- Email: [email protected]
Differential modulations of intracortical neural circuits between two intrinsic hand muscles
Clinical Neurophysiology 116 (2005) 2757–2764 www.elsevier.com/locate/clinph
Differential modulations of intracortical neural circuits between two intrinsic hand muscles Makoto Takahashia, Zhen Nia, Takamasa Yamashitab, Nan Liangb, Kenichi Sugawarac, Susumu Yahagid, Tatsuya Kasaia,* a
Division of Sports and Health Sciences, Graduate School for International Development and Cooperation, Hiroshima University, 1-5-1 Kagamiyama, Higashihiroshima 739-8529, Japan b Graduate School of Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan c Faculty of Health and Social Work, Kanagawa University of Human Services, 1-10-1 Heisei-cho, Yokosuka, Kanagawa 238-8522, Japan d Department of Human Environment Sciences, Hiroshima Shudo University, 11-1 Ozuka-higashi, Asaminami-ku, Hiroshima 731-3195, Japan Accepted 17 August 2005 Available online 25 October 2005
Abstract Objective: To investigate whether the intracortical inhibitory (ICI) and facilitatory (ICF) circuits in the primary motor cortex between the first dorsal interosseous (FDI) and abductor digiti minimi (ADM) muscles are modulated differently. Methods: We conducted paired-pulse transcranial magnetic stimulation in combination with different current directions (anterior-medially: AM, and posterior-laterally: PL) under relaxed and active muscle conditions with interstimulus intervals (ISIs) between 2 and 16 ms. Results: In both muscle conditions, the conditioned motor-evoked potential (MEP) responses obtained with the AM current direction (preferentially eliciting early I-waves) were similar between the two muscles at all ISIs, but the MEP responses obtained with the PL current direction (preferentially eliciting late I-waves) were different between FDI and ADM muscles, in that the conditioned MEP responses in FDI muscle were inhibited at all ISIs under both muscle conditions, whereas those in ADM muscle were suppressed at only short ISIs (2–4 ms). Conclusions: These results indicate that the inhibitory connections operating for the corticospinal tract neurons in FDI muscle are more potent, and, conversely, that those in ADM muscle are weaker. Significance: The different modulations of ICI circuits between FDI and ADM muscles is an important neural mechanism which may contribute to different functional demands (finger dexterity). q 2005 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Paired-pulse transcranial magnetic stimulation (TMS); Intracortical neural circuits; Current directions; I-waves; First dorsal interosseous (FDI) and abductor digiti minimi (ADM) muscles
1. Introduction The intracortical inhibitory circuits in the primary motor cortex (M1) play an important role in shaping motor output, and may contribute to selective activation of muscles for motor dexterity (Abbruzzese et al., 1999; Ridding et al., 1995; Stinear and Byblow, 2003; Zoghi et al., 2003). If the circuits do contribute to this selective activation, then the intracortical neural circuits in M1 between the first dorsal
* Corresponding author. Tel.: C81 82 424 6938; fax: C81 82 424 6904. E-mail address: [email protected] (T. Kasai).
interosseous (FDI) and abductor digiti minimi (ADM) muscles would likely be modulated differently. Because motor dexterity is definitely different between the index finger, which is controlled by FDI muscle, and the little finger, which is controlled by ADM muscle, in synergy with several intrinsic and extrinsic hand muscles (Rossini et al., 1999; Ziemann et al., 2004a). In fact, it was recently reported that the monosynaptic corticomotoneuronal projections, which provide the capacity for independent control of the digits and skilled use of the hand for fine motor tasks, are more powerful to the alpha-motoneurons of FDI muscle than those of ADM muscle depending on their different functional demands (Ziemann et al., 2004a,b). However, to
1388-2457/$30.00 q 2005 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2005.08.024
2758
M. Takahashi et al. / Clinical Neurophysiology 116 (2005) 2757–2764
our knowledge, it is not yet known whether or not the intracortical neural circuits between FDI and ADM muscles are actually modulated differently. To address this question, we investigated the intracortical inhibitory (ICI) and facilitatory (ICF) circuits of these muscles under relaxed and active muscle conditions using a paired-pulse transcranial magnetic stimulation (TMS) method with a subthreshold condition stimulus followed by a suprathreshold test stimulus (Kujirai et al., 1993; Ziemann et al., 1996). We also conducted the paired-pulse TMS in combination with different current directions in the brain so as to preferentially elicit different I-waves which could be recognizable early and late I-waves based on their different latencies (Hanajima et al., 1998; Sakai et al., 1997; Sugawara et al., 2005; Takahashi et al., 2004). This specifically allowed us to examine the role of the neural elements responsible for late I-waves, which are susceptible to ICI circuits (Di Lazzaro et al., 1998; Hanajima et al., 1998; Nakamura et al., 1997). The goal of the present study was, therefore, to address whether or not the ICI and/or ICF circuits between FDI and ADM muscles are modulated differently.
2. Methods 2.1. Subjects Six healthy right-handed (Oldfield, 1971) volunteers (five males and one female, mean age 26.5 yrs, range 23–34 yrs) participated in the experiments after giving their informed consent. Each subject participated in two experiments (relaxed and active muscle conditions) in a randomized order and at least 24 h apart. The experiments were performed in accordance with the Declaration of Helsinki and with the approval of the Local Ethics Committee of Hiroshima University. 2.2. Electromyographic (EMG) recording and cortical stimulation The surface EMGs were recorded from right FDI and ADM muscles with surface Ag/Agcl surface cup electrodes (9 mm in diameter). The active electrode was placed over each muscle belly and the reference electrode over the metacarpophalangeal joint of the index and little finger. The EMG signals were amplified at a bandwidth of 5 Hz to 5 kHz, sampled at 5 kHz, and fed to a computer for off-line analysis. TMS was given through a figure-of-eight-shaped coil (The Magstim Company, UK). At the beginning of each experiment, the position of the coil was systematically adjusted on the scalp over the left motor cortex to find the optimum location for the activation of each target muscle (FDI and ADM). As previous investigations have shown (Day et al., 1989; Di Lazzaro et al., 2001; Hanajima et al.,
1998; Sakai et al., 1997; Trompetto et al., 1999; Werhahn et al., 1994), it is possible to elicit different I-waves by different current directions in the brain. In a relaxed muscle, the temporal summation of multiple I-waves are required to produce a test motor-evoked potential (MEP), and consequently, MEPs to the anterior-medially (AM) current direction are produced by a combination of I1 and I2 waves, and other late I-waves, whereas MEPs to the posterior-laterally (PL) current direction are probably generated by I3 and I4 waves (Sugawara et al., 2005; Takahashi et al., 2004). On the other hand, since the excitability of spinal motoneurons increases in active muscle, MEPs are produced by I1 and I3 waves induced by the AM and PL current directions, respectively (Hanajima et al., 1998; Sakai et al., 1997). Thus, based on the different latencies of MEP, we confirmed whether early or late I-waves were preferentially elicited by these two different current directions. After adjustment of the coil position and orientation for each target muscle (FDI and ADM), the resting (RMT) and active (AMT) motor thresholds of each muscle were determined. RMT was defined as the lowest stimulus intensity which evoked MEP with amplitudes of about 50 mV in at least four out of eight (50%) successive trials in relaxed muscles. AMT was defined as the lowest stimulus intensity evoking MEP with amplitudes of about 200 mV in at least four out of eight successive trials in slightly isometric contracting muscles (5–10% maximum voluntary contraction as assessed visually on an oscilloscope screen). 2.3. Paired-pulse magnetic stimulation We investigated the effects of ICI and ICF circuits on two different I-waves evoked by magnetic stimulation with selected current directions under both relaxed and active muscle conditions. Data of FDI and ADM were separately collected in the same session using the TMS intensities and stimulation sites appropriate for each muscle. The conditioning and test stimuli were given through the same figure-of-eight-shaped coil by connecting two Magstim 200 stimulators via a Bistim module (The Magstim Company, UK). The TMS intensities of the conditioning stimulus were fixed at 90% of the RMT and AMT, respectively. The test stimulus was adjusted to elicit a MEP response with a peak-to-peak amplitude of approximately 1.0 mV in both muscles and under both conditions. We selected six interstimulus intervals (ISIs: 2, 4, 6, 9, 13, and 16 ms) based on previous reports (Kujirai et al., 1993; Ziemann et al., 1996), and these ISIs were randomly delivered. At least 8–10 responses were collected at each ISI. The mean peak-to-peak MEP amplitudes of each ISI were expressed as a percentage of the control MEP amplitudes induced by the test stimulus alone.
