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Connections to motor cortex from other areas of the brain studied with transcranial magnetic stimulation
International Congress Series 1226 (2002) 45 – 52
Connections to motor cortex from other areas of the brain studied with transcranial magnetic stimulation J.C. Rothwell* MRC Human Movement and Balance Unit, Institute of Neurology, Queen Square, London WC1N 3BG, UK
Abstract This chapter reviews some of the connections to the motor cortex that have been studied in humans using the technique of transcranial magnetic stimulation (TMS). In all cases a double pulse design has been used in which one stimulus is used to evaluate the excitability of the motor cortex at different times, after another stimulus has been given over a different site in order to activate connections between the two areas. Interhemispheric, cortico-cortical and cerebello-cortical effects are described. The first two have been shown to be task-sensitive and specifically affected in patients with neurological diseases such as epilepsy and movement disorders. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Transcranial magnetic stimulation; Transcallosal; Intracortical inhibition
1. Introduction This chapter will review some of the electrophysiological studies that have been performed using transcranial magnetic stimulation (TMS) to probe the connections to the motor cortex from other parts of the brain. The choice of the motor cortex is not arbitrary. The reason is as follows: unlike most other areas of cortex, its excitability can be easily monitored in a noninvasive way, by measuring the amplitude of EMG responses (MEPs, motor-evoked potentials) evoked by a standard test pulse. Thus, any inputs from other structures that change its excitability can be revealed through changes in the MEP. Metabolic imaging techniques (fMRI, PET) can be used to document connections between other areas of cortex [1], but they will not be discussed further in this chapter.
*
Tel.: +44-171-278-9836; fax: +44-171-829-8759.
0531-5131/02 D 2002 Elsevier Science B.V. All rights reserved. PII: S 0 5 3 1 - 5 1 3 1 ( 0 1 ) 0 0 4 9 5 - 2
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J.C. Rothwell / International Congress Series 1226 (2002) 45–52
2. General methods All the experiments reviewed here use a paired pulse design. That is, a standard test stimulus is given to, say, the hand area of the motor cortex of one hemisphere. This evokes an EMG response of a certain average size. A second magnetic stimulus, often called the conditioning stimulus, is then given at different times beforehand to activate other areas of the brain. If the conditioning stimulus changes the size of the test MEP, then we may have revealed a functional connection between the conditioned site and the motor cortex. There is one general control that has to be applied in such paired pulse designs. The amplitude of the test MEP depends not only on the excitability of the motor cortex, but also on the excitability of spinal motoneurones, and perhaps interneurones. Because of this, any changes in the size of the test MEP may be due to changes in cortical or spinal excitability. There are three main ways in which spinal effects can be tested noninvasively. (1) If H-reflexes can be obtained in the muscle under study, then they provide a measure of motoneuronal excitability. The test is not perfect because the size of an H-reflex can change because of presynaptic effects on transmission in Ia afferent terminals. In addition, we must also assume that we are testing the excitability of the same population of motoneurones as are recruited by the MEP, otherwise the comparison is invalid. Some studies on single motor units suggest that the units recruited by an H-reflex are not always the same as those recruited by an MEP [2]. However, another piece of evidence suggests that even if some of the units are not the same, others must be shared between H-reflex and MEP. Thus, H-reflexes can be facilitated by a suitably timed subthreshold cortical stimulus [3]. The only way this could happen is if some of the descending excitation evoked by the cortical stimulus overlapped at the motoneurones pool with excitation from the H-reflex. The conclusion is that H-reflexes must share some spinal motoneurones with the MEP, and therefore H-reflexes can be used as one, albeit imperfect, measure of spinal excitability in the present experiments. (2) F-waves can also be used in muscles where H-reflexes cannot be readily obtained. However, because the F-wave is more variable than the H-reflex, and often very small, it may be less reliable as an indicator of spinal excitability unless large numbers are collected. In addition, it is still not clear whether the motoneurones recruited in the F-wave are the same as those recruited by the MEP [4]. (3) The final method of probing spinal excitability is by using anodal electrical stimulation of the motor cortex. Unlike the usual method of magnetic stimulation (using a coil that induces a posterior – anterior current to flow across the central sulcus) that activates corticospinal neurones trans-synaptically, anodal stimulation tends to activate the axon of pyramidal neurones in the white matter [5,6]. This means that EMG responses to anodal stimulation are less sensitive to the level of cortical excitation than those evoked by TMS, and therefore give information about spinal excitability changes rather than cortical effects. However, there is one important proviso to this line of reasoning. It is that this distinction between anodal and magnetic stimulation of the cortical motor hand area only holds at threshold intensities of stimulation. At high intensities, both methods recruit corticospinal neurones both directly and trans-synaptically. To be sure of obtaining a relatively pure distinction between the techniques, it is important that the tests are done during tonic background contraction of the target muscle. This means that an EMG
