Clinical Neurophysiology 114 (2003) 2107–2117
www.elsevier.com/locate/clinph

Muscle afferent inputs from the hand activate human cerebellum
sequentially through parallel and climbing fiber systems
Isao Hashimotoa,c,*, Tomoaki Kimurab, Masato Tanosakic,
Yoshinobu Iguchic, Kensuke Sekiharada

Human Information Systems Laboratory, Tokyo Office, Kanazawa Institute of Technology, 6-8-7 Akasaka, Minato-ku, Tokyo 107-0052, Japanb
Department of Acupuncture, Tsukuba College of Technology, Tsukuba, Japanc
Department of Integrated Neuroscience, Tokyo Institute of Psychiatry, Tokyo, Japand
Department of Electronic Systems and Engineering, Tokyo Metropolitan Institute of Technology, Tokyo, Japan
Accepted 11 June 2003

Abstract
Objective: Spatio-temporal response characteristics of the human cerebellum to median nerve stimulation (MNS) were studied with theuse of a whole-head magnetoencephalographic (MEG) system covering the cerebellum and upper cervical spine.
Methods: Neuromagnetic responses from the cerebellum were recorded following electric stimulation of the right median nerve in 12
subjects. In 6 out of 12 subjects, the responses to the left median nerve and to the right index or middle finger stimulation were also recorded.
Results: The medial part of the cerebellum (spinocerebellum) was activated by MNS. In contrast, there were no responses from thecerebellum to the finger stimulation, suggesting that muscle afferent inputs are the source of cerebellar activation for MNS. The cerebellar
responses consisted of 3 or 4 components of alternating polarity within 90 ms post-stimulus: the current direction for the first component wasfrom the depth to the surface of the anterior lobe.
Conclusions: From the timing and current direction, we speculate that the 4 components reflect, respectively, (1) excitatory postsynaptic
potentials (EPSPs) of granule cells, (2) Purkinje cell EPSPs at the distal dendrites driven by parallel fibers, (3) Purkinje cell EPSPs at thesoma and the proximal dendrites mediated by climbing fibers and (4) second Purkinje cell EPSPs at the distal dendrites driven by parallel
fibers.
Significance: We first visualized serial activation of the human spinocerebellum following MNS noninvasively with MEG.
q 2003 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
Keywords: Magnetoencephalography; Muscle afferent input; Cerebellum; Granule cell; Purkinje cell; Parallel fiber system; Climbing fiber system

1. Introduction
Noninvasive neuroimaging techniques such as positronemission tomography (PET) and functional magnetic
resonance imaging (fMRI) have shown repeatedly thatvoluntary movements of the hand activate the vermal andintermediate zone (spinocerebellum) of ipsilateral anterior
lobe of human cerebellum (Grafton et al., 1993; Ellerman
et al., 1994; Nitschke et al., 1996; Sakai et al., 1998; Grodd
et al., 2001). On the other hand, although the temporal
relations between activities of the spinocerebellum andvarious aspects of hand movements were extensively studied* Corresponding author. Tel.: þ 81-3-5545-8197; fax: þ81-3-5545-8199.
E-mail address: ihashi@ael.kanazawa-it.ac.jp (I. Hashimoto).

electrophysiologically in animals, the input-output timing
relations still remained obscure (Harvey et al., 1977; Thach,
1978; Van Kan et al., 1993a,b; see Ghez and Thach, 2000 for
review). As a first step toward elucidating a complex neuralbehavioral coupling, we aimed to characterize the spatiotemporal patterns of the cerebellar activation in humans to
median nerve stimulation (MNS). Specifically, the timing ofmossy fiber activation of granule cells and the timing ofparallel and climbing fiber system activation of Purkinjecells with respect to peripheral inputs are crucial forunderstanding the underlying physiological mechanisms ofmonitoring and adjusting on-going movements in humans.
Tesche and Karhu (1997, 2000) were able to extract a
short-latency response or sustained oscillatory activity inthe human cerebellum to MNS on a priori assumption that1388-2457/$30.00 q 2003 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/S1388-2457(03)00233-5

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an equivalent current dipole (ECD) exists in the humancerebellum. Except for the reports above, no electroencephalographic (EEG) or magnetoencephalographic(MEG) observations of human cerebellar activity tosomatosensory stimulation appear in the literature. Thereare 3 main reasons for the difficulty in the noninvasive
physiological detection of the cerebellar activity. First,
extensive cortical foliation and diverse branching of thedendritic trees of Purkinje cells in the macro- and microstructure of the cerebellar cortex are clearly less than
optimal for generating an ‘open’ electric field (Lorente deNo, 1947). Second, the cerebellum is located fairly deep
within the cranium; it is closer to the center of the spherethan to the surface. Third, the previous commerciallyavailable whole-head MEG systems were designed forrecording cerebral activity and not for recording cerebellar
activity. In this situation, what we can do to detect themagnetic signals from the cerebellum is first to use a wholehead MEG system covering not only the cerebrum but also
the cerebellum and second to increase the signal-to-noise
ratio. Thus, we used a new MEG system covering both
cerebrum and cerebellum and averaged a massive number of
10 000 epochs in the present study.
We estimated the source of magnetic signals to MNSwith a single dipole modeling in a small number of subjects.
This approach, however, was not successful in locating the
cerebellar source in more than half of the subjects mainly
because of contamination by overwhelmingly strong
parallel cerebral responses. The issue has been complicatedfurther when the source localization for the activity ofrelatively wide areas of human cerebellum is to be estimatedusing a single dipole model.
The adaptive vector beamformer technique recently
developed by Sekihara et al. (2001) has provided us witha unique tool for the analysis of multiple sources locatednearby in primary somatosensory cortex (SI), which areactivated in parallel or successively (Hashimoto et al.,2001a,b). In the present study, we used this beamformer

technique and showed that the robust cerebellar activation
can be visualized at the latency range of 15– 90 ms
following MNS.

