Reduced cortical activity during maximal bilateral contractions of the index finger

Chapter 6

Reduced Cortical Activity during Maximal Bilateral

Contractions of the Index Finger

Marijn Post, Hiske van Duinen, Anneke Steens, Remco Renken, Bart

Kuipers, Natasha Maurits and Inge Zijdewind

Published in: NeuroImage (2007): 35, 16-27

Reduced Cortical Activity during Maximal Bilateral Contractions

113

Abstract

The bilateral deficit refers to the phenomenon in which homologous muscles produce

per muscle less force when contracting simultaneously than when contracting

individually. The mechanism underlying the bilateral deficit is still unknown but the

most likely cause is a decline in the activation of motor units during bilateral

contractions. In the present study we used functional magnetic resonance imaging

(fMRI) to measure the degree of brain activity during unilateral and bilateral maximal

contractions in combination with force and EMG measurements. Subjects performed,

in a semi-randomized order, maximal isometric contractions (MVC) with the right

index finger, the left index finger and with both fingers simultaneously. During the

task, brain activation was measured with a 3 Tesla MRI scanner, in combination with

force and EMG-recordings. The most important activated areas in the brain during

the contractions were the sensorimotor cortex (precentral and postcentral gyrus),

cerebellum, premotor cortex and supplementary motor area. During bilateral

contractions, a significant decline in force and EMG values was found and detailed

analysis of the brain activation data showed that this decline was accompanied with a

significant decline in the activation of the precentral gyrus. This result suggests that

the bilateral decline is the resultant of a decline in input to the primary motor area and

shows that the main source of the bilateral deficit lies upstream of the primary motor

cortex.

Acknowledgements

The authors like to thank Koen Vaartjes for his technical support, and Anita Kuiper for

operating the MRI scanner. Part of this work was supported in the framework of the

NWO Cognition Program with financial aid from the Netherlands Organization for

Scientific Research (NWO).

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Introduction

Several studies have shown that the force production per muscle during a bilateral

contraction of homologous muscles is less than the sum of forces obtained during

unilateral contractions (Henry and Smith, 1961; Kroll, 1965; Ohtsuki, 1981; Schantz

et al., 1989; Vandervoort et al., 1984). This phenomenon is called the bilateral deficit.

This bilateral deficit has been shown in a variety of tasks, for example knee extension

(Howard and Enoka, 1991; Schantz et al., 1989), ankle plantar flexion (Kawakami et

al., 1998), elbow flexion (Howard and Enoka, 1991; Oda and Moritani, 1994), wrist

flexion (Kroll, 1965), finger flexion (Ohtsuki, 1981; Van Dieen et al., 2003), thumb

abduction (Herbert and Gandevia, 1996), and index finger abduction (Zijdewind and

Kernell, 2001). The size of the bilateral deficit depends on factors such as training

(Howard and Enoka, 1991; Kuruganti et al., 2005; Taniguchi, 1998) and limb

dominance (Kroll, 1965; Ohtsuki, 1981) but not on age or gender (Hakkinen et al.,

1997; Hernandez et al., 2003; Kuruganti et al., 2005). Furthermore, the bilateral

deficit seems to be more pronounced in movements of the upper body (Jakobi and

Chilibeck, 2001). Importantly, no deficit is present when non-homologous muscles,

such as a left elbow flexor and right knee extensor, are activated simultaneously

(Howard and Enoka, 1991).

The neurophysiological mechanisms underlying bilateral deficits have been

studied with several techniques such as: electromyography (EMG), twitch

interpolation, transcranial magnetic stimulation (TMS) and electroencephalography

(EEG). We will discuss the data obtained by these various methods below.

Surface EMG is affected by factors such as the number of active motor units

and their firing frequencies. Therefore, if a bilateral deficit is caused by differences in

the activation of the motor units a decline in force is expected to be accompanied by

parallel changes in EMG. Several studies indeed demonstrated a deficit in EMG that

was related to the changes in force (Koh et al., 1993; Oda and Moritani, 1995; Van

Dieen et al., 2003; Vandervoort et al., 1984). Other authors, however, did not find

changes in EMG during bilateral contractions (Howard and Enoka, 1991; Schantz et

al., 1989) or found a large deficit in EMG that was accompanied by a small non-

significant force deficit (Jakobi and Cafarelli, 1998). The discrepancies between the

studies are probably caused by differences in the muscle (-groups) used,

experimental set-up or tasks. No consistent conclusion about the mechanisms

underlying the bilateral deficit can be drawn from these EMG studies.


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A few studies used electrical stimulation of the muscle or nerve (twitch

interpolation technique; (Jakobi and Cafarelli, 1998; Van Dieen et al., 2003) or

transcranial magnetic stimulation of the cortex (Herbert and Gandevia, 1996) to

examine the efficiency of the neural drive to the motoneuron pool during unilateral

and bilateral contractions. With these techniques a stimulus is delivered to the

muscle, nerve or cortex during a maximal contraction. When the stimulation evokes a

force increase, it is assumed that the activation of the muscle was suboptimal.

