- Email: [email protected]
Chapter 2 Studying higher cerebral functions by transcranial magnetic stimulation
Functional Neuroscience: Evoked Potentials and Related Techniques (Supplements to Clinical Neurophysiology, Vol. 59) Editors: C. Barber, S. Tsuji, S. Tobimatsu, T. Uozumi, N. Akamatsu, A. Eisen © 2006 Elsevier B.V. All rights reserved
9
Chapter 2
Studying higher cerebral functions by transcranial magnetic stimulation Yasuo Terao* and Yoshikazu Ugawa Department of Neurology, Division of Neuroscience, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655 (Japan)
1. What is the virtual lesion paradigm? Transcranial magnetic stimulation (TMS) is known to exert both excitatory and inhibitory effects on the cerebral cortex. While one major use of TMS is to elicit motor evoked potentials from the motor cortex (i.e. example of an excitatory effect), the inhibitory effect may be used to investigate the functions of cortical areas other than the motor cortex, from which no overt response can be elicited. Penfield and colleagues (Penfield and Rasmussen, 1949; Penfield and Roberts, 1959) explored the cortical surface by intraoperative electrical stimulation and found vast cortical regions whose functions cannot be revealed by electrical stimulation unless they are involved in a task that is currently being performed, which they named the elaborative cortex. Unfortunately, most cortical areas are “elaborative cortices” also in terms of TMS. In this chapter, we describe the use of TMS to study the function of nonmotor and non-visual cortical areas from which no overt stimulation signatures can be evoked. *Correspondence to: Yasuo Terao, M.D., Ph.D., Department of Neurology, Division of Neuroscience, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Tel: +81-3-3815-5411, ext. 33784; Fax: +81-3-5800-6548; E-mail: [email protected]
Before the advent of TMS, most investigations on the functions of elaborative cortices relied on lesion studies in neuropsychology. The purpose of lesion studies is to establish a correlation between a circumscribed region of damaged brain and changes in some aspects of an experimentally controlled behavioral performance. In a similar manner, TMS can produce a “virtual lesion” by adding noise to cortical processing. Using a figure-ofeight coil, such “lesions” can be made focal. In the virtual lesion paradigm, we applied TMS to focal regions of the brain to temporarily interfere with local information processing and observe the resultant behavioral changes, e.g. a change in reaction time (RT) in a RT task. Functional mapping of the brain is performed by assuming that if the performance of a task is delayed or facilitated by TMS at a certain time, the focal cortical area just underneath the coil is then active and necessary. If we plot the delay of RT induced by TMS as a function of the stimulus location, we would obtain a “functional map” which shows the location where TMS affects RT. By comparing the effect of TMS at various time periods, we can see how the physiological activities of those cortical regions evolve with time. Aspects of cognitive and higher functions addressed by the virtual lesion paradigm are not necessarily different from those that can be addressed by neuropsychology or other neuroimaging techniques. However, by
10 using the virtual lesions paradigm, a clear chain of cause and effect between the activity of the brain and behavior can be established; if you stimulate a certain cortical region and observe a resultant behavioral change, you can be certain that the “stimulated” cortical region is necessary to induce that behavior. In addition, another advantage of the virtual lesion paradigm is that you can produce lesions “wherever you want” without the confound of reorganization. Furthermore, the virtual lesion paradigm has a time resolution that lesion studies in neuropsychology lack. In other words, it is capable of realizing “real time neuropsychology” (Walsh and Pascual-Leone, 2003).
A
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Switch button
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DC amplifier
TV monitor
2. Visualization of the information flow through human oculomotor cortical regions by TMS Microcomputer
B
Here, we describe an attempt at functional mapping of the brain by TMS to visualize the information flow through oculomotor cortical regions during the performance of an antisaccade task (Terao et al., 1998). The subjects are seated in front of a dome-shaped screen of 90-cm diameter, with light-emitting diodes (LEDs) embedded in horizontal, vertical, and oblique arrays (Fig. 1A). The targets are presented as LEDs, and the magnetic stimulator can be triggered at a programmed time relative to their presentation. A 1–2 cm grid reference system covering the skull was constructed over a plastic cap worn by each subject, and TMS is delivered over each grid point while the subjects perform an oculomotor task (Fig. 1B). The most commonly used oculomotor task is the visually guided saccade task (Fig. 2A, top). In this paradigm, a fixation spot is presented at the center of the dome, on which the subjects have to fixate. After a random interval, a target is presented to the left or right of it, at the same time as the fixation spot goes off, and the subject is required to make a saccade toward it. We used the antisaccade paradigm in our experiments. In this paradigm, the target presentation is identical, but the subjects are required to make a saccade of the same size but in the opposite direction (Fig. 2A, bottom). Therefore, to produce an antisaccade, the subjects have to suppress the reflexive prosaccade made toward the presented target, and at the same time generate a saccade in a symmetrical position.
