- Email: [email protected]
Chapter 37 Neural correlates of cerebral plasticity after brain infarction
Advances in Clinical Neurophysiology (Supplements to Clinical Neurophysiology Vol. )4) Editors: R.C. Reisin, M.R. Nuwer, M. Hallett. C. Medina (i'j 2002 Elsevier Science B,y' All rights reserved.
248
Chapter 37
Neural correlates of cerebral plasticity after brain infarction Rudiger 1. Seitz", Cathrin M. Butefisch" and Volker Homberg" b
'Department ofNeurology, Heinrich-Heine-University Dusseldorf, D-40225 Dusseldorf (Germany) Neurological Therapy Center, Heinrich-Heine-University Dusseldorf, D-40591 Dusseldorf (Germany)
Introduction
Brain diseases such as ischemic brain infarction impair brain function by direct interference with key node areas in functional brain networks but allow for deficit compensation by brain plasticity. Plasticity is the process ofuse-dependent enhancement of synaptic efficacy and shaping of connectivity underlying the physiological development, learning, and post-lesional recovery. Great progress in understanding the mechanisms of functional recovery has been achieved by animal research. In animal experiments, lesions ofthe brain, spinal cord or peripheral nerves have been shown to affect brain function and induce adaptive changes in the cerebral cortex (Kaas and Florence 1997). Functional neuroimaging methods, such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRl), provide the means to study these mechanisms of reorganization in the living human brain (Chollet and Weiller 2000). These methods revealed that not only the infantile brain but also the brains of adults and even aged people can reorganize in response to imposed demands. While
* Correspondence to: Dr. R.I. Seitz, Department ofNeurology Center, Heinrich-Heine-University Dusseldorf, Moorenstrasse 5, D-40225 Dusseldorf, Germany. Fax: +492 11-81-18485. E-mail: Seitz@n.~urologie.uni-duesseldorf.de
plasticity can be maladaptive and may give rise to neurological disorders such as dystonia, epilepsy and pain, it is usually beneficial occurring in relation to memory and learning and to deficit compensation in neurological diseases such as stroke. In acute stroke a number of processes that become sequentially operative determine post-ischemic recovery. The events include rapid reperfusion due to acute therapeutic interventions, spontaneous regression of per i1esionaI and remote dysfunction in the subacute phase after infarction, and reorganization of large-scale networks in both cerebral hemispheres extending into the chronic stage of the disease (Herholz and Heiss 2000).
Systems level It appears from Fig. I that most patients recover
well and early. Three different patient groups with respect to different degrees of post-ischemic impairment and recovery can be differentiated (Binkofski et a1. 200 1a). One group that was severely impaired recovered, while other patients with a similar impairment did not recover at all. It is likely that the decisive distinctive feature is the absence of residual function and consequently of somatosensory feedback of the affected limb over a critical time span in the non-recovering patients. This hypothesis is supported by evidence from com-
249
32 26
20 ~
~'-
14
:E
8
.eo
2
3
7
14
21 28
35 42 49 56
Days after stroke Fig. I. Recovery of motor functions after hemiparetic brain infarction. Patients with a slight impairment, as indicated by a mean motor score of8, recover rapidly within 30 days. For comparison, patients with severe hemiplegia (mean motor score greater than 20) show a more protracted recovery course of many weeks. Note that patients with such a severe acute deficit may not recover at all. For details of the motor score and the relation of recovery to brain lesion volume see Binkofski et al. 2001a.
