J Neurophysiol 109: 2955–2962, 2013.
First published March 27, 2013; doi:10.1152/jn.00960.2012.
Short- and long-latency interhemispheric inhibitions are additive in human
motor cortex
Soumya Ghosh, Arpan R. Mehta, Guan Huang, Carolyn Gunraj, Tasnuva Hoque, Utpal Saha,
Zhen Ni, and Robert Chen
Division of Neurology, Department of Medicine, University of Toronto, Toronto Western Research Institute, Toronto,
Ontario, Canada
Submitted 5 November 2012; accepted in final form 22 March 2013
motor cortex; interhemispheric inhibition; transcranial magnetic stimulation
(TMS) has been used to
study cortical inhibitory processes in the human primary motor
cortex (M1), and many types of inhibition have been identified.
They include short-interval intracortical inhibition (SICI),
long-interval intracortical inhibition (LICI), and interhemispheric inhibition (IHI) (Ferbert et al. 1992; Kujirai et al. 1993;
Valls-Sole et al. 1992; Wassermann et al. 1996). Subsequently,
two distinct phases of IHI, short-latency interhemispheric inhibition (SIHI) and long-latency interhemispheric inhibition
(LIHI), were demonstrated (Chen et al. 2003; Kukaswadia et
al. 2005; Ni et al. 2009). To understand the relationship
between these processes, and whether they work through
common neurons and mechanisms, several studies have investigated how the different inhibitory processes interact with one
TRANSCRANIAL MAGNETIC STIMULATION
Address for reprint requests and other correspondence: S. Ghosh, Centre for
Neuromuscular and Neurological Disorders, ANRI, QEII Medical Centre,
Nedlands, WA 6009, Australia (e-mail: [email protected]).
www.jn.org
another. For example, it has been shown that SICI is reduced
in the presence of LICI, and it is likely that LICI inhibits SICI
(Sanger et al. 2001). In the originating hemisphere of transcallosal projections, SICI and LICI reduce both SIHI and LIHI
projecting to the opposite hemisphere (Lee et al. 2007). In the
target hemisphere, SIHI inhibits SICI while SIHI and LICI
have inhibitory interactions (Daskalakis et al. 2002; MüllerDahlhaus et al. 2008). Similarly, LICI and LIHI are reduced in
the presence of each other, whereas LIHI has an additive effect
with SICI (Udupa et al. 2010).
There is considerable interest in the neural mechanisms of
IHI, since IHI is abnormal in many neurological disorders
(Beck et al. 2009; Li et al. 2007; Murase et al. 2004; Nelson et
al. 2010) and modulation of interhemispheric connections is
being increasingly studied for potential therapeutic effects in
neurological conditions (Kirton et al. 2008; Mansur et al. 2005;
Pal et al. 2005). IHI is largely mediated by the corpus callosum
through long-range interhemispheric axons and local inhibitory
neurons (Di Lazzaro et al. 1999; Ferbert et al. 1992; Hanajima
et al. 2001). Since SIHI and LIHI are differentially influenced
by conditioning stimuli of varying intensities and locations,
they are thought to be mediated by different neuronal circuits
(Chen et al. 2003; Daskalakis et al. 2002; Kukaswadia et al.
2005; Ni et al. 2009; Udupa et al. 2010). LIHI is mediated by
GABAB receptors, while the neurotransmitter receptor involved with SIHI is unknown (Irlbacher et al. 2007). Although
the interactions between interhemispheric inhibitory processes
(SIHI and LIHI) and intracortical inhibitory circuits (SICI and
LICI) have been examined previously (Daskalakis et al. 2002;
Udupa et al. 2010), the interactions between SIHI and LIHI
have not been explored. Therefore, this study examined the
interactions between SIHI and LIHI. We hypothesized that,
since SIHI and LIHI are mediated by different neural circuits,
they would have additive effects. However, it is also possible
that LIHI may inhibit SIHI through presynaptic GABAergic
mechanisms similar to the interaction between LICI and SICI.
METHODS
Experiments were performed on 10 healthy right-handed subjects
(6 men and 4 women; mean age 43 yr, range 24 – 61 yr). All subjects
provided written informed consent. The experimental protocol was
approved by the University Health Network Research Ethics Board
(Toronto, Canada) in accordance with the Declaration of Helsinki on
the use of human participants in experiments.