Fig. 1. (A) Experimental setup for oculomotor tasks. (B) The subjects wore a plastic cap over which a grid system was constructed. TMS was applied over each of the grid points while the subjects performed a RT task.
Without TMS, antisaccades begin 200–250 ms after the target presentation (Fig. 2B). Delivered just before the expected saccade onset, TMS delays the latency by up to 50 ms over some scalp locations. As mentioned, the delay is assumed to occur because TMS interferes with cortical processing occurring at that time. Having the subjects perform the task while stimulating various scalp locations, we obtain a map showing the locations where TMS effectively delays
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Time Fig. 2. (A) The visually guided saccade (prosaccade) and antisaccade paradigm. In both paradigms, the targets were randomly presented 20° to the left and right of the fixation spot. (B) Schema of the TMS experiments. TMS applied just before the expected onset of saccade delays the saccade reaction time (lower trace) as compared to when no TMS is applied (top trace). The horizontal axis of the traces gives the time, and the vertical axis gives the angle.
saccade onset. Figure 3A is a map, color-coded according to the delay of saccade onset induced by TMS at each location. With TMS delivered at 80 ms after the target presentation, the maximal delay was induced over posterior scalp regions of bilateral hemispheres, 6–8 cm posterior to hand motor areas, and somewhat lateral, presumably covering the posterior parietal cortices (PPC). At 100 ms, the maximal delay was induced over the frontal regions, 2–4 cm anterior and 2–4 cm lateral to the hand motor areas bilaterally. These were considered to represent the frontal eye field (FEF) and perhaps also some part of the dorsolateral prefrontal cortex. Although not shown here, TMS at 120 ms did not result in any significant change of saccade latency over any of the regions. Therefore, there was information flow through human oculomotor cortical regions during the presaccadic period, i.e. from posterior (e.g. PPC) at an earlier interval (80 ms) to anterior cortical regions (e.g. FEF, dorsolateral prefrontal cortex) at a later interval (100 ms). TMS was also effective in inducing reflexive prosaccades in the direction of the target that should not be made (Fig. 3B). Prosaccades were induced significantly more frequently than the baseline when TMS was applied to the contralateral hemisphere. For example, as shown in this figure, rightward prosaccades were induced over the left PPC and FEF at 80 ms, and over the left FEF at 100 ms. The mechanism of antisaccade generation can be explained by a scheme shown in Fig. 4A. Let us consider a case in which the target is presented to the right. The visual input in the right hemifield reaches the left primary visual cortex by 40–60 ms, and is then transmitted to the parietal cortex by 80 ms. In the case of antisaccade, parietal information is sent to the corresponding region in the opposite (in this case, the right) hemisphere. At 100 ms, the bilateral information is sent to the frontal cortex including the FEF via cortico-cortical connections. The final saccadic motor output is sent out from the right FEF to produce a saccade to the left, opposite to the visual stimulus. For the bilateral effect of TMS to occur, there must be an interhemispheric transfer of information. This transfer may be mediated by callosal fibers, which are known to connect the FEFs and PPCs of both hemispheres.
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13 Fig. 3. Spatiotemporal shift of regions affecting saccade latency (A) and eliciting erroneous prosaccades. The delay in antisaccade latency (A) or increase in the error rate (B) induced by TMS was plotted (z axis) against the site (x–y axis), which was then transformed into a contour map. The map is shown as viewed from two sides. White dots mark the positions of the bilateral hand motor areas, and the white cross indicates the position of the vertex. The maps are color coded to help identify the effective regions; the red areas indicate regions where saccade delay or elicitation of prosaccades was maximal, and the green and blue areas indicate regions where these were minimal. For cues, see the panel linked to the right-hand side of each figure.
