Abstract

We can recognize handwritten letters despite the variability among writers. One possible strategy is exploiting the motor memory of orthography. By using TMS, we clarified the excitatory and inhibitory neural circuits of the motor corticospinal pathway that might be activated during the observation of handwritten letters. During experiments, participants looked at the handwritten or printed single letter that appeared in a random order. The excitability of the left and right primary motor cortex (M1) was evaluated by motor-evoked potentials elicited by single-pulse TMS. Short interval intracortical inhibition (SICI) of the left M1 was evaluated using paired-pulse TMS. F waves were measured for the right ulnar nerve. We found significant reduction of corticospinal excitability only for the right hand at 300–400 msec after each letter presentation without significant changes in SICI. This suppression is likely to be of supraspinal origin, because of no significant alteration in F-wave amplitudes. These findings suggest that the recognition of handwritten letters may include the implicit knowledge of “writing” in M1. The M1 activation associated with that process, which has been shown in previous neuroimaging studies, is likely to reflect the active suppression of the corticospinal excitability.

INTRODUCTION

To acquire literacy is to learn reading and writing. In that sense, the memory of motor commands for writing letters and that of visual/graphical images should be bound together in “literacy.” For example, air-writing or tracing shapes of letters in the air sometimes facilitates recalling the correct spelling. This implicit motor memory of “writing” might also help us in reading texts, despite an extreme variability of letter appearances in shapes and sizes, especially in the case of handwritten ones. Thus, the brain processing of letters as well as words might include both the visual and motor aspects. In other words, literacy includes the ability to decode most of any possible appearances of letters, where knowledge of writing may play an important role in this process.

However, the neural basis of this interplay between motor commands and visual perception during the observation of letters is not well understood. One candidate mechanism is the mirror-neuron system (MNS), which is similarly activated by own motor action and the observation of other people's action (Longcamp, Tanskanen, & Hari, 2006; Rizzolatti & Craighero, 2004; Longcamp, Anton, Roth, & Velay, 2003; Gallese, Fadiga, Fogassi, & Rizzolatti, 1996). Previous studies showed that even the observation of traces of motor act, such as sounds or photographs associated with action, can elicit MNS activation (Aziz-Zadeh, Iacoboni, Zaidel, Wilson, & Mazziotta, 2004; Johnson-Frey et al., 2003; Kohler et al., 2002; Nishitani & Hari, 2002; Kourtzi & Kanwisher, 2000). In this context, written texts might be regarded as the imprint of manual action of writing. The interplay between perception and production of handwriting has been investigated to account for our ability to recognize handwritten scripts accurately despite the extreme variability from one writer to another (Wada, Koike, Vatikiotis-Bateson, & Kawato, 1995; Zimmer, 1982), suggesting that we apply during the perception of handwritten traces our own knowledge about the implicit motor rules involved in writing.

Most of the previous neuroimaging and neuropsychological studies on letter perception/recognition focused on the functional relevance of the left occipito-temporal cortex (Cohen et al., 2003; Polk et al., 2002; Raij, Uutela, & Hari, 2000; Tarkiainen, Helenius, Hansen, Cornelissen, & Salmelin, 1999; Behrmann, Plaut, & Nelson, 1998; Puce, Allison, Asgari, Gore, & McCarthy, 1996; Allison, McCarthy, Nobre, Puce, & Belger, 1994) and additional involvement of the parietal and frontal areas (Cohen et al., 2003; Longcamp et al., 2003; Tarkiainen et al., 1999; Puce et al., 1996) in a less systematic way (Tarkiainen et al., 1999). The right fusiform damage has been shown to accompany the impared cognition of script style, which suggests that the right visual word form area may be involved in the cognition of the type faces of letters (Barton, Sekunova, et al., 2010).

One previous magneto-encephalography (MEG) study (Longcamp et al., 2006) reported a stronger desynchronization of 20-Hz oscillation at the left primary motor cortex (M1) while observing handwritten letters than printed ones, suggesting the involvement of the left M1 in recognizing handwritten letters. This result was also supported by a recent fMRI study (Longcamp, Hlushchuk, & Hari, 2011).

Extending previous studies, we investigated the temporary change of the excitability of neural circuits in the motor corticospinal pathway by TMS during the observation of printed and handwritten letters. Our hypothesis is that seeing letters is associated with corticospinal modulation. The “modulation” of the corticospinal pathway would occur as a consequence of the activation of M1 that mirrors motor traces implicated in the visual letter perception. However, this modulation may include inhibitory as well as excitatory function, where the former may play a role in preventing the explicit replication of manual writing action to occur.

