the transcranial stimulus (whether magnetic or electrical) can excite virtually all axons innervating the target muscle (Magistris et al., 1998; Btihler et al., 2001); • the reduction in size of the MEP (as compared to the peripheral response) is mainly caused by the desynchronisation of the motor unit potentials that compose the MEP (Fig. 3), and this size reduction is unpredictable and differs between subjects (Magistris et al., 1998; Rosler et al., 2(02); • when all motor units are driven to discharge by the transcranial stimulus, the variability of the MEP size from one response to the next is largely caused by changing degrees of discharge synchronicity (Magistris et al., 1998); Peripheral nervestimulus
Brainstimulus 1
• Multiple discharges of spinal motor neurons may importantly influence the size of a MEP (Magistris et al., 1998; Btihler et al., 2(01). 3.2. Clinical application of the TST Because of the methodological advantages described above, the TST allows detection of corticospinal conduction deficits in patients with central nervous system disorders (for examples see Fig. 2). In many of these patients, the conventional MEP recordings are normal. Thus, the sensitivity of the TST to detect a conduction disorder is considerably greater than that of conventional MEPs. In a large study of 271 patients with various disorders of corticospinal Brainstimulus 2
Brainstimulus 3
Fig. 3. Phase cancellation. Three identical action potentials 0, 2, and 3) are summated, and the sum potential is shown 0+ 2 + 3). The sum potential varies greatly in shape and size, which is caused by the varying degree of synchronicity of the 3 action potentials. The situation in the left panel is comparable to peripheral nerve stimulation, where action potentials are well aligned; here the amplitude of the sum potential is indicative of the number of action potentials of which it is composed. The situation in the three panels to the right is comparable to transcranial magnetic brain stimulation, where the synchronicity of the potentials varies from one stimulus to the next. The resulting sum varies from stimulus to stimulus, and the size of the resulting potential does not reflect the number of action potentials that composes it.
30 conduction, the TST disclosed conduction deficits in 212 of 489 arms, while conventional MEPs found abnormalities in 116 sides only (Magistris et al., 1999). Combining MEP and TST results led to an overall increase of diagnostic sensitivity of 1.9-fold. In all but one of the diseases studied, conduction deficits were more common than conduction slowing (Table 3). The only exception to this concerned patients with spondylotic cervical myelopathies, in which prolongations of the CMCT was found more often than deficits of conduction. Still, combining the results of the conventional MEPs with those of the TST increased the sensitivity to detect abnormalities in these patients also (Magistris et al., 1999). Favourable results were also reported in a large series of patients with amyotrophic lateral sclerosis (ALS; Resler et al., 2000). In ALS, the challenge for the
clinician and the electrophysiologist is to detect upper motor neuron dysfunction occurring along with (and masked by) lower motor neuron dysfunction. In our study, the TST-ADM disclosed central conduction deficits attributable to upper motor neuron loss in 15 of 42 sides without any clinical signs of pyramidal tract involvement (Resler et al., 2(00). Recordings from the AH muscle corroborated the results obtained from ADM, in that the sensitivity increase compared to the conventional MEPs was in a similar range (Buhler et al., 2001; Table 3). Combining the TST-ADM and the TST-AH further increased the diagnostic yield of the method (Table 4). The TST not only increases the sensitivity of transcranial stimulation to detect conduction deficits, but it also offers a way to quantify the deficit. The measured conduction deficit correlates to the
TABLE 3 NUMBER OF ABNORMAL SIDES IN PATIENTS WITH MS, ALS, OR CERVICAL MYELOPATHIES Disease
MS MS ALS ALS ALS Cerv. myelopathy Cerv. myelopathy
Recording Sides muscle n
ADM AH ADM ADM AH ADM AH
Total
Abnormal Abnormal MEPs TST
Abnormal Increase in MEP and TST sensitivity
Sides n
Sides n
Sides n
221 27 28 86 7 26 17
60 9 6 18 3 17 12
106 15 13 38 3 14 15
113 17 13 38 4 19 15
1.9x 1.9x 2.2x 2.1x 1.3 x 1.1 x 1.3x
412
125
204
219
1.8x
Reference
Magistris et al., 1999 BUhler et al., 2000 Magistris et al., 1999 Rosier et al., 2000 Biihler et al., 2000 Magistris et al., 1999 Buhler et al., 2000
TABLE 4 COMBINATION OF TST-ADM AND TST-AH, IN MS AND CERVICAL MYELOPATHY (EXTRACTED FROM BUHLER ET AL., 2000) Disease
Sides n
Abnormal TST-ADM
Abnormal TST-AH
Both abnormal
Additional gain by TST-AH
MS ALS Cervical myelopathy
25 7 6
12 4 2
12 2 4
17 5 4
lAx 1.3x 2.0x
31 Muscle force no weakness (n = 26 sides)
I
weakness (n = 16 sides)
I' I I I
t-LJJ1
:~: L.,---J--,-J I
Pyramldlal signs
hyperreflexia (n = 20 sides)
=16 sides)
I I I
I I I
I I I
i~ :~: I'~'I
I 0%
I
: :. lill
no hyperreflexia (n = 13 sides)
spasticity ± Babinski (n
:. r-n:
I
20% 40%
I 60%
I 80%
I 100%
TST amplitude ratio [%]
Fig. 4. Relation between motor deficit and TST amplitude ratio in patients with MS, ALS, and cervical myelopathies (extracted from Buhler et aI., 2(01). Boxes and whiskers give the 5th, 25th, 50th, 75th, and 95th percentiles.