A similar but somewhat different cortical information flow can be proposed for the mechanism of reflexive prosaccades (Fig. 4B). Antisaccades require the subject to inhibit prosaccade to the presented target, and instead to generate a saccade in the opposite direction. TMS presumably interferes with such a dual process, leading to an increased incidence of reflexive prosaccades. This time, the distribution of effective regions was unilateral, i.e. contralateral to the side of the visual stimulus, and no interhemispheric transfer of information was required. 3. Cortical motor preparation for human vocalization The same mapping procedure can be used to investigate the cortical preparation for vocalization. Penfield and Rasmussen (1949) could induce speech arrest by intraoperatively stimulating the lip–face motor representation of both hemispheres. To see the effect of TMS on vocalization, we asked the subject to produce a Japanese vowel sound “a” quickly in response to a visual signal (Fig. 5A). TMS was applied to various locations over the motor strip of bilateral hemispheres just before the expected onset of voice, which, without TMS, occurred at about 300–350 ms after the visual signal (Fig. 5B). A significant delay in voice onset was noted when TMS was delivered 0–150 ms before the expected onset, and the hotspot of the TMS effect was over locations 6 cm to the left and right of Cz irrespective of the time of stimulation (Fig. 5C and 5D). These locations correspond to the face or lip representation of the motor cortex of both hemispheres, consistent with the findings of Penfield et al. (1949, 1959).
We then investigated the time courses of TMS effect over the left and right face motor areas (Fig. 6A). There were two distinct phases in the prevocalization period; 50–150 ms before the expected onset, and a later phase, i.e. 0–50 ms before. Plotting the delay of RT against the time of TMS, the effect of TMS was larger over the left than over the right hemisphere 50–150 ms before the expected onset of voice, whereas this lateralization was reversed when TMS was applied just before vocalization onset, i.e. 0–50 ms before the expected onset of voice. This suggests that, during the cortical preparation for human vocalization, hemispheric lateralization alternates between the two motor cortices, with mild left hemispheric predominance at the early phase switching over to robust right hemispheric predominance during the late phase. A magnetoencephalographic study by Gunji et al. (2000) also demonstrated the involvement of bilateral motor areas during cortical motor preparation for vocalization. Although the authors did not mention it explicitly, activation of the left motor area precedes that of the right motor area, which is taken over by the predominant activity of the right motor area just before voice onset. In primates, the periaqueductal gray serves as a bottleneck region for vocalization that receives all the descending inputs from supraspinal centers, including the cerebral cortex, and relays these to the phonatory motoneuron pools located in the medulla and spinal cord (Jürgens, 1998). If we postulate a similar pathway for humans, the cortical preparation for vocalization may be considered a process through which motor buffer is formed within the bilateral motor cortices (motor programming phase) and released to relevant brainstem centers (motor output phase). We considered the early
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Elicitation of prosaccades Fig. 4. Schematic diagram showing the cortical processing presumed to occur during antisaccades (A) and elicited prosaccades (B). Black ellipses represent the active areas at each time shown in the top left-hand corner, and gray areas indicate regions whose activities are low or have subsided.
and late phases of the prevocalization period each representing the motor programming and motor output phases of vocalization. Given that bilateral motor areas are active during the cortical motor preparation for vocalization, what happens when both motor areas are stimulated simultaneously? We compared the effect of unilateral vs. bilateral TMS delivered over the left and right motor areas (Fig. 6B). During the period preceding the expected onset by 50–150 ms (early phase), the delay induced by unilateral TMS and bilateral TMS was almost identical. In comparison, during the period 0–50 ms before the
expected onset of voice, bilateral TMS induced a significantly larger delay than that induced by unilateral TMS (late phase). If TMS mainly interfered with motor buffer formation, the cortical process for this formation may be slowed, but the buffer itself would not disappear. Once formed and ready in both hemispheres, the motor buffer is released to relevant brainstem centers, so that the effect of TMS is not significant even if delivered bilaterally. If bilateral TMS delays buffer formation in both hemispheres by the same amount of time Δt, RT would also be delayed by Δt, because in both
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Fig. 5. An example of voice recordings (A) and sites of TMS over the scalp (B). (A) Each trace shows the superimposition of voice recordings for 10 trials. The bottom trace is a recording when the magnetic coil was delivered off the scalp, but the subject heard the clicking sound accompanying the magnetic pulse. The time of visual cue presentation is indicated by a vertical solid line, and the control reaction time is marked by a vertical dashed line. The time of TMS delivery is indicated by white triangles. In the top three traces, TMS was applied ~130, 80, and 30 ms before the expected onset of voice. The onsets of voice (marked by black triangles) were progressively more delayed in comparison with the control reaction time when TMS was applied at a later interval. (B) The figure-of-eight coil was placed over points spanning the motor strip, namely Cz, (point D), and points 3 cm to the left and right (points C and E), points 6 cm to the left and right (points B and F), and points 9 cm to the left and right (points A and G). The effect of TMS over the motor strip in one subject (C) and all subjects (D). The RT delay was plotted as a function of the site where focal TMS was delivered over the motor strip. The four curves in the top figure depict the delay when TMS was applied 0–50, 50–100, 100–150, and 150–200 ms before the expected onset of voice. In this and the following figures, the delay is expressed as a percentage of the control reaction time in the same session.
