Clinical Neurophysiology 113 (2002) 1301–1307
www.elsevier.com/locate/clinph
Different patterns of I-waves summation in ALS patients according to the
central conduction time
A. Quartarone*, F. Battaglia, G. Majorana, V. Rizzo, S. Bagnato, C. Messina, P. Girlanda
Department of Neuroscience, Psychiatric and Anaesthesiological Sciences University of Messina, Italy
Accepted 20 May 2002
Abstract
Objectives: To study facilitatory I-waves interaction, using two near threshold stimuli, to test both excitability and conductivity changes
related to cortico-motoneuronal involvement in amyotrophic lateral sclerosis (ALS) patients in different stages of the disease.
Methods: Pairs of threshold magnetic stimuli were applied over the motor cortex at inter-stimulus intervals (ISI) ranging from 1–1.5 to
2.5–3 ms and from 4 to 4.5 ms. The electromyogram responses were recorded from relaxed first dorsal interosseus (FDI).
Results: The data of I-waves summation were distributed according to the central conduction time (CCT) and all 3 peaks of facilitation
were considered for statistical analysis. Patients with normal CCT showed a normal I-waves summation for the first peak, whilst patients with
abnormal CCT had a significant reduction in facilitation ðP , 0:02Þ. Six out of 11 patients with normal CCT had facilitation in the first peak,
which exceeded 2 SD of normal values.
Conclusions: In conclusion ALS patients showed two different and opposite patterns of I-waves summation which could be related to
different stages of the disease. q 2002 Published by Elsevier Science Ireland Ltd.
Keywords: Amyotrophic lateral sclerosis; I-waves summation; Transcranial magnetic stimulation
1. Introduction
Transcranial electrical or magnetic stimulation (TMS) is
used to investigate the involvement of upper motor neuron
(UMN) in patients with motor neuron diseases (Eisen et al.,
1992; Ingram and Swash, 1987; Thompson et al., 1987). The
TMS findings in amyotrophic lateral sclerosis (ALS)
patients may vary significantly with respect to the clinical
stage. At the beginning of the illness, motor evoked potentials (MEPs) with a low threshold and large amplitude can
be recorded (Eisen et al., 1993; Desiato and Caramia, 1997).
As the disease progresses threshold rises, and MEPs amplitude decreases. Transcranial magnetic stimulation of the
human motor cortex using an intensity slightly above
motor threshold elicits I-waves (indirect) in the corticospinal tract (Boyd et al., 1986). I-waves refer to highfrequency (approximately 600 Hz) repetitive discharge of
cortico-spinal fibres produced by single-pulse stimulation
of the motor cortex (Ziemann and Rothwell, 2000). First
detected in animal preparations, this multiple discharge
* Corresponding author. Present address: Clinica Neurologia 2, Policlinico Universitario, 98125 Messina, Italy. Tel.: 139-90-2212791; fax: 13990-2212789.
E-mail address: angelo.quartarone@unime.it (A. Quartarone).
can also be recorded in humans with epidural electrodes
over the spinal cord (Di Lazzaro et al., 1998). The exact
nature of the generation of I-waves is still unclear, but there
is convincing evidence that they originate in the motor
cortex, mainly through activation of cortico-cortical projections onto cortico-spinal neurons. The physiology of Iwaves can be non-invasively investigated through recently
developed paired-pulse transcranial magnetic stimulation
protocols (Tokimura et al., 1996; Ziemann et al.,
1998a,b). The studies, so far, indicated that at very short
intervals (1.2–1.5 ms) a facilitatory I-waves interaction
occurs at the level of the motor cortex and that the mechanism responsible for the production of I-waves is under the
control of gamma-aminobutyric acid (GABA) related inhibition (Ziemann et al., 1998b). Post-mortem and in vivo
studies have shown that there is a loss of the glial glutamate
transporter and an increase of glutamate concentrations in
the motor cortex, spinal cord and CSF of ALS patients
(Rothstein, 1995; Aoki et al., 1998). Moreover, several
immunohistochemical studies have shown a selective loss
of parvoalbumin immunoreactive GABAergic inter-neurons
in ALS motor cortex (Nihei et al., 1993). These changes
suggest that a loss of local circuit inhibitory control (Eisen
et al., 1990; Enterzari-Taher et al., 1997; Nakajima et al.,
1997) along with glutamate induced hyperexcitability,
1388-2457/02/$ - see front matter q 2002 Published by Elsevier Science Ireland Ltd.
