involvement of the ipsilateral motor cortex in finger movements of different complexities

Involvement of the Ipsilateral Motor Cortex in Finger Movements of Different Complexities

Robert Chen, MBBChir, FRCPC, Christian Gerloff, MD, Mark Hallett, MD, and Leonard0 G. Cohen, MD

Functional imaging and behavioral studies suggest involvement of the ipsilateral hemisphere in hand movements, particularly of the left hand. If this is so, transient disturbance of the motor cortex (Ml) with repetitive transcranial magnetic stimulation (rTMS) may affect ipsilateral motor sequences, and the effects may differ on the two sides. We studied 15 right-handed subjects who played a simple and a complex piano sequence for 8 seconds each. Two seconds after the beginning of each sequence, rTMS was delivered to the ipsilateral or contralateral M1, or directed away from the head (control trial). Ipsilateral M1 stimulation on either side induced timing errors in both sequences, and with the complex sequence induced more timing errors in the left hand than in the right hand. Errors of the right hand with both sequences occurred in the stimulation period only, but errors of the left hand with the complex sequence occurred in both the stimulation and poststimulation periods. We conclude that the ipsilateral M1 is involved in fine finger movements. The left hemisphere plays a greater role in timing ipsilateral complex sequences than the right hemisphere and may be more involved in the processing of complex motor programs.

Chen R, Gerloff C, Hallett M, Cohen LG. Involvement of the ipsilateral motor cortex in finger movements of different complexities. Ann Neurol 1997;4 1 :247-254

Several studies have found ipsilateral motor deficits in patients with hemispheric lesions [ 1-31, especially with fine finger movements. The ipsilateral motor cortex (Ml) may play a significant role in functional recovery from stroke [4-71 and other hemispheric lesions [8]. Functional magnetic resonance imaging (fMRI) [9- 1 I] and positron emission tomography (PET) [12, 131 showed activation of the ipsilateral motor or sensorimotor cortex with finger movements in normal subjects, particularly with more complex sequences [ 1 1, 121. However, functional imaging studies lack the temporal resolution to reveal the timing of cortical activation. The role of the MI in ipsilateral motor functions is still poorly defined, and the effects of disruption of the M1 on ipsilateral motor performance in normal subjects have not been investigated.

Transcranial magnetic stimulation (TMS) in the form of single pulses or repetitive trains provides a noninvasive means of transiently blocking the functions of cortical neuronal networks [14-161. In some situations, repetitive TMS (rTMS) may be neces- sary to disrupt the stimulated areas long enough to make the effects on complex cortical functions detect- able [17, 181.

In the present study, we used rTMS to examine the effects of disruption of the MI on performance of ipsilateral finger sequences of different complexities. Our results confirm the involvement of the MI in the fine control of ipsilateral complex finger sequences.

Materials and Methods We studied 15 healthy, right-handed volunteers (9 men and 6 women), aged 21 to 64 years (mean, 38.6 years). Eleven subjects participated in rTMS studies, 10 subjects participated in peripheral magnetic stimulation studies, and 6 subjects participated in both. Handedness was assessed by the Edinburgh Inventory [19]. None of the subjects was a profes- sional or active piano player. All subjects gave their written informed consent for the study, and the protocol was ap- proved by the Institutional Review Board.

Task The subjects played two piano sequences, simple and complex (Fig 1). The simple sequence ( 5 = little finger; 4 = ring finger; 3 = middle finger; 2 = index finger) was 5-4- 3-2-5-4-3-2-5-4-3-2-5-4-3-2. The complex sequence was 2- 5-4-3-3-5-2-4-5-2-3-4-4-2-5-3. There were 16 key presses in each sequence, and each of the four keys was played four times. The simple sequence was ordered such that consecu-

From the Human Cortical Physiology Unit, Human Motor Control Section, Medical Neurology Branch, National Institute of Neuro- logical Disorders and Stroke, National Institutes of Health, 1428. Bethesda, MD. Received Feb 29, 1996, and in revised form May 24 and Jul 23. Accepted for publication Aug 5 , 1996.

