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The triple stimulation technique
Clinical Neurophysiology of Motor Neuron Diseases Handbook of Clinical Neurophysiology, Vol. 4 A. Eisen (Ed.) q 2004 Published by Elsevier B.V.
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CHAPTER 16
The triple stimulation technique Kai M. Ro¨slera,* and Michel R. Magistrisb a
Department of Neurology, University of Berne, CH-3010 Berne, Switzerland b Department of Neurology, University of Geneva, Geneva, Switzerland
16.1. Introduction Amyotrophic lateral sclerosis (ALS) is characterized by a progressive degenerative loss of corticospinal (“upper”) and spinal (“lower”) motor neurons (UMNs, LMNs). Clinically, it is often difficult to appreciate to what extent the respective loss of UMNs and LMNs contributes to the weakness experienced by the patient. In particular, prominent denervation due to LMN loss may mask signs of UMN loss. Electrophysiological methods are a potential solution to this problem. A number of established electrophysiological methods exist to measure the loss of LMNs. The size of compound muscle action potentials (CMAPs) is related to the number of innervated muscle fibers (Kelly et al., 1990) and allows a crude estimate of LMNs. Various more accurate methods have been described to estimate the number of motor units of a given muscle; they are described in Chapter 13 of this book. Quantification of UMN loss is more difficult. Corticospinal conduction can be examined using transcranial magnetic stimulation (TMS) and abnormalities of motor-evoked potentials (MEPs) were often described in ALS patients (Schriefer et al., 1989; Eisen et al., 1990; Miscio et al., 1999; Schulte-Mattler et al., 1999; Triggs et al., 1999). However, the conventional MEP parameters, in particular the central motor conduction time (CMCT), are not directly related to the number of UMNs lost (see Chapter 14 of this book). Moreover, abnormal CMCTs are not consistently found in all patients, and thus the sensitivity of the method to * Correspondence to: Dr. K. M. Ro¨sler, Department of Neurology, Inselspital, CH-3010 Berne, Switzerland. E-mail address: [email protected] (K.M. Ro¨sler). Tel.: þ 41-31-632-3098; fax: þ41-31-632-3011.
diagnose UMN disorder varies considerably between studies. Theoretically, the size of an MEP should reflect the number of conducting central motor neurons. In practice, this relation appears obscured, since in patients and healthy subjects, MEPs are usually smaller than CMAPs evoked by peripheral nerve stimulation. Moreover, the MEP size and configuration varies from one stimulus to another and between subjects (Hess et al., 1987; Britton et al., 1991; Kiers et al., 1993). It was shown that these MEP characteristics are mainly caused by varying synchronization of the descending action potentials (Magistris et al., 1998). The resulting phase cancellation phenomenon impedes direct conclusions on the number of activated motor neurons (Fig. 1). In ALS, desynchronization of the descending volleys after TMS is probably often abnormally high (Awiszus and Feistner, 1993; Mills, 1995; Kohara et al., 1999; Weber et al., 2000). A further difficulty pertinent to ALS is that the assessment of UMN integrity is complicated by the loss of LMNs, which may influence the size of MEPs dramatically. An ideal technique for UMN quantification in ALS should therefore: (i) solve the problem of varying (de-)synchronization of the descending activity after TMS; and (ii) allow elimination (or estimation) of the influence of LMN loss on the MEP. Recently, we demonstrated that a triple stimulation technique (TST) can solve these two problems. Use of this collision technique suppresses the effects of central action potential desynchronization (Magistris et al., 1998). As a consequence, it provides a quantitative measure of the percentage of spinal motor neurons that can be brought to discharge by TMS. In healthy subjects, this percentage is always near 100%. In patients with central motor disorders,
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Fig. 1. Principle of phase cancellation. In this scheme four identical biphasic motor unit potentials (1– 4) add to give rise to a compound muscle action potential (CMAP) (below, 1 þ 2 þ 3 þ 4). Left panel: the four MUPs are synchronized, the negative and positive phases add. This situation resembles peripheral nerve stimulation, where the CMAP size represents the number of activated motor units. Right panels: Different degrees of desynchronization of potentials 1 – 4 occur. The compound action potential changes its configuration and size in each condition. This situation resembles that observed in response to brain stimulation.
this percentage is often smaller as a result of the corticospinal conduction failure. Muscle weakness and TST result are quantitatively related, indicating that the TST indeed measures a central conduction parameter relevant for the clinical deficit. Moreover, the TST allows elimination of the influence of peripheral conduction on the result within the same measurement. In the following, we will highlight the method and its potential use in ALS. 16.2. The method The TST involves a transcranial brain stimulus, followed by two stimuli on the peripheral nerve. The three stimuli are appropriately timed to allow collisions of the evoked action potentials at the desired locations. Recording of conventional MEPs and of peripheral motor conduction are integrated elements of the measurement since they are required to define the individual stimulus intervals. Recording protocols have been defined for two muscles, m. abductor digiti minimi (ADM) and m. abductor hallucis (AH). 16.2.1. TST with recording from abductor digiti minimi 16.2.1.1. Peripheral conduction Recordings of the ADM are carried out using a standard muscle belly-tendon technique with
surface electrodes. Bandpass filtering is between 2 Hz and 10 kHz. A ground electrode is taped to the dorsum of the hand. The patient’s position is supine with the hand held in place by a 2.5– 5 kg sand bag; the geometry of the fingers is kept constant by taping fingers II– V together. In a first step, the CMAPs are recorded after maximal stimulation of the ulnar nerve at the wrist (CMAPwrist) and at Erb’s point (CMAPErb), both at rest and during a slight voluntary contraction of the ADM. For the following procedures, it is convenient to tape the stimulating electrodes over both stimulation sites. At the wrist, stimuli are applied via two silver electrodes (diameter ¼ 0.8 cm), the cathode being taped over the ulnar nerve proximal to the pisiform bone and the anode posteriorly on the wrist at the same level in order to avoid anodal stimulation. To avoid influences of volume conduction by median innervated muscles after Erb’s stimulation (see below), it may be helpful to stimulate the median nerve simultaneously with the ulnar nerve (i.e. by taping a second cathode over the median nerve and having a common anode with the ulnar nerve, or by using a second pair of stimulating electrodes). At Erb’s point, monopolar stimulation is used, as described previously (Roth and Magistris, 1987), with a small cathode electrode taped over Erb’s
THE TRIPLE STIMULATION TECHNIQUE
point (diameter ¼ 1 cm) and a large remote anode electrode (surface approx. 25 – 30 cm2) taped over the internal region of the suprascapular fossa. The large remote anode should be flexible to allow for maximal skin contact. We have successfully used two types: a custom-made thin lead sheet electrode (40 £ 70 mm) and a commercial 40 £ 60 mm rubber electrode for use in electrotherapy (EnrafNonius BV, Delft, The Netherlands). For the calculation of the CMCT, the peripheral conduction time (needed for the calculation of the CMCT) is determined using the minimal ulnar F-wave latency. 16.2.1.2. Conventional MEPs Conventional MEPs are obtained using a magnetic stimulator (if desired, an electrical brain stimulator can also be used). A standard round magnetic coil is placed at the vertex or slightly lateral toward the stimulated hemisphere. To ensure maximal stimulation, the position yielding the lowest threshold is searched. Magnetic stimuli are usually applied while the subject is slightly contracting the target ADM to facilitate the response. The MEP latency is defined as the
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shortest latency from several responses and the CMCT is calculated using the formula: CMCT ¼ MEP latency 2 (F latency þ CMAPwrist latency 2 1)=2 (Rossini et al., 1985).
16.2.1.3. TST To achieve the timing of the three stimuli, two external electrical stimulators (e.g. Digitimer DS7) and the magnetic stimulator may be triggered by an external timer (e.g. Digitimer D4030) (Fig. 2). Alternatively, for the Nicolet Viking EMG machines (Nicolet, Madison, USA), a dedicated software package may be installed, allowing triggering of the external magnetic stimulator and two internal electrical stimulators at the required intervals (Judex Datasystemer A/S, Lyngvej 8, DK9000 Aalborg). Three stimuli are given, leading to two collisions (Fig. 3A). A first stimulus is applied to the scalp overlying the motor cortex. After an appropriate delay, a second maximal stimulus is applied over the ulnar nerve at the wrist. The delay is chosen so that the action potentials descending from the cortex collide with the antidromic action potentials evoked at the wrist, with the collision
Fig. 2. Set-up of the triple stimulation technique (TST). Transcranial magnetic stimulator and two electrical stimulators are triggered at appropriate intervals by a timer (sequence for the TSTtest curve: transcranial stimulation –electrical ulnar nerve stimulation at wrist – electrical stimulation at Erb’s point; sequence for the TSTcontrol curve performed for comparison: electrical stimulation at Erb’s point– electrical ulnar nerve stimulation at wrist – electrical stimulation at Erb’s point). Electrical peripheral stimulations are maximal. Monopolar stimulation of the brachial plexus uses a small cathode at Erb’s point and a large anode over the upper aspect of the scapula. Recording performed with surface electrodes from abductor digiti minimi.
