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Transcranial Magnetic Stimulation

Transcranial magnetic stimulation provides a sensitive means for the assessment and monitoring of excitatory and inhibitory upper motor neuron function in motor neuron disease transcranial magnetic stimulation, amyotropic lateral sclerosis, depression, Lou Gehrig's disease, trans cranial magnetic stimulation, trancranial


Diagnosis of psychiatric and neurologic disease depends on unequivocal evidence of upper and lower motor neuron dysfunction. In practice, evidence of lower motor neuron degeneration is obtained readily with electromyography (EMG). In contrast, evidence of upper motor neuron (UMN) impairment in patients with motor neuron disease (MND) may be elusive, presumably obscured by the effects of spinal motor neuron loss.  The need for a noninvasive test to aid detection of UMN involvement in such patients has been detailed in a 

A number of studies have used transcranial electrical stimulation or transcranial magnetic stimulation (TMS) to investigate the integrity of UMN pathways in patients with MND. Abnormalities observed in these studies have included relative inexcitability of cortical motor pathways and prolongation of central motor conduction time (CMCT).

The sensitivity of transcranial magnetic stimulation in documenting UMN dysfunction in patients with ALS may be considerable. However, the sensitivity of this technique in patients with MND without definite UMN signs is not known. Schriefer et al. observed that TMS occasionally revealed subclinical UMN involvement in patients with MND. However, most patients in previous studies have had definite clinical evidence of UMN dysfunction; diagnosis of amyotropic lateral sclerosis has not been an issue. In part, we designed this study to determine the sensitivity of TMS in detecting UMN dysfunction in amyotropic lateral sclerosis and amyotropic lateral sclerosis with probable UMN signs (ALS-PUMNS). We postulated that TMS would show high sensitivity in 

Because weakness in ALS reflects mainly lower motor neuron degeneration,  methods other than strength testing are required to monitor UMN involvement. TMS might be used to document progression of UMN dysfunction in ALS. For example, TMS has inhibitory effects on tonic muscle contraction. In ALS, the cortical substrates mediating this effect of transcranial magnetic stimulation may be affected selectively and relatively late in the course of illness. However, longitudinal studies of cortical inhibitory function have not been described in patients with ALS. We postulated that longitudinal studies of patients with ALS and ALS-PUMNS would reveal progressive inexcitability of central motor pathways and a decrease in the inhibitory effects of TMS.

Forty-one patients had ALS, defined as definite evidence of upper and lower motor neuron dysfunction in at least two extremities. Forty patients had ALS-PUMNS, defined by the presence of deep tendon reflexes thought to be incongruously brisk relative to the degree of lower motor neuron impairment, but no Babinski sign or clonus. Eighteen patients had progressive bulbar palsy (PBP), defined by prominent bulbar signs and symptoms with little or no involvement of limb muscles. Twenty-two patients had progressive muscular atrophy (PMA). A group of 60 healthy volunteers (30 women), 21 to 57 (mean 37 9) years of age, and a second group of 24 healthy volunteers (6 women), 27 to -58 (mean 38 9) years of age, served as control subjects. 

In patients, we rated hand function as 0 = normal; 1 = mild to moderate hand weakness without impairment of dexterity; 2 = weak with significant impairment of dexterity (i.e., difficulty with handwriting and buttoning clothes); and 3 = marked weakness-major disability and loss of fine motor control.

Transcranial magnetic stimulation.