Address correspondence to Dr Cohen, Building 10, Room 5N226, 10 Center Drive MSC-1428, NINDS, NIH, Bethesda, MD 20892-

Presented, in part, at the Annual Meeting of the American Academy of Neurology, San Francisco, CA, March 1996, and as presentation for the Francis McNaughton prize at the 31st Meeting of the Cana- dian Congress of Neurological Sciences, London, Ontario, Canada, June 1996.

Copyright 0 1997 by the American Neurological Association 247

Complex sequence: 2-5-4-3-3-5-2-4-5-2-3-4-4-2-5-3

0 2 4 6 8 Time (seconds)

Fig I . Simple and complex key press sequences. Each key press is represented by a black bar, and different keys occupy dzffer- ent vertical positions. The fingers corresponding to the keys pressed are shown on the l e ? . The length o f each bar represents the duration o f the key press. For each trial, the sequence of keys pressed was used to determine key press errors, and the time interval between the beginning o f each key pess was gsed to determine timing eriws.

tively adjacent fingers moved in one direction. In contrast, the movement in the complex sequence was random. Each sequence was 8 seconds in duration and was paced at 2 Hz by a metronome. All subjects practiced before the study and were able to play each sequence 10 times in a row without error with either hand. The learning time was 15 minutes or less for the simple sequence and 30 minutes to 4 hours for the complex sequence.

Transcraniul Magnetic Stimulation A Cadwell rapid-rate magnetic stimulator (Cadwell Labora- tories Inc, Kennewick, WA) and a specially designed water- cooled 8-shaped coil, each loop of which was 7 cm in diame- ter, were used for rTMS. The magnetic stimulator was trig- gered by a stimulator (Grass S48, Grass Instruments, Quincy, MA). The coil’s optimal position on the scalp for eliciting motor evoked potentials (MEPs) in the contralateral first dorsal interosseous (FDI) muscle was determined for each hemisphere and was marked on the scalp or on a swim cap worn by the subject. Threshold stimulus intensity was the minimum percentage of the stimulator’s output that could evoke a visible twitch in the resting contralateral FDI muscle in at least 5 of 10 trials. A stimulus train consisted of 15 Hz TMS of 2.3 seconds’ duration. The stimulus intensity was 120% of threshold for stimulation of the motor cortex ipsilateral to the hand playing the piano. For contralateral stimulation, a stimulus intensity of 110% of threshold was used because disturbance of the sequences could be induced at lower intensities.

One of the subjects (a 26-year-old woman) had a simple partial, secondarily generalized seizure during rTMS (15 Hz, 120% of threshold, 2.3 seconds’ duration) ipsilateral to the playing hand. Results from this subject were excluded from the data analysis. Although the stimulus conditions used in this study were in the safe range [20], they were on the boundary of this range. These conditions are now considered unsafe and will not be used in our future rTMS protocols. This set of experiments was terminated after this event.

Experimental Setup for rTMS The subjects played an electronic piano (Yamaha pf85) con- nected via an interface (MIDI translator, Opcode Systems, Inc, Palo Alto, CA) to a laboratory computer, which recorded the individual keys pressed and their timing (Vision 1.4 software, Opcode Systems, Inc). Recording started when the subject pressed the first key in the sequence. The rTMS train was delivered after 2 seconds’ delay (four key presses into the sequence) (Fig 2). The subjects were instructed to continue playing the sequence in spite of interference by rTMS, or even if they felt they made mistakes, to not stop until the sequence was completed, and to not attempt to replay the parts where mistakes occurred. T o determine the relationship between MEPs and errors, and to detect ipsilateral MEPs, the surface electromyogram (EMG) was recorded from the FDI muscle bilaterally (Dantec Counterpoint Elec- tromyograph, Dantec Electronics, Skovlunde, Denmark) in the first 4 subjects. In Subject 1, the number of MEPs was counted and in Subjects 2, 3, and 4 the EMG was rectified, and the MEP areas contralateral to the stimulated side were determined. The EMG was not recorded for the other subjects because it did not correlate with the number of errors made during ipsilateral stimulation.