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Fig. 3. Principle of the triple stimulation technique (TST). The motor tract is simplified to four spinal motor neurons with their axons. Horizontal lines represent the muscle fibers of the four motor units. Solid arrows depict action potentials giving rise to a trace deflection, open arrows depict action potentials that are not recorded. (A1) In the example, only three of four motor neurons are brought to discharge by the brain stimulus due to upper motor neuron lesion. (A2) Following the brain stimulus, action potentials descend in axons 1– 3. Desynchronization of the three action potentials has occurred. Motor neurons 1 and 2 discharge twice so that a second action potential descends (p). After a delay, a maximal second stimulus is given at the wrist (W), leading to descending (orthodromic) action potentials causing a first negative deflection of TSTtest curve, and to ascending (antidromic) action potentials in all four axons. Three of the ascending action potentials collide and cancel with the action potentials descending in axons 1 – 3. The sites of collision are different due to the desynchronization of the descending action potentials. (A3) The multiple discharges (p) on motor neurons 1 and 2 are not cancelled and continue to descend. They give rise to a small deflection in the trace (p). The action potential on axon 4 continues to ascend, since no collision occurred. (A4) After a delay, a maximal third stimulus is given at Erb’s point, evoking action potentials, which descend on axons 1 – 3, while a collision occurs in axon 4. (A5) Finally, a synchronized response from the three axons (1– 3) which were initially excited by the transcranial stimulus is recorded as a second main deflection of the TSTtest curve. (B1 – B5): The TSTcontrol curve is recorded by replacing the first stimulus at the cortex by a supramaximal stimulus at Erbs point (succession of stimuli: Erb –wrist –Erb) with appropriate adjustments of the delays. (C): Superposition of TSTtest and TSTcontrol curves. The TST amplitude ratio is 75%, indicating that three of four neurons were excited by the transcranial stimulus.
site at the wrist and above. After another delay, a third stimulus is applied at Erb’s point. This delay is chosen so that ascending antidromic action potentials evoked by wrist stimulation collide slightly distal to Erb’s point. The delays are calculated as follows: †
†
Delay I (brain 2 wrist) ¼ minimal MEP latency 2 CMAPwrist latency Delay II (wrist 2 Erb) ¼ CMAPErb latency 2 CMAPwrist latency,
where the minimal MEP latency and the CMAPErb latency are rounded down to the nearest millisecond,
and the CMAPwrist latency is rounded up to the nearest millisecond. The response to the third stimulus is studied. It is often smaller than the response evoked by a single stimulus at Erb’s point, presumably by a “backresponse” caused by myo-axonal ephaptic excitation of axons by the wrist stimulus (Roth and Egloff-Baer, 1979). To account for this phenomenon, the TSTtest curve is compared with a TSTcontrol curve in which the first stimulus is applied to Erb’s point. Stimuli are thus applied successively to Erb’s point– wrist – Erb’s point (Fig. 3B); the delays between the stimuli are adjusted appropriately (delay I ¼ delay II ¼ CMAPErb latency 2 CMAPwrist latency). Quantification of the
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excited motor axons is then achieved by calculation of the amplitude ratio of the second main deflections of the TST test and control curves (TST amplitude ratio ¼ TSTtest : TSTcontrol; Fig. 3C). The area of the responses can also be measured, but the amplitude measurement was shown to be slightly more accurate (Magistris et al., 1998). The TSTtest:TSTcontrol ratio corresponds to the proportion of motor units excited in the target muscle, assuming as an approximation that all motor unit potentials composing the CMAP have a similar size: – If a cortical stimulus succeeds in exciting all spinal motor axons innervating the target muscle, a maximal motor response follows the third stimulus applied to Erb’s point and the ratio is 100%. – If all axons fail to conduct following brain stimulation, no motor response follows the third stimulus applied to Erb’s point and the ratio is 0%. – If a number of axons conduct while others do not, the motor response to Erb’s stimulus is reduced in amplitude and area (Fig. 3A). During a patient examination, the TSTtest trials are preceded and followed by recording of a TST control curve. Several TST test curves are recorded using increasing intensities of transcranial stimulation until the best possible superimposition of the TSTtest and TSTcontrol curves is achieved. In addition, facilitation maneuvers are applied, in particular slight contraction of the target ADM during the stimulus. Acoustic monitoring of the EMG activity allows judging about the degree of muscle relaxation or contraction. Exact superimposition of the first main negative deflection (CMAPwrist) of the TSTtest and TSTcontrol curves demonstrate that the position of the target muscle remained fixed throughout the examination (Roth and Magistris, 1989; Magistris et al., 1998). 16.2.2. Modifications for recording from m. abductor hallucis MEPs in small foot muscles are best obtained using a double cone coil, which delivers stronger stimuli. Hence, for the TST of AH, a double-cone coil is optimal, even though the standard round coil
is often sufficient to achieve maximal stimulation. Distal peripheral nerve stimulation is at the ankle, where maximal electrical stimuli are applied to the tibial nerve via two surface electrodes. The cathode is taped over the nerve proximal to the medial malleolus and the anode on the opposite side on the lateral malleolus in order to avoid anodal stimulation. Proximal nerve stimulation concerns the sciatic nerve in the gluteal region. To allow supramaximal stimulation with reasonable electrical stimulation intensity, a monopolar needle electrode is used as cathode, as described by Yap and Hirota (1967). We use a disposable needle electrode, which is insulated with the exception of the tip (TECA, Oxford Instruments Medical System Division, New York, USA; length 25 – 75 mm). The needle is inserted between the long head of the biceps femoris muscle and the semitendinosus muscle, at the level of the gluteal fold. A large remote surface anode electrode is taped over the ventral proximal thigh. The tip of the stimulation needle is then cautiously positioned close to the nerve (although not as close as in sensory “nearnerve needle” techniques) by maximizing the response size to repeated submaximal stimuli, so that the stimulus strength needed for maximal responses is low. 16.2.3. Other muscles The TST may be performed to other distal muscles, in particular to other small hand muscles. Recordings from the first dorsal interosseus (ID1) have the disadvantage that volume conducted activity from co-stimulated muscles innervated by the median nerve may be more important than in ADM, particularly with stimulation at Erb’s point. To correct this, co-stimulation of median and ulnar nerve at the wrist may be envisaged. A similar problem arises for recordings from thenar muscles, where ulnar mediated volume conduction may disturb the responses from median innervated muscles and vice versa. Also here, co-stimulation of both nerves at the wrist may be necessary. Normal values for ID1 and abductor pollicis brevis have not yet been defined, but activation of 100% of the target motor neurons is usually obtained. The TST cannot be performed to proximal muscles, since the short distances do not allow for sufficient stimulation delays, and proximal nerve stimulation
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sites may not be accessible. Combination of cranial nerve studies with the TST may be well suited for examinations of patients with bulbar forms of ALS (Truffert et al., 2000). 16.3. Results 16.3.1. Healthy subjects In all healthy subjects studied, and in both target muscles studied so far (ADM and AH), the maximally achieved TST amplitude and area ratios were close to 100%, indicating that nearly all target motor units can be driven to discharge by the transcranial stimulus (example in Fig. 4). Moreover, the variability of the TST amplitude and area ratios is markedly reduced compared with MEPs (Magistris et al., 1998). These observations demonstrate that size reduction and
Fig. 4. TST recordings from abductor digiti minimi of a healthy subject, during slight voluntary contraction. The three TSTtest curves are obtained with a stimulus intensity of 80% of the maximal output. TSTcontrol curve and response to wrist stimulation are shown below. There is a perfect superposition of TSTtest and TSTcontrol (TST amplitude ratio ¼ 100%), indicating that 100% of spinal motor neurons can be brought to discharge by brain stimulation. Calibration is 5 mV/5 ms; the sweep of the traces starts with wrist stimulation.