bined clinical and electrophysiological studies suggesting that in addition to the degree of motor impairment the presence of somatosensory evoked potentials indicated good recovery (Feys et al. 2000). Likewise, deafferented monkeys who were not using the affected limb many weeks after injury failed to recover (Taub et al. 1999). Conversely, animal experiments show an enlargement of the somatosensory representations during skill recovery after focal lesions of the primary somatosensory cortex (Xerri et al. 1998). From these observations the concept was derived that the animals learned not to use the affected limb because of discomfort, stress and frustration when doing so, but used the intact arm instead. This concept of 'learned non-use' laid the ground for subsequent therapy studies in severely impaired chronic human stroke victims. There is good evidence to support the view that reafferent somatosensory informa-
tion from the partly compromised limb is critically required for tuning the remaining network into function as may be evident from passive movements (Nelles et al. 1999). These data are corroborated further by the observation that there is a posterior shift of the sensorimotor area in patients with sensorimotor strokes (Rossini et al. 1998). Such changes of cortical representations may involve long-term potentiation (LTP) or enhanced synaptic efficiency. Using paired associated stimulation of trans cranial magnetic stimulation (TMS) and highly timed electrical median nerve stimulation it was shown that motor evoked potentials (MEPs) recorded from the abductorpollicis brevis muscle are significantly increased compared to the recording before the interventional paired stimulation (Stefan et al. 2000). Preliminary data of a collaborative study suggest that an increased activation area as measured with fMRI during individual thumb abductions is the neuroimaging correlate of this fast occurring cortical plasticity.
Temporal evolution
In acute brain infarction, the location and extent of impaired brain tissue perfusion and of changes of tissue diffusion are of paramount importance for functional recovery, since they determine the development ofthe manifest stroke lesion and, thus, to what degree the different mechanisms of cerebral reorganization may come into play subsequently (Seitz and Freund 1997). In the subacute stage after brain infarction the mechanisms of cerebral plasticity include regression of perilesional dysfunction and recruitment ofdistributed systems in both cerebral hemispheres. These infarct induced changes can be monitored by neuroimaging and electrophysiological measures and correspond to the concept of diaschisis (Witte et al. 2000). Functionally related pathways in either brain hemisphere have been shown to contribute to recovery and to be recruited by re-learning. Increasing evidence suggests that the human brain employs multiple, interconnected brain areas for information processing and control of behavior. Brain diseases are expected to affect these networks
250
directly by interference and indirectly as a consequence of deficit compensation. Covariance analyses applied to functional brain imaging data open the opportunity to study neural networks and their disease related changes in the human brain (Seitz et al. 2001). A hypothesis driven, multivariate analysis of resting regional cerebral metabolic data in patients with infarctions ofthe motor cortex showed that motor recovery from hemiparesis was associated with a relative enhancement of interregional interactions in a cerebello-thalamocortical network. Most important for recovery was the functional coupling between the ipsilesional thalamus and the contralesional cerebellum. Support for these data comes from categorical comparisons studying the decrease ofoxygen metabolism in frontomesial cortex and of glucose metabolism in the thalamus in hemiparesis with poor recovery (Seitz and Freund 1997; Iglesias et a1. 2000). In the chronic stage after stroke cross-modal recruitment of alternative strategies mostly involving the contralesional hemisphere have been shown to engage preferentially the visual cortex during sensorimotor activity as demonstrated in congenital blind subjects and in patients after stroke (Sadato et a1. 1998; Seitz et a1. 2001).
Recovery mechanisms These types of large-scale reorganization appear to involve facilitatory and compensatory engagement of pre-existing, hitherto latent pathways. Evidence for this hypothesis comes from neuroreceptor studies and studies with TMS by which functional systems of the human brain can be probed (Witte et a1. 2000). We wished to address the question whether the activity of excitatory and inhibitory interneurons in the motor cortex contralateral to the affected hemisphere is disturbed in stroke patients. Paired pulse TMS technique at short interstimulus intervals allows the measurement of intracortical inhibition which probably is mediated by GABAergic interneurons. In 12 stroke patients, we studied the motor cortex of the non-affected side using paired pulse TMS technique with an interstimulus interval of 2 ms. This was compared to results of
MEP-ratio
2 1,5
0,5
o -0,5 - t - - - - - - - , , - - - - - - - r - - - - - - ,
-1
20
40
60
% of stimulator's output Fig. 2. Altered excitability after brain infarction in the contralesional motor cortex. Shown is the intracortical inhibition and excitation as tested by paired pulse TMS at interstimulus interval of2 ms for different intensities of the subthreshold CS in patients (triangle) and healthy volunteers (square). The CS intensity is expressed as percentage of the stimulator's output; the amplitude ofMEP elicited by the succeeding, conditioned suprathreshold magnetic stimulation are expressed as ratio of the mean MEP amplitude evoked by five single test pulses. Different modulation of the MEPs between patients and controls (2-way factorial ANOYA; CS intensity p < 0.005; group x CS intensity p < 0.01).