To test the hypothesis mentioned above, the experiments were designed as follows. To detect the transient change in corticospinal excitability, an event-related TMS design was applied during the observation of printed and handwritten letters (Experiment 1). Second, to test the importance of prior knowledge of writing, the effects of seeing Arabic letters were examined in Japanese participants who do not know Arabic (Experiment 2). Third, because the dominant hand is used for writing letters, we tested the hemispheric dominance of this letter-related change in corticospinal activation (Experiment 3). Finally, to delineate the physiological process of corticospinal involvement, the intracortical inhibitory system (Experiment 4), and the spinal mechanism (Experiment 5) were investigated.

METHODS

Participants

Eleven participants (31.7 ± 4.3; 5 men) participated in Experiment 1, 14 (31.0 ± 4.6; 5 men) in Experiment 2-1, 10 (30.4 ± 7.2; 4 men) in Experiment 2-2, 11 (27.1 ± 4.4; 4 men) in Experiment 3-1, 9 (26.6 ± 4.3; 3 men) in Experiment 3-2, 11 (26.6 ± 5.0; 3 men) in Experiment 4, and 11 (31.0 ± 5.6; 7 men) in Experiment 5. Three of the participants of Experiment 1 participated also in Experiments 2-1, 2-2, and 3-1. All were naive of the experimental purpose, native Japanese speakers, unable to read or write Arabic letters, and right-handed, as confirmed by the Edinburgh Handedness Inventory (Oldfield, 1971). None had a history of psychiatric or neurological diseases. The protocol was approved by the ethics committee of Kyoto University Graduate School and Faculty of Medicine. The experiments were undertaken with the understanding and written consent of each participant.

Letter Stimuli

Eighty images of handwritten and printed letters were prepared as visual stimuli; 10 small letters of Latin characters, 10 Japanese hiragana and 10 Kanji characters, and 10 Arabic characters. Kanji characters are ideograms of Chinese origin. Hiragana characters are Japanese phonograms. Those letters were randomly selected from 26 Latin characters, all 51 Hiragana characters, 2600 commonly used fundamental Kanji characters, and 28 Arabic characters (Figure 1).

Figure 1. 

The images of the letters used as the stimuli. Images of handwritten letters are shown under the corresponding printed letters.

Figure 1. 

The images of the letters used as the stimuli. Images of handwritten letters are shown under the corresponding printed letters.

The familiarity for letters were tested by using a 1–5 Lickert scale in a preliminary behavioral experiment, which showed high familiarity to Hiragana, Kanji, and Latin characters (>4) but low familiarity (∼1) to Arabic characters.

Recording

EMG were recorded from the right (Experiments 1, 2 and 4) or the left (Experiment 3) first dorsal interosseous (FDI) and flexor carpi radialis muscles using 10-mm-diameter Ag–AgCl bipolar surface electrodes placed on the center of muscle belly and the distal tendon. EMGs of the flexor carpi radialis were monitored for the purpose of ensuring that the arm kept relaxed. The EMG signal was bandpass-filtered (5–500 Hz) and digitized at the rate of 2000 Hz (SYNAMP; Neuroscan, Herndon, VA).

TMS was performed with Magstim200 (Magstim Co., Whitland, United Kingdom) with the figure-of-eight coil (diameter = 70 mm, maximum magnetic field strength = 0.93 T). The coil was held by the examiner. The coil was placed over the optimal position in the left or right M1 to elicit the best motor response in the target FDI muscle with the coil held approximately 45° to the midsagittal line and tangentially to the surface of the scalp, thus inducing an anterior-to-posterior current flow. For Experiment 4, two Magstim200 connected to a BiStim module (Magstim) were used to deliver paired stimuli.

The resting motor threshold (rMT) was defined as the lowest stimulus intensity required to elicit motor-evoked potentials (MEP) with a peak-to-peak amplitude of 50 μV in the FDI muscle in at least 5 of 10 trials (Rossini et al., 1994). The active motor threshold (aMT) was recorded as the minimum intensity at which MEPs with an amplitude of ∼200 μV can be distinguished from the background activity in 50% of trials (Rothwell et al., 1999).

To evaluate the corticospinal excitability, the mean peak-to-peak MEP amplitudes of the right or left FDI muscle were measured. The intensity of the test stimulus was set to produce MEP of ∼1 mV from the relaxed FDI muscle before experiments (SI1mV).

Short-latency intracortical inhibition (SICI) was tested according to the paired-pulse TMS protocol (Ziemann, Rothwell, & Ridding, 1996; Kujirai et al., 1993), using a subthreshold conditioning pulse of 95% aMT followed by a test pulse of SI1mV with an ISI of 3 msec. SICI is expressed as the ratio of the mean conditioned MEP over the mean unconditioned MEP. This allows the noninvasive assessment of the GABA-A receptor-mediated intracortical inhibition (ICI) system of M1 (Fisher, Nakamura, Bestmann, Rothwell, & Bostock, 2002; Di Lazzaro et al., 1998; Nakamura, Kitagawa, Kawaguchi, & Tsuji, 1997; Kujirai et al., 1993), which has been demonstrated in pharmacological studies (Werhahn, Kunesch, Noachtar, Benecke, & Classen, 1999; Ziemann et al., 1996).