Study design. How two inhibitory systems interact with each other
has been examined by comparing the effects of applying the two
inhibitory systems together with the effects of the inhibitory systems
0022-3077/13 Copyright © 2013 the American Physiological Society
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Ghosh S, Mehta AR, Huang G, Gunraj C, Hoque T, Saha U, Ni
Z, Chen R. Short- and long-latency interhemispheric inhibitions are
additive in human motor cortex. J Neurophysiol 109: 2955–2962,
2013. First published March 27, 2013; doi:10.1152/jn.00960.2012.—
Transcranial magnetic stimulation (TMS) of the human primary motor
cortex (M1) at suprathreshold strength results in inhibition of M1 in
the opposite hemisphere, a process termed interhemispheric inhibition
(IHI). Two phases of IHI, termed short-latency interhemispheric
inhibition (SIHI) and long-latency interhemispheric inhibition (LIHI),
involving separate neural circuits, have been identified. In this study
we evaluated how these two inhibitory processes interact with each
other. We studied 10 healthy right-handed subjects. A test stimulus
(TS) was delivered to the left M1, and motor evoked potentials
(MEPs) were recorded from the right first dorsal interosseous (FDI)
muscle. Contralateral conditioning stimuli (CCS) were applied to the
right M1 either 10 ms or 50 ms prior to the TS, inducing SIHI and
LIHI, respectively, in the left M1. The effects of SIHI and LIHI alone,
and SIHI and LIHI delivered together, were compared. The TS was
adjusted to produce 1-mV or 0.5-mV MEPs when applied alone or
after CCS. SIHI and LIHI were found to be additive when delivered
together, irrespective of the strength of the TS. The interactions were
affected neither by varying the strength of the conditioning stimulus
producing SIHI nor by altering the current direction of the TS. Small
or opposing interactions, however, may not have been detected. These
results support previous findings suggesting that SIHI and LIHI act
through different neural circuits. Such inhibitory processes may be
used individually or additively during motor tasks and should be
studied as separate processes in functional studies.
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INTERHEMISPHERIC INHIBITORY INTERACTIONS
Table 1. Stimulus parameters and configurations used
in experiment 1
Right Motor Cortex
Condition
1
2
3
4
5
6
7
8
9
10
11
12
CCS50
⫹
⫹
⫹
⫹
⫹
⫹
CCS10
⫹
⫹
⫹
⫹
⫹
⫹
Left Motor Cortex TS
1mV
1mV
1mV
1mVCCS50
1mVCCS50
1mVCCS50
1mVCCS10
1mVCCS10
1mVCCS10
1mVCCS50
1mVCCS10
1mV
TS, test stimulus, CCS, contralateral conditioning stimulus delivered 10 ms
(CCS10) or 50 ms (CCS50) before TS; 1mV, minimum TS intensity required
to produce a peak-to-peak motor evoked potential (MEP) amplitude of 1 mV;
1mVCCS10 and 1mVCCS50, TS intensity adjusted to produce 1-mV MEPs in
the presence of CCS10 or CCS50, respectively.
and TS-evoked MEP amplitude in the presence and absence of IHI in
separate trials (Table 1). These conditions were delivered in random
order and repeated 10 times. In a subset of four subjects an additional
condition (condition 12) was tested in which TS intensity was left
unchanged (matched for MEP amplitude without SIHI or LIHI)
during the triple-pulse stimulation.
The TS intensities used varied between three stimulus strengths and
are named “1mV,” “1mVCCS10,” and “1mVCCS50” (Table 1).
Intensity of “1mV” is the minimum intensity required to produce a
peak-to-peak MEP amplitude of 1 mV in 5 of 10 trials in the relaxed
contralateral FDI muscle (Chen et al. 2003; Kukaswadia et al. 2005;
Ni et al. 2009; Udupa et al. 2010). TS1mVCCS10 or TS1mVCCS50
refers to the TS intensity adjusted to produce 1-mV MEPs in the
presence of CCS10 or CCS50, respectively.
The intensities of CCS10 and CCS50 were initially set to produce
a 1-mV MEP in the left FDI muscle but were subsequently increased
in some subjects, if necessary, to produce clearly identifiable SIHI and
LIHI (Table 3). Immediately after the experiments, the MEP amplitudes for conditions 1, 5, and 9 were measured to ensure that they
were matched and close to 1mV (i.e., the minimum intensity required
to produce a peak-to-peak MEP amplitude of 1 mV in 5 of 10 trials).
If necessary, the experimental run was repeated with adjusted stimulus
intensities.