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Fig. 6. (A) Comparison of the effects when TMS was applied over the left (gray curve) and right motor areas (black curve). (B) Comparison of the effects of unilateral (filled dots) and bilateral TMS (white circles). Dots represent unilateral TMS, whereas circles stand for bilateral TMS. In both these figures, the abscissa gives the time of TMS relative to the expected onset of voice, and the ordinate gives the delay induced by TMS. (C) Schematic illustration of the possible TMS effect when it was applied over the right or left hemisphere or bilaterally over both motor areas at the same time.
hemispheres, buffer formation is completed with delayed Δt. Unilateral TMS may delay buffer formation in the stimulated hemisphere by time Δt, but not in the unstimulated hemisphere. Here again, RT may be delayed by the same amount of time Δt, if we postulate that the motor buffers in both hemispheres should be completed for them to be released for motor output. TMS during the early phase may have interfered
mainly with buffer formation, because the induced delay was nearly identical to unilateral or bilateral TMS. On the other hand, if TMS blocked the release of motor buffer into relevant brainstem centers, bilateral TMS would induce RT delay well in excess of that induced by unilateral TMS. This is because bilateral TMS would abolish the descending commands from
17 both hemispheres, greatly reducing the motor output, whereas unilateral TMS would spare at least the motor output from the unstimulated hemisphere (Fig. 6C). Thus, we reasoned that the late phase was mainly dedicated to the release of motor commands into relevant brainstem centers. 4. Summary TMS can be used to study higher cerebral functions by the virtual lesion paradigm. The major advantages of this method are that it could be used to produce a lesion anywhere the researcher wants without confusing cortical reorganization, and that it helps to establish a chain of cause and effect between the activity of the brain and behavior. With elucidation of the mechanism underlying the cortical function blocking, this technique will open up new possibilities for studying higher cerebral functions. In contrast to the online method in which TMS is delivered while subjects perform a certain task, the off-line method uses repetitive TMS to achieve lasting effects even after stimulation has ceased. The application of the offline method will extend from improving cognitive
functions by TMS to the treatment of neurological and psychiatric patients. References Gunji, A., Kakigi, R. and Hoshiyama, M. (2000) Spatiotemporal source analysis of vocalization-associated magnetic fields. Cogn. Brain Res., 9: 157–163. Jürgens, U. (1998) Neuronal control of mammalian vocalization, with special reference to the squirrel monkey. Naturwissenschaft, 85: 376–388. Penfield, W. and Rasmussen, T. (1949) Vocalization and arrest of speech. Arch. Neurol. Psychiatry, 61: 21–27. Penfield, W. and Roberts, L. (1959) Speech and Brain Mechanism. Princeton University Press, Princeton, NY. Terao, Y., Fukuda, H., Ugawa, Y., Hikosaka, O., Hanajima, R., Furubayashi, T., Sakai, K., Miyauchi, S., Sasaki, Y. and Kanazawa, I. (1998) Visualization of the information flow through human oculomotor cortical regions by transcranial magnetic stimulation. J. Neurophysiol., 80: 936–946. Terao, Y., Ugawa, Y., Enomoto, H., Furubayashi, T., Shiio, Y., Machii, K., Hanajima, R., Nishikawa, M., Iwata, N.K., Saito, Y. and Kanazawa, I. (2001) Hemispheric lateralization in the cortical motor preparation for human vocalization. J. Neurosci., 21: 1600–1609. Walsh, V. and Pascual-Leone, A. (2003) Transcranial Magnetic Stimulation – A Neurochronometrics of the Mind. MIT Press, Cambridge, MA.