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response can be elicited with a minimal amount of descending activity, and therefore that the magnetic and electric stimuli are at near threshold intensities. Tests done with the muscle at rest are unreliable because higher intensities of stimulation are needed to recruit an EMG response. Most authors use a combination of methods because of the intrinsic uncertainty of any one of them. In special circumstances, however, there is an additional method that gives more direct information about the excitability of the motor cortex. Epidural spinal cord electrodes are sometimes implanted over the dorsal columns for relief of intractable pain. In some centres, the operation is carried out in two stages. In the first the electrodes are implanted, and their terminal left exposed on the skin so that the continuity of the leads can be tested post-operatively. If the electrodes work well, a second operation is then performed to connect the electrode to an electrical stimulator that is implanted subcutaneously, often in the subclavicular region. The interval between the first operation and the final implantation provides a unique opportunity to record from the electrodes in conscious human subjects. Such epidural electrodes can readily detect the descending volleys set up in the lateral columns by TMS, and the size and number of the volleys can be used as a direct measure of the output of the cortex to the standard test stimulus. In other words, there is no need to control for spinal excitability since the electrodes monitor cortical output before it reaches the spinal cord [6]. If the effects in paired pulse testing can be attributed to interactions at the cortex, then one advantage of the method is worth emphasising. The effect of the conditioning pulse will depend on the excitability of the connection to the motor cortex at the time the stimulus is given. For example, if that projection is actively being used, then it is likely to be more readily excited by the conditioning stimulus, and the effect on the response to the test pulse will be larger than in other circumstances. Thus, this paired pulse design not only tests anatomical connectivity, it also reveals some information about the activity in these connections.
3. Inputs to motor cortex 3.1. Transcallosal inputs The first studied connection to motor cortex was that from the motor area of the opposite hemisphere [7]. A single conditioning stimulus over the motor hand area of one cortex can affect the size of responses to a test pulse given over the opposite motor area. The major effect is inhibitory, beginning at an interstimulus interval of 6– 7 ms, and lasting for 30 ms or more depending on the intensity of the conditioning stimulus. An early facilitation can sometimes be seen to precede the inhibition [8]. The initial experiments, in which H-reflex testing and anodal stimulation were used to detect changes in spinal excitability, suggested that the whole of this effect was due to an influence on cortical excitability. However, a recent study has shown that some direct spinal inhibition can be produced on ipsilateral motoneurones by the conditioning stimulus [9]. Most authors think that this latter effect is relatively small. Indeed, direct recordings of
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descending volleys evoked by the test stimulus show that they are strongly suppressed by contralateral conditioning stimuli [10] (Fig. 1). In addition, the effect is not seen in patients with no corpus callosum [11], which is again consistent with the idea that the primary part of the inhibition occurs at the cerebral cortex. This transcallosal inhibition can be observed in the ongoing EMG of ipsilateral muscles as a silent period lasting about 30 ms, starting about 30 ms (for hand muscles) after the stimulus is given. This indicates that voluntary activity is suppressed similarly to the MEP. Transcallosal effects are site-specific, being most prominent when homologous parts of each motor area are stimulated. They seem to depend on activation of neurones different to
Fig. 1. Epidural volleys (left) and EMG responses (right) evoked by test stimulus alone (upper traces), both test and conditioning contralateral stimuli at different ISIs (middle traces) and conditioning stimulus alone (lower traces) in one subject. Recordings were performed at rest. Each trace is the mean of 10 sweeps. Test stimulus evokes multiple descending waves (three waves) and an EMG response of about 0.2 mV. When both stimuli were delivered, the EMG responses were dramatically suppressed at 7 – 10-ms ISIs. At 6 – 10-ms ISIs, the latest (I3) wave is suppressed, the second (I2) wave is slightly inhibited at 9 – 10-ms ISIs while the earliest (I1) wave is not modified (from Ref. [10] with permission).