PII: S 1388-245 7(02)00152-9
CLINPH 2001711
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A. Quartarone et al. / Clinical Neurophysiology 113 (2002) 1301–1307
within the motor cortex, may play a pivotal role in the
degeneration of the cortico-motoneuronal system especially
in the early stages of the disease. Short latency facilitation
between pairs of threshold magnetic stimuli on the motor
cortex of ALS patients has been recently assessed at interstimulus intervals (ISIs) 1–5 ms (Salerno and Georgesco,
2001). Compared to controls the facilitatory effects
normally recorded at ISI 1 and 3 ms were considerably
reduced suggesting an involvement in the circuits responsible for the generation of I-waves. However, there was no
correlation between the I-waves summation and the disease
duration. The aim of the present article was to correlate the
I-waves summation with the central conduction time (CCT)
which is the well-accepted marker of the integrity of
cortico-spinal tract.
2. Methods
Thirty consecutive patients with clinically definite sporadic ALS, according to the revised ‘El Escorial Criteria’,
were included in the present study (Brooks et al., 2000).
Five patients were excluded because no compound motor
action potential, after ulnar nerve stimulation, were elicitable or smaller than 3 mV. None of the included patients
(mean age 56.3 ^ 12 years; range 35–74 years; 14 men,
11 women) had any other obvious neurological disease. In
all patients the diagnosis of ALS was confirmed by electromyogram (EMG) evidence of lower motor neuron degeneration in at least 3 (bulbar, cervical, thoracic, lumbosacral)
regions. Three patients showed a pure bulbar form. The
average disease duration was 7.1 months for the CCT
normal group and 13.7 months in patients with abnormal
CCT. For better assessment of disease status of the ALS,
functional rating scale was used. (Cedarbaum and Stambler,
1997). The patients were all treated with riluzole. For
comparison, 10 healthy age matched control subjects
(mean age 56.8 ^ 10.2 years; range 35–75 years; 5 men, 5
women) were investigated.
2.1. Procedures
All subjects were seated in a comfortable reclining chair.
Surface EMG was recorded from the first dorsal interosseus
(FDI) using 0.9 cm diameter silver/chloride surface electrodes with a belly-tendon montage. Responses were amplified
using one channel with gain of 2000, and filtered by Neurolog System supplied by Digitimer with a time constant of
3 ms, and a high pass filter set at 3 kHz. Transcranial
magnetic stimulation was performed by using two Magstim
200 HP magnetic stimulators (Magstim, Whitland, UK),
which were connected through a bistim module to a figure
of 8 shaped coil. The coil was placed flat on the skull with
the handle pointing backwards and rotated about 458 away
from the midline. Thus, the current induced in the brain was
approximately perpendicular to the central sulcus. This
orientation of the induced electrical field is thought to be
optimal for a predominantly transynaptic mode of activation
of the cortico-spinal system. The position and site of the
coil, for optimal activation of the target muscle, was determined where the stimulation produced consistently the
largest MEPs at a slightly supra-threshold stimulus intensity. The threshold was determined according to the recommendation of the IFCN Committee (Rossini et al., 1994),
and was defined as the intensity of stimulation which did not
elicit at least 5 MEPs of 50 mV in 10 consecutive trials. Iwaves summation was studied in a paired TMS protocol.
The intensity of both stimuli, S1 and S2, was fixed at resting
threshold levels. ISIs from 0.5 to 4.5 ms, were tested in
0.2 ms steps ( ¼ 20 ISIs). Each session consisted of two
blocks of 120 trials each. Each block was composed of 12
conditions presented 10 times each: S1 and S2 given alone
and 10 paired conditions (S1 1 S2) at different ISIs.
The order of conditions within the blocks was randomised. The mean peak-to-peak size of each conditioned
response was measured and then expressed as a percentage
of the computed sum of S1 1 S2 given alone at that particular interval. Moreover, we determined the cut-off levels
(^2 SD) of abnormality for the first peak of facilitation at
1.5 ms. Signals were collected via a CED 1401 laboratory
interface (Cambridge Electronic Design, Cambridge, UK)
and fed into a personal computer for offline analysis
(sampling rate of 5 kHz per channel). Silent period duration
(ms), obtained using a stimulus intensity of 130% of resting
motor threshold, was measured from the end of the MEP
(considered as the coming back of the motor response to the
baseline) to the rebound of voluntary EMG activity.