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variability of MEPs are mainly caused by varying synchronization of the descending action potentials evoked by the transcranial stimulus, and by the associated phase cancellation phenomena. The mean values of the TST amplitude and area ratio in normal subjects are given along with the respective normal limits in Table 1. To achieve maximal stimulation (i.e. a brain stimulation resulting in discharge of 100% of the spinal motor neurons), facilitation maneuvers are almost always needed. This is particularly important if AH is the target muscle (Bu¨hler et al., 2001). The need for facilitatory precontraction of the target muscles implies that the subject has to cooperate during the study. In patients with psychogenic palsies, we were not always able to achieve normal TST amplitude ratios because of the lack of sufficient facilitation (Magistris et al., 1999). In practice, the amount of precontraction in ADM is not very important as long as it is above some 2– 5% of the maximal voluntary force, because above these force levels the facilitatory effect on TST amplitudes saturates (Ro¨sler et al., 2002). In a technique involving collisions, contraction of the target muscle may be a factor of error. Practically, its influence on TST recordings is probably not important. A 10% contraction of the target muscle implies at the most 20% of the total number of motor units firing, with a firing frequency of 10 Hz at most. If the voluntary activity involves 20 motor units, on average, one action potential fires every 5 ms. Only the action potentials interposed between the potentials evoked by transcranial and distal stimulation may modify the response to the third stimulation. This interval being roughly 5 ms (MEP duration divided by 2), on average only one action potential may interfere with the TST recording. In this case, the response to the third stimulus would increase by the response of one MUP, only if the very axon of this MU had not been depolarized by transcranial stimulation. This is not likely to be a significant source of error. Voluntary contractions during brain stimulation may influence the MEP by facilitation of double or multiple discharges of the spinal motor neurons in response to the brain stimulus (Day et al., 1987). These multiple discharges influence the size of conventional MEPs, but not that of the TST response. If spinal motor neurons discharge several times in response to the brain stimulus, only the first of the
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Table 1 Normal means and normal limits for examination of two muscles using the TST. ADMa
AHb
Mean (SD)
Normal limit
Mean (SD)
Normal limit
TST amplitude ratio
99.1% (2.14)
$ 93%
95.0% (4.06)
$ 88%
TST area ratio
98.5% (2.48)
$ 92%
96.1% (8.30)
$ 84%
MEP amplitude ratio
66.1% (12.99)
$ 33%
37.2% (9.72)
$ 21%
MEP area ratio
96.8% (17.95)
$ 52%
99.7% (38.45)
$ 43%
TST amplitude variability (CoV)
2.6%a
MEP amplitude variability (CoV)
8.1%a $ 5.4 mVc
CMAPErb amplitude a
Magistris et al. (1998). Bu¨hler et al. (2001). c Ro¨sler et al. (2000). b
descending action potentials on each neuron contributes to the size of the TST response, while all subsequent action potentials escape collision with the distal nerve stimulus. They are recorded between the two deflections of the TSTtest curve (Fig. 3A; for a detailed discussion, see Magistris et al., 1998, 1999; Bu¨hler et al., 2001). Multiple discharges are greatly facilitated by voluntary activity. Hence, they are particularly prominent in the recordings from AH, where more facilitation is needed than in ADM to obtain maximal responses (Bu¨hler et al., 2001). 16.3.2. TST amplitude ratio in ALS patients Two studies have used the TST in ALS patients (Table 2; all ALS patients of Magistris et al., 1999 were incorporated in the study of Ro¨sler et al., 2000).
In the larger study of 51 ALS patients, TST examinations of the ADM were done in 86 sides, and an abnormally reduced TST amplitude ratio was found in 38 sides (reduction below 93%; see reference values in Table 1; Ro¨sler et al., 2000). Examples of recordings are given in Fig. 5. The conventional MEP amplitude ratio was abnormal in 13 of 86 sides; and the CMCT was abnormally increased in 11 sides. The TST amplitude ratio was abnormal in all of these 13 and 11 sides. Similar results were obtained with recordings from the AH, where abnormal TST amplitude ratios were more often found than prolonged CMCT (Bu¨hler et al., 2001 and Fig. 5). The gain in sensitivity to detect a central conduction disorder – as compared with conventional MEPs performed in the same ALS patients – increased by 2.1-fold in ADM and by 1.3-fold in AH (Table 2;
Table 2 Number of abnormal sides in patients with ALS, available studies. Recording muscle
Sides, n
Abnormal MEPs, n
Abnormal TST, n
Abnormal MEP and TST, n
Increase in sensitivity
Reference
ADM
86
18
38
38
2.1 £
Ro¨sler et al. (2000)
7
3
3
4
1.3 £
Bu¨hler et al. (2001)
93
21
41
42
2.0 £
AH Total
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Fig. 5. TST recordings from patients; left, from abductor digiti minimi; right, from abductor hallucis. Calibration is 2 mV/5 ms; the sweep of the traces starts with the distal nerve stimulus. In both patients, the maximal TSTtest amplitude is considerably smaller than TSTcontrol. Thus, there is a marked central conduction failure of 41% (left) and 37% (right). The first deflection of the TST recording is the response to the peripheral nerve stimulation ( ¼ M-wave). Its amplitude is 6.9 mV (ADM, left) and 12.4 mV (AH, right), both considered normal.
Ro¨sler et al., 2000; Bu¨hler et al., 2001). Adding the TST examination of the AH to that of the ADM further increased the diagnostic yield by 1.3-fold (Bu¨hler et al., 2001). It was our impression that the method was particularly sensitive in early ALS, in situations where diagnostic certainty was especially needed (Ro¨sler et al., 2000). Moreover, the TST detected central conduction deficits in a considerable number of patients without clinical signs of pyramidal degeneration. We found an abnormal TST amplitude ratio in 15 of 42 arms with clinically pure LMN syndromes. Thus, if LMN signs are present or if they are possibly present, the clinical examination fails to detect UMN involvement in many cases. On the other hand, the TST amplitude ratio was normal in 13 of 44 sides with a clinical UMN syndrome. Often, this is probably explained by the fact that recordings were done only from ADM, which may have been spared by the pyramidal involvement. Recording from a larger number of muscles might thus increase the sensitivity of the method. Presently, we are performing TST to both ADM and AH in most patients with suspected ALS. The TST not only detects, but also quantifies the central conduction failure caused by loss of corticospinal motor neurons. In our patients, the central conduction deficit – as measured by the TST – correlated with the clinical parameters of UMN loss (i.e. weakness, spasticity and pyramidal signs; Fig. 6). Nevertheless, the accuracy of this measure needs to be discussed since it can be influenced by a number of pathophysiological and technical factors.
First, theoretically, a reduced TST amplitude ratio could not only result from the disease-related loss of conducting corticospinal neurons but also from a reduced corticospinal excitability to TMS (Triggs et al., 1999). Indeed, while in early ALS, the cortical threshold for excitation is low (Caramia et al., 1991; Yokota et al., 1996; Mills and Nithi, 1997; Eisen et al., 1998), it increases later (Mills and Nithi, 1997; Miscio et al., 1999; Triggs et al., 1999). Thus, later during the disease, the TST might overestimate the loss of corticospinal neurons if a number of neurons could not be excited. In our patients, the disease duration was usually short, since examinations took place during the initial diagnostic work-up. We also found a relationship between TST amplitude ratio and muscle force in our patients (Fig. 6). Since cortical excitability changes are probably subclinical, this favored loss of UMNs rather than excitability changes as the mechanism of TST amplitude reductions in our patients. Nevertheless, increased cortical stimulation thresholds might constitute a possible source of measurement error, especially in patients with longer disease duration. Another potential source of measurement inaccuracy is the degree of LMN degeneration (Fig. 7). Obviously, in situations where all LMNs are lost, the TST (as well as conventional MEPs) will not allow disclosure of loss of function of UMNs. If only few functional LMNs remain, the range of possible TST amplitude ratios may be severely limited. We observed one patient with severe LMN
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Fig. 6. Relationship between muscle force assessed with the surface EMG maximal voluntary activity (MRV, mean rectified voltage) and TST amplitude ratio. Sides have been grouped according to their MRV as indicated in the figure. Box plots give the 5th and 95th percentile (handles), the 25th and 75th percentile (edges of box), and the 50th percentile (thick lines). Shaded areas indicate abnormal values. Numbers of sides are given on top. In sides with UMN signs (shaded boxes on the left), increasing strength is associated with increasing TST amplitude ratios (P , 0:05; Kruskal – Wallis). This is not observed in sides presenting with LMN signs only (white boxes on the right). (Figure modified from Bu¨hler et al., 2001.)
loss in whom the TST amplitude ratio was either 0 or 100%, depending on the stimulation strength. Therefore, in situations with extreme loss of LMNs, the measure of the TST response becomes less reliable and may underestimate the loss of UMNs. In patients with severe LMN syndromes, some caution may thus be required in the interpretation of a normal TST. 16.3.3. Other abnormalities of the TST in ALS 16.3.3.1. Lower motor neuron loss Along with the assessment of central conduction, the TST provides a rough estimate of the number of muscle fibers that remain innervated, through measurement of the CMAP amplitude to the peripheral stimulus (Fig. 7). Measurement of the amplitude of the first deflection of the TST test or
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Fig. 7. Recording from abductor hallucis in a patient with a severe lower motor neuron syndrome. Calibration is 2 mV/5 ms; the sweep of the traces starts with the distal nerve stimulus. The CMAP to tibial nerve stimulation at the ankle has a markedly abnormal amplitude of 2.4 mV. The number of motor units is reduced, and peripheral conduction varies, probably due to ongoing voluntary activation causing variable refractoriness of single axons. The TST amplitude ratio is 95%, indicating that there is no central conduction disorder. Note the stimulation artifact from gluteal stimulation (arrow), and the marked presence of multiple discharges (p).