2. Materials and methods
Twelve normal subjects (2 females, 10 males, aged
22– 34 years, mean 25.6) were studied during wakefulness.
All subjects were right-handed according to the Edinburgh
inventory (Oldfield, 1971) and written informed consent
was obtained before the experiments. All experimental
protocols were conducted in accordance with the Declaration of Helsinki and were approved by the Institutional
Bioethics Committee of Tokyo Institute of Psychiatry.
Constant current pulses (rectangular shape, 0.2 ms
duration) were delivered at a stimulus rate of 4 Hz to theright median nerve at the wrist in 12 subjects and also to theleft median nerve in 6 out of 12 subjects. In 6 out of 12
subjects, the stimuli were delivered to the index (in 2subjects) or middle finger (in 4 subjects) via a pair of ring
electrodes with the cathode and anode placed at theproximal interphalangeal and distal interphalangeal joint,respectively. The stimulus intensity was 3 times sensory
threshold for the median nerve and finger stimulation. This
stimulus intensity elicited a mild twitch of the abductor
pollicis brevis muscle for MNS.
Magnetic signals (bandpass 3– 2000 Hz) were recorded ina magnetically shielded room using a 160-channel wholehead type gradiometer system (Yokogawa MEGVISION,
Yokogawa Electric Corp., Tokyo). The detection coils of thegradiometer are arranged in a uniform array on a helmetshaped surface of the bottom of the dewar, and the distance
between the centers of two adjacent coils is 25 mm; each coilmeasures 15.5 mm in diameter. The sensor array covers not
only the cerebrum but also the cerebellum and upper cervicalspine (Fig. 1). The sensors are configured as first-order axial
gradiometers with a baseline of 50 mm. The field sensitivities

Fig. 1. Sensor array superimposed on MRI in a subject. Note complete coverage of the cerebellum by the sensors.

I. Hashimoto et al. / Clinical Neurophysiology 114 (2003) 2107–2117
Fig. 2. Somatosensory evoked fields (SEFs) from 160 channels following right median nerve stimulation (MNS) in a representative subject are displayed at the approximate locations of the sensors. The time
window ranges from 0 to100 ms after MNS. Top view with nose up. The letters R and L indicate right and left hemispheres, respectively.

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I. Hashimoto et al. / Clinical Neurophysiology 114 (2003) 2107–2117

pﬃﬃﬃﬃ
of the sensors were 5 fT/ Hz or better. An epoch of 150 ms
duration (50 ms pre- and 100 ms post-stimulus) was digitizedat a 10 kHz/channel sampling rate and 10 000 responses wereaveraged on-line. DC offset was based on the pre-stimulus
period. The wide-band recorded responses were digitallyfiltered with a bandpass of 3 –300 Hz.
Magnetic resonance imaging (MRI) scans (Magnetom
System, Symphony 1.5 T, Siemens, 1.0 mm thickness) wereacquired with spherical lipid markers placed on the 5 MEG
fiduciary points to allow superposition of magnetic source
locations onto the MRI slices. The MRI head shape data
were used to determine the best-fit sphere for each subject’s
head. The head coordinate was defined as follows. The
origin was defined as the midpoint between the pre-auricularpoints. The x-axis passed from the origin to the nasion. The
y-axis was adjusted to be perpendicular to the x-axis on theplane made by the nasion and pre-auricular points, withpositive direction to the left. The z-axis pointed to the vertex
in a direction perpendicular to the x-y plane.
2.1. Data analysis
By using the adaptive vector beamformer technique, thesource localization was performed from the whole data set
between the period of 10 and 90 ms post-stimulus. The
results of the analysis were shown as maximum intensity
projections of current density for transverse, sagittal andcoronal sections of the generic head. The details of thisadaptive vector beamformer technique and its application to
SEF data were reported previously (Sekihara et al., 2001;
Hashimoto et al., 2001a,b). Therefore, it is only briefly
described here.
Let us define the magnetic field measured by themth sensor at time t as bm ðtÞ, and a column vectorbðtÞ ¼ ½b1 ðtÞ; …; bM ðtÞT as a set of measured data. Here
M is the total number of sensors and the superscript T
indicates the matrix transpose. A spatial location ðx; y; zÞis represented by a 3-dimensional vector r : r ¼ ðx; y; zÞ.
The source moment magnitude at r and time t is defined
as a 3-dimensional vector sðr; tÞ ¼ ½sx ðr; tÞ; sy ðr; tÞ; sz ðr; tÞ.
The estimate of the source moment is denoted as s^ðr; tÞ.
We define the lead field matrix LðrÞ that represents thesensitivity of the whole sensor array at r.