Motor central conduction time (CCT-ms), was calculated
by means of F-wave formula (Rossini et al., 1994).
Informed consent was obtained from patients and controls
according to the declaration of Helsinki and the protocol
was approved by the Ethical Committee of our Institution.
2.2. Statistical analysis
The statistical difference between controls and patients
regarding motor threshold, silent period duration and CCT
was determined by using a Student’s t test. Values of P ,
0:05 were considered to be significantly abnormal. For the Iwaves summation, as the sample size did not allow a Gaussian distribution of data, we used non-parametric tests such
as the two sample Mann–Whitney U test. The level of
significance was set at P , 0:05.
3. Results
3.1. Normal subjects
In FDI muscle, significant I-waves facilitation with MEPs
up to 4.5 times the algebraic sum of the single stimuli given
alone occurred at 3 distinct peaks at ISIs of 1.5, 2.9 and
4.5 ms (Fig. 1).
A. Quartarone et al. / Clinical Neurophysiology 113 (2002) 1301–1307
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Fig. 1. Short latency facilitation between pairs of threshold magnetic
stimuli applied to human motor cortex in normal subjects and in ALS
patients. Averaged motor responses in the relaxed FDI of 10 controls
(circles), 12 ALS patients with normal CCT (squares) and 13 ALS patients
with abnormal CCT (triangles), are plotted against the inter-stimulus interval. MEP size, after paired stimulation, is expressed as a percentage of the
sum of S1 1 S2 (see Section 2). The intensity of S1 and S2 was fixed at
resting motor threshold level.
3.2. ALS patients
The mean threshold intensity of MEP elicitation was
significantly higher ð52:9 ^ 21Þ with respect to control
values ðP , 0:02Þ. A dramatic reduction of the mean silent
period duration (obtained at 130% of RMT intensity) was
also recorded ðP , 0:001Þ. The CCT, calculated by means
of F-wave, was significantly prolonged ðP , 0:004Þ. The Iwaves interaction in ALS patients was evaluated by pooling
out the data according to CCT. As plotted in Fig. 1 the ALS
patients with abnormal CCT had a significant reduction of Iwaves summation in the first peak. On the other hand, in
patients with normal CCT, the I-waves summation was
normal except in 6 patients in which the I-waves summation
exceeded 2 SD. Statistical analysis considering the ISI of
1.5 ms, with respect to normal values, revealed a statistical
significant reduction of I-waves summation for ALS
patients with abnormal CCT ðP , 0:02Þ. The I-waves
summation did neither correlate with the disease duration
nor with ALS functional rating scale (linear regression
calculated by means of Pearson’s squared r test). The reduction of I-waves summation was statistically significant also
at ISI of 2.9 and 4.5 ms ðP , 0:01Þ. This was true for both
patients with normal and abnormal CCT.
In Fig. 2 we plotted the distribution of the first peak of
facilitation at 1.5 ms with respect to 95% of upper and lower
confidence limits of normal values. It is interesting to note
that at least 6 patients within the ALS population with
normal CCT, showed an I-waves summation, which
exceeded 12 SD of normal values. These patients showed
a low MEP threshold and presented particularly prominent
finger jerks. The remaining 6 patients showed an I-waves
summation within normal limits. On the other hand, most of
the patients with abnormal CCT presented an I-waves
summation which was below 22 SD of normal limits and
a few (6 out of 14) showed a normal pattern.
Fig. 2. Distribution of the first peak of facilitation at 1.5 ms with respect to
the 95% of upper and lower confidence limits of normal values. MEP size,
after paired stimulation at 1.5 ms ISI, is expressed as a percentage of the
sum of S1 1 S2. It is interesting to note that at least 6 patients with normal
CCT showed an I-waves summation, which exceeded 2 SD of normal
values. The two horizontal dashed lines refer to 95% of upper and lower
confidence limits of normal values.
The 6 patients, with an I-waves summation which
exceeded 12 SD of normal values, were re-tested after 1
year. The clinical picture was different compared with the
baseline: the deep tendon reflexes were absent and there was
a marked muscle hypotrophy, especially in hand and extensor muscles. In Fig. 3 we plotted the amount of I-waves
facilitation at the baseline and also 1 year later.