We used Magstim 200 magnetic stimulators (Magstim; Whitland, Wales, UK). We used a 9-cm mean diameter circular coil centered over the vertex of the scalp for all studies. Viewed from above, current direction in the coil was counterclockwise for stimulation of the left hemisphere and clockwise for stimulation of the right hemisphere. Twenty-seven patients were tested with a low-power (peak 1.5 T) magnetic coil between 1989 and 1992, and 94 patients were tested with a high-power (peak 2.0 T) coil thereafter.
Subjects were seated comfortably in a chair with Ag/AgCl electroencephalographic electrodes over the biceps, triceps, abductor pollicis brevis (APB), and abductor digiti minimi (ADM) muscles in belly-tendon derivation. On average, we used three of these four target muscles per limb, per patient. Surface EMG signals were recorded using a bandpass of 10 to 10,000 Hz, inspected on-line, and stored on EMG hard drives (Mystro [Teca, Pleasantville, NY] and Viking IIe [Nicolet, Madison, WI]) for analysis. We determined resting motor evoked potential (MEP) threshold in 5% increments of maximum stimulator output as the minimum stimulus intensity that evoked at least three discernible MEPs in six consecutive stimulations using a display gain of 100 muV/cm. Threshold was recorded as 100% if no MEP was elicited with 100% stimulus intensity. After threshold was recorded, we elicited MEPs during modest tonic isometric contraction (10 to 20% maximal effort) using TMS 25% of maximum stimulator output above threshold (within the limits of stimulator output). We expressed the baseline-to-peak amplitude of ADM MEPs as a percentage of the baseline-to-peak amplitude of the compound muscle action potential (CMAP) obtained with supramaximal electrical stimulation of the ulnar nerve. We used MEP latencies and cervical magnetic root stimulation to calculate CMCT. We used MEP and F-wave latencies to calculate the CMCT to APB and ADM in a small proportion of patients who were intolerant to cervical root stimulation. After eliciting MEPs, we then looked for dissociation between MEP threshold and the cortical stimulation silent period (CSSP) by reducing stimulus intensity in 5% increments of stimulator output until TMS no longer altered the appearance of the averaged rectified ADM EMG, as described previously. We defined dissociation between excitatory and inhibitory effects of TMS (hereafter termed failure of MEP facilitation) as EMG inhibition without a preceding MEP at two or more stimulus intensities.


Sensitivity of transcranial magnetic stimulation in the diagnosis of ALS. TMS provides a sensitive means for documenting UMN dysfunction in patients with clinically definite ALS. Furthermore, TMS also appears to have a high degree of sensitivity for detecting UMN dysfunction in patients with ALS-PUMNS, in whom the clinical diagnosis is less certain. Previous studies of TMS in MND undoubtedly documented abnormalities in some patients best classified as ALS-PUMNS. However, patients with ALS-PUMNS account for a small proportion of patients studied previously, and the sensitivity of TMS in patients with this clinical diagnosis has not been specified. Our results also confirm that TMS occasionally identifies clinically unsuspected UMN abnormalities.

The sensitivity of TMS in MND has varied considerably among previously reported studies. We suggest that this variation in sensitivity probably reflects sampling differences and differences in methodology. For example, in a group of 40 patients with obvious signs of upper and lower motor neuron degeneration, Eisen et al. found that the sensitivity of TMS approached 100%. In contrast, Claus et al. reported a relatively low sensitivity of TMS (<60%) in a study of 63 patients with definite or probable ALS. Compared with the patients studied by Claus et al., our patients had a longer symptom duration (25 versus 16 months). Thus, the sensitivity of TMS in MND may depend on when in the course of illness the patients are examined.

The sensitivity of TMS in MND also may depend on the methodology used. The sensitivity of TMS is probably related to the number of electrophysiologic variables that are assessed. For example, when Claus et al. concluded that TMS was an insensitive tool for the diagnosis of ALS, they confined their analyses to abnormalities of CMCT and MEP amplitude. In contrast, our results suggest that the sensitivity of TMS may be increased by including additional electrophysiologic measures such as MEP threshold and failure of MEP facilitation. Furthermore, our results suggest that the sensitivity of TMS in MND may be enhanced by studying patients longitudinally. Longitudinal studies in several of our patients disclosed abnormal interval increases in MEP threshold, despite values that remained within the normal range. This abnormality would have been missed without follow-up studies.

Our results suggest that using TMS to identify UMN dysfunction in MND may compare favorably with other methodologies. For example, proton MRS (1 H-MRS) has been used to demonstrate motor cortex abnormalities in ALS. However, these investigations have included relatively small numbers of patients and, in particular, have included relatively few patients with ALS-PUMNS, without clinically definite UMN signs. Furthermore, although previous studies using 1 H-MRS have shown significant group differences between patients with ALS and normal control subjects, there appears to be significant overlap between 1 H-MRS values obtained in these two groups. Indeed, individual 1 H-MRS values in patients with MND have not been compared with limits of normality established in healthy volunteers. Thus, the usefulness of this technique to aid detection of UMN loss in individual patients with ALS-PUMNS may be limited. In contrast, using limits of normality established in normal volunteers, we were able to use TMS to identify UMN dysfunction in individual patients with MND.