Although all studies found evidence for suboptimal neural drive in both the unilateral

and bilateral contractions, only one study found statistical evidence for a reduction in

voluntary muscle activation in bilateral contractions (Van Dieen et al., 2003). The

other two studies (Herbert and Gandevia, 1996; Jakobi and Cafarelli, 1998) just

found marginal differences.

Two studies have used EEG to examine the bilateral deficit. Oda and Moritani

(1995) studied movement-related potentials of the brain. In their study the deficit in

force and EMG during the bilateral contractions was associated with reductions in the

movement-related potential. Another EEG study, in which the bilateral reaction time

deficit - a phenomenon which is possibly related to the bilateral force deficit - was

investigated, found weaker motor cortical activity during bilateral contractions

(Taniguchi et al., 2001). Thus, these studies suggest that bilateral contractions are

accompanied by a decline in cortical excitability.

The results obtained with various techniques do not give an indisputable

explanation for the bilateral deficit. Several researchers (e.g. Van Dieen et al., 2003,

Oda and Moritani 1995, Taniguchi et al, 2001) suggest a decline in cortical

excitability while others - who do not find a bilateral deficit (e.g. Herbert and

Gandevia, 1996; Jakobi and Cafarelli, 1998) - suggest that the deficit might be

observed only in subjects who are unable to maintain their exact posture or who

activate antagonists during bilateral contractions. It is the aim of this study to

investigate the phenomenon of the bilateral deficit at various levels of motor control

simultaneously. We used functional Magnetic Resonance Imaging (fMRI) to measure

the activity in the brain during unilateral and bilateral abduction contractions of the

index finger in combination with EMG and force measurements.

Part of the data has been published as an abstract (Post et al., 2005).

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Methods

Subjects

We studied 22 healthy subjects, 10 men and 12 females (mean age 26.7 ± 6.1

years). All subjects gave their written informed consent prior to participation in this

study. Subjects were right-handed as confirmed by the Edinburgh Handedness

Inventory (Oldfield, 1971) and were free of neurological disorders. Before the start of

the experiment all subjects were included in a training session in which they were

instructed about the protocol and had to perform all contractions.

The local ethical committee of the University Hospital Groningen approved the

research procedures.

Force recording

Two custom-made MRI compatible force transducers measured the abduction force

of the index finger. Magnetic-compensated strain gauges (TML® MFLA-5.350-1L;

Tokyo Sokki Kenkyujo Co., Japan) were placed in a full bridge configuration on an

epoxy glass laminate bar (Tufnol® 10G/40 20mm diameter; RS-components number:

771-314) and registered the force. The index finger was placed parallel to the bar on

the force transducer and the proximal interphalangeal joint of the index finger was

taped to a wedge that was connected to the force transducer (see Fig. 1 for a

schematic illustration of the hand position). The ring and middle finger were taped to

the thumb to prevent changes in the hand position in relation to the force transducer.

Both force transducers (left and right hand) were connected with a silver-coated

cable to a shielded custom-made amplifier. The amplifiers were powered by lead

batteries (12V; 1.9A). The amplified signal (1000x) was sent via an optical cable to a

receiver in the operator room. The receiver was connected to a data-acquisition

interface and a laptop equipped with accompanying software (1401 micro and Spike

2 version 5.08, Cambridge Electronic Design, Cambridge, UK). The force recordings

were sampled at 500 Hz.

EMG recording

Surface electromyography (EMG) of the first dorsal interosseous (FDI) of both hands

was recorded using the BrainAmp MR plus system (Brain Products GmbH, Munich,

Germany). A detailed description of the EMG setup is given in Van Duinen et al.

(2005).


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Figure 1. A) A schematic illustration of the hand position in relation to the force transducers. B)

Typical example of the force, the EMG after artefact correction (van Duinen et al., 2005) and the

rectified and smoothed EMG (100ms; rsEMG) recordings during fMRI. The lowest trace shows the

trigger pulse at the start of the scanning period (5 s). A scanning period consists of 3-s scanning and

2-s non-scanning interval (sparse-sampling). Note the small residues of the scanner noise after the

artefact correction.

The skin lying over the FDI was scrubbed and cleaned with alcohol. One EMG

electrode was placed on the belly of the FDI and a second electrode on the

metacarpophalangeal joint of the index finger. A reference electrode was positioned

on the right processus styloideus radius, and a ground electrode on the left

processus styloideus radius. All electrodes were attached to an electrode input box

connected to an analog to digital converter (BrainAmp MR plus, Brain Products

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118

GmbH, Munich, Germany). An optical cable transferred the signal to a PC outside the

MR room. The PC was equipped with Brain Vision Recorder (sampling rate: 5000

Hz/channel). The MRI scanner sent a trigger to the PC at the start of every scan.

Brain Vision Analyser (version 1.05.0001) was used to pre-process the data. During

pre-processing, the raw signal was corrected for the artefact of the MRI scans. First,

the two monopolar EMG signals were subtracted (bipolar signal). Next, the signal

was filtered with a high pass filter of 10 Hz. Subsequently, a template of the mean

MRI artefact was determined and subtracted from the signal (see van Duinen et al.,

2005). After pre-processing, the data was imported into Spike2 for Windows (version

5.08; Cambridge Electronic Design, Cambridge, UK).