M. Takahashi et al. / Clinical Neurophysiology 116 (2005) 2757–2764
2759
direction were significantly lower than those with the PL current direction in both muscles and under both muscle conditions (paired t-test: P!0.05). These results indicate that early and late I-waves were preferentially elicited by the present experimental conditions using opposite current directions.
2.4. Data and Statistical analyses The differences in onset latencies, thresholds, and test TMS intensities between the AM and PL current directions were compared by paired t-test. First, in order to assess the general ICI/ICF curve, the conditioned MEP amplitudes for each muscle (FDI and ADM), each current direction (AM and PL), and each condition (relaxed and active muscle) were analyzed independently using one-way ANOVA with repeated measures (factor; ISIs). If a significant effect of ISIs was obtained, Dunnett’s multiple comparison tests were used to compare the values obtained at the different ISIs with the control (unconditioned) values. Second, in order to investigate the effects of the muscle, current direction and ISIs on the ICI and ICF circuits, we calculated representative data for the short (mean of 2 and 4 ms) and long (mean of 13 and 16 ms) ISIs. The mean data were independently analyzed for each muscle condition (relaxed and active) using three-way ANOVA with repeated measures [factors; muscle, current direction and ISIs (short and long)]. If a significant interaction between all three factors was obtained, post hoc analyses were done using the paired t-test with Bonferroni correction for multiple comparisons. The level of statistical significance was defined as P!0.05. The data are expressed as meansGSD.
3.2. ICI and ICF circuits under relaxed muscle condition Fig. 1A shows the MEP specimen records (superimposed three trials) in FDI (left side traces) and ADM (right side traces) muscles elicited at different ISIs and in different current directions (AM: upper traces and PL: lower traces) under the relaxed muscle condition obtained from a single subject. The conditioned MEP responses in both FDI and ADM muscles with the AM current direction were suppressed at an ISI of 2 ms, almost the same size as that at an ISI of 6 ms, and facilitated at an ISI of 13 ms. On the other hand, the conditioned response sizes in FDI muscle with the PL current direction were reduced at ISIs of 2, 6, and 13 ms. The conditioned MEP responses in ADM muscle with the PL current direction were also inhibited as well as those of FDI muscle at ISIs of 2 and 6 ms, but the conditioned responses were almost the same size as the control (unconditioned) responses at an ISI of 13 ms. Then, the means and standard deviations of all subjects tested (nZ6) were calculated and are shown in Fig. 1B. The conditioned MEP responses in both muscles with the AM current direction were similar to the previous observations, in that they consisted of an early inhibition followed by a later facilitation (Kujirai et al., 1993; Ziemann et al., 1996). Meanwhile, the conditioned responses of FDI muscle with the PL current direction were significantly suppressed at all ISIs (Dunnett’s test: P!0.05). In contrast, the conditioned MEP responses in ADM muscle with the PL current direction were significantly inhibited at ISIs of 2, 4 and 6 ms (Dunnett’s test: P!0.05), whereas inhibition and facilitation disappeared at ISIs of 9, 13 and 16 ms. Further, we calculated the representative data for short ISIs (2 and 4 ms) and long ones (13 and 16 ms), so as to investigate the effects of the muscle, current direction, and ISIs on the ICI and ICF circuits. As shown in Fig. 3A, there was a significant interaction between all three factors
3. Results 3.1. Onset latencies, thresholds, and test TMS intensities The onset latencies, thresholds, and test TMS intensities of FDI and ADM muscles with different current directions (AM and PL) under both the relaxed and active conditions are summarized in Table 1. The MEP latencies with the AM current direction were always significantly shorter than those with the PL current direction in both muscles and under both muscle conditions (paired t-test: P!0.05). In addition, the MEP latencies under the relaxed muscle condition were longer than those under the active muscle condition (paired t-test: P!0.05). On the other hand, the thresholds and test TMS intensities with the AM current
Table 1 Effect of different current directions (AM and PL) on the latencies, test intensities, and motor thresholds under relaxed and active muscle conditions Relaxed (nZ6)
Active (nZ6)
FDI
Latency (ms) Threshold intensity (%) Test intensity (%)
ADM
FDI
ADM
AM
PL
AM
PL
AM
PL
AM
PL
21.3G0.6 45.3G3.4 60.2G8.8
23.3G0.7* 59.2G8.6* 79.8G10.3*
21.4G0.9 50.3G8.2 71.7G9.3
23.3G0.8* 63.3G7.7* 84.2G7.4*
20.1G1.1† 35.3G6.2† 54.8G11.1†
22.5G0.9*† 49.5G9.1*† 68.2G14.6*†
19.8G0.9† 39.7G4.1† 58.3G9.3†
22.5G1.1*† 53.8G5.3*† 73.3G10.3*†
Values are meansGSD. n, no. of subjects; FDI, first dorsal interosseous; ADM, abductor digiti minimi muscles; AM, anterior-medially; PL, posterior-laterally current directions. *Significant difference (P!0.05) between the AM and PL current directions. †Significant difference between the relaxed and active muscle conditions.
2760
M. Takahashi et al. / Clinical Neurophysiology 116 (2005) 2757–2764
Fig. 1. (A) Specimen records of MEPs (superimposed three trials) of relaxed FDI (left) and ADM (right) muscles obtained from a single subject with the AM and PL current directed paired-pulse TMS. Vertical lines on each MEP recording indicate the onsets of each MEP. (B) The means and standard deviations of MEP amplitude of relaxed FDI and ADM muscles obtained from all six subjects with the AM (open circles) and the PL (filled circles) current directions. The MEPs are expressed as a percentage of the control MEP amplitudes induced by test TMS alone. *Significant difference from the control value (Dunnett’s multiple comparison tests).
(FZ3.587, P!0.05). The conditioned MEP responses in FDI and ADM muscles with both the AM and PL current directions were significantly inhibited at short ISIs (t-test with Bonferroni correction: P!0.001), although there were no significant differences among current directions and muscles. On the other hand, there were significant differences in both FDI and ADM muscles between the AM and PL current directions at long ISIs (t-test with Bonferroni correction: FDI: P!0.001, ADM: P!0.001). Furthermore, the conditioned MEP responses in FDI muscle were significantly suppressed, but those responses in ADM muscle were not inhibited. Thus, the conditioned MEP responses with the PL current direction were significantly different between FDI and ADM muscles at long ISIs (t-test with Bonferroni correction: PZ0.004). 3.3. ICI and ICF circuits under active muscle condition Fig. 2A shows the MEP specimen records of FDI and ADM muscles obtained from a single subject during slight voluntary contraction, similar to that shown in Fig. 1A. In both FDI and ADM muscles, the conditioned MEP responses obtained with the AM current direction were almost the same size as the control (unconditioned) responses. On the other hand, the conditioned MEP responses in FDI muscle with the PL current direction were suppressed at ISIs of 2, 6 and 13 ms. In contrast,
the conditioned MEP responses in ADM muscle with the PL current direction were suppressed at an ISI of 2 ms, but were almost the same size as the control (unconditioned) responses at ISIs of 6 and 13 ms. Then, the means and standard deviations of all subjects tested (nZ6) were calculated and are shown in Fig. 2B. The conditioned MEP responses in both muscles with the AM current direction were not significantly inhibited and facilitated, as reported previously (Ridding et al., 1995), while the conditioned MEP responses in FDI muscle with the PL current direction were significantly suppressed at all ISIs (Dunnett’s test: P! 0.05). In contrast, the conditioned MEP responses in ADM muscle with the PL current direction were significantly inhibited at ISIs of 2 and 4 ms (Dunnett’s test: P!0.05), whereas neither inhibition nor facilitation were observed at later ISIs. Further, we calculated the representative data for short ISIs (2 and 4 ms) and long ISIs (13 and 16 ms), and the results are shown in Fig. 3B. There was a significant interaction between all three factors (muscle, current direction and ISIs: FZ5.657, P!0.05). The conditioned MEP responses in both FDI and ADM muscles with the PL current direction were significantly suppressed at short ISIs, whereas those responses with the AM current direction were not suppressed. There were significant differences in both muscles between the AM and PL current directions (t-test with Bonferroni correction: FDI: P!0.001, ADM:
M. Takahashi et al. / Clinical Neurophysiology 116 (2005) 2757–2764
2761
Fig. 2. (A) Specimen records of MEPs (superimposed three trials) of active FDI (left) and ADM (right) muscles obtained from a single subject with the AM and PL current directed paired-pulse TMS. Vertical lines on each MEP recording indicate the onsets of each MEP. (B) The means and standard deviations of MEP amplitude of active FDI and ADM muscles obtained from all six subjects with the AM (open circles) and the PL (filled circles) current directions. The MEPs are expressed as a percentage of the control MEP amplitudes induced by test TMS alone. *Significant difference from the control value (Dunnett’s multiple comparison tests).