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The vector beamformer technique reconstructs thesource moment by applying the following linear operation.
s^ðr; tÞ ¼ WT ðrÞbðtÞ

ð1Þ

where the matrix WðrÞ is a weight matrix defined in Eq. (9)in the literature (Sekihara et al., 2001). Then, the source
moment at the location r is estimated using Eq. (1). Notethat when calculating the above weight matrix, the locationr is a controllable parameter. Therefore, the source-moment
distribution can be reconstructed by scanning the beamformer output over the region of interest in a completely
post-processing manner. Because this reconstruction is
performed at each instant in time, the spatio-temporal
reconstruction of the source activities can be obtained.
It should be emphasized that the adaptive beamformer
technique described above does not require any such priorassumptions on the source configuration as the source
location, the source orientation, or the number of sources.
In this technique, the spatial resolution depends
on the22 
input SNR, which is proportional
to
where
LðrÞ
s
s2





2
is the source power and  LðrÞ is the square of the leadfield norm. Since the square of the lead-field norm isinversely proportional to the fourth power of the source
depth, a deep source has a spatial resolution lower than thatfor a shallow source. Considering the average distance
between a source and sensors, the spatial resolution isapproximately estimated to be 1 cm for a source in the SI
region, whereas it is estimated to be 2 – 2.5 cm for a sourcein the cerebellar region (Sekihara et al., 2002).

3. Results
The primary N20m deflection was clearly identified insomatosensory evoked fields (SEFs) following MNS in all
subjects. In Fig. 2, the raw waveform data were displayed at
the approximate locations of the sensors. The isofield
contour maps around N20m peak at the latency of 18 ms
demonstrated a clear polarity reversal over the left 3b handarea to right MNS, indicating that the N20m can beapproximated by a single dipole (Fig. 3a). The time course
and the current-density maps of the typical cerebellar
activation are illustrated in Fig. 3b. The current-density map

Fig. 3. (a) Somatosensory evoked fields (SEFs) from 160 channels following right median nerve stimulation (MNS) are superimposed at the top. Four isofield
contour maps at the latencies indicated on top of each map are shown. The colors of the contours represent the relative intensity of the magnetic field as
indicated by the color bar. Vertical green lines on the superimposed traces indicate the selected time points for the maps. In addition to a dipolar pattern over theleft primary somatosensory cortex (SI), another dipolar pattern is clearly seen over the cerebellum at 38 ms post-stimulus. (b) Time-course of the cerebellar
activation and current density maps at the latencies of the isofield contour maps in (a). In addition to the SI source, cerebellar activation is shown at all latencies
indicted on the right of the maps. The 4 vertical lines on the time course of cerebellar activation also indicate these latencies. In each row, the maximumintensity projections onto the axial (left), sagittal (middle), and coronal (right) directions are shown. The circles depicting a human head show the projections of
the sphere used for the forward modeling. The colors of the contours represent the relative intensity of the source magnitude as indicated by the color bar. The
coordinate is the head coordinate expressed in cm. The small green bars originating from the center of the sources indicate the moment directions of thesesources. The letters R and L in the axial and coronal views indicate right and left hemispheres, respectively. Note that the source is stationary throughout, andonly the direction of the current changes from the first (18 ms) to the second (38 ms) component, from the second to the third (54 ms) and from the third to thefourth (80 ms) component.

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response occurred at the latency of 54 ms (Fig. 3b). Finally,
the fourth response with the same current direction as for thesecond response appeared at 80 ms post-stimulus (Fig. 3b).
Co-registration of the MEG sources onto the subject’s MRI
showed that the left SI and the medial zone of thecerebellum were activated at each time-slice following theright MNS (Fig. 4). In this figure, the cerebellar sources are
somewhat diffuse, and considerably large regions look
activated. However, this diffuse appearance of activation
was caused by the fact that the spatial resolution of theadaptive beamformer technique is relatively low in a deeparea such as the cerebellar region (Sekihara et al., 2002).
We were able to determine the locations and orientationsof the cerebellar sources in 7 out of 12 subjects for rightFig. 4. Superimposition of SI and cerebellar sources onto the subject’s MRI
for the data presented in Fig. 2. From the left to right columns are axial,
sagittal and coronal sections of the MRI. SI source at 18 ms post-stimulus(a) and 4 cerebellar sources (b) are shown. Here, the source intensities
above a certain threshold are color coded according to the color bar at theright and overlaid onto the subject MRI.

at the peak of N20m revealed initial activation of SI. The
first response with a relatively short duration at the latencyof 18 ms was observed over the cerebellum in parallel with
the N20m SI response (Fig. 3b). This component had themoment direction from inferior to superior. The second
cerebellar response with the current direction toward
inferior appeared at the latency of 38 ms, in addition to
the SI dipole (Fig. 3a,b). The dipolar pattern over the
cerebellum is clearly seen at this time slice (Fig. 3a). The
third response with the same current direction as for the first
Table 1
Latency (ms) of transit (T) from the first (T1) to fourth (T4) cerebellar
components
Stimulus

T1– 2

T2–3

T3–4

Right
Left
Total

36.0 ^ 9.9
28.3 ^ 9.0
31.8 ^ 9.8

59.4 ^ 14.4
46.8 ^ 15.7
52.5 ^ 15.7

67.0 ^ 8.5
68.5 ^ 19.8
68.1 ^ 17.1

Fig. 5. Superimposition of the first cerebellar source onto each subject’s
MRI in 3 subjects (a, b and c). From the left to right columns are axial,
sagittal and coronal sections of the MRI. Here, the source intensities above
a certain threshold are color coded according to the color bar at the right andoverlaid onto the subject MRI. For each subject, upper row illustrates
activation for left MNS and lower row activation for right MNS.