Excitability of spinal motor neurons was examined by F wave (Mercuri et al., 1996). The F wave at right FDI muscle was evoked by supramaximal electrical stimulation of the ulnar nerve at wrist.

Experimental Procedures

For all experiments, participants were seated in a comfortable armchair and asked to remain relaxed with their arms placed on the armrests. The visual stimuli were displayed on a 15-in. CRT monitor 1 m in front of the subject. The size of letters was 2.9–3.4° of visual angle in height. During the session, participants were asked to keep looking at the black cross-shaped fixation point on the white background displayed at the center of the monitor screen. A single black letter stimulus appeared on the white background for 400 msec in a pseudorandom order, 800 msec after the color of the fixation point turned from black red as the warning stimulus. SOA was randomly determined from 6 to 12 sec. Participants were not required to perform any active task during experiments to minimize an effect on corticospinal excitability originating from response generation (Figure 2).

Figure 2. 

Schematic diagram of Experiment 1. Affixation point appears at the center of the monitor screen. A warning stimulus appears for 800 msec, then a single letter stimulus appears for 400 msec in a random order. SOA varies randomly from 6 to 12 sec. A single TMS pulse is applied to the hotspot for the right FDI muscle at the timing of 100, 200, 300, 400, or 500 msec following the onset of each letter presentation. Participants keep relaxed watching at the monitor screen without performing any task during experiments.

Figure 2. 

Schematic diagram of Experiment 1. Affixation point appears at the center of the monitor screen. A warning stimulus appears for 800 msec, then a single letter stimulus appears for 400 msec in a random order. SOA varies randomly from 6 to 12 sec. A single TMS pulse is applied to the hotspot for the right FDI muscle at the timing of 100, 200, 300, 400, or 500 msec following the onset of each letter presentation. Participants keep relaxed watching at the monitor screen without performing any task during experiments.

For the purpose of confirming that participants kept awake and successfully maintained attention during the session, participants answered questionnaires at the end of each session, in which participants judged whether the questioned letters appeared in the session, except for Experiments 2-1 and 2-2, wherein unknown letters were used. The questionnaires consisted of five questions in which two questions were the letters included in the study and three others were not. Each participant underwent different questionnaires between sessions.

The duration of each experiment was 12–30 min. Experiments were conducted apart from each other. Visual stimuli and triggers for TMS were generated using MATLAB 6.5.1 (The MathWorks, Natick, MA) incorporated with Cogent 2000 (Welcome Department of Imaging Neuroscience, University College London, London, United Kingdom).

Experiment 1: Change of Corticospinal Excitability of the Right Hand Associated with Handwritten Letters

To delineate the excitability changes of corticospinal pathway for the right FDI, we measured MEPs during the observation of handwritten or printed letters of Latin, Hiragana, and Kanji characters. A single TMS pulse of SI1mV was applied to the hotspot for the right FDI muscle at the timing of 100, 200, 300, 400, or 500 msec following the onset of letter presentation. In the preliminary behavioral experiment, the RTs for the letter recognition task using the same stimuli were 250–400 msec. Thus, we expected that the earliest brain response associated with visual letter presentation should be within that time window. At least 10 MEPs were recorded for each condition. In addition, 10 MEPs were recorded while a participant was watching the fixation point during the experiment, at the timing of >5 sec apart from the letter stimulus presentation, which were averaged and used as a baseline.

Experiment 2: Change of Corticospinal Excitability of the Right Hand Associated with Unknown Letters

In Experiment 2-1, to test the effect of handwrittenness in unknown letters, we measured MEPs from the right FDI muscle during the observation of handwritten or printed Arabic characters, in the same way as Experiment 1.

In Experiment 2-2, to test the effect of the knowledge of letters, we measured MEPs from right FDI muscle during the observation of handwritten Latin and Arabic letters. For Experiment 2-2, only timings at 300 and 400 msec as well as baseline condition were tested for handwritten Latin and Arabic letters, because Experiments 1 showed that the change of corticospinal excitability is largest in those timings.

Experiment 3: Change of Corticospinal Excitability of the Left Hand Associated with Handwritten Letters

In Experiment 3-1, to test hemispheric dominance of this excitability change, we measured MEPs from the left FDI muscle by stimulating the right M1 during the observation of handwritten or printed Latin characters, in the same way as Experiment 1.