Ipsilateral rTMS was delivered to all subjects as they played the simple and complex sequences with both the right and the left hands. Control trials were conducted in exactly the same manner, except that the stimulus was directed away from the subject’s head. For both simple and complex sequences, 10 trials were performed for each of the following four experimental conditions: right hand, right-sided MI stimulation; left hand, left-sided M 1 stimulation; right hand, no MI stimulation (control); left hand, no M1 stimulation (control). Each trial of rTMS was alternated with a control trial. The first 4 subjects also had contralateral rTMS while playing the complex sequence with each hand.

The effects of rTMS of other cortical areas on the performance of the complex sequence were studied in 1 subject. The stimulus conditions for rTMS were modified in view of the seizure that had occurred in another subject. Five trials were performed with each hand, with rTMS (10 Hz, 110% of threshold, 2.3 seconds’ duration) delivered to each of the following areas: ipsilateral M1 (optimal position for activation of contralateral FDI), right and left premotor cortex (5 cm rostral to MI) , supplementary motor area (SMA) (2 cni rostral to the vertex), right and left parietal cortex (4 cm caudal to MI) . The results were compared with those of 10 control trials for each hand.

Experirnen tal Setup for Periphera L Stimulutio n Peripheral stimulation studies were performed to determine the effects of arm movements contralateral to the performing

248 Annals of Neurology Vol 41 No 2 February 1937

4 4

4 i 4 4 4 . C 4

I I I I I 0 2 4 6 8

Time (seconds)

rTMS U U U Yrestimulation Stimulation Poststimulation period period period

~ ~~ ~ ~

Fig 2. Examples o f sequences played during repetitive transcranial magnetic stimulation (r TMS). In a left-handed simple sequence with ipsilateral motor cortex (MI) stimulation, there were no keypress errors, but two timing errors occurred (arrows). The length o f each bar represents the duration o f the time interval. The plus (+) sign indicates a time interval that is too long and the minus (-) sign indicates a time interval that is too short. In the first error, the time interval was 0.529 sec and in the second error it was 0.469 sec. In a lefi-handed complex sequence with contralateral MI stimulation, there were five key press errors (top arrows). The wrong key was pressed at the fiFh key and the next four keys were missed. There were also seven timing errors (bottom arrows) consisting of two prolonged intervals Grst two arrows, 0.675 and 2.17 sec), four missed keys, and one shortened interval (last arrow, 0.423 sec). Most of the errors occurred during the stimulation period. In a lefi-handed complex sequence with ipsilateral MI stimulation, there were no key press errors, but four timing errors (arrows) occurred. The first interval (0.448 sec) was too short and the following three intervals (0.575, 0.56, and 0.542 sec) were too long Only one ofthe timing errors occurred during rTMS.

hand. The experimental setup was identical to that of rTMS, except that the stimulator was placed over the flexor surface of the contralateral forearm near the elbow. The stimulus intensity was set at a level that invariably caused a large number of key press errors when the stimulus train was applied to the performing arm. The stimulus intensity required was about 150% of the threshold for inducing a visible finger twitch with a single pulse and always caused a considerable jerking of the arm similar to or greater than that caused by rTMS. Each subject played 10 complex sequences with each hand with peripheral magnetic stimulation, and each test trial was alternated with a control trial in which the stimulus was directed away from the subject’s arm.