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MNS and in 5 out of 6 subjects for left MNS. Since the peaklatency of each cerebellar component was difficult to define,
we measured the latency of polarity reversal: the transit
from the first component into the second component, andfrom the second into the third, and from the third into thefourth, respectively (Table 1). Although there wereconsiderable variations in the latency of the transitions
across subjects, the mean duration was about 15 –30 ms forthe first response, 30– 50 ms for the second, 50 – 70 ms forthe third and . 70 ms for the fourth response.
For each subject, the initial 3 or 4 sources were locatedclose with each other in the medial part of the cerebellum
mainly ipsilateral to the stimulus. The mean locations of thefirst source for 3 subjects were overlaid on each subject’s
MRI in Fig. 5. Here, again the cerebellar sources lookconsiderably diffused due to the low spatial resolution of thesource reconstruction technique. In addition, the source was
localized slightly outside the border of the cerebellum forthe third subject (Fig. 5c). This is probably because the useof a spherically homogeneous conductor model for theforward modeling might cause small inaccuracy and thesource is localized closer to the surface than the actual
locations.
The locations of the maximum points of cerebellar
sources in 5 subjects for left MNS and in 7 subjects for right
MNS were schematically illustrated in Fig. 6. For the left
MNS, the sources were clustered in the medial zone mainly
ipsilateral to the stimulus. For the right MNS, the sourceswere somewhat scattered around the midline of thecerebellum.
The first cerebellar source was concurrent with the N20m
SI source and the current direction was from inferior tosuperior. Given the magnetic source in the cerebellar cortexof the anterior lobe demonstrated in fMRI studies (seeSections 1 and 4), it follows that an algebraic sum of theintracellular current is from the depth to the surface of2113

the cerebellar cortex, indicating the depth-sink and thesurface-source configuration of the field potential. This
current direction for the first source was consistent for all
subjects. For the second source, the direction was fromthe surface to the depth, reflecting the surface-sink andthe depth-source configuration. For the third source, thedirection was from the depth to the surface in all subjects.
For the fourth source, the direction was from the surface tothe depth.
Finally, for all 6 subjects studied, SI responses wererecorded from the cerebral cortex to the index or middle
finger stimulation. However, no responses from thecerebellum were observed, thus suggesting the possibility
that contribution from skin afferent inputs can beeliminated.

4. Discussion
The present results show that cerebellar SEFs canbe detected, without any anatomical or physiologicalconstraints, by the whole-head axial gradiometer covering
the cerebellum and that the activation of cerebellar sourceareas can be identified.
4.1. Muscle afferent inputs are the source of cerebellar
activation
In sharp contrast with the median nerve SEFs, there wereno responses from the cerebellum to the index or middle
finger stimulation, thus suggesting that contribution fromskin afferent inputs to the cerebellar responses can be ruledout. Since median nerve is a mixed nerve consisting of skinand muscle afferent fibers, it is reasonable to conclude thatmuscle afferent inputs are the source of the cerebellar
activation. The source areas in MEG recordings for MNS

Fig. 6. Schematic illustration of the locations of cerebellar sources. Open circles show locations of cerebellar source in each subject for left MNS (top row) andfor right MNS (bottom row). These locations were obtained as the locations of the maximum points of the cerebellar activations. In each row, the locations onto
the axial (left), sagittal (middle) and coronal (left) directions are shown. The letters R and L in the axial and coronal views indicate right and left hemispheres,
respectively.

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are in line with PET and fMRI studies that voluntary
movements of the hand activate the vermal and intermediatezone of ipsilateral anterior lobe of human cerebellum(Grafton et al., 1993; Ellerman et al., 1994; Nitschke et al.,
1996; Sakai et al., 1998; Grodd et al., 2001). It may beargued however that the failure to observe responses with
finger stimulation simply reflects a smaller number ofafferent fibers activated by the finger stimulation and/or thelack of sensitivity of the MEG imaging technique, since
somatosensory information from the skin reaches the
cerebellar cortex via a variety of pathways in animals(Oscarsson, 1973; Harvey et al., 1977; Rushmer et al.,1980). This may not be the case because we showedrepeatedly in our previous studies that the amplitude of thecerebral responses is not always linearly related to thenumber of activated fibers per se (see for example
Hashimoto et al., 1990). This non-linearity in the responses
in the cerebral cortex may also apply to those in the
cerebellar cortex. However, it is worthwhile to examine theabove possibility by stimulating the superficial radial nerveor multiple fingers simultaneously to increase the number offibers activated. We are planning to address this issue systematically to confirm the present results in a future study.
There is another possibility that cutaneous receptors areactivated as a result of limb movements and the cutaneous
inputs might be also transmitted to the cerebellum. A
microneurographic study clearly shows that cutaneous
mechanoreceptors in the dorsum of the human hand respondto hand or finger movements and provide the CNS withdetailed kinematic information for movements of the hand
(Edin and Abbs, 1991). Thus it is possible that not only
muscle afferents but also cutaneous afferents contribute to
the cerebellar responses. However, the cutaneous afferent
contribution to the cerebellar responses may be minimal, if
any, because pure cutaneous inputs with electric finger
stimulation elicit no detectable responses from the cerebellum. In support of this conjecture, cerebellar activation is
hard to detect in humans during tactile stimulation and there
has been only one fMRI study showing activation of thecerebellum to tactile stimulation of hand and foot (Bushara
et al., 2001). Thus, further studies are needed to clarify thediscrepancy between the present study and electrophysiological studies in animals or the fMRI study in man.
4.2. The first cerebellar response reflects activity inthe granule cells
The first response with a short duration at the latency of
15 –30 ms was observed over the medial zone of the anterior
lobe. Because fast mossy fibers from the external cuneate
nucleus activate granule cells at the shortest latency(Oscarsson, 1973; Murphy et al., 1973), the population of
granule cells is the most probable candidate for the initial
response. It was also shown that stimulation of the external
cuneate nucleus or the dorsal spinocerebellar tract evokedpostsynaptic currents in the granule cells in the form of N2