It is interesting to note that a year later there was a
substantial decrease in the amount of facilitation in all
peaks. Decrease in I-waves facilitation in the same patients
was probably caused by the degeneration of cortico-spinal
Fig. 3. Facilitatory I-waves interaction in the motor cortex of ALS patients:
follow-up after 1 year. Six patients, with I-waves summation exceeding 2
SD of normal values, were re-tested after 1 year. Averaged motor responses
in the relaxed FDI at baseline (squares) and 12 months later (circles) are
plotted against the inter-stimulus interval. MEP size after paired stimulation
is expressed as a percentage of the sum of S1 1 S2.
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A. Quartarone et al. / Clinical Neurophysiology 113 (2002) 1301–1307
patients were treated with riluzole, which is a drug with antiglutammatergic action, which might affect cortical excitability thus interfering with I-waves summation. However,
it has been shown that riluzole does not interfere with Iwaves summation that is rather under strict GABA-ergic
control (Ziemann et al., 1998b). In the following discussion
we will refer to the first peak of facilitation, which is the best
characterised. Experiments using either magnetic followed
by anodal electrical stimulation or pair of anodal electrical
stimuli, suggested that the first peak of I-waves facilitation
most likely occurs within the motor cortex (Tokimura et al.,
1996). Recent epidural spinal recordings made in conscious
humans, in the absence of anaesthetic agents that suppress
the generation of I-waves, have confirmed the cortical origin
of this first peak (Di Lazzaro et al., 1999).
There is one puzzling question about the nature of this
first facilitatory peak. Which neural elements are excited by
the second stimulus? One possibility is that the first stimulus
raises the excitability of some elements, without reaching
their threshold for producing an action potential. It might be
possible that the first stimulus depolarises regions such as
the initial axonal segment or the membranes of the cell
body, even if it is insufficient to trigger neuronal discharge
(Amassian et al., 1998; Di Lazzaro et al., 1999). In such
cases the second shock might be able to recruit these cells to
fire and the resulting cortico-spinal volley would be larger
than expected. Possible candidate regions for this effect
would be axonal hillock, at the pyramidal neurons themselves, or cortical inter-neurons of layers II and III and
experiments so far have suggested this. (Nakamura et al.,
1996; Ziemann et al., 1998a). The pattern of alteration of the
first facilitatory I-waves peak seems to be different according to the CCT, which is the widely accepted marker for the
relative integrity of the cortico-spinal tract. In patients with
inexcitability of cortical motor pathways and prolongation
of CCT, the reduction of the first peak of I-waves summation might reflect a functional impairment or a loss of the
cortico-motoneuronal projections converging on the spinal
motoneurons (SMN) under study. However, it might also be
Fig. 4. Disease duration in ALS patients with a hyperexcitable or hypoexcitable pattern of I-waves summation. Mean disease duration in the patients
with an I-waves summation exceeding 2 SD compared with that of ALS
patients showing an I-waves summation below 2 SD of normal values. It is
interesting to note a much shorter disease duration in the group with a
hyperexcitable pattern.
tract. Furthermore, the patients were pooled out in two
groups: the first group containing patients in which Iwaves summation exceeded 2 SD and a second group
with patients in which I-waves summation was below 2
SD. The disease duration in these two groups was completely different with a much shorter duration in patients with a
hyperexcitable pattern of I-waves summation P , 0:001
(Fig. 4). The threshold was significantly lower in patients
with enhanced I-waves summation compared to patients
with reduced I-waves summation ðP , 0:001Þ. The CSP
was not statistically different between these two groups
ðP , 0:4Þ. The raw data of RMT, AMT, CSP, I-waves
summation and disease duration are summarised in Tables
1 and 2.
4. Discussion
The main finding of our study is an alteration of I-waves
summation in ALS patients that affect all 3 peaks. All the
Table 1
Patients with normal CCT a
Patient
RMT
AMT
CSP
I-waves (1.5 ms)
Duration of
disease (months)
Dominant clinical findings
1
2
3
4
5
6
7
8
9
10
11
35
36
40
37
25
50
29
39
42
38
70
28
34
35
32
22
44
25
34
37
36
63
40
35
50
38
41
45
48
29
50
44
55
571
890
1100
1145
1500
1255
286
1100
672
173
245
6
9
8
4
2
4
16
7
4
10
8
Progressive dysphagia and dysartria
Progressive weakness, hyperreflexia
Progressive dysphagia and dysartria,hyperreflexia
Progressive dysphagia and dysartria
Progressive weakness, hyperreflexia
Progressive weakness, hyperreflexia
Progressive weakness, muscle atrophy
Progressive weakness, hyperreflexia
Progressive dysphagia and dysartria
Progressive weakness, muscle atrophy
Progressive weakness, muscle atrophy
a
Clinical and neurophysiological data in patients with normal CCT.