TST control curves will thus indicate prominent loss of LMNs. 16.3.3.2. Multiple spinal motor neuron discharges Multiple spinal motor neuron discharges are exaggerated in early ALS, indicating an increased excitability of the involved neurons (Mills and Nithi, 1997). As outlined above and in Fig. 3A, the TST recording contains an intermediate response composed entirely of multiple discharges, which can be quantified. Our preliminary experience indicates that the amount of multiple discharges in ALS is much more variable than in healthy subjects, ranging from increased (often probably due to increased motor unit size) to absent (later during the disease). The recordings in Fig. 7 give an example of exaggerated multiple discharges. The clinical significance of this quantification remains to be evaluated.
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16.3.4. Upper motor neuron damage in ALS: insights from the TST In our patients, severe loss of UMNs was usually associated with severe loss of LMNs. Probably, this association results from the general disease progression eventually leading to both, UMN and LMN degeneration. In a single patient, however, the degree of UMN loss is usually not predictable from that of LMN loss, because of great interindividual differences (Ro¨sler et al., 2000). Considerable differences are even observed between the sides of given patients. This is in accordance with autopsy studies, where loss of cortical motor neurons was independent from that of neurons in the associated ventral horns (Kiernan and Hudson, 1991). The TST results have implications on the interpretation of previous data obtained with brain stimulation in ALS, and in particular on the observation of increased CMCTs (see Chapter 14 of this book), because the TST allows relating the CMCT with a measure of corticospinal conduction failure. In our series of patients, the CMCT was increased in 11 of 81 sides, and was always associated with conduction failure. Conduction failures, on the other hand, were often found without prolonged CMCT (Ro¨sler et al., 2000). Thus, prolongation of CMCT in ALS may represent an indirect phenomenon reflecting loss of functional corticospinal fibers, rather than a genuine slowing of conduction. Loss of faster conducting UMNs (Hugon et al., 1987; Ingram and Swash, 1987; Schriefer et al., 1989; Mills and Nithi, 1998; Kohara et al., 1999) and increased need for temporal summation to reach the anterior horn cell firing threshold (Ingram and Swash, 1987; Schriefer et al., 1989) are possible mechanisms. 16.4. Summary and conclusions In healthy subjects, TMS allows excitation of virtually all motor neurons supplying the target muscle, resulting in a TST amplitude ratio of nearly 100% (Magistris et al., 1998; Bu¨hler et al., 2001). In ALS patients, the TST amplitude ratio is often reduced, and TST reductions are more common than abnormalities of conventional MEPs (prolonged CMCT or reduced MEP amplitude ratio). The reasons for the marked increase in sensitivity are 3-fold. First, the normal limits of the TST amplitude ratio are much narrower than those of the conventional MEP
amplitude ratio (Magistris et al., 1998). Second, central conduction failures (by dropout of functioning UMNs) are more frequent in ALS than prolonged CMCTs. In fact, prolonged CMCTs are usually only found in conjunction with conduction failures. Third, in ALS, it may be particularly difficult to detect a central conduction failure by conventional MEPs, since increased desynchronization of descending volleys after TMS is suggested in ALS by the dispersion of the primary peaks in peristimulus time histograms (Awiszus and Feistner, 1993; Mills, 1995; Kohara et al., 1999; Weber et al., 2000). Besides its increased sensitivity, the TST allows an estimation of the proportion of lost UMNs supplying the target muscle, and this electrophysiological measure relates to the clinical deficit. Finally, the TST is a promising technique to assess excitability changes of the corticospinal system by providing a simple means to quantify multiple spinal motor neuron discharges. The TST may, therefore, contribute to the understanding of the clinical deficit of a given ALS patient. It may also offer a means to follow the disorder progression in a disease for which no alternative measure of central nervous damage exists, such as for example, magnetic resonance imaging in multiple sclerosis or stroke.
References Awiszus, F and Feistner, H (1993) Abnormal EPSPs evoked by magnetic brain stimulation in hand muscle motoneurons of patients with amyotrophic lateral sclerosis. Electroencephalogr. Clin. Neurophysiol., 89: 408 – 414. Britton, TC, Meyer, B-U and Benecke, R (1991) Variability of cortically evoked motor responses in multiple sclerosis. Electroencephalogr. Clin. Neurophysiol., 81: 186 – 194. Bu¨hler, R, Magistris, MR, Truffert, A, Hess, CW and Ro¨sler, KM (2001) The triple stimulation technique to study central motor conduction to the lower limbs. Clin. Neurophysiol., 112: 938 – 949. Caramia, MD, Cicinelli, P, Paradiso, C, Mariorenzi, R, Zarola, F, Bernardi, G and Rossini, PM (1991) Excitability changes of muscular responses to magnetic brain stimulation in patients with central motor disorders. Electroencephalogr. Clin. Neurophysiol., 81: 243 – 250. Day, BL, Rothwell, JC, Thompson, PD, Dick, JPR, Cowan, JMA, Berardelli, A and Marsden, CD (1987) Motor
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cortex stimulation in intact man. (2) Multiple descending volleys. Brain, 110: 1191– 1209. Eisen, A, Shytbel, W, Murphy, K and Hoirch, M (1990) Cortical magnetic stimulation in amyotrophic lateral sclerosis. Muscle Nerve, 13: 146– 151. Eisen, A, Nakajima, M and Weber, M (1998) Corticomotorneuronal hyper-excitability in amyotrophic lateral sclerosis. J. Neurol. Sci., 160 (Suppl. 1): S64– S68. Hess, CW, Mills, KR and Murray, NMF (1987) Responses in small hand muscles from magnetic stimulation of the human brain. J. Physiol. (Lond.), 388: 397– 419. Hugon, J, Lubeau, M, Tabaraud, F, Chazot, F, Vallat, JM and Dumas, M (1987) Central motor conduction in motor neuron disease. Ann. Neurol., 22: 544– 546. Ingram, DA and Swash, M (1987) Central motor conduction is abnormal in motor neuron disease. J. Neurol. Neurosurg. Psychiatry, 50: 159– 166. Kelly, JJ Jr., Thibodeau, L, Andres, PL and Finison, LJ (1990) Use of electrophysiologic tests to measure disease progression in ALS therapeutic trials. Muscle Nerve, 13: 471 – 479. Kiernan, JA and Hudson, AJ (1991) Changes in sizes of cortical and lower motor neurons in amyotrophic lateral sclerosis. Brain, 114: 843– 853. Kiers, L, Cros, D, Chiappa, KH and Fang, J (1993) Variability of motor potentials evoked by transcranial magnetic stimulation. Electroencephalogr. Clin. Neurophysiol., 89: 415– 423. Kohara, N, Kaji, R, Kojima, Y and Kimura, J (1999) An electrophysiological study of the corticospinal projections in amyotrophic lateral sclerosis. Clin. Neurophysiol., 110: 1123 –1132. Magistris, MR, Ro¨sler, KM, Truffert, A and Myers, JP (1998) Transcranial stimulation excites virtually all motor neurones supplying the target muscle. A demonstration and a method improving the study of motor evoked potentials. Brain, 121: 437– 450. Magistris, MR, Ro¨sler, KM, Truffert, A, Landis, T and Hess, CW (1999) A clinical study of motor evoked potentials using a triple stimulation technique. Brain, 122: 265 – 279. Mills, KR (1995) Motor neuron disease. Studies of the corticospinal excitation of single motor neurons by magnetic brain stimulation. Brain, 118: 971– 982. Mills, KR and Nithi, KA (1997) Corticomotor threshold is reduced in early sporadic amyotrophic lateral sclerosis. Muscle Nerve, 20: 1137– 1141. Mills, KR and Nithi, KA (1998) Peripheral and central motor conduction in amyotrophic lateral solerosis. J. Neurol. Sci., 159: 82– 87. Miscio, G, Pisano, F, Mora, G and Mazzini, L (1999) Motor neuron disease: usefulness of transcranial magnetic stimulation in improving the diagnosis. Clin. Neurophysiol., 110: 975– 981.