P!0.001) at short ISIs. However, the conditioned responses were not different between the two muscles using both current directions at short ISIs. On the other hand, at long ISIs, the conditioned MEP responses in FDI muscle with the PL current direction were significantly inhibited, but the remaining other conditioned MEP responses were not inhibited. Thus, there were a significant difference in FDI muscle between the two current directions (PZ0.003), and a significant difference between the two muscles with the PL current direction (P!0.001) at long ISIs.
whereas those in ADM muscle were not suppressed. Thus, the conditioned MEP responses were differentially modulated between FDI and ADM muscle at long ISIs (13 and 16 ms), although those responses were not different at short ISIs (2 and 4 ms). In addition, the conditioned responses with the PL current directions were not facilitated in both muscles and under both muscle conditions. These findings indicate that the effectiveness of ICI is more potent in FDI muscle than in ADM muscle, which presumably reflects a use-dependent adaptation and different functional demands.
4. Discussion
4.1. The different modulation of ICI circuits between FDI and ADM muscle
The present study provides the first evidence that the ICI circuits of FDI and ADM muscles are differentially modulated under both relaxed and active muscle conditions. In both muscle conditions, the conditioned MEP responses with the AM current direction (preferentially elicited early components of I-waves) were similar between the two muscles, but those with the PL current direction (preferentially elicited late components of I-waves) were different between FDI and ADM muscles. That is, the conditioned MEP responses in FDI muscle were significantly inhibited at long ISIs (13 and 16 ms) under both muscle conditions,
The direction of the current flow does not affect the ability to activate the ICI circuits by conditioning TMS, but does affect the pattern of I-waves produced in CTNs by suprathreshold TMS (Hanajima et al., 1998; Ziemann et al., 1996). Using the PL current direction, it is possible to preferentially elicit late I-waves under both relaxed and active muscle conditions (Hanajima et al., 1998; Sakai et al., 1997; Sugawara et al., 2005; Takahashi et al., 2004). These late I-waves are more affected by ICI circuits than early I-waves, which are little affected by them (Di Lazzaro et al.,
2762
M. Takahashi et al. / Clinical Neurophysiology 116 (2005) 2757–2764
Fig. 3. (A) The means and standard deviations of MEP amplitude under the relaxed muscle condition at short ISIs (2 and 4 ms, left) and long ISIs (13 and 16 ms, right). Muscle, current direction and ISIs are reported in the abscissa. (B) The means and standard deviations of MEP amplitude under the active muscle condition as similar to shown in (A). The MEPs are expressed as a percentage of the control MEP amplitudes induced by test TMS alone. *Significant difference from the control value (t-test with Bonferroni correction). †Significant difference (t-test with Bonferroni correction).
1998; Hanajima et al., 1998; Nakamura et al., 1997; Trompetto et al., 1999). It follows that the paired-pulse TMS with the PL current direction provides a more sensitive evaluation of the differential modulation of ICI circuits than that with the AM current direction. In fact, the conditioned MEP responses obtained with the PL current direction under both relaxed and active conditions were different between FDI and ADM muscles, whereas those with the AM current direction were similar between the two muscles. Using the PL current direction, the conditioned MEP responses in FDI muscle were inhibited at long ISIs (13 and 16 ms) under both muscle conditions, which is consistent with previous reports which revealed that the suppression of conditioned responses in FDI muscle produced by later
I-waves continued for more than 20 ms (Hanajima et al., 1998). However, the ICI effects in ADM muscle disappeared under both muscle conditions at long ISIs. These findings indicate that the effectiveness of ICI on CTNs excitability is more potent in FDI muscle than in ADM muscle. The excitability of CTNs is modulated by the balance between the ICI and ICF circuits in M1. These ICI and ICF circuits are two separate phenomena, and their effects in M1 may be explained by the convergence of two independent inputs onto a common neuron, possibly the CTNs itself (Hanajima et al., 1998; Ziemann et al., 1996). In addition, regarding ICI at long ISIs, Hanajima et al. (1998) have suggested this suppression reflects the activity of a subset of intracortical GABAergic interneurons in M1 as well as at ISIs of 1–5 ms. Thus, the suppression in FDI muscle at long ISIs indicates that the GABAergic ICI input onto CTNs, rather than the ICF input, is dominant. On the other hand, the possible mechanisms for the reduced effectiveness of ICI at long ISIs in ADM muscle might be caused by decreased excitability of an inhibitory process and/or increased excitability of a facilitatory process that could counteract the ICI effects on CTNs. However, ICF is reduced with the PL current direction and with voluntary activation (see below), and consequently may not contribute to the reduced effectiveness of ICI in ADM muscle. Thus, the most likely explanation for the present results is that the GABAergic inhibitory connections operating for CTNs in FDI muscle are more potent, and, conversely, those in ADM muscle are weaker. On the other hand, the conditioned MEP responses with the PL current direction in both muscles were significantly suppressed not only under relaxed but also active muscle conditions at short ISIs (2 and 4 ms), as shown in previous reports (Hanajima et al., 1998; Zoghi et al., 2003). However, the conditioned responses were not different between FDI and ADM muscles using both current directions at short ISIs (Fig. 3). These findings imply that there are no ICI differences between the two muscles. However, we speculated that small ICI differences may escape detection, so that the inhibitory effect is predominate at ISIs of 1–5 ms. In support of this hypothesis, previous studies did not find inter-hemispheres differences of ICI associated with asymmetrical dexterity at short ISIs using the optimal conditioning stimulus intensity of 80% RMT (Cicinelli et al., 2000; Maeda et al., 2002). However, using a range of non-optimal intensities of the conditioning stimulus, other studies showed that ICI was more potent (Hammond et al., 2004) or less pronounced (Ilic et al., 2004) in the dominant than non-dominant hemispheres. Although the reason for this discrepancy is not entirely clear, it is suggested that adjusting the parameters of the paired-pulse TMS (e.g. the conditioning and test stimulus intensities and ISIs) may greatly influence the balance of the ICI and ICF effects on CTNs excitability. On the other hand, the conditioning intensities used for ADM were slightly higher (w10%) than for FDI when expressed as a % maximum stimulator output
M. Takahashi et al. / Clinical Neurophysiology 116 (2005) 2757–2764
(Table 1), and consequently we cannot rule out the possibility that these differences have had an effect on the present results. Thus, it would be useful to test with the paired-pulse TMS over a range of sub-threshold conditioning intensities so as to reveal subtle differences in ICI between FDI and ADM muscles. This testing needs to be conducted in a future study. 4.2. ICF circuits of FDI and ADM muscles Regarding activation of the ICF circuits by conditioning TMS, Ziemann et al. (1996) demonstrated that clear facilitation in the resting muscle occurred only when the conditioning current flowed perpendicular to the central sulcus, suggesting that ICF is mediated by neural elements which have a preferred current direction (AM direction). In addition, it has been speculated that the absence of ICF during muscle activation might be due to changes in the excitability of intracortical circuits induced by a voluntary drive (Hanajima et al., 1998; Ridding et al., 1995). Thus, these two mechanisms are considered to explain the present findings that the conditioned MEP responses induced by the PL current direction were not facilitated in both muscles and under both conditions. However, in the present experiments, we were not able to reveal the differences in the ICF circuits between FDI and ADM muscles. Previous studies have demonstrated that ICF was less effective in musicians than in normal subjects (Nordstrom and Butler, 2002), and less effective in a distal hand muscle than in a proximal muscle (Abbruzzese et al., 1999). Conversely, it has been shown that the ICF circuits are more prone in the dominant than non-dominant hemisphere, depending on the asymmetrical dexterity (Hammond et al., 2004). Therefore, it has not yet been clarified what role ICF circuits play in motor control as compared to ICI circuits, and further studies of this are needed.