Data Analysis The sequence of keys pressed and the time interval between each key press were analyzed. Two types of errors were defined, key press errors and timing errors. Key press errors were defined as pressing the wrong key, pressing an extra key, or omitting a key. Timing errors were analyzed separately for each time interval (the time from the beginning of one key press to the beginning of the next key press). With 16 key presses in each sequence, there were 15 different time intervals. The mean and standard deviation (SD) of each of the 15 time intervals in the 10 control trials were calculated for the type of sequence played (simple or complex) and the hand used (right or left) for each subject. Timing errors were defined as time intervals that were outside the mean 2 2.5 SD of the corresponding control interval. Each time interval was analyzed separately, because frequently there were consistent differences in the timing of the different intervals within the same subject and the pattern was different in different subjects. In addition to being a key press error, a missed key was also a timing error, because it represented a more severe disruption of the sequence than a delayed key. A single mis- timed note was sometimes counted as two timing errors if the subject attempted to compensate for the first timing error by prolonging or shortening the next time interval to keep pace with the metronome. The error rate for key press errors was calculated as the number of errors divided by the number of key presses (16 per sequence), and the error rate for timing errors was calculated as the number of errors divided by the number of time intervals (1 5 per sequence), with the rates expressed in percentages. The “prestimulation period” was the first four time intervals in the first 2 seconds of the sequence before rTMS. The “stimulation period” was the five intervals (5-9) in the next 2.5 seconds during rTMS (2.3 seconds of rTMS and 0.2 second immediately after- ward), and the “poststimulation period’ was the last six intervals (10-15) (see Fig 2).

Statistical Analysis The number of key press and timing errors in each experimental condition were compared by analysis of variance (ANOVA) with repeated measures using Scheffi’s test. ANOVA was also used to compare the timing errors in the prestimulation, stimulation, and poststimulation periods. Statistical significance was defined as p 5 0.05. The relation- ships between MEP areas and the number of errors were tested with simple regression analysis.

Results Control Condition In the control condition, the number of key press and timing errors was low for both sequences and both hands (Table). There were no significant differences in the number of key press and timing errors between the right hand and the left hand.

Ippsihteral MI Stimulation The r T M S caused considerable jerking of the a r m contralateral t o the performing hand, but the subjects were able t o play the sequence uninterrupted with t h e ipsi-

Chen et al: Role of Ipsilateral Motor Cortex 249

Key Press and Timinf Error Rates

Control Ipsilateral M1 rTMS Contralateral M 1 rTMS Task Sequences Key Press Timing Error Key Press Timing Error Key Press Timing Error and Hand Error (%) (YO) Error (Yo) (YO) Error (Yo) (Yo) ~~ ~ ~~

Simple Right 0 0.4 2 1.6 0.06 t 0.G 6.8 -+ 7.Y - - Left 0.06 -t- 0.1 0.5 % 2.1 0.G f 3.2 9.8 t 8.5" - -

Right 0.5 -t 2.3 0.8 i 2.5 1.0 t 4.5 8.3 f 10.3" 21.2 t 16.2' 36.4 t 166' Left 1.4 -+ 5.6 0.9 2 3.7 8.1 t 18 18.6 t 19.1d 18.2 t 13.5b 41.6 t 18.7h

Complex

Data are mean 2 SD values. ' p < 0.005; hp < 0.0001, for comparison with the corresponding control values.

M1 = motor cortex; rTMS = repetitive transcranial magnetic stimulation.

lateral hand. Figure 2 shows the records of a simple and complex sequence with ipsilateral M 1 stimulation, and Figure 3 shows the corresponding EMG. Although ipsilateral rTMS induced key press errors in both the simple and the complex sequences for both hands, the difference from control values was not significant (see Table). There was a much greater number of timing errors in both the simple and the complex sequences for both hands, and the difference from control values was significant (see Table). The greatest increase was in the complex sequence played with the left hand, with a mean increase in the error rate of 17.5%.

Ipsilateral M 1 stimulation caused significantly more timing errors, but not key press errors, when the complex sequence was played with the left hand than with the right hand (18.6% vs 8.3%; p = 0.019). There was no significant difference in key press or timing

Fig 3. Examples o f electromyographic recordings porn the ley5 hand playing the complex sequence. The traces correspond to the two complex sequences shown in Figure 2. The back- ground activity o f the ley5 j r s t dorsal interosseous (FDO muscle is porn playing the sequence. MEP = motor evoked potential; M1 = motor cortex.

