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Silent period (SP) is widely used in transcranial magnetic stimulation studies. Methodologically, SP is usually elicited at stimulus intensities corresponding to a certain percentage of corticomotor threshold. Because this approach might lead to factitious SP changes, the present study was designed to develop, in a stepwise manner, a method for investigating SP independently of corticomotor threshold. First, stimulus-response (S-R) curves of SP against stimulus intensity (SI) were constructed and quantitatively described in healthy volunteers. Second, various methodological issues such as the optimum model for describing the relationship between SP duration and SI and the importance of the type of stimulating coil were addressed. Finally, the proposed method and a commonly used method (eliciting SPs at 130% MT SI) were directly compared for a group of epileptic patients for whom administration of oxcarbazepine resulted in significant corticomotor threshold elevation. Twenty-one subjects (eleven females, median age, 38 years) were studied. SPs were obtained with a figure-of-eight coil using a standardized procedure (recording, FDI). Pilot experiments indicated that at least four trials were required, at each intensity level, to estimate the mean SP duration within 10% of the true mean. Therefore, SPs were determined from the average of four trials with 5% increments from 5 to 100% maximum SI. In a second set of experiments, SPs were obtained for fifteen subjects using a circular coil. In a third set of experiments, eight epileptic patients were studied before and after administration of oxcarbazepine (mean dose 1553 mg, range 900-1800 mg). The S-R curves were fitted to a Boltzman function and to first-order to fourth-order polynomial and sigmoid functions. The Boltzman function described the data accurately (R2=0.947-0.990). In addition, direct comparison of the six models with an F-test proved the superiority of the first. The best-fit parameters of the reference curve, i.e. the maximum and minimum values, the slope, and V50 (the SI at which SP duration is halfway between Min and Max) were 230.8+/-3.31 ms (x+/-SEM), -11.51+/-3.31 ms, 11.56+/-0.65%, and 49.82+/-0.65%, respectively. When the curves obtained with the circular coil were compared with those obtained with the figure-of-eight coil, there were differences between V50 (51.69+/-0.72 vs 47.95+/-0.82, P<0.001) and SP threshold (31.15 vs 24.77, P<0.01) whereas the other best-fit values did not differ significantly. Oxcarbazepine increased corticomotor threshold from 45.3+/-5.8% at baseline to 59.4+/-10.4% (P<0.001). According to the commonly used method, the drug significantly prolonged SP (from 117.6+/-42.4 ms to 143.5+/-46.5 ms, P<0.001) and, consequently, enhanced brain inhibition. In contrast, study of the SP curves led to the conclusion that oxcarbazepine does not affect the Max value and slope but significantly increases V50 and SP threshold (from 54.5+/-4.9% to 59.9+/-7.2% and from 29.1+/-6.4% to 34.6+/-6.8%, respectively, P<0.01). These findings imply that oxcarbazepine does not enhance brain inhibitory mechanisms. Thus, in situations characterized by significant changes in corticomotor threshold the proposed method provides results clearly different from a commonly used approach. It is concluded that S-R curves obtained with a figure-of-eight coil in 5% increments and fitted to a Boltzman function provide an accurate, comprehensive, and clinically applicable method for exploring SP.

Threshold (Th) is a neurophysiological parameter frequently used in TMS studies. The present study was designed to investigate the repeatability of the Th measurements by reexamining healthy subjects over various time points. Overall, 82 subjects (median age: 19 years, range: 12-65) entered the study. Following a baseline examination, there were six retest sessions: S0 (n = 8 hemispheres reexamined, mean interval x = 19 min), S1 (n = 34 hemispheres reexamined, mean interval x = 4 days), S2 (n = 32 hemispheres, x = 29 days), S3 (n = 30 hemispheres, x = 106 days), S4 (n = 30 hemispheres, x = 183 days) and S5 (n = 30 hemispheres, x = 1867 days). Stimulation was performed with a figure of eight coil and Th was defined at 1% steps. At baseline, controls had an MT of 41.1 +/- 8. Mean difference of MT from baseline was 0.62 on S0 (95% confidence interval (CI) of the difference: -1.04 to +2.29), 0.13 on S1 (95% CI: -1.2 to +1.5), -0.03 on S2 (95% CI: -1.1 to +1.06), -2.07 on S3 (95% CI: -4.33 to +0.19), 0.15 on S4 (95% CI: -0.98 to +1.28) and 0.87 on S5 (95% CI: -0.49 to +2.23). None of these differences were statistically significant (repeated measures ANOVA, P > 0.05). The upper limit of MT difference that an individual subject might have with a probability of 95% (measurement error) was 8. The repeatability of the method was found to be independent from the age of the subjects, the magnitude of threshold or the test-retest interval. The topography of corticomotor threshold was also investigated. Minimal threshold values were obtained from a restricted area of scalp sites that always included the fixed stimulation point of the current protocol. Therefore, using a fixed stimulation point is an adequate technique for measuring threshold. In conclusion, threshold is a stable parameter on an individual and group basis. These data quantify the repeatability of the method and may prove useful in the interpretation of findings during longitudinal studies.