9
Chapter 2
Studying higher cerebral functions by transcranial magnetic stimulation Yasuo Terao* and Yoshikazu Ugawa Department of Neurology, Division of Neuroscience, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655 (Japan)
1. What is the virtual lesion paradigm? Transcranial magnetic stimulation (TMS) is known to exert both excitatory and inhibitory effects on the cerebral cortex. While one major use of TMS is to elicit motor evoked potentials from the motor cortex (i.e. example of an excitatory effect), the inhibitory effect may be used to investigate the functions of cortical areas other than the motor cortex, from which no overt response can be elicited. Penfield and colleagues (Penfield and Rasmussen, 1949; Penfield and Roberts, 1959) explored the cortical surface by intraoperative electrical stimulation and found vast cortical regions whose functions cannot be revealed by electrical stimulation unless they are involved in a task that is currently being performed, which they named the elaborative cortex. Unfortunately, most cortical areas are “elaborative cortices” also in terms of TMS. In this chapter, we describe the use of TMS to study the function of nonmotor and non-visual cortical areas from which no overt stimulation signatures can be evoked. *Correspondence to: Yasuo Terao, M.D., Ph.D., Department of Neurology, Division of Neuroscience, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Tel: +81-3-3815-5411, ext. 33784; Fax: +81-3-5800-6548; E-mail: [email protected]
Before the advent of TMS, most investigations on the functions of elaborative cortices relied on lesion studies in neuropsychology. The purpose of lesion studies is to establish a correlation between a circumscribed region of damaged brain and changes in some aspects of an experimentally controlled behavioral performance. In a similar manner, TMS can produce a “virtual lesion” by adding noise to cortical processing. Using a figure-ofeight coil, such “lesions” can be made focal. In the virtual lesion paradigm, we applied TMS to focal regions of the brain to temporarily interfere with local information processing and observe the resultant behavioral changes, e.g. a change in reaction time (RT) in a RT task. Functional mapping of the brain is performed by assuming that if the performance of a task is delayed or facilitated by TMS at a certain time, the focal cortical area just underneath the coil is then active and necessary. If we plot the delay of RT induced by TMS as a function of the stimulus location, we would obtain a “functional map” which shows the location where TMS affects RT. By comparing the effect of TMS at various time periods, we can see how the physiological activities of those cortical regions evolve with time. Aspects of cognitive and higher functions addressed by the virtual lesion paradigm are not necessarily different from those that can be addressed by neuropsychology or other neuroimaging techniques. However, by
10 using the virtual lesions paradigm, a clear chain of cause and effect between the activity of the brain and behavior can be established; if you stimulate a certain cortical region and observe a resultant behavioral change, you can be certain that the “stimulated” cortical region is necessary to induce that behavior. In addition, another advantage of the virtual lesion paradigm is that you can produce lesions “wherever you want” without the confound of reorganization. Furthermore, the virtual lesion paradigm has a time resolution that lesion studies in neuropsychology lack. In other words, it is capable of realizing “real time neuropsychology” (Walsh and Pascual-Leone, 2003).
A
Central spot Target spots Video camera
Switch button
Controller AD convertor
DC amplifier
TV monitor
2. Visualization of the information flow through human oculomotor cortical regions by TMS Microcomputer
B
Here, we describe an attempt at functional mapping of the brain by TMS to visualize the information flow through oculomotor cortical regions during the performance of an antisaccade task (Terao et al., 1998). The subjects are seated in front of a dome-shaped screen of 90-cm diameter, with light-emitting diodes (LEDs) embedded in horizontal, vertical, and oblique arrays (Fig. 1A). The targets are presented as LEDs, and the magnetic stimulator can be triggered at a programmed time relative to their presentation. A 1–2 cm grid reference system covering the skull was constructed over a plastic cap worn by each subject, and TMS is delivered over each grid point while the subjects perform an oculomotor task (Fig. 1B). The most commonly used oculomotor task is the visually guided saccade task (Fig. 2A, top). In this paradigm, a fixation spot is presented at the center of the dome, on which the subjects have to fixate. After a random interval, a target is presented to the left or right of it, at the same time as the fixation spot goes off, and the subject is required to make a saccade toward it. We used the antisaccade paradigm in our experiments. In this paradigm, the target presentation is identical, but the subjects are required to make a saccade of the same size but in the opposite direction (Fig. 2A, bottom). Therefore, to produce an antisaccade, the subjects have to suppress the reflexive prosaccade made toward the presented target, and at the same time generate a saccade in a symmetrical position.