A. Quartarone et al. / Clinical Neurophysiology 113 (2002) 1301–1307
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Table 2
Patients with abnormal CCT a
Patient
RMT
AMT
CSP
I-waves (1.5 ms)
Duration of
disease (months)
Dominant clinical findings
1
2
3
4
5
6
7
8
9
10
11
12
14
67
59
65
55
63
65
68
54
58
68
65
68
75
55
53
57
50
54
59
60
45
54
63
60
57
66
40
45
29
35
39
30
45
41
25
56
48
56
60
110
111
120
160
102
62
252
110
85
116
90
98
115
28
24
3
4
20
16
5
22
7
18
22
25
9
Progressive weakness, muscle atrophy
Progressive dysphagia, dysartria and weakness
Progressive weakness, hyperreflexia
Progressive dysphagia, dysartria and weakness
Progressive dysphagia, dysartria and atrophy of upper extremities
Progressive weakness, muscle atrophy
Progressive weakness, hyperreflexia
Progressive weakness, muscle atrophy
Progressive weakness, hyperreflexia
Progressive weakness, muscle atrophy
Progressive weakness, muscle atrophy
Progressive weakness, muscle atrophy
Progressive dysphagia, dysartria and weakness
a
Clinical and neurophysiological data in patients with abnormal CCT.
argued that a reduced excitability of SMN, especially in
later stage of the disease, would preclude full facilitation
by the descending cortico-spinal volley and might therefore
be responsible for the lack of I-waves summation. There are
evidences that in ALS the excitability of spared SMN may
be normal. Eisen et al. using post-stimulus histogram
(PSTH) studies showed a normal generation of excitatory
post-synaptic potentials (EPSP) in ALS patients (see subsequently) at least early in the disease. In this case, which are
the mechanisms responsible for the reduction in the first of
peak I-waves summation in ALS? In the brain of ALS
patients there is a loss of pyramidal and Betz cells in the
motor cortex, with foci of gliosis in layers II and III and
deep subcortical white matter junction (Chou, 1992).
Considering that the I-waves summation in the first peak
occur at sites such as the axonal hillock of the pyramidal
neurons or cortical inter-neurons of layers II and III it is
reasonable to assume that the neuronal degeneration in
ALS would preclude a normal I-waves summation within
the motor cortex. Six out of 11 patients with normal CCT
showed a marked facilitation of the first peak. In the same
patients single pulse TMS studies have shown a reduced
motor threshold. Our data thus suggest that, at least in a
minority of patients with ALS, there is a hyperexcitability
of upper motoneurons. A number of neuroimaging and
neurophysiologic studies support the hypothesis that in
ALS the motor cortex may be hyperexcitable. As assessed
by PET, during unilateral hand movements, ALS patients
show significantly greater increases of metabolic activity
than control subjects in the hand/arm area of the primary
sensory motor cortex bilaterally, in the face area contralaterally and in the contralateral premotor and supplementary
motor cortices (Abrahams et al., 1996).
A variety of TMS experiments also indicate that the ALS
motor cortex may be hyperexcitable. The resting motor
threshold is frequently lowered (Eisen et al., 1990; Desiato
and Caramia, 1997), the cortical silent period is shortened
(Prout and Eisen, 1994) and intra-cortical inhibition at short
ISIs (,4 ms) is reduced in ALS (Yokota et al., 1996;
Ziemann et al., 1997).
Enhanced excitation or reduced inhibition could both be
key factors in the development of hyper-excitability of the
cortico-motoneurons. The evidence for increased accumulation of glutamate excitatory transmitter, which could stimulate the cortico-motoneurons to discharge excessively, is
compelling (Shaw, 1994; Rothstein, 1995). Moreover,
recent clinical trials have shown that anti-glutamate agents
can slow the progression of ALS in both transgenic mice
model of familial ALS (Rothstein, 1995) and in humans
(Bensimon et al., 1994). However, equally, cortical hyperexcitability in ALS could be secondary to failure of local
circuit inhibitory inter-neurons to properly modulate
cortico-motoneuronal firing. GABA is the most powerful
inhibitory transmitter in the nervous system and about
10% of all neocortical neurons are GABA accumulating
local circuit neurons (Deisz and Luhmann, 1995). GABA
receptors are even present on excitatory terminals and diffusion of GABA to adjacent glutamatergic terminals curtails
the release of excitatory aminoacids (Thompson et al.,
1993). Considering that the production of I-waves is primarily controlled by GABA related neuronal circuits it is likely
that the increased facilitation of the first peak may be
induced by the selective loss of GABA-ergic inter-neurons
in ALS motor cortex. It is interesting that the 6 patients with
a hyperexcitable pattern of I-waves summation who were
re-tested after 1 year showed a clear reduction of facilitation. These findings could indicate that there is a continuum
of abnormalities in the early and late stages of the disease.
