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Hemispheric asymmetry of surround inhibition in the human motor system
Clinical Neurophysiology 120 (2009) 816–819
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Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph
Hemispheric asymmetry of surround inhibition in the human motor system Hae-Won Shin a,c, Young H. Sohn a,b,*, Mark Hallett d a
Department of Neurology, Brain Research Institute, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemun-gu, Seoul 120-752, South Korea Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea Parkinson and Alzheimer Center, Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea d Human Motor Control Section, NINDS, National Institutes of Health, Bethesda, MD, USA b c
a r t i c l e
i n f o
Article history: Accepted 7 February 2009 Available online 18 March 2009 Keywords: Handedness TMS Motor cortex Inhibition
a b s t r a c t Objective: Surround inhibition (SI) in the motor system is an essential mechanism for the selective execution of desired movements. To investigate the relationship between the efficiency of SI operation in the motor system and handedness, we performed a transcranial magnetic stimulation (TMS) study in 10 healthy, right-handed volunteers. Methods: TMS was set to be triggered by self-initiated flexion of the index finger at different intervals ranging from 3 to 1000 ms. Average motor evoked potential (MEP) amplitudes obtained from self-triggered TMS were normalized to average MEPs of the control TMS at rest and expressed as a percentage. Normalized MEP amplitudes of the adductor digiti minimi (ADM) and the flexor digitorum superficialis (FDS) muscles were compared between the dominant and non-dominant hands. Results: During index finger flexion, MEP amplitudes of the ADM in the dominant hand were suppressed but not in the non-dominant hand, while MEP amplitudes of the FDS were comparably enhanced in both hands. F-wave amplitudes of ADM were comparably enhanced during index finger flexion in both hands. Conclusion: These results suggest that the functional operation of SI in the motor system is more efficient in the dominant hand than the non-dominant hand. More efficient SI in the dominant hand could lead to greater dexterity in the dominant hand. Significance: Hemispheric asymmetry of SI might be able to serve as a neurophysiological proxy for handedness. Ó 2009 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Handedness is the most prominent human behavioral asymmetry and refers either to hand preference or to the asymmetrical performance of motor tasks (Triggs et al., 2000). In monkeys, motor representations in the motor cortex (M1) of the dominant hand are larger and more complex than those of the non-dominant hand (Nudo et al., 1992). However, various studies investigating the neurophysiological differences responsible for handedness have failed to produce consistent results (Hammond, 2002). Surround inhibition (SI) in the human motor system is an essential mechanism for the selective execution of desired movements (Mink, 1996). Because appropriate movement selection is essential for the successful performance of various motor tasks, functional operation of SI could be an important factor in deciding hand dominance. Recently the functional existence of SI was demonstrated in the human motor cortex using a self-triggered transcranial mag-
* Corresponding author. Address: Department of Neurology, Brain Research Institute, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemungu, Seoul 120-752, South Korea. Tel.: +82 2 2228 1601; fax: +82 2 393 0705. E-mail address: [email protected] (Y.H. Sohn).
netic stimulation (TMS) technique (Sohn and Hallett, 2004b). We used this technique to measure SI in both hands of healthy volunteers to investigate the relationship between the efficiency of SI operation and hand dominance. 2. Subjects and methods 2.1. Subjects Ten healthy, right-handed volunteers (mean age: 23.8 years, range: 22–26; 9 men) participated in this study after giving their written informed consent. This study was approved by the Local Ethics Committee. Handedness of each subject was assessed using the 10 items related to hand dominance of the 12-item version of the Edinburgh Handedness Inventory (Oldfield, 1971). In all subjects, the calculated laterality quotients were +75 or higher (mean: +93). 2.2. TMS Surface electromyography (EMG) activity was recorded (bandpass, 10–2000 Hz) from the flexor digitorum superficialis (FDS)
1388-2457/$36.00 Ó 2009 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2009.02.004
817
H.-W. Shin et al. / Clinical Neurophysiology 120 (2009) 816–819
