J. Physiol. (1987), 388, pp.

397-419 With 15 text-figures Printed in Great Britain

397

RESPONSES IN SMALL HAND MUSCLES FROM MAGNETIC STIMULATION OF THE HUMAN BRAIN
BY C. W. HESS, K. R. MILLS AND N. M. F. MURRAY From the Department of Clinical Neurophysiology, The National Hospital, Queen Square, London WC1N 3BG

(Received 11 September 1986)

SUMMARY

1. The magnetic field generated by a brief current in a 9 cm diameter flat circular coil varies rapidly with time and when applied over the human scalp it is capable of exciting motor structures subserving the small hand muscles. With a peak magnetic field at the centre of the coil of 09-1-6 Tesla, single scalp stimuli produced twitches in the right abductor digiti minimi (a.d.m.), first dorsal interosseous (f.d.i.) and adductor pollicis muscles. Compound muscle action potentials (c.m.a.p.s) and single motor units from these muscles were recorded. 2. The twitch force and corresponding c.m.a.p. were greatly enhanced by voluntary background contraction of the muscle and depended on the direction and intensity of the magnetic field. Response amplitude was maximal with the stimulating coil centred near the vertex but precise coil position was not critical. 3. When the orthodromic volley set up in the peripheral nerve by magnetic stimulation of the brain collided with a maximal antidromic volley set up by stimulation at the wrist, remaining electromyographic (e.m.g.) activity gave evidence of multiple firing of some spinal motoneurones, provided that the muscle exerted a slight voluntary background contraction and the stimulus intensity was above threshold for relaxed muscle. 4. When the muscle changed from total relaxation to a slightly contracted state the onset latency of the c.m.a.p. was shortened by about 3 ms without further change when the background contraction increased. In slightly contracted muscle, c.m.a.p. onset latency was little affected over a wide range of stimulus intensities and was unaffected by the position of the stimulating coil within an area of 6 x 6 cm over the vertex. 5. Single motor units, recorded with needle electrodes in the a.d.m. or f.d.i. muscle, could be caused to discharge at a constant latency by threshold brain stimuli. Different single motor units had latencies varying from 22-4 to 32-1 ms. The same motor unit was activated from different coil positions up to 7 cm apart. These motor units had the lowest thresholds for voluntary activation. Stronger stimuli caused the same motor unit to discharge 1t5 ms earlier. 6. The threshold for excitation of pathways to the a.d.m. muscle was reduced by voluntary contraction of the contralateral a.d.m. and by contraction of the ipsilateral f.d.i. muscles. Using these procedures, the c.m.a.p. of totally relaxed a.d.m. muscle showed a more than 2-fold amplitude increase, a shortening of onset latency to a

C. W. HESS, K. R. MILLS AND N. M. F. MURRA Y similar degree as with contraction of the muscle itself, and single motor units in the a.d.m. muscle discharged 1-5 ms earlier. The threshold for excitation of the a.d.m. muscle was only minimally reduced by contraction of the contralateral f.d.i. and was unaffected by contraction of the ipsilateral quadriceps muscle. 7. It is likely that the enhancement of responses by voluntary background contraction is caused by additional recruitment of higher-threshold motor units in the motoneurone pool and by multiple firing of some motor units. 8. There may be two mechanisms of enhancement of responses to cortical stimulation, one related to a rise in excitability of homologous spinal motoneurone pools on the two sides, and a second operating at a higher level when the subject focuses his attention on the motor performance of a particular hand. The latter mechanism can be seen more easily with magnetic than with electrical brain stimulation, probably because the latter in part bypasses intracortical neuronal elements.
398
INTRODUCTION

It is possible to stimulate the human brain through the intact scalp and skull in conscious alert subjects. Stimuli may be electrical (Merton & Morton, 1980), using a high-output voltage, low-output impedance device, or magnetic (Barker, Freeston, Jalinous, Merton & Morton, 1985), in which a magnetic field varying with time induces intracranial currents. Central motor pathways can easily be excited by either type of stimulus (Day, Dick, Marsden & Thomson, 1986a; Hess, Mills & Murray, 1986b) and cause muscle responses on the contralateral side of the body with a latency consistent with conduction in fast central pathways. In contrast, excitation of sensory structures is more difficult to achieve and needs stronger stimuli (Merton & Morton, 1980). Because magnetic stimuli are almost without sensation whereas electrical stimulation causes marked scalp discomfort, the former are much more suitable for experiments where many stimuli are required or in clinical applications (Cowan, Dick, Day, Rothwell, Thomson & Marsden, 1984; Mills & Murray, 1985; Hess, Mills & Murray, 1986c). The magnetic stimulator (Polson, Barker & Freeston, 1982; Barker, Jalinous & Freeston, 1985; Barker, Freeston, Jalinous, Merton & Morton, 1985) consists of a copper coil which generates a brief intense magnetic pulse when a large current pulse is passed through it. The field is virtually unattenuated by the scalp and skull and induces brief intracranial currents. It is assumed that these induced currents, rather than a direct effect of the magnetic field, are responsible for stimulation of neural elements. Many factors will influence which structures are excited: coil location, shape and orientation, the intensity of the stimulus and the intrinsic excitability of neural elements. Clearly these factors and their influence on muscle responses need to be investigated in order that results can be interpreted. It is known that voluntary contraction of a muscle greatly enhances its response to brain stimulation (Bickford, Dodge & Uihlein, 1960; Merton, Morton, Hill & Marsden, 1982; Hess, Mills & Murray, 1986a), but little is known about the mechanism of this facilitation. On the basis of H-reflex studies and electrical brain stimulation it has been suggested that at least part of this facilitation occurs in the

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spinal cord (Berardelli, Cowan, Day, Dick & Rothwell, 1985), but the possibility of intracortical mechanisms remains. We report here results of experiments in which some of these factors have been investigated in twelve healthy subjects, with additional observations on a patient with motoneurone disease. Some of the present findings have already been published in preliminary (Hess & Mills, 1986; Hess et al, 1986a, b) or short form (Hess, Mills & Murray, 1986d, 1987).
METHODS

The subjects were hospital and laboratory personnel who gave their informed consent; the procedures were approved for use in healthy subjects and in patients by the National Hospital Medical Ethics Committee. They were ten males and two females with ages ranging from 26 to 62 years; all except one were right-handed. Subjects were specifically excluded if they had a history of epilepsy, had had neurosurgery or were fitted with a cardiac pace-maker. Results from a patient with motoneurone disease are also included (see Fig. 14); he had wasting of the small hand muscles with only a few surviving motor units.

