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1Movement Neuroscience Laboratory, University of Auckland, Auckland, New Zealand; and 2Department of Neurology, Johann Wolfgang Goethe-University, Frankfurt, Germany
Submitted 22 March 2007; accepted in final form 11 May 2007
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ABSTRACT |
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INTRODUCTION |
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; Jeka and Kelso 1995; Jeka et al. 1993; Wenderoth et al. 2004). This can be experienced by flexing and extending the wrist and ankle together and comparing the stability of movements made in the same direction (isodirectional) versus movements made in opposite directions (anisodirectional). The physiological origin of this preferred isodirectional mode of coordination is not well understood.
Within primary motor cortex (M1) there is no overlap or known anatomical connections linking arm and leg muscle representations (Brown et al. 1991; Huntley and Jones 1991). The synchrony of local field potential oscillations between M1 representations suggests common input arising from secondary motor areas rather than horizontal connectivity within M1 (Murthy and Fetz 1996). In secondary motor areas including dorsal and ventral premotor cortices (PMd and PMv, respectively), supplementary motor cortex (SMA), and cingulate, arm and leg areas overlap considerably (Fink et al. 1997). Given this overlap it is likely that coordination-related interactions between arm and leg originate upstream of M1.
The output of M1 contributes to the modulation of forearm H-reflexes to facilitate wrist movements that are isodirectional with respect to foot movement (Baldissera et al. 2002; Borroni et al. 2004; Cerri et al. 2003). However, the preference for isodirectional hand and foot movement reflects spatial rather than structural constraints. With the forearm pronated there is facilitation of wrist flexor pathways during plantarflexion, whereas with forearm resting supinated, wrist extensor pathways are facilitated during plantarflexion, and wrist flexor pathways are facilitated during dorsiflexion of the foot (Borroni et al. 2004). This previously identified reciprocal pattern of corticomotor excitability of forearm pathways is used as a basis for the current study.
In the first experiment we explored whether lower limb muscle activation in the presence or absence of joint movement was sufficient to alter forearm motor cortical excitability. We hypothesized that the neurophysiological underpinning of isodirectional coupling is activity dependent. In experiment 2, we examined changes in excitability and intracortical inhibition of M1 arm regions during active versus passive foot movement. We hypothesized that intracortical inhibition of arm representations in M1 would be reduced by active foot movement in a direction-dependent manner, but not altered during passive movement. In experiment 3, we used a paired-pulse dual-coil technique to chart the modulation of functional connectivity between brain areas during motor performance. To date, very few studies have used this approach (Bäumer et al. 2006; Civardi et al. 2001; Koch et al. 2006) and, to our knowledge, none has done so during motor task performance. Given the strong functional connectivity between premotor areas and M1 (Civardi et al. 2001; Koch et al. 2006; Matsumura et al. 1992; Münchau et al. 2002) and the disruptive nature of repetitive transcranial magnetic stimulation (TMS) over SMA on the performance of difficult bimanual coordination patterns (Serrien et al. 2002; Steyvers et al. 2003), we hypothesized that PMd, PMv, and SMA may have distinct functional roles during hand–foot coordination.
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METHODS |
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Twenty-six subjects with no neurological impairments participated in three experiments. Informed consent was obtained before participation. The local Ethics Committees approved the procedures (University of Auckland, experiments 1 and 2; JW Goethe University of Frankfurt, experiment 3) in accordance with the Declaration of Helsinki.
Experimental procedure
In all three experiments subjects were examined at rest and in tasks requiring right ankle dorsiflexion (DF) and plantarflexion (PF). The left hemisphere was tested for all subjects. In all experiments, the forearm muscles remained quiescent with the hand and arm resting in a prone posture. Forearm muscle relaxation was monitored using custom software, by use of auditory feedback of the electromyogram (EMG) signal provided to subjects, and confirmed by quantitative off-line analysis.