In conditions 10 and 11 (where triple stimuli were used, see Table
1), two conditioning stimuli (CCS10 and CCS50) were applied at an
interval of 40 ms, introducing the possibility of interaction in the right
(originating) hemisphere. For example, CCS50 may affect the response evoked by CCS10 through LICI or intracortical facilitation
(ICF; Valls-Sole et al. 1992). Therefore, the MEP amplitudes evoked
in the left FDI muscle by CCS10 alone (in conditions 3, 6, and 9) and
when preceded by CCS50 (in conditions 10 and 11) were measured
and compared. If necessary, the strength of CCS10 was adjusted to
evoke a mean MEP of at least 1 mV in the left FDI muscle in
conditions 10 and 11 and the experiments (conditions 1–11) were
repeated. The protocols were designed to allow for the calculation of
both the effects of LIHI on SIHI and the effects of SIHI on LIHI matched
for either test MEP amplitude or TS intensities. The effect of LIHI on
SIHI was calculated as a ratio of the MEP amplitude in right FDI muscle
elicited by triple-pulse TMS (1mVCCS10, 1mVCCS50, TS1mVCCS50,
condition 10) to that evoked by paired-pulse TMS (1mVCCS50,
TS1mVCCS50, condition 5; Table 2). Similarly, the effect of SIHI on
LIHI was calculated as a ratio of the MEP amplitude produced by
triple-pulse TMS (1mVCCS10, 1mVCCS50, TS1mVCCS10, condition
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applied alone (Chen 2004; Kukaswadia et al. 2005; Ni et al. 2009,
2011; Sanger et al. 2001; Udupa et al. 2010). The present study
examined the effects of LIHI and SIHI on each other. Each trial
consisted of one or more contralateral conditioning stimuli (CCS) to
the right M1 followed by a suprathreshold test stimulus (TS) to the left
M1. The timing of the pulses was controlled by the output features of
an analog-to-digital interface (Micro 1401, Cambridge Electronic
Design, Cambridge, UK). The CCS applied were delivered singly or
in combination 10 or 50 ms before the TS and are called CCS10 and
CCS50, respectively. These interstimulus intervals (ISIs) have been
shown to be optimal for recording maximal SIHI and LIHI (Ni et al.
2009).
Motor evoked potential recording. Motor evoked potentials
(MEPs) were recorded via surface electromyogram (EMG) readings
taken from the first dorsal interosseous (FDI) muscles of both hands
with disposable 9-mm-diameter Ag-AgCl disk electrodes. The active
electrode was placed over the muscle belly and the reference electrode
over the metacarpophalangeal joint of the index finger. The EMG
signal was amplified (⫻1,000), band-pass filtered (20 Hz to 2.5 kHz;
Intronix Technologies model 2024F, Bolton, ON, Canada), digitized
at 5 kHz by the analog-to-digital interface, and stored on a computer
for off-line analysis. The participants maintained relaxation, and EMG
activity was monitored visually with a computer monitor and aurally
through loudspeakers at high gain. Trials contaminated with voluntary
muscle contraction were discarded. Voluntary muscle activation occasionally contaminated MEPs, more often involving the TS-induced
MEPs. If in any one experiment more than the occasional voluntary
muscle activation (defined as more than 5 trials in an experiment or 2
trials in any 1 condition) was observed, the whole experiment was
repeated.
Transcranial magnetic stimulation. TMS was applied to the left
(TS) and right (CCS) M1 and was delivered by two figure-of-eight
coils of different sizes (see below) and five Magstim 200 stimulators
and three Bistim modules (Magstim, Dyfed, UK). The coils were
placed over the scalp areas, marked for reference, that were optimal
for eliciting MEPs in the contralateral FDI muscle, with the handle
pointing posteriorly and laterally, approximately perpendicular to the
central sulcus and ⬃45° to the midsagittal line. This orientation
induced a posterior-to-anterior (PA) current that transsynaptically
activated corticospinal neurons (Kaneko et al. 1996; Werhahn et al.
1994). This orientation is optimal for inducing SIHI and LIHI (Ni et
al. 2009). In experiment 3, an additional set of data was obtained (for
comparison) with the left hemisphere coil (delivering the TS) oriented
to produce an anterior-to-posterior (AP) current. This was achieved by
rotating the coil by 180° from the position for producing the PA
current, with the handle pointing anteriorly and medially.
The larger figure-of-eight coil (mean diameter 70 mm) was always
used to deliver the TS to the left M1. Three Magstim stimulators were
needed to provide the three different intensities of TS (Table 1 and
Table 2). The outputs of two Magstim 200 stimulators were directed
to a Bistim module. The output of this Bistim module and the output
of a third Magstim 200 stimulator were directed to a second Bistim
module, the output of which was directed to the larger figure-of-eight
coil. The smaller coil (mean diameter 60 mm) had a vertical handle
(“branding iron” type), was always used to deliver the CCS to the
right M1, and was connected to the fourth and fifth Magstim 200
stimulators (one for CCS10 and another for CCS50) working through
a third Bistim module. This “pyramid” arrangement allowed for the
delivery of pulses of different intensities at short intervals through the
same coil. This arrangement is associated with a power attenuation of
⬃15% (Sanger et al. 2001). The use of the smaller coil permitted
simultaneous placement of both coils over each subject’s head.