In Experiment 3-2, for the assessment of the within-participant effect of Side × Time, we additionally recorded the MEPs from left and right FDI muscle during the observation of the handwritten Latin letters at the timing of 300 and 400 msec following the onset of letter presentation as well as the baseline condition. The order of the left and right hand sessions were randomized across participants.

Experiment 4: Change of Intracortical Inhibition of the Right Hand Associated with Handwritten Letters

To clarify the possible involvement of the intracortical inhibitory process in M1, we measured SICI of the right FDI muscle during the observation of handwritten or printed Latin characters. For Experiments 4 and 5, only timings at 300 and 400 msec for Latin characters were tested, because Experiments 1–3 showed that the change of corticospinal excitability is largest in those timings. Thus, a single or paired pulse TMS was applied to the hotspot for the right FDI muscle at 300 or 400 msec following the onset of letter presentation. At least 10 MEPs were recorded for each condition. In addition, the baseline SICI was recorded in the same way as Experiment 1. The test MEP amplitudes were adjusted to be approximately 1 mV for all conditions.

Experiment 5: Change of Spinal Excitability of the Right Hand Associated with Handwritten Letters

To clarify the modulation of the excitability of spinal motor neurons during the task, we measured F waves of the right FDI muscle during the observation of handwritten or printed Latin characters. The right ulnar nerve was stimulated at 300 or 400 msec following the onset of letter presentation. In addition, the baseline F wave was recorded in the same way as Experiment 1. Following the previous studies (Lin & Floeter, 2004; Mercuri et al., 1996; Milanov, 1992), at least 32 trials were recorded for each condition.

Data Analysis

For the statistical analysis of MEP amplitudes, repeated-measures ANOVA was used (Type: handwritten or printed; Letter: Latin, Hiragana, Kanji; Time: 100, 200, 300, 400, 500 msec). The mean MEP amplitudes were normalized to the baseline MEP amplitudes and subjected for the statistical analysis. The Greenhouse–Geisser method was used for adjustment of sphericity. For post hoc analysis, paired t test with Bonferroni correction was used. For SICI and F-wave amplitudes, the factor Time was substituted for Condition (baseline, 300 msec, 400 msec). Significance limit was set to p < .05. Data are presented as mean ± SEM.

RESULTS

All participants for Experiments 1, 3, 4, and 5 correctly answered all the questions of the questionnaire that asked whether the questioned letters appeared in the sessions.

The mean rMT and aMT ± SD for the right FDI muscle was 52.2 ± 9.1 and 40.2 ± 7.4, the mean rMT ± SD for the left FDI muscle was 52.2 ± 6.9, and the mean SI1mV ± SD for the right and left FDI muscle was 64.3% ± 10.4% and 63.9% ± 7.3% of maximum output, respectively.

Experiment 1: Change of Corticospinal Excitability of the Right Hand Associated with Handwritten Letters

Repeated-measures ANOVA revealed a significant main effect of Time (F(5, 11) = 5.78; p = .001) and a significant Time × Type interaction (F(5, 50) = 6.63; p = .001). However, the effects of Time × Letter or Time × Type × Letter interactions were not significant. Post hoc t test comparing handwritten and printed letters for each timing revealed significantly smaller MEP amplitudes for handwritten compare to printed letters at 300 and 400 msec (p = .0391 and p = .0021), suggesting the effects of handwrittenness on corticospinal activation exist at this particular timing. Moreover, at these timings, the MEP amplitudes for the handwritten letters were significantly smaller than the baseline (p = .0125 for 300 msec, p = .0003 for 400 msec; Figure 3).

Figure 3. 

Mean MEP amplitudes (±SEM) for baseline and for handwritten and printed letters (Experiment 1) for each timing. The amplitudes of MEP were significantly smaller for the handwritten compared with baseline and printed letters at 300 and 400 msec following the letter presentation (*p < .05, **p < .01).

Figure 3. 

Mean MEP amplitudes (±SEM) for baseline and for handwritten and printed letters (Experiment 1) for each timing. The amplitudes of MEP were significantly smaller for the handwritten compared with baseline and printed letters at 300 and 400 msec following the letter presentation (*p < .05, **p < .01).

In addition, to see the effects of three kinds of letters, a t test was computed with Bonferroni-type correction (Figure 4). The significant differences were at 200 msec (p = .0098) and 400 msec (p = .0079) for Latin characters, 400 msec (p = .025) for Hiragana characters, and 400 msec (p = .027) for Kanji characters.

Figure 4. 

Trends of the time courses of the mean MEP amplitudes for Latin (A), Hiragana (B), and Kanji (C) letters (Experiment 1). Time courses are shown by ratios to the baseline MEP (±SEM). To see the effects of three kinds of letters, a t test was computed with Bonferroni-type correction (*p < .05, **p < .01).