EXPERIMENT 1. Eight subjects (six male; age 22–57 yr; seven right-handed) were tested. The aim was to investigate corticomotor excitability of extensor carpi radialis (ECR) and flexor carpi radialis (FCR) under two ipsilateral lower limb activation conditions: 1) phasic DF and PF of the foot and 2) isometric activation of tibialis anterior (TA) and soleus (SOL) muscles. Subjects were seated with their right hand and foot in a custom-built manipulandum (Fig. 1A). The right knee and elbow were positioned at 135 and 90° flexion, respectively. The left foot was supported at the same height as the right foot and the left hand was at rest in the subject's lap. The manipulandum consisted of hand and foot plates attached to horizontal spindles, aligned to the right wrist and ankle joint. Potentiometers were calibrated to record angular displacement of each joint. The spindle attached to the footplate was connected to a Brushless AC Servomotor (Baldor, Fort Smith, AR) programmed to provide a resistive torque (experiment 1) or to drive the foot passively through sinusoidal motion (experiment 2). Foot motion was restricted to a 30° range of motion by the apparatus. The combined weight of the subject's hand and the plate were opposed by an adjustable elastic support to set the wrist with equal and negligible resistance in flexion or extension (Fig. 1A).
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). A test stimulus (TS) intensity of 150% resting motor threshold (RMT) (Rossini et al. 1994) was used throughout the experiment. RMT was defined as the minimum intensity that produced small MEPs (>50 µV) in at least five of ten consecutive trials. A trial consisted of nine metronome beats (pitch 800 Hz, pulse duration 50 ms) at 1.5 Hz. Subjects were instructed either to stay completely relaxed or to perform DF or PF movements in time with the metronome. In the phasic condition subjects moved their foot rhythmically through 30° on each cycle and synchronized with the metronome at peak DF or PF. The resistive torque was programmed to obtain the full range of motion for each subject. In the isometric conditions subjects generated enough force to overcome the same torque, but maintained an isometric contraction at peak DF or PF. In all trials the TMS unit was triggered 150 ms before the seventh metronome beat (i.e., after some adaptation time for the subjects to synchronize with the metronome and well before the end of the trial) such that TMS was delivered during SOL or TA activation in the phasic conditions.
EXPERIMENT 2.
Ten subjects participated in experiment 2 (six male; age 21–39 yr; nine right-handed). Subject preparation and apparatus were as described in experiment 1. We used paired-pulse TMS to examine whether short-interval intracortical inhibition (SICI) of the ECR representation was modulated by foot movement during active and passive conditions. This allowed us to examine the possible contribution of afference elicited from foot movement (in the absence of any leg muscle activation) and to determine whether the direction of foot movement under active conditions produces a differential effect on SICI that is not seen during passive conditions. A subthreshold conditioning stimulus (CS) was delivered 3 ms before the TS (Hanajima et al. 2003). The CS was set initially to 90% active motor threshold (AMT), defined as the minimum intensity required to produce a 100-µV MEP in five of ten consecutive trials (Rossini et al. 1994). This intensity was chosen to produce maximal inhibition (Orth et al. 2003; Ziemann et al. 1996b), and then decreased in 1% steps of stimulator output until the conditioned (C) MEP size was 50% of the nonconditioned (NC) MEP. This procedure ensured that both increases and decreases in SICI would be detectable (Stinear and Byblow 2003). TS was adjusted to produce a MEP of approximately 1 mV in ECR in each condition and then NC and C MEPs were recorded (Fisher et al. 2002). FCR MEPs were not investigated in this experiment because of the requirement of matching NC ECR MEP amplitudes across conditions to assess changes in SICI. Trial duration and stimulation delivery were identical to those of experiment 1. Active and passive conditions were identical, except that the foot was moved by the servomotor in the passive condition. Subjects were instructed to keep their leg muscles relaxed during the movement. Conditions were pseudorandomized and counterbalanced across subjects. A behavioral measure of directional tuning within motor cortex was derived by examining the kinematics of TMS-evoked hand movements.