Brain imaging

Functional-MRI was conducted using a 3 T MRI scanner (Philips medical systems,

Best, the Netherlands) equipped with echo planar imaging (EPI) capability and a

standard TR-head coil. We used a sparse-sampling protocol (3 s scanning followed

by 2 s non-scanning). This protocol was used to compare force and EMG recordings

during scanning and non-scanning intervals. Pulse sequence parameters were:

single shot EPI; 46 slices; slice thickness 3.5 mm; no gap; field of view 224 mm;

matrix scan 64; transverse slice orientation; repetition time (TR) = 5 s; echo time (TE)

= 35 ms; minimal temporal slice timing (2884 ms); flip angle 90°. A total of 108 scans

were gathered during the task (total time: 540 s). After the protocol a T1-weighted

anatomical image of the entire brain was obtained for each subject using the

following pulse sequence parameters: field of view 256 mm; matrix scan size 256 by

256; 160 slices; slice thickness 1 mm; transverse slice orientation; TE = 4.6 ms; TR =

25 ms; flip angle 30°.

Task

Each subject performed nine maximal voluntary isometric contractions (MVCs) of the

index finger in abduction direction. Three conditions were specified: abduction of the

right index finger (unilateral-right), abduction of the left index finger (unilateral-left)

and abduction of both index fingers simultaneously (bilateral). Every condition was

repeated three times in a pseudo-random order to control for order effects. Every

MVC lasted for 10 seconds followed by a 50-s rest period (total time: 540 s). The

subjects started the MVCs after an acoustic signal presented through a headphone.


119

Visual feedback of the produced force was projected by a beamer on a screen, which

was visible to the subjects via a mirror. During the task, subjects lay in a supine

position in the 3 Tesla MR–scanner with both arms extended and parallel to the

body.

Analysis of force and EMG data

The blood oxygen level dependent (BOLD) response in the brain is influenced by the

strength of the contraction (Dai et al., 2001; Dettmers et al., 1995; Thickbroom et al.,

1998) but probably also by the duration of the contraction. For that reason, we have

used a parameter for the EMG and force data that also includes the duration of the

contraction (area under the curve). The area under the curve was calculated for

every contraction for both the force data and the rectified EMG (rEMG; Fig. 1). In

addition, mean force and mean rEMG were determined during the plateau phase of

the contraction. The maximal force (MVC) was defined as the largest peak force of

the three contractions.

For all variables (area under the curve of force and rEMG, mean force and

mean rEMG, and MVC), a 2x2 [contraction (Unilateral, Bilateral) x hand (Right, Left)]

repeated-measures analysis of variance was used to test for differences. Level of

significance was set to P<0.05. If a significant difference was found we estimated an

effect size; the partial eta squared (ηp²).

Data are presented as means ± standard deviation (SD) in the text, as means

± standard error (SE) in the figures. Statistical analyses were performed with SPSS

12.0 for windows.

Data preprocessing and analysis brain imaging

We used SPM99 (http://fil.ion.ucl.ac.uk/spm) implemented in MATLAB (MathWorks,

Natick, MA) to process and analyse the fMRI data. For each subject functional data

were realigned to the first image. The anatomical image was normalized to a T1

template, and the resulting transformation parameters were also applied to the

functional data. Prior to analysis, functional data were smoothed with a full-width-at-

half-maximum 8 mm Gaussian kernel.

Task specific effects were estimated using a general linear model (GLM) with

a delayed boxcar. No filtering was used. The analysis consisted of two levels; the first

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level was a subject based analysis while in the second level a group based analysis

was performed.

At the first level of analysis, activation maps were generated for each of the

three contractions by contrasting the activity during the contraction versus rest

(unilateral-left >rest, unilateral-right>rest, and bilateral >rest). For every contrast a

statistical map was calculated to determine significantly activated areas (Friston et

al., 1995).

A random effects analysis was used in the second level of the analysis. To

confirm activation, the contrast images obtained in every subject were used to

perform a one-sampled t-test. Significance was set at T≥7.65 (P<0.000005, without

correction for multiple comparisons) with a spatial extent of n=20 voxels. For the

comparisons between the unilateral and bilateral contractions a paired t-test was

performed. Significance was set at T≥4.02 which is equivalent to P<0.001 without

correction for multiple comparisons (n=5 voxels). MRIcro (www.mricro.com) was

used to examine which specific brain areas were active during the tasks.

In addition, we quantified the activity during the unilateral and bilateral

contractions in distinct motor areas. Therefore we performed a region of interest

(ROI) analysis. First, we defined functionally activated regions during unilateral and

bilateral contractions. Secondly, the activated brain areas were masked with an

anatomical region (Automated Anatomical Labeled; AAL (Tzourio-Mazoyer et al.,

2002). Using this method, we have defined functionally active regions within the

precentral gyrus, postcentral gyrus, cerebellum (lobule 4, 5 and 6) and

supplementary motor area (SMA).

Subsequently, using the functional activated regions, we have determined the

activity in areas active in both unilateral and bilateral contraction (unilateral-left ∩

bilateral and unilateral-right ∩ bilateral). We use the term ‘overlap ROI’ for this area.

