Exp Brain Res (1998) 119:265±268  Springer-Verlag 1998
RESEARCH NOTE
V. Di Lazzaro ´ D. Restuccia ´ A. Oliviero
P. Profice ´ L. Ferrara ´ A. Insola ´ P. Mazzone
P. Tonali ´ J.C. Rothwell
Magnetic transcranial stimulation at intensities below active motor
threshold activates intracortical inhibitory circuits
Received: 24 September 1997 / Accepted: 25 October 1997
V. Di Lazzaro (
)
) ´ D. Restuccia ´ A. Oliviero ´ P. Profice
L. Ferrara ´ P. Tonali
Istituto di Neurologia, Università Cattolica,
L.go A. Gemelli 8, I-00168 Rome, Italy
e-mail: dilazzar@rm.ats.it, Fax: + 39-6-3550-1909
A. Insola ´ P. Mazzone
Neurofisiologia, Neurochirurgia
CTO, Via S. Nemesio 21, I-00145 Rome, Italy
P. Tonali
IRCCS ªCasa Sollievo della Sofferenzaº,
San Giovanni Rotondo, Italy
J.C. Rothwell
MRC Human Movement and Balance Unit,
The National Hospital for Neurology and Neurosurgery,
Queen Square, London WC1N 3BG, UK
Abstract A magnetic transcranial conditioning stimulus
given over the motor cortex at intensities below threshold
for obtaining electromyographical (EMG) responses in
active hand muscles can suppress responses evoked in
the same muscles at rest by a suprathreshold magnetic test
stimulus given 1±5 ms later. In order to define the mech-
anism of this inhibitory effect, we recorded descending
volleys produced by single and paired magnetic transcra-
nial stimulation of motor cortex through high cervical,
epidural electrodes implanted for pain relief in two con-
scious subjects with no abnormality of the central nervous
system. The conditioning stimulus evoked no recognisa-
ble descending activity in the spinal cord, whilst the test
stimulus evoked 3±4 waves of activity (I-waves). Condi-
tioning stimulation suppressed the size of both the de-
scending spinal cord volleys and the EMG responses
evoked by the test stimulus. Inhibition of the descending
spinal volleys was most pronounced at ISI 1 ms and had
disappeared by ISI 5 ms. It was evident for all compo-
nents following the I
1
-wave, while the I
1
-wave itself
was not inhibited at all. We conclude that a small condi-
tioning magnetic stimulus can suppress the excitability of
human motor cortex, probably by activating local cortico-
cortical inhibitory circuits.
Key words Intracortical inhibitory circuits ´ Brain
stimulation ´ Motor cortex ´ descending volleys ´ Human
Introduction
Transcranial magnetic stimulation of human brain pro-
duces a mixture of excitatory and inhibitory phenomena.
Inhibition can be demonstrated by evaluating the silent
periods that follow electromyographic (EMG) responses
evoked by a suprathreshold magnetic stimulus (Day et
al. 1989). Alternatively a paired-pulse paradigm can be
used. One shock, the test shock, is large enough to evoke
an EMG response in relaxed muscle. If a smaller, condi-
tioning, stimulus is given 1±5 ms beforehand, the test re-
sponse is suppressed. This inhibition becomes apparent
when the intensity of the conditioning shock is less than
the threshold needed to evoke any EMG response in ac-
tive muscle. As the intensity of the stimulus is increased,
then inhibition changes to facilitation (Kujirai et al. 1993;
Tokimura et al. 1996; Ziemann et al. 1996).
On the basis of indirect arguments, Kujirai et al. (1993)
originally suggested that the inhibition occurred because
of synaptic interactions within the motor cortex. Recent
recordings of the descending spinal cord volleys evoked
by the stimuli have tended to confirm this assumption.
Nakamura et al. (1997) made direct recordings in con-
scious, awake humans and showed that the size of the de-
scending corticospinal volleys set up by the test shock
was suppressed when a conditioning stimulus was given.
However, the conditioning stimulus used by Nakamura et
al. (1997) was quite large, being above threshold for
evoking activity in actively contracting muscle. On its
own, it evoked a corticospinal volley composed of two
to four waves. Thus it could be argued that the effect
on the response to the test volley was due to the refractory
period of corticospinal axons or to afterhyperpolarisation
of pyramidal neurone rather than synaptic inhibition in
the cortex. In addition, Nakamura et al. (1997) recorded
EMG responses from biceps brachii, rather than from
hand muscles as used in previous studies. Since biceps re-

266
ceives a much sparser monosynaptic projection than the
hand, the relationship between the amount of the inhibi-
tion of biceps EMG and the size of the descending volleys
is more difficult to interpret.
The present experiment is an attempt to characterise
more precisely the inhibitory phenomena produced by
paired transcranial magnetic stimulation. As in the previ-
ous study, we have recorded the descending volleys di-
rectly, but have used a sub-threshold conditioning stimu-
lus that produced no recognisable descending activity. We
then correlated the effect with that on EMG responses in
distal hand muscles. The results were obtained in two
conscious patients who had a stimulator implanted in
the cervical cord for the treatment of intractable pain.