left hemispheric stimulation in 9 healthy right handed volunteers. As illustrated in Fig. 2, the size of the test MEP was significantly influenced by the intensity of the conditioning pulse (CS) and modulated differently in patients and normal volunteers. At small intensities of CS (25-30% of maximal stimulator output), a reduction in the conditioned test MEP amplitude was seen in both groups. In contrast, at higher stimulus intensities, patients and normal volunteers showed a different pattern: the conditioned test MEP amplitudes increased at a steeper rate in patients and exceeded the size of the MEP amplitude evoked by the single test pulse. This facilitatory effect was not seen in the healthy subjects. These first results support the hypothesis that in the motor cortex the threshold for activation of inhibitory interneurons is lower than for excitatory interneurons (Ziemann et a1. 1996; Chen et a1. 1998) and that changes in the excitability of brain areas remote from a stroke lesion occur. Interestingly, stroke patients may engage an alternative strategy for coping with a post-ischemic neurological deficit. Similar observations were
251
made recently in monkeys with focal lesions of motor cortex (Friel and Nudo 1998). Such an alternative strategy is likely to activate the premotor cortex, since premotor cortex plays a critical role for coding motor acts (Rizzolatti et al. 1998). In particular, patients who have recovered from hemiparetic brain infarction were shown to engage premotor cortex, both after subcortical as well as cortical brain infarctions (Chollet and Weiller 2000; Seitz et a1. 2000). In addition, an enhanced activation of prefrontal cortex was observed corresponding to an enhanced cognitive load related to enhanced difficulty of task performance (Seitz et al, 2000). Two aspects are challenging in this context and deserve further studies. First, there is good evidence that lesions of the parietal cortex induce persistent deficits of well defined delicate motor functions such as the shaping of the hand for prehension of objects, tactile object exploration, mirror transformation (Binkofski et a1. 1998, 1999, 2001 b). No comparable deficits were observed in frontal brain lesions, although highly organized parietal-premotor circuits have been identified and ascribed to different subfunctions of sensorimotor activity. Apparently, parietal functions have a highly specialized modular organization and, therefore, are lateralized precluding substitution by the contralesional homologue area whereas the premotor cortex has, a more bilateral organization pattern. The latter seems to be supported by the imaging data both in healthy volunteers and in patients who recovered from brain lesions such as brain infarction (Chollet and Weiller 2000). A further surprising observation is the preponderance of dorsal premotor cortical activations in motor activity in stroke victims while the inferior parts of the premotor cortex was not active. This part of the premotor cortex is very much involved in movement ideation and movement observation probably corresponding to the premotor cortical sub-area F5 which was shown in primates to accommodate socalled mirror neurons (Parsons et al. 1995; Binkofski et a1. 2000; Gerardin et a1. 2001). These neurons are active both during observation and actual performance of movements thus being candidate structures for movement imitation. We are now testing the hypothesis that imaginative-cognitive learning strat-
egies may improve recovery after brain infarction by tasks known to activate this structure.