2763
contribute to their different functional demands (finger dexterity). This hypothesis is partially supported by the recent finding that the monosynaptic corticomotoneuronal projections, which provide the capacity for independent control of the digits and skilled use of the hand for fine motor tasks as well as the ICI, are more powerful to the alpha-motoneurons of FDI muscle than those of ADM muscle, depending on functional capacity when defined by maximal finger movement rate; index finger abduction (prime mover, FDI) is higher than little finger abduction (prime mover, ADM) (Ziemann et al., 2004a). On the other hand, this neural mechanism presumably reflects a usedependent adaptation, since the use of the index finger is more commonplace during the execution of daily manipulative tasks, providing the index finger with greater opportunities for qualitative and quantitative training than the little finger (Kamakura et al., 1980). Prolonged use of the fingers induces persistent plastic changes in the ICI and/ or ICF circuits as suggested by Nordstrom and Butler (2002). Thus, the paired-pulse TMS paradigm with the PL current direction is useful to investigate differential modulation of the ICI circuits associated with motor learning and pathological changes.
Acknowledgements This study was supported by a Research Projects Grantin-Aid for Ministry of Education, Culture, Sports and Technology in Japan (TK; C; 16500380). We thank Assoc. Prof. Norma Johnson (Graduate School of Health Sciences, Hiroshima University) for making valuable comments and editing English.
4.3. Functional implications
References
Inhibitory control, even during voluntary contraction, might contribute to finely controlled motor tasks, which require a sharp and sudden modulation of the produced force (Abbruzzese et al., 1999). In addition, ICI acts to limit the spread of activation and so shapes the spatiotemporal patterns of activation in M1 that result in dexterous movements (Ridding et al., 1995; Stinear and Byblow, 2003; Zoghi et al., 2003). This concept was also supported by pathological studies which have found that unilateral brain lesions which impair dexterity disturb inhibitory processes (Liepert et al., 2000; Manganotti et al., 2002), and that the pharmacological manipulation of inhibitory GABAergic circuits in M1 of monkeys interferes with the fine manipulative ability of the hands (Brochier et al., 1999; Matsumura et al., 1991). These findings suggest that the superior effectiveness of ICI of FDI muscle over that of ADM muscle is an important neural mechanism which may
Abbruzzese G, Assini A, Buccolieri A, Schieppati M, Trompetto C. Comparison of intracortical inhibition and facilitation in distal and proximal arm muscles in humans. J Physiol 1999;514:895–903. Brochier T, Boudreau MJ, Pare M, Smith AM. The effects of muscimol inactivation of small regions of motor and somatosensory cortex on independent finger movements and force control in the precision grip. Exp Brain Res 1999;128:31–40. Cicinelli P, Traversa R, Oliveri M, Palmieri MG, Filippi MM, Pasqualetti P, Rossini PM. Intracortical excitatory and inhibitory phenomena to paired transcranial magnetic stimulation in healthy human subjects: differences between the right and left hemisphere. Neurosci Lett 2000;288: 171–4. Day BL, Dressler D, Maertens de Noordhout A, Marsden CD, Nakashima K, Rothwell JC, Thompson PD. Electric and magnetic stimulation of human motor cortex: surface EMG and single motor unit responses. J Physiol 1989;412:449–73. Di Lazzaro V, Restuccia D, Oliviero A, Profice P, Ferrara L, Insola A, Mazzone P, Tonali P, Rothwell JC. Magnetic transcranial stimulation at intensities below active motor threshold activates intracortical inhibitory circuits. Exp Brain Res 1998;119:265–8.
2764
M. Takahashi et al. / Clinical Neurophysiology 116 (2005) 2757–2764
Di Lazzaro V, Oliviero A, Saturno E, Pilato F, Insola A, Mazzone P, Profice P, Tonali P, Rothwell JC. The effect on corticospinal volleys of reversing the direction of current induced in the motor cortex by transcranial magnetic stimulation. Exp Brain Res 2001;138:268–73. Hammond G, Faulkner D, Byrnes M, Mastaglia F, Thickbroom G. Transcranial magnetic stimulation reveals asymmetrical efficacy of intracortical circuits in primary motor cortex. Exp Brain Res 2004;155:19–23. Hanajima R, Ugawa Y, Terao Y, Sakai K, Furubayashi T, Machii K, Kanazawa I. Paired-pulse magnetic stimulation of the human motor cortex: differences among I waves. J Physiol 1998;509:607–18. Ilic TV, Jung P, Ziemann U. Subtle hemispheric asymmetry of motor cortical inhibitory tone. Clin Neurophysiol 2004;115:330–40. Kamakura N, Matsuo M, Ishii H, Mitsuboshi F, Miura Y. Patterns of static prehension in normal hands. Am J Occup Ther 1980;34:437–45. Kujirai T, Caramia MD, Rothwell JC, Day BL, Thompson PD, Ferbert A, Wroe S, Asselman P, Marsden CD. Corticocortical inhibition in human motor cortex. J Physiol 1993;471:501–19. Liepert J, Storch P, Fritsch A, Weiller C. Motor cortex disinhibition in acute stroke. Clin Neurophysiol 2000;111:671–6. Maeda F, Gangitano M, Thall M, Pascual-Leone A. Inter- and intraindividual variability of paired-pulse curves with transcranial magnetic stimulation (TMS). Clin Neurophysiol 2002;113:376–82. Manganotti P, Patuzzo S, Cortese F, Palermo A, Smania N, Fiaschi A. Motor disinhibition in affected and unaffected hemisphere in the early period of recovery after stroke. Clin Neurophysiol 2002;113:936–43. Matsumura M, Sawaguchi T, Oishi T, Ueki K, Kubota K. Behavioral deficits induced by local injection of bicuculline and muscimol into the primate motor and premotor cortex. J Neurophysiol 1991;65:1542–53. Nakamura H, Kitagawa H, Kawaguchi Y, Tsuji H. Intracortical facilitation and inhibition after transcranial magnetic stimulation in conscious humans. J Physiol 1997;498:817–23. Nordstrom MA, Butler SL. Reduced intracortical inhibition and facilitation of corticospinal neurons in musicians. Exp Brain Res 2002;144:336–42. Oldfield RC. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 1971;9:97–113. Ridding MC, Taylor JL, Rothwell JC. The effect of voluntary contraction on cortico-cortical inhibition in human motor cortex. J Physiol 1995; 487:541–8.
Rossini PM, Rossi S, Pasqualetti P, Tecchio F. Corticospinal excitability modulation to hand muscles during movement imagery. Cereb Cortex 1999;9:161–7. Sakai K, Ugawa Y, Terao Y, Hanajima R, Furubayashi T, Kanazawa I. Preferential activation of different I waves by transcranial magnetic stimulation with a figure-of-eight-shaped coil. Exp Brain Res 1997;113: 24–32. Stinear CM, Byblow WD. Role of intracortical inhibition in selective hand muscle activation. J Neurophysiol 2003;89:2014–20. Sugawara K, Furubayashi T, Takahashi M, Ni Z, Ugawa Y, Kasai T. Remote effects of voluntary teeth clenching on excitability changes of the human hand motor area. Neurosci Lett 2005;377:25–30. Takahashi M, Sugawara K, Hayashi S, Kasai T. Excitability changes in human hand motor area dependent on afferent inputs induced by different motor tasks. Exp Brain Res 2004;158:527–32. Trompetto C, Assini A, Buccolieri A, Marchese R, Abbruzzese G. Intracortical inhibition after paired transcranial magnetic stimulation depends on the current flow direction. Clin Neurophysiol 1999;110: 1106–10. Werhahn KJ, Fong JK, Meyer BU, Priori A, Rothwell JC, Day BL, Thompson PD. The effect of magnetic coil orientation on the latency of surface EMG and single motor unit responses in the first dorsal interosseous muscle. Electroencephalogr Clin Neurophysiol 1994;93: 138–46. Ziemann U, Rothwell JC, Ridding MC. Interaction between intracortical inhibition and facilitation in human motor cortex. J Physiol 1996;496: 873–81. Ziemann U, Ilic TV, Alle H, Meintzschel F. Cortico-motoneuronal excitation of three hand muscles determined by a novel pentastimulation technique. Brain 2004a;127:1887–98. Ziemann U, Ilic TV, Alle H, Meintzschel F. Estimated magnitude and interactions of cortico-motoneuronal and Ia afferent input to spinal motoneurones of the human hand. Neurosci Lett 2004b;364: 48–52. Zoghi M, Pearce SL, Nordstrom MA. Differential modulation of intracortical inhibition in human motor cortex during selective activation of an intrinsic hand muscle. J Physiol 2003;550:933–46.
