NeuroImage 19 (2003) 156 –162

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An event-related optical topography study of cortical activation inducedby single-pulse transcranial magnetic stimulation
Yasuki Noguchi,a Eiju Watanabe,b,c and Kuniyoshi L. Sakaia,c,*a

Department of Cognitive and Behavioral Science, Graduate School of Arts and Sciences, The University of Tokyo, Komaba, Tokyo, Japanb
Department of Neurosurgery, Tokyo Metropolitan Police Hospital, Tokyo, Japanc
SORST, Japan Science and Technology Corporation, Kawaguchi-shi, Japan
Received 9 September 2002; revised 25 November 2002; accepted 11 December 2002

Abstract
To visualize cortical activations during transcranial magnetic stimulation (TMS), it is necessary to measure those activations at highspatiotemporal resolution while preventing interference with the magnetic property of a coil. One suitable method that satisfies thesedemands is optical topography (OT), which has been used in cortical activation studies. In the present study, single-pulse TMS was applied
to the left primary motor area, and cortical responses at the stimulation site were measured simultaneously with event-related OT. When
TMS was applied at 110% motor threshold (MT), we observed significant oxyhemoglobin increases that were both time-locked andcorrelated with the hemodynamic basis function. Moreover, when TMS was applied at 90% MT, significant oxyhemoglobin increases weredetected even though there were no motor-evoked potentials. These results demonstrate that OT can directly measure cortical responses tosubthreshold single-pulse TMS, independent of the afferent feedback from the peripheral neuromuscular activity.
© 2003 Elsevier Science (USA). All rights reserved.
Keywords: Transcranial magnetic stimulation; Optical topography; Near-infrared spectroscopy; Simultaneous measurement; Oxyhemoglobin; Motor cortex

Introduction
Transcranial magnetic stimulation (TMS) has been applied recently to the study of various cognitive functions in
the human brain (Pascual-Leone et al., 2000; Hallett, 2000),allowing the examination of the causal link between corticalactivity and function. Two types of TMS have been usedthus far: repetitive TMS (rTMS) and single-pulse (or pairedpulse) TMS. In rTMS, multiple magnetic pulses are applied
at a rapid rate (⬎ 1 Hz) to produce larger effects on corticalactivity than single-pulse TMS. The effects of rTMS havebeen observed in recent imaging studies that combinedrTMS with positron emission tomography (PET) (Fox et al.,
1997; Paus et al., 1997; Mottaghy et al., 2000; Siebner et al.,* Corresponding author. Department of Cognitive and Behavioral Science, Graduate School of Arts and Sciences, The University of Tokyo,
Komaba, 3-8-1 Komaba, Meguro-ku, Tokyo 153-8902, Japan. Fax: ⫹813-5454-6261.
E-mail address: sakai@mind.c.u-tokyo.ac.jp (K.L. Sakai).

2001) or functional magnetic resonance imaging (fMRI)(Bohning et al., 1999; Baudewig et al., 2001). By measuring
the cortical activations induced by rTMS, these studies haverevealed TMS-induced cortical responses covarying withstimulation frequency or intensity, further revealing thetranscortical propagation of TMS-induced activations.
Single- or paired-pulse TMS has a maximal temporal
resolution of ⬃20 ms (Pascual-Leone et al., 2000), which isan obvious advantage of this technique. Recent TMS studies
have clarified cortical mechanisms of human cognitive
functions such as motion perception (Pascual-Leone andWalsh, 2001) and syntactic processing (Sakai et al., 2002).
On the other hand, only a limited number of functional
imaging studies have examined cortical activations inducedby single-pulse TMS, because of several technical difficulties. First, an interference with the coil-generated magnetic
field is a major problem in fMRI studies. Another type ofinterference is caused by the mere presence of the TMS coil,whose magnetic property interferes with the magnetic fieldof an MR scanner. In the previous fMRI studies, where MR