EXPERIMENT 3. Eight right-handed subjects participated in experiment 3 (three male; age 24–42 yr). EMG data were recorded from right ECR, FCR, TA, and SOL using a belly-tendon montage for each muscle and a common ground electrode. The EMG was amplified and filtered (10 Hz to 2 kHz, Counterpoint Mk2 Electromyograph, Dantec Electronics, Skovlunde, Denmark), passed through a CED Micro 1401 laboratory interface [Cambridge Electronic Design (CED), Cambridge, UK], digitized at 4 kHz, and fed into a personal computer for on-line display and off-line analysis, using customized data collection and conditional averaging software (Spike2 for Windows, CED). Participants were seated comfortably, with their elbows flexed to approximately 90° and forearms resting pronated on the armrests of a chair. The wrist joints were supported in a neutral position and the forearm muscles were maintained at rest throughout the experiment. The right foot was fully supported on a flat surface during the rest condition. During DF, the right heel remained on this surface while the ankle was fully dorsiflexed. During PF, the right heel was supported by the edge of the surface, allowing full plantarflexion without making contact with the floor. The left foot was supported on a flat surface at the same height as the right foot.
Pairs of magnetic stimuli were delivered with two small figure-of-eight coils (outer wing diameter 50 mm), each connected to a Magstim 200 stimulator. The test coil was oriented to induce a posterior-to-anterior current flow in the underlying cortex. The TS was delivered over the optimal location of the left M1 for evoking MEPs in right ECR. RMT and AMT were determined in ECR with leg muscles at rest. AMT was also evaluated during DF, but this did not differ from rest for any subject. Conditioning stimuli (CS) were delivered at three sites: dorsal (PMd) and ventral premotor (PMv) areas and supplementary motor area (SMA, encompassing pre-SMA and SMA proper) following procedures reported in previous studies (Civardi et al. 2001). For PMd stimulation, the scalp was marked 5 cm anterior to the ECR hotspot. To target SMA, the scalp was marked on the midline, 6 cm anterior to the ECR hotspot. For PMv the site was marked 5 cm anterior and 4 cm lateral of the ECR hotspot. The sites targeted are shown in Fig. 1B using a three-dimensional (3D) rendered and peeled anatomical MRI from a single participant examined in this experiment and specialized software and coregistration system (Brainsight, Rogue Research, Montreal, Canada) to confirm placement of the stimulating coils with respect to each motor area. As in previous studies, the conditioning coil was oriented to induce an anterior-to-posterior current flow in the underlying cortex. The interstimulus interval (ISI) between CS and TS was 6 ms (Civardi et al. 2001).
The TS was set to produce a 1-mV MEP in ECR at rest in a block of eight stimuli. The same TS were then delivered during DF and PF in separate blocks of eight stimuli each, to confirm directional modulation of ECR and FCR MEPs. For DF and PF, participants were instructed to raise or lower their foot, in such a way that the stimuli occurred during isometric muscle activation at peak joint excursion. Participants were instructed to maintain the contraction after each stimulus, before relaxing, returning to the starting position, and again contracting before the next stimulus. An experimenter monitored performance and was able to reject trials on-line. Subjects performed the task without difficulty. After these data were obtained, the three sites of CS (PMd, PMv, and SMA) were tested in a random order for each participant. The TS intensity was adjusted to produce 1-mV ECR MEPs in each Direction condition (Rest, DF, and PF). Within each block, CS was delivered at eight different intensities from 70 to 140% AMT, in 10% increments. In each block eight paired stimuli were delivered at each CS intensity, with a further eight NC stimuli. This resulted in a total of 72 stimuli (64 C and 8 NC) per block delivered in a randomized order by custom software and a random intertrial interval of 3.75–6.25 s. Stimulator intensity was automatically controlled by the PC through an 8-bit socket in the rear panel of the magnetic stimulator (resolution 1% of maximum stimulator output) through in-house customized software (Spike2 for Windows). A short break was taken at midpoint to allow for coil cooling, to confirm coil placement, and for subject rest. Altogether, nine blocks (3 sites of CS x 3 Direction conditions) of 72 trials were undertaken with each subject.
Data analysis
Because of the sometimes polyphasic nature of MEPs in forearm muscles (Stinear and Byblow 2004b), the ECR/FCR MEP area was used as the primary dependent measure. The MEP area was calculated over a 30-ms window from MEP onset determined for each individual. For each Direction, the MEP area was normalized to rest and expressed as a percentage. Trials with pretrigger root mean squared EMG (rmsEMG) activity of either forearm muscle were discarded if >10 µV for the 50 ms before TMS (experiment 3, 30 µV for the 90 ms before TMS). ECR and FCR pretrigger rmsEMGs were subject to the same repeated-measures (RM) ANOVA as MEP data.