Magnetic stimulation The stimulating coil (Fig. 1A) is composed of twenty-six concentric circular turns of copper wire and has a mean diameter of 9 cm. Cotton cross-strands taped to the coil facilitated its accurate placement over the scalp. A 1 cm diameter single-turn search coil was used to measure the magnitude and time course of the field produced by the coil. At maximum output of the device, the field generated at the centre of the coil was 2X1 Tesla. The field fell off linearly with distance within 5 cm of its centre, but less beyond this (Fig. 1B). Measured in parallel to the coil at different distances, the magnitude ofthe field was virtually constant within the area beneath the inner border of the coil and fell off steeply beyond that; i.e. beneath the coil the breadth of the effective field

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C. W. HESS, K. R. MILLS AND N. M. F. MURRA Y

was 5 cm in diameter. The time course of the field (Fig. 1C) showed a peak at approximately 150 us and then fell exponentially towards zero with a time constant of 340 ,us; the time course of the induced currents followed the first derivative of the magnetic field and peaked around 80 ,us. The output of the device was displayed as a percentage of its maximum output and it was confirmed by field measurements with the search coil to be linear within this range. Stimuli were applied to the scalp, with the centre of the coil over the vertex and with the inducing currents clockwise when viewed from above. In all experiments subjects were warned orally 1 - 2 s before the stimulus was delivered. Stimuli were never given more frequently than about once per ten seconds; the maximum repetition rate of the device was once per three seconds, this time being required to recharge the capacitors. It was decided that no more than thirty shocks should be given to any one subject in one experimental session. For this reason, it was not always possible to perform investigations in one experimental session as would have been desirable (see Figs. 8 and 10). No side-effects were reported by any of the subjects. The technique of electrical brain stimulation has been described in detail (Mills & Murray, 1985). It uses a high-voltage low-impedance output device (Digitimer D180) with anodal scalp shocks applied over the motor area.

Recording Silver-silver chloride cup electrodes of 0-7 cm diameter were taped over the belly and tendon of the right abductor digiti minimi (a.d.m.), first dorsal interosseous (f.d.i.) or adductor pollicis muscle. Responses were amplified (bandpass of amplifiers, 20 Hz to 2 kHz), and where it was necessary to measure onset latency accurately or to be certain of full relaxation of a muscle two amplifiers were used, one with a gain appropriate to measuring amplitude and the second at higher gain for latency measurement. Audio monitoring of the high-gain surface electromyogram (e.m.g.) signal was used throughout. Responses were stored digitally for subsequent measurement and plotting using a laboratory microcomputer (Research Machines 380Z). Needle recordings were made from the a.d.m. and f.d.i. muscles using concentric electrodes (Dantec Type 13L58). Responses were amplified with a bandpass of 500 Hz-10 kHz. The voluntary and twitch forces of abduction of the second or fifth digit and adduction of the thumb were measured with the hand and forearm immobilized on a wooden board; a strain gauge was placed against the proximal interphalangeal joint to record isometric force. Knee extension force was measured with the subjects sitting in a muscle-testing chair (Edwards, Young, Hosking & Jones, 1977); an inextensible strap around the ankle was connected to a strain gauge. The signal was displayed on an ultraviolet recorder, as were the force targets. Threshold for excitation of the totally relaxed a.d.m. muscle (checked by the audio e.m.g. signal at high gain from a.d.m.) was determined by increasing the intensity of scalp stimuli in small steps. The lowest intensity which gave a reproducible response was defined as threshold. In all twelve subjects threshold fell between 40 and 65 % of the maximum output of the stimulator. Stimulus intensities were then calculated in terms of this threshold for relaxed muscle and are quoted relative to this threshold in all the Figures.

Experimental procedures Effects of coil orientation and location (three subjects). The coil was lying on the scalp over the vertex and subjects were asked to remain relaxed or to make a small contraction of the right a.d.m. muscle (5-10 % maximum voluntary isometric force). Magnetic stimuli were then delivered at increasing intensities until compound muscle action potentials (c.m.a.p.s) from the right a.d.m. muscle of adequate size (3-5 mV) were obtained. The coil was then positioned anteriorly, posteriorly or laterally from the vertex in 1 or 2 cm steps and four to six stimuli of the same intensity were given at each site. Leaving the stimulus intensity unchanged and at a position found to be optimal, the coil was turned over to change the current flow from clockwise to anticlockwise. Comparison ofmagnetic with electrical brain stimulation (twelve subjects). Surface recordings from the slightly contracted (5-10 % maximum voluntary isometric force) right a.d.m. muscle were made and electrical and magnetic brain stimuli were applied. Stimuli of both types were increased in intensity until no substantial further increase in amplitude was obtained. The earliest and largest c.m.a.p. for each method was then taken for latency and amplitude measurement, respectively. Collision experiments (three subjects). Surface recordings from the right f.d.i. muscle were made and several responses to supramaximal electrical stimulation of the ulnar nerve at the wrist were