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those involved in the contralateral MEP since the threshold for inhibition may be different from that of the contralateral MEP [7]. This is consistent with the anatomical data that show that transcallosally projecting fibres originate in cortical layer III whereas the corticospinal neurones are found in layer V. One feature of the transcallosal effect is puzzling. Although it is strongest between the motor hand areas, anatomical studies show that these are the very regions where transcallosal connections are the least dense. One possible explanation is that the effect comes mainly from activation of neuronal population in areas surrounding the hand representation. This ‘‘surround’’ might then elicit a strong inhibitory response in the opposite hemisphere. A final feature of the transcallosal connectivity is that it is sensitive to the motor task being performed by the subjects. For example, inhibition from right to left motor cortex is enhanced compared to rest if subjects actively contract the left hand muscles [7]. This was the first demonstration that the paired pulse design was indeed sensitive to the excitability as well as the anatomy of cortical connections. 3.2. Inputs from the cerebellum The second description of inputs to motor cortex involved stimulation over the cerebellum [12]. The initial experiments used transcranial electrical stimulation across the posterior parts of the mastoid process. As with transcallosal conditioning, the main effect was inhibitory and was maximum when the anode of the stimulator was over the cerebellum contralateral to the motor cortex that was used to testing. Inhibition began about 5 ms after the conditioning stimulus and continued for 10 ms or more. However, the later part of the inhibitory effect was complex. Testing spinal excitability with H-reflexes and anodal electric stimulation of the motor cortex suggested that the first 3 ms or so was a purely cortical effect, probably produced by activation of a cerebello-cortical projection, but that later portions might be of mixed spinal and cortical origin. Electrical stimulation of the cerebellum is relatively uncomfortable because the stimulus produces a large contraction of neck muscles. Ugawa et al. [13] showed that it was possible to obtain similar effects using a magnetic stimulator. However, like electrical stimulation, only the initial part of the effect on motor cortex excitability is likely to be due to a cerebellar projection to cerebral cortex. Magnetic stimulation, particularly with the large coils that are sometimes needed to obtain such effects from the cerebellum, often activates cervical nerve roots [14]. The afferent volley produced by this stimulus can itself affect cortical excitability and complicate interpretation of the results. 3.3. Cortico-cortical connections within the motor cortex Kujirai et al. [15] found that if two stimuli were given through the same coil over the motor cortex, then it was possible to observe short latency interactions between them. A subthreshold conditioning stimulus suppresses the response to a larger suprathreshold test stimulus if the interval between the stimuli is less than 5 ms. At longer intervals the test response is facilitated. The threshold for evoking inhibition is slightly lower and less sensitive to coil orientation than facilitation, indicating that two separate mechanisms are involved [16].
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Several lines of evidence show that this interaction occurs because of activation of circuits in the cerebral cortex. First, the intensity of the conditioning stimulus can be lower than that required to evoke any descending corticospinal volley. Second, the conditioning stimulus has no effect on spinal H-reflexes, or responses to anodal electrical stimulation of the motor cortex. Third, direct recordings from the spinal epidural space show that the conditioning stimulus reduces the size and number of descending corticospinal volleys evoked by the test shock [17] (Fig. 2). The amount of inhibition and facilitation produced by a given conditioning stimulus is less during activation than at rest, suggesting that voluntary activity can affect the
Fig. 2. Epidural volleys (left) and MEPs (right) evoked by test stimulus alone (control), conditioning stimulus alone (lower traces) and both stimuli at different ISIs (middle traces) in one subject. The responses to the test stimulus alone and both stimuli together were recorded when the subject was at rest. The response to the conditioning stimulus alone was delivered during voluntary contraction at about 20% of the maximum. Each trace is the average of 10 sweeps. The test stimulus evokes multiple descending waves (four waves) and an MEP of about 1 mV. The conditioning shock alone evoked neither MEP nor descending volleys. When both stimuli were delivered the MEPs were dramatically suppressed at ISI = 1 – 3 ms. At ISI = 1 ms all the descending waves except the I1 were suppressed; at longer ISIs the I3 and I4 waves were particularly well suppressed (from Ref. [17] with permission).
