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1Human Cortical Physiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland; and 2Division of Neurology and Toronto Western Research Institute, University of Toronto, Toronto, Ontario, Canada
Submitted 18 December 2006; accepted in final form 5 January 2007
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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; Gazzaniga 1964, 1969; Swinnen 2002), are disrupted after lesions in the CNS like stroke and multiple sclerosis (Murase et al. 2004; Schmierer et al. 2002). IHI, tested noninvasively using transcranial magnetic stimulation (TMS; Ferbert et al. 1992), links homologous distal hand representations of the primary motor cortex (M1; Di Lazzaro et al. 1999). The strength of this linkage between other homologous body part representations in humans has not been explored in detail. The existence of morphological and functional differences between proximal and distal arm muscle representations suggests that physiological interactions between these homologous regions may differ. For example, in nonhuman primates transcallosal projections linking proximal muscle representations are more prominent than those connecting distal muscle representations (Gould et al. 1986; Jenny 1979; Pandya et al. 1971; Roullier et al. 1994). One caveat to this finding is that, because of the mosaic-like organization of the arm representation in M1, areas with dense transcallosal projections can be found in both proximal and distal arm representations (Gould et al. 1986). Additionally, corticospinal projections to distal hand muscles are on one hand stronger and more numerous (Kuypers 1978; Palmer and Ashby 1992) and on the other hand more contralaterally distributed (Aglioti et al. 1993; Brinkman and Kuypers 1972; Muller et al. 1997) than those targeting proximal arm muscles, presumably facilitating performance of skilled fractionated finger movements.
These anatomical and physiological differences may support relatively different contributions to motor behavior. Tasks requiring skilled control of distal muscles tend to be more precise, less forceful, often unilateral, requiring more inhibition of mirror activity (Duque et al. 2004; Swinnen 2002). Writing and playing musical instruments are examples of this type of behavior. On the other hand, proximal muscles are often involved in less precise, more forceful, often bilateral symmetrical movements such as lifting, pushing, and carrying, in addition to playing a stabilizing role in performance of more phasic skilled distal hand movements. These differences raise the hypothesis that IHI between proximal and distal arm muscles may differ.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Seventeen right-handed healthy volunteers (ten female, seven male) with an average age of 28.7 ± 5.7 yr participated in the study. All subjects gave their informed consent to the experimental procedure, which was approved by the National Institute of Neurological Disorders and Stroke Institutional Review Board. The study was performed in accordance with the Declaration of Helsinki.
Electromyographic recordings
Subjects were seated in an armchair with their hands resting on a pillow and forearms pronated. Surface electrodes were positioned on the skin overlying the left and right first dorsal interosseous (FDI), triceps brachii (TB), and biceps brachii (BB) muscles in a bipolar montage (interelectrode distance, 2 cm). The amplified electromyographic (EMG) signals were filtered (band-pass, 20 Hz to 2 kHz), sampled at 5 kHz, and stored on a PC for off-line analysis (LabVIEW version 7.1, CED 1401+ with Signal software, Cambridge Electronic Devices, Cambridge, UK).
Transcranial magnetic stimulation (TMS)
TMS was delivered to the optimal scalp positions for activation of the FDI, BB, and TB muscles. Motor-evoked potentials (MEPs) were elicited by TMS stimuli delivered from a Magstim 200 stimulator (Magstim, Dyfed, UK) through two figure-of-eight coils (loop diameter, 8 and 10 cm; type no. SP15560). Measures of cortical excitability included the resting motor threshold (RMT) defined as the lowest intensity of TMS output required to evoke MEPs of 
50 µV in peak-to-peak amplitude in at least five of ten consecutive trials (Rossini et al. 1994) and IHI. IHI targeting the left (nondominant) arm was measured because inhibition is reported to be strongest from the dominant to the nondominant hemisphere (Leocani et al. 2000).