However, if the voxels with the strongest activation are different for the unilateral and

the bilateral contractions then the intensity would be underestimated. Therefore, we

have also determined the activity in the total area; that is the sum of the voxels

activated during the unilateral plus the voxels that are activated during the bilateral

contraction (unilateral-left U bilateral and unilateral-right U bilateral; summation ROI).

MarsBaR (Brett et al., 2002) was used to build these regions of interest for every

subject, separately .


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In contrast with the other cortical regions in which the ROIs consisted of the

functional activated regions in contralateral hemisphere, the ROIs of the cerebellum

consisted of activated regions ipsilateral to the target muscles.

For the SMA, a region of interest was constructed for the left and right SMA

separately. Because the SMA is involved in both contralateral and ipsilateral

contractions the regions of interests were constructed from the activity during both

the unilateral contractions and the bilateral contraction (unilateral-left ∩ unilateral-

right ∩ bilateral; overlap ROI); a second region of interest was build from the

summation of these activated regions (unilateral-left U unilateral-right U bilateral;

summation-ROI).

Figure 2. BOLD (A), EMG (B) and force (C) measurements from simultaneous recordings in a

representative subject. Activation values (effect size in arbitrary units); A) obtained in the left

(interrupted line) and the right precentral gyrus (non-interrupted line) for each scan (5 s). B & C) Mean

values of rEMG (µV; B) and force (N; C) of the right (interrupted line) and left index finger (non-

interrupted line) for each scan (5 s). All graphs show data obtained during an abduction of the right

index finger (R), left index finger (L) or both index fingers (BI).

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The mean raw BOLD signal was extracted for all functional scans (see Fig. 2).

Subsequently, baseline activity was calculated for the scans made during rest and

subtracted from all values. Hereafter, a mean value was calculated for each contrast

(unilateral-right, unilateral-left, and bilateral) using the corresponding scans.

A 2x2 [contraction (Unilateral, Bilateral) x hemisphere (Left, Right)] repeated-

measures analysis of variance was used to detect differences between unilateral and

bilateral contractions for volumes of functional activated areas and the effect sizes in

the overlap and summation ROIs. For the SMA a 3x2 [contraction (Contralateral,

Ipsilateral, Bilateral) x hemisphere (Left, Right)] repeated-measures analysis of

variance was used. If the analysis of variance showed a significant effect, Bonferroni-

corrected post hoc tests were performed. In all statistical analyses, the level of

significance was set at P<0.05 and an effect size (ηp²) was estimated for significant

differences.

Results

Subjects

Nine subjects were excluded from further analysis because their head movements

strongly correlated with the task; one subject was excluded because this subject did

not execute the task as requested. In total, data from 12 subjects are presented in

here.

Table 1. The area (SD) under the curve for force, mean force, MVC, the area under the curve of the

rEMG, mean rEMG, and the percentage of bilateral/unilateral for unilateral and bilateral contractions

of the right and left index finger. Asterisk denotes significant difference between unilateral and

bilateral contraction (P<0.05).

Force and EMG

We used sparse sampling (3 s scanning and 2 s non-scanning) to evaluate the

effects of the MR-scanner on the force and EMG data. However, as can be seen in

figure 1 both the force and the corrected EMG data were scarcely influenced by the

Right Left

Unilateral Bilateral %Bi/Uni Unilateral Bilateral %Bi/Uni

Area force (Ns)* 236.3 (49.5) 230.3 (58.3) 97.1 (10.7) 339.2 (90.9) 323.2 (86.1) 95.5 (6.4)

Mean force (N)* 23.8 (5.6) 22.9 (5.7) 96.3 (8.4) 33.4 (9.0) 32.4 (8.6) 97.1 (6.01)

MVC (N) 26.8 (5.9) 26.4 (6.2) 98.2 (6.0) 45.3 (11.0) 44.2 (11.5) 97.4 (5.1)

Area rEMG (µVs)* 7233.4 (3152.4) 6518.5 (3290.8) 90.1 (14.7) 5892.9 (3097.6) 5818.0 (2818.0) 95.5 (11.7)

Mean rEMG (µV)* 716.4 (316.2) 651.5 (322.4) 89.9 (9.0) 567.8 (306.4) 547.9 (276.3) 97.4 (8.2)


123

scanner van (see also van Duinen et al., 2005). Therefore, no distinction was made

between the behavioural data collected during scanning and non-scanning intervals.

Statistical analysis of the area under the curve data obtained during unilateral

and bilateral contractions revealed significantly lower values for bilateral contractions

for both force (F(1,11)=5.114, P=0.045; ηp²=0.317) and rEMG data (F(1,11)=5.476,

P=0.039; ηp²=0.332; Table 1, Fig. 3). No interaction was found between contraction

and hand (force: F(1,11)=0.882, P=0.368; rEMG: F(1,11)=2.136, P=0.172). The

difference in area under the curve was not due to a difference in the duration of the

contraction (F(1,11)=0.305, P=0.592). This finding is supported by the significantly

lower values of the mean force (F(1,11)=4.836, P=0.05; ηp²=0.305) and mean rEMG

(F(1,11)=12.007, P=0.005; ηp²=0.522) during the bilateral contractions.

Figure 3. Areas under the

curve for force (Ns ± SEM;

A) and rectified EMG (mVs

± SEM; B) for the right and

left index finger during

unilateral ( □ ) and bilateral

( ■ ) contractions.