Experiment 1: interactions between SIHI and LIHI. Since IHI
decreases with increasing TS intensity and MEP amplitude (Daskalakis et al. 2002; Kukaswadia et al. 2005; Udupa et al. 2010) and MEP
amplitude and stimulus intensity cannot be matched in the same trial,
11 conditions were tested to allow for matching of the TS intensity
INTERHEMISPHERIC INHIBITORY INTERACTIONS
Table 2. Ratio calculations used in experiment 1
Effect
Calculation
SIHI in the presence of LIHI
SIHI alone matched for MEP amplitude
SIHI alone matched for TS intensity
LIHI in the presence of SIHI
LIHI alone matched for MEP amplitude
LIHI alone matched for TS intensity
Condition
Condition
Condition
Condition
Condition
Condition
10/5
3/1
6/4
11/9
2/1
8/7
SIHI, short-latency interhemispheric inhibition; LIHI, long-latency interhemispheric inhibition.
operate through different intracortical circuits, we examined the SIHILIHI interactions at different intensities of SIHI by comparing SIHI
alone (matched for TS intensity) with SIHI in the presence of LIHI
using CCS10 at intensities of 0.9, 1.0, 1.1, 1.2, 1.3, and 1.4 times the
resting motor threshold (RMT). RMT was defined as the minimum
stimulator output that induced MEPs of ⬎200 ␮V in at least 5 of 10
consecutive trials with the muscle relaxed. Owing to the longer
duration of the experiment, similar to experiment 3, fewer conditions
were tested at varying CCS intensities (4, 5, 6, and 10; Table 1).
Conditions 1–3 were performed at CCS10 intensities of 0.9 and 1
RMT only. The experimental conditions were otherwise similar to
those in experiment 1. TS intensity was set to 1 mV.
Data and statistical analysis. MEP amplitudes were measured peak
to peak off-line with Signal software (Cambridge Electronic Design).
The MEP amplitude evoked by CCS and TS was expressed as a ratio
of the mean MEP amplitude evoked by TS alone. Ratios below 1
indicate inhibition, and ratios above 1 indicate facilitation. Unless
otherwise stated, values are reported as means ⫾ SE. Repeatedmeasures analysis of variance (ANOVA) was used for statistical
analysis with StatView 5.01 software (SAS Institute, Cary, NC). Post
hoc tests were used when the ANOVA showed significant main
effects. The significance level was set at P ⬍ 0.05. Regression
analysis was used to test the effects of increasing CCS10 intensity on
SIHI alone and SIHI in the presence of LIHI. Two-way repeatedmeasures ANOVA was used to evaluate interactions between coil
orientation and SIHI with and without LIHI and between SIHI
intensity and SIHI with and without LIHI.
RESULTS
There were no adverse effects following TMS.
Experiment 1: interactions between SIHI and LIHI. Data
from one subject showed that very small MEPs were evoked in
the left FDI muscle by CCS10 in the presence of CCS50 in
conditions 10 and 11, which was missed during the TMS
session. Data from that subject were not analyzed further. Data
from the other nine subjects were analyzed.
Representative recordings from one subject are shown in
Fig. 1. The figure shows averaged MEP traces recorded from
the right FDI muscle after a single stimulus (condition 1 in Fig.
1A), paired stimuli (conditions 2, 3, 5, and 9 in Fig. 1, B–E,
respectively), and triple stimuli (conditions 10 and 11 in Fig. 1,
F and G, respectively; Table 1). In condition 1, the TS was set
to evoke an average MEP of ⬃1 mV in the right FDI muscle
(Fig. 1A). In conditions 2 and 3, CCS were applied 50 ms
(CCS50) or 10 ms (CCS10) preceding the TS, respectively,
resulting in a reduction in the size of the MEP produced by the
TS in Fig. 1, B (LIHI) and C (SIHI). In condition 5, the TS
(1mVTSCCS50) was set to evoke an average MEP of ⬃1 mV
Table 3. Data from individual subjects in experiment 1
Subject
TS MEP, mV
CCS50 Intensity,
%RMT
CCS50 MEP
Amplitude, mV
CCS10 Intensity,
%RMT
CCS10 MEP
Amplitude, mV
Baseline SIHI
(condition 3/1)
Baseline LIHI
(condition 2/1)
Baseline SIHI⫹LIHI
(condition 12/1)
B
C
F
G
H
I
K
L
M
1.29
0.82
1.27
1.12
1.21
0.72
0.93
1.88
1.96
1.3
1.2
1.1
1.2
1.2
1.1
1.5
1.3
1.2
5.28
0.89
0.74
1.98
1.50
1.89
0.97
4.30
1.77
1.3
1.2
1.3
1.2
1.4
1.1
1.5
1.2
1.2
7.70
1.69
2.25
2.20
5.26
1.26
0.83
2.82
0.70
0.34
0.58
0.43
0.37
0.36
0.68
0.49
0.39
0.13
0.76
0.81
0.53
0.86
0.43
0.60
0.65
0.09
0.28
0.36
0.46
0.07
0.10
TS-evoked mean MEP amplitudes, CCS intensities, CCS-evoked mean MEP amplitudes (in contralateral first dorsal interosseous muscle), and level of baseline
SIHI and LIHI are shown. RMT, resting motor threshold.
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11) to that evoked by paired-pulse TMS (1mVCCS10, TS1mVCCS10,
condition 9). Thus the ratios of the MEPs recorded from conditions 2/1
and 3/1 gave LIHI and SIHI alone matched for MEP amplitude and
the ratios of conditions 6/4 and 8/7 gave LIHI and SIHI alone matched
for TS intensity. The MEP ratios of conditions 10/5 and 11/9 gave
SIHI in the presence of LIHI and LIHI in the presence of SIHI,
respectively.