References Binkofski, F., Dohle, C., Posse, S., Stephan, K.M., Hefter, H., Seitz, R.J. and Freund, H.-J. Human anterior intraparietal area subserves prehension. A combined lesion and functional MRI activation study. Neurology, 1998, 50: 1253-1259. Binkofski, F.. Buccino, G., Dohle, C., Seitz, RJ., Freund, H.-J. Mirror agnosia and mirror ataxia constitute different parietal lobe disorders. Ann. Neurol., 1999,46: 51--61. Binkofski, F., Amunts, K., Stephan, K.M., Posse, S., Schorrnann, T., Zilles, K. and Seitz, RJ. Broca's area subserves imagery of motion: a combined cytoarchitectonic and MRI study. Hum. Brain Mapp., 2000, 11: 273-285. Binkofski, F.. Seitz, R.J., Hacklander, T., Pawelec, D., Mau, J. and Freund, H.-J. The recovery of motor functions following hemiparetic stroke: a clinical and MR-morphometric study. Cerebravase. Dis., 2001a, I]: 273-281. Binkofski, F" Seitz, R.J., Kunesch, E., Dohlc, e. and Freund, H.-J. Tactile apraxia. Unimodal apractic disorder of tactile object exploration associated with parietal lobe lesions. Brain, 200 Ib, 124: 132--144. Chen, R., Tam, A., Butefisch, e.M., Corwell, B., Ziemann, U., Rothwell, J. and Cohen, L.G. Intracortical inhibition and facilitation in different representations of the human motor cortex. J Neurophysiol., 1998,80: 2870-2881. Chollet, F. and Weiller, e. Recovery of neurological function. In: J.C. Mazziotta, A.W. Toga and RS.1. Frackowiak (Eds.), Brain Mapping. The Disorders. Academic Press, San Diego, CA, 2000: 588-597. Feys, H., Van Hees, 1., Bruyninckx, E, Mercelis, R. and De Weerdt, W. Value of somatosensory and motor evoked potentials in predicting arm recovery after a stroke. J Neural. Neurosurg. Psychiatry, 2000, 68: 323-331. Friel, K.M. and Nudo, R.J. Recovery of motor function after focal cortical injury in primates: compensatory movement patterns used during rehabilitative training. Somatosens Mot. Res., 1998, 153: 173-189. Gerardin, E, Sirigu, A., Lehericy, S., Poline, J.B., Gaymard, B., Marsault, e., Agid, Y. and Le Bihan, D. Partially overlapping neural networks for real and imagined hand movements. Cereb. Cortex, 2000,10: 1093-1104. Herholz, K. and Heiss, W.-D. Functional imaging correlates of recovery after stroke in humans. J Cereb. Blood Flow Metab., 2000,12: 1619-1631. Iglesias, S., Marchal, G., Viader, F. and Baron, J.e. Delayed intrahemispheric remote hypometabolism. Correlations with early recovery after stroke. Cerebrovase. Dis. 2000,10: 391-402. Kaas, J.H. and Florence, S.L. Mechanisms of reorganization in sensory systems of primates after peripheral nerve injury. In: H.-J. Freund, B.A. Sabel and O.w. Witte (Eds.), Brain Plasticity. Lippincott-Raven, Philadelphia, PA, 1997: 147-158. Nelles, G., Spiekermann, G., Jueptner, M., Leonhardt, G., Muller, S., Gerhard, H. and Diener, H.e. Evolution of functional reorganization in hemiplegic stroke: a serial positron emission tomographic activation study. Ann. Neurol., 1999,46: 901-909.