Differential modulations of intracortical neural circuits between two intrinsic hand muscles Makoto Takahashia, Zhen Nia, Takamasa Yamashitab, Nan Liangb, Kenichi Sugawarac, Susumu Yahagid, Tatsuya Kasaia,* a
Division of Sports and Health Sciences, Graduate School for International Development and Cooperation, Hiroshima University, 1-5-1 Kagamiyama, Higashihiroshima 739-8529, Japan b Graduate School of Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan c Faculty of Health and Social Work, Kanagawa University of Human Services, 1-10-1 Heisei-cho, Yokosuka, Kanagawa 238-8522, Japan d Department of Human Environment Sciences, Hiroshima Shudo University, 11-1 Ozuka-higashi, Asaminami-ku, Hiroshima 731-3195, Japan Accepted 17 August 2005 Available online 25 October 2005
Abstract Objective: To investigate whether the intracortical inhibitory (ICI) and facilitatory (ICF) circuits in the primary motor cortex between the first dorsal interosseous (FDI) and abductor digiti minimi (ADM) muscles are modulated differently. Methods: We conducted paired-pulse transcranial magnetic stimulation in combination with different current directions (anterior-medially: AM, and posterior-laterally: PL) under relaxed and active muscle conditions with interstimulus intervals (ISIs) between 2 and 16 ms. Results: In both muscle conditions, the conditioned motor-evoked potential (MEP) responses obtained with the AM current direction (preferentially eliciting early I-waves) were similar between the two muscles at all ISIs, but the MEP responses obtained with the PL current direction (preferentially eliciting late I-waves) were different between FDI and ADM muscles, in that the conditioned MEP responses in FDI muscle were inhibited at all ISIs under both muscle conditions, whereas those in ADM muscle were suppressed at only short ISIs (2–4 ms). Conclusions: These results indicate that the inhibitory connections operating for the corticospinal tract neurons in FDI muscle are more potent, and, conversely, that those in ADM muscle are weaker. Significance: The different modulations of ICI circuits between FDI and ADM muscles is an important neural mechanism which may contribute to different functional demands (finger dexterity). q 2005 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Paired-pulse transcranial magnetic stimulation (TMS); Intracortical neural circuits; Current directions; I-waves; First dorsal interosseous (FDI) and abductor digiti minimi (ADM) muscles
1. Introduction The intracortical inhibitory circuits in the primary motor cortex (M1) play an important role in shaping motor output, and may contribute to selective activation of muscles for motor dexterity (Abbruzzese et al., 1999; Ridding et al., 1995; Stinear and Byblow, 2003; Zoghi et al., 2003). If the circuits do contribute to this selective activation, then the intracortical neural circuits in M1 between the first dorsal
* Corresponding author. Tel.: C81 82 424 6938; fax: C81 82 424 6904. E-mail address: [email protected] (T. Kasai).
interosseous (FDI) and abductor digiti minimi (ADM) muscles would likely be modulated differently. Because motor dexterity is definitely different between the index finger, which is controlled by FDI muscle, and the little finger, which is controlled by ADM muscle, in synergy with several intrinsic and extrinsic hand muscles (Rossini et al., 1999; Ziemann et al., 2004a). In fact, it was recently reported that the monosynaptic corticomotoneuronal projections, which provide the capacity for independent control of the digits and skilled use of the hand for fine motor tasks, are more powerful to the alpha-motoneurons of FDI muscle than those of ADM muscle depending on their different functional demands (Ziemann et al., 2004a,b). However, to
1388-2457/$30.00 q 2005 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2005.08.024
2758
M. Takahashi et al. / Clinical Neurophysiology 116 (2005) 2757–2764
our knowledge, it is not yet known whether or not the intracortical neural circuits between FDI and ADM muscles are actually modulated differently. To address this question, we investigated the intracortical inhibitory (ICI) and facilitatory (ICF) circuits of these muscles under relaxed and active muscle conditions using a paired-pulse transcranial magnetic stimulation (TMS) method with a subthreshold condition stimulus followed by a suprathreshold test stimulus (Kujirai et al., 1993; Ziemann et al., 1996). We also conducted the paired-pulse TMS in combination with different current directions in the brain so as to preferentially elicit different I-waves which could be recognizable early and late I-waves based on their different latencies (Hanajima et al., 1998; Sakai et al., 1997; Sugawara et al., 2005; Takahashi et al., 2004). This specifically allowed us to examine the role of the neural elements responsible for late I-waves, which are susceptible to ICI circuits (Di Lazzaro et al., 1998; Hanajima et al., 1998; Nakamura et al., 1997). The goal of the present study was, therefore, to address whether or not the ICI and/or ICF circuits between FDI and ADM muscles are modulated differently.
2. Methods 2.1. Subjects Six healthy right-handed (Oldfield, 1971) volunteers (five males and one female, mean age 26.5 yrs, range 23–34 yrs) participated in the experiments after giving their informed consent. Each subject participated in two experiments (relaxed and active muscle conditions) in a randomized order and at least 24 h apart. The experiments were performed in accordance with the Declaration of Helsinki and with the approval of the Local Ethics Committee of Hiroshima University. 2.2. Electromyographic (EMG) recording and cortical stimulation The surface EMGs were recorded from right FDI and ADM muscles with surface Ag/Agcl surface cup electrodes (9 mm in diameter). The active electrode was placed over each muscle belly and the reference electrode over the metacarpophalangeal joint of the index and little finger. The EMG signals were amplified at a bandwidth of 5 Hz to 5 kHz, sampled at 5 kHz, and fed to a computer for off-line analysis. TMS was given through a figure-of-eight-shaped coil (The Magstim Company, UK). At the beginning of each experiment, the position of the coil was systematically adjusted on the scalp over the left motor cortex to find the optimum location for the activation of each target muscle (FDI and ADM). As previous investigations have shown (Day et al., 1989; Di Lazzaro et al., 2001; Hanajima et al.,
1998; Sakai et al., 1997; Trompetto et al., 1999; Werhahn et al., 1994), it is possible to elicit different I-waves by different current directions in the brain. In a relaxed muscle, the temporal summation of multiple I-waves are required to produce a test motor-evoked potential (MEP), and consequently, MEPs to the anterior-medially (AM) current direction are produced by a combination of I1 and I2 waves, and other late I-waves, whereas MEPs to the posterior-laterally (PL) current direction are probably generated by I3 and I4 waves (Sugawara et al., 2005; Takahashi et al., 2004). On the other hand, since the excitability of spinal motoneurons increases in active muscle, MEPs are produced by I1 and I3 waves induced by the AM and PL current directions, respectively (Hanajima et al., 1998; Sakai et al., 1997). Thus, based on the different latencies of MEP, we confirmed whether early or late I-waves were preferentially elicited by these two different current directions. After adjustment of the coil position and orientation for each target muscle (FDI and ADM), the resting (RMT) and active (AMT) motor thresholds of each muscle were determined. RMT was defined as the lowest stimulus intensity which evoked MEP with amplitudes of about 50 mV in at least four out of eight (50%) successive trials in relaxed muscles. AMT was defined as the lowest stimulus intensity evoking MEP with amplitudes of about 200 mV in at least four out of eight successive trials in slightly isometric contracting muscles (5–10% maximum voluntary contraction as assessed visually on an oscilloscope screen). 2.3. Paired-pulse magnetic stimulation We investigated the effects of ICI and ICF circuits on two different I-waves evoked by magnetic stimulation with selected current directions under both relaxed and active muscle conditions. Data of FDI and ADM were separately collected in the same session using the TMS intensities and stimulation sites appropriate for each muscle. The conditioning and test stimuli were given through the same figure-of-eight-shaped coil by connecting two Magstim 200 stimulators via a Bistim module (The Magstim Company, UK). The TMS intensities of the conditioning stimulus were fixed at 90% of the RMT and AMT, respectively. The test stimulus was adjusted to elicit a MEP response with a peak-to-peak amplitude of approximately 1.0 mV in both muscles and under both conditions. We selected six interstimulus intervals (ISIs: 2, 4, 6, 9, 13, and 16 ms) based on previous reports (Kujirai et al., 1993; Ziemann et al., 1996), and these ISIs were randomly delivered. At least 8–10 responses were collected at each ISI. The mean peak-to-peak MEP amplitudes of each ISI were expressed as a percentage of the control MEP amplitudes induced by the test stimulus alone.
