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‘Excitability’ changes of muscular responses to magnetic brain stimulation in patients with central motor disorders
Electroencephalography and clinical Neurophysiology , 81 (1991)243-250 © 1991 Elsevier Scientific Publishers Ireland, Ltd. 0924-980X/91/$03.50 ADONIS 0924980X9100080B
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ELMOCO 89616
'Excitability' changes of muscular responses to magnetic brain stimulation in patients with central motor disorders Maria D. Caramia, Paola Cicinelli, Claudio Paradiso a, Roberto Mariorenzi, Flora Zarola, Giorgio Bernardi and Paolo M. Rossini Clinica Neurologica, H Universit?l di Roma 'Tor Vergata, ' Dipartimento Sanit?l Pubblica, 00173 Rome (Italy) and a Clinica Malattie Nert:ose e Mentali, Universit?l di Siena, 53100 Siena (Italy) (Accepted for publication: 22 March 1991)
Summary The 'excitability' and 'conductivity' of motor pathways during transcranial stimulation (TCS) have been investigated in 49 patients affected by multiple sclerosis (34), amyotrophic lateral sclerosis (7), spino-cerebellar ataxia (3), primary lateral sclerosis (4) and brain metastasis (1). Hyper-reflexia, spasticity and weakness were correlated with the central motor conduction time (CCT) and with the threshold intensity of TCS required to produce a motor evoked potential (MEP). MEPs to magnetic TCS were recorded from hand and foot muscles during relaxation, contraction and after tendon vibration. Thresholds and CCTs of the patients were compared with those of 30 healthy controls. Increased threshold was found in 37 out of 49 patients (75.5%). Prolongation of the CCT was found in 38 out of 63 clinically affected upper limbs (60.3%) and in 56 out of 77 clinically affected lower limbs (72.7%). Absent motor responses to maximal TCS were found in 20 out of 98 lower limbs (20.4%). Excluding ALS patients (in whom there was a lower threshold for MEP elicitation), a significant linear correlation was found between prolonged CCT and increased threshold. While MEPs with prolonged CCTs have elevated TCS threshold, it is important to note that an elevated threshold was found in 14 out of 49 patients (28.5%) despite unchanged CCT. Spasticity a n d / o r hyper-reflexia were more frequently associated with increased threshold than with prolonged CCT, while weakness was correlated equally well with both these parameters. In this respect magnetic TCS proves to represent a new tool for the detection of abnormal 'excitability' of the central motor tracts. Key words: Brain stimulation; Excitability; Spasticity; Motor disorders
Non-invasive electrical stimulation of the brain has been found suitable for testing healthy volunteers as well as patients with lesions affecting the corticospinal tract (Merton and Morton 1980; Marsden et al. 1982; Levy et al. 1984; Hassan et al. 1985; Rossini et al. 1985). Such a technique is now currently employed in clinical practice, although its use is usually limited to the investigation of the innervation of the upper limbs (Mills and Murray 1985; Day et al. 1986; Berardelli et al. 1987; Hess et al. 1987; Ingrain and Swash 1987; Caramia et al. 1988). Motor pathways directed to lower limb motoneurons require higher intensities of transcranial stimulation (TCS) with consequent undue discomfort (Rossini et al. 1985). Recently, magnetic pulses have been introduced to achieve brain TCS (Barker et al. 1985). Besides being virtually painless, magnetic stimulation is also 'blind' to the smearing effects of the extracerebral layers, thereby
Correspondence to: Maria D. Caramia, M.D., Laboratorio di Neurofisiologia Clinica, Dipartimento di Sanit~ Pubblica, Universit~ di Roma 'Tor Vergata,' Via O. Raimondo 8, 00173 Rome (Italy).
allowing more precise measurement of the threshold for elicitation of motor evoked potentials than is possible with electric TCS. Amplitude/latency changes of MEPs have been analyzed in some detail in healthy humans subject to modifications of the stimulus parameters with either electric or magnetic TCS (stimulus intensity, electrode positioning and coil orientation), as well as of the muscular state (relaxed, contracted, premovement) (Gandevia and Rothwell 1987; Starr et al. 1988). While delayed MEPs with prolonged central conduction times (CCTs) have been described in a variety of neurological disorders, yet other aspects related to the abnormal responses deserve further observation. In particular, little attention has been devoted to excitability changes of motor responses to brain stimulation in patients with motor impairments. The aim of the present study is to investigate MEP characteristics in patients affected by disorders predominantly featuring weakness and spasticity through the analysis of the 'excitability' and 'conductivity' properties of the system mediating muscular responses to magnetic brain stimulation.
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Subjects and methods The group of patients (30 males; 19 females; age range 12-65 years) was composed of 49 subjects affected by multiple sclerosis (MS, 34), amyotrophic lateral sclerosis (ALS, 7), spinocerebellar ataxia (3), primary lateral sclerosis (4) and brain tumor (1). They were examined with their informed consent and with the approval of the Local Ethical Committee. Before each recording session all the patients underwent complete neurological examination. Muscle strength was assessed and scored according to the Medical Research Council (MRC) scale. Deep tendon reflexes (DTRs) were classified as absent, exaggerated or normal. Increased spastic tone, brisk finger jerks, trunk and limb ataxia as well as finger/nose and heel/knee dysmetria were judged as either present or absent. Patients affected by peripheral neuropathy were excluded from the present investigation.
Stimulation parameters Magnetic TCS. A copper coil (inner diameter of 7 cm), positioned on the scalp region overlying the motor strip delivered time-varying magnetic pulses of brief duration (160/zsec, peak voltage 6.4 V, Cadwell MES 10). The coil was moved in a fiat position over the scalp until the optimal stimulation site was localized for eliciting threshold motor responses in the contralateral muscles. The coil orientation in this type of stimulating device has been demonstrated not to influence the MEP latency/amplitude characteristics (Claus et al. 1990) because of the morphology of the induced field (bipolar voltage with negative-positive phases). The individual threshold intensity of TCS for a given muscle was identified during complete relaxation (Table I); the stimulus strength was thereafter increased by 10% over the threshold value to record reproducible MEPs in the voluntarily activated muscle(s) (Caramia
et al. 1989). We define the 'threshold' for magnetic TCS as the intensity required to elicit, with a 50% probability, detectable 'relaxed MEPs' with an amplitude of about 0.1 mV. Since commercially available magnetic stimulators do not provide direct measurement of the induced magnetic field, threshold values are expressed as a percentage of the stimulator's maximal output (2.0 tesla at the peak of the field induced by a pulse current in the coil approaching 6000 A). In patients, whose motor responses were not elicited at rest (even with maximal stimulator discharge), stimuli with increasing intensity were delivered during moderate contraction until a MEP could be obtained.