clinical motor deficit suffered by the patients. An example of such a relation is given in Fig. 4. Thus, TST recordings assess the effect of lesions that are relevant in causing the patients deficit. It may be inferred that the TST could serve as a tool to follow the disease progression, e.g. in treatment trials. Pathophysiologically a reduction of the TST amplitude ratio in a patient can relate to different pathologies. Loss ofaxons, central conduction block, or increased stimulation threshold will equally affect the response. Considering the result of TST together with the CMCT and with the clinical deficit, helps to distinguish these abnormalities.
3.3. Limitations of the TST The TST faces several limitations: The proximal nerve stimulus (third stimulus) is uncomfortable for the subject. In the TST-ADM, the discomfort of Erb's point stimulus is reduced by use of "monopolar" stimulation (Roth and Magistris, 1987). For the TST-AH, proximal stimulation may be delivered in different ways. Percutaneous trans-
abdominal stimulation, as described by Troni et al. (1996) is very unpleasant, so that one may prefer use of needle stimulation performed at the gluteal fold (Yap and Hirota, 1967). • The TST cannot use recording from a proximal muscle since this does not allow for a sufficient interval between second and third stimuli. • An accurate quantification of a corticospinal conduction deficit is sometimes difficult and may require several trials using transcranial stimuli of increasing intensities and different facilitation manoeuvres (Fig. 2). Indeed, whereas the TST easily demonstrates the absence of a corticospinal conduction deficit (when superimposition of test and control curves has been obtained), it is more difficult to determine the precise value of a deficit when the "ceiling effect" given by a control value is no longer available. One has to ascertain that the transcranial stimulus is supramaximal; this is more difficult to achieve than at the peripheral nerve level, due to the larger number of factors that influence corticospinal excitability. • On some occasions, such as coma, general anaesthesia, hysteria, malingering, absent cooperation of
32 the subject during the facilitation manoeuvres may be a limitation. In this case, other facilitation manoeuvres that do not require the collaboration of the subject may be of interest (Magistris et al., in preparation). • Eventually, the TST does not distinguish the causes of a corticospinal conduction deficit that may relate to conduction block, neuronal (cellular) or axonal lesion. Despite these limitations, the TST is a powerful tool to study corticospinal conduction. 4. Conclusions The TST improved our understanding of corticospinal conduction. It explained the small size and variable configuration of the conventional MEPs and demonstrated that transcranial stimuli were able to depolarize virtually all motor units of the target muscle. The TST markedly improves the study of corticospinal conduction. It allows better detection and quantification of corticospinal conduction deficits. It offers interesting perspectives for studies that conventional MEPs do not allow. In particular, it may be used as an objective method of assessment of the effects of treatments. Eventually, it will play a role in the further understanding of the physiology of the corticospinal conduction. Acknowledgements This work was supported by the Swiss National Foundation for Research (Grants 31-43454.95 and 31-53748.98). References Andersen. B.• Rosier. K.M. and Lauritzen. M. Non-specific facilitation of responses to transcranial magnetic stimulation. Muscle Nerve, 1999. 22: 857-863. Beer, S.. Rosier. K.M. and Hess. C.W. Diagnostic value of paraclinical tests in multiple sclerosis. Relative sensitivities and
specificities for reclassification according to the Poser committee criteria. J. Neurol. Neurosurg. Psychiatry. 1995. 59: 152-159. Buhler, R, Magistris, M.R, Truffert, A.• Hess. CW. and Rosier. K.M. The triple stimulation technique to study central motor conduction to the lower limbs. Clin. Neurophysiol.• 2001. ll2: 938-949. Hess, C.W.• Mills, KR. and Murray. N.M. Magnetic stimulation of the human brain: facilitation of motor responses by voluntary contraction of ipsilateral and contralateral muscles with additional observations on an amputee. Neurosci. Lett., 1986. 71: 235-240. Hess. e.W., Mills. K.R.• Murray, N.M. and Schriefer, T.N. Magnetic brain stimulation: central motor conduction studies in multiple sclerosis. Ann. Neurol.. 1987, 22: 744-752. Kischka, U., Fajfr. R. Fellenberg, T. and Hess. CW. Facilitation of motor evoked potentials from magnetic brain stimulation in man: a comparative study of different target muscles. J. Clin. Neurophys .• 1993. 10: 505-512. Magistris, M.R. Rosier. KM.