field potential (Sasaki and Strata, 1967). The depth profile ofthis field potential showed the maximum negativity in the
granular layer, which fell off toward the superficial
molecular layer. The direction of the current for the first
cerebellar source was from the depth to the surface of theanterior lobe of the cerebellum and was in agreement with
its source in the granule cells. It is well established that the
mossy fiber-granule cell system occupies as much as two
thirds of the whole cerebellar mass and a large number ofthe granule cells are activated simultaneously by the cuneocerebellar inputs (Ito, 1984). The first cerebellar response in
humans, therefore, may reflect the N2 potential representing
the short-latency excitatory postsynaptic potentials (EPSPs)of granule cells.
Axonal volleys at 13 and 14 ms with duration of 1 ms anda postsynaptic activity at 15 ms with duration of 6 ms wererecorded directly from the human dorsal pons and midbrain
following MNS (Hashimoto, 1984). These local potentials
are detected as P13 and P14 far-field potentials and as N15
potential at the scalp. The sharp P13 and P14 potentials
reflect the earliest medial lemniscus volleys, and the slow
N15 potential in the pons and midbrain represents excitationof various brain-stem nuclei receiving projections from thecuneate nucleus. The P13 and P14 also elicit postsynaptic
P16 in the thalamus (Katayama and Tsubokawa, 1987;
Morioka et al., 1989; Klostermann et al., 2002). Thus, if wecompare the earliest response in the brain-stem andcerebellum, the brain-stem potentials were earlier than thefirst cerebellar activation, supporting the notion that the
granule cells are the generator for the first cerebellar
response.
On the other hand, there is a slower component generated
in the brain-stem: widespread N18 component over thescalp, according to Sonoo et al. (1992, 1999), reflects
primary afferent depolarization (PAD) of the presynaptic
terminals in the cuneate nucleus. The PAD, i.e. EPSPs of thepresynaptic terminals of the dorsal column fibers is
produced disynaptically by activation of interneurons via
collaterals of cuneate neurons. This slow rising anddecaying response persists when the earliest activity
ascends, passes the brain-stem nuclei and thalamus, andeven after it reaches the cortex. Because of a similar timing
between N18 and the initial cerebellar response, one may
argue that the first ‘cerebellar activation’ reflects postsynaptic activity of the cuneate nucleus. This possibility
seems to be slim, because there is a relatively wide distance
between the two structures. In addition, the activity of thebrain-stem, located deeper than the cerebellum, is muchharder to detect with our new gradiometer system with abaseline of 5 cm.
4.3. Purkinje cells are the major generator of the following
cerebellar responses
Purkinje cell dendrites in the cerebellar fissures and gyri
produce a coherent intracellular current flow and may

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generate magnetic fields that can be detectable over the
cerebellum. Okada et al. (1987) and Okada and Nicholson(1988) recorded magnetic fields from an isolated turtle
cerebellum to electric stimulation of the cerebellar surface.
Based on the field pattern, they ascribed the magnetic fields
to postsynaptic intracellular current flow in Purkinje cell
dendrites. They also showed that a synchronous activity in a
1 mm3 of in vitro cerebellar tissue could lead to a magnetic
field of 100 f T at a distance of 2 cm (Okada et al., 1987). An
fMRI study for thumb movements showed an activation
volume of 2100 mm3 in the cerebellum (Grodd et al., 2001).
Assuming that the similar volume is activated synchronously for MNS as for thumb movements, a magnetic fieldof 210 pT at a distance of 2 cm will be produced. However,in vivo responses from the human cerebellum may beconsiderably reduced because of (1) cancellation ofmagnetic fields due to a complex macro- and microstructure of the cerebellar folia, (2) a sharp decay in fieldstrength due to its deep location within the cranium, and(3) temporal dispersion due to less coherent activation asshown in the present study. Although no cerebellar
responses were observed in 5 out of 12 subjects for right
MNS and in 1 out of 6 subjects for left MNS, the present
results suggest that cerebellar activity can be detected in the
majority of cases. The robustness of our observations argues
against the traditional concept of a ‘closed’ electric field for
cerebellar activity, and suggests that there is somesystematic asymmetry in the cerebellar structure that
produces a ‘semi-open’ electric field. In fact, the amplitudeof the second and third cerebellar responses was on the orderof the amplitude of the N20m primary response in SI.
However, in subjects without observable cerebellar
responses to MNS, it is likely that the ‘systematic
asymmetry’ in the anatomical structure is lost, which
produces a closed electric field.
About the functions of the cerebellum, there is growing
evidence that the cerebellum might filter out predictableaspects of the sensory input to reveal the unexpected (Bell,2001). It is tempting to speculate that, through the process ofextensive averaging of responses to the rhythmic 4 Hz stimuli, the cerebellar responses have been filtered out. And, asa result, no responses were detected in some of our subjects.
4.4. The second cerebellar activation reflects Purkinje cell
EPSPs at the distal dendrites driven by the parallel fibers
The second activation occurred at the latency of 30 –50
ms and the current direction of this source was from thecerebellar surface of the anterior lobe toward the depth,
reflecting the surface-sink and the depth-source configuration of the field potentials. As the parallel fiber excitatory
synapses are concentrated on the most superficial dendritic
branches of the Purkinje cells, the distal dendrites become
sinks for extracellular return current from the passive
sources on the deeper dendrites (Eccles et al., 1966a). The
latencies of Purkinje cell responses in cats are 3 – 4 ms