Ipsilateral (left) Contralateral (right) M1 stimulation MI stimulation

MEPs n

n ' I '

Left FDI

200 UV L 1 s

errors between the right and left hands in the simple sequence with ipsilateral M 1 stimulation.

Contralateral MI Stimulation There was considerable jerking of the arm during contralateral rTMS, and the sequence was invariably inter- rupted. Figure 2 shows a recorded sequence, and Figure 3 shows the corresponding EMG. As expected, contralateral stimulation produced numerous key press and timing errors, the rates of which were Significantly higher than those with ipsilateral stimulation or in control trials (see Table and Fig 2).

Stimulation o f Dzferent Cortical Areas For the complex sequence played with the left hand, the key press and timing error rates, at different stimulation sites, were, respectively, for SMA, 0%, 3.3%; left premotor cortex, 1,25940, 8%; right premotor cortex, 1.25%, 10.6%; left parietal cortex, OYo, 5.3%; right parietal cortex, O%, 2.7%; and control trials, 3%, 0%, compared with ipsilateral MI , 109'0, 25.3%. For the complex sequence played with the right hand, only one key press error occurred (during SMA stimulation). The timing error rates were for SMA, 6.7%; right premotor cortex, 4%; left premotor cortex, 4%; right parietal cortex, 6.7%; left parietal cortex, 1.3%; control trials, 1%, compared with ipsilateral MI, 10%. Thus, stimulation of the ipsilateral motor complex produced more errors than the other cortical areas studied in this experiment.

Peripheral M a p e t i c Stimulation The key press and timing error rates in the complex sequence were low for both the right (key press error rate, 0.1 +- 0.6%; timing error rate, 2.5 -t 4.5%) and the left hand (key press error rate, 0.6 t 4.4%; timing error rate, 2.9 2 6.7%) and were not significantly different from the error rates in the control condition (right hand key press error rate, 0.4 I 3.9%; timing


- l oo 80 1 z

F b

v

6 0 -

4 0 -

*p<0.005 7 1 i -

* * m E

+ E 20-

Pre Stim. Post Pre Stim. Post Pre Stim. Post stim. stim. stim. stim. stim. st im. --- Simple sequence Complex sequence Complex sequence lpsilateral lpsi lateral Contralateral M I stimulation M1 Stimulation M1 stimulation

Fig 4. Timing error rates during prestimulation, stimulation, and poststimulation periods in different experimental conditions. Each error bar represents 1 SD. Error rates in the stimulation and poststimulation periods were compared with those in the prestimulation period (analysis of variance). LH, left hand; RH, right hand; MI , motor cortex.

error rate, 0.7 1- 4.3%; left hand key press error rate, 0.5 ? 3.4%; timing error rate, 0.5 t 2.4%). There were no significant differences in the error rates between the right and left hands.

Occurrence of Timing Errors in the Sequence With the simple sequence and ipsilateral M1 stimulation, timing errors occurred predominantly during rTMS (Fig 4) . The prestimulation timing error rate was 3.5 5 6.6% for the right hand and 6.7 t 9.7% for the left hand. The stimulation period timing error rate was 13.8 t 20% for the right hand and 14 t 13.6% for the left hand. The poststimulation period timing error rate was 4.83 t 9.5% for the right hand and 8.5 2 13.5% for the left hand. The timing error rates in the stimulation period were significantly higher than those in the prestimulation period for both hands ( p = 0.002, right hand; p = 0.03, left hand). The timing error rates in the stimulation period were also higher than those in the poststimulation period for the right hand ( p = 0.003). The timing error rates in the pre- and poststimulation periods were not significantly different for either hand.