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excitability of the cortical circuits involved [18]. However, the interpretation of this is complicated by the fact that the conditioning stimulus primarily suppresses the I3 and later waves of corticospinal activity set up by the test shock [19]. With the usual orientation of test stimulus, inducing current in the brain from posterior to anterior across the central sulcus, the I3 wave is usually recruited only at moderate intensities above threshold. I1 and I2 waves are recruited at lower intensities. When subjects are tested at rest, the intensity of the test stimulus is usually relatively low, and may not recruit a large I3 wave. This in itself will mean that the amount of inhibition from the conditioning stimulus may appear small. Proper comparison of the effectiveness of conditioning stimuli requires that the intensity of the test shock be approximately the same in the active and relaxed state. The initial inhibition from the conditioning stimulus appears to be GABAergic in nature since it is affected by drugs that act on central GABAA receptors [20]. The level of inhibition is reduced in many pathological states, including epilepsy involving the motor cortex and many basal ganglia diseases [21,22]. Cerebellar disease seems to have little effect [23].
4. Conclusions Three types of connection have been described from other areas of the brain onto the motor cortex. They are readily revealed by paired pulse testing and show task dependency. Recently, another connection from probable premotor areas has been reported and it is presently the subject of active investigation.
References [1] T. Paus, R. Jech, C.J. Thompson, R. Comeau, T. Peters, A.C. Evans, Transcranial magnetic stimulation during positron emission tomography: a new method for studying connectivity of the human cerebral cortex, J. Neurosci. 17 (1997) 3178 – 3184. [2] J. Nielsen, J. Baumgarten, N. Petersen, L.O.D. Christensen, Task-related changes in the effect of TMS on spinal neurones, Electroencephalogr. Clin. Neurophysiol. 107 (1999) 83P (Abstract). [3] J.M. Cowan, B.L. Day, C. Marsden, J.C. Rothwell, The effect of percutaneous motor cortex stimulation on H reflexes in muscles of the arm and leg in intact man, J. Physiol. (London) 377 (1986) 333 – 347. [4] H. Hultborn, J.B. Nielsen, H-reflexes and F-responses are not equally sensitive to changes in motoneuronal excitability [comment], Muscle Nerve. 18 (1995) 1471 – 1474. [5] B.L. Day, D. Dressler, N.A. Maertens-de, et al., Electric and magnetic stimulation of human motor cortex: surface EMG and single motor unit responses [published erratum appears in J Physiol (Lond) 1990 Nov;430:617], J. Physiol. (London) 412 (1989) 449 – 473. [6] V. Di Lazzaro, A. Oliviero, P. Profice, et al., Comparison of descending volleys evoked by transcranial magnetic and electric stimulation in conscious humans, Electroencephalogr. Clin. Neurophysiol. 109 (1998) 397 – 401. [7] A. Ferbert, A. Priori, J.C. Rothwell, B.L. Day, J.G. Colebatch, C.D. Marsden, Interhemispheric inhibition of the human motor cortex, J. Physiol. (London) 453 (1992) 525 – 546. [8] Y. Ugawa, R. Hanajima, I. Kanazawa, Interhemispheric facilitation of the hand area of the human motor cortex, Neurosci. Lett. 160 (1993) 153 – 155. [9] C. Gerloff, L.G. Cohen, M.K. Floeter, R. Chen, B. Corwell, M. Hallet, Inhibitory influence of the ipsilateral motor cortex on responses to stimulation of the human cortex and pyramidal tract, J. Physiol. (London) 510 (1998) 249 – 259.