252 Parsons, L.M., Fox, P.T., Downs, J.H., Glass, T., Hirsch, T.B., Martin, e.e., Jerabek, P.A. and Lancaster, J.L. Use of implicit motor imagery for visual shape discrimination as revealed by PET. Nature, 1995, 375: 54-58. Rizzolatti, G., Luppino, G. and Matelli, M. The organization of the cortical motor system: new concepts. Electroencephalogr. Clin. Neurophysiol., 1998, 106: 283-296. Rossini, P.M., Tecchic, F., Pizzella, V., Lupoi, D., Cassetta, E. and Pasqualetti, P. On the reorganization of sensory hand areas after mono-hemispheric lesion: a functional (MEG)/anatomical (MRI) integrative study. Brain Res., 1998,782: 153-166. Sadato, N., Pascual-Leone, A., Grafman, J., Deiber, M.P., Ibanez, V and Hallett, M. Neural networks for Braille reading by the blind. Brain, 1998,121: 1213-1229. Seitz, R.J. and Freund, H.-J. Plasticity of the human motor cortex. In: H.-J. Freund, B.A. Sabel and D.W. Witte (Eds.), Brain Plasticity. Adv. Neurol., 1997,73: 321-333. Seitz, R.J., Stephan, K.M. and Binkofski, F. Control of action as mediated by the human fronta/lobe. Exp. Brain Res., 2000, /33: 71-80. Seitz, R.J., Knorr, D., Azari, N.P. and Weder, B. Cerebral networks
in sensorimotor disturbances. Brain Res. Bull., 2001, 54: 299305. Stefan, K., Kunesch, E., Cohen, L.G., Benecke, R. and Classen, J. Induction of plasticity in the human motor cortex by paired associative stimulation. Brain, 2000,123: 572-584. Taub, E., Uswatte, G. and Pidikiti, R. Constraint-induced movement therapy: a new family of techniques with broad application to physical rehabilitation - a clinical review. 1. Rehabil. Res, Dev., 1999,36: 237-251. Xerri, e., Merzenich, M.M., Peterson, B.E. and Jenkins, W. Plasticity of primary somatosensory cortex paralleling sensorimotor skill recovery from stroke in adult monkeys. 1. Neurophysial., 1998,79:2119-2148. Witte, D.W., Bidmon, H.-J., Schiene, K., Redecker, e. and Hagemann, G. Functional differentiation of multiple perilesional zones after focal cerebral ischemia. 1. Cereb. Blood Flow Metab., 2000, 20: 1149-1165. Ziemann, U., Lonnecker, S., Steinhoff, B.J. and Paulus, W. Effects of different antiepileptic drugs on motor cortex excitability in humans: a transcranial magnetic stimulation study. Ann, Neurol., 1996,40: 367-378.
248
Chapter 37
Neural correlates of cerebral plasticity after brain infarction Rudiger 1. Seitz", Cathrin M. Butefisch" and Volker Homberg" b
'Department ofNeurology, Heinrich-Heine-University Dusseldorf, D-40225 Dusseldorf (Germany) Neurological Therapy Center, Heinrich-Heine-University Dusseldorf, D-40591 Dusseldorf (Germany)
Introduction
Brain diseases such as ischemic brain infarction impair brain function by direct interference with key node areas in functional brain networks but allow for deficit compensation by brain plasticity. Plasticity is the process ofuse-dependent enhancement of synaptic efficacy and shaping of connectivity underlying the physiological development, learning, and post-lesional recovery. Great progress in understanding the mechanisms of functional recovery has been achieved by animal research. In animal experiments, lesions ofthe brain, spinal cord or peripheral nerves have been shown to affect brain function and induce adaptive changes in the cerebral cortex (Kaas and Florence 1997). Functional neuroimaging methods, such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRl), provide the means to study these mechanisms of reorganization in the living human brain (Chollet and Weiller 2000). These methods revealed that not only the infantile brain but also the brains of adults and even aged people can reorganize in response to imposed demands. While
* Correspondence to: Dr. R.I. Seitz, Department ofNeurology Center, Heinrich-Heine-University Dusseldorf, Moorenstrasse 5, D-40225 Dusseldorf, Germany. Fax: +492 11-81-18485. E-mail: Seitz@n.~urologie.uni-duesseldorf.de
plasticity can be maladaptive and may give rise to neurological disorders such as dystonia, epilepsy and pain, it is usually beneficial occurring in relation to memory and learning and to deficit compensation in neurological diseases such as stroke. In acute stroke a number of processes that become sequentially operative determine post-ischemic recovery. The events include rapid reperfusion due to acute therapeutic interventions, spontaneous regression of per i1esionaI and remote dysfunction in the subacute phase after infarction, and reorganization of large-scale networks in both cerebral hemispheres extending into the chronic stage of the disease (Herholz and Heiss 2000).