average EMG duration of the FDS was comparable between the right ð127 14:7 msÞ and left hand ð126 12:6 msÞ, and that the ADM was usually quiet or slightly active with a small and brief EMG during index finger movement (peak-to-peak EMG amplitude, 41:3 3:9 lV in the dominant ADM and 46:5 4:1 lV in the non-dominant ADM). RMT was also comparable between the dominant and non-dominant ADM muscles (53:2 1:8% and 54:9 1:9%). MEPs were suppressed or unchanged in the dominant ADM during index finger movement while those were unchanged in the non-dominant ADM (Fig. 1A). MEPs were significantly enhanced both in the dominant and in the non-dominant FDS (Fig. 1B). Repeated measures ANOVA revealed a significant effect of the interaction of the tested side and the intervals on normalized MEPs of both the ADM (df = 6, F = 3.48, p < 0:005), but no effect on those of the FDS (df = 6, F = 1.02). This analysis revealed no effect of the tested side on normalized MEPs of both the FDS (df = 1, F = 1.67; Fig. 1A) or the ADM (df = 1, F = 0.73; Fig. 1B) when all stimulus intervals were included in the analysis. However, if only the stimulus intervals during index finger movement (i.e., 3, 15, 40 and 80 ms) were included, this analysis yielded a significant effect on normalized ADM MEPs of the tested side (df = 1, F = 5.56, p < 0:05), but still no effect on normalized MEP amplitudes of the FDS (df = 1, F = 1.97). Compared to the resting state, ADM MEP amplitudes were significantly reduced at intervals of
A. ADM 150
*
125
% Resting MEP
and the abductor digiti minimi (ADM) muscles of both hands using a conventional amplifier (P511 High Performance AC Preamplifier, GRASS Instrument, West Warwick, USA). The signal was digitized at a frequency of 5 kHz and fed into a laboratory computer for further off-line analysis. A figure-of-eight shaped coil (each loop measuring 70 mm in diameter) connected to a Magstim 200 magnetic stimulator (Magstim, Whitland, Dyfed, UK) was placed flat on the scalp over the M1 at the optimal site for eliciting maximal amplitude motor evoked potentials (MEPs) in the contralateral ADM. The individual resting motor threshold (RMT) was determined to the nearest 1% of the maximum stimulator output and was defined as the minimal stimulus intensity required to produce MEPs of >50 lV in at least 5 of 10 consecutive trials. Using a LabVIEW program (National Instrument, Austin, TX, USA) and a Schmidt discriminator, TMS was set to be triggered by EMG activity of FDS (self-triggered TMS) similar to the previous studies (Sohn and Hallett, 2004a,b). The sensitivity of the Schmidt discriminator was set at a level sufficient to correctly detect the onset of EMG activity, but not to produce triggering at rest (usually 100—150 lV peak-to-peak EMG amplitude). ‘Go’ signals were given at random intervals between 5 and 9 s. Subjects were asked to flex their index finger briefly after the ‘go’ signal with a selfpaced delay (subjects were instructed not to react immediately). Before the experiment, subjects practiced making a brief (duration around 100 ms) and selective movement while monitoring their own EMG activity. Seven sessions of self-triggered TMS were performed in a random order at variable intervals (3, 15, 40, 80, 200, 500 and 1000 ms) between EMG onset and TMS triggering. Two control sessions without self-triggering were administered before and after self-triggered sessions. Both hands were tested in a single experimental session; the dominant hand was tested first in half of the subjects, while in the others the non-dominant hand was tested first. MEP size was determined by averaging the peak-topeak amplitudes over 18 trials for each session at a stimulus intensity of 140% individual RMT in both self-triggered and control sessions. Average MEP amplitudes obtained from self-triggered TMS were normalized to average MEPs of the control TMS and expressed as a percentage.
*
*
100 75 50 Dominant Non-dominant
25
2.3. Peripheral nerve stimulation
2.4. Statistical analysis Data are expressed as mean SEM. Normalized MEP and Fwave amplitudes for the self-triggered sessions at the different intervals were compared between hands, by using a repeated measures ANOVA. RMT, average EMG duration of FDS, background EMG activity of the ADM during index finger movement, and normalized MEP amplitude at each interval were compared between hands by using paired t-tests. MEP amplitudes at each interval in self-triggered TMS sessions were compared to those in resting state by using paired t-test. P < 0:05 was regarded as significant. 3. Results All subjects performed index finger flexion selectively and briefly. Off-line analysis of the EMG recordings revealed that the
3 ms
15 ms
40 ms
80 ms 200 ms 500 ms 1000 ms
Interval from EMG onset to TMS
B. FDS 400
Dominant Non-dominant
350
% Resting MEP
In 4 of 10 subjects, with supramaximal electrical stimulation of the ulnar nerve at the wrist, peak-to-peak amplitude of F-waves (average, 12 trials) of the ADM was determined in both control and self-triggered sessions. Average F-wave amplitudes obtained from self-triggered sessions were normalized to average F-wave amplitudes of the control TMS and expressed as a percentage. Normalized F-wave amplitudes were compared between both hands.
0
300 250 200 150 100 50 0
3 ms
15 ms
40 ms
80 ms 200 ms 500 ms 1000 ms
Interval from EMG onset to TMS Fig. 1. Changes in MEP amplitudes of tested muscles in self-triggered TMS at each interval from EMG onset of the FDS to TMS compared to the resting state. An asterisk indicates a significant difference between the dominant and the nondominant hands, analyzed by a paired t-test. (A) During index finger flexion, MEP amplitudes of the ADM were suppressed in the dominant hand at intervals of 3, 15 and 40 ms, but unchanged in the non-dominant hand. (B) MEP amplitudes of the FDS were comparably enhanced in both hands during index finger flexion.