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scanning and TMS pulses were temporally separated, thesusceptibility-induced signal loss was reported especially inthe area under the coil (Bohning et al., 1999, 2000). In PET
studies, measurements were conducted with or withoutmagnetic shielding for PET photomultipliers, and several
studies have recommended the use of the shielding (Thompson et al., 1998). Second, the hemodynamic responses associated with single-pulse TMS are too transient and small
to be detected by the current sensitivities of PET. To overcome low signal-to-noise ratios for TMS responses in fMRI
studies, stronger TMS pulses must be applied to the cortex.
However, as previous studies have indicated (Ilmoniemi etal., 1997; Bohning et al., 1999; Siebner et al., 2001;
Strafella and Paus, 2001), the motor cortex activation owing
to the sensory feedback from the peripheral neuromuscular
activity, which is induced by TMS pulses, could conceivably confound the response observed in the above-mentioned fMRI study (Bohning et al., 2000). Therefore, it isnecessary to develop new techniques, besides PET or fMRI,
that can measure the cortical activations induced by singlepulse TMS while preventing interference with the magnetic
property of a coil.
One suitable noninvasive method that satisfies these demands is optical imaging for measuring cortical activations,in which measurement devices can be well separated from a
TMS coil, by transmitting optical signals through glass
fibers. Near-infrared spectroscopy (NIRS) is one of the
optical imaging techniques for measuring changes in hemoglobin concentration in brain tissues by using the difference
between the light absorption spectra of oxy- and deoxyhemoglobin (Jöbsis, 1977; Chance et al., 1988; Villringer etal., 1993). Optical topography (OT), a recently developed
extension of NIRS, measures light reflection and scatteringfrom multiple measurement points (Maki et al., 1995; Yamashita et al., 1996; Koizumi et al., 1999), whereas in early
NIRS studies optical signals were measured with only one
pair or widely separated pairs of an emitter and a detector.
In OT, measurements from closely placed pairs are achievedby independently modulating the intensity of each radiatedlaser beam; that is, by the frequency encoding of spatial
information. Here we applied an event-related paradigm of
OT, which was established in our previous study (Noguchi
et al., 2002), to the measurement of each event with singlepulse TMS. In the present study, a higher and more reliable
signal-to-noise ratio was achieved by measuring a single
region with multiple pairs of an emitter and a detector. We
examined whether or not this measurement was sensitive
enough to detect cortical responses to single-pulse TMS.

Materials and methods
Subjects
Six male subjects (ages, 22– 49 years) participated in thepresent study. They showed right-handedness (laterality

157

quotients, 53–100) by the Edinburgh inventory (Oldfield,
1971). During the experiments, their heads were held inplace with a TMS coil and a chin rest. Informed consent was
obtained from each subject after the nature and possible
consequences of the studies were explained. All experiments strictly followed the safety guidelines of TMS experiments (Wassermann, 1998) and those adapted by the Japan
Neuroscience Society. Approval for these experiments was
obtained from the institutional review board of The University of Tokyo, Komaba.
TMS methods and electromyogram measurements
Before the experiments, a 3D magnetic resonance (MR)image of the brain was taken of each subject, who wore acap with multiple MR markers (alfacalcidol beads; diameter, 3 mm) on its surface. Using the MR image, we estimated the vertically projected position of the center of theleft hand motor area (Boroojerdi et al., 1999) relative tothese markers (Fig. 1A and B). This position was thentransferred to the distance from Cz position in the electroencephalogram (EEG) international 10 –20 system.
We applied single-pulse TMS to the left hand motor areaof each subject by using a Magstim 200 stimulator (Magstim, Carmarthenshire, UK). Magnetic pulses were delivered through a figure-8-shaped coil (dual 70-mm coil), sothat the induced electric current flowed in a posterior–anterior direction (Paus et al., 1998; Terao et al., 1998). As
an index of TMS effects on peripheral nerves, motor-evoked
potentials (MEPs) were recorded from the right first dorsalinterosseous (FDI) muscle with surface electrodes. Electromyogram (EMG) signals were amplified and recorded witha 10- to 1000-Hz bandpass filter (MEG-2100; NihonKohden, Tokyo, Japan).
We determined the tonically active motor threshold(MT) for each subject from the FDI muscle in 10%
maximal voluntary contraction (Terao et al., 1998). The
active MT was defined as the lowest TMS intensity
sufficient to elicit five MEPs, each of at least 50 ␮V
peak-to-peak amplitude, in a series of 10 stimulations.
During the simultaneous OT measurement, the TMS
intensity was set to each of 110, 90, and 70% MT,
and EMG data were monitored online. There was novoluntary contraction during the OT measurement to ensure that no MEPs would be induced at 90% MT condition while maintaining MEPs at 110% MT condition.
Each session contained 20 single TMS pulses with variable intertrial intervals (20, 22, 24, 26, and 28 s, pseudorandomized within a session). The 1-day experimentconsisted of six sessions (two sessions for each intensity), and the experiment was repeated for each subject
twice to four times in separate days. The order of thesession sequences was counterbalanced within and acrosssubjects.