Figure 4. 

Trends of the time courses of the mean MEP amplitudes for Latin (A), Hiragana (B), and Kanji (C) letters (Experiment 1). Time courses are shown by ratios to the baseline MEP (±SEM). To see the effects of three kinds of letters, a t test was computed with Bonferroni-type correction (*p < .05, **p < .01).

The mean baseline MEP amplitude was 1128 ± 190 μV. The mean MEP amplitudes during the observation of handwritten letters were 1063 ± 182, 1023 ± 155, 976 ± 157, 891 ± 142, and 1041 ± 192 μV at 100, 200, 300, 400, and 500 msec, respectively. Those during the observation of printed letters were 1049 ± 174, 1093 ± 178, 1108 ± 203, 1040 ± 173, and 1000 ± 164 μV, respectively.

Experiment 2: Change of Corticospinal Excitability of the Right Hand Associated with Unknown Letters

Experiment 2-1

For Arabic letters, repeated-measures ANOVA of MEPs for the right FDI muscle revealed no significant main effect of Time, Type, or Time × Type interaction (Figure 5A).

Figure 5. 

(A) Trends of the time courses for handwritten and printed Arabic letters are shown by the MEP ratios to the baseline (±SEM; Experiment 2-1). *p < .05. (B) Mean MEP amplitudes (±SEM) for baseline and for handwritten letters of Latin and Arabic character sets for each timing (Experiment 2-2).

Figure 5. 

(A) Trends of the time courses for handwritten and printed Arabic letters are shown by the MEP ratios to the baseline (±SEM; Experiment 2-1). *p < .05. (B) Mean MEP amplitudes (±SEM) for baseline and for handwritten letters of Latin and Arabic character sets for each timing (Experiment 2-2).

The mean baseline MEP amplitude was 914 ± 149 μV. The mean MEP amplitudes during the observation of handwritten letters were 950 ± 147, 1037 ± 182, 881 ± 148, 945 ± 142, and 955 ± 174 μV at 100, 200, 300, 400, and 500 msec, respectively. Those during the observation of printed letters were 956 ± 145, 1023 ± 149, 949 ± 154, 929 ± 162, and 910 ± 144 μV at 100, 200, 300, 400, and 500 msec, respectively.

Experiment 2-2

For the comparison between handwritten Latin and Arabic letters at 300 and 400 msec, repeated-measures ANOVA revealed the significant effect of Stimuli (Baseline, Arabic at 300 and 400 msec, Latin at 300 and 400 msec; F(4, 36) = 3.917; p = .010), confirming the results of Experiment 2-1 (Figure 5B). The post hoc t test revealed the significant decrease of MEP amplitudes during the observation of handwritten Latin letters at 300 and 400 msec compared with the baseline or those during the observation of Arabic letters.

The mean baseline MEP amplitude was 1415.0 ± 210.3 μV. The mean MEP amplitudes during the observation of Arabic letters were 1365.3 ± 222.4 and 1426.2 ± 210.1 μV at 300 and 400 msec. Those during the observation of Latin letters were 1223.2 ± 196.1 and 1267.8 ± 181.9 μV at 300 and 400 msec, respectively.

Experiment 3: Change of Corticospinal Excitability of the Left Hand Associated with Handwritten Letters

Experiment 3-1

For the left FDI muscle of right-handed participants, repeated-measures ANOVA revealed no significant main effect of Time, Type, or Time × Type interaction (Figure 6).

Figure 6. 

Trends of the time courses of the mean MEP amplitudes for handwritten and printed Latin letters elicited from the left hand. Time courses are shown by ratios to the baseline (±SEM).

Figure 6. 

Trends of the time courses of the mean MEP amplitudes for handwritten and printed Latin letters elicited from the left hand. Time courses are shown by ratios to the baseline (±SEM).

The mean baseline MEP was 866 ± 123 μV. The mean MEP amplitudes during the observation of handwritten letters were 866 ± 123, 789 ± 108, 888 ± 134, 913 ± 127, 802 ± 109, and 813 ± 122 μV at 100, 200, 300, 400, and 500 msec, respectively. Those during the observation of printed letters were 863 ± 122, 875 ± 134, 859 ± 126, 792 ± 107, and 834 ± 125 μV at 100, 200, 300, 400, and 500 msec, respectively.

Experiment 3-2

For the comparison between right and left FDI muscles for handwritten Latin letters at 300 and 400 msec, repeated-measures ANOVA revealed significant effects of Time (baseline, 300 and 400 msec; F(2, 16) = 3.782; p = .045) and Side × Time interaction (F(2, 9) = 4.935; p = .021). Post hoc t tests showed the significant decrease of MEP amplitudes compared with the baseline only for the right FDI muscle (p = .03 for 300 msec, p = .04 for 400 msec).