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[10] V. Di Lazzaro, A. Oliviero, P. Profice, et al., Direct demonstration of interhemispheric inhibition of the human motor cortex produced by transcranial magnetic stimulation, Exp. Brain Res. 124 (1999) 520 – 524. [11] S. Roricht, B.U. Meyer, K. Irlbacher, A.C. Ludolph, Impairment of callosal and corticospinal system function in adolescents with early-treated phenylketonuria: a transcranial magnetic stimulation study, J. Neurol. 246 (1999) 21 – 30. [12] Y. Ugawa, B.L. Day, J.C. Rothwell, P.D. Thompson, P.A. Merton, C.D. Marsden, Modulation of motor cortical excitability by electrical stimulation over the cerebellum in man, J. Physiol. (London) 441 (1991) 57 – 72. [13] Y. Ugawa, Y. Uesaka, Y. Terao, R. Hanajima, I. Kanazawa, Magnetic stimulation over the cerebellum in humans, Ann. Neurol. 37 (1995) 703 – 713. [14] K.J. Werhahn, J. Taylor, M. Ridding, B.U. Meyer, J.C. Rothwell, Effect of transcranial magnetic stimulation over the cerebellum on the excitability of human motor cortex, Electroencephalogr. Clin. Neurophysiol. 101 (1996) 58 – 66. [15] T. Kujirai, M.D. Caramia, J.C. Rothwell, et al., Corticocortical inhibition in human motor cortex, J. Physiol. (London) 471 (1993) 501 – 519. [16] U. Ziemann, J.C. Rothwell, M.C. Ridding, Interaction between intracortical inhibition and facilitation in human motor cortex, J. Physiol. (London) 496 (1996) 873 – 881. [17] V. Di Lazzaro, D. Restuccia, A. Oliviero, et al., Magnetic transcranial stimulation at intensities below active motor threshold activates intracortical inhibitory circuits, Exp. Brain Res. 119 (1998) 265 – 268. [18] M.C. Ridding, J.L. Taylor, J.C. Rothwell, The effect of voluntary contraction on cortico-cortical inhibition in human motor cortex, J. Physiol. (London) 487 (1995) 541 – 548. [19] R. Hanajima, Y. Ugawa, Y. Terao, et al., Paired-pulse magnetic stimulation of the human motor cortex: differences among I waves, J. Physiol. (London) 509 (1998) 607 – 618. [20] U. Ziemann, D. Bruns, W. Paulus, Enhancement of human motor cortex inhibition by the dopamine receptor agonist pergolide: evidence from transcranial magnetic stimulation, Neurosci. Lett. 208 (1996) 187 – 190. [21] M.C. Ridding, R. Inzelberg, J.C. Rothwell, Changes in excitability of motor cortical circuitry in patients with Parkinson’s disease, Ann. Neurol. 37 (1995) 181 – 188. [22] P. Brown, M.C. Ridding, K.J. Werhahn, J.C. Rothwell, C.D. Marsden, Abnormalities of the balance between inhibition and excitation in the motor cortex of patients with cortical myoclonus, Brain 119 (1996) 309 – 317. [23] Y. Ugawa, R. Hanajima, I. Kanazawa, Motor cortex inhibition in patients with ataxia, Electroencephalogr. Clin. Neurophysiol. 93 (1994) 225 – 229.
Connections to motor cortex from other areas of the brain studied with transcranial magnetic stimulation J.C. Rothwell* MRC Human Movement and Balance Unit, Institute of Neurology, Queen Square, London WC1N 3BG, UK
Abstract This chapter reviews some of the connections to the motor cortex that have been studied in humans using the technique of transcranial magnetic stimulation (TMS). In all cases a double pulse design has been used in which one stimulus is used to evaluate the excitability of the motor cortex at different times, after another stimulus has been given over a different site in order to activate connections between the two areas. Interhemispheric, cortico-cortical and cerebello-cortical effects are described. The first two have been shown to be task-sensitive and specifically affected in patients with neurological diseases such as epilepsy and movement disorders. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Transcranial magnetic stimulation; Transcallosal; Intracortical inhibition
1. Introduction This chapter will review some of the electrophysiological studies that have been performed using transcranial magnetic stimulation (TMS) to probe the connections to the motor cortex from other parts of the brain. The choice of the motor cortex is not arbitrary. The reason is as follows: unlike most other areas of cortex, its excitability can be easily monitored in a noninvasive way, by measuring the amplitude of EMG responses (MEPs, motor-evoked potentials) evoked by a standard test pulse. Thus, any inputs from other structures that change its excitability can be revealed through changes in the MEP. Metabolic imaging techniques (fMRI, PET) can be used to document connections between other areas of cortex [1], but they will not be discussed further in this chapter.