315 Ro¨sler, KM, Truffert, A, Hess, CW and Magistris, MR (2000) Quantification of upper motor neuron loss in amyotrophic lateral sclerosis. Clin. Neurophysiol., 111: 2208– 2218. Ro¨sler, KM, Petrow, E, Mathis, J, Ara´nyi, Z, Hess, CW and Magistris, MR (2002) Effect of discharge desynchronization on the size of motor evoked potentials: an analysis. Clin. Neurophysiol., 113: 1680– 1687. Rossini, PM, Marciani, MG, Caramia, MD, Roma, V and Zarola, F (1985) Nervous propagation along “central” motor pathways in intact man: characteristics of motor responses to “bifocal” and “unifocal” spinal and scalp non-invasive stimulation. Electroencephalogr. Clin. Neurophysiol., 61: 272 – 286. Roth, G and Egloff-Baer, S (1979) Ephaptic response in man. Eur. Neurol., 18: 261 – 266. Roth, G and Magistris, MR (1987) Detection of conduction block by monopolar percutaneous stimulation of the brachial plexus. Electromyogr. Clin. Neurophysiol., 27: 45 – 53. Roth, G and Magistris, MR (1989) Identification of motor conduction block despite desynchronisation. A method. Electromyogr. Clin. Neurophysiol., 29: 305 – 313. Schriefer, TN, Hess, CW, Mills, KR and Murray, NMF (1989) Central motor conduction in motor neurone disease using magnetic brain stimulation. Electroencephalogr. Clin. Neurophysiol., 74: 431 – 437. Schulte-Mattler, WJ, Mu¨ller, T and Zierz, S (1999) Transcranial magnetic stimulation compared with upper motor neuron signs in patients with amyotrophic lateral sclerosis. J. Neurol. Sci., 170: 51 – 56. Triggs, WJ, Menkes, D, Onorato, J, Yan, RS, Young, MS, Newell, K, Sander, HW, Soto, O, Chiappa, KH and Cros, D (1999) Transcranial magnetic stimulation identifies upper motor neuron involvement in motor neuron disease. Neurology, 53: 605 – 611. Truffert, A, Ro¨sler, KM and Magistris, MR (2000) Amyotrophic lateral sclerosis versus cervical spondylotic myelopathy: a study using transcranial magnetic stimulation with recordings from the trapezius and limb muscles. Clin. Neurophysiol., 111: 1031– 1038. Weber, M, Eisen, A and Nakajima, M (2000) Corticomotoneuronal activity in ALS: changes in the peristimulus time histogram over time. Clin. Neurophysiol., 111: 169 – 177. Yap, CB and Hirota, T (1967) Sciatic nerve motor conduction velocity study. J. Neurol. Neurosurg. Psychiatry, 30: 233 – 239. Yokota, T, Yoshino, A, Inaba, A and Saito, Y (1996) Double cortical stimulation in amyotrophic lateral sclerosis. J. Neurol. Neurosurg. Psychiatry, 61: 596 – 600.
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CHAPTER 16
The triple stimulation technique Kai M. Ro¨slera,* and Michel R. Magistrisb a
Department of Neurology, University of Berne, CH-3010 Berne, Switzerland b Department of Neurology, University of Geneva, Geneva, Switzerland
16.1. Introduction Amyotrophic lateral sclerosis (ALS) is characterized by a progressive degenerative loss of corticospinal (“upper”) and spinal (“lower”) motor neurons (UMNs, LMNs). Clinically, it is often difficult to appreciate to what extent the respective loss of UMNs and LMNs contributes to the weakness experienced by the patient. In particular, prominent denervation due to LMN loss may mask signs of UMN loss. Electrophysiological methods are a potential solution to this problem. A number of established electrophysiological methods exist to measure the loss of LMNs. The size of compound muscle action potentials (CMAPs) is related to the number of innervated muscle fibers (Kelly et al., 1990) and allows a crude estimate of LMNs. Various more accurate methods have been described to estimate the number of motor units of a given muscle; they are described in Chapter 13 of this book. Quantification of UMN loss is more difficult. Corticospinal conduction can be examined using transcranial magnetic stimulation (TMS) and abnormalities of motor-evoked potentials (MEPs) were often described in ALS patients (Schriefer et al., 1989; Eisen et al., 1990; Miscio et al., 1999; Schulte-Mattler et al., 1999; Triggs et al., 1999). However, the conventional MEP parameters, in particular the central motor conduction time (CMCT), are not directly related to the number of UMNs lost (see Chapter 14 of this book). Moreover, abnormal CMCTs are not consistently found in all patients, and thus the sensitivity of the method to * Correspondence to: Dr. K. M. Ro¨sler, Department of Neurology, Inselspital, CH-3010 Berne, Switzerland. E-mail address: [email protected] (K.M. Ro¨sler). Tel.: þ 41-31-632-3098; fax: þ41-31-632-3011.
diagnose UMN disorder varies considerably between studies. Theoretically, the size of an MEP should reflect the number of conducting central motor neurons. In practice, this relation appears obscured, since in patients and healthy subjects, MEPs are usually smaller than CMAPs evoked by peripheral nerve stimulation. Moreover, the MEP size and configuration varies from one stimulus to another and between subjects (Hess et al., 1987; Britton et al., 1991; Kiers et al., 1993). It was shown that these MEP characteristics are mainly caused by varying synchronization of the descending action potentials (Magistris et al., 1998). The resulting phase cancellation phenomenon impedes direct conclusions on the number of activated motor neurons (Fig. 1). In ALS, desynchronization of the descending volleys after TMS is probably often abnormally high (Awiszus and Feistner, 1993; Mills, 1995; Kohara et al., 1999; Weber et al., 2000). A further difficulty pertinent to ALS is that the assessment of UMN integrity is complicated by the loss of LMNs, which may influence the size of MEPs dramatically. An ideal technique for UMN quantification in ALS should therefore: (i) solve the problem of varying (de-)synchronization of the descending activity after TMS; and (ii) allow elimination (or estimation) of the influence of LMN loss on the MEP. Recently, we demonstrated that a triple stimulation technique (TST) can solve these two problems. Use of this collision technique suppresses the effects of central action potential desynchronization (Magistris et al., 1998). As a consequence, it provides a quantitative measure of the percentage of spinal motor neurons that can be brought to discharge by TMS. In healthy subjects, this percentage is always near 100%. In patients with central motor disorders,
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Fig. 1. Principle of phase cancellation. In this scheme four identical biphasic motor unit potentials (1– 4) add to give rise to a compound muscle action potential (CMAP) (below, 1 þ 2 þ 3 þ 4). Left panel: the four MUPs are synchronized, the negative and positive phases add. This situation resembles peripheral nerve stimulation, where the CMAP size represents the number of activated motor units. Right panels: Different degrees of desynchronization of potentials 1 – 4 occur. The compound action potential changes its configuration and size in each condition. This situation resembles that observed in response to brain stimulation.