The timing error rates at different time intervals for the complex sequence and ipsilateral M 1 stimulation are shown in Figure 5. With the right hand, timing errors occurred mainly during rTMS. The error rate was significantly higher during the stimulation period (13.8 1- 14.8%) than during the prestimulation period (5.5 1- 10.4%) (ANOVA, p = 0.005) or the poststimulation period (6.17 2 9.4%, p = 0.004), whereas the

1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 1 5

Time intervals

Fig 5. Timing error rate at different time intervals for the complex sequence with ipsilateral motor cortex (Ml) repetitive transcranial magnetic stimulation (rTMS), Each error bar represents I SD. For the right hand, mistakes occurred mainly during the stimulation period, and error rates in the pre- and poststimulation periods were similar. In contrast, for the left hand, error rates were signij5cantly higher during both the stimulation period and the poststimulation period compared with the prestimuhtion period bee text).

values for the pre- and poststimulation periods were not significantly different. In contrast, for the left hand, numerous timing errors occurred in both the stimulation period (25 t 23.9%) and the poststimulation period (21.7 2 21.7%), compared with 7 +- 10.4% in the prestimulation period, and the differences were significant ( p = 0.0002, stimulation period; p = 0.002, poststimulation period). The timing error rates in the stimulation and poststimulation periods were not significantly different (see Figs 4 and 5) .

With the complex sequence and contralateral MI stimulation, most of the timing errors occurred during rTMS (error rate, 7 2 2 29.3% for right hand, 7 2 5 30% for left hand). The mean timing error rate during the poststimulation period (20.8 1- 17.7% for right hand, 28.3 5 23% for left hand) was higher than the prestimulation error rate (3.3 t 4.9% for right hand, 7.5 t 9.7% for left hand), but the differences were not significant (see Fig 4) .

Motor Evoked Potentials Ipsilateral MEPs occurred occasionally in 1 subject with right-sided M1 stimulation and playing with the right hand. None occurred with the left hand. In [his subject, the error rates for ipsilateral M1 stimulation were similar for the right hand (key press errors, 9.3%; timing errors, 20%) and the left hand (key press errors, 10%; timing errors, 20%). Ipsilateral MEPs did not occur in any of the trials in the other 3 subjects in


whom the EMG was recorded. The MEP area with MI stimulation contralateral to the playing hand (170.7 t

that they were unable to play the sequences because of the induced movements. The error rates correlated

104.8 msec.mV) was larger than. that recorded with M1 stimulation ipsilateral to the playing hand (113.3 2 83.9 msec.mV) ( p = 0.001, unpaired t test). MEP areas for contralateral M 1 stimulation correlated with key press errors ( r = 0.43, p = 0.004) and timing errors ( 7 = 0.43, p = 0.006). In contrast, with ipsilat- era1 stimulation, MEP areas (measured in contralateral FDI) did not correlate with the number of key press errors ( p = 0.30) ot timing errors ( p = 0.44).

Discussion We showed that disruption of the motor cortex by rTMS impairs the timing of ipsilateral finger sequences. More timing errors were induced by left-sided than by right-sided M1 stimulation during playing of the complex sequence. Accurate performance of the sequences requires not only pressing the correct key, but also appropriate timing of the key presses. The electronic piano used in our study allowed precise measure- ments of both the timing and the key press of the finger sequences executed. In timing errors we detected subtle mistakes and inconsistencies not evident in key press errors. The subjects were usually aware of key press errors but often unaware of timing errors. The timing error rates in the prestimulation periods were higher than in the control trials, perhaps because of anticipation of rTMS. The error rates in the stimulation periods were significantly higher than in the prestimulation periods (see Fig 4) , confirming that rTMS caused an increase in error rate. Analysis of the data by an alternative method of defining errors with refer- ence to the prestimulation intervals instead of the un- stimulated control trials also showed similar results.