M. Takahashi et al. / Clinical Neurophysiology 116 (2005) 2757–2764
2759
direction were significantly lower than those with the PL current direction in both muscles and under both muscle conditions (paired t-test: P!0.05). These results indicate that early and late I-waves were preferentially elicited by the present experimental conditions using opposite current directions.
2.4. Data and Statistical analyses The differences in onset latencies, thresholds, and test TMS intensities between the AM and PL current directions were compared by paired t-test. First, in order to assess the general ICI/ICF curve, the conditioned MEP amplitudes for each muscle (FDI and ADM), each current direction (AM and PL), and each condition (relaxed and active muscle) were analyzed independently using one-way ANOVA with repeated measures (factor; ISIs). If a significant effect of ISIs was obtained, Dunnett’s multiple comparison tests were used to compare the values obtained at the different ISIs with the control (unconditioned) values. Second, in order to investigate the effects of the muscle, current direction and ISIs on the ICI and ICF circuits, we calculated representative data for the short (mean of 2 and 4 ms) and long (mean of 13 and 16 ms) ISIs. The mean data were independently analyzed for each muscle condition (relaxed and active) using three-way ANOVA with repeated measures [factors; muscle, current direction and ISIs (short and long)]. If a significant interaction between all three factors was obtained, post hoc analyses were done using the paired t-test with Bonferroni correction for multiple comparisons. The level of statistical significance was defined as P!0.05. The data are expressed as meansGSD.
3.2. ICI and ICF circuits under relaxed muscle condition Fig. 1A shows the MEP specimen records (superimposed three trials) in FDI (left side traces) and ADM (right side traces) muscles elicited at different ISIs and in different current directions (AM: upper traces and PL: lower traces) under the relaxed muscle condition obtained from a single subject. The conditioned MEP responses in both FDI and ADM muscles with the AM current direction were suppressed at an ISI of 2 ms, almost the same size as that at an ISI of 6 ms, and facilitated at an ISI of 13 ms. On the other hand, the conditioned response sizes in FDI muscle with the PL current direction were reduced at ISIs of 2, 6, and 13 ms. The conditioned MEP responses in ADM muscle with the PL current direction were also inhibited as well as those of FDI muscle at ISIs of 2 and 6 ms, but the conditioned responses were almost the same size as the control (unconditioned) responses at an ISI of 13 ms. Then, the means and standard deviations of all subjects tested (nZ6) were calculated and are shown in Fig. 1B. The conditioned MEP responses in both muscles with the AM current direction were similar to the previous observations, in that they consisted of an early inhibition followed by a later facilitation (Kujirai et al., 1993; Ziemann et al., 1996). Meanwhile, the conditioned responses of FDI muscle with the PL current direction were significantly suppressed at all ISIs (Dunnett’s test: P!0.05). In contrast, the conditioned MEP responses in ADM muscle with the PL current direction were significantly inhibited at ISIs of 2, 4 and 6 ms (Dunnett’s test: P!0.05), whereas inhibition and facilitation disappeared at ISIs of 9, 13 and 16 ms. Further, we calculated the representative data for short ISIs (2 and 4 ms) and long ones (13 and 16 ms), so as to investigate the effects of the muscle, current direction, and ISIs on the ICI and ICF circuits. As shown in Fig. 3A, there was a significant interaction between all three factors
3. Results 3.1. Onset latencies, thresholds, and test TMS intensities The onset latencies, thresholds, and test TMS intensities of FDI and ADM muscles with different current directions (AM and PL) under both the relaxed and active conditions are summarized in Table 1. The MEP latencies with the AM current direction were always significantly shorter than those with the PL current direction in both muscles and under both muscle conditions (paired t-test: P!0.05). In addition, the MEP latencies under the relaxed muscle condition were longer than those under the active muscle condition (paired t-test: P!0.05). On the other hand, the thresholds and test TMS intensities with the AM current
Table 1 Effect of different current directions (AM and PL) on the latencies, test intensities, and motor thresholds under relaxed and active muscle conditions Relaxed (nZ6)
Active (nZ6)
FDI
Latency (ms) Threshold intensity (%) Test intensity (%)
ADM
FDI
ADM
AM
PL
AM
PL
AM
PL
AM
PL
21.3G0.6 45.3G3.4 60.2G8.8
23.3G0.7* 59.2G8.6* 79.8G10.3*
21.4G0.9 50.3G8.2 71.7G9.3
23.3G0.8* 63.3G7.7* 84.2G7.4*
20.1G1.1† 35.3G6.2† 54.8G11.1†
22.5G0.9*† 49.5G9.1*† 68.2G14.6*†
19.8G0.9† 39.7G4.1† 58.3G9.3†
22.5G1.1*† 53.8G5.3*† 73.3G10.3*†
Values are meansGSD. n, no. of subjects; FDI, first dorsal interosseous; ADM, abductor digiti minimi muscles; AM, anterior-medially; PL, posterior-laterally current directions. *Significant difference (P!0.05) between the AM and PL current directions. †Significant difference between the relaxed and active muscle conditions.
2760
M. Takahashi et al. / Clinical Neurophysiology 116 (2005) 2757–2764
Fig. 1. (A) Specimen records of MEPs (superimposed three trials) of relaxed FDI (left) and ADM (right) muscles obtained from a single subject with the AM and PL current directed paired-pulse TMS. Vertical lines on each MEP recording indicate the onsets of each MEP. (B) The means and standard deviations of MEP amplitude of relaxed FDI and ADM muscles obtained from all six subjects with the AM (open circles) and the PL (filled circles) current directions. The MEPs are expressed as a percentage of the control MEP amplitudes induced by test TMS alone. *Significant difference from the control value (Dunnett’s multiple comparison tests).
(FZ3.587, P!0.05). The conditioned MEP responses in FDI and ADM muscles with both the AM and PL current directions were significantly inhibited at short ISIs (t-test with Bonferroni correction: P!0.001), although there were no significant differences among current directions and muscles. On the other hand, there were significant differences in both FDI and ADM muscles between the AM and PL current directions at long ISIs (t-test with Bonferroni correction: FDI: P!0.001, ADM: P!0.001). Furthermore, the conditioned MEP responses in FDI muscle were significantly suppressed, but those responses in ADM muscle were not inhibited. Thus, the conditioned MEP responses with the PL current direction were significantly different between FDI and ADM muscles at long ISIs (t-test with Bonferroni correction: PZ0.004). 3.3. ICI and ICF circuits under active muscle condition Fig. 2A shows the MEP specimen records of FDI and ADM muscles obtained from a single subject during slight voluntary contraction, similar to that shown in Fig. 1A. In both FDI and ADM muscles, the conditioned MEP responses obtained with the AM current direction were almost the same size as the control (unconditioned) responses. On the other hand, the conditioned MEP responses in FDI muscle with the PL current direction were suppressed at ISIs of 2, 6 and 13 ms. In contrast,
the conditioned MEP responses in ADM muscle with the PL current direction were suppressed at an ISI of 2 ms, but were almost the same size as the control (unconditioned) responses at ISIs of 6 and 13 ms. Then, the means and standard deviations of all subjects tested (nZ6) were calculated and are shown in Fig. 2B. The conditioned MEP responses in both muscles with the AM current direction were not significantly inhibited and facilitated, as reported previously (Ridding et al., 1995), while the conditioned MEP responses in FDI muscle with the PL current direction were significantly suppressed at all ISIs (Dunnett’s test: P! 0.05). In contrast, the conditioned MEP responses in ADM muscle with the PL current direction were significantly inhibited at ISIs of 2 and 4 ms (Dunnett’s test: P!0.05), whereas neither inhibition nor facilitation were observed at later ISIs. Further, we calculated the representative data for short ISIs (2 and 4 ms) and long ISIs (13 and 16 ms), and the results are shown in Fig. 3B. There was a significant interaction between all three factors (muscle, current direction and ISIs: FZ5.657, P!0.05). The conditioned MEP responses in both FDI and ADM muscles with the PL current direction were significantly suppressed at short ISIs, whereas those responses with the AM current direction were not suppressed. There were significant differences in both muscles between the AM and PL current directions (t-test with Bonferroni correction: FDI: P!0.001, ADM:
M. Takahashi et al. / Clinical Neurophysiology 116 (2005) 2757–2764
2761
Fig. 2. (A) Specimen records of MEPs (superimposed three trials) of active FDI (left) and ADM (right) muscles obtained from a single subject with the AM and PL current directed paired-pulse TMS. Vertical lines on each MEP recording indicate the onsets of each MEP. (B) The means and standard deviations of MEP amplitude of active FDI and ADM muscles obtained from all six subjects with the AM (open circles) and the PL (filled circles) current directions. The MEPs are expressed as a percentage of the control MEP amplitudes induced by test TMS alone. *Significant difference from the control value (Dunnett’s multiple comparison tests).