Experiment 2: effects of lower TS MEP amplitude on interactions
between SIHI and LIHI. Previous studies showed that IHI decreases at
higher test MEP amplitudes (Daskalakis et al. 2002; Kukaswadia et al.
2005; Udupa et al. 2010). We therefore tested the interactions between
SIHI and LIHI at a lower test MEP amplitude in a subset of five
subjects. TS was set at the minimum intensity required to produce a
peak-to-peak MEP amplitude of 0.5 mV in 5 of 10 trials in the relaxed
right FDI muscle (TS0.5mV). TS intensity was also adjusted to
produce TS0.5mVCCS10 (MEPs of ⬎0.5 mV in at least 5 of 10
consecutive trials when CCS10 was applied with TS) or
TS0.5mVCCS50 (MEPs of ⬎0.5 mV in at least 5 of 10 consecutive
trials when CCS50 was applied with TS). The experimental conditions
were otherwise the same as in experiment 1 (Table 1).
Experiment 3: effects of changing coil orientation of TS on interactions between SIHI and LIHI. The population of cortical neurons
activated by TMS is dependent on the direction of induced current,
and anteriorly and posteriorly directed currents preferentially activate
different cortical circuits (Di Lazzaro et al. 2001; Sakai et al. 1997).
To investigate whether the interactions between SIHI and LIHI are
preferentially influenced by activation of different neural circuits in
the left (target) hemisphere, we tested the interactions between SIHI
and LIHI with the TS delivered with two coil orientations, producing
currents in either a PA or AP direction in the target hemisphere. Since
this was a longer experiment, fewer conditions were tested, focusing
on those that evaluate SIHI alone (matched for stimulus and amplitude) and SIHI in the presence of LIHI (1, 2, 3, 4, 5, 6, 10; Table 1).
The experimental conditions were otherwise similar to that in experiment 1. TS intensity was set to 1 mV.
Experiment 4: effects of changing SIHI intensity on interactions
between SIHI and LIHI. SIHI or LIHI increases with increasing CCS
intensity (Ni et al. 2009). To further evaluate whether SIHI and LIHI
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INTERHEMISPHERIC INHIBITORY INTERACTIONS
when preceded by CCS50 (Fig. 1D); addition of a third
stimulus (CCS10) in condition 10 resulted in further reduction
in the MEP amplitude evoked by 1mVTSCCS50 (SIHI in the
presence of LIHI; Fig. 1F). Similarly, in condition 9 the TS
(1mVTSCCS10) was set to evoke an average MEP of ⬃1 mV
when preceded by CCS10 (Fig. 1E); addition of a third stimulus (CCS50) in condition 11 resulted in further reduction in
the MEP amplitude evoked by 1mVTSCCS10 (LIHI in the
presence of SIHI; Fig. 1G).
Across all subjects, the MEP amplitude (mean ⫾ SE) in the
right FDI muscle from TS alone (condition 1) was 1.24 ⫾ 0.18
mV. The mean MEP amplitudes for conditions 5 (1.42 ⫾ 0.19
mV) and 9 (1.41 ⫾ 0.21 mV) were well matched to condition
1. For the left FDI muscle, the MEP amplitude produced by
CCS10 alone delivered to the right hemisphere (conditions 3,
6, and 9) was 2.73 ⫾ 0.52 mV. In the presence of CCS50, the
MEP amplitude induced by CCS10 (in conditions 10 and 11)
was 2.75 ⫾ 0.77 mV. The MEP amplitude in the left FDI
muscle evoked by CCS50 was 2.15 ⫾ 0.53 mV. Table 3 shows
data from individual subjects, including the TS-evoked MEPs,
CCS intensities, CCS-evoked MEPs, SIHI and LIHI (matched
for MEP amplitude), as well as SIHI ⫹ LIHI (matched for
stimulus amplitude without either SIHI or LIHI).
The group results are illustrated in Fig. 2. This figure
compares the effect of delivering SIHI or LIHI alone with that
of SIHI and LIHI together on the MEP evoked by the TS
Fig. 2. Ratios of MEPs (means ⫾ SE) calculated from the data in experiment
1 comparing SIHI and LIHI alone (conditioned MEP/unconditioned MEP)
with SIHI and LIHI induced together. In experiment 1, TS alone evoked an
MEP of ⬃1 mV in the right FDI muscle. Ratios ⬍ 1 indicate inhibition, and
ratios ⬎ 1 indicate facilitation.