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Y. Noguchi et al. / NeuroImage 19 (2003) 156 –162

Fig. 1. A region in the motor cortex for TMS and OT measurements. MR images of the dorsal surface (A) and a horizontal slice (B) of a representative
subject’s brain are shown. An open circle in (A) represents the projected position of an MR marker on the left hand motor area, where magnetic pulses wereapplied. The horizontal slice (B) is a transection (z ⫽ 48, the slice 48-mm above the anterior commissure and posterior commissure line) below the levelof the projected position, which includes the hand motor area (an arrow pointing to the omega-shaped precentral gyrus). (C) The configuration of four optodes
over the left hand motor area. Open circles and rectangles represent the positions of emitters and detectors, respectively. This configuration formed four
emitter-detector pairs around the center of a TMS coil (⫹). Filled circles denote the measurement points, each of which is located at the midpoint of a single
emitter– detector pair.

OT measurements
We used an OT system (ETG-A1; Hitachi Medical
Corporation, Tokyo, Japan) to measure the cortical responses at the stimulation site. Near-infrared laser diodes with two wavelengths (ranges, 783–793 and 823–
833 nm) were used as the light sources (intensity, 1.5
mW/mm2, modulation, 1–10 kHz), and transmittancedata of the light beams were obtained every 500 ms.
We used two emitters and two detectors, each of which
was connected to a bundle (diameter, 1 mm) of flexible glass fibers running in parallel with the subject’s
scalp (Fig. 1C). The tips of the fibers were bent into an
L shape and fixed to the head shell (size, 6 ⫻ 4 cm2),
which was placed on the scalp over the hand motor
area. The midpoint of the diagonal emitter– detector
pairs, which corresponded to a measurement point(Maki et al., 1996), was placed on the center of the hand
motor area. The midpoints of the parallel emitter– detector pairs were located 5 mm apart from this center.
The TMS coil was placed over the fibers while maintaining the vertical placement of the fiber tips on the scalp.
The minimum distance between the coil and the scalp
was 8.5 mm.
OT data were analyzed according to the event-relatedparadigm established in our previous study (Noguchi et al.,2002), in which oxyhemoglobin changes were successfully
observed. Twenty event periods, each of which corresponded to a single pulse of TMS, were extracted fromtime-series data in each session, allowing for overlaps during the baseline. Each event period ranged from 6 s before
the stimulation onset to 20 s after the onset. Excluding theactivation period during the first 12 s after the stimulation
onset, time points were baseline-corrected with a curve ofthe third degree (Sato et al., 1999). The event data of thedifferent TMS intensities were averaged separately at eachwavelength. After averaging, the relative changes in oxyhemoglobin concentration and deoxyhemoglobin concentration were calculated for each subject using the equation
below (Maki et al., 1995). The relation between light absorbance changes at wavelength ␭1 (⌬A(␭1)) and oxy- anddeoxyhemoglobin concentration changes (⌬Coxy and⌬Cdeoxy) can be expressed as⌬A 共␭1兲 ⬇ ␧ oxy共␭1兲⌬C oxyd ⫹ ␧ deoxy共␭1兲⌬C deoxyd,(1)

where ␧oxy(␭1) and ␧deoxy(␭1) are the wavelength-dependent
molar absorption coefficients of oxy- and deoxyhemoglobin
at wavelength ␭1, respectively. The effective path length d
is a distance on the trajectory of light beams in the graymatter. A previous theoretical study of NIRS reported thatits value is approximately 5 mm in 3-cm emitter– detector
spacing (Firbank et al., 1998). By solving the simultaneous
equations for two wavelengths (1), the relative hemoglobin
concentration changes, ⌬Coxy d and ⌬Cdeoxy d, were calculated in units of millimolar-millimeter (mMmm). We thenobtained the grand average of ⌬Coxy d or ⌬Cdeoxy d acrossall tested subjects. To statistically examine whether TMSinduced hemodynamic changes were present in each condition, we calculated correlation coefficients (r values) between the averaged data and a basis function of theperistimulus time for hemodynamics (Friston et al., 1998),
which depicts a typical hemodynamic change associatedwith neural activity.