Recording parameters MEPs were recorded from hand (thenar) and foot (flexor hallucis) muscles of both sides via surface electrodes applied with a conventional belly-tendon montage. Signals were amplified (gain 10) and filtered between 1.6 and 1600 Hz ( - 6 dB/oct roll-off). A ground electrode was placed proximally to the recording site in order to minimize stimulus artifact produced by the coil discharge. Acoustic feedback was provided from the recording electrodes to monitor the EMG background. When MEPs were recorded during contraction, 3-5 MEPs were averaged using a 10 kHz sampling rate and a post-stimulus epoch of 50-100 msec in order to attenuate the 'muscular noise.' Stimulus repetition rates ranged between 0.2 and 0.3 c/sec. Individual responses were recorded at threshold in the relaxed muscles, and whenever possible during contraction, and were stored on diskettes for off-line evaluation of the following parameters: (1) Threshold. TCS intensity necessary for eliciting MEPs in about half of 10 individual trials gathered in cascade during complete relaxation and right/left hemisphere threshold asymmetries for the hand MEP elicitation (Table I).
TABLE I TCS threshold, motor central conduction time (CCT) and side asymmetry (SA) of MEPs recorded from patients and control subjects. Patients with ALS are not included in the upper part of the table (hand muscles). N = number of examined limbs; ( % ) = percentage of magnetic stimulator output; SA = side asymmetry = right-left differencce of the absolute values of threshold TCS. Magnetic TCS MEPs
N
Threshold (%) Mean
Hand muscles
Foot muscles
* P < 0.001.
Control subjects Patients
60 84
40.2 65.0 *
Control subjects Patients
60 98
67.9 88.0 *
CCT (msec) S.D.
Range
SA
S.D.
Mean
S.D.
2.5 18.0
37- 45 48-100
1.5 5.2
1.3 2.4
6.3 11.5 *
0.4 5.5
5.0 7.4
55- 75 80-100
/ /
/ /
11.9 20.1 *
1.5 5.6
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THRESHOLD EXCITABILITY FOR MEPs 1N MOTOR DISORDERS TABLE II Mean amplitude, duration and phases of MEPs to magnetic TCS as recorded from patients and control subjects. Magnetic TCS
Amplitude (mV)
MEPs
Mean
Hand muscles
Foot muscles
Control subjects Patients
6.11 2.47 *
Control subjects Patients
1.90 0.89 *
Phases
Duration (msec) S.D.
Mean
S.D.
Mean
S.D.
2.40 1.60
24.00 31.50 *
4.00 7.80
2.91 5.09 *
0.71 2.10
0.80 0.64
29.20 42.20 *
7.30 12.10
2.30 5.70 *
0.70 2.20
* P < 0.001.
(2) Central conduction time (CCT). CCT was calculated by means of the following equation:
of items (1) and (2) above 3 S.D.s beyond the control mean. A linear regression plot was employed to assess possible correlations between threshold and CCT values in the patient population. Normal data were gathered from 30 informed healthy volunteers (15 males, 15 females, age range from 21 to 54 years) matched for age and sex with the patient group.
CCT (msec) = M E P - [ ( F - MAP - 1)/2] + MAP in which MEP is the latency of the motor responses to TCS, during contraction (Rossini et al. 1987), F is the latency of the earliest F waves, 1 is the delay for the spinal alpha-motoneuron backfiring, and MAP is the latency of the motor potential to peripheral nerve stimulation (Kimura 1983; Table I). (3) MEP amplitude: measured from the maximal peak-to-peak deflection (Table II). (4) MEP duration: measured as the time interval during which the trace abandoned and regained the baseline (Table II). (5) MEP phases: calculated as the number of reproducible baseline crossings (Table II). In 4 patients (3 definite MS, 1 spinocerebellar degeneration) with MEPs that were potentiated only slightly by voluntary contraction, the target muscles were vibrated for 120 sec at 50 Hz immediately before TCS, in an attempt to facilitate MEP elicitation (Rossini et al. 1987; Claus et al. 1988). Abnormalities were considered to be the following: absent MEPs during relaxation with maximal TCS, unidentifiable MEPs after muscle contraction, values
Results
Absolute thresholds for MEP elicitation in different muscles as well as right/left hemisphere threshold differences are listed in Table I for the control population, together with the CCT values. With our type of stimulator and recording conditions, we did not find a systematic difference between right and left hemisphere TCS or a difference linked to the subjects' hand dominance. MEP amplitude, duration and phases are detailed in Table II. The relationships between clinical signs, CCT and threshold abnormalities in the patients are summarized in Table III.
TABLE II1 Incidence of threshold and CCT abnormalities in upper and lower limbs, according with clinical involvement of the corticospinal pathways. Patients with ALS are not included in the upper part of the table (hand muscles). N = number of clinically affected limbs; % = percentage of clinically affected limbs with altered threshold a n d / o r CCT. Clinical signs
Hand muscles
Foot muscles
Limbs
Increased threshold
Abnormal CCT
N
N
%
N
%
Hyper-reflexia increased tone Weakness
48 15
44/48 12/15
91.6 80.0
25/28 13/15
52.2 86.0
Hyper-reflexia increased tone Weakness
58 19
48/58 17/19
82.7 89.0
40/58 16/19
68.9 84.0
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M.D. C A R A M I A ET AL.
Multiple sclerosis
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The patients with MS selected for this study were clinically classified as definite (14), probable (6) and possible (14) (MeAlpine et al. 1972). Upper limb recordings. An increased threshold for eliciting magnetic MEPs in relaxed muscles was the most frequently altered parameter (26 out of 34 MS patients = 76.4% 38 out of 68 limbs). In 12 patients the increased threshold represented the only abnormal finding for the upper limbs. This was associated with hyper-reflexia and with mild motor complaints such as rapid fatigability or impaired movement dexterity (in 5 of these 12 patients, CCT for the lower limbs was prolonged). CCT prolongation combined with increased threshold was found in 13 patients. In 9 of them (14 limbs) the MEPs were polyphasic and of low amplitude. In 4 MS patients, who had the highest thresholds (from 70% to 100% of the stimulator output) MEPs could not be identified even during strong contractions producing much background E M G activity (Fig. 1). In these patients, the clinical picture was dominated by brisk DTRs, finger jerks and moderate spasticity, combined with a slightly decreased strength (degree 4 on MRC scale). In 1 patient with definite MS a prolongation of the CCT was found without an associated threshold increase. A significant right/left asymmetry of threshold TCS for hand MEPs (with normal absolute values) was found in 3 patients. The threshold was higher on the hemisphere governing the side with the greater clinical deficit and the longer CCT. Lower limb recordings. Increased intensity of magnetic stimulation required to evoke responses during relaxation was found in 23 out of 34 patients ( = 67.6%; .................i..............7.......................................................................................................... i...................................i! L....~cJs
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41 out of 68 limbs). Absent motor responses to maximal magnetic TCS were found in 14 out of 68 limbs (20.6% of patients). In these patients voluntary contraction gave rise to an E M G activity pattern in which MEPs could not be identified in single trials or after averaging (Fig. 2). Polyphasic MEPs with reduced amplitude and prolonged CCT, from one side, were recorded in 16 patients. Four patients did not show threshold as well as CCT alterations of the motor paths governing the foot muscles, while these parameters were both abnormal during hand muscle testing.