IHI
IHI was tested following a randomized conditioning-test design previously reported (Ferbert et al. 1992). A suprathreshold conditioning stimulus (CS) was given 10 ms before a test stimulus (TS) delivered to the contralateral side. The CS was always given to the left motor cortex and the TS to the right motor cortex. In 13 subjects, the coils were positioned at the optimal location for activating the left and right FDI and TB, respectively. The magnetic coil for the TS was positioned tangentially over the scalp with the handle pointing backward and perpendicular to the presumed direction of the central sulcus, about 45° relative to the midsagittal line (Werhahn et al. 1994). The CS coil was oriented at 90° relative to the midsagittal line (Sakai et al. 1997; Werhahn et al. 1994). The TS was adjusted to produce an MEP of about 0.3 mV peak to peak in each of the target muscles. The CS was set at 110, 120, 130, 140, and 150% RMT. Stimuli were delivered in five sets of 20 trials (10 conditioned and 10 unconditioned trials randomly intermixed) for each muscle. IHI targeting the left BB was tested in seven subjects in a separate session. In four subjects, IHI in each muscle was measured at five additional interstimulus intervals: 3, 5, 6, 8, and 40 ms, with the CS at 120% RMT and the TS adjusted to produce an MEP of about 0.3 mV. EMG signals were monitored continuously for voluntary EMG background activity. Trials with mirror or background EMG activity were excluded from analysis.
H-reflex
To investigate a possible spinal contribution to the effects of the paired-pulse IHI protocol in a proximal muscle we tested the effect of a CS of 120% RMT on: 1) test MEP amplitude and 2) H-reflex of a similar size in the ipsilateral BB in four subjects. Subjects were seated with the left arm supported in 90° of shoulder abduction and external rotation. The H-reflex was evoked by stimulating the musculocutaneous nerve in the axillary fold through a monopolar electrode (1-ms rectangular pulse) using a constant-current stimulator (model DS7A, Digitimer, Hertfordshire, UK). H-reflexes were measured as peak-to-peak amplitude of the nonrectified reflex response. Stimulus intensities were increased in steps of 0.05 mA, starting below H-reflex threshold and increasing to supramaximal intensity to measure the maximal motor response (M-max). The sensitivity of the H-reflex to facilitatory or inhibitory conditioning effects was previously shown to depend crucially on its size (Crone et al. 1990). Therefore the size of the BB H-reflex was maintained at 10–15% of M-max. Because the latency for the BB MEP (13.5 ± 1) and the H-reflex (13.8 ± 0.76) were similar the CS was delivered 10 ms before the test pulse in both cases. Fifteen test and conditioned H-reflexes and MEPs were averaged during off-line analysis. Stimuli were applied every 5 s.
Data analysis
IHI (and inhibition of the H-reflex) was calculated as the ratio between the mean peak-to-peak MEP (or H-reflex) amplitude in conditioned versus unconditioned trials. In the initial analysis, Mauchly's test of sphericity was followed by a repeated-measures ANOVA with factors Muscle and Conditioning Stimulus Intensity. Subsequent planned comparisons between muscles were made using Student's paired t-test (
= 0.05). In a separate analysis similar to that used by Chen et al. (1998) to examine the absolute CS intensity required to elicit intracortical inhibition in different arm muscle groups, IHI targeting each muscle was grouped by CS intensity expressed as a percentage of maximum stimulator output in 10% increments. For each muscle that had at least three data points at a given CS intensity range, a single-factor t-test with the test value = 1 (i.e., no inhibition or facilitation) was used to determine whether significant inhibition had occurred ( = 0.05). Finally, a Student's paired t-test was used to compare the effect of CS intensity of 120% RMT on the BB test MEP and BB test H-reflex. The mean and the SE were calculated for each condition.
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RESULTS |
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IHI in FDI and TB
RMTs were lower in FDI (38.9 ± 9.8%) than in TB (46.9 ± 10.1%; P < 0.01). On average, IHI was deeper in FDI (0.45 ± 0.41) than in TB (0.78 ± 0.38; P < 0.01) with matched-test MEP absolute amplitudes of about 0.3 mV (Fig. 1). In three subjects in whom TS intensities expressed as percentage of RMT for FDI and TB muscles were comparable (115 ± 19 and 124 ± 22% RMT, respectively), IHI was also deeper in the FDI (0.28 ± 0.17) than in TB (0.85 ± 0.31; P < 0.05) muscles.
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In six of the seven subjects in whom BB IHI was tested, TB IHI was also tested. Despite the finding that RMTs were not different between the TB (44.8 ± 8.2%) and the BB (46.0 ± 9.3%, ns, n = 6), IHI was deeper in BB (0.52 ± 0.32) than in TB (0.80 ± 0.26; P < 0.05).
