- Email: [email protected]
Imaging recovery of function following brain injury
Imaging recovery of function following brain injury FranCois Chollet and Cornelius Weiller Department of Neurology and INSERM U230, Toulouse, France and Neurologische Universitatklinik, Essen, Germany The
past years
have seen significant
recovery of function of sophisticated
after brain
methods
by using positron
for exploring
emission
tomography
appears that two main mechanisms recruitment
advances
lesions.
This
in our
results
the human
understanding
living
especially it
in the recovery process:
of cortical areas in the undamaged hemisphere specialized
brain,
scans. From the recent literature,
may participate
of
from the development
and extension
of
areas adjacent to the lesioned site.
Current Opinion
in Neurobiology
Introduction Recovery is very often observed after brain injury. It is well known by neurologists that traumatic, inflammatory and vascular lesions of the human brain produce acute neurological deficits that may recover in the days, weeks or months following the insult. This phenomenon is particularly true in patients who have suffered a stroke, as in some cases recovery is listed as one of the diagnostic criteria. On the other hand, recovery of neurological functions remains unpredictable and poorly understood. Sometimes recovery occurs late after the stroke and in a very limited fashion, whereas at other times it may be observed soon after the stroke and there may be complete or nearly complete recovery of the motor, sensory, visual or linguistic function affected. It is becoming increasingly important for physicians (and for patients) to be aware of these differences because it could help determine which pharmacological therapy would best accelerate recovery and because it would assist making more rational decisions about the methods of rehabilitation. Until recently, the mechanisms responsible for recovery were largely unknown. Dramatic improvement in non-invasive imaging techniques have recently allowed for insights into the changes occurring in the damaged human brain during the recovery period. In particular, positron emission tomography (PET) scanning, with the emergence of new highly sensitive cameras and with the improvement of image analysis software, now allows for the study of individuals (instead of groups) and for comparisons of individual patterns of reactivity to controls. Recently, important data about normal human brains have been obtained using the activation technique, which gives quantitative images of the brain during the performance of tasks and contributes information on the functional architecture of
1994,
4:226-230
the brain 11-61. One can also foresee that in the near future, functional magnetic resonance imaging (MRI) 1731 will allow for complementary approaches to the mapping of the human brain functions, as will electrophysiology and magnetoencephalography, with their main advantage: good time resolution. Most of the studies published until now in the literature have focused on recovery of motor function in patients presenting with lesions to the cortocospinal tract and other major descending motor pathways from the cortex to the brainstem and spinal cord [9,10”,11**,12*1. Recovery of other neurological functions is starting to be studied with these new techniques 1131. Stroke represents an appropriate model for the study of recovery of function after acute brain injury. Nevertheless, it may be that the adaptative processes in the brain are somewhat different in cases of chronic or non-vascular damage. Degenerative disorders such as amyotrophic lateral sclerosis (ALS) offer a possibility to investigate adaptative processes to progressive neuronal degeneration or loss 114.1. In this review, we will discuss the two main mechanisms involved in brain recovery, namely recruitment of remote cortical areas and extension of areas adjacent to the lesion site.
Recruitment
of cortical
areas in undamaged
hemispheres Several neurobiological mechanisms can be evoked to account for recovery from insults to the brain; apart from the resolution of the initial shock and edema, bilateral representation of function, creation of new connections, release of inhibition and synaptic sprouting are the most common proposed mechanisms. In a
Abbreviations ALS-amyotrophic lateral sclerosis; EMC-electromyography; PET-positron emission tomography; rCBF-regional
226
0 Current
Biology
GABA-yaminobutyric acid; MRI-magnetic resonance imaging; cerebral blood flow; WA-supplementary motor area.