This is also supported by the fact that the disease duration
was shorter in patients with enhanced I-waves summation
than in patients with reduced I-waves summation. This
reduction was statistically significant also at ISI of 2.9 and
4.5 ms ðP , 0:01Þ. This was true for patients both with
normal or abnormal CCT. The exact nature of the facilita-
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A. Quartarone et al. / Clinical Neurophysiology 113 (2002) 1301–1307
tory I-waves interaction at 3 and 4–5 ms is not well established. Given that such intervals are close to the known
periodicity of I-waves, it is tempting to suggest that the
first magnetic stimulus might initiate activity in circuits
involved in I-waves generation and evoke a series of
EPSPs in cortico-spinal neurons. If excitatory input from
the second stimulus coincided with this, then cortical output
would be enhanced and EMG responses facilitated.
However, this interaction could also occur at subcortical
levels (Tokimura et al., 1996; Ziemann et al., 1998a). It is
intriguing to note that the I-waves summation of the II and
III peak was reduced in both ALS patients with normal or
abnormal CCT.
We can speculate that a loss of periodicity of I-waves
might account for this reduction of I-waves summation at
3–5 ms intervals. However, a spinal cord involvement
cannot be excluded especially in the late stage of the
disease. The findings of the present article are partially in
keeping with those of Salerno and Georgesco. One major
point of difference is the presence of a normal or even
facilitatory pattern of I-waves summation in ALS patients
with normal conduction time. However, it is likely that the
patients studied by Salerno and Georgesco, considering
their high motor threshold, were tested in a later stage of
the disease with a clear alteration of the CCT.
4.1. Comparison with PSTH studies
Some insight into the behaviour of I-waves can also be
obtained from single motor unit recordings using needle
electromyography (peri-stimulus time histograms or
PSTHs). These studies provide information regarding the
synaptic input to single SMNs and have demonstrated that
they receive a sequence of EPSPs consistent with the arrival
of multiple monosynaptic from D and I-waves volleys (Day
et al., 1987, 1990).
The results of our study are in keeping with the data
reported by Eisen et al. (1996). In this article PSTHs of a
discharging single motor units, during TMS, were obtained
in ALS patients and in controls. Normal subjects, as
reported in literature (Day et al., 1987), had an early period
of increased firing probability of motor unit occurring at
about 20 ms post-stimulus, reflecting an underlying
compound EPSP induced by fast-conducting, descending
volleys of the cortico-motoneuronal core facilitating the
single SMN. Compared with age-matched controls, the
EPSP in most patients with ALS were reduced in amplitude
(Eisen et al., 1996). These data suggest again that in ALS a
reduction of the cortico-motoneuronal core projecting on
the spinal motor neurons is responsible for the lack of Iwaves summation. In the same study patients in the early
stages of the disease showed the presence of large EPSP in
PSTH studies after TMS which might account for the
increase of facilitation of the fist peak found in our study.
Although the PSTHs studies provide valuable information on the physiology of I-waves it must be taken into
account that the cortico-spinal volley also activate other
inter-neurons in the spinal cord, such as the Ia inhibitory
inter-neurons, which then project to SMNs. The consequence is that cortico-spinal activity can result in a sequence
of EPSP inhibitory post-synaptic potentials (IPSPs) at the
motoneurons (Cowan et al., 1986).
In conclusion, ALS patients showed two different and
opposite patterns of I-waves summation. It could be
hypothesized that the hyper-excitability of motor cortex is
present in an earlier stage of the disease when the corticospinal tracts are almost intact (normal CCT) but there is a
loss of GABA-ergic inter-neurons with a glutamatergic
overactivity. On the other hand in the later stage of the
disease there is a reduction of I-waves summation when
the glutamate toxicity has caused a substantial reduction
in the cortico-spinal projections converging on the SMNs.