Y. Noguchi et al. / NeuroImage 19 (2003) 156 –162

Fig. 2. MEPs induced by TMS pulses at three different intensities: 110%
MT (A), 90% MT (B), and 70% MT (C). Data obtained from six subjects
were averaged. An arrow in each figure indicates the artifact of TMS
pulses, at which the time is set to zero. Note that MEPs were detectable
only at 110% MT.

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which were calculated from these transmittance data (seeMaterials and methods), also showed time-locked patternsof signal increases at all of four measurement points (Fig.
3B). Each of the time courses was highly correlated with thebasis function of hemodynamics (r values, 0.78, 0.82, 0.81,
and 0.84), indicating that significant oxyhemoglobin increases were induced by the TMS pulses at all measurement
points. The oxyhemoglobin increases were also observed inall subjects (Fig. 4). Therefore, we averaged the data acrossall measurement points and all subjects and calculated therelative oxyhemoglobin concentration changes under thethree conditions of different TMS intensities (Fig. 5). Significant oxyhemoglobin increases were observed at both
110% MT (Fig. 5A) and 90% MT (Fig. 5B), but not at 70%
MT (Fig. 5C). The signal changes at 110 and 90% MT werehighly correlated with the hemodynamic basis function (r ⫽0.93 and 0.87, respectively), whereas there was no significant correlation at 70% MT (r ⫽ ⫺0.17). We fitted the basis
function of hemodynamics to the time courses with a leastsquare method and confirmed that the signal changes exactly followed the basis function at both 110 and 90% MT.
There were significant oxyhemoglobin increases at the peakof 110 and 90% MT time series (one-group t test, P ⬍ 0.01).
On the other hand, we confirmed that signal changes were
not significant for any time points at 70% MT (P ⬎ 0.05, forall). We further calculated mean changes of relative oxyhemoglobin concentration, averaging temporal points from 3
to 9 s after each TMS pulse (Fig. 6). One-way ANOVA
indicated a significant main effect of TMS intensity [F(2,15) ⫽ 9.6, P ⬍ 0.01], and a t test performed for eachcondition showed significant oxyhemoglobin increases atboth 110 and 90% MT (P ⬍ 0.05), but not at 70% MT (P⬎ 0.1). We performed the same analyses for deoxyhemoglobin data and observed no significant concentration
changes under any of the three conditions (P ⬎ 0.1, for all).

Results

Discussion

The MEPs averaged across six subjects are shown in Fig.
2. At 110% MT, MEPs of 100 ␮V peak-to-peak amplitude
were clearly observed from the FDI muscle (Fig. 2A). The
latency of the MEPs was 20 ms, which is comparable to thatof previous studies (Pascual-Leone et al., 1998; Strafella
and Paus, 2001). In contrast, there were no MEPs at 90 or
70% MT (Fig. 2B and C). We monitored all EMG data
online and confirmed that no magnetic pulses induced an
MEP under these two conditions. These results confirmedthat the subthreshold TMS pulses did not induce any neuromuscular activity in the FDI muscle.
Next, we present the results of OT measurements at
110% MT in Fig. 3. Averaged data (N ⫽ 6) obtained at eachof four measurement points are separately shown. In transmittance data (Fig. 3A), decreases of light intensity timelocked to the TMS pulse were detected at all measurement
points. The relative oxyhemoglobin concentration changes,

To our knowledge, this is the first OT experiment tosimultaneously measure the oxyhemoglobin changes at thestimulation site during TMS. The oxyhemoglobin time series measured with OT were highly correlated with thehemodynamic basis function, which reliably depicted hemodynamic changes induced by each event of single-pulse
TMS. Moreover, the present study succeeded in detecting
the cortical responses to subthreshold single-pulse TMS.
The activation at 90% MT directly reflected the TMS effects
on the motor cortex, even though it did not induce detectable responses in the FDI muscle. These results establishedthat subthreshold single-pulse TMS activates the motor cortex, which cannot be explained by the sensory feedback
from the peripheral nerves.
There has been a controversy about whether blood flowchanges in the motor area induced by TMS are increases ordecreases. One PET study by Fox et al. (1997) has reported