Ltd ISSN 0959-4388
Imaging recovery of function following brain injury Chollet and Weiller
series of three articles 19,10..,11**1, starting from 1991, the group from the Hammersmith Hospital in London describe their work using PET to identify two main brain mechanisms that compensate for a motor deficit and contribute to the functional reorganization of the brain. Firstly, uncrossed ipsilateral motor pathways from the undamaged hemisphere may be accessed to channel signals coding for movements down to the spinal cord, and, secondly, cortical areas in the damaged hemisphere may contain representations of movement and these may access the spinal cord via alternative pathways that bypass the lesioned pyramidal tract. In the first paper, Chollet et al. [91 reported on a study of six patients recovering from their first hemiplegic stroke. The authors noticed that when the patients’ affected hand was performing a finger to thumb opposition task, there was bilateral activation of the motor cortices, whereas movements of the unaffected hand were accompanied only by activation of the contralatera1 motor cortices. No contralateral-associated movements were observed when the affected hand was moving. The results from this paper strongly suggest that ipsilateral cortices play a role in the recovery processes. In this first work of the series, the contralateral unaffected hand served as a control for the recovered hand [91. In the second paper of the series llO”l, the pattern of activation elicited by movement of the affected (recovered), as well as the contralateral, hand was compared with the pattern of activation measured in 10 healthy controls. The recording of regional cerebral blood flow (rCBF) in patients and controls, at rest, showed‘a basic functional reorganization of the brain [lo”]. Some areas showed lower rCBF in patients than in controls; this was not only true for the site of the lesion but also for remote areas of the cortex (insula, premotor cortex) and the brainstem, all corresponding to functional disconnection of these areas. Conversely, measurements of rCBF in other cortical areas (mainly in the undamaged hemisphere) was found to be higher in patients than in controls, demonstrating a positive effect, probably related to the release of cortico-cortical inhibitions. When patterns of motor activation in patients were compared with those of normals, a signihcantly greater activation was found in the ipsilateral premotor cortices and in the contralateral cerebellum of patients, as well as strong bilateral activation in other areas in the lower parietal cortices (BA40) and in the insula near to the frontal operculum. Those changes of rCBF pattern at rest and during motor activation were observed several weeks after the stroke, and at the time of the PET study, the recovery of motor function was complete or nearly complete. So, one can assume that these changes are related to the recovery processes. Nevertheless, we must admit that, until now, no longitudinal data support this hypothesis. This paper [lO**l confirms that functional reorganization occurs in a damaged brain and supports the idea that cortical areas ipsilateral to the deficit participate in the recovery processes.
These conclusions were challenged in a recent article by Palmer et al. 112.1. They studied 10 patients, recovering from a single cerebral or brainstem infarct and with an Initial severe hemiplegia, who were able to maintain a contraction of their hemiplegic biceps muscle at the time of the study. When the subjects’ unaffected hemispheres were electromagnetically stimulated, no short-latency depolarization of their ipsilateral biceps motoneurons was detected, whereas short-latency depolarization of their contralateral biceps was easily recorded. The authors concluded that fast Torticospinal ipsilateral pathways do not develop after stroke. Apart from the fact that short-latency depolarization of ipsilateral neurons may not have been detected because of too high thresholds for magnetic stimulation or too small evoked postsynaptic potentials, it appears that ipsilateral pathways, if they participate in motor recovery, may be mediated by slowly conducting or polysynaptic ipsilateral pathways. In fact, stimulation of the unaffected hemisphere resulted in late (50 msec) facilitation in 30% of the contralateral biceps motor units and in 20% of the ipsilateral biceps motor units.
Extension
of specialized
areas
In the third paper of the series from Hammersmith [9,10**,11~~1, Weiller et al. [ll”l studied eight patients with a lesion of their internal capsule, who also suffered from acute hemiplegia and made a complete recovery from their motor deficit. A similar motor task (to the one described above) was used and the patients had to perform a finger to thumb opposition in turn during the time of data recording. A technical advance is developed in this article. The authors describe a statistical method that allows for a comparison of the rCBF changes recorded during the execution of a motor task of each individual to the pattern of motor activation of a group of 10 controls. This method consists of generating maps of 2 score, comparing for each image voxel, rCBF change of individuals to mean rCBF change of 10 healthy controls. Thus, using this method, individual patterns of brain re-organization underlying recovery may be identified. One of the main results of this article is that very different patterns of activation exist. This may result from an underlying variability in neuronal hard-wiring, the functional anatomy, the lesion site, or the extent and the time course of the process of recovery. Greater activation than in normal subjects was recorded in variable combinations of the supplementary motor area (SMA), insula, frontal operculum and parietal cortex. Ipsilateral motor pathways were also found to be more activated than in controls. Activation of ipsilateral sensori-motor cortex was found in four subjects who exhibited associated movements of the unaffected hand when the recovered (affected) hand performed the task So, the role of ipsilateral motor pathways in the recovery of motor function remains controversial, and it is