In experiment 1, RM ANOVA factors were Muscle (ECR, FCR), Direction (DF, PF), and Activation (Phasic, Isometric).
In experiment 2, SICI was expressed as a percentage using the formula, %Inhibition = 100 – (C/NC x 100), where C and NC correspond to conditioned and nonconditioned ECR MEP area for each condition. RM ANOVA factors were Direction (DF, PF) and Condition (Passive, Active). The measure of %Inhibition allows for increases or decreases in SICI relative to resting levels (
50%) to be evaluated for each Direction and Condition. TMS-evoked hand movements were measured using displacement data obtained from the potentiometer signals, which were differentiated twice to derive wrist velocity and acceleration. The velocity at the time of the first acceleration peak after TMS, denoted as stimulus-evoked velocity (SEV), was used as an estimate of directional tuning. This event occurred within 100 ms of stimulation. SEVs during DF and PF were normalized to SEV at rest. SEVs were analyzed with factors Direction (DF, PF) and Condition (Active, Passive). Finally, rmsEMG of TA and SOL were monitored and trials rejected on-line, to ensure complete relaxation of leg muscles (<10 µV) during Passive conditions.
In experiment 3, the MEP area was expressed as a percentage (C/NC) and analyzed with a RM ANOVA. For C MEPs, factors were Direction (Rest, DF, PF) and CS intensity (70, 80, 90, 100, 110, 120, 130, 140% AMT) analyzed separately for each site of conditioning stimulation. For NC MEPs, factors were Muscle (ECR, FCR) and Direction (Rest, DF, and PF). The pretrigger rmsEMG ANOVA design was 3 Direction (Rest, DF, PF) x 9 CS intensity (all CS Intensities and NC).
Planned contrasts were conducted using paired t-tests to compare DF and PF where there were interactions or trends between Direction and other factors. To prevent an escalation of the family-wise error rate, in experiment 3, paired t-tests were used to examine differences between rest, DF, and PF at only selected low (80, 90% AMT) and high (120, 130% AMT) CS intensities. Statistical significance was set to 
= 0.05. Mean ± SD are reported in results.
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RESULTS |
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Experiment 1: phasic versus isometric muscle activation
Figure 2A illustrates ECR, FCR, TA, and SOL EMG and foot displacement for a single participant during phasic DF and PF trials.
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There were no effects or interactions for forearm pretrigger rmsEMG (all P > 0.1) and muscles of the forearm remained consistently at rest throughout testing.
Experiment 2: SICI and TMS-evoked movements
There was a main effect of Condition for the NC ECR MEPs [F(1,9) = 54.5, P < 0.001; see Fig. 3A] with larger MEPs obtained during active versus passive movement, and no other main effects or interactions. ECR MEPs were larger during active DF and PF than during Rest. Conversely, MEPs were smaller during passive PF and DF than during Rest (all P < 0.01). Comparing Direction under active and passive conditions revealed no differences (all P > 0.05) in ECR NC MEP area indicating that NC ECR MEP area was matched within activation conditions. For ECR SICI, %Inhibition at Rest was 42.8% (range 31–61%) as intended by the procedure. There was a Direction x Condition interaction [F(1,9) = 5.1, P < 0.05; see Fig. 3B] and no other effects (all P > 0.1). ECR SICI was less during DF than during PF for the active condition (P < 0.05), but not the passive condition (P > 0.1), and lower during active dorsiflexion than during rest (P < 0.01) but there was no difference with rest in any other condition (all P > 0.1).
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The data from one participant were excluded because this person was unable to maintain forearm muscle relaxation.