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Fig. 3. Event-related changes of transmittance and relative oxyhemoglobin concentration at 110% MT. Averaged data (N ⫽ 6) obtained at each of fourmeasurement points are separately calculated. The left two columns show data from diagonal emitter– detector pairs, while the right two columns show datafrom parallel pairs (Fig. 1C). (A) The transmittance data are shown for each wavelength in an arbitrary unit (a.u.); thick lines: 780 nm, thin lines: 830 nm.
(B) The vertical axis represents relative oxyhemoglobin changes (mMmm), which were calculated from the transmittance data. In each figure, a TMS pulse
was delivered at time zero. Similar patterns of signal changes were observed across all measurement points.

that rTMS applied to the motor cortex induces increases ofblood flow at the stimulation site. On the other hand, another PET study by Paus et al. (1998) has reported the
opposite result: the decrease of blood flow in the motor
cortex. Because these studies measured the cumulative effects of magnetic pulses, the contradicting changes might
result from stimulation parameters such as pulse frequency,
duration of the train, and the number of trains (PascualLeone et al., 1998, Siebner et al., 2001). Our results with an
event-related design clearly indicate that single-pulse TMS

increases, rather than decreases, the regional cerebral blood
flow, because oxyhemoglobin changes correlate positively
with blood flow changes.
A couple of NIRS studies have measured the effects of
TMS (Oliviero et al., 1999; Eschweiler et al., 2000), although they have not employed event-related designs.
These studies have reported cumulative effects of a numberof magnetic pulses continuously delivered for a period of 2or 20 min. In addition, these measurements were conducted
before and after the TMS period, not during TMS. By

Fig. 4. Relative oxyhemoglobin concentration changes observed in individual subjects at 110% MT. The relative oxyhemoglobin concentration changes
obtained from each subject were averaged across the four measurement points. The event-related oxyhemoglobin increases induced by a TMS pulse (deliveredat time zero) were observed in all six subjects.

Y. Noguchi et al. / NeuroImage 19 (2003) 156 –162

combining the event-related techniques for OT measurements with TMS, the present study demonstrates that realtime measurements of TMS effects are possible by opticalimaging with a signal-to-noise ratio and temporal resolutionthat are both high enough to follow the cortical responses tosingle-pulse TMS.
Previous EEG studies have measured cortical responses
to single-pulse TMS (Ilmoniemi et al., 1997; Paus et al.,2001). Although EEG techniques have a relatively higher
temporal resolution, the conduction of electric signals often
makes the precise estimation of the activation source difficult. The multichannel EEG system and the cortically constrained minimum-norm estimation of neural activity arenecessary to overcome this problem. On the other hand, OT
can measure the TMS effects without these correction techniques, thus extending the findings in previous EEG studies.
According to a previous theoretical study of near-infrared
imaging, the measurement area in each emitter– detector
pair (spacing, 3 cm) is confined to a small region on thecortical gray matter, the spatial extent of which is approximately 1.8 cm in full width at half-maximum (FWHM)

161

Fig. 6. Mean changes of relative oxyhemoglobin concentration (3–9 s after
each TMS pulse). Error bars indicate standard errors of the mean across six
subjects. *P ⬍ 0.05 (t test).

centered on the measurement point (Firbank et al., 1998). If
a larger region is measured with OT, the cortical spread or
remote effects of TMS may be studied with this spatial
resolution. Therefore, we believe that the combination of
OT with TMS is a promising approach to investigate thevarious effects of magnetic stimulation.

Acknowledgments
We thank Dr. Yoshikazu Ugawa for technical advice on
TMS and EMG; Dr. Hideaki Koizumi and Dr. Atsushi Makifor technical advice on OT; Mr. Noriyoshi Ichikawa, Mr.
Michiyuki Fujiwara, and Mr. Takashi Nagashima for theirtechnical expertise; Dr. Noriaki Yahata, Mr. Ryuichiro
Hashimoto, Mr. Fumitaka Homae, Mr. Tatsuya Takeuchi,
Mr. Kei Suzuki, and Mr. Yasuki Hashimoto for their technical assistance; and Ms. Hiromi Matsuda for her administrative assistance. This study was supported in part by a
SORST grant from the Japan Science and Technology Corporation and by a Research Grant from the Mitsubishi
Foundation to K.L.S.

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Fig. 5. Relative oxyhemoglobin concentration changes induced by TMS
pulses at three different intensities: 110% MT (A), 90% MT (B), and 70%
MT (C). In each figure, the basis function of hemodynamics (thin line) was
fitted to the grand average data (thick line) with a least square method.
Error bars indicate standard errors of the mean across six subjects.

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