*
Tel.: +44-171-278-9836; fax: +44-171-829-8759.
0531-5131/02 D 2002 Elsevier Science B.V. All rights reserved. PII: S 0 5 3 1 - 5 1 3 1 ( 0 1 ) 0 0 4 9 5 - 2
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J.C. Rothwell / International Congress Series 1226 (2002) 45–52
2. General methods All the experiments reviewed here use a paired pulse design. That is, a standard test stimulus is given to, say, the hand area of the motor cortex of one hemisphere. This evokes an EMG response of a certain average size. A second magnetic stimulus, often called the conditioning stimulus, is then given at different times beforehand to activate other areas of the brain. If the conditioning stimulus changes the size of the test MEP, then we may have revealed a functional connection between the conditioned site and the motor cortex. There is one general control that has to be applied in such paired pulse designs. The amplitude of the test MEP depends not only on the excitability of the motor cortex, but also on the excitability of spinal motoneurones, and perhaps interneurones. Because of this, any changes in the size of the test MEP may be due to changes in cortical or spinal excitability. There are three main ways in which spinal effects can be tested noninvasively. (1) If H-reflexes can be obtained in the muscle under study, then they provide a measure of motoneuronal excitability. The test is not perfect because the size of an H-reflex can change because of presynaptic effects on transmission in Ia afferent terminals. In addition, we must also assume that we are testing the excitability of the same population of motoneurones as are recruited by the MEP, otherwise the comparison is invalid. Some studies on single motor units suggest that the units recruited by an H-reflex are not always the same as those recruited by an MEP [2]. However, another piece of evidence suggests that even if some of the units are not the same, others must be shared between H-reflex and MEP. Thus, H-reflexes can be facilitated by a suitably timed subthreshold cortical stimulus [3]. The only way this could happen is if some of the descending excitation evoked by the cortical stimulus overlapped at the motoneurones pool with excitation from the H-reflex. The conclusion is that H-reflexes must share some spinal motoneurones with the MEP, and therefore H-reflexes can be used as one, albeit imperfect, measure of spinal excitability in the present experiments. (2) F-waves can also be used in muscles where H-reflexes cannot be readily obtained. However, because the F-wave is more variable than the H-reflex, and often very small, it may be less reliable as an indicator of spinal excitability unless large numbers are collected. In addition, it is still not clear whether the motoneurones recruited in the F-wave are the same as those recruited by the MEP [4]. (3) The final method of probing spinal excitability is by using anodal electrical stimulation of the motor cortex. Unlike the usual method of magnetic stimulation (using a coil that induces a posterior – anterior current to flow across the central sulcus) that activates corticospinal neurones trans-synaptically, anodal stimulation tends to activate the axon of pyramidal neurones in the white matter [5,6]. This means that EMG responses to anodal stimulation are less sensitive to the level of cortical excitation than those evoked by TMS, and therefore give information about spinal excitability changes rather than cortical effects. However, there is one important proviso to this line of reasoning. It is that this distinction between anodal and magnetic stimulation of the cortical motor hand area only holds at threshold intensities of stimulation. At high intensities, both methods recruit corticospinal neurones both directly and trans-synaptically. To be sure of obtaining a relatively pure distinction between the techniques, it is important that the tests are done during tonic background contraction of the target muscle. This means that an EMG
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response can be elicited with a minimal amount of descending activity, and therefore that the magnetic and electric stimuli are at near threshold intensities. Tests done with the muscle at rest are unreliable because higher intensities of stimulation are needed to recruit an EMG response. Most authors use a combination of methods because of the intrinsic uncertainty of any one of them. In special circumstances, however, there is an additional method that gives more direct information about the excitability of the motor cortex. Epidural spinal cord electrodes are sometimes implanted over the dorsal columns for relief of intractable pain. In some centres, the operation is carried out in two stages. In the first the electrodes are implanted, and their terminal left exposed on the skin so that the continuity of the leads can be tested post-operatively. If the electrodes work well, a second operation is then performed to connect the electrode to an electrical stimulator that is implanted subcutaneously, often in the subclavicular region. The interval between the first operation and the final implantation provides a unique opportunity to record from the electrodes in conscious human subjects. Such epidural electrodes can readily detect the descending volleys set up in the lateral columns by TMS, and the size and number of the volleys can be used as a direct measure of the output of the cortex to the standard test stimulus. In other words, there is no need to control for spinal excitability since the electrodes monitor cortical output before it reaches the spinal cord [6]. If the effects in paired pulse testing can be attributed to interactions at the cortex, then one advantage of the method is worth emphasising. The effect of the conditioning pulse will depend on the excitability of the connection to the motor cortex at the time the stimulus is given. For example, if that projection is actively being used, then it is likely to be more readily excited by the conditioning stimulus, and the effect on the response to the test pulse will be larger than in other circumstances. Thus, this paired pulse design not only tests anatomical connectivity, it also reveals some information about the activity in these connections.