P!0.001) at short ISIs. However, the conditioned responses were not different between the two muscles using both current directions at short ISIs. On the other hand, at long ISIs, the conditioned MEP responses in FDI muscle with the PL current direction were significantly inhibited, but the remaining other conditioned MEP responses were not inhibited. Thus, there were a significant difference in FDI muscle between the two current directions (PZ0.003), and a significant difference between the two muscles with the PL current direction (P!0.001) at long ISIs.
whereas those in ADM muscle were not suppressed. Thus, the conditioned MEP responses were differentially modulated between FDI and ADM muscle at long ISIs (13 and 16 ms), although those responses were not different at short ISIs (2 and 4 ms). In addition, the conditioned responses with the PL current directions were not facilitated in both muscles and under both muscle conditions. These findings indicate that the effectiveness of ICI is more potent in FDI muscle than in ADM muscle, which presumably reflects a use-dependent adaptation and different functional demands.
4. Discussion
4.1. The different modulation of ICI circuits between FDI and ADM muscle
The present study provides the first evidence that the ICI circuits of FDI and ADM muscles are differentially modulated under both relaxed and active muscle conditions. In both muscle conditions, the conditioned MEP responses with the AM current direction (preferentially elicited early components of I-waves) were similar between the two muscles, but those with the PL current direction (preferentially elicited late components of I-waves) were different between FDI and ADM muscles. That is, the conditioned MEP responses in FDI muscle were significantly inhibited at long ISIs (13 and 16 ms) under both muscle conditions,
The direction of the current flow does not affect the ability to activate the ICI circuits by conditioning TMS, but does affect the pattern of I-waves produced in CTNs by suprathreshold TMS (Hanajima et al., 1998; Ziemann et al., 1996). Using the PL current direction, it is possible to preferentially elicit late I-waves under both relaxed and active muscle conditions (Hanajima et al., 1998; Sakai et al., 1997; Sugawara et al., 2005; Takahashi et al., 2004). These late I-waves are more affected by ICI circuits than early I-waves, which are little affected by them (Di Lazzaro et al.,
2762
M. Takahashi et al. / Clinical Neurophysiology 116 (2005) 2757–2764
Fig. 3. (A) The means and standard deviations of MEP amplitude under the relaxed muscle condition at short ISIs (2 and 4 ms, left) and long ISIs (13 and 16 ms, right). Muscle, current direction and ISIs are reported in the abscissa. (B) The means and standard deviations of MEP amplitude under the active muscle condition as similar to shown in (A). The MEPs are expressed as a percentage of the control MEP amplitudes induced by test TMS alone. *Significant difference from the control value (t-test with Bonferroni correction). †Significant difference (t-test with Bonferroni correction).
1998; Hanajima et al., 1998; Nakamura et al., 1997; Trompetto et al., 1999). It follows that the paired-pulse TMS with the PL current direction provides a more sensitive evaluation of the differential modulation of ICI circuits than that with the AM current direction. In fact, the conditioned MEP responses obtained with the PL current direction under both relaxed and active conditions were different between FDI and ADM muscles, whereas those with the AM current direction were similar between the two muscles. Using the PL current direction, the conditioned MEP responses in FDI muscle were inhibited at long ISIs (13 and 16 ms) under both muscle conditions, which is consistent with previous reports which revealed that the suppression of conditioned responses in FDI muscle produced by later
I-waves continued for more than 20 ms (Hanajima et al., 1998). However, the ICI effects in ADM muscle disappeared under both muscle conditions at long ISIs. These findings indicate that the effectiveness of ICI on CTNs excitability is more potent in FDI muscle than in ADM muscle. The excitability of CTNs is modulated by the balance between the ICI and ICF circuits in M1. These ICI and ICF circuits are two separate phenomena, and their effects in M1 may be explained by the convergence of two independent inputs onto a common neuron, possibly the CTNs itself (Hanajima et al., 1998; Ziemann et al., 1996). In addition, regarding ICI at long ISIs, Hanajima et al. (1998) have suggested this suppression reflects the activity of a subset of intracortical GABAergic interneurons in M1 as well as at ISIs of 1–5 ms. Thus, the suppression in FDI muscle at long ISIs indicates that the GABAergic ICI input onto CTNs, rather than the ICF input, is dominant. On the other hand, the possible mechanisms for the reduced effectiveness of ICI at long ISIs in ADM muscle might be caused by decreased excitability of an inhibitory process and/or increased excitability of a facilitatory process that could counteract the ICI effects on CTNs. However, ICF is reduced with the PL current direction and with voluntary activation (see below), and consequently may not contribute to the reduced effectiveness of ICI in ADM muscle. Thus, the most likely explanation for the present results is that the GABAergic inhibitory connections operating for CTNs in FDI muscle are more potent, and, conversely, those in ADM muscle are weaker. On the other hand, the conditioned MEP responses with the PL current direction in both muscles were significantly suppressed not only under relaxed but also active muscle conditions at short ISIs (2 and 4 ms), as shown in previous reports (Hanajima et al., 1998; Zoghi et al., 2003). However, the conditioned responses were not different between FDI and ADM muscles using both current directions at short ISIs (Fig. 3). These findings imply that there are no ICI differences between the two muscles. However, we speculated that small ICI differences may escape detection, so that the inhibitory effect is predominate at ISIs of 1–5 ms. In support of this hypothesis, previous studies did not find inter-hemispheres differences of ICI associated with asymmetrical dexterity at short ISIs using the optimal conditioning stimulus intensity of 80% RMT (Cicinelli et al., 2000; Maeda et al., 2002). However, using a range of non-optimal intensities of the conditioning stimulus, other studies showed that ICI was more potent (Hammond et al., 2004) or less pronounced (Ilic et al., 2004) in the dominant than non-dominant hemispheres. Although the reason for this discrepancy is not entirely clear, it is suggested that adjusting the parameters of the paired-pulse TMS (e.g. the conditioning and test stimulus intensities and ISIs) may greatly influence the balance of the ICI and ICF effects on CTNs excitability. On the other hand, the conditioning intensities used for ADM were slightly higher (w10%) than for FDI when expressed as a % maximum stimulator output
M. Takahashi et al. / Clinical Neurophysiology 116 (2005) 2757–2764
(Table 1), and consequently we cannot rule out the possibility that these differences have had an effect on the present results. Thus, it would be useful to test with the paired-pulse TMS over a range of sub-threshold conditioning intensities so as to reveal subtle differences in ICI between FDI and ADM muscles. This testing needs to be conducted in a future study. 4.2. ICF circuits of FDI and ADM muscles Regarding activation of the ICF circuits by conditioning TMS, Ziemann et al. (1996) demonstrated that clear facilitation in the resting muscle occurred only when the conditioning current flowed perpendicular to the central sulcus, suggesting that ICF is mediated by neural elements which have a preferred current direction (AM direction). In addition, it has been speculated that the absence of ICF during muscle activation might be due to changes in the excitability of intracortical circuits induced by a voluntary drive (Hanajima et al., 1998; Ridding et al., 1995). Thus, these two mechanisms are considered to explain the present findings that the conditioned MEP responses induced by the PL current direction were not facilitated in both muscles and under both conditions. However, in the present experiments, we were not able to reveal the differences in the ICF circuits between FDI and ADM muscles. Previous studies have demonstrated that ICF was less effective in musicians than in normal subjects (Nordstrom and Butler, 2002), and less effective in a distal hand muscle than in a proximal muscle (Abbruzzese et al., 1999). Conversely, it has been shown that the ICF circuits are more prone in the dominant than non-dominant hemisphere, depending on the asymmetrical dexterity (Hammond et al., 2004). Therefore, it has not yet been clarified what role ICF circuits play in motor control as compared to ICI circuits, and further studies of this are needed.