Systems level It appears from Fig. I that most patients recover
well and early. Three different patient groups with respect to different degrees of post-ischemic impairment and recovery can be differentiated (Binkofski et a1. 200 1a). One group that was severely impaired recovered, while other patients with a similar impairment did not recover at all. It is likely that the decisive distinctive feature is the absence of residual function and consequently of somatosensory feedback of the affected limb over a critical time span in the non-recovering patients. This hypothesis is supported by evidence from com-
249
32 26
20 ~
~'-
14
:E
8
.eo
2
3
7
14
21 28
35 42 49 56
Days after stroke Fig. I. Recovery of motor functions after hemiparetic brain infarction. Patients with a slight impairment, as indicated by a mean motor score of8, recover rapidly within 30 days. For comparison, patients with severe hemiplegia (mean motor score greater than 20) show a more protracted recovery course of many weeks. Note that patients with such a severe acute deficit may not recover at all. For details of the motor score and the relation of recovery to brain lesion volume see Binkofski et al. 2001a.
bined clinical and electrophysiological studies suggesting that in addition to the degree of motor impairment the presence of somatosensory evoked potentials indicated good recovery (Feys et al. 2000). Likewise, deafferented monkeys who were not using the affected limb many weeks after injury failed to recover (Taub et al. 1999). Conversely, animal experiments show an enlargement of the somatosensory representations during skill recovery after focal lesions of the primary somatosensory cortex (Xerri et al. 1998). From these observations the concept was derived that the animals learned not to use the affected limb because of discomfort, stress and frustration when doing so, but used the intact arm instead. This concept of 'learned non-use' laid the ground for subsequent therapy studies in severely impaired chronic human stroke victims. There is good evidence to support the view that reafferent somatosensory informa-
tion from the partly compromised limb is critically required for tuning the remaining network into function as may be evident from passive movements (Nelles et al. 1999). These data are corroborated further by the observation that there is a posterior shift of the sensorimotor area in patients with sensorimotor strokes (Rossini et al. 1998). Such changes of cortical representations may involve long-term potentiation (LTP) or enhanced synaptic efficiency. Using paired associated stimulation of trans cranial magnetic stimulation (TMS) and highly timed electrical median nerve stimulation it was shown that motor evoked potentials (MEPs) recorded from the abductorpollicis brevis muscle are significantly increased compared to the recording before the interventional paired stimulation (Stefan et al. 2000). Preliminary data of a collaborative study suggest that an increased activation area as measured with fMRI during individual thumb abductions is the neuroimaging correlate of this fast occurring cortical plasticity.
Temporal evolution
In acute brain infarction, the location and extent of impaired brain tissue perfusion and of changes of tissue diffusion are of paramount importance for functional recovery, since they determine the development ofthe manifest stroke lesion and, thus, to what degree the different mechanisms of cerebral reorganization may come into play subsequently (Seitz and Freund 1997). In the subacute stage after brain infarction the mechanisms of cerebral plasticity include regression of perilesional dysfunction and recruitment ofdistributed systems in both cerebral hemispheres. These infarct induced changes can be monitored by neuroimaging and electrophysiological measures and correspond to the concept of diaschisis (Witte et al. 2000). Functionally related pathways in either brain hemisphere have been shown to contribute to recovery and to be recruited by re-learning. Increasing evidence suggests that the human brain employs multiple, interconnected brain areas for information processing and control of behavior. Brain diseases are expected to affect these networks
250
directly by interference and indirectly as a consequence of deficit compensation. Covariance analyses applied to functional brain imaging data open the opportunity to study neural networks and their disease related changes in the human brain (Seitz et al. 2001). A hypothesis driven, multivariate analysis of resting regional cerebral metabolic data in patients with infarctions ofthe motor cortex showed that motor recovery from hemiparesis was associated with a relative enhancement of interregional interactions in a cerebello-thalamocortical network. Most important for recovery was the functional coupling between the ipsilesional thalamus and the contralesional cerebellum. Support for these data comes from categorical comparisons studying the decrease ofoxygen metabolism in frontomesial cortex and of glucose metabolism in the thalamus in hemiparesis with poor recovery (Seitz and Freund 1997; Iglesias et a1. 2000). In the chronic stage after stroke cross-modal recruitment of alternative strategies mostly involving the contralesional hemisphere have been shown to engage preferentially the visual cortex during sensorimotor activity as demonstrated in congenital blind subjects and in patients after stroke (Sadato et a1. 1998; Seitz et a1. 2001).