Fig. 1. (A) Experimental setup for oculomotor tasks. (B) The subjects wore a plastic cap over which a grid system was constructed. TMS was applied over each of the grid points while the subjects performed a RT task.
Without TMS, antisaccades begin 200–250 ms after the target presentation (Fig. 2B). Delivered just before the expected saccade onset, TMS delays the latency by up to 50 ms over some scalp locations. As mentioned, the delay is assumed to occur because TMS interferes with cortical processing occurring at that time. Having the subjects perform the task while stimulating various scalp locations, we obtain a map showing the locations where TMS effectively delays
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Time Fig. 2. (A) The visually guided saccade (prosaccade) and antisaccade paradigm. In both paradigms, the targets were randomly presented 20° to the left and right of the fixation spot. (B) Schema of the TMS experiments. TMS applied just before the expected onset of saccade delays the saccade reaction time (lower trace) as compared to when no TMS is applied (top trace). The horizontal axis of the traces gives the time, and the vertical axis gives the angle.
saccade onset. Figure 3A is a map, color-coded according to the delay of saccade onset induced by TMS at each location. With TMS delivered at 80 ms after the target presentation, the maximal delay was induced over posterior scalp regions of bilateral hemispheres, 6–8 cm posterior to hand motor areas, and somewhat lateral, presumably covering the posterior parietal cortices (PPC). At 100 ms, the maximal delay was induced over the frontal regions, 2–4 cm anterior and 2–4 cm lateral to the hand motor areas bilaterally. These were considered to represent the frontal eye field (FEF) and perhaps also some part of the dorsolateral prefrontal cortex. Although not shown here, TMS at 120 ms did not result in any significant change of saccade latency over any of the regions. Therefore, there was information flow through human oculomotor cortical regions during the presaccadic period, i.e. from posterior (e.g. PPC) at an earlier interval (80 ms) to anterior cortical regions (e.g. FEF, dorsolateral prefrontal cortex) at a later interval (100 ms). TMS was also effective in inducing reflexive prosaccades in the direction of the target that should not be made (Fig. 3B). Prosaccades were induced significantly more frequently than the baseline when TMS was applied to the contralateral hemisphere. For example, as shown in this figure, rightward prosaccades were induced over the left PPC and FEF at 80 ms, and over the left FEF at 100 ms. The mechanism of antisaccade generation can be explained by a scheme shown in Fig. 4A. Let us consider a case in which the target is presented to the right. The visual input in the right hemifield reaches the left primary visual cortex by 40–60 ms, and is then transmitted to the parietal cortex by 80 ms. In the case of antisaccade, parietal information is sent to the corresponding region in the opposite (in this case, the right) hemisphere. At 100 ms, the bilateral information is sent to the frontal cortex including the FEF via cortico-cortical connections. The final saccadic motor output is sent out from the right FEF to produce a saccade to the left, opposite to the visual stimulus. For the bilateral effect of TMS to occur, there must be an interhemispheric transfer of information. This transfer may be mediated by callosal fibers, which are known to connect the FEFs and PPCs of both hemispheres.
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13 Fig. 3. Spatiotemporal shift of regions affecting saccade latency (A) and eliciting erroneous prosaccades. The delay in antisaccade latency (A) or increase in the error rate (B) induced by TMS was plotted (z axis) against the site (x–y axis), which was then transformed into a contour map. The map is shown as viewed from two sides. White dots mark the positions of the bilateral hand motor areas, and the white cross indicates the position of the vertex. The maps are color coded to help identify the effective regions; the red areas indicate regions where saccade delay or elicitation of prosaccades was maximal, and the green and blue areas indicate regions where these were minimal. For cues, see the panel linked to the right-hand side of each figure.