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401

recorded to measure M-responses and F-waves. That stimuli were supramaximal was ensured by using a stimulus intensity at least 20 % above that which gave a maximum amplitude M-response. The possibility of picking up in the f.d.i. muscle volume-conducted responses from the median innervated thenar muscles was checked by continuing to record from the f.d.i. muscles whilst supramaximal stimuli were delivered to the median nerve at the wrist. In no case did the volume-conducted response exceed 2 % of the amplitude of the maximal M-response from ulnar stimulation. Brain stimuli 20 % above threshold and supramaximal ulnar nerve stimuli at the wrist were then delivered with the wrist stimulus being later by 7-15 ms. With this timing there was no possibility that the fastest Ia afferents activated peripherally could influence the excitability of motoneurones before the latter had fired in response to the brain stimulus and collision in motor fibres must have occurred in the peripheral nerve. At each interstimulus interval four trials were performed with the muscle relaxed and slightly contracted. Effects of stimulus intensity and voluntary force in the a.d.m. muscle (five subjects). The maximum force of abduction of the fifth digit or adduction of the thumb was measured and target forces ranging from 1-5 to 25 % of this maximum were set. With the intensity set at 20 % below threshold (defined as above), just below threshold and 20% above threshold, c.m.a.p.s. and, in some experiments, the twitch force were then recorded with a sequence of diminishing target forces. The accurate recording of small hand-muscle isometric force requires rigid hand and forearm fixation even with peripheral nerve stimulation at the wrist. Consideration of this factor is even more important with brain stimulation where muscles of any peripheral innervation in the hand and forearm may also contract. However, the specific facilitatory effect of a background contraction allows force recording from a single muscle within a limited range of stimulus intensities, provided that other muscles in the arm are relaxed. To reduce the contribution of wrist adductors to twitch-force measurements in the a.d.m. muscle, high-gain audio monitoring and recording of the e.m.g. from the ulnar aspect of the forearm was used. This helped to keep forearm muscles as relaxed as possible and prevented them from producing large twitches with brain stimulation, and at the same time gave a rough estimate of their possible contribution to the total recorded force. Because of this factor twitch-force measurements became unreliable when stimulus intensity exceeded 20 % above threshold and background contraction of the small hand muscles exceeded 25 % maximum isometric force (see Fig. 8). In three separate experiments the effect of increasing intensities up to 60 % above threshold with relaxed and slightly contracted muscle was assessed. Additionally, in order to assess the inherent variability of the responses, a series of fifteen shocks was given, with voluntary force maintained constant at 5 % maximum and stimulus intensity at 20 % above threshold in three subjects. Effects of contraction of other muscles (five subjects). Using high-gain audio monitoring, surface electrode recordings from the totally relaxed right a.d.m. were made. After measuring the maximum force of the corresponding muscle, graded contractions between 1-5 and 25 % of maximum force of the right f.d.i., left f.d.i., left a.d.m., and right quadriceps were performed in different experiments with stimuli at threshold and 20 % above threshold intensities. Audio monitoring was particularly important in these experiments since, with increasing force level, some subjects found it difficult to keep the a.d.m. totally relaxed whilst maintaining a steady contraction of another hand muscle, particularly of the ipsilateral f.d.i. For this reason the effect of force levels above 25 % maximum were not investigated. Responses which were contaminated by ongoing e.m.g. activity in the right a.d.m. muscle were rejected. Single-motor-unit recordings (four subjects and one patient). The needle electrode was inserted into the a.d.m. or f.d.i. muscle and with the subject instructed to make a small voluntary contraction, the needle site was adjusted until a sharp single unit was recorded which could be discriminated reliably. The earliest recruited motor units were displayed using a delay line and stored. With the needle left undisturbed and the muscle totally relaxed, magnetic stimuli were then applied over the vertex at increasing intensities until a motor-unit response was obtained in the muscle. On some occasions the coil was positioned at different sites over the scalp 4-7 cm apart and the first motor units obtained were compared. In three experiments the effect of contraction of the contralateral homologous or another ipsilateral hand muscle on motor-unit responses was

investigated.

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C. W. HESS, K. R. MILLS AND N. M. F. MURRA Y

RESULTS

It proved easy to evoke c.m.a p.s of 2 mV amplitude or more in small hand muscles by stimuli applied at the vertex in relaxed healthy subjects. The small hand muscles were usually among the first arm muscles to be activated. The sensation reported by subjects during the shock were those of muscle twitch and an audible click produced in the coil. There was little sensation from the scalp. The initial components of the c.m.a.p.s were of the same general shape as c.m.a.p.s produced by stimulation of the peripheral nerve at the wrist (Fig. 2) suggesting that the volley set up by the shock had been transmitted to the muscle relatively synchronously.

Wrist

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10 ms Fig. 2. Surface recordings of the compound muscle action potentials (c.m.a.p.s) from the, abductor digiti minimi (a.d.m.) muscle in two subjects. Supramaximal electrical stimuli were applied to the ulnar nerve at the wrist and over the C7 - Ti interspinous space in the mid line; magnetic stimuli were applied over the vertex. The c.m.a.p.s from the three stimulation sites are comparable in amplitude and shape allowing for some temporal

It was noticed that the threshold for excitation of the relaxed muscle showed some variation with time (up to 5 % over a 5 min period), but this did not appear to be related to the attention or alertness of the subject in any obvious way or to fluctuation in the output of the stimulator. Even when the force of contraction, stimulus intensity and coil position were kept constant there was some variability in c.m.a.p. amplitude and onset latency. The effect was most noticeable at low stimulus intensities, but was evident also at higher intensities. In three subjects the fluctuation in amplitude and latency of responses was assessed by giving fifteen stimuli of identical intensity and with constant background contraction. Taking the responses from the subject who showed most variability, amplitude varied by up to 2-4 mV (61 % of this subject's mean of the fifteen responses), onset latency by up to 3-2 ms (15-4 % of the mean) and latency to half-maximum amplitude by up to 2-1 ms (9-6 % of the mean). The fluctuations of centrally evoked motor responses contrasts with the constancy in amplitude and latency of maximal c.m.a.p.s evoked by peripheral nerve stimu-

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403

1I i

mV

C1

j5 mV

10 ms Fig. 3. Surface recordings of the c.m.a.p.s from the first dorsal interosseus (f.d.i.) muscle in one subject. A, six superimposed responses to supramaximal shocks to the ulnar nerve at the wrist showing F-waves. Wrist shocks were delivered 3 ms after sweep start; M-response is chopped in this high-gain display. B, four superimposed responses from magnetic brain stimuli 20 % above threshold intensity delivered 3 ms after sweep start and with 5-10 % voluntary background contraction of the f.d.i. muscle. C, magnetic brain stimuli and background contraction as above. Supramaximal wrist shocks were delivered 9 ms (top traces), 11 ms (middle), and 13 ms (bottom) after the brain stimuli; four responses at each interstimulus interval superimposed. Note that remaining e.m.g. activity from uncollided nerve impulses follows the M-responses at different intervals and is time-locked to the brain stimulus. Amplitude gain is the same in B and C.

lation, and although a potential limitation for clinical applications, is clearly an important property of the system under study. The spread of onset-latency measurements could be reduced by taking the lowest value from a series of consecutive c.m.a.p.s. Thus, again using values from the subject showing most variability, the shortest onset latency of groups of three, four and five successive c.m.a.p.s from the fifteen responses did not differ by more than 1-2, 0-8 and 0-5 ms, respectively.

Effect of coil orientation and location

With the inducing current clockwise viewed from above and using increasing stimulus intensities, the small hand muscles of the right hand were activated before those on the left and vice versa. Taking the mean of four to six shocks at each site, amplitudes and, to a greater extent, onset latencies were stable over a relatively wide area over the vertex for slightly contracted as well as relaxed muscle. Thus as long

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C. W. HESS, K. R. MILLS AND N. M. F. MURRA Y

as the centre of the coil was positioned in either the sagittal or coronal planes within 2 cm of the vertex no change of amplitude was observed. No change was observed in latency of c.m.a.p.s with the coil similarly positioned up to 3 cm from the vertex (Hess et al. 1987).