Furthermore, we determined the ratio between unilateral and bilateral

contractions for force and EMG data. We found significant correlations between the

ratio calculated for the force data and EMG data (right finger R2=0.744, P<0.001; left

finger R2=0.692 P<0.001; Fig. 4).

Figure 4. Scatterplot of the ratio

bilateral/unilateral (*100) for the areas under the

curve of force and rEMG during contractions of

the right (○) and left (▲) index finger. The

interrupted line represents the trend line (y =

0.5247x + 47.575; R2 = 0.6472).

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Brain imaging

Activation patterns

Similar brain activation patterns were found in unilateral and bilateral contractions. In

general, activated voxel clusters were found in motor, frontal (premotor), occipital,

parietal and cerebellar regions. Detailed presentation of the significantly activated

cortical regions during right, left and bilateral index finger contractions are shown in

figure 5. Activated brain areas and their stereotaxic coordinates, T-values and cluster

sizes are listed in table 2 and 3.

Unilateral versus Bilateral contractions

Cortical areas which showed significantly stronger activation during unilateral

contractions compared to bilateral contractions are listed in table 4 (see Fig. 6).

During unilateral contractions with the right index finger, the left precentral gyrus

showed more activity compared with the activity during bilateral contractions,

whereas no increase in activity in the right precentral gyrus was found during the

unilateral contractions with the left index finger. However, significantly stronger

activation was found - during unilateral contractions of the left index finger - in a voxel

cluster in the right superior frontal gyrus, partly located in the SMA. Furthermore, the

right ventral premotor area and the right superior frontal gyrus were more active in

both unilateral conditions. In comparison with the bilateral contraction the activation

during the unilateral contraction of the right index finger was stronger in the medial

cingulate gyrus, insula and calcarine fissure, whereas during the unilateral

contraction of the left index finger significant stronger activity was seen in lobule IX of

the cerebellum.


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Table 2 Activated brain areas

and their stereotaxic

coordinates, T-values and

cluster sizes for the right and

left unilateral contractions

(uncorrected T≥7.65,

k=20voxels).

Anatomical region (functional region) side X y z Cluster T

unilateral-right> rest

Postcentral gyrus (SMC) L -32 -34 64 1901 21.00

Supramarginal gyrus L -54 -32 36 14.10

Precentral gyrus (SMC) L -46 -16 56 12.22

Medial cingulate gyrus L -4 -10 48 11.64

Superior frontal gyrus (SMA) L -8 -4 58 8.09

Superior temporal lobe L -26 -52 62 7.96

Cerebellum lobule VI R 4 -64 -10 3957 20.10

Cerebellum lobule IV/V R 14 -48 -16 18.97

Cerebellum lobule VI L -4 -66 -16 18.94

Inferior orbicular frontal gyrus L -22 36 -6 80 10.27

Medial occipital gyrus R 44 -64 4 204 16.93

Inferior frontal gyrus pars opercularis (PMv) R 58 14 18 162 14.15

Supramarginal gyrus R 60 -34 32 170 13.65

R 42 -34 44 151 12.17

Superior frontal gyrus R 14 16 48 417 12.07

Medial cingulate gyrus L -8 8 36 11.48

Inferior frontal gyrus pars opercularis (PMv) L -46 12 24 24 11.38

Precentral gyrus (SMC) R 28 -14 54 41 11.34

Caudate nucleus R 16 -6 18 55 10.96

Putamen L -36 -4 -4 48 10.80

Cerebellum lobule IX R 8 -56 -46 20 9.92

Superior temporal gyrus L -58 -22 10 38 8.98

Precuneus R 12 -56 58 25 8.82

unilateral-left> rest


Supramarginal gyrus R 52 -26 32 16.98

Postcentral gyrus (SMC) R 46 -24 56 15.97

Cerebellum lobule VI L -22 -52 -28 427 13.27

Cerebellum vermis VI L -6 -64 -16 11.82

Cerebellum lobule IV/V L -12 -54 -18 11.08

Supramarginal gyrus L -56 -34 36 127 13.17

Medial cingulate gyrus R 6 0 46 205 11.02

Superior frontal gyrus (SMA) R 4 -10 50 9.95

Thalamus R 18 -22 -2 181 10.99

Superior frontal gyrus (SMA) R 6 -4 68 56 10.62

Inferior parietal gyrus L -48 -40 52 31 10.24

Insula R 46 2 0 127 10.23

Inferior precentral gyrus (PMv) L -56 4 6 54 10.20

Superior parietal gyrus R 20 -54 66 24 10.15

Putamen R 32 -12 -2 23 10.11


Table 3 Activated brain areas and

their stereotaxic coordinates, T-

values and cluster sizes for the

bilateral contraction (uncorrected

T≥7.65, k=20 voxels).