A similar but somewhat different cortical information flow can be proposed for the mechanism of reflexive prosaccades (Fig. 4B). Antisaccades require the subject to inhibit prosaccade to the presented target, and instead to generate a saccade in the opposite direction. TMS presumably interferes with such a dual process, leading to an increased incidence of reflexive prosaccades. This time, the distribution of effective regions was unilateral, i.e. contralateral to the side of the visual stimulus, and no interhemispheric transfer of information was required. 3. Cortical motor preparation for human vocalization The same mapping procedure can be used to investigate the cortical preparation for vocalization. Penfield and Rasmussen (1949) could induce speech arrest by intraoperatively stimulating the lip–face motor representation of both hemispheres. To see the effect of TMS on vocalization, we asked the subject to produce a Japanese vowel sound “a” quickly in response to a visual signal (Fig. 5A). TMS was applied to various locations over the motor strip of bilateral hemispheres just before the expected onset of voice, which, without TMS, occurred at about 300–350 ms after the visual signal (Fig. 5B). A significant delay in voice onset was noted when TMS was delivered 0–150 ms before the expected onset, and the hotspot of the TMS effect was over locations 6 cm to the left and right of Cz irrespective of the time of stimulation (Fig. 5C and 5D). These locations correspond to the face or lip representation of the motor cortex of both hemispheres, consistent with the findings of Penfield et al. (1949, 1959).
We then investigated the time courses of TMS effect over the left and right face motor areas (Fig. 6A). There were two distinct phases in the prevocalization period; 50–150 ms before the expected onset, and a later phase, i.e. 0–50 ms before. Plotting the delay of RT against the time of TMS, the effect of TMS was larger over the left than over the right hemisphere 50–150 ms before the expected onset of voice, whereas this lateralization was reversed when TMS was applied just before vocalization onset, i.e. 0–50 ms before the expected onset of voice. This suggests that, during the cortical preparation for human vocalization, hemispheric lateralization alternates between the two motor cortices, with mild left hemispheric predominance at the early phase switching over to robust right hemispheric predominance during the late phase. A magnetoencephalographic study by Gunji et al. (2000) also demonstrated the involvement of bilateral motor areas during cortical motor preparation for vocalization. Although the authors did not mention it explicitly, activation of the left motor area precedes that of the right motor area, which is taken over by the predominant activity of the right motor area just before voice onset. In primates, the periaqueductal gray serves as a bottleneck region for vocalization that receives all the descending inputs from supraspinal centers, including the cerebral cortex, and relays these to the phonatory motoneuron pools located in the medulla and spinal cord (Jürgens, 1998). If we postulate a similar pathway for humans, the cortical preparation for vocalization may be considered a process through which motor buffer is formed within the bilateral motor cortices (motor programming phase) and released to relevant brainstem centers (motor output phase). We considered the early
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Elicitation of prosaccades Fig. 4. Schematic diagram showing the cortical processing presumed to occur during antisaccades (A) and elicited prosaccades (B). Black ellipses represent the active areas at each time shown in the top left-hand corner, and gray areas indicate regions whose activities are low or have subsided.
and late phases of the prevocalization period each representing the motor programming and motor output phases of vocalization. Given that bilateral motor areas are active during the cortical motor preparation for vocalization, what happens when both motor areas are stimulated simultaneously? We compared the effect of unilateral vs. bilateral TMS delivered over the left and right motor areas (Fig. 6B). During the period preceding the expected onset by 50–150 ms (early phase), the delay induced by unilateral TMS and bilateral TMS was almost identical. In comparison, during the period 0–50 ms before the
expected onset of voice, bilateral TMS induced a significantly larger delay than that induced by unilateral TMS (late phase). If TMS mainly interfered with motor buffer formation, the cortical process for this formation may be slowed, but the buffer itself would not disappear. Once formed and ready in both hemispheres, the motor buffer is released to relevant brainstem centers, so that the effect of TMS is not significant even if delivered bilaterally. If bilateral TMS delays buffer formation in both hemispheres by the same amount of time Δt, RT would also be delayed by Δt, because in both
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Fig. 5. An example of voice recordings (A) and sites of TMS over the scalp (B). (A) Each trace shows the superimposition of voice recordings for 10 trials. The bottom trace is a recording when the magnetic coil was delivered off the scalp, but the subject heard the clicking sound accompanying the magnetic pulse. The time of visual cue presentation is indicated by a vertical solid line, and the control reaction time is marked by a vertical dashed line. The time of TMS delivery is indicated by white triangles. In the top three traces, TMS was applied ~130, 80, and 30 ms before the expected onset of voice. The onsets of voice (marked by black triangles) were progressively more delayed in comparison with the control reaction time when TMS was applied at a later interval. (B) The figure-of-eight coil was placed over points spanning the motor strip, namely Cz, (point D), and points 3 cm to the left and right (points C and E), points 6 cm to the left and right (points B and F), and points 9 cm to the left and right (points A and G). The effect of TMS over the motor strip in one subject (C) and all subjects (D). The RT delay was plotted as a function of the site where focal TMS was delivered over the motor strip. The four curves in the top figure depict the delay when TMS was applied 0–50, 50–100, 100–150, and 150–200 ms before the expected onset of voice. In this and the following figures, the delay is expressed as a percentage of the control reaction time in the same session.