Our findings may be relevant for enrollment of patients in clinical therapeutic trials. The recombinant human ciliary neurotrophic factor ALS Study group recently proposed liberalizing diagnostic criteria for ALS to include patients with lower motor neuron signs in two limbs and UMN signs in one limb. In the absence of clinically definite UMN signs, none of our 40 ALS-PUMNS patients would have met these liberalized criteria, let alone the more stringent El Escorial World Federation of Neurology criteria.  However, TMS was abnormal in 30 of these 40 patients. If TMS abnormalities are included as an indication of UMN damage, then 30 of 40 (75%) of our ALS-PUMNS patients could be classified as having ALS. This illustrates that TMS might be used to facilitate the diagnosis of ALS for enrollment in future clinical therapeutic trials.

There are limitations inherent in using TMS as a diagnostic tool in MND. Our results indicate that the abnormality detected most frequently using TMS in such patients is an increase in excitation threshold. When this increase is such that MEPs are not elicited at maximum stimulator output, there can be little doubt regarding the presence of UMN involvement. However, identifying lesser degrees of threshold elevation requires comparison of individual patient results to limits of normality established in large numbers of healthy volunteers. Although the MEP threshold was not related to age in our control data, our volunteers were significantly younger than our patients. Future studies should preferably include age-matched control subjects. Our results do suggest, however, that increased MEP threshold is frequently accompanied by failure of MEP facilitation, often confirming the presence of UMN involvement in patients with marginal increases in MEP threshold. Less frequently, TMS may also identify UMN involvement by showing increased CMCT.

Failure of motor evoked potential facilitation.
In some patients, failure of MEP facilitation was the sole abnormality detected with TMS. In these patients, the threshold for eliciting an MEP at rest was normal. However, when TMS was administered during voluntary muscle contraction, the MEP became obscured in the background contraction, leaving only a CSSP. This failure of MEPs to facilitate during voluntary contraction has been noted incidentally in previous studies.  However, considering that voluntary contraction of the target muscle causes dramatic facilitation of MEPs elicited in normal people, the absence of such facilitation in clinical studies has received surprisingly little attention. Uozumi et al.  reported an increased ratio of background EMG activity to MEPs elicited in patients with ALS and implied that failure of MEP facilitation resulted from increased motor unit size. We believe that this possibility is unlikely because we never observed failure of MEP facilitation in patients with PMA, despite obvious electrophysiologic evidence of chronic denervation and reinnervation. We cannot exclude the possibility that patients with ALS recruited a higher proportion of available motor units than did normal volunteers. However, MEPs are readily recorded during even maximum voluntary contraction in patients with ALS. Furthermore, we and others have observed failure of MEP facilitation in patients with MS, in whom lower motor neuron function is presumably normal. Therefore, we suggest that failure of MEPs to facilitate during voluntary contraction is a sign of UMN impairment. Mills reached a similar conclusion in a subgroup of patients with ALS in whom TMS with single motor unit analysis revealed excitation thresholds that were normal at rest but were increased during voluntary motor unit activation.

Progression of cortical dysfunction in ALS.
The abnormality observed most frequently in this study of patients with MND was an increase in MEP threshold. However, several investigators have actually observed reduced excitation thresholds in patients with ALS, particularly in the early stages of the disease. Reduction in MEP threshold in these patients has been interpreted as reflecting spinal or cortical motor neuron hyperexcitability or defective intracortical inhibition.  It has been suggested that MEP thresholds are initially reduced in ALS, increasing as the disease progresses. We failed to observe patients with significant reductions in MEP thresholds. This discrepancy may have occurred for several reasons. First, mean symptom duration in our patients was 25 months. In contrast, Mills and Nithi have emphasized the brief symptom duration of patients with reduced MEP thresholds. Second, we used a relatively conservative definition of abnormality (mean 3 SDs) in analyzing MEP variables. We were also unable to replicate any meaningful correlation between symptom duration and MEP threshold. However, we suggest that questions regarding neurophysiologic changes associated with disease progression may best be answered through longitudinal assessment of individual patients.
This investigation is the first to use longitudinal TMS studies to document changes in cortical motor excitatory and inhibitory function during progression of ALS. We found that the cortical elements mediating MEPs are affected relatively early in the course of the disease, manifested largely by progressive increases in threshold. This is consistent with previous observations of increased MEP thresholds in patients with ALS with normal M waves and of progressive inexcitability of central motor pathways in the course of ALS. Similarly, Uozumi et al. illustrated progressive loss of MEP amplitude with longitudinal studies in a single patient with ALS. However, previous investigators did not examine changes in the inhibitory effects of TMS with disease progression. Serial studies of our patients indicated that the neural substrates mediating the inhibitory effects of TMS are affected relatively later in the course of the disease, manifested by loss of the CSSP in patients in whom initial studies showed increased MEP thresholds.


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