Primary lateral sclerosis Three out of 4 patients with primary lateral sclerosis, affected by tetrahyper-reflexia and spastic paraparesis, had increased thresholds and prolonged CCT both for upper and lower limb MEPs. The patient who did not show MEP abnormalities had been ill for the longest time.
Amyotrophic lateral sclerosis Patients affected by ALS each presented a heterogeneous picture of MEP abnormalities with different patterns in different muscles. For at least one of the examined muscles in each patient, the intensity of TCS required to elicit threshold responses in the upper limb muscles was below the lowest control limits (Table I). In 1 case this was observed in MEPs recorded from the lower limbs. Fasciculations were frequent in the muscles with lower than normal threshold and the presence of such spontaneous activity induced a MEP with a m p l i t u d e / l a t e n c y characteristics similar to that of the MEPs obtained during moderate voluntary activation. Moreover, relaxed MEPs were often indistinguishable from spontaneous fasciculations (Fig. 3). Finally, an increment of MEP threshold was encountered in muscles with severe atrophy a n d / o r with spasticity.
T H R E S H O L D EXCITABILITY F O R MEPs IN M O T O R D I S O R D E R S
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Motor CCT was prolonged by up to 4 S.D.s from the control mean in 6 out of 14 upper limbs and in 12 out of 14 lower limbs of ALS patients.
Spino-cerebellar ataxia In 2 of the 3 patients with the adult form of this disease, foot MEPs were absent at rest after maximal TCS. The clinical picture was represented by limb ataxia, spastic gait, diffuse exaggeration of DTRs, but preserved muscle power. The threshold of thenar MEPs was markedly elevated during relaxation. In these patients an E M G pattern of full interference was recorded, although reproducible MEPs were not obtained during contraction (Fig. 4). The third patient of this group was a 12-year-old boy. He started to develop gait disturbances at the age of 4 and difficulties in coordinating hand movements 14 months prior to examination. The combination of ataxia, brisk DTRs and finger jerks represented the main physical signs, fitting a type II 'early onset cerebellar ataxia with retained tendon reflexes' according to Harding's classification (Harding 1983). MEPs from the hand muscles showed alterations of both threshold and CCT, while recordings gathered from the lower limbs were normal. Brain metastasis The patient with brain metastasis was referred for acute paresis of the intrinsic hand and wrist extensor muscles on the left side, similar to the 'hand drop' of a radial nerve lesion. The right side was normal. CCTs were virtually the same on both sides. However, the asymmetric condition of the patient was reflected in asymmetric threshold measurements; left hand MEPs
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were elicited at rest with 70% of the maximal stimulator output delivered over the right hemisphere, while from the unaffected side relaxed responses were obtained by delivering a stimulus of 36% over the left hemisphere (Fig. 5). A C T scan revealed the presence of a metastatic lesion from a breast carcinoma, selectively involving the right pre-rolandic area.
Other obseruations In a small sample of patients with severe weakness and spasticity MEPs were recorded during active contraction following tendon vibration. Amplitude facilita-
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Fig. 5. Bilateral recordings from thenar muscles in a patient with a metastatic lesion involving the right pre-ro]andic area. No MEP could be elicited at rest by delivering magnetic pulses up to 60% of the stimulator output over the right hemisphere (upper traces), while reproducible threshold responses were recorded from the unaffected side by stimulating the left hemisphere using normal intensities (third pair of traces). Notice also the remarkable right-left asymmetry of MEP amplitudes during contraction.
248
M.D. CARAMIA ET AL.
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u p p e r limb MEPs (mean of TCS intensity = 32% of the stimulator's output). Spasticity a n d / o r hyper-reflexia were more frequently associated with increased threshold than with prolonged CCT, while weakness showed a similar degree of correlation with both p a r a m e t e r s (Table III). MEPs
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Fig. 6. MEPs from the hand muscles recorded in a patient with severe spasticity and weakness (degree 2). Threshold responses during rest were obtained with maximal TCS intensity (upper traces). During contraction there was poor MEP facilitation (middle traces). The voluntary activation, immediately performed after tendon vibration of the target muscles, produced a remarkable increase in MEP amplitude (up to 5 times) and duration (bottom traces).
tion, up to 5 times greater than the control value, was reached in muscles from which unreproducible MEPs with low amplitude had been recorded during contraction without vibration (Fig. 6). A significant linear correlation between C C T prolongation and increased threshold was found by matching part of the patient population (upper limbs R = 0.67 P 0.001, Fig. 7; lower limbs R = 0.61; P 0.001). The data from the patients with ALS were excluded from these regressions since, in at least one of the examined muscles, they displayed a lowering of threshold for
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Previous studies dealing with electric unifocal TCS have indicated that MEPs were either absent or required unusually strong stimuli in patients with demyelinating lesions of CNS, brain tumors or spinal cord compressions (Caramia et al. 1988). In a high percentage of patients with spasticity and hyper-reflexia, the maximal output of the stimulator failed to elicit MEPs during unifocal electric TCS even though the subjects retained the ability to activate the examined muscle (Merton and Morton 1980; Hess et al. 1987; Rossini et al. 1987). This is the case for both upper and lower limb recordings. An important aspect of the present investigation is the observation of a contrasting pattern as regarding the use of magnetic stimulation. With magnetic stimulation applied to patients with some degree of preserved voluntary muscle activation it was found that MEPs from the u p p e r limbs were invariably recorded. However, M E P could not be recorded from foot muscles in 20% of the patient population, not only during rest but also during muscle contraction. This finding is in line with previous demonstrations that threshold intensity for eliciting MEPs is normally higher for foot, axial, leg and pelvic muscles than for those of the hand, arm and shoulder (Rossini and Caramia 1988). There may be a variety of possible causes. These include a deeper location and different orientation with respect to the transcranial current flow of the excitable neurons buried in the mesial portions of the motor strip. Alternatively it might also be caused by the decrease in the pyramidal cell density between the face, arm and leg motor areas, as well as by the progressively larger time dispersion of the impulses traveling the length of the spinal cord c o m p a r e d with those ending in the cervical myelomers. Finally, a higher threshold for foot M E P elicitation could be due to a multisynaptic network, as seen in proximal and axial muscles where the alpha-motoneurons are mainly indirectly activated via spinal interneurons (Kuypers 1973). These factors in the presence of altered impulse propagation along the corticospinal fibers directed to the myelomers controlling the foot muscles might explain why even the maximal output of the stimulator can fail to elicit detectable responses. An abnormal impulse propagation which might account for an increase in the threshold for M E P elicita-
THRESHOLD EXCITABILITY FOR MEPs IN MOTOR DISORDERS