Although the magnetic field induced by the 8- shaped coil is more focal than that of a circular coil, activation of cortical areas adjacent to M 1, such as the premotor cortex (area 6) and the somatosensory cortex, cannot be excluded. However, rTMS is unlikely to affect more distant areas such as the prefrontal cortex, posterior parietal cortex, and the SMA. In the 1 subject we studied, stimulation of these distant areas caused much less disturbance of the piano sequences than stimulation of the ipsilateral MI . Stimulation of the somatosensory cortex is unlikely to account for a significant number of errors, as we found in separate experiments that patients with severe sensory neuropathy were able to play the sequences well, and deafferenta- tion by limb ischemia has little effect on performance (unpublished observations).

Efects of Contrdlateral and Ipsiluteral MI Stimulation Contralateral M I stimulation induced numerous key press and timing errors. Subjects generally reported

with MEP areas, suggesting that sequence disruption was related to direct muscle activation.

Ipsilateral M1 stimulation caused a different type of sequence disruption. There was no significant increase in key press errors, and timing error rates did not correlate with MEP areas. In the absence of direct muscle activation and key press errors, the more subtle distur- bances of bilateral impairment of timing in both simple and complex sequences are unveiled, suggesting involvement of the ipsilateral M1 in fine finger movements. This is supported by fMRI studies showing activation of the ipsilateral M1 with thumb-to-finger opposition movements [ lo , 111 but not with simple finger tapping [21]. We found more errors with ipsilat- era1 M1 stimulation in the complex sequence than in the simple sequence, which is consistent with the finding of fMRI [l l] and PET [12] studies that complex finger movements activated the ipsilateral sensorimotor cortex more than simple finger movements. About 8% of the task-related neurons in the motor cortex of the monkey showed a change in activity before ipsilateral but not contralateral distal forelimb movements [22]. A subregion of the monkey M1 containing cells that are active before both ipsilateral and contralateral movements have been identified, and intracortical mi- crostimulation of these cells evoked both ipsilateral and contralateral responses in digits [23].

Mechanisms fir Ipsilaterul Effects It is unlikely that the errors were due to nonspecific distraction caused by movement of the arm contralat- era1 to the performing hand, because arm movement of similar magnitude induced by peripheral magnetic stimulation has little effect on the performance of the complex sequence. The effects of ipsilateral M1 stimulation may be due to disruption of cortical processing ot may be mediated directly by ipsilateral motor pathways. We observed ipsilateral MEPs only on one side in 1 subject, and they did not appear to have a significant effect on the error rates. The influence of ipsilat- era1 MEPs cannot be ruled out, however, as they may be revealed only by EMG averaging [24]; but the effect is likely to be insignificant. There was no interruption of the EMG of the ipsilateral hand during rTMS, which suggests that ipsilateral silent periods [25] probably do not play a major role in producing the errors. Stimulation of the MI can inhibit the response to TMS of the contralateral M 1, possibly through transcallosal inhibition [26]. Although subtle transcallosal effects cannot be ruled out, they are unlikely to account for the effects we observed because there was no interruption or inhibition of the EMG.

Several subjects reported that while playing the complex sequence with ipsilateral M 1 stimulation, espe-


cially left-sided stimulation, they transiently “forgot” the sequence or “did not know what key to play next.” Subjects were generally unaware of their timing errors, and none of them reported difficulty in moving their fingers. These observations and the absence of EMG interruption during ipsilateral stimulation suggest that the errors are due to interruption of higher cortical processing. In addition, because the key press or timing error rates were not correlated with MEP area, the effects of ipsilateral stimulation are probably not related to direct motor effects. Although subclinical seizures may be induced by rTMS, they probably did not con- tribute significantly to the errors as they cannot account for the differences between the right and left hemispheres or the differences between the simple and complex sequences. Moreover, there were no MEPs following rTMS. When applied over the appropriate area at the scalp, TMS can interrupt normal brain activity and suppress visual perception [14] or detection of somatosensory stimuli [16], cause speech arrest [17], or interrupt motor programs [27]. It is likely that rTMS causes transient and nonspecific activation of both excitatory and inhibitory neurons, leading to disruption of cortical processing, which depends on a deli- cate balance of excitatory and inhibitory influences.