.227
228
Cognitive neuroscience
difficult to know if they correspond to the recruitment of cortico-spinal pathways or if they represent only an epiphenomenon related to artefactual mirror movements. An argument against the latter hypothesis is the symmetrical activation of cerebellar hemispheres during recovered hand movement, as shown by Chollet et al. 191 in their original paper. In that study, no ipsilateral-associated movements of the unaffected hand were detected by the authors, but then again, EMG (electromyography) recordings were not made. So, infraclinical-associated movements cannot be dismissed. In the original study 191, a 10% rCBF increase was observed in both cerebellar hemispheres of patients when their affected hand was moving. Primary sensor&motor cortices were also bilaterally activated during movements of the affected hand, but the magnitude of activation was very different in contralatera1 and in ipsilateral sensori-motor cortices (23 % rCBF increase in contralateral primary sensori-motor cortex and 10.1% rCBF increase in ipsilateral primary sensorimotor cortex). Sabatini and Chollet and colleagues [15*1 in a further motor activation study on normals have shown that, as in the sensori-motor cortex, the magnitude of activation in the cerebellar hemispheres appears to be dependent of the way the movement was executed (rate and amplitude of finger movements). According to these experimental data, one can say that it appears unlikely that small mirror movements can account for a high magnitude activation of the contralateral cerebellar hemisphere. The second important idea developed in this paper [ll**l is the detection of a large ventral extension of the hand field of the contralateral sensori-motor cortex in four patients with lesions of the posterior limb of the internal capsule. In these patients, the cortical motor field associated with finger movements appears to have enlarged significantly into that area normally associated with the face. Interestingly,
similar findings were published by Kew
et al. [14*f a few weeks later. Using PET, they studied the motor function of 12 patients with ALS, a degenerative disease characterized by a progressive loss of pyramidal cells and of motoneurones. They compared these patients with six age-matched controls. Scans were performed at rest and while subjects moved a joystick with their right hand. The authors showed that in patients at rest, ICBF was significantly reduced in primary and secondary motor areas (primary sensori-motor cortex, premotor cortex, SMA, paracentral lobule, anterior cingulate cortex, and superior and inferior parietal cortex). This reduction in rCBF has to be related to the generalized neuronal loss and with the loss of synaptic connections in all areas that project through the cortico-spinal tract. During motor activation, AIS patients have greater activation than normals in the ventral third (face area; 28 mm instead of 44 mm above the AC-PC bicommissural line) of the contralateral primary sensori-motor cortex and in the adjacent contralateral ventral premotor and parietal cortices [I4**]. The authors suggest that the recruitment
of the face area may represent a cortical adaptation to pyramidal tract disruption. In the literature, evidence is accumulating that cortical maps may undergo plastic changes in adult animals as the result of various peripheral injuries. Pons et al. [161, for example, demonstrated a 10 mm to 14mm extension of the face area into the area of the upper limb in the primary sensory cortex of adult macaques after upper limb deafferentiation. Magnetic brain stimulation studies in man have shown that following upper limb amputation, surviving limb muscles may be excited from a larger number of scalp position than in normal subjects 1171. Similar findings have been reported in patients with paraplegia and quadriplegia. To our knowledge, this is the first time that such phenomena can be directly illustrated in humans. The cellular mechanisms underlying the extension of the motor area remain to be elucidated. Its rapid occurrence after stroke (less than three months) suggests that a reinforcement of existing circuits is more probable than the growth of new connections. This is not the case in ALS patients, where the neuronal loss is progressive and no recovery is observed. Axons of sensorimotor cortex pyramidal cells have up to five collateral axons that synapse at a distance of up to 6 mm with inhibitory interneurons that are thought to connect to adjacent Betz cells. In animals, GABA antagonists placed in the sensor&motor cortex results in the evocation of more widespread movements in response to local stimulation than normal. GABA-mediated inhibitory activity modified by a lesion could facilitate the cortical spread of activation. Another explanation for the extension of the motor map could be that an alteration in sensory input may induce a reorganization of the motor cortex. This is suggested by Kew et al. 114’.1, who suspect that in patients with ALS, the deep sensory input is somewhat different from that of controls, as the execution of the motor task was not strictly similar. The four patients with posterior limb capsular ischaemic lesions studied by Weiller et al. [ll**l, however, all recovered, all executed motor tasks normally and all showed similar ventral extensions of their motor maps. It is interesting to note that the precise site of the lesion in these four patients was located in the posterior part of the posterior limb of the internal capsule, and that the sparing of the genu (classically reported as the location of the face fibres into the internal capsule) was associated with the ventral extension of the arm area into the face area. The authors suggest that this finding corresponds to a somatotopic organization of cortico-spinal fibres in the internal capsule. Acceptance for such an organization remains controversial. In a recent clinical and experimental study, Fries et al. 118”l performed an assessement of motor function in twenty-three patients with capsular or striatocapsular stroke. They found that selective lesions of basal ganglia do not affect voluntary movements of the extremities. Lesions of the anterior limb and of the posterior limb of the internal capsule lead to an initially severe motor impairment of the extremities followed by an ex-