With conditioning stimulation applied over PMd there was a main effect of CS Intensity [F(7,42) = 2.85, P < 0.02] and a Direction x CS Intensity interaction [F(14,84) = 2.13, P < 0.02; see Fig. 5, PMd]. The source of this interaction was investigated using post hoc comparisons. It was found that ECR MEP area was larger during DF than during Rest with conditioning at 90% AMT (P < 0.05) and 130% AMT (P < 0.05) but not at 80 or 120% AMT (both P > 0.1). MEPs were larger during DF than during PF with conditioning at 130% AMT only (P < 0.05, other P > 0.1). MEP areas did not differ between PF and Rest with either CS intensity (all P > 0.09).
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There were no significant effects or interactions of ECR MEPs with conditioning applied over PMv (all P > 0.1). The analysis of pretrigger rmsEMG of ECR confirmed there were no effects of CS Intensity, Direction, or any interactions (all P > 0.1) during stimulation of any site, confirming that subjects maintained ECR and FCR relaxation during all testing.
NC ECR MEPs were deemed to be successfully matched in the paired-pulse sessions as confirmed by the Conditioning Site x Direction RM ANOVA, which revealed no effects or interactions (all P > 0.1; see Fig. 6A). For single-pulse trials, the ANOVA of unmatched NC ECR and FCR MEPs revealed the expected Muscle x Direction interaction [F(1,6) = 3.3, P < 0.01; see Fig. 6B]. ECR MEPs were larger during DF than during PF, and FCR MEPs were larger during PF than during DF (both P < 0.05), confirming the result of experiment 1 (Fig. 2B). Analysis of pretrigger rmsEMG of leg muscle activation revealed an effect of Muscle, Direction, and Muscle x Direction interaction [F(2,12) = 14.4, P < 0.001]. As expected, activation of TA was greater during DF than during PF (P < 0.01), and activation of SOL was greater during PF than during DF (P < 0.05), indicating successful task performance by the group during the experiment.
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DISCUSSION |
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) by demonstrating that upper limb corticomotor excitability and SICI were altered by movement conditions involving leg muscle activation, but not during passive leg movement. These neurophysiological changes occurred in parallel with TMS-evoked hand movements that revealed an isodirectional coupling between hand and foot. Because there are no known anatomical connections between arm and leg regions within M1 (Huntley and Jones 1991), we used a novel dual-coil paired-pulse TMS protocol to examine functional connectivity between secondary and primary motor areas during active ankle dorsiflexion and plantarflexion. Our results demonstrate that networks involving PMd–M1 facilitate the production of isodirectional movements between the hand and foot. Conversely, networks involving SMA–M1 facilitate forearm corticospinal excitability in a nonspecific manner, perhaps as a mechanism underlying postural stability. Each of these findings and their implications are discussed in turn. SICI and activity-dependent coupling
ECR SICI was significantly reduced during active dorsiflexion compared with plantarflexion, thereby facilitating isodirectional movement patterns between hand and foot. This supports earlier findings that foot movement produces changes in excitability within upper limb regions of M1 (Baldissera et al. 2002; Borroni et al. 2004) and extends these findings by demonstrating modulation of 
-aminobutyric acid (GABA)–mediated inhibitory networks (Ilic et al. 2002; Ziemann et al. 1995, 1996a, 1998) during these movements. In M1, the inhibitory networks responsible for SICI play a crucial role in spatial and temporal modulation of corticospinal output before (Reynolds and Ashby 1999), during (Stinear and Byblow 2003, 2004a), and at the termination of movement (Buccolieri et al. 2004). Interestingly, SICI of hand muscle representations increases during the production of more difficult coordination patterns compared with easy coordination patterns (Byblow and Stinear 2006; Stinear and Byblow 2002). We propose that PMd networks may interact with these inhibitory networks within M1 (Münchau et al. 2002) to facilitate corticospinal excitability in support of isodirectional movements.
Functional connectivity between PMd and M1
At rest, ECR MEPs tended to be inhibited by conditioning applied over PMd at 90% AMT, in agreement with previous studies (Civardi et al. 2001). However, during ankle dorsiflexion, PMd conditioning facilitated ECR MEPs, whereas there was no evidence that ECR excitability was suppressed during plantarflexion. ECR SICI was modulated by movement direction in active conditions only, with a significant decrease in SICI during dorsiflexion compared with plantarflexion (experiment 2). Although there was no evidence for suppressive influences on ECR M1 excitability to countermand anisodirectional movement patterns, this is not surprising given that the intention of the participants was to move only the foot (while the forearm remained stationary and at rest). Facilitation along the PMd–M1 pathway specifies the preferred coordination mode, but from the current study, it cannot be determined whether this is the sole pathway through which one mode or the other is selected during interlimb coordination.