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Fig. 6. (A) Comparison of the effects when TMS was applied over the left (gray curve) and right motor areas (black curve). (B) Comparison of the effects of unilateral (filled dots) and bilateral TMS (white circles). Dots represent unilateral TMS, whereas circles stand for bilateral TMS. In both these figures, the abscissa gives the time of TMS relative to the expected onset of voice, and the ordinate gives the delay induced by TMS. (C) Schematic illustration of the possible TMS effect when it was applied over the right or left hemisphere or bilaterally over both motor areas at the same time.
hemispheres, buffer formation is completed with delayed Δt. Unilateral TMS may delay buffer formation in the stimulated hemisphere by time Δt, but not in the unstimulated hemisphere. Here again, RT may be delayed by the same amount of time Δt, if we postulate that the motor buffers in both hemispheres should be completed for them to be released for motor output. TMS during the early phase may have interfered
mainly with buffer formation, because the induced delay was nearly identical to unilateral or bilateral TMS. On the other hand, if TMS blocked the release of motor buffer into relevant brainstem centers, bilateral TMS would induce RT delay well in excess of that induced by unilateral TMS. This is because bilateral TMS would abolish the descending commands from
17 both hemispheres, greatly reducing the motor output, whereas unilateral TMS would spare at least the motor output from the unstimulated hemisphere (Fig. 6C). Thus, we reasoned that the late phase was mainly dedicated to the release of motor commands into relevant brainstem centers. 4. Summary TMS can be used to study higher cerebral functions by the virtual lesion paradigm. The major advantages of this method are that it could be used to produce a lesion anywhere the researcher wants without confusing cortical reorganization, and that it helps to establish a chain of cause and effect between the activity of the brain and behavior. With elucidation of the mechanism underlying the cortical function blocking, this technique will open up new possibilities for studying higher cerebral functions. In contrast to the online method in which TMS is delivered while subjects perform a certain task, the off-line method uses repetitive TMS to achieve lasting effects even after stimulation has ceased. The application of the offline method will extend from improving cognitive
functions by TMS to the treatment of neurological and psychiatric patients. References Gunji, A., Kakigi, R. and Hoshiyama, M. (2000) Spatiotemporal source analysis of vocalization-associated magnetic fields. Cogn. Brain Res., 9: 157–163. Jürgens, U. (1998) Neuronal control of mammalian vocalization, with special reference to the squirrel monkey. Naturwissenschaft, 85: 376–388. Penfield, W. and Rasmussen, T. (1949) Vocalization and arrest of speech. Arch. Neurol. Psychiatry, 61: 21–27. Penfield, W. and Roberts, L. (1959) Speech and Brain Mechanism. Princeton University Press, Princeton, NY. Terao, Y., Fukuda, H., Ugawa, Y., Hikosaka, O., Hanajima, R., Furubayashi, T., Sakai, K., Miyauchi, S., Sasaki, Y. and Kanazawa, I. (1998) Visualization of the information flow through human oculomotor cortical regions by transcranial magnetic stimulation. J. Neurophysiol., 80: 936–946. Terao, Y., Ugawa, Y., Enomoto, H., Furubayashi, T., Shiio, Y., Machii, K., Hanajima, R., Nishikawa, M., Iwata, N.K., Saito, Y. and Kanazawa, I. (2001) Hemispheric lateralization in the cortical motor preparation for human vocalization. J. Neurosci., 21: 1600–1609. Walsh, V. and Pascual-Leone, A. (2003) Transcranial Magnetic Stimulation – A Neurochronometrics of the Mind. MIT Press, Cambridge, MA.