Anatomical region (functional region) side x y z Cluster T

bilateral>rest

Supramarginal gyrus L -50 -30 40 2385 24.53

Postcentral gyrus (SMC) L -40 -34 60 18.83

Superior frontal gyrus (SMA) L -16 -2 64 14.95

Precentral gyrus (SMC) L -40 -20 56 11.35

Postcentral gyrus (SMC) R 46 -24 52 1161 20.07

Precentral gyrus (SMC) R 40 -24 60 18.10

Superior frontal gyrus (SMA) R 12 -18 66 8.54

Cerebellum lobule IV-V L -22 -48 -26 5276 18.60

Thalamus L -6 -24 6 18.46

Cerebellum lobule IV-V R 6 -64 12 15.52

Thalamus R 2 -22 10 15.51

Cerebellum vermis IV L -4 -64 -16 14.92

Caudate nucleus R 12 -22 2 14.92

Putamen L -30 -16 10 13.37

Thalamus R 12 -4 14 11.91

Thalamus L -16 -10 -4 11.46

Globus pallidus R 14 6 2 10.99


Inferior triangular frontal gyrus R 40 40 2 59 12.84

Superior frontal gyrus (SMA) L -16 -2 64 86 14.94

Superior temporal gyrus L -52 30 18 106 12.62


Inferior precentral gyrus (PMv) R 52 6 0 129 11.60

Cerebellum vermis VIII R 4 -72 -38 87 10.13

Superior temporal gyrus L -62 -22 10 20 9.57

Inferior precentral gyrus (PMv) L -58 6 2 40 9.27

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Figure 6. Significantly activated areas for the contrasts unilateral right>bilateral (red) and unilateral

left>bilateral (yellow) overlaid on slices of a T1-weighted standard brain. Panel A shows the precentral

gyrus (red) and the SMA (yellow). The arrow in panel B shows the stronger activation of the right

ventral premotor area during the unilateral contraction with both the right (red) and left (yellow) index

finger. Peak activations with the corresponding T-values and their corresponding anatomical areas are

listed in table 4.

Table 4 Activated brain areas

and their stereotaxic

coordinates, T-values and

cluster sizes for the contrasts

unilateral-right>bilateral and

unilateral-left>bilateral

(uncorrected T≥4.05, k=5

voxels).

anatomical region side x Y z Cluster T

unilateral-right>bilateral

Medial frontal gyrus R 40 8 38 31 7.26


Medial cingulate gyrus R 2 6 44 17 5.89

Precentral gyrus L -32 -14 60 50 5.50


Insular cortex L -26 18 -16 9 5.37



Calcarine fissure L -6 -74 14 9 4.39

unilateral-left>bilateral

Medial superior frontal gyrus R 8 56 6 19 6.91


Superior frontal gyrus (SMA) R 16 -10 62 41 5.28

Anterior superior frontal gyrus R 22 62 12 7 5.15

Cerebellum lobule IX L -12 -54 -38 5 5.03


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Bilateral versus Unilateral contractions

Cortical areas which were significantly more activated during bilateral contractions

compared to unilateral contractions with their stereotaxic coordinates, T-values and

cluster sizes are listed in table 5. In the comparison bilateral>unilateral we have

focused on activity in the contralateral areas, and for cerebellum on the ipsilateral

areas. Significantly stronger activation was found in the right thalamus and left

cerebellum during the bilateral versus the left unilateral contraction.

Table 5 Activated brain areas and their

stereotaxic coordinates, T-values and

cluster sizes for the contrasts

bilateral>unilateral-right and

bilateral>unilateral-left (uncorrected

T≥4.05, k=5 voxels).

* Activity in the ipsilateral hemisphere and the contralateral hemisphere for the cerebellum is most likely due to the activation of the ‘contralateral hand’ in the bimanual task.

ROI analysis

A more quantitative examination of the cortical activity was performed using region of

interest (ROI) analyses (see Fig. 7, 8 and 9). Since the results for the data in the

overlap ROI and the summation ROI appeared to be very similar, we will only present

data of the summation ROI.

Precentral gyrus. The volume of the activated region in the precentral gyrus was not

different in the unilateral and bilateral contractions (F(1,11) =1.506; P=0.245; Fig. 7).

Yet, the intensity of the activated regions in the precentral gyrus was significantly

stronger during unilateral contractions (F(1,11)=6.283, P=0.029; ηp²=0.364; Fig. 8).

Additionally, we found that the volumes of the activated regions were larger in

the right precentral gyrus than the regions in the left precentral gyrus (F(1,11) =6.559,

P=0.026; ηp²=0.374; Fig. 7). Also, the intensity in the right precentral gyrus was

anatomical region side x Y z Cluster T

bilateral>unilateral-right

Superior frontal gyrus (SMA) R* 10 -18 52 316 17.54

Postcentral gyrus R* 28 -26 66 1776 17.47

Precentral gyrus R* 40 -24 58

Cerebellum lobule VI L* -4 -62 -20 1085 15.05

Thalamus R* 16 -20 4 569 7.69

Inferior frontal gyrus R* 28 10 30 19 7.39

Putamen R* 34 -2 -2 14 5.04

Caudate nucleus R* 18 18 16 5 4.37

bilateral>unilateral-left

Postcentral gyrus L* -36 -26 48 1464 14.81

Cerebellum lobule IV/V R* 18 -50 -24 677 12.00

Superior frontal gyrus (SMA) L* -10 -16 50 110 8.49

Cingulate gyrus L* -12 -10 44 5.52

Cerebellum lobule III L -2 -34 -24 41 5.13

Thalamus R 20 -28 -46 30 5.08

Cerebellum lobule VIII R* 24 -58 -46 8 4.77

Thalamus L* -18 -22 4 6 4.41

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significantly stronger (F(1,11)=12.767, P=0.004; ηp²=0.537; Fig. 8). No interaction

between hemisphere and contraction was found.