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longer than those of granule cells in the immediate vicinity(Murphy et al., 1973). Consideration of the current direction
and timing in human and animal studies suggests that thesecond activation reflects the Purkinje cell activity in the
spinocerebellum elicited by the parallel fiber system.
Proprioceptive inputs carried over parallel fiber pathways produce narrow beams of pure inhibition of Purkinjecells (off-beam) on either side of a wide zone of excitation(on-beam) along the transverse axis of the folia (Ito, 1984).
However, only 3% of Purkinje cells were inhibited by the
proprioceptive inputs (Murphy et al., 1973), suggesting thatproprioceptive inputs via the parallel fibers elicit mainly
excitatory response.
4.5. The third cerebellar activation reflects Purkinje cell
EPSPs at the proximal dendrites mediated by the climbing
fibers
The third cerebellar activation occurred at the latency of
50 – 70 ms and the direction of the current was fromthe depth to the surface, indicating the depth-sink and thesurface-source configuration. The third activation appears tobe through the climbing fiber system, because the climbing
fibers terminate on the soma and proximal dendrites of the
Purkinje cells and produce the current sink at the depth andthe source at the surface. The mass activity in the Purkinjecells to climbing fiber stimulation can be recorded as anegative potential in the Purkinje cell and molecular layers
and as a positive potential at the cerebellar surface (Eccles
et al., 1966b, 1968; Oscarsson, 1973). In addition, thesequential timing of the second and third responses isconcordant with electrophysiology of the cerebellum inanimals that the conduction velocity for the parallel fibers isfaster than for the climbing fibers, and also the latency forthe parallel fiber activation of Purkinje cells is shorter thanfor the climbing fiber mediated Purkinje cell responses(Eccles et al., 1968; Oscarsson, 1973; Murphy et al., 1973).
Oscarsson (1973) has outlined the pertinent pathways
through the spinal cord and the inferior olive to the
cerebellum (spino-olivo-cerebellar pathways) that mediate
the climbing fiber responses. Among 3 physiologicallydefined climbing fiber pathways, the dorsal spino-olivocerebellar pathway transmits the muscle afferent information to the Purkinje cells in the vermis and intermediatepart of the anterior lobe. The inferior olivary neurons
belonging to the dorsal spino-olivo-cerebellar pathway arealso monosynaptically activated by stimulation of the
primary motor cortex (MI) and SI (Oscarsson, 1973).
Mima et al. (1996, 1997) reported proprioception-related
somatosensory evoked potentials (SEPs) from the scalp andepicortical recordings elicited by brisk passive flexion
movement at the proximal interphalangeal joint of the
middle finger (48 in 25 ms). Although the exact trigger point
for eliciting the muscle afferents cannot be defined within
the rise time (25 ms) of finger movement, they showed
an early positivity with the peak latency of about 35 ms.

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I. Hashimoto et al. / Clinical Neurophysiology 114 (2003) 2107–2117

In the data by Kimura et al. (1999a,b), the onset latency of
the first SI/MI response (P70 and P70m) was about 30 ms
for pure muscle afferent inputs from the abductor pollicis
brevis muscle. Thus it is possible that MI or SI activation
elicits the third cerebellar response.
4.6. The fourth cerebellar activation reflects secondary
activation of parallel fiber mediated Purkinje cell
population
The fourth cerebellar activation with the latency of . 70
ms was present in all subjects for right MNS and in 2 out of
5 subjects for left MNS. The direction of the current wasfrom the surface to the depth. The surface-sink and thedepth-source field configuration suggests that the Purkinje
cell population is activated by parallel fiber inputs. Further
studies are needed to clarify the pathway mediating this latecerebellar response. The populations of neurons, which are
candidates of successive responses, are schematicallyillustrated in Fig. 7.
4.7. Further studies are needed to bridge the gap between
human MEG studies and electrophysiological studies inanimals
Although the cerebellar responses are robust andreproducible in the majority of subjects, there are stillsome problems in the localization and timing of thecerebellar activation. First, there was no distinct ipsilateral
activation of the intermediate zone for MNS as was shownin fMRI studies for hand movements. In addition, some of
the activation foci were out of the cerebellum. Thus the
localization from MEG data would need to be confirmed byanother technique such as fMRI. With application of MNS
and finger stimulation to the same group of subjects, thecontribution of muscle afferents to the cerebellar responses
can be verified by fMRI studies. Second, the timing of
cerebellar signals was extremely variable among the
subjects as compared with SI responses. We have noplausible explanation for the apparent discrepancy between
the temporal properties of cerebellar and cerebral signals.
Finally, one of the most serious problems in this study is therelation between the directions of intracellular current in a
population of granule and Purkinje cells calculated from the
MEG data and those in individual granule and Purkinje cell
dendrites comprising the mass. The relation should be very
complex and our present explanation of ‘systematic
asymmetry’ in the cerebellar structure seems to be too
simplistic. In order to approach the issue, an animal model
would be preferable. For example, delivering the same
stimulations to monkeys and measuring MEG signals fromthe monkey cerebellum and at the same time recording fieldand extracellular unit-potentials from the cerebellar cortex,
and the multimodal characterization of cerebellar activity
can clarify the relation between the mass and local
activities.