+40%

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Threshold

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Fig. 4. Surface recordings of c.m.a.p.s. from the a.d.m. muscle in one subject. Magnetic stimuli were applied at the vertex at four intensities related to the threshold for relaxed muscle. Responses were recorded first with the muscle totally relaxed (dashed lines) and then with the subject maintaining a 1-5 % maximium contraction ofthe muscle (continuous lines). Onset latency of responses with the muscle relaxed is at 22-6 ms, but when the muscle contracts the onset latency falls to 19-3-20-1 ms even when the stimulus is subthreshold for the relaxed muscle (bottom trace).

Collision experiments After the orthodromic motor volley set up in the peripheral nerve by magnetic stimulation of the brain at an intensity 20% above threshold collided with the antidromic volley from a supramaximal nerve stimulus, unblocked e.m.g. activity remained following the M-response and was earlier than the F-response (Fig. 3). It only arose during slight voluntary background contraction, but not in relaxed muscle. When shifting the wrist stimulus relative to the brain stimulus, the remaining e.m.g. activity was time-locked to the brain stimulus rather than to the wrist stimulus. It was 34-5'3 ms later in onset latency than the uncollided response to the brain stimulus so that a substantial part of it fell in the positive phase of the c.m.a.p. from the brain stimulus. In different subjects, the amplitude of the remaining e.m.g. activity varied from 4 to 40 % of the uncollided c.m.a.p. from brain stimulation. Such remaining e.m.g. activity was interpreted as being produced by a second orthodromic potential in some nerve fibres not affected by collision and was, therefore, taken as evidence for double or multiple firing of some motoneurones.

Effects of voluntary force and stimulus intensity Because ofthe range of amplitudes and latencies of successive c.m.a.p.s from cortical

MAGNETIC BRAIN STIMULATION

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Fig. 5. Response size related to stimulus intensity. Twitch force (U) and c.m.a.p. measurements from a.d.m. muscle with voluntary background contraction of 5-10 % maximum from brain stimuli of different stimulus intensities (defined as in Fig. 4) in one subject. Area (V) beneath the negative component and amplitude (0) of negative component of c.m.a.p. were measured. Mean values of four shocks at each intensity.
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Fig. 6. Amplitude (filled symbols) and onset latencies (open symbols) related to stimulus intensity (defined as in Fig. 4). Responses from brain stimuli of different intensities in one subject with slight voluntary background contraction (circles) or total relaxation (diamonds). Mean values of four shocks at each intensity.

stimulation they were expressed as a mean value obtained from a series of four stimuli with the same intensity. Examples of c.m.a.p.s produced by stimuli at increasing intensities but at the same voluntary force are shown in Fig. 4 and the relationship between stimulus intensity and size of c.m.a.p.s or twitch force in two subjects is shown in Figs. 5 and 6. As expected, higher intensities of stimulation produced larger twitches and c.m.a.p.s. With the muscle relaxed, a linear increase of amplitudes was found and did not saturate within the stimulus range of the equipment. The

C. W. HESS, K. R. MILLS AND N. M. F. MURRA Y amplitude remained always well below that achieved with the same stimulus strength in a contracting muscle. With slight voluntary contraction the amplitudes tended to saturate with high stimulus intensities, although, with the stimulus intensities tested, this was not always achieved (Fig. 6). With a stimulus intensity 20 % above threshold and a slight voluntary background contraction the mean c.m.a.p. amplitude from five subjects was 91 % of that from stimuli 40 % above threshold, which could be considered as virtually 'maximal'. In contrast, twitch force and the area beneath the negative c.m.a.p. component increased further with high stimulus intensities and were better correlated with each other than with the amplitude of the c.m.a.p. Although force measurements of brain stimulus-induced twitches tend to become inaccurate with stronger stimuli which will involve other muscles, the discrepancy between the nearly saturating c.m.a.p. amplitude and the still-increasing twitch force and c.m.a.p. area is compatible with the suggestion of multiple firing of motor units with stronger stimuli. Over a wide range, stimulus intensity did not influence the latency of the responses in a consistent manner (Fig. 6). The mean onset latencies of c.m.a.p.s in slightly contracted muscle did not change with stimuli between threshold and 40 % above threshold. For example, using threshold stimulus intensity and a voluntary contraction of 10 % maximum, the mean onset latency in five subjects was 21-0 + 1-8 ms (S.D.), and when stimulus intensity was increased to 20 % above threshold with voluntary contraction the same, the onset latency was 21-1 + 1 9 ms (S.D.). With a stimulus intensity 40 % above threshold, an early component of the c.m.a.p. sometimes shortened the latency by a few milliseconds. Hence for clinical latency measurements it is sufficient to use a small voluntary contraction and a stimulus intensity at or just above threshold and there is no point in trying to achieve a 'maximal' response. The relationship between voluntary background force and amplitude of c.m.a.p. and twitch force is shown in Figs. 7 and 8. Using stimuli 20 % above threshold, voluntary contraction of as little as 1-5 % of maximum induced a 3-fold increase in c.m.a.p amplitude; with voluntary contraction of 100% maximum and above this facilitation of the response was virtually complete. As reported previously (Hess et al. 1986 a) and shown in the lower dashed curve of Fig. 8, with stimuli below threshold, a more gradual and linear rise in amplitude (and twitch force) was found. Twitch forces were found to be well correlated with c.m.a.p. amplitude, except with higher forces and stronger stimuli, where no saturation of twitch forces was observed (upper continuous line in Fig. 8). This again can be attributed to increasing multiple firing of some motor units but might additionally be due to contamination of force measurement by twitches of other muscles (see above). Merely touching or squeezing the finger with the muscle relaxed produced no enhancing effect, confirming that the facilitation produced was associated with the very small force and not solely related to a sensory input from the touch of the strain gauge. Neither concentrating attention on the muscle, nor imagining that it was making a contraction, caused facilitation, provided the relaxed state of muscle was ensured by high-gain audio e.m.g. and care was taken not to contract other hand muscles (see below). Responses also changed in onset latency when voluntary activity was present but showed little dependence on the degree of voluntary force (open symbols in Fig. 7). Very small contractions produced a marked shift in latency but little further shift
406