this percentage is often smaller as a result of the corticospinal conduction failure. Muscle weakness and TST result are quantitatively related, indicating that the TST indeed measures a central conduction parameter relevant for the clinical deficit. Moreover, the TST allows elimination of the influence of peripheral conduction on the result within the same measurement. In the following, we will highlight the method and its potential use in ALS. 16.2. The method The TST involves a transcranial brain stimulus, followed by two stimuli on the peripheral nerve. The three stimuli are appropriately timed to allow collisions of the evoked action potentials at the desired locations. Recording of conventional MEPs and of peripheral motor conduction are integrated elements of the measurement since they are required to define the individual stimulus intervals. Recording protocols have been defined for two muscles, m. abductor digiti minimi (ADM) and m. abductor hallucis (AH). 16.2.1. TST with recording from abductor digiti minimi 16.2.1.1. Peripheral conduction Recordings of the ADM are carried out using a standard muscle belly-tendon technique with
surface electrodes. Bandpass filtering is between 2 Hz and 10 kHz. A ground electrode is taped to the dorsum of the hand. The patient’s position is supine with the hand held in place by a 2.5– 5 kg sand bag; the geometry of the fingers is kept constant by taping fingers II– V together. In a first step, the CMAPs are recorded after maximal stimulation of the ulnar nerve at the wrist (CMAPwrist) and at Erb’s point (CMAPErb), both at rest and during a slight voluntary contraction of the ADM. For the following procedures, it is convenient to tape the stimulating electrodes over both stimulation sites. At the wrist, stimuli are applied via two silver electrodes (diameter ¼ 0.8 cm), the cathode being taped over the ulnar nerve proximal to the pisiform bone and the anode posteriorly on the wrist at the same level in order to avoid anodal stimulation. To avoid influences of volume conduction by median innervated muscles after Erb’s stimulation (see below), it may be helpful to stimulate the median nerve simultaneously with the ulnar nerve (i.e. by taping a second cathode over the median nerve and having a common anode with the ulnar nerve, or by using a second pair of stimulating electrodes). At Erb’s point, monopolar stimulation is used, as described previously (Roth and Magistris, 1987), with a small cathode electrode taped over Erb’s
THE TRIPLE STIMULATION TECHNIQUE
point (diameter ¼ 1 cm) and a large remote anode electrode (surface approx. 25 – 30 cm2) taped over the internal region of the suprascapular fossa. The large remote anode should be flexible to allow for maximal skin contact. We have successfully used two types: a custom-made thin lead sheet electrode (40 £ 70 mm) and a commercial 40 £ 60 mm rubber electrode for use in electrotherapy (EnrafNonius BV, Delft, The Netherlands). For the calculation of the CMCT, the peripheral conduction time (needed for the calculation of the CMCT) is determined using the minimal ulnar F-wave latency. 16.2.1.2. Conventional MEPs Conventional MEPs are obtained using a magnetic stimulator (if desired, an electrical brain stimulator can also be used). A standard round magnetic coil is placed at the vertex or slightly lateral toward the stimulated hemisphere. To ensure maximal stimulation, the position yielding the lowest threshold is searched. Magnetic stimuli are usually applied while the subject is slightly contracting the target ADM to facilitate the response. The MEP latency is defined as the
307
shortest latency from several responses and the CMCT is calculated using the formula: CMCT ¼ MEP latency 2 (F latency þ CMAPwrist latency 2 1)=2 (Rossini et al., 1985).
16.2.1.3. TST To achieve the timing of the three stimuli, two external electrical stimulators (e.g. Digitimer DS7) and the magnetic stimulator may be triggered by an external timer (e.g. Digitimer D4030) (Fig. 2). Alternatively, for the Nicolet Viking EMG machines (Nicolet, Madison, USA), a dedicated software package may be installed, allowing triggering of the external magnetic stimulator and two internal electrical stimulators at the required intervals (Judex Datasystemer A/S, Lyngvej 8, DK9000 Aalborg). Three stimuli are given, leading to two collisions (Fig. 3A). A first stimulus is applied to the scalp overlying the motor cortex. After an appropriate delay, a second maximal stimulus is applied over the ulnar nerve at the wrist. The delay is chosen so that the action potentials descending from the cortex collide with the antidromic action potentials evoked at the wrist, with the collision
Fig. 2. Set-up of the triple stimulation technique (TST). Transcranial magnetic stimulator and two electrical stimulators are triggered at appropriate intervals by a timer (sequence for the TSTtest curve: transcranial stimulation –electrical ulnar nerve stimulation at wrist – electrical stimulation at Erb’s point; sequence for the TSTcontrol curve performed for comparison: electrical stimulation at Erb’s point– electrical ulnar nerve stimulation at wrist – electrical stimulation at Erb’s point). Electrical peripheral stimulations are maximal. Monopolar stimulation of the brachial plexus uses a small cathode at Erb’s point and a large anode over the upper aspect of the scapula. Recording performed with surface electrodes from abductor digiti minimi.
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Fig. 3. Principle of the triple stimulation technique (TST). The motor tract is simplified to four spinal motor neurons with their axons. Horizontal lines represent the muscle fibers of the four motor units. Solid arrows depict action potentials giving rise to a trace deflection, open arrows depict action potentials that are not recorded. (A1) In the example, only three of four motor neurons are brought to discharge by the brain stimulus due to upper motor neuron lesion. (A2) Following the brain stimulus, action potentials descend in axons 1– 3. Desynchronization of the three action potentials has occurred. Motor neurons 1 and 2 discharge twice so that a second action potential descends (p). After a delay, a maximal second stimulus is given at the wrist (W), leading to descending (orthodromic) action potentials causing a first negative deflection of TSTtest curve, and to ascending (antidromic) action potentials in all four axons. Three of the ascending action potentials collide and cancel with the action potentials descending in axons 1 – 3. The sites of collision are different due to the desynchronization of the descending action potentials. (A3) The multiple discharges (p) on motor neurons 1 and 2 are not cancelled and continue to descend. They give rise to a small deflection in the trace (p). The action potential on axon 4 continues to ascend, since no collision occurred. (A4) After a delay, a maximal third stimulus is given at Erb’s point, evoking action potentials, which descend on axons 1 – 3, while a collision occurs in axon 4. (A5) Finally, a synchronized response from the three axons (1– 3) which were initially excited by the transcranial stimulus is recorded as a second main deflection of the TSTtest curve. (B1 – B5): The TSTcontrol curve is recorded by replacing the first stimulus at the cortex by a supramaximal stimulus at Erbs point (succession of stimuli: Erb –wrist –Erb) with appropriate adjustments of the delays. (C): Superposition of TSTtest and TSTcontrol curves. The TST amplitude ratio is 75%, indicating that three of four neurons were excited by the transcranial stimulus.
site at the wrist and above. After another delay, a third stimulus is applied at Erb’s point. This delay is chosen so that ascending antidromic action potentials evoked by wrist stimulation collide slightly distal to Erb’s point. The delays are calculated as follows: †
†
Delay I (brain 2 wrist) ¼ minimal MEP latency 2 CMAPwrist latency Delay II (wrist 2 Erb) ¼ CMAPErb latency 2 CMAPwrist latency,
where the minimal MEP latency and the CMAPErb latency are rounded down to the nearest millisecond,
and the CMAPwrist latency is rounded up to the nearest millisecond. The response to the third stimulus is studied. It is often smaller than the response evoked by a single stimulus at Erb’s point, presumably by a “backresponse” caused by myo-axonal ephaptic excitation of axons by the wrist stimulus (Roth and Egloff-Baer, 1979). To account for this phenomenon, the TSTtest curve is compared with a TSTcontrol curve in which the first stimulus is applied to Erb’s point. Stimuli are thus applied successively to Erb’s point– wrist – Erb’s point (Fig. 3B); the delays between the stimuli are adjusted appropriately (delay I ¼ delay II ¼ CMAPErb latency 2 CMAPwrist latency). Quantification of the
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THE TRIPLE STIMULATION TECHNIQUE
excited motor axons is then achieved by calculation of the amplitude ratio of the second main deflections of the TST test and control curves (TST amplitude ratio ¼ TSTtest : TSTcontrol; Fig. 3C). The area of the responses can also be measured, but the amplitude measurement was shown to be slightly more accurate (Magistris et al., 1998). The TSTtest:TSTcontrol ratio corresponds to the proportion of motor units excited in the target muscle, assuming as an approximation that all motor unit potentials composing the CMAP have a similar size: – If a cortical stimulus succeeds in exciting all spinal motor axons innervating the target muscle, a maximal motor response follows the third stimulus applied to Erb’s point and the ratio is 100%. – If all axons fail to conduct following brain stimulation, no motor response follows the third stimulus applied to Erb’s point and the ratio is 0%. – If a number of axons conduct while others do not, the motor response to Erb’s stimulus is reduced in amplitude and area (Fig. 3A). During a patient examination, the TSTtest trials are preceded and followed by recording of a TST control curve. Several TST test curves are recorded using increasing intensities of transcranial stimulation until the best possible superimposition of the TSTtest and TSTcontrol curves is achieved. In addition, facilitation maneuvers are applied, in particular slight contraction of the target ADM during the stimulus. Acoustic monitoring of the EMG activity allows judging about the degree of muscle relaxation or contraction. Exact superimposition of the first main negative deflection (CMAPwrist) of the TSTtest and TSTcontrol curves demonstrate that the position of the target muscle remained fixed throughout the examination (Roth and Magistris, 1989; Magistris et al., 1998). 16.2.2. Modifications for recording from m. abductor hallucis MEPs in small foot muscles are best obtained using a double cone coil, which delivers stronger stimuli. Hence, for the TST of AH, a double-cone coil is optimal, even though the standard round coil