Our finding of increased timing errors with ipsilat- era1 stimulation is consistent with reports that patients with brain damage on either the right or the left side have deficits in temporal discrimination, but the deficits are more severe in those with left-sided lesions [28]. These results may also explain ipsilateral impairment of complex hand functions in patients with stroke [2].

Dzfferences Between Right and Lefi Hemisphere For the complex sequence, we found significantly more timing errors with ipsilateral M1 stimulation on the left side than on the right side. These results suggest that the left MI is more involved in the control of ipsilateral sequences than the right side, especially with complex sequences. Consistent with this is an fMRI study showing that activation of the ipsilateral motor cortex with thumb-to-finger opposition movements was much more prominent on the left side than on the right side [9]. In a similar manner, EEG spectral analysis demonstrated bilateral cortical activation with a complex finger sequence and unilateral activation with a simple sequence [29], and a study of movement- related cortical potentials showed ipsilateral direct cur- rent potentials with left-handed but not right-handed movements [30].

The finding of more timing errors from left-sided stimulation supports the suggestion that the left hemisphere is superior to the right in the processing of rapid, temporal information [28, 311. Patienrs with left hemispheric damage had more deficits in temporal dis-

crimination [28] and timing of movement sequences [3 1, 321 than patients with right hemispheric damage. Studies in normal subjects also showed finer temporal resolution of stimuli presented first to the left hemisphere [28].

Our results may explain the clinical observation that patients with left hemispheric damage have more ipsilateral deficits than those with right-sided lesions. The deficits involve tapping speed [33], manual sequences [34], and tasks involving eye-arm precision [35]. Rapid sequential hand movements may be particularly involved [31, 32, 36, 371, and the difference exists in patients without apraxia [31].

Disruption of Motor Programs Single-pulse TMS to the contralateral motor cortex de- lays movement onset, possibly because the motor program is disrupted or information transmission through the motor cortex is inhibited [27]. A small ipsilateral effect has also been observed [27]. In the present study, examination of the error rate at different time intervals allowed analysis of how the motor programs were disrupted. With left-sided ipsilateral M1 stimulation, disruption of timing extended into the poststimulation period for the complex sequence but was limited to the stimulation period for the simple sequence. Timing disruption was limited to the stimulation period with ipsilateral right-sided MI stimulation for the simple and complex sequences. One explanation for these observations is that for ipsilateral finger movements, the right MI is mainly involved in the execution of motor programs. In addition, the left M1 is involved in processing or temporary storage of motor programs, particularly with regard to timing of movements. Thus, left-sided ipsilateral M1 stimulation disrupts the sequence for a longer period, while the effects of right- sided ipsilateral M1 stimulation occur only during the stimulation period.

The difference in the effects of the complex and simple sequences may be due to their different require- ments in motor programs. There is no repetition in the complex sequence and, therefore, its motor program requires 16 key presses. The program for the simple sequence consists of four ordered key presses that are repeated four times. There are at least two possible ex- planations for the different effects of left M1 stimulation on the ipsilateral simple and complex sequences. The left-sided MI may be preferentially involved in the programming of complex sequences. O n the other hand, although the motor programs for both the simple and complex sequences are disrupted by rTMS, the simple program is recalculated much faster than the complex program. These findings are consistent with reports that patients with left hemispheric damage had bilateral difficulties in copying unfamiliar sequences,


suggesting a motor control disorder [36, 381 and difficulty with scheduling motor programs [31, 381.

In conclusion, we found evidence of ipsilateral M1 involvement in finger sequences, and greater involvement with greater sequence complexity. The left M1 plays a greater role than the right M1 in the timing of ipsilateral complex sequences and may be more involved in processing motor programs for coinplex movements.

We thank B. J. Hessie for skillful editing.

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involvement of the ipsilateral motor cortex in finger movements of different complexities

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