Degeneration of spinal motoneurons has been well documented in amyotrophic lateral sclerosis (ALS), but the evolution of central motor abnormalities is largely unknown. It has been suggested that glutamate-mediated neuroexcitotoxicity may be involved in the pathogenesis of ALS and that this may be manifest as an increase in corticomotor excitability early in the disease. Serial measurements of corticomotor threshold, central motor conduction time (CMCT), silent period duration and the amplitude of compound muscle action potentials (CMAPs) from ulnar nerve stimulation in the right and left first dorsal interosseous muscles were made in 76 patients with idiopathic ALS, 49 of whom were followed from presentation to death. Threshold to transcranial magnetic stimulation was determined by standard methods and CMCT was measured using the F-wave method. Silent period was estimated during a small background contraction of the muscle. Patients were classified according to the region of onset and the physical signs in the hands. The region of onset was bulbar in 17 patients, lower limb in 31 patients and upper limb in 28 patients. At presentation, 23 patients had no abnormal physical signs in the hands, 25 had lower motoneuron signs only, 14 had upper motoneuron signs only and the remainder (14) had mixed upper and lower motoneuron signs in the hands. Evolution of the central conduction parameters was determined in relation to time from onset of symptoms and also as a function of normalized total disease duration in the patients who had died. Corticomotor threshold and CMCT showed no change as the disease evolved except for patients with mixed signs, who had a terminal increase in threshold and prolongation of CMCT. Silent period duration was shorter than normal early in the disease and showed progressive lengthening throughout the illness, but nevertheless remained within the normal range regardless of the region of onset. CMAP amplitude showed a linear decline over the course of the disease. There was therefore no evidence of a phase of increased corticomotor hyperexcitability at any stage of disease progression. The early shortening of silent period, however, probably represents a shift in the balance of excitatory and inhibitory inputs to the cortical output cells responsible for voluntary action, and could be a reflection of degeneration of cortical interneurons. None of the measures of central motor function in ALS are likely to be useful for monitoring patients in a clinical trial setting.

We devised a method to investigate the cortical organization of corticomotoneurons (CMs) to upper limb muscles. A spike-triggering technique was used, in which a tonically discharging single motor unit (SMU) triggered transcranial magnetic stimulation (TMS) of motor cortex, and the probability of producing short-latency discharges (primary excitatory responses [PERs]) was measured. PER probabilities were mapped in 34 SMUs, using a 16 cm(2) scalp grid with the central reference point having a probability of 0.5. Maps showed a single optimum point of scalp stimulation and significant decreases in PER probability with shifts of 2 cm from this point, for all subjects. These findings suggest that the colony of CMs projecting to an individual SMN is contained within a small volume of motor cortex. Changes in PER probability with shifts in stimulation site may reflect the organization of other intracortical neurons mediating TMS activation of these CMs., (Copyright 2000 John Wiley & Sons, Inc.)

Conventional peripheral motor conduction studies and transcranial magnetic stimulation (TMS) studies, to measure central motor conduction time (CMCT), to the first dorsal interosseous muscle (FDI) were performed on 65 patients with amyotrophic lateral sclerosis (ALS). The hands of each patient were classified into one of four groups depending on the presence of physical signs of lower motor neurone (LMN) and/or upper motor neurone (UMN) involvement. Statistical analysis was made of the results from patients compared with previously established normal values and with those from a control group of 53 normal subjects. Results between the four groups of patients were compared in order to assess any correlation between neurophysiological findings and physical signs. A reduction in the amplitude of compound muscle action potentials (CMAP), prolongation of distal motor latency (DML) and F wave latency were found in 36%, 34% and 19% of hands respectively. These abnormalities were more common in hands with LMN signs. In nine hands, prolongation of DML occurred in the absence of muscle wasting or weakness. CMCT abnormalities were present in 17% of patients with ALS but did not appear to correlate with physical signs.