is often sufficient to achieve maximal stimulation. Distal peripheral nerve stimulation is at the ankle, where maximal electrical stimuli are applied to the tibial nerve via two surface electrodes. The cathode is taped over the nerve proximal to the medial malleolus and the anode on the opposite side on the lateral malleolus in order to avoid anodal stimulation. Proximal nerve stimulation concerns the sciatic nerve in the gluteal region. To allow supramaximal stimulation with reasonable electrical stimulation intensity, a monopolar needle electrode is used as cathode, as described by Yap and Hirota (1967). We use a disposable needle electrode, which is insulated with the exception of the tip (TECA, Oxford Instruments Medical System Division, New York, USA; length 25 – 75 mm). The needle is inserted between the long head of the biceps femoris muscle and the semitendinosus muscle, at the level of the gluteal fold. A large remote surface anode electrode is taped over the ventral proximal thigh. The tip of the stimulation needle is then cautiously positioned close to the nerve (although not as close as in sensory “nearnerve needle” techniques) by maximizing the response size to repeated submaximal stimuli, so that the stimulus strength needed for maximal responses is low. 16.2.3. Other muscles The TST may be performed to other distal muscles, in particular to other small hand muscles. Recordings from the first dorsal interosseus (ID1) have the disadvantage that volume conducted activity from co-stimulated muscles innervated by the median nerve may be more important than in ADM, particularly with stimulation at Erb’s point. To correct this, co-stimulation of median and ulnar nerve at the wrist may be envisaged. A similar problem arises for recordings from thenar muscles, where ulnar mediated volume conduction may disturb the responses from median innervated muscles and vice versa. Also here, co-stimulation of both nerves at the wrist may be necessary. Normal values for ID1 and abductor pollicis brevis have not yet been defined, but activation of 100% of the target motor neurons is usually obtained. The TST cannot be performed to proximal muscles, since the short distances do not allow for sufficient stimulation delays, and proximal nerve stimulation
310
sites may not be accessible. Combination of cranial nerve studies with the TST may be well suited for examinations of patients with bulbar forms of ALS (Truffert et al., 2000). 16.3. Results 16.3.1. Healthy subjects In all healthy subjects studied, and in both target muscles studied so far (ADM and AH), the maximally achieved TST amplitude and area ratios were close to 100%, indicating that nearly all target motor units can be driven to discharge by the transcranial stimulus (example in Fig. 4). Moreover, the variability of the TST amplitude and area ratios is markedly reduced compared with MEPs (Magistris et al., 1998). These observations demonstrate that size reduction and
Fig. 4. TST recordings from abductor digiti minimi of a healthy subject, during slight voluntary contraction. The three TSTtest curves are obtained with a stimulus intensity of 80% of the maximal output. TSTcontrol curve and response to wrist stimulation are shown below. There is a perfect superposition of TSTtest and TSTcontrol (TST amplitude ratio ¼ 100%), indicating that 100% of spinal motor neurons can be brought to discharge by brain stimulation. Calibration is 5 mV/5 ms; the sweep of the traces starts with wrist stimulation.
¨ SLER AND M.R. MAGISTRIS K.M. RO
variability of MEPs are mainly caused by varying synchronization of the descending action potentials evoked by the transcranial stimulus, and by the associated phase cancellation phenomena. The mean values of the TST amplitude and area ratio in normal subjects are given along with the respective normal limits in Table 1. To achieve maximal stimulation (i.e. a brain stimulation resulting in discharge of 100% of the spinal motor neurons), facilitation maneuvers are almost always needed. This is particularly important if AH is the target muscle (Bu¨hler et al., 2001). The need for facilitatory precontraction of the target muscles implies that the subject has to cooperate during the study. In patients with psychogenic palsies, we were not always able to achieve normal TST amplitude ratios because of the lack of sufficient facilitation (Magistris et al., 1999). In practice, the amount of precontraction in ADM is not very important as long as it is above some 2– 5% of the maximal voluntary force, because above these force levels the facilitatory effect on TST amplitudes saturates (Ro¨sler et al., 2002). In a technique involving collisions, contraction of the target muscle may be a factor of error. Practically, its influence on TST recordings is probably not important. A 10% contraction of the target muscle implies at the most 20% of the total number of motor units firing, with a firing frequency of 10 Hz at most. If the voluntary activity involves 20 motor units, on average, one action potential fires every 5 ms. Only the action potentials interposed between the potentials evoked by transcranial and distal stimulation may modify the response to the third stimulation. This interval being roughly 5 ms (MEP duration divided by 2), on average only one action potential may interfere with the TST recording. In this case, the response to the third stimulus would increase by the response of one MUP, only if the very axon of this MU had not been depolarized by transcranial stimulation. This is not likely to be a significant source of error. Voluntary contractions during brain stimulation may influence the MEP by facilitation of double or multiple discharges of the spinal motor neurons in response to the brain stimulus (Day et al., 1987). These multiple discharges influence the size of conventional MEPs, but not that of the TST response. If spinal motor neurons discharge several times in response to the brain stimulus, only the first of the
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Table 1 Normal means and normal limits for examination of two muscles using the TST. ADMa
AHb
Mean (SD)
Normal limit
Mean (SD)
Normal limit
TST amplitude ratio
99.1% (2.14)
$ 93%
95.0% (4.06)
$ 88%
TST area ratio
98.5% (2.48)
$ 92%
96.1% (8.30)
$ 84%
MEP amplitude ratio
66.1% (12.99)
$ 33%
37.2% (9.72)
$ 21%
MEP area ratio
96.8% (17.95)
$ 52%
99.7% (38.45)
$ 43%
TST amplitude variability (CoV)
2.6%a
MEP amplitude variability (CoV)
8.1%a $ 5.4 mVc
CMAPErb amplitude a
Magistris et al. (1998). Bu¨hler et al. (2001). c Ro¨sler et al. (2000). b
descending action potentials on each neuron contributes to the size of the TST response, while all subsequent action potentials escape collision with the distal nerve stimulus. They are recorded between the two deflections of the TSTtest curve (Fig. 3A; for a detailed discussion, see Magistris et al., 1998, 1999; Bu¨hler et al., 2001). Multiple discharges are greatly facilitated by voluntary activity. Hence, they are particularly prominent in the recordings from AH, where more facilitation is needed than in ADM to obtain maximal responses (Bu¨hler et al., 2001). 16.3.2. TST amplitude ratio in ALS patients Two studies have used the TST in ALS patients (Table 2; all ALS patients of Magistris et al., 1999 were incorporated in the study of Ro¨sler et al., 2000).
In the larger study of 51 ALS patients, TST examinations of the ADM were done in 86 sides, and an abnormally reduced TST amplitude ratio was found in 38 sides (reduction below 93%; see reference values in Table 1; Ro¨sler et al., 2000). Examples of recordings are given in Fig. 5. The conventional MEP amplitude ratio was abnormal in 13 of 86 sides; and the CMCT was abnormally increased in 11 sides. The TST amplitude ratio was abnormal in all of these 13 and 11 sides. Similar results were obtained with recordings from the AH, where abnormal TST amplitude ratios were more often found than prolonged CMCT (Bu¨hler et al., 2001 and Fig. 5). The gain in sensitivity to detect a central conduction disorder – as compared with conventional MEPs performed in the same ALS patients – increased by 2.1-fold in ADM and by 1.3-fold in AH (Table 2;
Table 2 Number of abnormal sides in patients with ALS, available studies. Recording muscle
Sides, n
Abnormal MEPs, n
Abnormal TST, n
Abnormal MEP and TST, n
Increase in sensitivity
Reference
ADM
86
18
38
38
2.1 £
Ro¨sler et al. (2000)
7
3
3
4
1.3 £
Bu¨hler et al. (2001)
93
21
41
42
2.0 £
AH Total
312
¨ SLER AND M.R. MAGISTRIS K.M. RO
Fig. 5. TST recordings from patients; left, from abductor digiti minimi; right, from abductor hallucis. Calibration is 2 mV/5 ms; the sweep of the traces starts with the distal nerve stimulus. In both patients, the maximal TSTtest amplitude is considerably smaller than TSTcontrol. Thus, there is a marked central conduction failure of 41% (left) and 37% (right). The first deflection of the TST recording is the response to the peripheral nerve stimulation ( ¼ M-wave). Its amplitude is 6.9 mV (ADM, left) and 12.4 mV (AH, right), both considered normal.