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Fig. 1. Averaged (10 trials) motor evoked potentials (MEPs) recorded from the
right first dorsal interosseous (FDI) muscle in 1 participant after test stimulus (TS)
alone (A: condition 1), paired-pulse stimuli [B: contralateral conditioning stimulus
(CCS) delivered 50 ms before TS (CCS50) ⫹ TS, condition 2; C: CCS delivered
10 ms before TS (CCS10) ⫹ TS, condition 3; D: CCS50 ⫹ TS intensity adjusted
to produce 1-mV MEPs in presence of CCS50 (1mVCCS50), condition 5;
E: CCS10 ⫹ TS intensity adjusted to produce 1-mV MEPs in presence of CCS10
(1mVCCS10), condition 9], and triple-pulse stimuli (F: condition 10, G: condition
11). Horizontal (20 ms) and vertical (0.5 mV) calibrations apply to all traces.
(conditioned MEP/unconditioned MEP; Table 2). Since IHI
decreases with increasing TS intensity and MEP amplitude, TS
intensities and MEP amplitudes were matched for this comparison (in separate trials since they could not be matched in
the same trial). Fig. 2 compares SIHI alone with SIHI in the
presence of LIHI. To match TS intensity of SIHI alone with
SIHI in the presence of LIHI, they were tested with the TS
intensity set to evoke a test MEP of ⬃1 mV in the presence of
LIHI (1mVCCS50). To match MEP amplitude of SIHI alone
with SIHI in the presence of LIHI, SIHI alone was tested with
TS intensity set to evoke an MEP of ⬃1 mV (unconditioned
MEP). The bottom three histograms in Fig. 2 compare LIHI
alone with LIHI in the presence of SIHI, and similar comparisons were made. Repeated-measures ANOVA showed no
significant difference in SIHI between the SIHI-alone conditions and SIHI in the presence of LIHI (P ⫽ 0.76). Similarly,
there was no significant difference between the LIHI-alone
conditions and LIHI in the presence of SIHI (P ⫽ 0.82).
Experiment 2: effects of lower TS MEP amplitude on interactions between SIHI and LIHI. For a subset of five subjects,
data were obtained with the TS MEP of 0.5 mV. The MEP
amplitude in the right FDI muscle from TS alone was 0.65 ⫾
0.04 mV. The MEP amplitude in the left FDI muscle from
CCS50 was 3.25 ⫾ 0.64 mV and from CCS10 was 3.09 ⫾ 0.95
mV (conditions 10 and 11) and 3.13 ⫾ 0.69 mV (conditions 3,
6, and 9). The group results are shown in Fig. 3. This figure
compares the effect of SIHI or LIHI alone with that of SIHI
and LIHI together (conditioned MEP/unconditioned MEP; Table 2) when the TS was set to evoke an unconditioned MEP of
⬃0.5 mV. Repeated-measures ANOVA showed no significant
difference between the SIHI-alone conditions and SIHI in the
presence of LIHI (P ⫽ 0.30) or between the LIHI-alone
conditions and LIHI in the presence of SIHI (P ⫽ 0.86).
Experiment 3: effects of changing TS coil orientation on
interactions between SIHI and LIHI. In eight subjects, data
were compared with the TS coil oriented to induce current in
either the PA or the AP direction in the left (target) hemisphere. TS was adjusted to produce an MEP of 1 mV. The
INTERHEMISPHERIC INHIBITORY INTERACTIONS
2959
MEP amplitude in the right FDI muscle from TS alone was
0.96 ⫾ 0.17 mV in the PA direction and 0.69 ⫾ 0.15 mV in the
AP direction. The group results are shown in Fig. 4. Repeatedmeasures ANOVA showed no significant difference between
the SIHI-alone conditions and SIHI in the presence of LIHI in
either the PA TS current direction (P ⫽ 0.43) or the AP
direction (P ⫽ 0.71). Similarly, a two-way repeated-measures
ANOVA did not show any interaction between coil orientation
and SIHI in the presence of LIHI (P ⫽ 0.53; Table 4).
Experiment 4: effects of changing CCS10 intensity on interactions between SIHI and LIHI. In eight subjects, SIHI alone
(matched for TS intensity) was compared with SIHI in the
presence of LIHI at different CCS10 intensities (0.9, 1.0, 1.1,
1.2, 1.3, and 1.4 times RMT). TS were adjusted to produce
MEPs of 1 mV. Across all subjects, the MEP amplitude (mean ⫾
SE) in the right FDI muscle from TS alone (condition 1) was
1.29 ⫾ 0.25 mV. The group results are plotted in Fig. 5. The
MEP ratios (⫾SE) indicate the amount of SIHI (the smaller the
value, the greater the inhibition) calculated at different CCS10
intensities. SIHI was found to increase with increasing CCS
intensities, whether it was alone (R2 ⫽ 0.926, P ⫽ 0.002) or in
the presence of LIHI (R2 ⫽ 0.854, P ⫽ 0.008). Furthermore,
repeated-measures ANOVA did not show a significant difference between SIHI alone and SIHI in the presence of LIHI
(P ⫽ 0.65). Similarly, a two-way repeated-measures ANOVA
did not show any interaction between SIHI intensity and the
effect of LIHI on SIHI (P ⫽ 0.99; Table 5). Thus varying
CCS10 intensities did not change the interactions between
SIHI and LIHI.