3. Inputs to motor cortex 3.1. Transcallosal inputs The first studied connection to motor cortex was that from the motor area of the opposite hemisphere [7]. A single conditioning stimulus over the motor hand area of one cortex can affect the size of responses to a test pulse given over the opposite motor area. The major effect is inhibitory, beginning at an interstimulus interval of 6– 7 ms, and lasting for 30 ms or more depending on the intensity of the conditioning stimulus. An early facilitation can sometimes be seen to precede the inhibition [8]. The initial experiments, in which H-reflex testing and anodal stimulation were used to detect changes in spinal excitability, suggested that the whole of this effect was due to an influence on cortical excitability. However, a recent study has shown that some direct spinal inhibition can be produced on ipsilateral motoneurones by the conditioning stimulus [9]. Most authors think that this latter effect is relatively small. Indeed, direct recordings of
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descending volleys evoked by the test stimulus show that they are strongly suppressed by contralateral conditioning stimuli [10] (Fig. 1). In addition, the effect is not seen in patients with no corpus callosum [11], which is again consistent with the idea that the primary part of the inhibition occurs at the cerebral cortex. This transcallosal inhibition can be observed in the ongoing EMG of ipsilateral muscles as a silent period lasting about 30 ms, starting about 30 ms (for hand muscles) after the stimulus is given. This indicates that voluntary activity is suppressed similarly to the MEP. Transcallosal effects are site-specific, being most prominent when homologous parts of each motor area are stimulated. They seem to depend on activation of neurones different to
Fig. 1. Epidural volleys (left) and EMG responses (right) evoked by test stimulus alone (upper traces), both test and conditioning contralateral stimuli at different ISIs (middle traces) and conditioning stimulus alone (lower traces) in one subject. Recordings were performed at rest. Each trace is the mean of 10 sweeps. Test stimulus evokes multiple descending waves (three waves) and an EMG response of about 0.2 mV. When both stimuli were delivered, the EMG responses were dramatically suppressed at 7 – 10-ms ISIs. At 6 – 10-ms ISIs, the latest (I3) wave is suppressed, the second (I2) wave is slightly inhibited at 9 – 10-ms ISIs while the earliest (I1) wave is not modified (from Ref. [10] with permission).