Ro¨sler et al., 2000; Bu¨hler et al., 2001). Adding the TST examination of the AH to that of the ADM further increased the diagnostic yield by 1.3-fold (Bu¨hler et al., 2001). It was our impression that the method was particularly sensitive in early ALS, in situations where diagnostic certainty was especially needed (Ro¨sler et al., 2000). Moreover, the TST detected central conduction deficits in a considerable number of patients without clinical signs of pyramidal degeneration. We found an abnormal TST amplitude ratio in 15 of 42 arms with clinically pure LMN syndromes. Thus, if LMN signs are present or if they are possibly present, the clinical examination fails to detect UMN involvement in many cases. On the other hand, the TST amplitude ratio was normal in 13 of 44 sides with a clinical UMN syndrome. Often, this is probably explained by the fact that recordings were done only from ADM, which may have been spared by the pyramidal involvement. Recording from a larger number of muscles might thus increase the sensitivity of the method. Presently, we are performing TST to both ADM and AH in most patients with suspected ALS. The TST not only detects, but also quantifies the central conduction failure caused by loss of corticospinal motor neurons. In our patients, the central conduction deficit – as measured by the TST – correlated with the clinical parameters of UMN loss (i.e. weakness, spasticity and pyramidal signs; Fig. 6). Nevertheless, the accuracy of this measure needs to be discussed since it can be influenced by a number of pathophysiological and technical factors.
First, theoretically, a reduced TST amplitude ratio could not only result from the disease-related loss of conducting corticospinal neurons but also from a reduced corticospinal excitability to TMS (Triggs et al., 1999). Indeed, while in early ALS, the cortical threshold for excitation is low (Caramia et al., 1991; Yokota et al., 1996; Mills and Nithi, 1997; Eisen et al., 1998), it increases later (Mills and Nithi, 1997; Miscio et al., 1999; Triggs et al., 1999). Thus, later during the disease, the TST might overestimate the loss of corticospinal neurons if a number of neurons could not be excited. In our patients, the disease duration was usually short, since examinations took place during the initial diagnostic work-up. We also found a relationship between TST amplitude ratio and muscle force in our patients (Fig. 6). Since cortical excitability changes are probably subclinical, this favored loss of UMNs rather than excitability changes as the mechanism of TST amplitude reductions in our patients. Nevertheless, increased cortical stimulation thresholds might constitute a possible source of measurement error, especially in patients with longer disease duration. Another potential source of measurement inaccuracy is the degree of LMN degeneration (Fig. 7). Obviously, in situations where all LMNs are lost, the TST (as well as conventional MEPs) will not allow disclosure of loss of function of UMNs. If only few functional LMNs remain, the range of possible TST amplitude ratios may be severely limited. We observed one patient with severe LMN
THE TRIPLE STIMULATION TECHNIQUE
Fig. 6. Relationship between muscle force assessed with the surface EMG maximal voluntary activity (MRV, mean rectified voltage) and TST amplitude ratio. Sides have been grouped according to their MRV as indicated in the figure. Box plots give the 5th and 95th percentile (handles), the 25th and 75th percentile (edges of box), and the 50th percentile (thick lines). Shaded areas indicate abnormal values. Numbers of sides are given on top. In sides with UMN signs (shaded boxes on the left), increasing strength is associated with increasing TST amplitude ratios (P , 0:05; Kruskal – Wallis). This is not observed in sides presenting with LMN signs only (white boxes on the right). (Figure modified from Bu¨hler et al., 2001.)
loss in whom the TST amplitude ratio was either 0 or 100%, depending on the stimulation strength. Therefore, in situations with extreme loss of LMNs, the measure of the TST response becomes less reliable and may underestimate the loss of UMNs. In patients with severe LMN syndromes, some caution may thus be required in the interpretation of a normal TST. 16.3.3. Other abnormalities of the TST in ALS 16.3.3.1. Lower motor neuron loss Along with the assessment of central conduction, the TST provides a rough estimate of the number of muscle fibers that remain innervated, through measurement of the CMAP amplitude to the peripheral stimulus (Fig. 7). Measurement of the amplitude of the first deflection of the TST test or
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Fig. 7. Recording from abductor hallucis in a patient with a severe lower motor neuron syndrome. Calibration is 2 mV/5 ms; the sweep of the traces starts with the distal nerve stimulus. The CMAP to tibial nerve stimulation at the ankle has a markedly abnormal amplitude of 2.4 mV. The number of motor units is reduced, and peripheral conduction varies, probably due to ongoing voluntary activation causing variable refractoriness of single axons. The TST amplitude ratio is 95%, indicating that there is no central conduction disorder. Note the stimulation artifact from gluteal stimulation (arrow), and the marked presence of multiple discharges (p).
TST control curves will thus indicate prominent loss of LMNs. 16.3.3.2. Multiple spinal motor neuron discharges Multiple spinal motor neuron discharges are exaggerated in early ALS, indicating an increased excitability of the involved neurons (Mills and Nithi, 1997). As outlined above and in Fig. 3A, the TST recording contains an intermediate response composed entirely of multiple discharges, which can be quantified. Our preliminary experience indicates that the amount of multiple discharges in ALS is much more variable than in healthy subjects, ranging from increased (often probably due to increased motor unit size) to absent (later during the disease). The recordings in Fig. 7 give an example of exaggerated multiple discharges. The clinical significance of this quantification remains to be evaluated.
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16.3.4. Upper motor neuron damage in ALS: insights from the TST In our patients, severe loss of UMNs was usually associated with severe loss of LMNs. Probably, this association results from the general disease progression eventually leading to both, UMN and LMN degeneration. In a single patient, however, the degree of UMN loss is usually not predictable from that of LMN loss, because of great interindividual differences (Ro¨sler et al., 2000). Considerable differences are even observed between the sides of given patients. This is in accordance with autopsy studies, where loss of cortical motor neurons was independent from that of neurons in the associated ventral horns (Kiernan and Hudson, 1991). The TST results have implications on the interpretation of previous data obtained with brain stimulation in ALS, and in particular on the observation of increased CMCTs (see Chapter 14 of this book), because the TST allows relating the CMCT with a measure of corticospinal conduction failure. In our series of patients, the CMCT was increased in 11 of 81 sides, and was always associated with conduction failure. Conduction failures, on the other hand, were often found without prolonged CMCT (Ro¨sler et al., 2000). Thus, prolongation of CMCT in ALS may represent an indirect phenomenon reflecting loss of functional corticospinal fibers, rather than a genuine slowing of conduction. Loss of faster conducting UMNs (Hugon et al., 1987; Ingram and Swash, 1987; Schriefer et al., 1989; Mills and Nithi, 1998; Kohara et al., 1999) and increased need for temporal summation to reach the anterior horn cell firing threshold (Ingram and Swash, 1987; Schriefer et al., 1989) are possible mechanisms. 16.4. Summary and conclusions In healthy subjects, TMS allows excitation of virtually all motor neurons supplying the target muscle, resulting in a TST amplitude ratio of nearly 100% (Magistris et al., 1998; Bu¨hler et al., 2001). In ALS patients, the TST amplitude ratio is often reduced, and TST reductions are more common than abnormalities of conventional MEPs (prolonged CMCT or reduced MEP amplitude ratio). The reasons for the marked increase in sensitivity are 3-fold. First, the normal limits of the TST amplitude ratio are much narrower than those of the conventional MEP
amplitude ratio (Magistris et al., 1998). Second, central conduction failures (by dropout of functioning UMNs) are more frequent in ALS than prolonged CMCTs. In fact, prolonged CMCTs are usually only found in conjunction with conduction failures. Third, in ALS, it may be particularly difficult to detect a central conduction failure by conventional MEPs, since increased desynchronization of descending volleys after TMS is suggested in ALS by the dispersion of the primary peaks in peristimulus time histograms (Awiszus and Feistner, 1993; Mills, 1995; Kohara et al., 1999; Weber et al., 2000). Besides its increased sensitivity, the TST allows an estimation of the proportion of lost UMNs supplying the target muscle, and this electrophysiological measure relates to the clinical deficit. Finally, the TST is a promising technique to assess excitability changes of the corticospinal system by providing a simple means to quantify multiple spinal motor neuron discharges. The TST may, therefore, contribute to the understanding of the clinical deficit of a given ALS patient. It may also offer a means to follow the disorder progression in a disease for which no alternative measure of central nervous damage exists, such as for example, magnetic resonance imaging in multiple sclerosis or stroke.
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