DISCUSSION
Interactions between different excitatory and inhibitory processes can be studied by comparing the effects of applying
different conditioning stimuli individually and then together
(Daskalakis et al. 2002; Lee et al. 2007; Muller-Dahlhaus et al.
2008; Ni et al. 2011; Sanger et al. 2001; Udupa et al. 2010).
The possible outcomes from applying two inhibitory systems
together are addition (the inhibitory effects are additive), potenti-
Fig. 4. Ratios of MEPs (means ⫾ SE) calculated from the data in experiment
3 comparing SIHI alone (conditioned MEP/unconditioned MEP) with SIHI
and LIHI induced together (SIHI in the presence of LIHI). The TS coil was
oriented to induce current in either the anterior-to-posterior (AP) direction (A)
or the posterior-to-anterior (PA) direction (B). Ratios ⬍ 1 indicate inhibition,
and ratios ⬎ 1 indicate facilitation.
ation (inhibition greater than additive effects), or inhibitory interaction (inhibition less than additive effects). The results of the
present study suggest that SIHI remains the same in the presence
of LIHI and vice versa, and that their effects are additive when
induced together (experiment 1). Changes in TS intensity
did not influence the interactions between SIHI and LIHI
(experiment 2), both of which are reduced when TS intensity
is increased (Daskalakis et al. 2002; Kukaswadia et al. 2005;
Udupa et al. 2010).
Interactions between SIHI and LIHI may take place in the
originating hemisphere of the transcallosal projections (the
right hemisphere in this study) or in the target hemisphere
(the left hemisphere in this study). A previous study suggested that SIHI and LIHI are mediated by separate populations of neurons in the originating hemisphere (Ni et al.
2009). The population of cortical neurons activated by TMS
Table 4. Experiment 3: 2-way repeated-measures ANOVA with
factors SIHI ⫾ LIHI and coil orientation
SIHI ⫾ LIHI
Coil orientation
SIHI ⫾ LIHI ⫻ coil orientation
J Neurophysiol • doi:10.1152/jn.00960.2012 • www.jn.org
df
F
P
2
1
2
0.62
0.08
0.64
0.5415
0.7806
0.5299
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Fig. 3. Ratios of MEPs (means ⫾ SE) calculated from the data in experiment
2 comparing SIHI and LIHI alone (conditioned MEP/unconditioned MEP)
with SIHI and LIHI induced together. In experiment 2, the TS alone evoked an
MEP of ⬃0.5 mV in the right FDI muscle. Ratios ⬍ 1 indicate inhibition, and
ratios ⬎ 1 indicate facilitation.
2960
INTERHEMISPHERIC INHIBITORY INTERACTIONS
depends on the direction of induced current (Di Lazzaro et al.
2001; Sakai et al. 1997; Werhahn et al. 1994). PA- and
AP-directed currents are thought to activate different cortical
circuits. PA stimulation preferentially recruits I1 corticospinal
descending volleys, whereas AP stimulation recruits I3 volleys
(Di Lazzaro et al. 2001; Sakai et al. 1997). Ni et al. (2009)
previously showed that changes in the conditioning coil orientation had no effect on SIHI and LIHI. SIHI preferentially
reduces the I3 descending volley (Di Lazzaro et al. 1999). In
experiment 3 of this study we tested whether the interaction
between SIHI and LIHI varied depending on the circuits
activated by the TS. We found no difference between SIHI and
SIHI/LIHI interaction with TS coil orientations inducing either
AP or PA currents in the target hemisphere. Thus the interaction between SIHI and LIHI remained additive and was not
influenced by the direction of the TS current, thereby activating
different intracortical circuits in the target hemisphere. This
finding is consistent with suggestions that SIHI and LIHI act
through different intracortical circuits in the target hemisphere.
Both SIHI and LIHI are increased by increasing CSS intensities (Ni et al. 2009). Theoretically, SIHI and LIHI may
operate through the same intracortical circuits and still have
additive effects when induced together. One way to investigate
this further would be to use higher intensities of SIHI to
“saturate” the SIHI intracortical circuits and determine whether
SIHI in the presence of LIHI was still additive. This was tested
in the present study by comparing SIHI alone (matched for
TS intensity) with SIHI in the presence of LIHI at different
intensities of CCS (for SIHI). Increased CCS in this way
increased SIHI alone as well as SIHI in the presence of LIHI
equally, suggesting that SIHI and LIHI are not only additive
but mediated by distinct neural circuits. This corroborates
previous studies, showing that target muscle activation reduces
SIHI but has no effect on LIHI (Chen et al. 2003), and LIHI
Table 5. Experiment 4: 2-way repeated-measures ANOVA with
factors SIHI ⫾ LIHI and SIHI intensity
SIHI ⫾ LIHI
SIHI intensity
SIHI ⫾ LIHI ⫻ SIHI intensity
J Neurophysiol • doi:10.1152/jn.00960.2012 • www.jn.org
df
F
P
1
5
5
0.58
5.26
0.10
0.4486
0.0003
0.9927
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Fig. 5. Ratios of MEPs (means ⫹ SE) calculated from the data in experiment
4 plotting SIHI and LIHI alone (conditioned MEP/unconditioned MEP) and
SIHI and LIHI induced together (SIHI in the presence of LIHI) at different
CCS10 intensities [as multiples of resting motor threshold (RMT)]. Ratios ⬍
1 indicate inhibition, and ratios ⬎ 1 indicate facilitation.
