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, transcranial
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).
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
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
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
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.
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
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
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.
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.
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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