Figure 7. Mean volume of the functionally activated regions in the precentral gyrus (A), postcentral

gyrus (B) and cerebellum (C) during unilateral (□) and bilateral (■) contractions in the right (R) and left

(L) hemisphere.

Postcentral gyrus. Similar to the precentral gyrus, in the postcentral gyrus no

difference in the volume of the activated region between the unilateral and bilateral

contraction was found (F(1,11) =0.377, P=0.552; Fig. 7). Also no difference in intensity

of the activity was observed (F(1,11)=2.406, P=0.149; Fig. 8). A significant difference in

intensity was observed between the two hemispheres (F(1,11)=5.265, P=0.042; effect

size ηp²=0.324; no significant effect was found in the overlap ROI), pointing to a

stronger activation in the right postcentral gyrus. No effects were found in the

interaction between hemisphere and contraction.

Figure 8. Mean brain activity (effect size ± SE) in the left (L) and right (R) precentral gyrus (A), left and

right postcentral gyrus (B), and left and right cerebellum (C) measured during unilateral (□) and

bilateral (■) contractions of the index fingers.

Cerebellum. In the cerebellum no significant differences in volume or intensity was

found between the unilateral and bilateral contractions (volume: F(1,11)=0.002,

P=0.967, intensity: F(1,11)=0.365, P=0.558).


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The activated region in the left cerebellum was significant larger than in the

right cerebellum (F(1,11)=5.286, P=0.042; ηp²=0.325; Fig. 7), the intensity of the

regions, however, did not differ between hemispheres (F(1,11)=0.243, P=0.632; Fig. 8).

No interaction effects were found for hemisphere and contraction.

Supplementary motor area. The region of interest of the SMA, consisted of the areas

active during both unilateral contractions and the bilateral contraction. Only 10 (out of

12) subjects showed significant activity during all contractions. The volumes of the

activated regions in the SMA (Fig. 9) showed an interaction between hemisphere and

contraction (F(2,18) =5.914, P=0.011). Additional statistical analysis revealed that the

activated regions did not differ in size in the left SMA. However, the activated regions

in the right SMA were larger during the contralateral contractions than during the

ipsilateral contractions (P=0.021; corrected for repeated measurements; Fig. 9).

Also, the intensity revealed an interaction between contraction and

hemisphere (F(1,9) =5.300, P=0.015; Fig. 9). The additional statistical analysis

revealed no difference in intensity of the activity between the contractions in the left

SMA. Yet, the intensity in the right SMA was significantly stronger during the

contralateral (P=0.003) and the bilateral contractions (P=0.015) than during the

ipsilateral contractions. Thus, the volume of the region that is activated and the

intensity of the activity are similar between the different contractions for the left SMA

while in the right SMA the volume and intensity during the ipsilateral contraction is

smaller than during the contralateral and bilateral contractions.

Figure 9. Mean volume of the activated

regions (A) and mean intensity of the

activation (effect size; B) in the SMA of the

left (□) and right (■) hemisphere during the

contraction of the contralateral (C), ipsilateral

(I) or bilateral (BI) index finger. *significant

difference at P<0.05, **significant difference

at P<0.001; corrected for repeated

measurements.

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Discussion

Our data showed that the force deficit during maximal bilateral index finger abduction

was accompanied by a decline in muscle activity (EMG) of the first dorsal interosseus

and a decline in the input to the precentral gyrus, the most important motor output

area. These findings suggest that the primary source of the bilateral deficit lies

upstream of the motor cortex.

The force decline during the bilateral contractions was comparable to an

earlier study of the same muscle group (Zijdewind and Kernell, 2001) and was

accompanied by a similar decline in EMG activity (Van Dieen et al., 2003). A decline

in EMG may relate to changes within the muscle fibers, changes in excitability of the

motoneurons, or to changes in excitability within the motor cortex. Our fMRI data

showed a significant decline in the BOLD activity in the precentral gyrus during

bilateral contractions. It is demonstrated that the BOLD response correlates stronger

with the local field potential than with the firing patterns of the active neurons

(Logothetis, 2002).This observation implies that our findings reflect a decrease in the

input to the primary motor cortex. A reduction in the input to the primary motor cortex

would be expected to result in a decline in the output to the motoneurons, and thus a

decline in EMG activity. Data obtained with EEG (Oda and Moritani, 1996) suggested

there was a decline in activity of the primary motor cortex during bilateral

contractions. Our results extend this observation and suggest that the main cause of

the bilateral deficit is not within the primary motor area but upstream of the primary

motor cortex.

Both facilitating and inhibitory effects from one hemisphere to the other (e.g

Chen, 2004) are known and it is thought that most of these inputs cross via the

corpus callosum. It is possible that the bilateral deficit is the consequence of

activation of these inhibitory transcallosal pathways.