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3, 15, 40 ms during self-triggered TMS in the dominant hand, while those were unchanged at all intervals in the non-dominant hand. Normalized MEP amplitudes of the dominant ADM were significantly smaller than those of the non-dominant ADM at intervals of 3, 15 and 40 ms. Average of normalized ADM MEPs at intervals of 3, 15, 40 ms in the dominant hand is less than 80% in 8 subjects, while that in the non-dominant hand is higher than 80% in 7 subjects. In all subjects, average of normalized ADM MEPs at intervals of 3, 15, 40 ms in the dominant hand was smaller than that in the non-dominant hand (Fig. 2). The ratio of the dominant/non-dominant ADM MEPs ranged from 49% to 91% (mean: 71%). During index finger movement, average F-wave amplitudes were enhanced compared to the resting state (160 8:6% in the dominant ADM, and 151 5:1% in the non-dominant ADM). ADM F-wave enhancement was comparable between hands (df = 1, F = 1.00). 4. Discussion Our results demonstrate that during index finger flexion, MEPs of the ADM in both hands were suppressed or unchanged with enhanced F-wave amplitudes, as shown in the previous studies (Sohn and Hallett, 2004a,b). Unchanged MEPs, despite enhanced spinal excitability, indicate that supraspinal inhibition is exerted on the ADM during index finger flexion and counterbalances the influence of spinal excitation on that muscle. Thus, more suppressed MEPs in the ADM in the dominant hand compared to the non-dominant hand may indicate that supraspinal inhibition exerted on the ADM is greater in the dominant hand than in the non-dominant hand, because the enhancement of spinal excitability between both hands was comparable (as measured by F-wave amplitude). Off-line analysis of the EMG recordings revealed comparable EMG activity in the ADM between hands; this excludes a difference in co-contraction of the ADMs during index finger movement that might also explain the difference in SI. If the co-contraction had been less in the dominant hand, then that could be partly etiologic. Although the independence of finger movement is a well developed human activity, it is not perfect. Close analysis of all fingers when normal humans attempt to move just one finger showed that
Normalized MEP (%) of non-dominant hand
160
140
120
100
80
60
40 40
60
80
100
120
140
160
Normalized MEP (%) of dominant hand Fig. 2. Average of normalized ADM MEPs at 3, 15 and 40 ms in both hands in each subject. All subjects show lower normalized MEPs in the dominant hand compared to that in the non-dominant hand.
the other fingers were not completely immobile (Hager-Ross and Schieber, 2000; Reilly and Hammond, 2000). Accordingly, in this study, the ADM was not completely silent during index finger movements, but was usually active with a small EMG activity. Therefore, SI is not necessarily manifested as complete silence of surround muscles, but means much less activation of those muscles compared with movement-related muscles. This non-instructed movement may result in part from passive mechanical connections between finger muscles, but derives also from distributed neural controls of the hand (Hager-Ross and Schieber, 2000). The fact that the degree of individuation of the fingers is not different between dominant and non-dominant hands (Hager-Ross and Schieber, 2000; Reilly and Hammond, 2000, 2004) suggests that handedness is not related simply to a greater independence of finger movements, but is rather associated with more accurate control of movements involving multiple digits simultaneously in the dominant hand. Pyramidal neurons in the motor cortex (M1) that exert excitatory influences on their postsynaptic targets have horizontal axon collaterals that are connected locally to other pyramidal neurons as well as to inhibitory interneurons (Kang et al., 1991). The connections between pyramidal neurons presumably provide feedforward excitatory interactions between groups of cells related to the same movement, whereas the connections with inhibitory interneurons may form a basis for SI between representation zones related to the activation of different muscles (Keller, 1993). Compared to the non-dominant M1, the dominant M1 has a greater area of hand representation and shows a greater dispersion of elementary movement representations with more profuse horizontal connections (Amunts et al., 1997, 1996; Nudo et al., 1992; Volkmann et al., 1998; Hammond, 2002). More profuse interconnections in the dominant