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Fig. 7. Amplitude (@) and latencies (0) related to voluntary background contraction from stimuli 20 % above threshold; mean values and S.D. from five subjects ofthe c.m.a.p.s. recorded from the a.d.m. muscle. The amplitudes were normalized to the maximum in each subject and the latencies expressed as difference (in ms) from value in relaxed muscle. (For the sake of accuracy, the actual voluntary force exerted was measured from the strain-gauge records after the experiment and linear interpolation from individual graphs provided amplitude and latency values at defined force levels for calculating avarages.)
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Fig. 8. Twitch force (continuous lines) and c.m.a.p. amplitude (dashed lines) related to voluntary background force with stimulus intensity 20 % above threshold (squares) and just below threshold (triangles); from two separate experiments (different subjects). Mean of four values at each background force level. In both subjects maximum force of the muscle was ca. 170 N. The two scales of the ordinate are adjusted so as to superimpose the corresponding two lower diagrams which show an approximately linear relationship between response size and background force. With stronger stimuli (upper diagrams) the relationship is more complex and the two curves diverge with higher background forces and would do so even if the scales were adjusted so as to superimpose the points at zero or very low background force level. With background forces of over 40 N and stronger stimuli measurements were not feasible for methodological reasons (see text).

was produced by stronger contractions. This may be useful in clinical applications where careful monitoring of force would tend to make the technique cumbersome. Reduction in onset latency when the muscle is voluntarily activated was found in all subjects. With stimulus intensities 20 % above threshold, the mean onset latency

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C. W. HESS, K. R. MILLS AND N. M. F. MURRA Y

TABLE 1. Comparison of compound muscle action potentials from abductor digiti minimi from magnetic and electrical brain stimulation and with slight voluntary background contraction (5- 10% maximum) in twelve healthy subjects Magnetic Electrical Difference Brain stimulation... (Mean+s.D.) (Mean+ S.D.) Mean+s.D. Min Max Onset latency (ms)* 20-9+1-12 18-8+1-42 2-1+0-67 1-3 3.7 Amplitude (% wrist response)t 54O0+18-0 38-0+883 16-0+13-6 -2-0 44-0 Duration (ms)t 8'0+0-83 -4-3+2-08 -0 7 -7.3 37 + 18 * Earliest of three responses taken. t Largest of three responses taken. t From the onset to the first zero crossing.

5 mV
10ms

Fig. 9. Surface recordings of the c.m.a.p.s from the a.d.m. muscle in one subject from magnetic (A) and electrical(B) brain stimulation at an intensity 20 % above threshold in relaxed muscle (small responses, continuous lines), with voluntary background contraction of 10 % maximum (dashed curves), and with voluntary contraction of 25 % maximum (large responses, continuous lines) by each method. The responses of corresponding background contraction are 14-3 ms earlier using the electrical method. Note the marked difference in c.m.a.p. shape and amplitude between the two methods with voluntary background contraction of 10 % (dashed curves).

in ten subjects was 24-1 + 1-6 ms (S.D.) with the muscle totally relaxed, but when contractions of 5-10 % maximum of voluntary isometric force were made, mean onset latency fell by 3.3 12 ms (S.D.) (minimum 16 ms, maximum 51 ms) a difference which was statistically highly significant (P < 0 0001, paired t test).

Comparison of magnetic with electrical brain stimulation As reported previously (Day, Dick, Marsden & Thomson, 1986a; Hess et al. 1986b) responses from electrical stimuli have shorter onset latencies by approximately 2 ms (Table 1), suggesting a different site of action of the stimulus within the brain. Furthermore, as compared to magnetic stimulation, the electrical stimulus produced differently shaped c.m.a.p.s. With a voluntary background contraction of about 5-10 % maximum and stimuli well above threshold with each method, responses from electrical stimulation were smaller in amplitude in all but one subject (mean

MAGNETIC BRAIN STIMULATION

409

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20 Al

n.s.

6 Relaxed 25 Voluntary force (% maximum)

Fig. 10. Amplitudes of the c.m.a.p. from relaxed a.d.m. muscle during voluntary contraction of ipsilateral f.d.i. (A) or contralateral a.d.m. (U) muscles at two different force levels. The amplitudes are normalized to the maximum achieved with voluntary contraction of the muscle itself. Mean and S.D. of five subjects; statistical comparison using the paired t-test and one-tailed Mann-Whitney U test provide the same results.

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.,

.|~~~~~~~~~~- mVA

10 ms Fig. 11. Needle recording from f.d.i. muscle from four subjects; examples of single motor units recruited during minimal voluntary activation of the muscle (left) and then during threshold magnetic stimulation at the vertex (right). In each case the same motor unit has fired.

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A V

5 mV ~~~~~0

C L r~~~~J]0.5mV
0 5 mV
D

-_
10 ms

Fig. 12. Needle recordings from a.d.m. muscle in one subject. A, a single motor unit has discharged during weak voluntary contraction. B, the same unit has fired after threshold magnetic brain stimulation, with an onset latency of 27-7 ms. C, stimulus intensity has been increased to 30 % above threshold and a compound response is recorded from the muscle, with an onset latency of 22-7 ms. D, gradually increasing electrical stimuli were applied to the ulnar nerve at the elbow and at threshold a different motor unit has fired.

amplitude difference: 1-47 + 1-09 (S.D.) mV, range: -0-35 to 2-65 mV), were always longer in duration (Table 1) and often showed a biphasic configuration (dashed curve in Fig. 9B). Only with a stronger voluntary background contraction could a c.m.a.p. of similar amplitude and shape (but still earlier onset) to that from magnetic stimulation be achieved (large responses with continuous lines in Fig. 9A and B). Thus, the marked facilitating effect of a small background contraction is a characteristic feature of magnetic brain stimulation and not found in electrical brain stimulation, where the relationship between background force and c.m.a.p. amplitude is approximately linear (Rossini, Marciani, Caramia, Roma & Zarola, 1985).