The PMd–M1 pathway facilitates the production of isodirectional patterns by a direct facilitatory pathway between PMd and M1, the modulation of inhibitory projections between PMd and M1 circuits mediating SICI, or both. ECR MEP facilitation occurred across two widely separated CS intensity ranges. Separate PMd neuronal populations may have given rise to the two distinct peaks of facilitation observed in Fig. 5 (PMd). This result is consistent with reports of independent PMd–M1 networks (Bäumer et al. 2003, 2006; Civardi et al. 2001; Koch et al. 2006). Subthreshold conditioning of ipsilateral PMd produces inhibition of M1 at rest (Civardi et al. 2001). The first phase of facilitation observed with PMd conditioning during dorsiflexion may reflect a disfacilitation of inhibitory networks within M1. At rest, higher PMd conditioning intensities did not produce facilitation of ECR MEPs in contrast to Civardi et al. (2001). Because these authors investigated an intrinsic hand muscle, this may reflect differences between PMd–M1 networks that operate on hand versus forearm muscle representations. However, higher PMd conditioning intensities facilitated ECR MEPs during dorsiflexion, again suggesting that PMd–M1 cortico-cortical connections are modulated in a manner that facilitates isodirectional movement. At this time, it is not known whether low versus high conditioning stimulation operates through separate intracortical inhibitory versus facilitatory mechanisms within M1. To ascertain the interaction between these putative independent networks between PMd and M1, further investigation using triple-pulse paradigms (Koch et al. 2007) in the context of interlimb coordination is warranted. The idea that ECR MEP facilitation during dorsiflexion is mediated through PMd activation is also consistent with functional MRI studies of hand and foot coordination (Heuninckx et al. 2005). PMd contains neural representations of relative position codes (Pesaran et al. 2006) and thus may provide a general solution to the spatial problem of coordinating different body parts.
Functional connectivity between SMA and M1
At rest, ECR MEPs were inhibited by conditioning SMA at 90% AMT in agreement with previous studies (Civardi et al. 2001). However, ECR MEPs were facilitated by SMA conditioning during dorsiflexion and plantarflexion relative to rest (90% AMT). This nonspecific facilitation of ECR during both movement directions may reflect a cortico-cortical mechanism that subserves postural stability. SMA is known to be involved in the maintenance of anticipatory postural adjustments (Aruin and Latash 1995; Aruin et al. 1996, 2001) and may also stabilize posture during coincident hand and foot movements (Cerri et al. 2003).
The SMA is involved in the stabilization of difficult coordination patterns as demonstrated by the disruption of difficult, but not easy, bimanual coordination patterns after repetitive TMS over SMA (Serrien et al. 2002; Steyvers et al. 2003), as well as maximum intensity single-pulse TMS (Meyer-Lindenberg et al. 2002; Serrien et al. 2002; Steyvers et al. 2003). When SMA was conditioned at 130% AMT, ECR MEPs were significantly larger during plantarflexion than during dorsiflexion or rest, which did not differ from each other. Interpreting this result is difficult. Although SMA–M1 networks may subserve the production of difficult coordination patterns, we do not favor this interpretation on the basis of the present findings because the observed difference in MEPs between conditions resulted from suppression during rest and dorsiflexion, rather than ECR MEP facilitation during plantarflexion (compare Fig. 5, SMA with Fig. 5, PMd). A more detailed examination of SMA–M1 functional connectivity during the production of difficult coordination patterns does seem warranted.
Functional connectivity between PMv and M1
PMv conditioning had no effect on ECR MEPs at rest, nor was it modulated by foot direction. It is known from animal studies that PMv is involved in transformations from extrinsic to intrinsic coordinates that are required in the context of certain goal-directed movements of the upper limb (Kakei et al. 2001, 2003). PMv neurons with terminations in M1 may convey information linking representations within the upper limb, such as linking digits with hand and arm regions (Dancause et al. 2006). However, our results lend no support for PMv involvement in linking representations of ipsilateral hand and foot.