M1 compared to the non-dominant M1 may provide a greater potential for movement representations to interact in the M1 (Hammond, 2002) and may form a neural substrate for more efficient SI in the motor system of the dominant hemisphere, as observed in this study. More efficient SI in the motor system of the dominant hemisphere could provide greater dexterity of the dominant hand. More efficient SI does not simply mean more independent movements of the digits in the dominant hand as observed by previous studies (Hager-Ross and Schieber, 2000; Reilly and Hammond, 2000, 2004), but rather indicates more efficient spatial and temporal coordination of representation zones related to different hand movements that may facilitate hand dexterity. Various TMS studies have been performed to evaluate the hemispheric asymmetry of M1 excitability responsible for handedness. Some studies have demonstrated a larger size of the motor representation area in the dominant hemisphere compared to the nondominant hemisphere (Wassermann et al., 1992; Triggs et al., 1999), while other studies have shown a similar size in both hemispheres (Cicinelli et al., 1997; Classen et al., 1998). Some studies have reported a lower MEP threshold in the dominant hemisphere compared to the non-dominant hemisphere (Macdonell et al., 1991; Triggs et al., 1994), while others have not found similar findings (Cicinelli et al., 1997; Civardi et al., 2000; Priori et al., 1999; Triggs et al., 1999). Studies investigating the hemispheric differences of intracortical inhibitory and facilitatory function have also failed to show consistent results (Civardi et al., 2000; Cicinelli et al., 1997; Priori et al., 1999; Ilic et al., 2004; Lefaucheur et al., 2008; Hammond et al., 2004). These controversial results suggest that current TMS measurements evaluating M1 excitability may be insufficient to detect subtle neurophysiological asymmetry related to handedness. The cortical substrate of SI is still unclear, but GABAergic intracortical inhibition (i.e., short-interval intracortical inhibition, SICI) has been proposed to mediate SI in humans (Sohn and Hallett, 2004b; Stinear and Byblow, 2003; Zoghi et al., 2003). However, previous studies comparing SICI between both hands have
H.-W. Shin et al. / Clinical Neurophysiology 120 (2009) 816–819
shown controversial results, in which SICI was either enhanced (Hammond et al., 2004), reduced (Ilic et al., 2004), or unchanged (Civardi et al., 2000) in the dominant M1, partly because of different techniques used to measure SICI. Because the degree of SI operation is variable among subjects, it is difficult to provide a specific cut-off value of SI for the discrimination of the dominant and the non-dominant hand (for example, less than 80% resting MEP at the 3 ms interval indicates that the tested hand is dominant, and so on). However, the fact that the operation of SI in the dominant hand is greater than that in the non-dominant hand in all subjects suggests that SI measurements used in this study might be an optimal method for detecting neurophysiological asymmetry related to handedness. Acknowledgements This work was supported by the Brain Korea 21 Project for Medical Science, Yonsei University. The authors report no conflict of interest. References Amunts K, Schlaug G, Schleicher A, Steinmetz H, Dabringhaus A, Roland PE, et al. Asymmetry in the human motor cortex and handedness. Neuroimage 1996;4:216–22. Amunts K, Schmidt-Passos F, Schleicher A, Zilles K. Postnatal development of interhemispheric asymmetry in the cytoarchitecture of human area 4. Anat Embryol (Berl) 1997;196:393–402. Cicinelli P, Traversa R, Bassi A, Scivoletto G, Rossini PM. Interhemispheric differences of hand muscle representation in human motor cortex. Muscle Nerve 1997;20:535–42. Civardi C, Cavalli A, Naldi P, Varrasi C, Cantello R. Hemispheric asymmetries of cortico-cortical connections in human hand motor areas. Clin Neurophysiol 2000;111:624–9. Classen J, Knorr U, Werhahn KJ, Schlaug G, Kunesch E, Cohen LG, et al. Multimodal output mapping of human central motor representation on different spatial scales. J Physiol 1998;512(Pt. 1):163–79. Hager-Ross C, Schieber MH. Quantifying the independence of human finger movements: comparisons of digits, hands, and movement frequencies. J Neurosci 2000;20:8542–50. Hammond G. Correlates of human handedness in primary motor cortex: a review and hypothesis. Neurosci Biobehav Rev 2002;26:285–92. 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.