Effects of contraction of other muscles

As reported previously, an increase in c.m.a.p. amplitude of the completely relaxed right a.d.m. muscle was also produced by contraction of the left a.d.m. and right f.d.i., but only little effect was seen with contraction of the left f.d.i., and none at all with the right quadriceps (Hess et al. 1986d). With a voluntary force of 25 % maximum in the ipsilateral f.d.i. or contralateral a.d.m. muscle, the c.m.a.p. amplitude of the relaxed a.d.m. reached approximately one-half of the maximal amplitude achieved by background activity of the muscle itself. However, facilitation produced by contraction ofthese two muscles showed a different relationship between background force and c.m.a.p. amplitude. As with facilitation from contraction of the muscle itself, and using stimuli well above threshold, the facilitation from contraction of the ipsilateral f.d.i. muscle was marked with very low forces (<5 %

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411

C
D 0|5 mV]

10 ms Fig. 13. Needle recordings of a single motor unit from the f.d.i. muscle. A, during weak voluntary activation of the muscle. B, during magnetic brain stimulation around threshold. C, with the stimulus intensity slightly reduced; the unit discharges 1-4 ms later. D, with stimulus intensity increased to about 10 % above threshold; the unit discharges again 1-6 ms earlier, i.e. virtually at the same latency as in B. In C and D the unit's wave form has been contaminated by other more distant units but its principal feature can still be discemed. Latencies were measured to the main positive spike component (arrows).

maximum) and did not significantly increase any further. In contrast, facilitation produced by contraction of the homologous contralateral muscle (left a.d.m.) rose progressively with increasing voluntary force (Fig. 10), more like facilitation produced by the muscle itself when using weak stimuli (below threshold) (triangles in Fig. 8). Contraction of the contralateral a.d.m. and ipsilateral f.d.i. muscles also caused a shift in onset latency compared to the relaxed state. The shift was similar to that obtained when facilitation was produced by contraction of the muscle itself.

Single-motor-unit recordings
It is remarkable that single motor units can be excited from what must be a relatively gross stimulus to the brain (Hess & Mills, 1986), but with threshold stimuli and recordings with a small concentric electrode we succeeded in fifteen consecutive trials in four subjects in showing the the motor unit which was activated by brain stimulation was always among the first three of those (within the pick-up area of the needle) recruited by voluntary activation (Fig. 11). The onset latency of these single lowest-threshold motor-unit potentials ranged from 22-4 to 32-1 ms. By placing the stimulating coil at different sites over the scalp and following the same procedure, the same motor units were activated. For instance, with the coil 1 cm anterior and

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A~~4

0C5 mVJ

Fig. 14. Needle recording from a.d.m. muscle in a patient with motoneurone disease with few surviving motor units in the muscle. A, voluntary activation of the muscle shows the discharge of two motor units. B, threshold magnetic brain stimulation has caused the discharge of both units which are superimposed (note the wave form at the start of the first unit and the small satellite potential at the end of the second unit). C, the stimulus was increased to well above threshold; the onset latency (arrowed) of the response, which is very similar in wave form to B, has shortened by 1-6 ms.

110 ms

6 cm posterior to the vertex the same motor unit was activated with threshold stimuli, the latency being 02 ms longer and the threshold intensity being noticeably higher at the posterior site. With more intense brain stimulation then a compound response was seen in the muscle due to the activation of many motor units; the onset latency of this was up to 4-9 ms shorter. Attempts to activate the same single motor units by threshold stimulation of peripheral nerve at the wrist or elbow resulted in activation of a different unit or units in the muscle (Fig. 12). On three occasions with a suitable site in the muscle, the effects of just suprathreshold stimuli were investigated on single motor units which had been identified as the earliest recruited by volition at that site. It was seen that the same motor-unit potential shifted by 14-116 ms to an earlier latency with stronger stimuli (Fig. 13). Because of the difficulty in recording single motor units when stimulus intensities are well above threshold, the patient with motoneurone disease was studied. He had a very few surviving motor units in the muscle. It was evident that two ofthese were active during weak voluntary effort, and on brain stimulation at threshold intensity a potential which was the superposition of the two units was seen

MAGNETIC BRAIN STIMULATION

A

~~1

413

10 Ms

Fig. 15. Needle recordings of two motor units from right a.d.m. muscle in one subject during weak voluntary activation (A) and the threshold magnetic brain stimulation (B). In B, successive responses are shown in a totally relaxed state (1), during voluntary contraction of the ipsilateral f.d.i. muscle (2), during voluntary contraction of the contralateral a.d.m. muscle (3), during voluntary contraction of the ipsilateral quadriceps muscle (4) and in the totally relaxed state again (5). In B, the voluntary contraction of the other muscles was about 50 % maximum, a force which proved possible without any co-contraction of the right a.d.m. muscle. Both motor units discharged earlier during contraction of ipsilateral f.d.i. and contralateral a.d.m. but not during contraction of the quadriceps muscle. The more spiky motor unit potential shifted by P-8 ms and the smaller and later motor unit potential shifted by 3-9 ms or (first trace in B3) 1-7 ins. The range of variation under identical conditions was 0-2 ins. Latency was measuredl to the first positive spike component in each potential.

Fig. 14). With stimulus intensity increased well above threshold, these motor units
activated at a latenc'y 1-6 ms shorter. On no occasion in healthy subjects nor in this patient did we see repetitive firing of the same motor unit. Evidence of multiple firing from the collision experiments was only seen when there was background contraction. The effect of contraction of other muscles on motor-unit responses is shown in Fig. 15. In this example, two motor-unit potentials, one of which was remote from the needle tip, could easily be activated voluntarily as well as by threshold brain stimulation. The motor units had a tendency to discharge at preferred latencies; during contraction of an ipsilateral hand muscle or the contralateral homologous muscle both motor units discharged earlier by 1-8 and 3.9 (or 1-7) ms respectively, and in another experiment by 1-3 ins. There was, however, no shift during contraction of a contralateral non-homologous muscle (Fig. 15). That is, the motor-unit potential shift occurred under the same conditions as those which, with stronger stimuli, caused facilitation of the surface-recorded responses and twitches.
were
DISCU-SSION

motor structures

It has been shown that magnetic stimulation applied to the human scalp excites subserving the small hand muscles and that the size of responses