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those involved in the contralateral MEP since the threshold for inhibition may be different from that of the contralateral MEP [7]. This is consistent with the anatomical data that show that transcallosally projecting fibres originate in cortical layer III whereas the corticospinal neurones are found in layer V. One feature of the transcallosal effect is puzzling. Although it is strongest between the motor hand areas, anatomical studies show that these are the very regions where transcallosal connections are the least dense. One possible explanation is that the effect comes mainly from activation of neuronal population in areas surrounding the hand representation. This ‘‘surround’’ might then elicit a strong inhibitory response in the opposite hemisphere. A final feature of the transcallosal connectivity is that it is sensitive to the motor task being performed by the subjects. For example, inhibition from right to left motor cortex is enhanced compared to rest if subjects actively contract the left hand muscles [7]. This was the first demonstration that the paired pulse design was indeed sensitive to the excitability as well as the anatomy of cortical connections. 3.2. Inputs from the cerebellum The second description of inputs to motor cortex involved stimulation over the cerebellum [12]. The initial experiments used transcranial electrical stimulation across the posterior parts of the mastoid process. As with transcallosal conditioning, the main effect was inhibitory and was maximum when the anode of the stimulator was over the cerebellum contralateral to the motor cortex that was used to testing. Inhibition began about 5 ms after the conditioning stimulus and continued for 10 ms or more. However, the later part of the inhibitory effect was complex. Testing spinal excitability with H-reflexes and anodal electric stimulation of the motor cortex suggested that the first 3 ms or so was a purely cortical effect, probably produced by activation of a cerebello-cortical projection, but that later portions might be of mixed spinal and cortical origin. Electrical stimulation of the cerebellum is relatively uncomfortable because the stimulus produces a large contraction of neck muscles. Ugawa et al. [13] showed that it was possible to obtain similar effects using a magnetic stimulator. However, like electrical stimulation, only the initial part of the effect on motor cortex excitability is likely to be due to a cerebellar projection to cerebral cortex. Magnetic stimulation, particularly with the large coils that are sometimes needed to obtain such effects from the cerebellum, often activates cervical nerve roots [14]. The afferent volley produced by this stimulus can itself affect cortical excitability and complicate interpretation of the results. 3.3. Cortico-cortical connections within the motor cortex Kujirai et al. [15] found that if two stimuli were given through the same coil over the motor cortex, then it was possible to observe short latency interactions between them. A subthreshold conditioning stimulus suppresses the response to a larger suprathreshold test stimulus if the interval between the stimuli is less than 5 ms. At longer intervals the test response is facilitated. The threshold for evoking inhibition is slightly lower and less sensitive to coil orientation than facilitation, indicating that two separate mechanisms are involved [16].
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Several lines of evidence show that this interaction occurs because of activation of circuits in the cerebral cortex. First, the intensity of the conditioning stimulus can be lower than that required to evoke any descending corticospinal volley. Second, the conditioning stimulus has no effect on spinal H-reflexes, or responses to anodal electrical stimulation of the motor cortex. Third, direct recordings from the spinal epidural space show that the conditioning stimulus reduces the size and number of descending corticospinal volleys evoked by the test shock [17] (Fig. 2). The amount of inhibition and facilitation produced by a given conditioning stimulus is less during activation than at rest, suggesting that voluntary activity can affect the
Fig. 2. Epidural volleys (left) and MEPs (right) evoked by test stimulus alone (control), conditioning stimulus alone (lower traces) and both stimuli at different ISIs (middle traces) in one subject. The responses to the test stimulus alone and both stimuli together were recorded when the subject was at rest. The response to the conditioning stimulus alone was delivered during voluntary contraction at about 20% of the maximum. Each trace is the average of 10 sweeps. The test stimulus evokes multiple descending waves (four waves) and an MEP of about 1 mV. The conditioning shock alone evoked neither MEP nor descending volleys. When both stimuli were delivered the MEPs were dramatically suppressed at ISI = 1 – 3 ms. At ISI = 1 ms all the descending waves except the I1 were suppressed; at longer ISIs the I3 and I4 waves were particularly well suppressed (from Ref. [17] with permission).
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excitability of the cortical circuits involved [18]. However, the interpretation of this is complicated by the fact that the conditioning stimulus primarily suppresses the I3 and later waves of corticospinal activity set up by the test shock [19]. With the usual orientation of test stimulus, inducing current in the brain from posterior to anterior across the central sulcus, the I3 wave is usually recruited only at moderate intensities above threshold. I1 and I2 waves are recruited at lower intensities. When subjects are tested at rest, the intensity of the test stimulus is usually relatively low, and may not recruit a large I3 wave. This in itself will mean that the amount of inhibition from the conditioning stimulus may appear small. Proper comparison of the effectiveness of conditioning stimuli requires that the intensity of the test shock be approximately the same in the active and relaxed state. The initial inhibition from the conditioning stimulus appears to be GABAergic in nature since it is affected by drugs that act on central GABAA receptors [20]. The level of inhibition is reduced in many pathological states, including epilepsy involving the motor cortex and many basal ganglia diseases [21,22]. Cerebellar disease seems to have little effect [23].
4. Conclusions Three types of connection have been described from other areas of the brain onto the motor cortex. They are readily revealed by paired pulse testing and show task dependency. Recently, another connection from probable premotor areas has been reported and it is presently the subject of active investigation.
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