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Ilic TV, Jung P, Ziemann U. Subtle hemispheric asymmetry of motor cortical inhibitory tone. Clin Neurophysiol 2004;115:330–40. Kang Y, Endo K, Araki T. Differential connections by intracortical axon collaterals among pyramidal tract cells in the cat motor cortex. J Physiol 1991;435:243–56. Keller A. Intrinsic synaptic organization of the motor cortex. Cereb Cortex 1993;3:430–41. Lefaucheur JP, Lucas B, Andraud F, Hogrel JY, Bellivier F, Del Cul A, et al. Interhemispheric asymmetry of motor corticospinal excitability in major depression studied by transcranial magnetic stimulation. J Psychiatr Res 2008;42:389–98. Macdonell RA, Shapiro BE, Chiappa KH, Helmers SL, Cros D, Day BJ, et al. Hemispheric threshold differences for motor evoked potentials produced by magnetic coil stimulation. Neurology 1991;41:1441–4. Mink JW. The basal ganglia: focused selection and inhibition of competing motor programs. Prog Neurobiol 1996;50:381–425. Nudo RJ, Jenkins WM, Merzenich MM, Prejean T, Grenda R. Neurophysiological correlates of hand preference in primary motor cortex of adult squirrel monkeys. J Neurosci 1992;12:2918–47. Oldfield RC. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 1971;9:97–113. Priori A, Oliviero A, Donati E, Callea L, Bertolasi L, Rothwell JC. Human handedness and asymmetry of the motor cortical silent period. Exp Brain Res 1999;128:390–6. Reilly KT, Hammond GR. Independence of force production by digits of the human hand. Neurosci Lett 2000;290:53–6. Reilly KT, Hammond GR. Human handedness: is there a difference in the independence of the digits on the preferred and non-preferred hands? Exp Brain Res 2004;156:255–62. Sohn YH, Hallett M. Disturbed surround inhibition in focal hand dystonia. Ann Neurol 2004a;56:595–9. Sohn YH, Hallett M. Surround inhibition in human motor system. Exp Brain Res 2004b;158:397–404. Stinear CM, Byblow WD. Role of intracortical inhibition in selective hand muscle activation. J Neurophysiol 2003;89:2014–20. Triggs WJ, Calvanio R, Macdonell RA, Cros D, Chiappa KH. Physiological motor asymmetry in human handedness: evidence from transcranial magnetic stimulation. Brain Res 1994;636:270–6. Triggs WJ, Subramanium B, Rossi F. Hand preference and transcranial magnetic stimulation asymmetry of cortical motor representation. Brain Res 1999;835:324–9. Triggs WJ, Calvanio R, Levine M, Heaton RK, Heilman KM. Predicting hand preference with performance on motor tasks. Cortex 2000;36:679–89. Volkmann J, Schnitzler A, Witte OW, Freund H. Handedness and asymmetry of hand representation in human motor cortex. J Neurophysiol 1998;79:2149–54. Wassermann EM, McShane LM, Hallett M, Cohen LG. Noninvasive mapping of muscle representations in human motor cortex. Electroencephalogr Clin Neurophysiol 1992;85:1–8. 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.
Contents lists available at ScienceDirect
Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph
Hemispheric asymmetry of surround inhibition in the human motor system Hae-Won Shin a,c, Young H. Sohn a,b,*, Mark Hallett d a
Department of Neurology, Brain Research Institute, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemun-gu, Seoul 120-752, South Korea Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea Parkinson and Alzheimer Center, Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea d Human Motor Control Section, NINDS, National Institutes of Health, Bethesda, MD, USA b c
a r t i c l e
i n f o
Article history: Accepted 7 February 2009 Available online 18 March 2009 Keywords: Handedness TMS Motor cortex Inhibition
a b s t r a c t Objective: Surround inhibition (SI) in the motor system is an essential mechanism for the selective execution of desired movements. To investigate the relationship between the efficiency of SI operation in the motor system and handedness, we performed a transcranial magnetic stimulation (TMS) study in 10 healthy, right-handed volunteers. Methods: TMS was set to be triggered by self-initiated flexion of the index finger at different intervals ranging from 3 to 1000 ms. Average motor evoked potential (MEP) amplitudes obtained from self-triggered TMS were normalized to average MEPs of the control TMS at rest and expressed as a percentage. Normalized MEP amplitudes of the adductor digiti minimi (ADM) and the flexor digitorum superficialis (FDS) muscles were compared between the dominant and non-dominant hands. Results: During index finger flexion, MEP amplitudes of the ADM in the dominant hand were suppressed but not in the non-dominant hand, while MEP amplitudes of the FDS were comparably enhanced in both hands. F-wave amplitudes of ADM were comparably enhanced during index finger flexion in both hands. Conclusion: These results suggest that the functional operation of SI in the motor system is more efficient in the dominant hand than the non-dominant hand. More efficient SI in the dominant hand could lead to greater dexterity in the dominant hand. Significance: Hemispheric asymmetry of SI might be able to serve as a neurophysiological proxy for handedness. Ó 2009 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Handedness is the most prominent human behavioral asymmetry and refers either to hand preference or to the asymmetrical performance of motor tasks (Triggs et al., 2000). In monkeys, motor representations in the motor cortex (M1) of the dominant hand are larger and more complex than those of the non-dominant hand (Nudo et al., 1992). However, various studies investigating the neurophysiological differences responsible for handedness have failed to produce consistent results (Hammond, 2002). Surround inhibition (SI) in the human motor system is an essential mechanism for the selective execution of desired movements (Mink, 1996). Because appropriate movement selection is essential for the successful performance of various motor tasks, functional operation of SI could be an important factor in deciding hand dominance. Recently the functional existence of SI was demonstrated in the human motor cortex using a self-triggered transcranial mag-
* Corresponding author. Address: Department of Neurology, Brain Research Institute, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemungu, Seoul 120-752, South Korea. Tel.: +82 2 2228 1601; fax: +82 2 393 0705. E-mail address: [email protected] (Y.H. Sohn).