Experiment 4: Change of Intracortical Inhibition of the Right Hand Associated with Handwritten Letters

For the intracortical inhibitory system within M1, repeated-measures ANOVA revealed no significant effect of Conditions on SICI of the right FDI muscle at the timing of interest when MEP amplitudes were suppressed for handwritten letters.

The mean baseline SICI was 0.40 ± 0.05. The mean SICIs during the observation of handwritten letters were 0.41 ± 0.04, 0.40 ± 0.03 at 300 and 400 msec. Those during the observation of printed letters were 0.44 ± 0.05 and 0.41 ± 0.05 at 300 and 400 msec, respectively.

Experiment 5: Change of Spinal Excitability of the Right Hand Associated with Handwritten Letters

For the spinal motor neurons, repeated-measures ANOVA of the F waves of the right FDI muscle revealed no significant effect of Conditions at the timing of interest when MEP amplitudes were suppressed for handwritten letters.

The mean baseline F wave was 149 ± 23 μV. The mean F-wave amplitudes during the observation of handwritten letters were 104 ± 12 and 84 ± 8 μV at 300 and 400 msec, respectively. Those during the observation of printed letters were 127 ± 35 and 87 ± 15 μV at 300 and 400 msec, respectively.

DISCUSSION

We found the significant reduction of corticospinal excitability for the right but not left hand of the right-handed participants during the observation of handwritten letters at 300–400 msec after the onset of letter stimulus, which was not present for printed letters or unknown letters that participants cannot write or read. At that timing, there was no significant alteration of intracortical inhibitory system within M1 measured by paired TMS or significant change of spinal excitability measured by F wave for both handwritten and printed letters. These findings suggest that the excitability of the left M1 is transiently suppressed during the recognition of handwritten known letters.

Our results suggest the M1 involvement in the recognition of handwritten letters, although this involvement includes the suppression of the corticospinal excitability. This finding is somewhat paradoxical, because most of previous TMS studies have shown the increases in MEPs when observing overt or implied actions (Aziz-Zadeh et al., 2004; Aziz-Zadeh, Maeda, Zaidel, Mazziotta, & Iacoboni, 2002; Fadiga, Craighero, Buccino, & Rizzolatti, 2002; Maeda, Kleiner-Fisman, & Pascual-Leone, 2002). It is possible that this decrease of M1 excitability in this study may be because of the fact that our stimuli were static, contrary to dynamic videos or sounds in most of previous studies. Although our main purpose is to compare printed and handwritten letters, further studies comparing the static handwritten images and dynamic handwriting would be fruitful project in the future.

Papathanasiou, Filipovic, Whurr, Rothwell, and Jahanshahi (2004) showed the increase of the left M1 excitability during visual searching/matching tasks of letters or geometric shapes and suggested the possibility that low-level nonmotor linguistic task can modulate the M1 excitability via MNS. This divergence between Papathanasiou et al.'s study and our study may be a consequence of different task designs. For example, it is likely that active visual searching/matching tasks in their study may accompany more visuospatial attention load than our present study. The present finding of the different effects on M1 excitability for handwritten and printed letters cannot be explained by the functional modulation of the dominant hemisphere by the low-level linguistic tasks (Papathanasiou et al., 2004), because the linguistic values of the handwritten and printed letters would be almost the same. However, because we did not utilize the purely nonletter stimuli, it is still possible that minute difference in linguistic processing might contribute to the present results.

Supporting our findings, certain stimuli that imply actions may suppress corticospinal excitability. For example, listening to action-related sentences was shown to suppress the corticospinal excitability (Buccino et al., 2005). For the mental rotation task of hands, a decrease in MEPs of the right FDI muscle occurred during the visual presentation of the rotated left hand at the timing of 300–100 msec before RT (Sauner, Bestmann, Siebner, & Rothwell, 2006). Because active motor inhibition can suppress the MEP amplitudes (Badry et al., 2009; Begum et al., 2005; Buccolieri, Abbruzzese, & Rothwell, 2004), it is likely that written letter stimuli as well as rotated hands automatically suppressed the motor activation induced by stimuli to avoid inappropriate automatic motor responses.