can be obtained from stimulating wider cortical areas of the
opposite hemisphere and with lower stimulus intensities than
SIHI (Ni et al. 2009).
We set our experimental parameters to ensure that we
evoked high intensities of SIHI and LIHI, so that interactions
(for example, inhibition of SIHI by LIHI) could be easily
detected. However, it is possible that small interactions were not
detected in the study. Post hoc power calculations showed that,
assuming a statistical significance level of 0.05 and standard
deviation of SIHI and LIHI of 0.17– 0.37 (calculated from the
study), a difference of 0.35 in the mean ratios would be detected
as significant with a power of 0.8, whereas the differences in the
mean ratios were ⬃0.1 in the different experiments of our
study. This is also reflected in the large P values obtained in the
different experiments.
The cortical neurons mediating the different inhibitory processes investigated by TMS have not been identified. There is
increasing evidence that these processes, including SICI, LICI,
SIHI, and LIHI, appear to operate through different neural
circuits (Daskalakis et al. 2002; Lee et al. 2007; MullerDahlhaus et al. 2008; Sanger et al. 2001; Udupa et al. 2010).
Many of these inhibitory processes interact with one another,
suggesting that some of these processes involve common
circuit elements. Most of the inhibitory processes studied have
inhibitory interactions (Daskalakis et al. 2002; Lee et al. 2007;
Müller-Dahlhaus et al. 2008; Sailer et al. 2002; Sanger et al.
2001; Udupa et al. 2010). However, such inhibitory interactions are not universal, as shown in this study and in previous
studies (Sailer et al. 2002; Udupa et al. 2010). Some of the
short-latency cortical inhibitory processes appear to work
through GABAA receptor-mediated mechanisms (e.g., SICI)
and the longer-latency processes through GABAB receptormediated mechanisms (e.g., LIHI and LICI), but the mechanisms associated with SIHI remain unclear (Irlbacher et al.
2007; Müller-Dahlhaus et al. 2008; Ziemann et al. 1996). Since
GABAB receptors are known to inhibit GABAA mechanisms
through presynaptic inhibition, our findings further suggest that
SIHI is not directly related to GABAA-mediated inhibition.
Interactions between SIHI and LIHI may occur in either the
conditioning or the target hemisphere. Notably, one such interaction in the conditioning hemisphere is the effect of CCS50
on CCS10 through processes that may overlap with LICI and
ICF, which can be monitored by measuring CCS10-evoked
MEPs in the contralateral muscles. Although these interactions
were observed in some subjects, the mean MEP amplitude
evoked by CCS10 alone (2.73 mV) was similar to that evoked
by CCS10 in the presence of CCS50 (2.75 mV), suggesting
that these interactions did not affect our overall results. We
cannot, however, exclude the possibility that LIHI and SIHI
interact with each other in both the conditioning and test
INTERHEMISPHERIC INHIBITORY INTERACTIONS
ACKNOWLEDGMENTS
We thank the participants for volunteering their time to partake in the study.
Present address of A. R. Mehta: Nuffield Dept. of Clinical Neurosciences
(Div. of Clinical Neurology), University of Oxford, Oxford, UK.
GRANTS
The study was supported by the Canadian Institutes of Health Research
(MOP 62917). A. R. Mehta was supported by Parkinson’s UK and Gonville
and Caius College, Cambridge, UK.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
AUTHOR CONTRIBUTIONS
Author contributions: S.G., A.R.M., G.H., C.G., T.H., U.S., Z.N., and R.C.
conception and design of research; S.G., A.R.M., G.H., C.G., T.H., U.S., Z.N.,
and R.C. performed experiments; S.G., A.R.M., G.H., C.G., T.H., U.S., Z.N.,
and R.C. analyzed data; S.G., A.R.M., G.H., C.G., T.H., U.S., Z.N., and R.C.
interpreted results of experiments; S.G., A.R.M., G.H., C.G., T.H., U.S., Z.N.,
and R.C. prepared figures; S.G., A.R.M., G.H., C.G., T.H., U.S., Z.N., and
R.C. drafted manuscript; S.G., A.R.M., G.H., C.G., T.H., U.S., Z.N., and R.C.
edited and revised manuscript; S.G., A.R.M., G.H., C.G., T.H., U.S., Z.N., and
R.C. approved final version of manuscript.
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