References
Abrahams S, Goldstein LH, Kew JJM, Leigh PN, Brooks DJ, Lloyd CM,
Frith CD, Leigh PN. Frontal lobe dysfunction in amyotrophic lateral
sclerosis, a PET study. Brain 1996;119:2105–2120.
Amassian VE, Rothwell JC, Cracco RQ, Maccabee PJ, Vergara M, Hassan
N, Eberle L. What is excited by near-threshold twin magnetic stimuli
over human cerebral cortex? J Physiol 1998;506:122–123.
Aoki M, Lin CL, Rothstein JD, Geller BA, Hosler BA, Munsat TL, Horvitz
HR, Brown Jr RH. Mutations in the glutamate transporter EAAT2 gene
do not cause abnormal EAAT2 transcripts in amyotrophic lateral sclerosis. Ann Neurol 1998;43(5):645–653.
Bensimon G, Lacomblez L, Meininger V. Als/Riluzole study Group. A
controlled trial of riluzole in amyotrophic lateral sclerosis. N Engl J
Med 1994;330:585–591.
Boyd SG, Rothwell JC, Cowan JC, Webb JM, Morley T, Asselmann P,
Marsden CD. A method of monitoring function in cortico-spinal pathways during scoliosis surgery with a note on motor conduction velocities. J Neurol Neurosurg Psychiatry 1986;49:251–257.
Brooks BR, Miller RG, Swash M, Munsat TL. World Federation of Neurology Research Group on Motor Neuron Diseases. El Escorial revisited:
revised criteria for the diagnosis of amyotrophic lateral sclerosis.
Amyotroph Lateral Scler Other Motor Neuron Disord 2000;1(5):293–
299.
Cedarbaum JM, Stambler N. Performance of the amyotrophic lateral sclerosis functional rating scale (ALSFRS) in multicenter clinical trials. J
Neurol Sci 1997;152(Suppl 1):S1–S9.
Chou SM. Pathology light microscopy of amyotrofic lateral sclerosis. In:
Smith RA, editor. Handbook of amyotrophic lateral sclerosis, New
York, NY: Marcel Dekker, 1992. pp. 133–181.
Cowan JM, Day BL, Marsden C, Rothwell JC. The effect of percutaneous
motor cortex stimulation on H reflexes in muscles of the arm and leg in
intact man. J Physiol 1986;377:333–347.
Day BL, Rothwell JC, Thompson PD, Dick JP, Cowan JM, Berardelli A,
Marsden CD. Motor cortex stimulation in intact man. 2 Multiple
descending volleys. Brain 1987;110:1191–1209.
Day BL, Dressler D, Maertens de Noordhout A, Marsden CD, Nakashima
K, Rothwell JC, Thompson PD. Electric and magnetic stimulation of
human motor cortex: surface EMG and single motor unit responses. J
Physiol (Lond) 1990;430:617.
Deisz RA, Luhmann HJ. Development of cortical excitation and inhibition.
In: Gutnik MJ, Mody I, editors. The cortical neuron, New York, Oxford:
Oxford University Press, 1995. pp. 220–246.
Desiato MT, Caramia MD. Towards a neurophysiological marker of amyo-
A. Quartarone et al. / Clinical Neurophysiology 113 (2002) 1301–1307
trophic lateral sclerosis as revealed by changes in cortical excitability.
Electroenceph clin Neurophysiol 1997;105:1–7.
Di Lazzaro V, Restuccia D, Oliviero A, Profice P, Ferrara L, Insola A,
Mazzone P, Tonali P, Rothwell JC. Effects of voluntary contraction
on descending volleys evoked by transcranial stimulation in conscious
humans. J Physiol 1998;508(Pt 2):625–633.
Di Lazzaro V, Rothwell JC, Oliviero A, Profice P, Insola A, Mazzone P,
Tonali P. Intracortical origin of the short latency facilitation produced
by pairs of threshold magnetic stimuli applied to human motor cortex.
Exp Brain Res 1999;129(4):494–499.
Eisen A, Shytbel W, Murphy K, Hoirch M. Cortical magnetic stimulation in
amyotrophic lateral sclerosis. Muscle Nerve 1990;13(2):146–151.
Eisen A, Kim S, Pant B. Amyotrophic lateral sclerosis: a phylogenetic
disease of the corticomotoneuron? Muscle Nerve 1992;15:219–228.