• Truffert, A. and Myers. P. Transcranial stimulation excites virtually all motor neurons supplying the target muscle: A demonstration and a method improving the study of motor evoked potentials. Brain. 1998. 121: 437-450. Magistris, M.R., Rosier. KM.• Truffert, A.• Landis. T. and Hess, e.W. A clinical study of motor evoked potentials using a triple stimulation technique. Brain. 1999. 122: 265-279. Mills, K.R. (Ed.). Magnetic Stimulation of the Human Nervous System. Oxford University Press, Oxford, 2000. Naka, D. and Mills, K.R Further evidence for corticomotor hyperexcitability in amyotrophic lateral sclerosis. Muscle Nerve. 2000. 23: 1044-1150. Rosier. K.M.• Etter. C.• Truffert, A., Hess. C.W. and Magistris, M.R. Cortical motor output map changes assessed by the triple stimulation technique. Neurokeport, 1999. 10: 579-583. Rosier. KM.. Truffert, A.. Hess. C.W. and Magistris, M.R. Quantification of upper motor neuron loss in amyotrophic lateral sclerosis. Clin. Neurophysiol.• 2000. Ill: 2208-2218. Rosier. K.M., Petrow, E., Mathis. J., Aranyi Z.• Hess. C.W. and Magistris, M.R Effect of discharge desynchronisation on the size of motor evoked potentials: an analysis. Clin. Neurophysiol.• 2002. 113: 1680-1687. Roth. G. and Magistris, M.R. Detection of conduction block by monopolar percutaneous stimulation of the brachial plexus. Electromyogr. Clin. Neurophysiol.; 1987. 27: 45-53. Roth. G. and Magistris, M.R. Identification of motor conduction block despite desynchronisation. A method. Electromyogr. Clin. Neurophysiol., 1989, 29: 305-313. Yap. C.B. and Hirota, T. Sciatic nerve motor conduction velocity study. J. Neurol. Neurosurg. Psychiatry, 1967. 30: 233-239.
24
Chapter 3
The triple stimulation technique to study corticospinal conduction M.R. Magistris-" and K.M. Resler" Departments of Neurology, University Hospitals of "Geneva and bBeme (Switzerland)
1. Introduction Motor evoked potentials (MEPs) are presently widely used to study the physiology of corticospinal conduction in healthy subjects and in patients with diseases of the central nervous system (cf. review in Mills, 2000). Main parameters studied by "conventional" MEPs are the central motor conduction time (CMCT) and the size of the MEP (amplitude, duration and area); other parameters of interest (such as stimulation thresholds, silent period, etc.) will not be considered in this chapter. Measurement of the CMCT is of interest since it can disclose slowings of central conduction that could otherwise remain subclinical (Beer et al., 1995). The evaluation of the size of the MEP should allow assessing deficits of corticospinal conduction causing the handicap of a patient, because theoretically the size of a MEP should be related to the number of conducting corticospinal motor neurons. However, this relation is obscured by some particular characteristics of MEPs, making the
* Correspondence to: Prof. Michel R. Magistris, Unite d'Electroneuromyographie et des Affections Neuromusculaires, Clinique de Neurologie, Hepitaux Universitairesde Geneve,CH-1211 Geneva 14,Switzerland. Tel: (+4122) 37 28 348; Fax (+4122) 37 28 350; E-mail: [email protected]
interpretation of MEP size measurements difficult. First, the size of a MEP is reduced (as compared to the peripheral response), and it varies from subject to subject and from one stimulus to the next (Hess et al., 1987). The magnitude of this reduction of amplitude, varies among subjects and is unpredictable (Magistris et al., 1998; Resler et al., 2002). Second, the MEP is influenced by the excitability of the corticospinal pathway, which is variable and can be facilitated by a number of mechanisms (Hess et al., 1986; Andersen et al., 1999). In particular, voluntary "background" contraction of the target muscle facilitates the MEP, reducing its threshold, shortening its latency and - most notably - increasing its size. The relation between MEP size and background contraction force is not linear and differs between muscles (Hess et al., 1987; Kischka et aI., 1993; Resler et al., 2002). Finally, a MEP includes responses of spinal motor neurons discharging more than once in response to the transcranial stimulus. Probably, the number of such multiple spinal motor neuron discharges differs between subjects, may be facilitated by voluntary contraction, and may be affected by diseases (Naka and Mills, 2000), yet their contribution to the MEP size of a given subject or patient is not known. For these reasons, conventional MEPs do not allow for an accurate assessment of corticospinal deficits.
25 The triple stimulation technique (TST) was first developed to measure conduction blocks at the peripheral nerve level (Roth and Magistris, 1989). It has been adapted for the use with transcranial brain stimulation (Magistris et al., 1998). It resolves the above mentioned difficulties of conventional MEPs. We shall describe the technique and discuss its yield and limitations in the study of corticospinal conduction.