tion may be due to: (1) partial block and increased time dispersion of the impulse propagation due to demyelination of the corticospinal tracts; (2) loss of corticospinal fibers due to a lesion in the motor cortex a n d / o r in the spinal cord; (3) abnormal activity of spinal interneurons regulating the impulse transmission between cortical and spinal motoneurons; (4) resting membrane potential changes of the cortical a n d / o r spinal motoneurons. It might be postulated that in spastic patients (e.g., those with MS) a stronger than normal TCS must be delivered in order to engage corticospinal fibers affected by demyelination and so produce a MEP. In such a condition, an increase of TCS is likely to be needed for propagating the impulse outflow along fibers with scattered partial conduction blocks. It is possible that in spasticity the lack of descending inputs to spinal motoneurons results in an excessive engagement by group I fibers (resulting, for example, in exaggeration of the H reflex; Hunt and Paintal 1958; Delwaide 1973; Burke 1985; Meinck et al. 1985; Wiesendanger 1985). In particular, defective descending control on the spinal pre-synaptic mechanisms could lead to failure of the interneuronal network exerting pre-synaptic inhibition of the Ia terminals on spinal MNs both at rest and at movement initiation (PierrotDeseilligny et al. 1981; Sanes and Evarts 1983; Schieppati and Crenna 1984; Hultborn et al. 1987a,b; Katz et al. 1988). An increased threshold for MEP elicitation might thus depend on the greater difficulty in getting a synchronized descending volley through to the alphamotoneuron, given this background of excessive segmental excitation of alpha-motoneurons. In this framework, the spinal motoneurons would therefore be occupied by group I reafference and so be less able to respond with a MEP to a reduced amount of descending impulses. This hypothesis is supported by studies showing that muscle vibration, by inducing pre-synaptic inhibition of Ia fibers, reduces reafference on alphamotoneurons (Hagbarth and Eklund 1968; Delwaide 1969; Hagbarth 1973). In fact, when vibration was applied to spastic and weak muscles under contraction, it provoked a MEP facilitation up to 5 times greater than that obtained by voluntary activation alone (Fig. 6). Instead of facilitating motor responses to TCS as it does in normal subjects, the contraction of spastic muscles paradoxically may give rise to a brief silent period without a detectable MEP (Fig. 2). This also indicates that the excitation (MEP) and inhibition (post-excitatory silent period) which are induced by TCS may either run through separate descending routes or travel along the same tract but discharged at different thresholds. Repetitive discharges due to abnormal disinhibition of the spinal mot0neurons might partly contribute to
249
the temporal dispersion of MEPs as witnessed by their polyphasicity and increased duration. A peculiar pattern of MEP abnormalities was found among patients affected by ALS. Those patients in whom delayed MEPs with prolonged CCT were recorded frequently showed a tendency toward low threshold values for TCS. This was particularly evident when MEPs were recorded from patients whose muscles displayed spontaneous EMG activity with abundant fasciculations in the absence of spasticity. This threshold lowering is presumably due to the pathologically enhanced excitability of alpha-motoneurons, also manifested in these patients as fasciculation. The moderate prolongation of the CCT evaluated in patients with diffuse muscular hypotrophy in middle and late ALS stages could be ascribed to the loss of fast propagating pyramidal neurons, combined with the relative slowing of peripheral nerve conduction velocity which follows the loss of the large diameter spinal alpha-motoneurons (Thomas 1971; Dyck et al. 1975; Conradi 1982). TCS abnormalities in spino-cerebellar degeneration could be partially explained by the presence of spasticity, which has been found in association with increased TCS threshold and MEP dispersion. Nevertheless, the role played by the altered cerebellar function cannot be established on the basis of the present data. This study has shown that CCT measurements alone provide a partial view of motor tract functionality if not combined with information relating to the threshold. In particular, threshold measurement has turned out to be a useful additional parameter for the clinical assessment of those symptoms, such as hyper-reflexia, which on their own often reflect a rather questionable expression of central motor tract involvement. The diagnostic value of this approach indicates that magnetic TCS may be employed as a probe for the detection of altered excitability, as a frequent early neurophysiological marker of motor pathway involvement. We thank Mr. F. Lavaroni for his excellent and tireless technical assistance in the various phases of this study. We also acknowledge the help of Drs. M.T. Desiato, G. Martino and R. Traversa in collecting data.
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tion in patients with sensorimotor disturbances. Electroenceph. clin. Neurophysiol., 1988, 70: 16-25. Caramia, M.D., Pardal, A.M., Zarola, F. and Rossini, P.M. Electric vs. magnetic transcranial stimulation of the brain in healthy humans: a comparative study of central motor tracts 'conductivity' and 'excitability.' Brain Res., 1989, 479: 98-104. Claus, D., Mills, K.R. and Murray, N.M.F. The influence of vibration on the excitability of alpha motoneurons. Electroenceph. clin. Neurophysiol., 1988, 69: 431-436. Claus, D., Murray, N.M.F., Spitzer, A. and Flugel, D. The influence of stimulus type on the magnetic excitation of nerve structures. Electroenceph. clin. Neurophysiol., 1990, 75: 342-349. Conradi, F.G. Motor neuron disease and toxic metals. In: L.P. Rowland (Ed.), Human Motor Neuron Disease. Raven Press, New York, 1982: 201-231. Day, B.L., Dick, J.P.R., Marsden, C.D. and Thompson, P.D. Differences between electric and magnetic stimulation of the human brain. J. Physiol. (Lond.), 1986, 378: 36. Delwaide, P.J. Approche de la physiopathologie de la spasticit6: r6flexe de Hoffmann et vibrations appliqu6s sur le tendon d'Achille. Rev. Neurol., 1969, 121: 72-74. Delwaide, P.J. Human monosynaptic reflexes and presynaptic inhibition. In: J.E. Desmedt (Ed.), New Developments in Electromyography and Clinical Neurophysiology, Vol. 3. Karger, Basel, 1973: 508-552.
Dyck, P.J., Stevens, J., Mulder, D.W. and Espinosa, R.E. Frequency of nerve fiber degeneration of peripheral, motor, and sensory neurons in amyotrophic lateral sclerosis. Morphometry of deep and superficial peroneal nerves. Neurology, 1975, 25: 781. Gandevia, S.C. and Rothwell, J.C. Knowledge of motor commands and the recruitment of human motoneurons. Brain, 1987, 110: 1117-1130. Hagbarth, K.E. The effect of muscle vibration in normal man and in patients with motor disorders. In: J.E. Desmedt (Ed.), New Developments in Electromyography and Clinical Neurophysiology, Vol. 3. Karger, Basel, 1973: 428-443. Hagbarth, K.E. and Eklund, G. The effect of muscle vibration in spasticity, rigidity and cerebellar disorders. J. Neurol. Neurosurg. Psychiat., 1968, 31: 207-213. Harding, A.F. Classification of the hereditary ataxias and paraplegias. Lancet, 1983, i: 1151-1155. Hassan, H.F., Rossini, P.M., Cracco, R.Q. and Cracco, J.B. Unexposed motor cortex activation by low voltage stimuli. In: C. Morocutti and P.A. Rizzo (Eds.), Evoked Potentials Neurophysiological and Clinical Aspects. Elsevier, Amsterdam, 1985:107-113. Hess, W.H., 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. Hultborn, H., Meunier, S., Morin, C. and Pierrot-Deseilligny, E. Assessing changes in presynaptic inhibition of Ia fibres: a study in man and cat. J. Physiol. (Lond.), 1987a, 389: 729-756. Hultborn, H., Meunier, S., Pierrot-Deseilligny, E. and Shindo, M. Changes in presynaptic inhibition of Ia fibers at the onset of voluntary contraction in man. J. Physiol. (Lond.), 1987b, 389: 757-772. Hunt, C.C. and Paintal, A.S. Regulation of spinal reflexes and motoneurons. J. Physiol. (Lond.), 1958, 143: 195-212. Ingram, D. and Swash, M. Central motor conduction is abnormal in motorneuron disease. J. Neurol. Neurosurg. Psychiat., 1987, 50: 692-694. Katz, R., Meunier, S. and Pierrot-Deseilligny, E. Changes in presynaptic inhibition of Ia fibres in man while standing. Brain, 1988, 111: 417-437.