2763
contribute to their different functional demands (finger dexterity). This hypothesis is partially supported by the recent finding that the monosynaptic corticomotoneuronal projections, which provide the capacity for independent control of the digits and skilled use of the hand for fine motor tasks as well as the ICI, are more powerful to the alpha-motoneurons of FDI muscle than those of ADM muscle, depending on functional capacity when defined by maximal finger movement rate; index finger abduction (prime mover, FDI) is higher than little finger abduction (prime mover, ADM) (Ziemann et al., 2004a). On the other hand, this neural mechanism presumably reflects a usedependent adaptation, since the use of the index finger is more commonplace during the execution of daily manipulative tasks, providing the index finger with greater opportunities for qualitative and quantitative training than the little finger (Kamakura et al., 1980). Prolonged use of the fingers induces persistent plastic changes in the ICI and/ or ICF circuits as suggested by Nordstrom and Butler (2002). Thus, the paired-pulse TMS paradigm with the PL current direction is useful to investigate differential modulation of the ICI circuits associated with motor learning and pathological changes.
Acknowledgements This study was supported by a Research Projects Grantin-Aid for Ministry of Education, Culture, Sports and Technology in Japan (TK; C; 16500380). We thank Assoc. Prof. Norma Johnson (Graduate School of Health Sciences, Hiroshima University) for making valuable comments and editing English.
4.3. Functional implications
References
Inhibitory control, even during voluntary contraction, might contribute to finely controlled motor tasks, which require a sharp and sudden modulation of the produced force (Abbruzzese et al., 1999). In addition, ICI acts to limit the spread of activation and so shapes the spatiotemporal patterns of activation in M1 that result in dexterous movements (Ridding et al., 1995; Stinear and Byblow, 2003; Zoghi et al., 2003). This concept was also supported by pathological studies which have found that unilateral brain lesions which impair dexterity disturb inhibitory processes (Liepert et al., 2000; Manganotti et al., 2002), and that the pharmacological manipulation of inhibitory GABAergic circuits in M1 of monkeys interferes with the fine manipulative ability of the hands (Brochier et al., 1999; Matsumura et al., 1991). These findings suggest that the superior effectiveness of ICI of FDI muscle over that of ADM muscle is an important neural mechanism which may
Abbruzzese G, Assini A, Buccolieri A, Schieppati M, Trompetto C. Comparison of intracortical inhibition and facilitation in distal and proximal arm muscles in humans. J Physiol 1999;514:895–903. Brochier T, Boudreau MJ, Pare M, Smith AM. The effects of muscimol inactivation of small regions of motor and somatosensory cortex on independent finger movements and force control in the precision grip. Exp Brain Res 1999;128:31–40. Cicinelli P, Traversa R, Oliveri M, Palmieri MG, Filippi MM, Pasqualetti P, Rossini PM. Intracortical excitatory and inhibitory phenomena to paired transcranial magnetic stimulation in healthy human subjects: differences between the right and left hemisphere. Neurosci Lett 2000;288: 171–4. Day BL, Dressler D, Maertens de Noordhout A, Marsden CD, Nakashima K, Rothwell JC, Thompson PD. Electric and magnetic stimulation of human motor cortex: surface EMG and single motor unit responses. J Physiol 1989;412:449–73. Di Lazzaro V, Restuccia D, Oliviero A, Profice P, Ferrara L, Insola A, Mazzone P, Tonali P, Rothwell JC. Magnetic transcranial stimulation at intensities below active motor threshold activates intracortical inhibitory circuits. Exp Brain Res 1998;119:265–8.
2764
M. Takahashi et al. / Clinical Neurophysiology 116 (2005) 2757–2764
Di Lazzaro V, Oliviero A, Saturno E, Pilato F, Insola A, Mazzone P, Profice P, Tonali P, Rothwell JC. The effect on corticospinal volleys of reversing the direction of current induced in the motor cortex by transcranial magnetic stimulation. Exp Brain Res 2001;138:268–73. Hammond G, Faulkner D, Byrnes M, Mastaglia F, Thickbroom G. Transcranial magnetic stimulation reveals asymmetrical efficacy of intracortical circuits in primary motor cortex. Exp Brain Res 2004;155:19–23. Hanajima R, Ugawa Y, Terao Y, Sakai K, Furubayashi T, Machii K, Kanazawa I. Paired-pulse magnetic stimulation of the human motor cortex: differences among I waves. J Physiol 1998;509:607–18. Ilic TV, Jung P, Ziemann U. Subtle hemispheric asymmetry of motor cortical inhibitory tone. Clin Neurophysiol 2004;115:330–40. Kamakura N, Matsuo M, Ishii H, Mitsuboshi F, Miura Y. Patterns of static prehension in normal hands. Am J Occup Ther 1980;34:437–45. Kujirai T, Caramia MD, Rothwell JC, Day BL, Thompson PD, Ferbert A, Wroe S, Asselman P, Marsden CD. Corticocortical inhibition in human motor cortex. J Physiol 1993;471:501–19. Liepert J, Storch P, Fritsch A, Weiller C. Motor cortex disinhibition in acute stroke. Clin Neurophysiol 2000;111:671–6. Maeda F, Gangitano M, Thall M, Pascual-Leone A. Inter- and intraindividual variability of paired-pulse curves with transcranial magnetic stimulation (TMS). Clin Neurophysiol 2002;113:376–82. Manganotti P, Patuzzo S, Cortese F, Palermo A, Smania N, Fiaschi A. Motor disinhibition in affected and unaffected hemisphere in the early period of recovery after stroke. Clin Neurophysiol 2002;113:936–43. Matsumura M, Sawaguchi T, Oishi T, Ueki K, Kubota K. Behavioral deficits induced by local injection of bicuculline and muscimol into the primate motor and premotor cortex. J Neurophysiol 1991;65:1542–53. Nakamura H, Kitagawa H, Kawaguchi Y, Tsuji H. Intracortical facilitation and inhibition after transcranial magnetic stimulation in conscious humans. J Physiol 1997;498:817–23. Nordstrom MA, Butler SL. Reduced intracortical inhibition and facilitation of corticospinal neurons in musicians. Exp Brain Res 2002;144:336–42. Oldfield RC. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 1971;9:97–113. Ridding MC, Taylor JL, Rothwell JC. The effect of voluntary contraction on cortico-cortical inhibition in human motor cortex. J Physiol 1995; 487:541–8.
Rossini PM, Rossi S, Pasqualetti P, Tecchio F. Corticospinal excitability modulation to hand muscles during movement imagery. Cereb Cortex 1999;9:161–7. Sakai K, Ugawa Y, Terao Y, Hanajima R, Furubayashi T, Kanazawa I. Preferential activation of different I waves by transcranial magnetic stimulation with a figure-of-eight-shaped coil. Exp Brain Res 1997;113: 24–32. Stinear CM, Byblow WD. Role of intracortical inhibition in selective hand muscle activation. J Neurophysiol 2003;89:2014–20. Sugawara K, Furubayashi T, Takahashi M, Ni Z, Ugawa Y, Kasai T. Remote effects of voluntary teeth clenching on excitability changes of the human hand motor area. Neurosci Lett 2005;377:25–30. Takahashi M, Sugawara K, Hayashi S, Kasai T. Excitability changes in human hand motor area dependent on afferent inputs induced by different motor tasks. Exp Brain Res 2004;158:527–32. Trompetto C, Assini A, Buccolieri A, Marchese R, Abbruzzese G. Intracortical inhibition after paired transcranial magnetic stimulation depends on the current flow direction. Clin Neurophysiol 1999;110: 1106–10. Werhahn KJ, Fong JK, Meyer BU, Priori A, Rothwell JC, Day BL, Thompson PD. The effect of magnetic coil orientation on the latency of surface EMG and single motor unit responses in the first dorsal interosseous muscle. Electroencephalogr Clin Neurophysiol 1994;93: 138–46. Ziemann U, Rothwell JC, Ridding MC. Interaction between intracortical inhibition and facilitation in human motor cortex. J Physiol 1996;496: 873–81. Ziemann U, Ilic TV, Alle H, Meintzschel F. Cortico-motoneuronal excitation of three hand muscles determined by a novel pentastimulation technique. Brain 2004a;127:1887–98. Ziemann U, Ilic TV, Alle H, Meintzschel F. Estimated magnitude and interactions of cortico-motoneuronal and Ia afferent input to spinal motoneurones of the human hand. Neurosci Lett 2004b;364: 48–52. Zoghi M, Pearce SL, Nordstrom MA. Differential modulation of intracortical inhibition in human motor cortex during selective activation of an intrinsic hand muscle. J Physiol 2003;550:933–46.