It is known that damage to the left hemisphere can lead to movement deficits, and that patients with apraxia have difficulty in selecting movements. Neurophysiological recording studies and lesion studies have shown that the premotor cortex is important for the selection of movements in monkeys. In this study we used transcranial magnetic stimulation (TMS) to disrupt the processing in human premotor cortex. We applied TMS to normal healthy volunteers over the premotor and primary motor areas while they carried out choice reaction time and simple reaction-time tasks. We measured response times of either hand as subjects were stimulated over the left and right hemisphere separately. We found that we were able to delay responses by stimulating at short cue-stimulus intervals (100-140 ms) over premotor cortex and at longer cue-stimulus intervals (300-340 ms) over primary motor cortex while subjects performed the choice reaction-time task with the contralateral hand. We were also able to delay responses with the ipsilateral hand while stimulating over the left premotor cortex, but not while stimulating over the right premotor cortex or either sensorimotor cortex. Premotor cortex stimulation alone disrupts an early stage of movement selection; motor cortex stimulation disrupts the movements at a later stage of execution. There was no distinguishing short cue-stimulus interval effect when premotor cortex was stimulated in the simple reaction time paradigm, where the movement selection demands of the task are kept to a minimum. We conclude that the premotor cortex is important for selecting movements after a visual cue and that the left hemisphere is dominant for the rapid selection of action.

The pathogenesis of idiopathic amyotrophic lateral sclerosis (ALS) remains unknown, but accumulating evidence suggests a neuroexcitotoxic mechanism may have some credence. Glutamate-induced hyperexcitability of cortical or spinal motoneurons may be expected to manifest itself as a reduced threshold for activation of these structures. We have measured corticomotor threshold to the first dorsal interosseous (FDI) muscles of 48 patients with sporadic ALS using magnetic brain stimulation and have correlated the findings with physical signs of upper and/or lower motor neuron degeneration. We find that if FDI in patients with ALS shows no weakness, wasting, or signs of an upper motor neuron lesion, mean corticomotor threshold is significantly lower than in 102 healthy control FDI muscles (P = 0.02). In contrast, FDI muscles showing signs of lower motor neuron degeneration only or mixed upper and lower motor neuron signs are associated with a raised corticomotor threshold (P = 0.008, P < 0.001, respectively). We conclude that early in ALS, at a time when hand muscle function is normal, corticomotor threshold is reduced and suggest that this may be a manifestation of abnormal excitability of cortical or spinal motoneurons to neurotransmitters, whose action will ultimately lead to cell death.

The threshold for corticomotor excitation by magnetic stimuli is a clinically important parameter in the assessment of central motor conduction. Hitherto, arbitrary criteria have been adopted to define threshold and there are few published data using a figure of eight coil. A new method is described in which the highest stimulus intensity evoking responses in the relaxed first dorsal interosseous muscle with a probability of zero [lower threshold (LT)] and the lowest intensity evoking responses with a probability of one [upper threshold (UT)] have been determined. The method, which utilizes a coil located and optimally oriented over hand motor cortex, minimizes the number of stimuli needed. Both LT and UT are normally distributed and are independent of age, gender, and hemisphere. In 102 healthy hands of 55 control subjects 23-84 years of age, mean +/- SD UT was 46.6 +/- 9.4% and LT was 38.0 +/- 8.6% maximum stimulator output. Repeatability estimates indicated an absolute change of more than 13% or 11% in UT or LT respectively in the same individual over 1-3 months was significant at the 5% level.

In a ballistic forearm flexion movement, a centrally programmed triphasic pattern of electromyogram (EMG) is seen with two bursts in biceps and a single burst in triceps. Rapid abduction of the index finger, in contrast, is achieved with a single agonist burst. Transcranial magnetic and electrical stimuli, triggered at the onset of the EMG burst, have been used to probe cortical and spinal cord excitability during and after self-paced ballistic finger and forearm movements. The first phase is coincident with the initial agonist burst. The second phase in biceps is associated with the second agonist burst, but in the finger movement, the raised motor cortical excitability is not associated with any EMG. It is argued that the motor program for the two movements may be similar, despite there being large differences in the EMG pattern generated.

The human motor cortex can be excited by currents induced by a transient magnetic field generated in a coil over the scalp. A 9 cm mean diameter circular coil centered at the vertex is optimally placed for exciting the hand area. Anticlockwise current flow in the coil preferentially excites the left hemisphere and vice versa. A double coil has been used to investigate the orientation of inducing currents at which activation of cortical neural elements is maximal. The inducing current flowed in the same direction in the central segment of the coil and followed a monophasic wave form. The coil was rotated through 360 degrees over the motor area in increments of 45 degrees and compound muscle action potentials from the first dorsal interosseous muscle were recorded. The largest responses were obtained with the coil at about 50 degrees to the parasagittal plane with a backward flowing inducing current. The optimal angle did not depend on stimulus intensity or background voluntary contraction. This orientation corresponds to an maximal induced current flowing forwards approximately at right angles to the central sulcus. It is postulated that horizontal neural elements are aligned in this direction and are preferentially excited by these monophasic magnetic stimuli. The results have important implications for mapping the motor areas with magnetic stimulators.