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can be greatly enhanced by concurrent weak contraction of the target muscle itself, and to a lesser extent by concurrent contraction of ipsilateral or homologous contralateral small hand muscles; however the relationship between force exerted and facilitation is different for these latter two muscles. The onset latencies of c.m.a.p.s shorten by about 3 ms when they are facilitated by contraction. It has been shown that the same single motor units can be caused to discharge by threshold magnetic stimuli applied over different parts of the scalp, and that these motor units are the same ones within the pick-up area of the needle that are activated first in voluntary contraction. With concurrent contraction of ipsilateral or homologous contralateral small hand muscles these motor units discharge 1P2-1P6 ms earlier, and the same latency shift can be induced by increasing the stimulus intensity without background contraction. At first sight it seems paradoxical that the optimal coil position for excitation of hand muscles is at the vertex when it is well known that the position of the hand area is about 3-4 cm down the motor strip. Although the magnetic field passes virtually unattenuated into the brain, the strength and path of induced currents will depend on the impedance of intracranial structures, which is anisotropic, and so it is difficult to predict where the effective current path will be. In addition, it is conceivable that cortical cells projecting to hand muscle motoneurones have lower thresholds than other cortical cells. The first question to be addressed is which corticospinal system is being activated by these stimuli. The conduction time from scalp to muscle of about 20 ms comprises a central and a peripheral component. The peripheral contribution can be estimated by stimulating electrically over the cervical spine (known to excite the motor roots at their exit foramina from the spinal canal (Mills & Murray, 1986)) which gives a mean conduction time from motor root to muscle of 13 ms. The remaining time, 7 ms, comprises central conduction, synaptic delay at the motoneurone, and conduction down a short intradural segment of the motor root. If we assume a monosynaptic delay of 1 0 ms, and root conduction of 0 3 ms, then 5-7 ms remains for the central component which therefore must represent conduction over a fast pathway like the cortico-motoneuronal tract, known to have a monosynaptic in addition to oligosynaptic connection with motoneurones in primates (Preston & Whitlock, 1961; Landgren, Phillips & Porter, 1962; Phillips & Porter, 1964), rather than less direct routes to the motoneurone like the cortico-reticulospinal, cortico-rubrospinal or cortico-cerebellospinal pathways or more slowly conducting corticospinal neurones, which nevertheless may contribute later components to the c.m.a.p. It is also possible, though unlikely, that stimuli act on pre-motor areas or the thalamus and then cause secondary excitation of the main efferent system. The suggestion that the volley is transmitted over few synapses is supported by the similarity of wave forms of c.m.a.p.s from central and peripheral stimuli. The next question is which neural elements in the cortex are excited. Clearly presynaptic terminals, dendrites, cell bodies, axons or a combination of structures are all possibilities. Central conduction time from electrical anodal stimulation is 2 ms shorter than with magnetic stimulation. This latency difference is unlikely to represent a different site of excitation from the cell body down its axon, because, for an axon conducting at 60 m/s, it would represent a shift of 12 cm. Therefore it has

MAGNETIC BRAIN STIMULATION 415 been suggested that the electrical stimulus, reaching further down in the brain, would, in part, directly excite the axon of the corticospinal cell whereas the magnetic stimulus would excite presynaptic structures in the cortex (Day et al. 1986; Hess et al. 1986b). From animal work it has been concluded that with the anode on the surface of the cortex, electrical stimulation primarily acts through virtual cathodes directly on the axons beneath the cell bodies (Phillips & Porter, 1962). The difference in latency between the corticospinal volley from direct axonal and the first volley from indirect excitation was found to be of the same order of magnitude as found here, that is 1-2 ms (Hern, Landgren, Phillips & Porter, 1962; Kernell & Wu, 1967). The strikingly short duration of c.m.a.p.s from magnetic stimulation as compared to those from electrical stimulation implies that the firing of spinal motoneurones is more synchronized with magnetic stimulation, even though the latency of the c.m.a.p. is 2 ms later. The mechanism of this phenomenon is unclear but it is possible that magnetic stimuli have a more homogeneous site of action in the cortex. To be successful, the electrical stimulus must be focused over the corresponding motor area where corticospinal axons subserving the muscles are bundled, whereas the location of the relatively large magnetic stimulating coil is not critical and can be moved by large distances and yet still cause similar compound muscle responses or, with threshold stimuli, identical single motor units to discharge. It seems unlikely that what must be a gross stimulus to the brain, even at threshold could cause the discharge of a single cortical cell or small group of cells and hence the discharge of a single motor unit. More probable is that a volley arising from a relatively wide area within the cortex beneath the stimulating coil is set plp, and the 'size principle' which recruits the smaller low-threshold motor units (Henneman, 1957; Milner-Brown, Stein & Yemm, 1973) then operates at the motoneurone-pool level to cause activation of low-threshold motoneurones in the same way that voluntary activation is thought to be mediated. Since it is known that in subhuman primates many pyramidal tract neurones converge on the same a-motoneurone (Liddell & Phillips 1952; Phillips & Porter, 1964; Asanuma & Sakata, 1967), and that such cells may be distributed over a cortical area up to 20 mm2 (Phillips, 1986) it is possible that stimuli at threshold may activate a critical number of such cells which presumably have relatively low thresholds, and cause discharge of single spinal skeletomotor neurones. Collision experiments suggest that facilitation causes some motor units to discharge twice or more with an interval of about 4 ms. Bawa & Calancie (1983) have shown that forearm flexor motor units can discharge as doublets with interspike intervals within this range. Multiple firing of motor units has also been shown to arise from single electrical brain shocks in humans (Day et al. 1986b). Multiple descending volleys set up by a single surface stimulus to the cortex have been demonstrated in subhuman primates (Kernell & Wu, 1967; Patton & Amassian, 1954) and it is likely that this repetitive firing of motor units is induced by multiple volleys of corticospinal activity (Rothwell, Day, Thomson, Dick & Marsden, 1986). The mechanism of facilitation of responses will next be considered. Small voluntary contraction of the target muscle enhances the responses greatly and causes c.m.a.p.s to occur at a latency about 3 ms earlier than in the relaxed state, in which we know that with weak stimuli the lowest threshold, relatively slow motor axons are activated. As is demonstrated in Fig. 4, the shift also takes place with