Eisen A, Pant B, Stewart H. Cortical excitability in amyotrophic lateral
sclerosis: a clue to pathogenesis. Can J Neurol Sci 1993;20:11–16.
Eisen A, Entezari-Taher M, Stewart H. Cortical projections to spinal motoneurons. Changes with aging and amyotrophic lateral sclerosis. Neurology 1996;46:1396–1404.
Enterzari-Taher M, Eisen A, Stewart H, Nakajima M. Abnormalities of
cortical inhibitory neurons in amyotrophic lateral sclerosis. Muscle
Nerve 1997;20(1):65–71.
Ingram DS, Swash M. Central motor conduction is abnormal in motor
neuron disease. J Neurol Neurosurg Psychiatry 1987;50:159–166.
Nakajima M, Eisen A, Stewart H. Diverse abnormalities of corticomotoneuronal projections in individual patients with amyotrophic lateral
sclerosis. Electroenceph clin Neurophysiol 1997;105(6):451–457.
Nakamura H, Kitagawa H, Kawaguchi Y, Tsuji H. Direct and indirect
activation of human corticospinal neurons by transcranial magnetic
stimulation. Neurosci Lett 1996;210:45–48.
Nihei K, McKee AC, Kowall NW. Pattern of neuronal degeneration in the
motor cortex of amyotrophic lateral sclerosis patients. Acta Neuropathol 1993;86:55–64.
Prout AJ, Eisen A. The cortical silent period and amyotrophic lateral sclerosis. Muscle Nerve 1994;17:217–223.
Rossini PM, Barker AT, Berardelli A, Caramia MD, Caruso G, Cracco RQ,
Dimitrijevic MR, Hallett M, Katayama Y, Licking CH. Non invasive
electrical and magnetic stimulation of the brain, spinal cord and roots:
basic principles and procedures for routine clinical application. Report
1307
of an IFCN committee. Electroenceph clin Neurophysiol 1994;91:79–
92.
Rothstein JD. Excitotoxic mechanisms in the pathogenesis of amyotrophic
lateral sclerosis. Pathogenesis and therapy of amyotrophic lateral
sclerosis. Adv Neurol 1995;68:7–20.
Rothstein JD, Van Kammen M, Levey AI, Martin LJ, Kuncl RW. Selective
loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol 1997;38(1):73–84.
Salerno A, Georgesco M. Short latency facilitation between pairs of threshold magnetic stimuli studied in amyotrophic lateral sclerosis. Neurophysiol Clin 2001;31(1):48–52.
Shaw PJ. Excitotoxicity and motor neuron disease: a review of the
evidence. J Neurol Sci 1994;124(Suppl).
Thompson PD, Day BL, Rothwell JC. The interpretation of electromyographic responses to electrical stimulation of the motor cortex in
diseases the upper motor neurone. J Neurol Sci 1987;80:91–110.
Thompson SM, Capogna M, Scanziani M. Presynaptic inhibition in the
hippocampus. Trends Neurosci 1993;16:22–227.
Tokimura H, Ridding MC, Tokimura Y, Amassian VE, Rothwell JC. Short
latency facilitation between pairs of threshold magnetic stimuli applied
to human motor cortex. Electroenceph clin Neurophysiol
1996;101(4):263–272.
Yokota T, Yoshino A, Saito Y. Double cortical stimulation in amyotrophic
lateral sclerosis. J Neurol Neurosurg Psychiatry 1996;61:596–600.
Ziemann U, Rothwell JC. I-waves in motor cortex. J Clin Neurophysiol
2000;17(4):397–405.
Ziemann U, Winter M, Reimers CD, Reiemers K, Tergau F, Paulus W.
Impaired motor cortex inhibition in patients with amyotrophic lateral
sclerosis. Evidence from paired transcranial stimulation. Neurology
1997;49:1292–1298.
Ziemann U, Tergau F, Wassermann EM, Wischer S, Hildebrandt J, Paulus
W. Demonstration of facilitatory I-waves interaction in the human
motor cortex by paired transcranial magnetic stimulation. J Physiol
1998a;511(Pt 1):181–190.
Ziemann U, Tergau F, Wischer S, Hildebrandt J, Paulus W. Pharmacological control of facilitatory I-wave interaction in the human motor
cortex. A paired transcranial magnetic stimulation study. Electroenceph
clin Neurophysiol 1998b;109(4):321–330.