The human brain can be stimulated by a single intense magnetic pulse over the scalp. Currents induced within the cranium excite the motor cortex and cause limb muscles to contract. The discharge of single motor units, the firing of which is maintained by voluntary effort, can be modulated by magnetic stimuli. Peri-stimulus time histograms suggest that after a cortical stimulus spinal motoneurones are induced to fire by a sequence of EPSPs arising from a train of impulses transmitted monosynaptically over fast-conducting corticospinal fibres. In multiple sclerosis both dispersion of this descending volley and partial transmission failure can impair motoneurone excitation and may explain motor symptoms in these patients.

Central motor conduction to small hand muscles was measured using magnetic stimulation of the motor cortex and electrical stimulation of proximal motor roots in 11 patients with Friedreich's ataxia, 10 patients with early onset cerebellar ataxia with retained tendon reflexes (EOCA) and 13 patients with late onset degenerative cerebellar disease (LOCD). Central motor conduction was abnormal in 91% with Friedreich's ataxia, 70% with EOCA and 38% with LOCD. Central motor conduction abnormalities were not specific to individual disorders but were more severe and were related to disease duration in Friedreich's ataxia and EOCA.

Central motor conduction time (CMCT) to abductor digiti minimi was measured in 18 healthy subjects and in 15 patients with multiple sclerosis. A novel percutaneous magnetic stimulator was used to stimulate the motor cortex painlessly and CMCT was calculated by subtracting the onset latency of muscle responses obtained by electrical stimulation over the C7/T1 interspace from that obtained from stimulation over the scalp. In healthy subjects CMCT was 6.0 +/- 0.76 ms. In multiple sclerosis patients with pyramidal signs in the arms, CMCT was almost always prolonged, the longest conduction time being 39 ms. In 10 patients CMCT was prolonged despite normal strength in the muscle.

The human brain can be stimulated by electric shocks or by brief intense magnetic fields. The latter cause only a trivial scalp sensation. Stimuli exciting the motor cortex cause contralateral muscle responses, but the threshold for excitation is markedly reduced by slight voluntary contraction of the target muscle. For small hand muscles, the overall latency from scalp to muscle is shorter by 1.8 ms when electrical stimuli are used than when stimuli are magnetic. Central motor conduction time (CMCT) can be estimated by stimulating over the scalp and then over the cervical area. In healthy subjects, the CMCT is 6.1 +/- 0.8 (SD) (n = 29). Physiological studies have shown that the facilitation of responses in hand muscles produced by voluntary contraction is also present when contralateral muscles are used, but not when a leg muscle is contracted. The mechanism of facilitation may involve neural activity at both spinal and cortical levels. Single motor units can be caused to discharge by threshold brain stimuli. These motor units are the same ones activated first during weak voluntary contractions. Clinical studies have shown that the CMCT may be greatly prolonged in patients with multiple sclerosis and that subclinical motor pathway lesions can be detected. Central conduction may also be abnormal in patients with motor neuron disease and cervical myelopathy. Side effects have not been encountered with either type of stimulator.

Two electrophysiological investigations were used to study 18 patients with multiple sclerosis--F wave characteristics including amplitude, persistence and frequency, which can provide a measure of motoneurone excitability, and magnetic stimulation of the cortex, which enables measurement of conduction along central motor pathways. There was an increase in the mean amplitude and persistence of the F response in patients with abnormal central motor conduction (CMC), although no correlation between the degree of abnormality of CMC and increase in F response amplitude was found. Increase in mean amplitude and persistence of the F response were also found in patients with normal CMC but clinical evidence of a UMN disorder (spasticity and/or weakness); there was no correlation, however, between any single F response characteristic and any particular clinical sign. CMC appears to be the preferred test for detecting subclinical motor lesions in MS: of the patient sides with normal clinical examination, 36% showed abnormal CMC, whereas 23% showed abnormal F responses.