Fig. 7. The populations of neurons, which are candidates of successive
responses, are illustrated on a schematic presentation of the main cell types
and their synaptic arrangements in the cerebellar cortex. From the timing
and current direction, we speculate that the 4 components reflect,respectively, (1) excitatory postsynaptic potentials (EPSPs) of granulecells, (2) Purkinje cell EPSPs at the distal dendrites driven by parallel fibers,(3) Purkinje cell EPSPs at the soma and the proximal dendrites mediated byclimbing fibers and (4) second Purkinje cell EPSPs at the distal dendrites
driven by parallel fibers. Black signifies excitatory transmission throughclimbing fibers, mossy fibers, granule cell and parallel fibers. The 3 kinds ofinhibitory interneurons (Golgi cells, stellate cells and basket cells) areillustrated in gray. Although the granule cells are disynaptically inhibitedby Golgi cells, and also Purkinje cells by stellate and basket cells, these
inhibitory actions were not considered for simplicity. However, according
to an animal study in cats by Murphy et al. (1973), only 3% of Purkinje cells
were inhibited by the proprioceptive inputs. It is unknown what percentagesof Purkinje cells were inhibited by the same inputs in humans. We infer thatthe percentages are not so much different between the two species.

Acknowledgements
We thank Gabriel Curio, Riitta Hari and Claudia
D. Tesche for useful discussions, and Masato Taira forproviding MRI data. The MR images were obtained at theFirst Department of Physiology, Nihon University School of
Medicine.

References
Bell CC. Memory-based expectations in electrosensory systems. Curr Opin
Neurobiol 2001;11:481 –7.
Bushara KO, Wheat JM, Khan A, Mock BJ, Turski PA, Sorenson J, Brooks
BR. Multiple tactile maps in the human cerebellum. Neuroreport 2001;
12:2483– 6.

I. Hashimoto et al. / Clinical Neurophysiology 114 (2003) 2107–2117
Eccles JC, Llinas R, Sasaki K. Parallel fibre stimulation and the responses
induced thereby in the Purkinje cells of the cerebellum. Exp Brain Res
1966a;1:17–39.
Eccles JC, Llinas R, Sasaki K. The excitatory synaptic action of climbing
fibres on the Purkinje cells of the cerebellum. J Physiol 1966b;182:
268–296.
Eccles JC, Provini L, Strata P, Taborikova H. Analysis of electricalpotentials evoked in the cerebellar anterior lobe by stimulation ofhindlimb and forelimb nerves. Exp Brain Res 1968;6:171–94.
Edin BB, Abbs JH. Finger movement responses of cutaneous mechanoreceptors in the dorsal skin of the human hand. J Neurophysiol 1991;
65:657–70.
Ellerman JM, Flament D, Kim S-G, Fu QG, Merkle H, Ebner TJ, Ugurbil K.
Spatial patterns of functional activation of the cerebellum investigatedusing high field (4T) MRI. NMR Biomed 1994;7:63– 8.
Ghez C, Thach WT. The cerebellum. In: Kandel E, Schwartz JH, Jessell
TM, editors. Principles of neural science, 4th ed. New York: McGrawHill; 2000. p. 832 –52.
Grafton SC, Woods RP, Mazziotta JC. Within arm somatotopy in humanmotor areas determined by positron emission tomography imaging of
cerebral blood flow. Exp Brain Res 1993;95:172–6.
Grodd W, Hulsmann E, Lotze M, Wildgruber D, Erb M. Sensorimotor
mapping of the human cerebellum: fMRI evidence of somatotopic
organization. Hum Brain Mapp 2001;13:55–73.
Harvey RJ, Porter R, Rawson JA. The natural discharges of Purkinje cells inparavermal regions of lobules V and VI of the monkey’s cerebellum.
J Physiol 1977;271:515 –36.
Hashimoto I. Somatosensory evoked potentials from the human brain-stem:
origins of short latency potentials. Electroenceph clin Neurophysiol
1984;57:221 –7.
Hashimoto I, Yoshikawa K, Sasaki M. Latencies of peripheral nerve andcerebral evoked responses to air-puff and electrical stimuli. Muscle
Nerve 1990;13:1099–104.
Hashimoto I, Kimura T, Iguchi Y, Takino R, Sekihara K. Dynamic
activation of distinct cytoarchitectonic areas of the human S1 cortex
after median nerve stimulation. Neuroreport 2001a;12:1891–7.
Hashimoto I, Sakuma K, Kimura T, Iguchi Y, Sekihara K. Serial activationof distinct cytoarchitectonic areas of the human S1 cortex after posterior
tibial nerve stimulation. Neuroreport 2001b;12:1857–62.
Ito M. The cerebellum and neural control. New York: Raven; 1984.
Katayama Y, Tsubokawa T. Somatosensory evoked potentials from thethalamic sensory relay nucleus (VPL) in human: correlations with shortlatency somatosensory evoked potentials recorded at the scalp.
Electroenceph clin Neurophysiol 1987;68:187 –201.
Kimura T, Nishijo K, Hashimoto I. Somatosensory evoked potentials
elicited by motor point stimulation. In: Barber C, Celesia GG,
Hashimoto I, Kakigi R, editors. Functional Neuroscience: Evoked
Potentials and Magnetic Fields. EEG Suppl, 49. Amsterdam: Elsevier;
1999a. p. 73–6.
Kimura T, Nishijo K, Hashimoto I. Somatosensory evoked magnetic fields
following motor point stimulation. In: Yoshimoto T, Kotani M, Kuriki
S, Karibe H, Nakasato N, editors. Recent Advances in Biomagnetism.
Sendai: Tohoku University Press; 1999b. p. 458 –61.
Klostermann F, Gobbele R, Buchner H, Curio G. Intrathalamic nonpropagating generators of high-frequency (1000 Hz) somatosensory
evoked potential (SEP) bursts recorded subcortically in man. Clin
Neurophysiol 2002;113:1001–5.
Lorente de No R. Action potential of the motoneurons of the hypoglossus
nucleus. J Cell Comp Physiol 1947;29:207 –87.
Mima T, Terada K, Maekawa M, Nagamine T, Ikeda A, Shibasaki H.
Somatosensory evoked potentials following proprioceptive stimulationof finger in man. Exp Brain Res 1996;111:233 –45.