2. Methods The TST has been described in detail in several publications (Magistris et al., 1998, 1999; Rosier et al., 1999, 2000; BUhler et aI., 2001). In short, three sequential stimuli are given with appropriate delays (Fig. 1). Two collisions of the evoked action potentials can occur. The first stimulus is the transcranial
brain stimulus. It is followed by two supramaximal stimuli of the nerve supplying the target muscle. distal then proximal. Two different TST protocols were developed, one for the study of a small hand muscle (abductor digiti minimi; ADM), and one for a foot muscle (abductor hallucis; AH). The peripheral stimuli in the TST-ADM procedure are applied over the ulnar nerve at the wrist, and over the brachial plexus (Magistris et al., 1998). Those for the TSTAH are given over the tibial nerve at the internal malleolus, and to the sciatic nerve at the gluteal fold (BUhler et al., 2001). For the latter, a monopolar needle electrode is used, which is brought into the nerve's proximity to reduce the current needed to reach supramaximal stimulation (Yap and Hirota, 1967). The descending action potentials evoked by the transcranial stimulus collide with the action
T8Tt88t
TM8
W
T8Tcontroi
Plex.
Plexus
-- -wrist
test 1
test 2
-- -teat 3
teat 4
wrist
~-- control 1 control 2 control 3 control 4
Fig. I. Triple stimulation technique (TST) principle. The motor tract is simplified to three spinal motor neurons; horizontal lines represent the muscle fibres of the three motor units. Black arrows depict action potentials that cause a trace deflection, open arrows those that do not. (test I) A submaximaltranscranial stimulus excites two spinal motor neurons out of three (large open arrows). (test 2) On 2/3 neurons, TMS induced action potentials descend. Desynchronisation of the two action potentials has occurred (possibly at spinal cell level). After a delay, a maximal stimulus is applied to the peripheral nerve at the wrist. It gives rise to a first negative deflection of the recording trace. The antidromic action potentials collide with the descending action potentials on motor neurons I and 2. The action potential on neuron 3 continues to ascend. (test 3) after a second delay a maximal stimulus is applied at the brachial plexus (Plex.), On motor neuron 3, the descending action potential collides with the ascending action potential. (test 4) A synchronised response from the two motor neurons that were initially excited by the transcranial stimulus is recorded as the second deflection of the TST test trace. (control I) A maximal stimulus is applied at Erb's point. (control 2) after a delay, a maximal stimulus applied at the wrist is recorded as the first deflection of the TST control trace. (control 3) after a delay a maximal stimulus is applied at Erb's point. (control 4) a synchronised response from the three motor neurons is recorded as the second deflection of the TST control trace. The test response is quantified as the ratio of TST test (test 4): TST control (control 4).
26 potentials evoked by the second, distal stimulus, which is given after a first delay (Fig. 1). After a second delay, the third stimulus, proximal, evokes the response that will be studied. This is the response of those motor units which were initially excited by the transcranial stimulus. However, whereas the descending activity evoked by the brain stimulus was desynchronised, the activity of the same motor units is now synchronised by the collisions, in the same manner as it would in response to a single proximal nerve stimulus (Fig. 1). The response is compared to that of a control curve, obtained by a triple stimulation procedure performed on the peripheral nerve (where the first transcranial stimulus is replaced by a stimulus applied at the proximal site, Fig. 1). The size ratio of the TST test and TST control curves was termed "TST amplitude ratio" or ''TST area ratio"; it is an estimate of the proportion of the motor neuron pool of the target muscle that was driven to discharge by the transcranial stimulus. The TST procedure, which originally required additional external stimulators, has recently been simplified by a dedicated software package for the Nicolet Viking apparatus (Judex Datasystemer AlS, Lyngvej 8, DK-9000 Aalborg, and Nicolet, Madison, WI, USA). Using this software, the two stimulators of the
EMG machine are sequentially triggered at preselected intervals, to provide the stimulations needed during both TST test and TST control procedures. For transcranial stimulation, a standard magnetic stimulator is used, and choice of coils and coil placements are the same as for conventional MEPs. A high voltage electrical stimulator (Digitimer, Welwyn Garden City, UK) may replace the magnetic stimulator when direct stimulation of the pyramidal axon hillock is required. Table 2 details the TST procedures.
3. Results 3.1. Neurophysiological aspects The three stimuli of the TST couple central and peripheral conductions through the two collisions (Fig. 1). This results in a "resynchronisation" of the action potentials evoked by the transcranial stimulus. Moreover, the influence of multiple discharges of spinal neurons is avoided. Indeed, the collision affects only the first descending action potential descending on a given peripheral axon, whereas any following action potentials (i.e. the multiple discharges) escape collision. The latter are recorded between the two main deflections of the TST curve.