Cortico-cortical connectivity between PMd, SMA, and M1
The present study is the first to show that networks involving PMd–M1 facilitate isodirectional tendencies between the hand and foot. There is evidence for left PMd involvement in action selection involving limbs on either side of the body (Schluter et al. 2001), whereas a preferential role of right PMd has been implicated in the maintenance of bimanual coordination (Meyer-Lindenberg et al. 2002; Sadato et al. 1997). Although the extent of lateralization of PMd–M1 networks for movements made on either side of the body, or across the midline, is not yet known, the modulation of cortico-cortical connectivity between PMd and M1 provides directionally specific facilitation to support isodirectional movements of hand and foot. It is conceivable that leg motor practice may induce lasting effects on upper limb M1 excitability. This may be of potential value in the context of motor rehabilitation given the importance of PMd during recovery of motor function after stroke (Frost et al. 2003; Johansen-Berg et al. 2002a,b; Seitz et al. 1998; Ward et al. 2003).
Limitations and significance of the present findings
One limitation of the paradigm used in the current studies is that the direction-dependent modulation of ECR/FCR MEPs during foot muscle activation occurs in the absence of forearm muscle activation. Therefore the importance of modulation of excitability of these pathways in the production of hand–foot coordination is assumed. We infer that increases in M1 excitability and decreases in SICI reflect changes that may facilitate voluntary movement of the upper limb (Reynolds and Ashby 1999). The fact that TMS-evoked hand movements were also direction dependent lends support to this assumption.
In the present studies, the excitability of motor pathways was not assessed by applying stimulation below the level of the cortex. Although it is possible that segmental or propriospinal networks may have caused alterations in motor neuron excitability in these experiments, this is unlikely for several reasons. First, subthreshold conditioning applied in the evaluation of SICI and with two-coil paired-pulse TMS (
90%AMT) are unlikely to reflect, or induce, effects at or below the corticospinal elements within M1 (Di Lazzaro et al. 1999). Therefore changes in excitability occurring below the motor cortex cannot explain the differential modulation of conditioned MEPs across foot movement conditions. Second, it has been demonstrated that there are no changes to H-reflexes recorded in intrinsic hand muscles in response to conditioning over PMd or SMA 120% AMT (Civardi et al. 2001). The extent to which stimulation intensities >120% AMT applied over secondary areas directly influence spinal motor neuron excitability cannot be known from the present study. However, the findings of differential modulation with foot movement tasks and no facilitation at rest support the interpretation that the effects from this stimulation protocol reflect cortico-cortical interactions.
It is possible that the conditioning stimulation in experiment 3 may have spread to adjacent cortical areas, but this seems unlikely given the low CS intensities used in this study. Although the effects of stimulation spread cannot be discounted entirely, direct connections from prefrontal or inferior frontal areas to M1 are known to be sparse. The time course of effects given our chosen ISI suggest direct cortico-cortical connections between the targeted premotor /SMA areas and M1, where anatomically it is known there are direct connections between these areas (Godschalk et al. 1995).
Another point of difference with the study of Civardi and colleagues is the muscle examined, which was FDI in their study and ECR in ours. There may be important differences between the cortico-cortical connections for these muscle representations that might explain slight differences between studies in conditioning of PMd or SMA at rest.
In conclusion, the present experiments identify a context of limb movement that modulates the functional connectivity between PMd, SMA, and M1. Modulation of M1 excitability by PMd may subserve the preferred isodirectional pattern of hand–foot coordination. This may be of particular relevance in motor rehabilitation after stroke, considering the involvement of PMd during motor tasks in patients who exhibit good recovery (Frost et al. 2003; Johansen-Berg et al. 2002a,b; Seitz et al. 1998; Ward et al. 2003).
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Address for reprint requests and other correspondence: W. D. Byblow, Movement Neuroscience Laboratory, University of Auckland, Auckland, New Zealand (E-mail: w.byblow{at}auckland.ac.nz)
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ABSTRACT
INTRODUCTION