Recovery mechanisms These types of large-scale reorganization appear to involve facilitatory and compensatory engagement of pre-existing, hitherto latent pathways. Evidence for this hypothesis comes from neuroreceptor studies and studies with TMS by which functional systems of the human brain can be probed (Witte et a1. 2000). We wished to address the question whether the activity of excitatory and inhibitory interneurons in the motor cortex contralateral to the affected hemisphere is disturbed in stroke patients. Paired pulse TMS technique at short interstimulus intervals allows the measurement of intracortical inhibition which probably is mediated by GABAergic interneurons. In 12 stroke patients, we studied the motor cortex of the non-affected side using paired pulse TMS technique with an interstimulus interval of 2 ms. This was compared to results of
MEP-ratio
2 1,5
0,5
o -0,5 - t - - - - - - - , , - - - - - - - r - - - - - - ,
-1
20
40
60
% of stimulator's output Fig. 2. Altered excitability after brain infarction in the contralesional motor cortex. Shown is the intracortical inhibition and excitation as tested by paired pulse TMS at interstimulus interval of2 ms for different intensities of the subthreshold CS in patients (triangle) and healthy volunteers (square). The CS intensity is expressed as percentage of the stimulator's output; the amplitude ofMEP elicited by the succeeding, conditioned suprathreshold magnetic stimulation are expressed as ratio of the mean MEP amplitude evoked by five single test pulses. Different modulation of the MEPs between patients and controls (2-way factorial ANOYA; CS intensity p < 0.005; group x CS intensity p < 0.01).
left hemispheric stimulation in 9 healthy right handed volunteers. As illustrated in Fig. 2, the size of the test MEP was significantly influenced by the intensity of the conditioning pulse (CS) and modulated differently in patients and normal volunteers. At small intensities of CS (25-30% of maximal stimulator output), a reduction in the conditioned test MEP amplitude was seen in both groups. In contrast, at higher stimulus intensities, patients and normal volunteers showed a different pattern: the conditioned test MEP amplitudes increased at a steeper rate in patients and exceeded the size of the MEP amplitude evoked by the single test pulse. This facilitatory effect was not seen in the healthy subjects. These first results support the hypothesis that in the motor cortex the threshold for activation of inhibitory interneurons is lower than for excitatory interneurons (Ziemann et a1. 1996; Chen et a1. 1998) and that changes in the excitability of brain areas remote from a stroke lesion occur. Interestingly, stroke patients may engage an alternative strategy for coping with a post-ischemic neurological deficit. Similar observations were
251
made recently in monkeys with focal lesions of motor cortex (Friel and Nudo 1998). Such an alternative strategy is likely to activate the premotor cortex, since premotor cortex plays a critical role for coding motor acts (Rizzolatti et al. 1998). In particular, patients who have recovered from hemiparetic brain infarction were shown to engage premotor cortex, both after subcortical as well as cortical brain infarctions (Chollet and Weiller 2000; Seitz et a1. 2000). In addition, an enhanced activation of prefrontal cortex was observed corresponding to an enhanced cognitive load related to enhanced difficulty of task performance (Seitz et al, 2000). Two aspects are challenging in this context and deserve further studies. First, there is good evidence that lesions of the parietal cortex induce persistent deficits of well defined delicate motor functions such as the shaping of the hand for prehension of objects, tactile object exploration, mirror transformation (Binkofski et a1. 1998, 1999, 2001 b). No comparable deficits were observed in frontal brain lesions, although highly organized parietal-premotor circuits have been identified and ascribed to different subfunctions of sensorimotor activity. Apparently, parietal functions have a highly specialized modular organization and, therefore, are lateralized precluding substitution by the contralesional homologue area whereas the premotor cortex has, a more bilateral organization pattern. The latter seems to be supported by the imaging data both in healthy volunteers and in patients who recovered from brain lesions such as brain infarction (Chollet and Weiller 2000). A further surprising observation is the preponderance of dorsal premotor cortical activations in motor activity in stroke victims while the inferior parts of the premotor cortex was not active. This part of the premotor cortex is very much involved in movement ideation and movement observation probably corresponding to the premotor cortical sub-area F5 which was shown in primates to accommodate socalled mirror neurons (Parsons et al. 1995; Binkofski et a1. 2000; Gerardin et a1. 2001). These neurons are active both during observation and actual performance of movements thus being candidate structures for movement imitation. We are now testing the hypothesis that imaginative-cognitive learning strat-
egies may improve recovery after brain infarction by tasks known to activate this structure.