Central motor conduction (CMC) to abductor digiti minimi (ADM) was evaluated in 22 patients with motor neurone disease (MND) using magnetic stimulation of the motor cortex and electrical stimulation at the C7/T1 interspace. CMC was abnormal in 14 patients; prolonged CMC time and absence of response to brain stimulation were more frequent abnormalities than low amplitude responses without prolonged CMC time. The technique can reveal subclinical upper motor neurone involvement and document central motor pathway dysfunction in MND. The patterns of abnormality are not specific to MND; all may occur in other neurological disorders including multiple sclerosis.

A conspicuous feature of rapid eye movement (REM) sleep is atonia of postural muscles due to a powerful brainstem inhibitory effect on spinal motoneurones. However, small myoclonic jerks occur during REM sleep and increased activity of cortical neurones is suggested by the EEG. Transcranial cortical stimulation with magnetic pulses has been used to investigate motor excitability during sleep in man. Motor responses were evoked during sleep using stimuli identical to those used in wakefulness. Response amplitudes were depressed during slow wave sleep (SWS) and enhanced or the same during REM sleep. These findings suggest that the susceptibility of the human motor cortex to stimulation is enhanced during REM sleep.

Central motor conduction (CMC) was evaluated in 32 normal subjects and 83 patients with multiple sclerosis, and the findings were correlated with clinical signs and evoked potential data. CMC time was obtained from the latency difference in responses from the abductor muscle of the little finger to magnetic stimulation of the motor cortex and electrical stimulation at the C-7/T-1 interspace. Mean CMC time in normal subjects was 6.2 msec (SD 0.86 msec), and amplitudes of responses to cortical stimuli were at least 18% of those obtained with stimuli at the wrist. CMC was abnormal in 60 patients with multiple sclerosis (72%); this correlated well with brisk finger flexor jerks (p less than 0.005). CMC was abnormal in 79% of patients with weakness of the abductor muscle of the little finger and in 54% with a normal muscle. Neurological examination was normal in 7 arms with abnormal CMC. Visual evoked potentials were abnormal in 67%, somatosensory evoked potentials in 59%, and brainstem auditory evoked potentials in 39% of those tested. For each procedure more subjects had abnormal CMC and normal evoked potentials than the reverse. The technique is of value for demonstrating and documenting central motor pathway lesions in multiple sclerosis, especially when physical signs are equivocal.

Using concentric needle electrode recording from hand muscles (abductor digiti minimi, first dorsal interosseus, or abductor pollicis brevis muscle) the latencies of single motor unit potentials in response to threshold magnetic brain stimuli were studied under different conditions. It has been shown that the motor units activated by threshold brain stimuli had the lowest threshold for voluntary activation (A = vol. activated, B = brain stim.). Onset latencies of 23 motor unit potentials from different sites in the relaxed muscles of four healthy subjects ranged from 22.4 to 32.4 ms (average: 26.4 ms; SD: 2.80 ms) but proved to be relatively stable when stimulating and recording conditions were kept constant (variation less than 0.5 ms, see poststimulus time histogram in Fig. 2). With concurrent contraction of an ipsilateral neighbouring or of the contralateral homologous muscle the motor unit potentials from the relaxed target muscle jumped to an earlier latency by 1.2 to 1.7 ms (C in Fig. 3 and B-2 in Fig. 4). On one occasion another motor unit of higher threshold was alternatively activated by this procedure (B-3 in Fig. 4). Since the same procedures are known to enhance the compound muscle action potentials as recorded from the relaxed muscle with surface electrodes, the shorter latencies of single motor units are considered to be caused by a facilitatory influence on the motoneurones. A possible explanation for these latency shifts would be that the motor units discharge later in response to the brain stimulus induced repetitive cortico-spinal impulses when there is no facilitation, whereas during facilitation the firing level is reached earlier.(ABSTRACT TRUNCATED AT 250 WORDS)

Anodal shocks of 400 to 700 V from a low-output impedance stimulator applied percutaneously over the motor cortex evoke muscle action potentials in partially voluntarily activated contralateral muscles. Cathodal shocks from the same device applied to the cervical spinal cord produce maximal ipsilateral muscle action potentials in a relaxed limb. This technique was used to study the central motor pathway in 15 healthy subjects and 8 patients with clinically definite multiple sclerosis. As stimuli were applied in the axilla, over the C7 vertebral level, and over the arm area of the motor cortex, recordings were made of muscle action potentials of forearm flexor muscles. In controls, cord-to-axilla conduction time was 4.1 +/- 0.61 ms, and cortex-to-cord time was 4.4 +/- 0.75 ms. In patients, cord-to-axilla conduction times were normal, while central conduction times were either markedly prolonged (6.4 to 31 ms) or absent. This technique is a potentially powerful tool for the investigation of central motor pathways in healthy subjects and patients with neurological disease.