Kimura, J. The F-wave. In: Electrodiagnosis in Disease of Nerve and Muscle: Principles and Practice. Davis, Philadelphia, PA, 1983: 671-683. Kuypers, H. The anatomical organization of the descending pathways and their contributions to motor control especially in primates. In: J.E, Desmedt (Ed.), New Developments in Electromyography and Clinical Neurophysiology, Vol. 3. Karger, Basel, 1973: 38-68. Lance, J.W., Burke, D. and Andrews, C.J. The reflex effects of muscle vibration. Studies of tendon jerk irradiation, phasic reflex inhibition and the tonic vibration reflex. In: J.E. Desmedt (Ed.), New Developments in Electromyography and Clinical Neurophysiology, Vol. 3. Karger, Basel, 1973: 444-462. Levy, W.J., York, D.H., McCaffrey, M. and Tanzer, F. Motor evoked potentials from transcranial stimulation of the motor cortex in humans. Neurosurgery, 1984, 15: 287-302. Marsden, C.D., Merton, P.A. and Morton, H.B. Percutaneous stimulation of spinal cord and brain: pyramidal tract conduction velocity in man. J. Physiol. (Lond.), 1982, 328: 6P. McAlpine, D., Lumsden, C.E. and Acheson, E.D. Multiple Sclerosis: A Reappraisal. Churchill Livingstone, Edinburgh, 1972. Meinck, H.M., Benecke, R. and Conrad, B. Spasticity and the flexor reflex. In: P.J. Delwaide and R.R. Young (Eds.), Clinical Neurophysiology in Spasticity. Elsevier, Amsterdam, 1985: 41-54. Merton, P.A. and Morton, H.B. Stimulation of the cerebral cortex in the intact human subjects. Nature, 1980, 285: 227. Mills, K.R. and Murray, N.M.F. Corticospinal tract conduction time in multiple sclerosis. Ann. Neurol., 1985, 18: 601-605. Pierrot-Deseilligny, E., Morin, C., Bergego, C. and Tankov, N. Pattern of group I fibre projections from ankle flexor and extensor muscles in man. Exp, Brain Res., 1981, 42: 337-350. Rossini, P.M. and Caramia, M.D. Methodological and physiological considerations on the electric or magnetic transcranial stimulation. In: P.M. Rossini and C.D. Marsden (Eds.), Non-Invasive Stimulation of Brain and Spinal Cord: Fundamentals and Clinical Applications. Alan R. Liss, New York, 1988: 37-65. Rossini, P.M., Marciani, M.G., Caramia, M., Roma, V. and Zarola, F. Nervous propagation along central motor pathways in intact man: characteristics of motor responses to 'bifocal' and 'unifocal' spine and scalp stimulation. Electroenceph. clin. Neurophysiol., 1985, 61: 272-286. Rossini, P.M., Caramia, M. and Zarola, F. Central motor tract propagation in man: studies with non-invasive unifocal scalp stimulation. Brain Res., 1987, 415:211-225. Sanes, J. and Evarts, E. Regulatory role of proprioceptive input in motor control of phasic or maintained contractions in man. In: J.E. Desmedt (Ed.), Motor Control Mechanisms in Health and Disease. Advances in Neurology, Vol. 39. Raven Press, New York, 1983: 443-457. Schieppati, M. and Crenna, P. From activity to rest: gating of excitatory autogenetic afferences from the relaxing muscle in man. Exp. Brain Res., 1984, 56: 448-457. Starr, A., Caramia, M., Zarola, F. and Rossini, P.M. Facilitation of non-invasive electrical stimulation of human brain hand motor area occurs before voluntary movement. Electroenceph. clin. Neurophysiol., 1988, 70: 26-32. Thomas, P.K. Morphological basis for alterations in nerve conduction in peripheral neuropathies. Proc. Roy. Soc. Med., 1971, 64: 295-298. Wiesendanger, M. Is there an animal model of spasticity? In: P.J. Delwaide and R.R. Young (Eds.), Clinical Neurophysiology in Spasticity. Elsevier, Amsterdam, 1985:1-11,
243
ELMOCO 89616
'Excitability' changes of muscular responses to magnetic brain stimulation in patients with central motor disorders Maria D. Caramia, Paola Cicinelli, Claudio Paradiso a, Roberto Mariorenzi, Flora Zarola, Giorgio Bernardi and Paolo M. Rossini Clinica Neurologica, H Universit?l di Roma 'Tor Vergata, ' Dipartimento Sanit?l Pubblica, 00173 Rome (Italy) and a Clinica Malattie Nert:ose e Mentali, Universit?l di Siena, 53100 Siena (Italy) (Accepted for publication: 22 March 1991)
Summary The 'excitability' and 'conductivity' of motor pathways during transcranial stimulation (TCS) have been investigated in 49 patients affected by multiple sclerosis (34), amyotrophic lateral sclerosis (7), spino-cerebellar ataxia (3), primary lateral sclerosis (4) and brain metastasis (1). Hyper-reflexia, spasticity and weakness were correlated with the central motor conduction time (CCT) and with the threshold intensity of TCS required to produce a motor evoked potential (MEP). MEPs to magnetic TCS were recorded from hand and foot muscles during relaxation, contraction and after tendon vibration. Thresholds and CCTs of the patients were compared with those of 30 healthy controls. Increased threshold was found in 37 out of 49 patients (75.5%). Prolongation of the CCT was found in 38 out of 63 clinically affected upper limbs (60.3%) and in 56 out of 77 clinically affected lower limbs (72.7%). Absent motor responses to maximal TCS were found in 20 out of 98 lower limbs (20.4%). Excluding ALS patients (in whom there was a lower threshold for MEP elicitation), a significant linear correlation was found between prolonged CCT and increased threshold. While MEPs with prolonged CCTs have elevated TCS threshold, it is important to note that an elevated threshold was found in 14 out of 49 patients (28.5%) despite unchanged CCT. Spasticity a n d / o r hyper-reflexia were more frequently associated with increased threshold than with prolonged CCT, while weakness was correlated equally well with both these parameters. In this respect magnetic TCS proves to represent a new tool for the detection of abnormal 'excitability' of the central motor tracts. Key words: Brain stimulation; Excitability; Spasticity; Motor disorders
Non-invasive electrical stimulation of the brain has been found suitable for testing healthy volunteers as well as patients with lesions affecting the corticospinal tract (Merton and Morton 1980; Marsden et al. 1982; Levy et al. 1984; Hassan et al. 1985; Rossini et al. 1985). Such a technique is now currently employed in clinical practice, although its use is usually limited to the investigation of the innervation of the upper limbs (Mills and Murray 1985; Day et al. 1986; Berardelli et al. 1987; Hess et al. 1987; Ingrain and Swash 1987; Caramia et al. 1988). Motor pathways directed to lower limb motoneurons require higher intensities of transcranial stimulation (TCS) with consequent undue discomfort (Rossini et al. 1985). Recently, magnetic pulses have been introduced to achieve brain TCS (Barker et al. 1985). Besides being virtually painless, magnetic stimulation is also 'blind' to the smearing effects of the extracerebral layers, thereby
Correspondence to: Maria D. Caramia, M.D., Laboratorio di Neurofisiologia Clinica, Dipartimento di Sanit~ Pubblica, Universit~ di Roma 'Tor Vergata,' Via O. Raimondo 8, 00173 Rome (Italy).