Threshold for IHI across muscle representations
When examining IHI in each muscle at conditioning stimulus intensities expressed as a percentage of RMT, we observed that IHI for FDI, TB, and BB could be elicited at CS intensities of 120% RMT (Fig. 2 A); yet it remained apparent that the depth of IHI differed between the muscles (Fig. 1). This difference in IHI between muscles was also observed when the absolute CS intensity required to elicit significant IHI was examined (Fig. 2B). Clearly, IHI was elicited in different muscles at different CS intensities (expressed as percentage of maximum stimulator output; Fig. 2B). Specifically, minimum CS intensities of 30–39 or 40–49% maximum stimulator output were required to elicit significant IHI in the FDI and BB, respectively, but minimum intensities of 60% were required to elicit significant IHI in TB. Because the lowest CS intensity used to test IHI was 110% RMT and the RMT for BB and TB tended to be >40%, there are no data to report for BB or TB at CS intensities of 30–39% of stimulator output (Fig. 2B).
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For the BB and TB, the strongest IHI was observed at the 10-ms ISI (Fig. 3). Deep IHI was observed in the FDI at both the 8- and 10-ms ISIs.
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The size of the BB test MEP (11.1 ± 2.6% of M-max) and test H-reflex (13.8 ± 3.7% of M-max) were comparable (P = 0.3). The CS elicited clear and prominent IHI in the BB in all individual subjects in the absence of changes in H-reflexes. A paired t-test showed that the CS suppressed the test MEP amplitude (IHI = 0.47 ± 0.08) to a significantly larger extent than the test H-reflex (inhibition = 1.02 ± 0.03; P = 0.01; Fig. 4 B).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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; Gerloff et al. 1998).
Previous studies suggested that the strength of inhibition between homologous muscle representations may differ along a stereotyped proximal–distal gradient (Sohn et al. 2003). Our results suggest that such a difference can indeed be observed between proximal and distal representations when comparing certain muscle groups (e.g., FDI and TB) but not others (e.g., FDI and BB). For example, IHI between BB muscle representations was comparable to that between FDI, a distal hand muscle. Consistent with this finding, similar CS intensities induced significant IHI between distal FDI and proximal BB (Fig. 2B), but not between TB. Clearly TB representations appear to exhibit a different threshold for expressing IHI than the other two muscles. These results are consistent with those of Chen et al. (1998). These authors found that the absolute CS intensity required to induce intracortical inhibition was relatively similar among different proximal and distal arm muscles despite widely varying RMTs, concluding that the mechanisms governing intracortical inhibition are not related to RMT or to the strength of corticospinal projections. The present results suggest that a similar conclusion can be drawn for IHI.
Cortical inhibitory processes like IHI are thought to underlie the ability to produce skilled, finely controlled movements. If this is the case, one would expect that IHI is operationally important in performance of ecologically focal and skilled motor tasks. Recent work by Graziano et al. (2002, 2004) showed that intracortical stimulation of M1 in monkeys elicited a stereotyped flexion of the elbow accompanied by a grasping hand posture moving toward the opening mouth in a feeding gesture. Stimulation of a different M1 area resulted in eye closing with head turning away, raised arm, and elbow extended, in a massive muscle response mimicking a protective posture. The first type of movement (feeding) engaged unilateral biceps and distal hand muscles and had a very precise and repeatable final posture (Graziano et al. 2002, 2004), whereas the second (more protective) engaged less focal, massive, and perhaps more bilateral activity with active involvement of TB. It is possible that in our experimental design, greater IHI observed between BB and FDI representations could contribute to performance of more precise, skilled motor actions geared to inhibit mirroring, whereas the lesser IHI between TB representations could be ecologically meaningful to secure bilateral rapid, massive protective responses as required for defensive arm movements. More experiments are required to determine whether such differential organization of IHI across body part representations may represent one of the strategies by which human and nonhuman primates modulate aspects of motor control required for survival. Finally, with magnetic stimulation of M1, Palmer and Ashby (1992) showed an initial inhibitory response in contralateral triceps and deltoid motor units in contrast to the short-latency facilitation observed in contralateral BB and FDI motor units. These findings further suggest a possible difference in control of movement synergies involving the different muscle groups, with more direct inhibition to the triceps and deltoid from the contralateral motor cortex, whereas control of synergies involving BB and FDI may rely more on IHI.
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GRANTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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FOOTNOTES |
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Address for reprint requests and other correspondence: L. G. Cohen, Human Cortical Physiology Section, National Institute of Neurological Disorders and Stroke, 10 Center Drive, MSC 1428, Bldg. 10, Rm 5N226, Bethesda, MD 20892 (E-mail: cohenl{at}ninds.nih.gov)
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REFERENCES |
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