Brain areas

The primary motor cortex (precentral gyrus) is part of a large motor network that

receives dense cortical input from several motor areas, e.g. the premotor cortex

(PM), supplementary motor area (SMA) and cerebellum. Our contrast analysis

indeed revealed more activity in the ventral premotor area (PMv) during the unilateral

contractions, whereas SMA and cerebellum only showed marginal differences. This


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observation suggests that also the input to the premotor area is lower during bilateral

contractions; this may result in a lower output from the premotor area and thereby

cause the lower activation values in the primary motor cortex. Interestingly, unilateral

contractions with both the left and right hand resulted in a higher activation values for

the right PMv. A recent experiment (Aramaki et al., 2006) showed activity within this

region during the transition from mirror tapping (both index fingers simultaneously) to

parallel tapping (left index and right middle finger alternated with right index and left

middle finger) suggesting an important contribution of this area during bilateral

hemispheric interactions.

Many studies suggest that the supplementary motor area has an important

role in bilateral coordination (Cardoso de Oliveira, 2002; Rouiller et al., 1994;

Stephan et al., 1999). Nevertheless, we only found small changes in cortical activity

in this area during maximal bilateral contractions. Several other studies that looked at

the SMA during (submaximal) bilateral movements have found no difference between

unilateral or bilateral movements (Koeneke et al., 2004; Sadato et al., 1997;

Toyokura et al., 2002) while other studies found enhanced neuronal activity (Jancke

et al., 2000; Stephan et al., 1999). The SMA is, however, not only associated with

bilateral coordination, but also with initiation, programming, planning, learning, and

complexity of the motor task (Roland et al., 1980); see for review: (Picard and Strick,

1996). Hence, differences in motor task complexity could explain the discrepancies

between the various studies.

EMG and force data

Other studies that have evaluated the drive to the motoneurons during bilateral

contractions show inconsistent results. Several studies have used EMG as a

measure of the central drive (e.g. Jakobi and Cafarelli, 1998; Koh et al., 1993; Van

Dieen et al., 2003; Vandervoort et al., 1984). However, EMG-recordings can be

affected by activity in nearby synergist or even antagonist muscles. Furthermore,

force differences between unilateral and bilateral contractions are often small. In

addition, these recordings can be influenced by activity of antagonist muscles,

especially within large muscle groups. For the muscle used in this experiment, the

first dorsal interosseous, it is known that a large part of the index finger abduction

force is produced by this muscle (Chao et al., 1989). Furthermore, the antagonistic

muscles, such as the second palmar interosseous, are relatively small muscles

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compared to the first dorsal interosseous and their contribution to the surface EMG

would thus be relatively small.

Studies that have used stimulation of the cortex, nerve or muscle to evaluate

the efficiency of the corticospinal drive to the motoneuron pool found some

indications of a suboptimal drive to the motoneurons during bilateral contractions

(Herbert and Gandevia, 1996; Jakobi and Cafarelli, 1998; Van Dieen et al., 2003).

During twitch superimposition a stimulus is given during a maximal contraction and

the extra force evoked by this stimulation gives a measure of the efficiency of the

corticospinal drive. During the maximal contractions subjects are encouraged to

produce a real maximal contraction and the variability in the evoked twitch during

these contractions shows that producing a ‘real’ maximal contraction is very difficult

(Allen et al., 1995). In the fMRI environment no encouragement to the subjects can

be given during the task. Although, our subjects were trained before they went into

the scanner, it is expected that they were more prone to produce a suboptimal effort

because of lack of encouragement. From the combined literature (see for review:

Jakobi and Chilibeck, 2001) on the bilateral deficit one can conclude that producing a

suboptimal maximal contraction is more likely to occur during maximal bilateral

contractions than during maximal unilateral contractions. Therefore, it is noteworthy

that our brain activation patterns indeed reveal a decline in input to the primary motor

cortex during maximal bilateral contractions.

ROI analysis

We have chosen to define our regions of interest on the basis of 1) the summation of

the areas that are activity during both unilateral and bilateral contractions and 2) the

overlap of activity during the two contractions. The information obtained by the

analysis of the two ROIs could have different implications. We were interested in the

activity in the areas that were commonly active in both unilateral and bilateral

contractions; therefore, we have chosen to use the overlap ROI. However, if the main

activity falls outside this area the activity during a contraction is underestimated. This

was the main reason for defining a summation ROI. On the other hand, if the volume

of the active areas is significantly different between the two tasks this would

underestimate the mean activation value for the task that activates a relatively small

number of voxels. In our experimental conditions no difference in the activated

volume was seen during the unilateral and bilateral contractions, therefore, we have


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focussed our analysis on the summation ROI. The fact that our statistical analysis

gave similar results for both ROIs also suggests that similar regions are activated

during unilateral and bilateral contractions and that the strongest activated regions

overlap. It is unclear however, whether this is also the case for other (motor) tasks

and therefore this potential complication should be born in mind in the analysis of

fMRI data.

In conclusion, our data showed that the reduction in force during bilateral

index finger abduction is accompanied by a decline in EMG and BOLD-response in

the precentral gyrus. As the BOLD response is modulated by the input to neurons

these results suggest that the input to the precentral gyrus is diminished during

bilateral contractions and that the most likely source of the bilateral deficit lies

upstream of the motor cortex.

Reduced cortical activity during maximal bilateral contractions of the index finger

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