allowing more precise measurement of the threshold for elicitation of motor evoked potentials than is possible with electric TCS. Amplitude/latency changes of MEPs have been analyzed in some detail in healthy humans subject to modifications of the stimulus parameters with either electric or magnetic TCS (stimulus intensity, electrode positioning and coil orientation), as well as of the muscular state (relaxed, contracted, premovement) (Gandevia and Rothwell 1987; Starr et al. 1988). While delayed MEPs with prolonged central conduction times (CCTs) have been described in a variety of neurological disorders, yet other aspects related to the abnormal responses deserve further observation. In particular, little attention has been devoted to excitability changes of motor responses to brain stimulation in patients with motor impairments. The aim of the present study is to investigate MEP characteristics in patients affected by disorders predominantly featuring weakness and spasticity through the analysis of the 'excitability' and 'conductivity' properties of the system mediating muscular responses to magnetic brain stimulation.
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Subjects and methods The group of patients (30 males; 19 females; age range 12-65 years) was composed of 49 subjects affected by multiple sclerosis (MS, 34), amyotrophic lateral sclerosis (ALS, 7), spinocerebellar ataxia (3), primary lateral sclerosis (4) and brain tumor (1). They were examined with their informed consent and with the approval of the Local Ethical Committee. Before each recording session all the patients underwent complete neurological examination. Muscle strength was assessed and scored according to the Medical Research Council (MRC) scale. Deep tendon reflexes (DTRs) were classified as absent, exaggerated or normal. Increased spastic tone, brisk finger jerks, trunk and limb ataxia as well as finger/nose and heel/knee dysmetria were judged as either present or absent. Patients affected by peripheral neuropathy were excluded from the present investigation.
Stimulation parameters Magnetic TCS. A copper coil (inner diameter of 7 cm), positioned on the scalp region overlying the motor strip delivered time-varying magnetic pulses of brief duration (160/zsec, peak voltage 6.4 V, Cadwell MES 10). The coil was moved in a fiat position over the scalp until the optimal stimulation site was localized for eliciting threshold motor responses in the contralateral muscles. The coil orientation in this type of stimulating device has been demonstrated not to influence the MEP latency/amplitude characteristics (Claus et al. 1990) because of the morphology of the induced field (bipolar voltage with negative-positive phases). The individual threshold intensity of TCS for a given muscle was identified during complete relaxation (Table I); the stimulus strength was thereafter increased by 10% over the threshold value to record reproducible MEPs in the voluntarily activated muscle(s) (Caramia
et al. 1989). We define the 'threshold' for magnetic TCS as the intensity required to elicit, with a 50% probability, detectable 'relaxed MEPs' with an amplitude of about 0.1 mV. Since commercially available magnetic stimulators do not provide direct measurement of the induced magnetic field, threshold values are expressed as a percentage of the stimulator's maximal output (2.0 tesla at the peak of the field induced by a pulse current in the coil approaching 6000 A). In patients, whose motor responses were not elicited at rest (even with maximal stimulator discharge), stimuli with increasing intensity were delivered during moderate contraction until a MEP could be obtained.
Recording parameters MEPs were recorded from hand (thenar) and foot (flexor hallucis) muscles of both sides via surface electrodes applied with a conventional belly-tendon montage. Signals were amplified (gain 10) and filtered between 1.6 and 1600 Hz ( - 6 dB/oct roll-off). A ground electrode was placed proximally to the recording site in order to minimize stimulus artifact produced by the coil discharge. Acoustic feedback was provided from the recording electrodes to monitor the EMG background. When MEPs were recorded during contraction, 3-5 MEPs were averaged using a 10 kHz sampling rate and a post-stimulus epoch of 50-100 msec in order to attenuate the 'muscular noise.' Stimulus repetition rates ranged between 0.2 and 0.3 c/sec. Individual responses were recorded at threshold in the relaxed muscles, and whenever possible during contraction, and were stored on diskettes for off-line evaluation of the following parameters: (1) Threshold. TCS intensity necessary for eliciting MEPs in about half of 10 individual trials gathered in cascade during complete relaxation and right/left hemisphere threshold asymmetries for the hand MEP elicitation (Table I).
TABLE I TCS threshold, motor central conduction time (CCT) and side asymmetry (SA) of MEPs recorded from patients and control subjects. Patients with ALS are not included in the upper part of the table (hand muscles). N = number of examined limbs; ( % ) = percentage of magnetic stimulator output; SA = side asymmetry = right-left differencce of the absolute values of threshold TCS. Magnetic TCS MEPs
N
Threshold (%) Mean
Hand muscles
Foot muscles
* P < 0.001.
Control subjects Patients
60 84
40.2 65.0 *
Control subjects Patients
60 98
67.9 88.0 *
CCT (msec) S.D.
Range
SA
S.D.
Mean
S.D.
2.5 18.0
37- 45 48-100
1.5 5.2
1.3 2.4
6.3 11.5 *
0.4 5.5
5.0 7.4
55- 75 80-100
/ /
/ /
11.9 20.1 *
1.5 5.6
245
THRESHOLD EXCITABILITY FOR MEPs 1N MOTOR DISORDERS TABLE II Mean amplitude, duration and phases of MEPs to magnetic TCS as recorded from patients and control subjects. Magnetic TCS
Amplitude (mV)
MEPs
Mean
Hand muscles
Foot muscles
Control subjects Patients
6.11 2.47 *
Control subjects Patients
1.90 0.89 *
Phases
Duration (msec) S.D.
Mean
S.D.
Mean
S.D.
2.40 1.60
24.00 31.50 *
4.00 7.80
2.91 5.09 *
0.71 2.10
0.80 0.64
29.20 42.20 *
7.30 12.10
2.30 5.70 *
0.70 2.20
* P < 0.001.
(2) Central conduction time (CCT). CCT was calculated by means of the following equation:
of items (1) and (2) above 3 S.D.s beyond the control mean. A linear regression plot was employed to assess possible correlations between threshold and CCT values in the patient population. Normal data were gathered from 30 informed healthy volunteers (15 males, 15 females, age range from 21 to 54 years) matched for age and sex with the patient group.