References Binkofski, F., Dohle, C., Posse, S., Stephan, K.M., Hefter, H., Seitz, R.J. and Freund, H.-J. Human anterior intraparietal area subserves prehension. A combined lesion and functional MRI activation study. Neurology, 1998, 50: 1253-1259. Binkofski, F.. Buccino, G., Dohle, C., Seitz, RJ., Freund, H.-J. Mirror agnosia and mirror ataxia constitute different parietal lobe disorders. Ann. Neurol., 1999,46: 51--61. Binkofski, F., Amunts, K., Stephan, K.M., Posse, S., Schorrnann, T., Zilles, K. and Seitz, RJ. Broca's area subserves imagery of motion: a combined cytoarchitectonic and MRI study. Hum. Brain Mapp., 2000, 11: 273-285. Binkofski, F.. Seitz, R.J., Hacklander, T., Pawelec, D., Mau, J. and Freund, H.-J. The recovery of motor functions following hemiparetic stroke: a clinical and MR-morphometric study. Cerebravase. Dis., 2001a, I]: 273-281. Binkofski, F" Seitz, R.J., Kunesch, E., Dohlc, e. and Freund, H.-J. Tactile apraxia. Unimodal apractic disorder of tactile object exploration associated with parietal lobe lesions. Brain, 200 Ib, 124: 132--144. Chen, R., Tam, A., Butefisch, e.M., Corwell, B., Ziemann, U., Rothwell, J. and Cohen, L.G. Intracortical inhibition and facilitation in different representations of the human motor cortex. J Neurophysiol., 1998,80: 2870-2881. Chollet, F. and Weiller, e. Recovery of neurological function. In: J.C. Mazziotta, A.W. Toga and RS.1. Frackowiak (Eds.), Brain Mapping. The Disorders. Academic Press, San Diego, CA, 2000: 588-597. Feys, H., Van Hees, 1., Bruyninckx, E, Mercelis, R. and De Weerdt, W. Value of somatosensory and motor evoked potentials in predicting arm recovery after a stroke. J Neural. Neurosurg. Psychiatry, 2000, 68: 323-331. Friel, K.M. and Nudo, R.J. Recovery of motor function after focal cortical injury in primates: compensatory movement patterns used during rehabilitative training. Somatosens Mot. Res., 1998, 153: 173-189. Gerardin, E, Sirigu, A., Lehericy, S., Poline, J.B., Gaymard, B., Marsault, e., Agid, Y. and Le Bihan, D. Partially overlapping neural networks for real and imagined hand movements. Cereb. Cortex, 2000,10: 1093-1104. Herholz, K. and Heiss, W.-D. Functional imaging correlates of recovery after stroke in humans. J Cereb. Blood Flow Metab., 2000,12: 1619-1631. Iglesias, S., Marchal, G., Viader, F. and Baron, J.e. Delayed intrahemispheric remote hypometabolism. Correlations with early recovery after stroke. Cerebrovase. Dis. 2000,10: 391-402. Kaas, J.H. and Florence, S.L. Mechanisms of reorganization in sensory systems of primates after peripheral nerve injury. In: H.-J. Freund, B.A. Sabel and O.w. Witte (Eds.), Brain Plasticity. Lippincott-Raven, Philadelphia, PA, 1997: 147-158. Nelles, G., Spiekermann, G., Jueptner, M., Leonhardt, G., Muller, S., Gerhard, H. and Diener, H.e. Evolution of functional reorganization in hemiplegic stroke: a serial positron emission tomographic activation study. Ann. Neurol., 1999,46: 901-909.
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