2117

Mima T, Ikeda A, Terada K, Yazawa S, Mikuni N, Kunieda T, Taki W,
Kimura J, Shibasaki H. Modality-specific organization for cutaneousand proprioceptive sense in human primary sensory cortex studied bychronic epicortical recording. Electroenceph clin Neurophysiol 1997;
104:103–7.
Morioka T, Shima F, Kato M, Fukui M. Origin and distribution of thalamic
somatosensory evoked potentials in humans. Electroenceph clin
Neurophysiol 1989;74:186 –93.
Murphy JT, MacKay WA, Johnson F. Differences between cerebellar
mossy and climbing fibre responses to natural stimulation of forelimbmuscle proprioceptors. Brain Res 1973;55:263–89.
Nitschke MF, Kleinschmidt A, Wessel K, Frahm J. Somatotopic motor
representation in the human anterior cerebellum. A high-resolutionfunctional MRI study. Brain 1996;119:1023–9.
Oldfield RC. The assessment and analysis of handedness: the Edinburgh
inventory. Neuropsychologia 1971;9:97–113.
Okada YC, Nicholson C. Magnetic evoked field associated withtranscortical currents in turtle cerebellum. Biophys J 1988;53:723– 31.
Okada YC, Lauritzen M, Nicholson C. Magnetic field associated withneural activities in an isolated cerebellum. Brain Res 1987;412:
151– 5.
Oscarsson O. Functional organization of spinocerebellar paths. In: Iggo A,
editor. Somatosensory system. Handbook of sensory physiology, vol. 2.
New York: Springer; 1973. p. 339–80.
Rushmer DS, Woollacott MH, Robertson LT, Laxter KD. Somatotopic
organization of climbing fiber projections from low threshold cutaneousafferents to pars intermedia of cerebellar cortex in cat. Brain Res 1980;
181:17–30.
Sakai K, Takino R, Hikosaka O, Miyauchi S, Sasaki Y, Putz B, Fijimaki N.
Separate cerebellar areas for motor control. Neuroreport 1998;9:2359–63.
Sasaki K, Strata P. Responses evoked in the cerebellar cortex by stimulating
mossy fiber pathways to the cerebellum. Exp Brain Res 1967;3:95–110.
Sekihara K, Nagarajan SS, Poeppel D, Marantz A, Miyashita Y.
Reconstructing spatio-temporal activities of neural sources using an
MEG vector beamformer technique. IEEE Trans Biomed Eng 2001;48:760– 71.
Sekihara K, Nagarajan SS, Robinson S, Vrba JY. Spatial resolution,
leakage, and signal-to-noise ratio in adaptive beamformer sourcereconstruction technique. In: Nowak H, Haueisen J, Giessler F,
Huonker R, editors. Proceedings of the 13th International Conference
on Biomagnetism. Berlin: VDE; 2002. p. 813.
Sonoo M. How much has been solved regarding SEP generators? In: Barber
C, Celesia GG, Hashimoto I,, Kakigi R, editors. Functional Neuroscience: Evoked Potentials and Magnetic Fields. EEG Suppl, 49.
Amsterdam: Elsevier; 1999. p. 47 –51.
Sonoo M, Genba K, Zai W, Iwata M, Mannen T, Kanazawa I. Origin of thewidespread N18 in median nerve SEP. Electroenceph clin Neurophysiol
1992;84:418–25.
Tesche CD, Karhu J. Somatosensory evoked magnetic fields arising fromsources in the human cerebellum. Brain Res 1997;744:23–31.
Tesche CD, Karhu J. Anticipatory cerebellar responses during somatosensory omission in man. Hum Brain Mapp 2000;9:119 –42.
Thach WT. Correlation of neural discharge with pattern and force ofmuscular activity, joint position, and direction of intended next
movement in motor cortex and cerebellum. J Neurophysiol 1978;41:
74– 94.
Van Kan PLE, Houk JC, Gibson AR. Output organization of intermediate
cerebellum of monkey. J Neurophysiol 1993a;69:57–73.
Van Kan PLE, Gibson AR, Houk JC. Movement-related inputs tointermediate cerebellum of the monkey. J Neurophysiol 1993b;69:
74– 94.