Materials and methods
Corticospinal volleys evoked by transcranial magnetic and electrical
stimulation of the motor cortex were recorded from the high cervical
cord in two subjects with no abnormality of the central nervous sys-
tem (aged 56 and 84 years). Both subjects had a spinal cord stimu-
lator implanted for treatment of intractable dorso-lumbar pain. The
electrode (Model Quad 3487A Medtronic; Minneapolis) was im-
planted percutaneously in the epidural space at C1±2 level and re-
cordings of descending activity made 2±3 days after implantation
during the trial screening period when the electrode connections
were externalised. The subjects gave informed consent to the study
that was performed with the approval of the appropriate Institutional
Ethics Committee.
Recordings were made simultaneously from the epidural elec-
trode and from the relaxed first dorsal interosseous muscle (FDI)
of the left hand. Epidural potentials were recorded between the most
proximal and most distal of the four electrode contacts on each im-
plant. These had a surface area of 2.54 mm
2
and were 30 mm apart.
The distal contact was connected to the reference input of the ampli-
fier. Surface EMGs were obtained via two 9-mm-diameter Ag-AgCl
electrodes, with the active electrode over the motor point of the mus-
cle and the reference on the metacarpophalangeal joint of the index
finger. EMG responses and the corticospinal volleys were amplified
and filtered (bandwidth 3 Hz to 3 kHz) by D150 amplifiers (Digitim-
er, Welwyn Garden City, Herts, UK). Data were collected on a com-
puter and stored for later analysis using a CED 1401 A-D converter
(Cambridge Electronic Design, Cambridge, UK).
Magnetic stimulation was performed with a high-power Magstim
200 (Magstim, Whitland, Dyfed). A figure-of-eight coil, with exter-
nal loop diameters of 9 cm, was held over the right motor cortex (at
the optimum scalp position to elicit motor responses in the contralat-
eral FDI) with the induced current flowing in a postero-anterior di-
rection. Intensities were expressed as a percentage of the maximum
output of the stimulator. Active motor threshold (AMT) was defined
according to the recommendations of the IFCN Committee (Rossini
et al. 1994) as the minimum stimulus intensity that produced a lim-
inal EMG response (more than 50 mV in 50% of trials) during iso-
metric contraction of the tested muscle at about 20%. Cortico-corti-
cal inhibition was studied using the technique of Kujirai et al.
(1993). Two magnetic stimuli were given through the same stimulat-
ing coil, using a Bistim module, over the motor cortex and the effect
of the first (conditioning) stimulus on the second (test) stimulus was
investigated. The conditioning stimulus was set at an intensity of 5%
(of stimulator output) below active threshold. The second, test,
shock intensity was adjusted to evoke a muscle response in relaxed
FDI with an amplitude of approximately 1 mV peak-to-peak. The
timing of the conditioning shock was altered in relation to the test
shock. Interstimulus intervals (ISIs) between 1 and 5 ms were inves-
tigated. Five stimuli were delivered at each ISI. For these record-
ings, muscle relaxation is very important, and the patient was given
audio-visual feedback at high gain to assist in maintaining complete
relaxation. Measurements were made on mean EMG responses and
mean components in the descending volleys. Amplitude of the con-
ditioned EMG responses and conditioned descending waves, at each
ISI, was expressed as percentage of the amplitude of the test EMG
responses and the test descending waves. We also recorded the ac-
tivity from epidural electrodes evoked by the conditioning shock
alone.
Anodal stimulation of the motor cortex was used to identify the
latency of the earliest (probable D-wave) descending volley in sub-
ject 1. Electrical stimulation was performed with a Digitimer D180
stimulator, with a 50-ms time constant. The anode was located at the
vertex and the cathode 7 cm laterally. The responses to ten liminal
stimuli at an intensity of 5% of maximum stimulator output above
AMT were averaged during a 20% maximum contraction.
The latency of each component of the descending volley was
measured to its peak, because the precise onset was often difficult
to define for all but the first component. Amplitudes were measured
from the peak to the next trough in order to minimise distortions due
to stimulus artefact. Only consistent deflections with a mean ampli-
tude over ten responses of more than 2 mV were analysed.
Statistics
Because only two subjects were used, we analysed the data from
each of them separately. Thus, at each ISI we compared the size
Fig. 1A, B Epidural volleys (A) and EMG responses (B) evoked by
test stimulus alone (upper traces), conditioning stimulus alone (low-
er traces) and both stimuli at different ISIs (middle traces) in subject
1. Recordings were performed at rest during test and paired magnet-
ic stimulation, while a conditioning stimulus alone was delivered
during voluntary contraction at about 20% of maximum. Each trace
is the mean of five sweeps. Test stimulus evokes multiple descend-
ing waves (four waves) and an EMG response of about 1 mV. Con-
ditioning shock alone evoked neither EMG response nor descending
volleys. When both stimuli were delivered, the EMG responses were
dramatically suppressed at 1±3 ms ISIs. At 1 ms ISI, all the descend-
ing waves except the I
1
were suppressed; at longer ISIs, it was evi-
dent there was a clear reduction of amplitude of later waves, the last
wave partially recovered only at longer ISIs