netic stimulation (TMS) technique (Sohn and Hallett, 2004b). We used this technique to measure SI in both hands of healthy volunteers to investigate the relationship between the efficiency of SI operation and hand dominance. 2. Subjects and methods 2.1. Subjects Ten healthy, right-handed volunteers (mean age: 23.8 years, range: 22–26; 9 men) participated in this study after giving their written informed consent. This study was approved by the Local Ethics Committee. Handedness of each subject was assessed using the 10 items related to hand dominance of the 12-item version of the Edinburgh Handedness Inventory (Oldfield, 1971). In all subjects, the calculated laterality quotients were +75 or higher (mean: +93). 2.2. TMS Surface electromyography (EMG) activity was recorded (bandpass, 10–2000 Hz) from the flexor digitorum superficialis (FDS)
1388-2457/$36.00 Ó 2009 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2009.02.004
817
H.-W. Shin et al. / Clinical Neurophysiology 120 (2009) 816–819
average EMG duration of the FDS was comparable between the right ð127 14:7 msÞ and left hand ð126 12:6 msÞ, and that the ADM was usually quiet or slightly active with a small and brief EMG during index finger movement (peak-to-peak EMG amplitude, 41:3 3:9 lV in the dominant ADM and 46:5 4:1 lV in the non-dominant ADM). RMT was also comparable between the dominant and non-dominant ADM muscles (53:2 1:8% and 54:9 1:9%). MEPs were suppressed or unchanged in the dominant ADM during index finger movement while those were unchanged in the non-dominant ADM (Fig. 1A). MEPs were significantly enhanced both in the dominant and in the non-dominant FDS (Fig. 1B). Repeated measures ANOVA revealed a significant effect of the interaction of the tested side and the intervals on normalized MEPs of both the ADM (df = 6, F = 3.48, p < 0:005), but no effect on those of the FDS (df = 6, F = 1.02). This analysis revealed no effect of the tested side on normalized MEPs of both the FDS (df = 1, F = 1.67; Fig. 1A) or the ADM (df = 1, F = 0.73; Fig. 1B) when all stimulus intervals were included in the analysis. However, if only the stimulus intervals during index finger movement (i.e., 3, 15, 40 and 80 ms) were included, this analysis yielded a significant effect on normalized ADM MEPs of the tested side (df = 1, F = 5.56, p < 0:05), but still no effect on normalized MEP amplitudes of the FDS (df = 1, F = 1.97). Compared to the resting state, ADM MEP amplitudes were significantly reduced at intervals of
A. ADM 150
*
125
% Resting MEP
and the abductor digiti minimi (ADM) muscles of both hands using a conventional amplifier (P511 High Performance AC Preamplifier, GRASS Instrument, West Warwick, USA). The signal was digitized at a frequency of 5 kHz and fed into a laboratory computer for further off-line analysis. A figure-of-eight shaped coil (each loop measuring 70 mm in diameter) connected to a Magstim 200 magnetic stimulator (Magstim, Whitland, Dyfed, UK) was placed flat on the scalp over the M1 at the optimal site for eliciting maximal amplitude motor evoked potentials (MEPs) in the contralateral ADM. The individual resting motor threshold (RMT) was determined to the nearest 1% of the maximum stimulator output and was defined as the minimal stimulus intensity required to produce MEPs of >50 lV in at least 5 of 10 consecutive trials. Using a LabVIEW program (National Instrument, Austin, TX, USA) and a Schmidt discriminator, TMS was set to be triggered by EMG activity of FDS (self-triggered TMS) similar to the previous studies (Sohn and Hallett, 2004a,b). The sensitivity of the Schmidt discriminator was set at a level sufficient to correctly detect the onset of EMG activity, but not to produce triggering at rest (usually 100—150 lV peak-to-peak EMG amplitude). ‘Go’ signals were given at random intervals between 5 and 9 s. Subjects were asked to flex their index finger briefly after the ‘go’ signal with a selfpaced delay (subjects were instructed not to react immediately). Before the experiment, subjects practiced making a brief (duration around 100 ms) and selective movement while monitoring their own EMG activity. Seven sessions of self-triggered TMS were performed in a random order at variable intervals (3, 15, 40, 80, 200, 500 and 1000 ms) between EMG onset and TMS triggering. Two control sessions without self-triggering were administered before and after self-triggered sessions. Both hands were tested in a single experimental session; the dominant hand was tested first in half of the subjects, while in the others the non-dominant hand was tested first. MEP size was determined by averaging the peak-topeak amplitudes over 18 trials for each session at a stimulus intensity of 140% individual RMT in both self-triggered and control sessions. Average MEP amplitudes obtained from self-triggered TMS were normalized to average MEPs of the control TMS and expressed as a percentage.