Previous studies using oscillatory MEG signals or fMRI showed the involvement of the left M1 activation for the handwritten letter observation (Longcamp et al., 2006, 2011). For the MEG study, in which the oscillatory activity in the ∼20-Hz frequency band was shown to be suppressed from 0 to 1500 msec. Because they used the oscillatory activities in the beta band whose cycle is 50 msec (Longcamp et al., 2006), the temporal resolution of MEG oscillatory activities is not very good. Moreover, it is known that the change of beta band activities can last more than a few hundred milliseconds (Toma et al., 2002) for a single brisk movement. By using the event-related TMS design, we studied the time course of the activity in detail and found that the change of the corticospinal excitability starts around 300 msec and ends before 500 msec, following the presentation of handwritten letter stimuli. This timing window is consistent with the simple RTs for the preliminary behavioral study of letter cognition task, which showed the RTs of 250–400 msec poststimulus. This timing is also similar to the ERP associated with the recognition of odd stimuli (P300; Picton, 1992; Sutton, Braren, Zubin, & John, 1965).

We found that the M1 suppression associated with the observation of handwritten letters occurs only in the left hemisphere. This finding is in accord with the result of the previous MEG study, in which the activity in the ∼20-Hz frequency band was significantly different between the handwritten and printed letter conditions in the left hemisphere (Longcamp et al., 2006). However, the involvement of the right hemisphere has been suggested in the identification of handwritten cursive (Hellige & Adamson, 2007). The significant activation of the right hemisphere has been reported in previous fMRI studies using the letter recognition task (Barton, Fox, Sekunova, & Iaria, 2010; Qiao et al., 2010). In the fMRI study using the similar experimental paradigm, in addition to the left M1, the brain activation was also found in the middle occipital and parahippocampal gyri, which may constitute a gateway toward regions more directly involved in processing the “motor” status of handwritten letters (Longcamp et al., 2011). Thus, regarding the corticospinal pathway, the left hemispheric dominance has been consistently found using MEG, fMRI, and TMS.

Moreover, the observation of Arabic letters did not induce the significant change in the MEP amplitudes, which indicates that the corticospinal involvement depends on the literacy of the presented letters. Although any written traits may connote certain actions of the dominant hand done in the past, our finding suggests that this implicit involvement of the motor system is experience dependent, because unfamiliar shapes failed to induce any change in corticospinal excitability.

In the main experiment (Experiment 1), we used three different characters, assuming that Kanji character, which has the most complex visual features and require writing knowledge, would modulate the motor system more strongly. However, this prediction was wrong, possibly because the familiarity or the knowledge of the letter is more important than graphical complexity. Although there was no significant difference among known letters, Latin characters produced an earlier effect at 200 msec compared with Hiragana or Kanji characters, which failed to reach the significance. It is possible that Latin characters might have been easy to be perceived because the total number of letters is as small as 26 and their shapes are relatively simple.

As for the physiological mechanism of this change in corticospinal pathway, the result of our F-wave experiment suggests that the suppression of the corticospinal excitability may be of supraspinal origin, possibly in the M1 (Mercuri et al., 1996). Although one previous study using H-reflex showed the decrease of spinal excitability during action observation (Baldissera, Cavallari, Craighero, & Fadiga, 2001), this study using the static image of handwritten letters implying action did not modulate the spinal excitability. However, we cannot fully exclude the possibility that the spinal mechanism might be involved in the present findings, because the F wave reflects only small part of the spinal motoneuron excitability (Peioglou-Harmoussi, Fawcett, Howel, & Barwick, 1985; Fisher, 1980).

Paired-pulse stimulation of short ISIs (1–5 msec) is a technique that can evaluate the intracortical inhibitory process within M1, through excitation of low threshold GABAergic inhibitory interneurons within M1 (Di Lazzaro et al., 1998, 2003; Fisher et al., 2002; Ilic et al., 2002; Hanajima et al., 1998; Ridding, Taylor, & Rothwell, 1995; Kujirai et al., 1993). Although SICI has been shown to actively suppress unwanted motor cortical output (Coxon, Stinear, & Byblow, 2006; Floeter & Rothwell, 1999), the change in SICI is not necessarily associated with task-related change in M1 excitability (Soto, Valls-Sole, & Kumru, 2010). Our finding, in which no significant change of SICI was observed, indicates that this type of inhibitory interneurons may not be involved in the suppression of M1 induced by handwritten letter stimuli. Therefore, it is most likely that the suppression of the left M1 excitability is associated with the decrease of the excitatory projection to M1 or the increase of the inhibitory projection to M1. Because the premotor area is known to have tight anatomical and functional connection with M1 (Munchau, Bloem, Irlbacher, Trimble, & Rothwell, 2002; Civardi, Cantello, Asselman, & Rothwell, 2001; Ghosh, Brinkman, & Porter, 1987; Godschalk, Lemon, Kuypers, & Ronday, 1984; Matsumura & Kubota, 1979; Muakkassa & Strick, 1979) and to receive abundant visual information (Grol et al., 2007), it is possible that the premotor area controls the M1 excitability during the letter observation. This area may include the hypothetic “writing center” that has been historically speculated to be located at certain site of premotor area (Exner's area; Roux, Draper, Kopke, & Demonet, 2009; Exner, 1881).