CCT (msec) = M E P - [ ( F - MAP - 1)/2] + MAP in which MEP is the latency of the motor responses to TCS, during contraction (Rossini et al. 1987), F is the latency of the earliest F waves, 1 is the delay for the spinal alpha-motoneuron backfiring, and MAP is the latency of the motor potential to peripheral nerve stimulation (Kimura 1983; Table I). (3) MEP amplitude: measured from the maximal peak-to-peak deflection (Table II). (4) MEP duration: measured as the time interval during which the trace abandoned and regained the baseline (Table II). (5) MEP phases: calculated as the number of reproducible baseline crossings (Table II). In 4 patients (3 definite MS, 1 spinocerebellar degeneration) with MEPs that were potentiated only slightly by voluntary contraction, the target muscles were vibrated for 120 sec at 50 Hz immediately before TCS, in an attempt to facilitate MEP elicitation (Rossini et al. 1987; Claus et al. 1988). Abnormalities were considered to be the following: absent MEPs during relaxation with maximal TCS, unidentifiable MEPs after muscle contraction, values
Results
Absolute thresholds for MEP elicitation in different muscles as well as right/left hemisphere threshold differences are listed in Table I for the control population, together with the CCT values. With our type of stimulator and recording conditions, we did not find a systematic difference between right and left hemisphere TCS or a difference linked to the subjects' hand dominance. MEP amplitude, duration and phases are detailed in Table II. The relationships between clinical signs, CCT and threshold abnormalities in the patients are summarized in Table III.
TABLE II1 Incidence of threshold and CCT abnormalities in upper and lower limbs, according with clinical involvement of the corticospinal pathways. Patients with ALS are not included in the upper part of the table (hand muscles). N = number of clinically affected limbs; % = percentage of clinically affected limbs with altered threshold a n d / o r CCT. Clinical signs
Hand muscles
Foot muscles
Limbs
Increased threshold
Abnormal CCT
N
N
%
N
%
Hyper-reflexia increased tone Weakness
48 15
44/48 12/15
91.6 80.0
25/28 13/15
52.2 86.0
Hyper-reflexia increased tone Weakness
58 19
48/58 17/19
82.7 89.0
40/58 16/19
68.9 84.0
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M.D. C A R A M I A ET AL.
Multiple sclerosis
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The patients with MS selected for this study were clinically classified as definite (14), probable (6) and possible (14) (MeAlpine et al. 1972). Upper limb recordings. An increased threshold for eliciting magnetic MEPs in relaxed muscles was the most frequently altered parameter (26 out of 34 MS patients = 76.4% 38 out of 68 limbs). In 12 patients the increased threshold represented the only abnormal finding for the upper limbs. This was associated with hyper-reflexia and with mild motor complaints such as rapid fatigability or impaired movement dexterity (in 5 of these 12 patients, CCT for the lower limbs was prolonged). CCT prolongation combined with increased threshold was found in 13 patients. In 9 of them (14 limbs) the MEPs were polyphasic and of low amplitude. In 4 MS patients, who had the highest thresholds (from 70% to 100% of the stimulator output) MEPs could not be identified even during strong contractions producing much background E M G activity (Fig. 1). In these patients, the clinical picture was dominated by brisk DTRs, finger jerks and moderate spasticity, combined with a slightly decreased strength (degree 4 on MRC scale). In 1 patient with definite MS a prolongation of the CCT was found without an associated threshold increase. A significant right/left asymmetry of threshold TCS for hand MEPs (with normal absolute values) was found in 3 patients. The threshold was higher on the hemisphere governing the side with the greater clinical deficit and the longer CCT. Lower limb recordings. Increased intensity of magnetic stimulation required to evoke responses during relaxation was found in 23 out of 34 patients ( = 67.6%; .................i..............7.......................................................................................................... i...................................i! L....~cJs
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41 out of 68 limbs). Absent motor responses to maximal magnetic TCS were found in 14 out of 68 limbs (20.6% of patients). In these patients voluntary contraction gave rise to an E M G activity pattern in which MEPs could not be identified in single trials or after averaging (Fig. 2). Polyphasic MEPs with reduced amplitude and prolonged CCT, from one side, were recorded in 16 patients. Four patients did not show threshold as well as CCT alterations of the motor paths governing the foot muscles, while these parameters were both abnormal during hand muscle testing.
Primary lateral sclerosis Three out of 4 patients with primary lateral sclerosis, affected by tetrahyper-reflexia and spastic paraparesis, had increased thresholds and prolonged CCT both for upper and lower limb MEPs. The patient who did not show MEP abnormalities had been ill for the longest time.
Amyotrophic lateral sclerosis Patients affected by ALS each presented a heterogeneous picture of MEP abnormalities with different patterns in different muscles. For at least one of the examined muscles in each patient, the intensity of TCS required to elicit threshold responses in the upper limb muscles was below the lowest control limits (Table I). In 1 case this was observed in MEPs recorded from the lower limbs. Fasciculations were frequent in the muscles with lower than normal threshold and the presence of such spontaneous activity induced a MEP with a m p l i t u d e / l a t e n c y characteristics similar to that of the MEPs obtained during moderate voluntary activation. Moreover, relaxed MEPs were often indistinguishable from spontaneous fasciculations (Fig. 3). Finally, an increment of MEP threshold was encountered in muscles with severe atrophy a n d / o r with spasticity.
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Motor CCT was prolonged by up to 4 S.D.s from the control mean in 6 out of 14 upper limbs and in 12 out of 14 lower limbs of ALS patients.
Spino-cerebellar ataxia In 2 of the 3 patients with the adult form of this disease, foot MEPs were absent at rest after maximal TCS. The clinical picture was represented by limb ataxia, spastic gait, diffuse exaggeration of DTRs, but preserved muscle power. The threshold of thenar MEPs was markedly elevated during relaxation. In these patients an E M G pattern of full interference was recorded, although reproducible MEPs were not obtained during contraction (Fig. 4). The third patient of this group was a 12-year-old boy. He started to develop gait disturbances at the age of 4 and difficulties in coordinating hand movements 14 months prior to examination. The combination of ataxia, brisk DTRs and finger jerks represented the main physical signs, fitting a type II 'early onset cerebellar ataxia with retained tendon reflexes' according to Harding's classification (Harding 1983). MEPs from the hand muscles showed alterations of both threshold and CCT, while recordings gathered from the lower limbs were normal. Brain metastasis The patient with brain metastasis was referred for acute paresis of the intrinsic hand and wrist extensor muscles on the left side, similar to the 'hand drop' of a radial nerve lesion. The right side was normal. CCTs were virtually the same on both sides. However, the asymmetric condition of the patient was reflected in asymmetric threshold measurements; left hand MEPs
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were elicited at rest with 70% of the maximal stimulator output delivered over the right hemisphere, while from the unaffected side relaxed responses were obtained by delivering a stimulus of 36% over the left hemisphere (Fig. 5). A C T scan revealed the presence of a metastatic lesion from a breast carcinoma, selectively involving the right pre-rolandic area.