TABLE 1 NORMAL MEANS AND NORMAL LIMITS FOR EXAMINATION OF TWO MUSCLES USING THE TST ADM
*
AH
**
Mean (SD)
Normal limit
Mean (SD)
Normal limit
TST amplitude ratio TST area ratio
99.1% (2.14) 98.5% (2.48)
~93%
95.0% (4.06) 96.1% (8.30)
~84%
MEP amplitude ratio MEP area ratio
66.1% (12.99) 96.8% (17.95)
~33%
37.2% (9.72) 99.7% (38.45)
~43%
Mean amplitude loss Mean area loss
34.3% 16.2%
TST amplitude variability (CoV) MEP amplitude variability (CoV)
* Magistris et aI.,
1998.
2.6% 8.1%
*** ***
~92%
~52%
57.8% (9.12) 58.9% (11.36)
* *
** BUhler et al., 2000. *** Rosier et aI., 2002. CoY: Coefficient of Variation.
~88%
~21%
27 Nonnalsubjecl
MSpallenl2
MS~llenl1
TSTcontrol
TST llI8l
100"'" 90% lIO%
Cond uct.on deficit: 22%
Conducbon defICit: 54%
(Cent,al conduction time: 7.3 ms)
(Central conduction t,me: 7.1 ms)
Fig. 2. Examples of TST recordings in a normal subject and in two patients with multiple sclerosis. Several recordings are superimposed: The TST control curve (which calibrates the TST test recordings), and TST test curves obtained with increasing stimulus intensity. Note that in the normal subjects, a superposition of the TST test and TST control curves is obtained (TST amplitude ratio = 100%), whereas in the two MS patients, the TST test curve does not reach the TST control curve even with 100% of stimulator output. Thus, the TST demonstrates a conduction deficit in both patients. The central motor conduction time is normal in both patients.
In both target muscles (ADM and AH) and in all healthy subjects studied, the TST amplitude and area ratios were close to 100%, indicating that nearly all target motor units were driven to discharge by the transcranial stimulus (an example is given in Fig. 2). Moreover, the variability of the TST amplitude and area ratios was markedly reduced compared to MEPs (Magistris et al., 1998). These observations demonstrate that size reduction and variability of MEPs are mainly caused by varying synchronisation of the descending action potentials evoked by the transcranial stimulus, and by the associated phase cancellation phenomena (Fig. 3). The mean values of the TST amplitude and area ratio in normal subjects are given along with the respective nonnallimits in Table 1. Comparison of the TST results with those of the conventional MEPs allows an estimate of the degree of size reduction caused by the discharge desynchronisation. For ADM, four previous studies suggested a rather uniform average MEP amplitude loss in healthy subjects and patients, of about one third of the "true" size (Magistris et al., 1998, 1999; Rosler et al., 2000, 2002; Table 1). For AH, the average amplitude loss is greater (approximately
55%), due to the considerably greater degree of discharge desynchronisation (Biihler et al., 2001; Table 1). The size reducing effect of the discharge desynchronisation was not influenced by submaximal stimulation, but differed greatly (and unpredictably) between subjects (Rosler et al., 2(02). An important aspect of the TST is the fact that it does not only resynchronise the motor unit discharges, but that it also suppresses the effects of multiple spinal motor neuron discharges. This effect appeared particularly important for studies involving the AH (Biihler et al., 2(01), where multiple spinal motor neuron discharges sometimes appeared to artificially amplify the MEP responses. One of the reasons for the proneness of AH-MEP to be contaminated by multiple discharges probably relates to the fact that the background contraction needed to obtain discharge of all motor units is higher than in ADM. Multiple spinal motor neuron discharges are markedly facilitated by voluntary background contraction (Naka and Mills, 2000; Magistris, Rosler et al., in preparation). Summarised, the following conclusions can be drawn from the TST studies in healthy subjects:
28 TABLE 2 CLINICAL APPLICATION OF THE TRIPLE STIMULATION TECHNIQUE WITH RECORDING FROM M. ABDUCTOR DIGm MINIMI (ADM); AND MODIFICATION TO USE WITH M. ABDUCTOR HALLUCIS (AB) (1) Muscle recording: (a) Standard recording electrodes, just as for motor nerve conduction studies, belly-tendon technique. (b) Fix fingers by tape around fingers II-V to keep muscle geometry constant. Use sandbag (2.5-5 kg) to hold hand down. (c) Bandpass filters 2 Hz-to kHz.
(2) Peripheral nerve stimulation:
(a) Supramaximal stimulation of ulnar nerve at the wrist. (b) Use external stimulator triggered through external timer, or internal stimulator of EMG apparatus with timer software. (c) Silver stimulation electrodes (8 mID diameter), taped over the nerve. (d) To account for volume conduction from brachial plexus by Erb stimulation, the median nerve may be stimulated simultaneously. (e) Apply same facilitation manoeuvre during peripheral stimulation than during transcranial magnetic stimulation (e.g. slight voluntary contraction).