Another possible mechanism for the suppression of corticospinal excitability is the corticospinal inhibitory projection in which the M1 activation predominantly involves the corticospinal neurons targeting spinal inhibitory neurons. This type of disynaptic inhibition of motoneurons has been reported in previous studies (Begum et al., 2005; Schmidt & McIntosh, 1990; Lemon, Muir, & Mantel, 1987; Cheney, Fetz, & Palmer, 1985; Jankowska, Padel, & Tanaka, 1976). However, this mechanism is not likely because of the absent F-wave change.

It is probable that the involvement of corticospinal system for the visual processing of handwritten letters might be associated with the MNS (Longcamp et al., 2006). Mirror neurons are defined as a particular class of visuomotor neurons, originally discovered in the monkey premotor cortex, that discharge both when the monkey does a particular action and when it observes another individual (monkey or human) doing a similar action (Gallese et al., 1996; Rizzolatti, Fadiga, Gallese, & Fogassi, 1996; di Pellegrino, Fadiga, Fogassi, Gallese, & Rizzolatti, 1992). Several functional brain imaging studies were performed to investigate the MNS in the human brain, showing that the observation of an action recruits a consistent network of cortical areas, including the ventral premotor area, the inferior frontal gyrus, the inferior parietal lobule, and the superior temporal cortex (Cattaneo & Rizzolatti, 2009; Lui et al., 2008; Filimon, Nelson, Hagler, & Sereno, 2007; Sakreida, Schubotz, Wolfensteller, & von Cramon, 2005; Rizzolatti & Craighero, 2004; Buccino et al., 2001).

Although the MNS has been typically studied in the context of dynamic display of actions (Rizzolatti & Craighero, 2004), the MNS activation can be observed for still photographs representing actions (Johnson-Frey et al., 2003; Nishitani & Hari, 2002; Kourtzi & Kanwisher, 2000) and action-related sounds (Aziz-Zadeh et al., 2004). Because many human actions are not directly perceptible but instead leave into the environment traces from which they can be identified afterwards, it is possible that the MNS is also activated during the observation of handwritten letters.

Previous studies have elucidated the mirror neuron properties of M1 showing a task-dependent increase of the excitability of the concerning muscles. The desynchronization of an EEG rhythm recorded from central derivations (the so-called mu rhythm) occurs not only during active movements of studied participants but also when the participants observed actions done by others (Ulloa & Pineda, 2007; Muthukumaraswamy, Johnson, & McNair, 2004; Cochin, Barthelemy, Roux, & Martineau, 1999; Cochin, Barthelemy, Lejeune, Roux, & Martineau, 1998). These findings were supported by MEG technique, showing that the desynchronization during action observation includes rhythms originating from M1 (Hari et al., 1998; Hari & Salmelin, 1997; Salmelin & Hari, 1994).

Because it has been proposed that these desynchronizations are associated with preparation and execution of a voluntary movement (Pfurtscheller & Lopes da Silva, 1999; Salmelin & Hari, 1994), the previous study using MEG (Longcamp et al., 2006) interpreted the stronger desynchronization of ∼20-Hz activity at M1 during the observation of handwritten letters as a reflection of the increased M1 excitability. However, it must be noted that the activation associated with ∼20-Hz desynchronization of the M1 might not necessarily mean the augmentation of the corticospinal excitability. For example, the voluntary relaxation of hand muscles accompanies the suppression of the excitability of M1 (Terada, Ikeda, Nagamine, & Shibasaki, 1995) as well as the ∼20-Hz desynchronization (Toma et al., 2000), whereas the activation of the corresponding M1 area occurs measured by fMRI (Toma et al., 1999). Therefore, although the desynchronization at M1 may reflect the activation of M1, it may represent either the increase or decrease of the corticospinal excitability as a final output function.

In the spinal cord, the existence of an inhibitory mechanism that prevents the execution of an observed action has been reported, which might prohibit the overt movement generation (Baldissera et al., 2001). In a similar way, the “inverse MNS” may also exist at the cortical level. That is to say, an orchestration of excitatory and inhibitory processes occurs, the former dominating the latter in the case of direct observation of actions. However, in the case of the observation of the traces of actions, the latter may dominate.

Acknowledgments

This study is partly supported by the Strategic Research Program for Brain Sciences for T. M. from the MEXT of Japan and Grant-in-Aid for Scientific Research (C) 21613003 for T. M. from Japan Society for the Promotion of Science.

Reprint requests should be sent to Tatsuya Mima, Human Brain Research Center, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan, or via e-mail: mima@kuhp.kyoto-u.ac.jp.

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