*
*
100 75 50 Dominant Non-dominant
25
2.3. Peripheral nerve stimulation
2.4. Statistical analysis Data are expressed as mean SEM. Normalized MEP and Fwave amplitudes for the self-triggered sessions at the different intervals were compared between hands, by using a repeated measures ANOVA. RMT, average EMG duration of FDS, background EMG activity of the ADM during index finger movement, and normalized MEP amplitude at each interval were compared between hands by using paired t-tests. MEP amplitudes at each interval in self-triggered TMS sessions were compared to those in resting state by using paired t-test. P < 0:05 was regarded as significant. 3. Results All subjects performed index finger flexion selectively and briefly. Off-line analysis of the EMG recordings revealed that the
3 ms
15 ms
40 ms
80 ms 200 ms 500 ms 1000 ms
Interval from EMG onset to TMS
B. FDS 400
Dominant Non-dominant
350
% Resting MEP
In 4 of 10 subjects, with supramaximal electrical stimulation of the ulnar nerve at the wrist, peak-to-peak amplitude of F-waves (average, 12 trials) of the ADM was determined in both control and self-triggered sessions. Average F-wave amplitudes obtained from self-triggered sessions were normalized to average F-wave amplitudes of the control TMS and expressed as a percentage. Normalized F-wave amplitudes were compared between both hands.
0
300 250 200 150 100 50 0
3 ms
15 ms
40 ms
80 ms 200 ms 500 ms 1000 ms
Interval from EMG onset to TMS Fig. 1. Changes in MEP amplitudes of tested muscles in self-triggered TMS at each interval from EMG onset of the FDS to TMS compared to the resting state. An asterisk indicates a significant difference between the dominant and the nondominant hands, analyzed by a paired t-test. (A) During index finger flexion, MEP amplitudes of the ADM were suppressed in the dominant hand at intervals of 3, 15 and 40 ms, but unchanged in the non-dominant hand. (B) MEP amplitudes of the FDS were comparably enhanced in both hands during index finger flexion.
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3, 15, 40 ms during self-triggered TMS in the dominant hand, while those were unchanged at all intervals in the non-dominant hand. Normalized MEP amplitudes of the dominant ADM were significantly smaller than those of the non-dominant ADM at intervals of 3, 15 and 40 ms. Average of normalized ADM MEPs at intervals of 3, 15, 40 ms in the dominant hand is less than 80% in 8 subjects, while that in the non-dominant hand is higher than 80% in 7 subjects. In all subjects, average of normalized ADM MEPs at intervals of 3, 15, 40 ms in the dominant hand was smaller than that in the non-dominant hand (Fig. 2). The ratio of the dominant/non-dominant ADM MEPs ranged from 49% to 91% (mean: 71%). During index finger movement, average F-wave amplitudes were enhanced compared to the resting state (160 8:6% in the dominant ADM, and 151 5:1% in the non-dominant ADM). ADM F-wave enhancement was comparable between hands (df = 1, F = 1.00). 4. Discussion Our results demonstrate that during index finger flexion, MEPs of the ADM in both hands were suppressed or unchanged with enhanced F-wave amplitudes, as shown in the previous studies (Sohn and Hallett, 2004a,b). Unchanged MEPs, despite enhanced spinal excitability, indicate that supraspinal inhibition is exerted on the ADM during index finger flexion and counterbalances the influence of spinal excitation on that muscle. Thus, more suppressed MEPs in the ADM in the dominant hand compared to the non-dominant hand may indicate that supraspinal inhibition exerted on the ADM is greater in the dominant hand than in the non-dominant hand, because the enhancement of spinal excitability between both hands was comparable (as measured by F-wave amplitude). Off-line analysis of the EMG recordings revealed comparable EMG activity in the ADM between hands; this excludes a difference in co-contraction of the ADMs during index finger movement that might also explain the difference in SI. If the co-contraction had been less in the dominant hand, then that could be partly etiologic. Although the independence of finger movement is a well developed human activity, it is not perfect. Close analysis of all fingers when normal humans attempt to move just one finger showed that
Normalized MEP (%) of non-dominant hand
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Normalized MEP (%) of dominant hand Fig. 2. Average of normalized ADM MEPs at 3, 15 and 40 ms in both hands in each subject. All subjects show lower normalized MEPs in the dominant hand compared to that in the non-dominant hand.