(3) Proximal nerve stimulation:
(a) Brachial plexus stimulation using monopolar cathode at Erb's point (surface 1 cnr') and large remote anode (30 em') taped over internal region of suprascapular fossa. Supramaximal stimulation often requires application of some external pressure on the stimulating cathode. (b) Use external stimulator triggered through external timer, or internal stimulator of EMG apparatus with timer software. (c) Supramaximal stimulation! (is always possible). (d) Apply same facilitation manoeuvre during peripheral stimulation than during transcranial magnetic stimulation (e.g. slight voluntary contraction).
(4) Transcranial magnetic stimulation:
(a) Any magnetic stimulator can be used. (b) Circular coil (or other coils depending on purpose of study, e.g, mapping with figure-of-eight coil). (c) Coil placement as for conventional motor evoked potentials.
(5) Procedure: (a) Patient lays supine. Fingers fixed by tape and hand fixed by sandbag. (b) Supramaximal ulnar nerve stimulation at wrist, during slight voluntary contraction. (c) Supramaximal stimulation at Erb's point, during slight voluntary contraction. (d) Conventional TMS, several stimuli using increasing stimulation intensity and slight voluntary contraction to facilitate the responses. Measurement of shortest latency and largest amplitude of the motor evoked potential (MEP). (e) Calculation of delay I latency of MEP - latency of CMAP wrist (rounded down to nearest ms). (f) Calculation of delay II latency of CMAP Erb - latency of CMAP wrist (rounded down to nearest ms). (g) TST control curve: 3 stimuli are given: Erb - wrist - Erb. Interval between stimuli = delay II. (h) TST test curve: 3 stimuli are given: TMS - wrist - Erb, Interval between stimuli delay I (TMS - wrist) and delay II (wrist - Erb). (i) Several TST test curves are obtained by increasing stimulation intensity of TMS, and applying facilitation manoeuvres, until TST test response size does not increase further. (j) Repeat TST control curve, perform wrist stimulation alone to insure that no change has occurred during the procedure. (k) Evoke F-waves by wrist stimulation, for calculation of central motor conduction time.
=
=
=
6) Measurement:
(a) Compare size of TST test curve with that of TST control curve (see Fig. 2). TST amplitude ratio = TST test: TST control; in normal subjects always near 100%; may be reduced in patients in case of conduction failure. Normal limit for ADM> 93% (Table 1).
29 TABLE 2
CONTINUED «7) Modifications for leg examination: (a) Recording from m. abductor hallucis (AH) (b) Distal nerve stimulation: tibial nerve at ankle. (c) Proximal nerve stimulation: sciatic nerve at gluteal fold, using "near nerve" needle cathode electrode with large surface anode (30 cm-) over ventral thigh. (d) Patient prone; assistant (technician) needed to hold leg. (e) Double cone coil. (t) To facilitate responses: flexion and abduction of big toe.
• the transcranial stimulus (whether magnetic or electrical) can excite virtually all axons innervating the target muscle (Magistris et al., 1998; Btihler et al., 2001); • the reduction in size of the MEP (as compared to the peripheral response) is mainly caused by the desynchronisation of the motor unit potentials that compose the MEP (Fig. 3), and this size reduction is unpredictable and differs between subjects (Magistris et al., 1998; Rosler et al., 2(02); • when all motor units are driven to discharge by the transcranial stimulus, the variability of the MEP size from one response to the next is largely caused by changing degrees of discharge synchronicity (Magistris et al., 1998); Peripheral nervestimulus
Brainstimulus 1
• Multiple discharges of spinal motor neurons may importantly influence the size of a MEP (Magistris et al., 1998; Btihler et al., 2(01). 3.2. Clinical application of the TST Because of the methodological advantages described above, the TST allows detection of corticospinal conduction deficits in patients with central nervous system disorders (for examples see Fig. 2). In many of these patients, the conventional MEP recordings are normal. Thus, the sensitivity of the TST to detect a conduction disorder is considerably greater than that of conventional MEPs. In a large study of 271 patients with various disorders of corticospinal Brainstimulus 2
Brainstimulus 3
Fig. 3. Phase cancellation. Three identical action potentials 0, 2, and 3) are summated, and the sum potential is shown 0+ 2 + 3). The sum potential varies greatly in shape and size, which is caused by the varying degree of synchronicity of the 3 action potentials. The situation in the left panel is comparable to peripheral nerve stimulation, where action potentials are well aligned; here the amplitude of the sum potential is indicative of the number of action potentials of which it is composed. The situation in the three panels to the right is comparable to transcranial magnetic brain stimulation, where the synchronicity of the potentials varies from one stimulus to the next. The resulting sum varies from stimulus to stimulus, and the size of the resulting potential does not reflect the number of action potentials that composes it.