Other obseruations In a small sample of patients with severe weakness and spasticity MEPs were recorded during active contraction following tendon vibration. Amplitude facilita-
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248
M.D. CARAMIA ET AL.
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tion, up to 5 times greater than the control value, was reached in muscles from which unreproducible MEPs with low amplitude had been recorded during contraction without vibration (Fig. 6). A significant linear correlation between C C T prolongation and increased threshold was found by matching part of the patient population (upper limbs R = 0.67 P 0.001, Fig. 7; lower limbs R = 0.61; P 0.001). The data from the patients with ALS were excluded from these regressions since, in at least one of the examined muscles, they displayed a lowering of threshold for
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98 %
Fig. 7. Linear regression plot showing the significant correlation between prolonged CCT (y-axis) and increased threshold (x-axis) of the upper limb MEPs. R = 0.67, P < 0.001.
Previous studies dealing with electric unifocal TCS have indicated that MEPs were either absent or required unusually strong stimuli in patients with demyelinating lesions of CNS, brain tumors or spinal cord compressions (Caramia et al. 1988). In a high percentage of patients with spasticity and hyper-reflexia, the maximal output of the stimulator failed to elicit MEPs during unifocal electric TCS even though the subjects retained the ability to activate the examined muscle (Merton and Morton 1980; Hess et al. 1987; Rossini et al. 1987). This is the case for both upper and lower limb recordings. An important aspect of the present investigation is the observation of a contrasting pattern as regarding the use of magnetic stimulation. With magnetic stimulation applied to patients with some degree of preserved voluntary muscle activation it was found that MEPs from the u p p e r limbs were invariably recorded. However, M E P could not be recorded from foot muscles in 20% of the patient population, not only during rest but also during muscle contraction. This finding is in line with previous demonstrations that threshold intensity for eliciting MEPs is normally higher for foot, axial, leg and pelvic muscles than for those of the hand, arm and shoulder (Rossini and Caramia 1988). There may be a variety of possible causes. These include a deeper location and different orientation with respect to the transcranial current flow of the excitable neurons buried in the mesial portions of the motor strip. Alternatively it might also be caused by the decrease in the pyramidal cell density between the face, arm and leg motor areas, as well as by the progressively larger time dispersion of the impulses traveling the length of the spinal cord c o m p a r e d with those ending in the cervical myelomers. Finally, a higher threshold for foot M E P elicitation could be due to a multisynaptic network, as seen in proximal and axial muscles where the alpha-motoneurons are mainly indirectly activated via spinal interneurons (Kuypers 1973). These factors in the presence of altered impulse propagation along the corticospinal fibers directed to the myelomers controlling the foot muscles might explain why even the maximal output of the stimulator can fail to elicit detectable responses. An abnormal impulse propagation which might account for an increase in the threshold for M E P elicita-
THRESHOLD EXCITABILITY FOR MEPs IN MOTOR DISORDERS
tion may be due to: (1) partial block and increased time dispersion of the impulse propagation due to demyelination of the corticospinal tracts; (2) loss of corticospinal fibers due to a lesion in the motor cortex a n d / o r in the spinal cord; (3) abnormal activity of spinal interneurons regulating the impulse transmission between cortical and spinal motoneurons; (4) resting membrane potential changes of the cortical a n d / o r spinal motoneurons. It might be postulated that in spastic patients (e.g., those with MS) a stronger than normal TCS must be delivered in order to engage corticospinal fibers affected by demyelination and so produce a MEP. In such a condition, an increase of TCS is likely to be needed for propagating the impulse outflow along fibers with scattered partial conduction blocks. It is possible that in spasticity the lack of descending inputs to spinal motoneurons results in an excessive engagement by group I fibers (resulting, for example, in exaggeration of the H reflex; Hunt and Paintal 1958; Delwaide 1973; Burke 1985; Meinck et al. 1985; Wiesendanger 1985). In particular, defective descending control on the spinal pre-synaptic mechanisms could lead to failure of the interneuronal network exerting pre-synaptic inhibition of the Ia terminals on spinal MNs both at rest and at movement initiation (PierrotDeseilligny et al. 1981; Sanes and Evarts 1983; Schieppati and Crenna 1984; Hultborn et al. 1987a,b; Katz et al. 1988). An increased threshold for MEP elicitation might thus depend on the greater difficulty in getting a synchronized descending volley through to the alphamotoneuron, given this background of excessive segmental excitation of alpha-motoneurons. In this framework, the spinal motoneurons would therefore be occupied by group I reafference and so be less able to respond with a MEP to a reduced amount of descending impulses. This hypothesis is supported by studies showing that muscle vibration, by inducing pre-synaptic inhibition of Ia fibers, reduces reafference on alphamotoneurons (Hagbarth and Eklund 1968; Delwaide 1969; Hagbarth 1973). In fact, when vibration was applied to spastic and weak muscles under contraction, it provoked a MEP facilitation up to 5 times greater than that obtained by voluntary activation alone (Fig. 6). Instead of facilitating motor responses to TCS as it does in normal subjects, the contraction of spastic muscles paradoxically may give rise to a brief silent period without a detectable MEP (Fig. 2). This also indicates that the excitation (MEP) and inhibition (post-excitatory silent period) which are induced by TCS may either run through separate descending routes or travel along the same tract but discharged at different thresholds. Repetitive discharges due to abnormal disinhibition of the spinal mot0neurons might partly contribute to
249
the temporal dispersion of MEPs as witnessed by their polyphasicity and increased duration. A peculiar pattern of MEP abnormalities was found among patients affected by ALS. Those patients in whom delayed MEPs with prolonged CCT were recorded frequently showed a tendency toward low threshold values for TCS. This was particularly evident when MEPs were recorded from patients whose muscles displayed spontaneous EMG activity with abundant fasciculations in the absence of spasticity. This threshold lowering is presumably due to the pathologically enhanced excitability of alpha-motoneurons, also manifested in these patients as fasciculation. The moderate prolongation of the CCT evaluated in patients with diffuse muscular hypotrophy in middle and late ALS stages could be ascribed to the loss of fast propagating pyramidal neurons, combined with the relative slowing of peripheral nerve conduction velocity which follows the loss of the large diameter spinal alpha-motoneurons (Thomas 1971; Dyck et al. 1975; Conradi 1982). TCS abnormalities in spino-cerebellar degeneration could be partially explained by the presence of spasticity, which has been found in association with increased TCS threshold and MEP dispersion. Nevertheless, the role played by the altered cerebellar function cannot be established on the basis of the present data. This study has shown that CCT measurements alone provide a partial view of motor tract functionality if not combined with information relating to the threshold. In particular, threshold measurement has turned out to be a useful additional parameter for the clinical assessment of those symptoms, such as hyper-reflexia, which on their own often reflect a rather questionable expression of central motor tract involvement. The diagnostic value of this approach indicates that magnetic TCS may be employed as a probe for the detection of altered excitability, as a frequent early neurophysiological marker of motor pathway involvement. We thank Mr. F. Lavaroni for his excellent and tireless technical assistance in the various phases of this study. We also acknowledge the help of Drs. M.T. Desiato, G. Martino and R. Traversa in collecting data.
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