the other fingers were not completely immobile (Hager-Ross and Schieber, 2000; Reilly and Hammond, 2000). Accordingly, in this study, the ADM was not completely silent during index finger movements, but was usually active with a small EMG activity. Therefore, SI is not necessarily manifested as complete silence of surround muscles, but means much less activation of those muscles compared with movement-related muscles. This non-instructed movement may result in part from passive mechanical connections between finger muscles, but derives also from distributed neural controls of the hand (Hager-Ross and Schieber, 2000). The fact that the degree of individuation of the fingers is not different between dominant and non-dominant hands (Hager-Ross and Schieber, 2000; Reilly and Hammond, 2000, 2004) suggests that handedness is not related simply to a greater independence of finger movements, but is rather associated with more accurate control of movements involving multiple digits simultaneously in the dominant hand. Pyramidal neurons in the motor cortex (M1) that exert excitatory influences on their postsynaptic targets have horizontal axon collaterals that are connected locally to other pyramidal neurons as well as to inhibitory interneurons (Kang et al., 1991). The connections between pyramidal neurons presumably provide feedforward excitatory interactions between groups of cells related to the same movement, whereas the connections with inhibitory interneurons may form a basis for SI between representation zones related to the activation of different muscles (Keller, 1993). Compared to the non-dominant M1, the dominant M1 has a greater area of hand representation and shows a greater dispersion of elementary movement representations with more profuse horizontal connections (Amunts et al., 1997, 1996; Nudo et al., 1992; Volkmann et al., 1998; Hammond, 2002). More profuse interconnections in the dominant M1 compared to the non-dominant M1 may provide a greater potential for movement representations to interact in the M1 (Hammond, 2002) and may form a neural substrate for more efficient SI in the motor system of the dominant hemisphere, as observed in this study. More efficient SI in the motor system of the dominant hemisphere could provide greater dexterity of the dominant hand. More efficient SI does not simply mean more independent movements of the digits in the dominant hand as observed by previous studies (Hager-Ross and Schieber, 2000; Reilly and Hammond, 2000, 2004), but rather indicates more efficient spatial and temporal coordination of representation zones related to different hand movements that may facilitate hand dexterity. Various TMS studies have been performed to evaluate the hemispheric asymmetry of M1 excitability responsible for handedness. Some studies have demonstrated a larger size of the motor representation area in the dominant hemisphere compared to the nondominant hemisphere (Wassermann et al., 1992; Triggs et al., 1999), while other studies have shown a similar size in both hemispheres (Cicinelli et al., 1997; Classen et al., 1998). Some studies have reported a lower MEP threshold in the dominant hemisphere compared to the non-dominant hemisphere (Macdonell et al., 1991; Triggs et al., 1994), while others have not found similar findings (Cicinelli et al., 1997; Civardi et al., 2000; Priori et al., 1999; Triggs et al., 1999). Studies investigating the hemispheric differences of intracortical inhibitory and facilitatory function have also failed to show consistent results (Civardi et al., 2000; Cicinelli et al., 1997; Priori et al., 1999; Ilic et al., 2004; Lefaucheur et al., 2008; Hammond et al., 2004). These controversial results suggest that current TMS measurements evaluating M1 excitability may be insufficient to detect subtle neurophysiological asymmetry related to handedness. The cortical substrate of SI is still unclear, but GABAergic intracortical inhibition (i.e., short-interval intracortical inhibition, SICI) has been proposed to mediate SI in humans (Sohn and Hallett, 2004b; Stinear and Byblow, 2003; Zoghi et al., 2003). However, previous studies comparing SICI between both hands have
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shown controversial results, in which SICI was either enhanced (Hammond et al., 2004), reduced (Ilic et al., 2004), or unchanged (Civardi et al., 2000) in the dominant M1, partly because of different techniques used to measure SICI. Because the degree of SI operation is variable among subjects, it is difficult to provide a specific cut-off value of SI for the discrimination of the dominant and the non-dominant hand (for example, less than 80% resting MEP at the 3 ms interval indicates that the tested hand is dominant, and so on). However, the fact that the operation of SI in the dominant hand is greater than that in the non-dominant hand in all subjects suggests that SI measurements used in this study might be an optimal method for detecting neurophysiological asymmetry related to handedness. Acknowledgements This work was supported by the Brain Korea 21 Project for Medical Science, Yonsei University. The authors report no conflict of interest. References Amunts K, Schlaug G, Schleicher A, Steinmetz H, Dabringhaus A, Roland PE, et al. Asymmetry in the human motor cortex and handedness. Neuroimage 1996;4:216–22. Amunts K, Schmidt-Passos F, Schleicher A, Zilles K. Postnatal development of interhemispheric asymmetry in the cytoarchitecture of human area 4. Anat Embryol (Berl) 1997;196:393–402. Cicinelli P, Traversa R, Bassi A, Scivoletto G, Rossini PM. Interhemispheric differences of hand muscle representation in human motor cortex. Muscle Nerve 1997;20:535–42. Civardi C, Cavalli A, Naldi P, Varrasi C, Cantello R. Hemispheric asymmetries of cortico-cortical connections in human hand motor areas. Clin Neurophysiol 2000;111:624–9. Classen J, Knorr U, Werhahn KJ, Schlaug G, Kunesch E, Cohen LG, et al. Multimodal output mapping of human central motor representation on different spatial scales. J Physiol 1998;512(Pt. 1):163–79. Hager-Ross C, Schieber MH. Quantifying the independence of human finger movements: comparisons of digits, hands, and movement frequencies. J Neurosci 2000;20:8542–50. Hammond G. Correlates of human handedness in primary motor cortex: a review and hypothesis. Neurosci Biobehav Rev 2002;26:285–92. 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.
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