30 conduction, the TST disclosed conduction deficits in 212 of 489 arms, while conventional MEPs found abnormalities in 116 sides only (Magistris et al., 1999). Combining MEP and TST results led to an overall increase of diagnostic sensitivity of 1.9-fold. In all but one of the diseases studied, conduction deficits were more common than conduction slowing (Table 3). The only exception to this concerned patients with spondylotic cervical myelopathies, in which prolongations of the CMCT was found more often than deficits of conduction. Still, combining the results of the conventional MEPs with those of the TST increased the sensitivity to detect abnormalities in these patients also (Magistris et al., 1999). Favourable results were also reported in a large series of patients with amyotrophic lateral sclerosis (ALS; Resler et al., 2000). In ALS, the challenge for the
clinician and the electrophysiologist is to detect upper motor neuron dysfunction occurring along with (and masked by) lower motor neuron dysfunction. In our study, the TST-ADM disclosed central conduction deficits attributable to upper motor neuron loss in 15 of 42 sides without any clinical signs of pyramidal tract involvement (Resler et al., 2(00). Recordings from the AH muscle corroborated the results obtained from ADM, in that the sensitivity increase compared to the conventional MEPs was in a similar range (Buhler et al., 2001; Table 3). Combining the TST-ADM and the TST-AH further increased the diagnostic yield of the method (Table 4). The TST not only increases the sensitivity of transcranial stimulation to detect conduction deficits, but it also offers a way to quantify the deficit. The measured conduction deficit correlates to the
TABLE 3 NUMBER OF ABNORMAL SIDES IN PATIENTS WITH MS, ALS, OR CERVICAL MYELOPATHIES Disease
MS MS ALS ALS ALS Cerv. myelopathy Cerv. myelopathy
Recording Sides muscle n
ADM AH ADM ADM AH ADM AH
Total
Abnormal Abnormal MEPs TST
Abnormal Increase in MEP and TST sensitivity
Sides n
Sides n
Sides n
221 27 28 86 7 26 17
60 9 6 18 3 17 12
106 15 13 38 3 14 15
113 17 13 38 4 19 15
1.9x 1.9x 2.2x 2.1x 1.3 x 1.1 x 1.3x
412
125
204
219
1.8x
Reference
Magistris et al., 1999 BUhler et al., 2000 Magistris et al., 1999 Rosier et al., 2000 Biihler et al., 2000 Magistris et al., 1999 Buhler et al., 2000
TABLE 4 COMBINATION OF TST-ADM AND TST-AH, IN MS AND CERVICAL MYELOPATHY (EXTRACTED FROM BUHLER ET AL., 2000) Disease
Sides n
Abnormal TST-ADM
Abnormal TST-AH
Both abnormal
Additional gain by TST-AH
MS ALS Cervical myelopathy
25 7 6
12 4 2
12 2 4
17 5 4
lAx 1.3x 2.0x
31 Muscle force no weakness (n = 26 sides)
I
weakness (n = 16 sides)
I' I I I
t-LJJ1
:~: L.,---J--,-J I
Pyramldlal signs
hyperreflexia (n = 20 sides)
=16 sides)
I I I
I I I
I I I
i~ :~: I'~'I
I 0%
I
: :. lill
no hyperreflexia (n = 13 sides)
spasticity ± Babinski (n
:. r-n:
I
20% 40%
I 60%
I 80%
I 100%
TST amplitude ratio [%]
Fig. 4. Relation between motor deficit and TST amplitude ratio in patients with MS, ALS, and cervical myelopathies (extracted from Buhler et aI., 2(01). Boxes and whiskers give the 5th, 25th, 50th, 75th, and 95th percentiles.
clinical motor deficit suffered by the patients. An example of such a relation is given in Fig. 4. Thus, TST recordings assess the effect of lesions that are relevant in causing the patients deficit. It may be inferred that the TST could serve as a tool to follow the disease progression, e.g. in treatment trials. Pathophysiologically a reduction of the TST amplitude ratio in a patient can relate to different pathologies. Loss ofaxons, central conduction block, or increased stimulation threshold will equally affect the response. Considering the result of TST together with the CMCT and with the clinical deficit, helps to distinguish these abnormalities.