C. W. HESS, K. R. MILLS AND N. M. F. MURRA Y 416 very weak stimuli (subthreshold for relaxed muscle) when voluntary contraction is present (continuous line in lowest record), whilst a strong stimulus will not suffice to produce the shift in the relaxed state (dashed line in upper record). This considerable shift in latency could easily be accounted for by the additional excitation of higher-threshold motor units which are known to have faster conducting peripheral motor axons (Freund, Biidingen & Dietz, 1975). Hence it seems that regardless of stimulus intensity the high-threshold motor units are only activated when there is background voluntary activity. Furthermore, there exists the possibility that the latency shift of single motor units during facilitation also contributes to the earlier onset of the c.m.a.p. The mechanism of facilitation might take place in the cord, or the brain, or both. From other experimental work (Marsden, Merton & Morton, 1972, 1976; Matthews, 1986), we know the reflex responses are also enhanced by pre-existing motoneuronal activity recruiting higher-threshold motor units, and that this enhancement, which is thought to serve the mechanism of automatic gain compensation, can easily be attributed to the known organization of the motoneurone pool. These workers found a linear relationship between the level of pre-existing force and the size of the response. We have also found such a uniform facilitation with increasing background voluntary activation either when using weak stimuli (Hess et al. 1986a) or when contracting the contralateral homologous muscle (Hess et al. 1986d). Therefore, it seems reasonable to assume that a similar spinal mechanism determines the efficacy of the descending excitatory volley set up by brain stimulation, and it is interesting to note that the contralateral homologous motoneurone pool would also be subject to a similar rise in excitability. There appears, however, to be an additional mechanism of facilitation which comes into action at very low background forces. This sharp rise in twitch force and c.m.a.p. amplitude is seen with stimuli above threshold when activating the target muscle itself (Fig. 7 and squares in Fig. 8) where it obscures the underlying progressive facilitation of weak stimuli by the effect becoming saturated. Interestingly, this marked facilitation during low background forces cannot be produced to the same extent with electrical brain stimulation (Fig. 9), where consistently smaller and more dispersed responses are produced with low background forces (Table 1) and a progressive rise of amplitude with increasing background force is found (Rossini et al. 1985). With magnetic stimulation and facilitation by contraction of another ipsilateral hand muscle (as opposed to the contralateral homologous muscle), again a sharp initial rise of c.m.a.p. amplitudes with low background forces can be observed (Fig. 10). It may be that when a subject focuses his attention on the motor performance of a particular hand, then there is a preferential rise in excitability of pathways to that hand, which does not depend on the degree ofpre-existing voluntary force exerted; this mechanism would most probably reside in the cortex. The fact that it is not produced with electrical brain stimulation would favour this idea, since the electrical stimulus with its presumed direct action on cortico-spinal axons, in part bypasses the intracortical neuronal elements which would allow for such a regulation of the descending volleys. Evidence of multiple descending volleys from single brain shocks in animals was only obtained by stimulation of the cortex but not by direct stimulation of the corticospinal fibres in the subcortical white matter (Patton

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417

& Amassian, 1954). It is, therefore, conceivable that this enhanced excitability of descending pathways which we found with magnetic brain stimulation acts by increasing the number of multiple descending volleys. The next question is whether facilitation depends in part on muscle-afferent input to the cord. Muscle afferents are also known to project to area 3a in primates (Phillips, Powell & Wiesendanger, 1971), and so it is probable that such input will indirectly influence the response of cortical as well as spinal neurones to scalp stimuli. Using illusory movements in the phantom limb of an amputee to facilitate the contralateral side, it has been shown that afferent input is not obligatory for facilitation to occur (Hess et al. 1986d). Finally, it is interesting to note that threshold shocks cause single motor units to discharge at alternative latencies, depending on the stimulating conditions chosen. They can be caused to discharge about 1-5 ms earlier by using the same procedures which would facilitate the response to a suprathreshold stimulus and a similar shift can be induced by increasing the stimulus intensities. Rothwell, Day, Thomson, Dick & Marsden (1986) found preferred latencies of motor units using post-stimulus time histograms and suspected that multiple corticospinal volleys were the cause. In experimental studies in baboons, high-frequency bursts of synchronously discharging pyramidal fibres from single cortex stimuli showed an interval between the discharges of about 1-5 ms (Kernell & Wu, 1967). Hence, it is possible that low-threshold motor units fire in response to monosynaptic action of, say, either the first or second descending volley, and this would depend on the preceding excitatory activity on the motor-unit cell (temporal summation) and on the number of active corticospinal synapses during the first volley (spatial summation). Another possible explanation for this shift would be that without facilitation the motor unit is activated indirectly through an interneurone which would be bypassed during facilitation or with a stronger stimulus. Fast conducting corticospinal neurones act on the az-motoneurones directly as well as via interneurones, and therefore, bypassing of interneurones could take place in the motoneurone pool.
We are grateful to Professor P. A. Merton and Dr R. G. Willison for their helpful discussions, to Dr A. Harding for allowing us to examine her patient and to Dr A. T. Barker, Mr R. Jalinous and Dr I. L. Freeston (University of Sheffield) who devised and constructed the stimulator. This work was supported by grants from the Multiple Sclerosis Society (K.R.M. and N.M.F.M.), the Roche Research Foundation and the H. Neuenschwander Fonds, University of Berne (C.W.H.).
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MILLS, K. R. & MURRAY, N. M. F. (1986). Electrical stimulation over the human vertebral column: which neural elements are excited? Electroencephalography and Clinical Neurophysiology 63, 582-589. PATTON, H. D. & AMASSIAN, V. E. (1954). Single- and multiple-unit analysis of cortical stage of pyramidal tract activation. Journal of Neurophysiology 17, 345-363. PHILLIPS, C. G. (1986). Movements of the Hand. Liverpool: Liverpool University Press. PHILLIPS, C. G. & PORTER, R. (1962). Unifocal and bifocal stimulation of the motor cortex. Journal of Physiology 162, 532-538. PHILLIPS, C. G. & PORTER, R. (1964). The pyramidal projection to motoneurones of some muscle groups of the baboon's forelimb. In Physiology of Spinal Neurons. Progress in Brain Research 12, 222-245. PHILLIPS, C. G., POWELL, T. P. S. & WIESENDANGER, M. (1971). Projection from low threshold muscle afferents of hand and forearm to area 3a of baboon's cortex. Journal of Physiology 217, 419-446. POLSON, M. J. R., BARKER, A. T. & FREESTON, I. L. (1982). Stimulation of nerve trunks with time varying magnetic fields. Medical and Biological Engineering and Computing 20, 112-124. PRESTON, J. B. & WHITLOCK, D. G. (1961). Intracellular potentials recorded from motoneurons following pre-central gyrus stimulation in primate. Journal of Neurophysiology 24, 91-100. RoSSINI, P. M., MARCIANI, M. G., CARAMIA, M., ROMA, V. & ZAROLA, F. (1985). Nervous propagation along 'central' motor pathways in intact man: characteristics of motor responses to 'bifocal' and 'unifocal' spine and scalp non-invasive stimulation. Electroencephalography and Clinical Neurophysiology 61, 272-286. ROTHWELL, J. C., DAY, B. L., THOMPSON, P. D., DICK, J. P. R. & MARSDEN, C. D. (1986). Electrical cortical stimulation, a new technique in evaluating motor function Muscle and Nerve 9, suppl., 25.

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