3.3. Limitations of the TST The TST faces several limitations: The proximal nerve stimulus (third stimulus) is uncomfortable for the subject. In the TST-ADM, the discomfort of Erb's point stimulus is reduced by use of "monopolar" stimulation (Roth and Magistris, 1987). For the TST-AH, proximal stimulation may be delivered in different ways. Percutaneous trans-
abdominal stimulation, as described by Troni et al. (1996) is very unpleasant, so that one may prefer use of needle stimulation performed at the gluteal fold (Yap and Hirota, 1967). • The TST cannot use recording from a proximal muscle since this does not allow for a sufficient interval between second and third stimuli. • An accurate quantification of a corticospinal conduction deficit is sometimes difficult and may require several trials using transcranial stimuli of increasing intensities and different facilitation manoeuvres (Fig. 2). Indeed, whereas the TST easily demonstrates the absence of a corticospinal conduction deficit (when superimposition of test and control curves has been obtained), it is more difficult to determine the precise value of a deficit when the "ceiling effect" given by a control value is no longer available. One has to ascertain that the transcranial stimulus is supramaximal; this is more difficult to achieve than at the peripheral nerve level, due to the larger number of factors that influence corticospinal excitability. • On some occasions, such as coma, general anaesthesia, hysteria, malingering, absent cooperation of
32 the subject during the facilitation manoeuvres may be a limitation. In this case, other facilitation manoeuvres that do not require the collaboration of the subject may be of interest (Magistris et al., in preparation). • Eventually, the TST does not distinguish the causes of a corticospinal conduction deficit that may relate to conduction block, neuronal (cellular) or axonal lesion. Despite these limitations, the TST is a powerful tool to study corticospinal conduction. 4. Conclusions The TST improved our understanding of corticospinal conduction. It explained the small size and variable configuration of the conventional MEPs and demonstrated that transcranial stimuli were able to depolarize virtually all motor units of the target muscle. The TST markedly improves the study of corticospinal conduction. It allows better detection and quantification of corticospinal conduction deficits. It offers interesting perspectives for studies that conventional MEPs do not allow. In particular, it may be used as an objective method of assessment of the effects of treatments. Eventually, it will play a role in the further understanding of the physiology of the corticospinal conduction. Acknowledgements This work was supported by the Swiss National Foundation for Research (Grants 31-43454.95 and 31-53748.98). References Andersen. B.• Rosier. K.M. and Lauritzen. M. Non-specific facilitation of responses to transcranial magnetic stimulation. Muscle Nerve, 1999. 22: 857-863. Beer, S.. Rosier. K.M. and Hess. C.W. Diagnostic value of paraclinical tests in multiple sclerosis. Relative sensitivities and
specificities for reclassification according to the Poser committee criteria. J. Neurol. Neurosurg. Psychiatry. 1995. 59: 152-159. Buhler, R, Magistris, M.R, Truffert, A.• Hess. CW. and Rosier. K.M. The triple stimulation technique to study central motor conduction to the lower limbs. Clin. Neurophysiol.• 2001. ll2: 938-949. Hess, C.W.• Mills, KR. and Murray. N.M. Magnetic stimulation of the human brain: facilitation of motor responses by voluntary contraction of ipsilateral and contralateral muscles with additional observations on an amputee. Neurosci. Lett., 1986. 71: 235-240. Hess. e.W., Mills. K.R.• Murray, N.M. and Schriefer, T.N. Magnetic brain stimulation: central motor conduction studies in multiple sclerosis. Ann. Neurol.. 1987, 22: 744-752. Kischka, U., Fajfr. R. Fellenberg, T. and Hess. CW. Facilitation of motor evoked potentials from magnetic brain stimulation in man: a comparative study of different target muscles. J. Clin. Neurophys .• 1993. 10: 505-512. Magistris, M.R. Rosier. KM.• Truffert, A. and Myers. P. Transcranial stimulation excites virtually all motor neurons supplying the target muscle: A demonstration and a method improving the study of motor evoked potentials. Brain. 1998. 121: 437-450. Magistris, M.R., Rosier. KM.• Truffert, A.• Landis. T. and Hess, e.W. A clinical study of motor evoked potentials using a triple stimulation technique. Brain. 1999. 122: 265-279. Mills, K.R. (Ed.). Magnetic Stimulation of the Human Nervous System. Oxford University Press, Oxford, 2000. Naka, D. and Mills, K.R Further evidence for corticomotor hyperexcitability in amyotrophic lateral sclerosis. Muscle Nerve. 2000. 23: 1044-1150. Rosier. K.M.• Etter. C.• Truffert, A., Hess. C.W. and Magistris, M.R. Cortical motor output map changes assessed by the triple stimulation technique. Neurokeport, 1999. 10: 579-583. Rosier. KM.. Truffert, A.. Hess. C.W. and Magistris, M.R. Quantification of upper motor neuron loss in amyotrophic lateral sclerosis. Clin. Neurophysiol.• 2000. Ill: 2208-2218. Rosier. K.M., Petrow, E., Mathis. J., Aranyi Z.• Hess. C.W. and Magistris, M.R Effect of discharge desynchronisation on the size of motor evoked potentials: an analysis. Clin. Neurophysiol.• 2002. 113: 1680-1687. Roth. G. and Magistris, M.R. Detection of conduction block by monopolar percutaneous stimulation of the brachial plexus. Electromyogr. Clin. Neurophysiol.; 1987. 27: 45-53. Roth. G. and Magistris, M.R. Identification of motor conduction block despite desynchronisation. A method. Electromyogr. Clin. Neurophysiol., 1989, 29: 305-313. Yap. C.B. and Hirota, T. Sciatic nerve motor conduction velocity study. J. Neurol. Neurosurg. Psychiatry, 1967. 30: 233-239.