Imaging recovery of function following brain injury Chollet and Weiller
cellent recovery. In contrast, lesions of the posterior limb, in combination with damage to the lateral thalamus, compromise motor outcome. It is shown once more in this paper [18**1 that lesions of the anterior limb of the internal capsule (believed to be free of corticospinal motor fibres) can induce severe paralysis, and that an impairment of sensory feedback may compromise recovery. In a second part of this study [IS**], using experimental tracing of the internal capsule in macaque monkeys, the authors showed that fibres coming from primary motor cortex passed through the middle third of the posterior limb of the internal capsule. Fibres coming from the SMA pass through the anterior part of the posterior limb. Fibres coming from premotor cortex are located first in the anterior limb of the internal capsule then around the genu. These results look very interesting as they contribute to modifying our hierarchical view of the organization of the motor system. It might be that primary motor cortex, premotor cortex and SMA (which all contain pyramidal cells) participate in a parallel, rather than in a sequential, way to the motricity, with each of the three subsystems (primary motor cortex, premotor cortex and SMA) being able to compensate partially or totally for deficits in the other. If it is obvious that the study of recovery of motor function with appropriate imaging tools will allow significant advances in our comprehension of the motor system, in the same way, the study of recovery of other neurological functions will give us insights into their physiology. This is becoming apparent in the area of language and aphasia. Several studies of language in normals have been published in the last few years Pi-61. Weiller et al. 1131studied six right-handed male patients recovering from Wernicke’s aphasia. They all had an infarction of the posterior part of the superior temporal gyrus and were making good recovery. Six right-handed males were used as controls. Using PET, brain activation was measured during three conditions: rest, performance of a semantic task (internal generation of verbs) and silent repetition of non-words. Both tasks induced an increase of rCBF in premotor cortex, putamen, superior temporal gyrus on the left hemisphere, and an activation of homologous regions in the right hemisphere. Significant activation was found in the right superior temporal gyrus, in the right BA44 and in lateral prefrontal cortex of patients. Right-sided activations were significantly higher in patients. Conversely, no obvious compensating processes were detected in the left hemisphere, with no extension of language areas comparable to those found in the recovery of motor function. The authors assume that in these patients there is a radical reorganization of activity within pre-exising bilateral language networks.
Conclusions Participation of ipsilateral motor pathways and anatomical extension of specialized cortical areas are two
mechanisms by which reoganization of the human brain occurs after a lesion. Recent experimental data lend support to such conclusions. One can speculate that further developments in techniques and of experimental paradigms will contribute in the near future to a better understanding of individual patterns of recovery and what determines them.
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WEIILER C, CHOLLET F, FRISTON KJ, WISE RJS, FKACKOWIAK RSJ: Functional Reorganization of the Brain in Recovery from Capsulostriatal Infarction in Man. Ann Nmrol 1992, 31:463-472. In the first paper I91of a series of three [9,10**,11**1 by the group at the Hammersmith Hospital in London, it was shown that ipsiiateral motor cortices were activated when ‘recovered’ fingers were moving. The authors concluded that ipsilateral motor pathways may play a role in recovery processes. The second paper HO**1 compares patients to healthy controls. The motor task used was similar to one used in the previous paper i91. At rest, deafferented areas were shown. During the performance of the task, ipsilateral motor pathways were more activated in recovered patients than in controls. 10 ..
11. ..
WELLER C, RAMSAY SC, WISE RJS, FRISTON KJ, FRACKOWIAK
RSJ: Individual
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in the
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Cognitive neuroscience Human Cerebral Cortex After Capsular Infarction. Ann Nerrrol 1993, 33:181-189. In the third paper Ill”1 of the series [9,10’.,11’*1, rCBF changes during motor activation are analyzed in individual patients. The motor task was still the same as in [9,10”1. Individual patterns of reorganization of motor function were all different. A ventral extension of the hand field of the contralateral sensori-motor cortex was found in patients with lesion of the posterior limb of the internal capsule. 12. .
PALMER E, ASHBY P, HAJECKVE: Ipsilateral
WEILLER C, RIJNTJES M, ISENSEE C, MULLERSP, KA~PEKLER CH, HLIUER W, DIENERHC: Right Hemisphere Contribution to Re-
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trophic Lateral Sclerosis. Bruin 1993, 116:655-680. A ventral extension of the face area was also observed in patients with ALS, a degenerative disease characterized by a chronic loss of motoneurons and pyramid4 cells. 15.
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PONS T, GARRAGHTYPE, OMMAYA AK, KAAS JH, TAUB E, MISHKIN M: Massive Cortical Reorganization After Sensory Deafferentation in Adult Macaques. Science 1991, 252:1857-&O.
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COHEN LG, BANDINELLI S, FINDLEYTW, HALL!?? M: IMotor Reorganization After Motor Limb Amputation in Man. Brain
Fast Corticospinal in Stroke. Ann Nets-
Pathwars Do Not Account for Recovery rol 1992, 32:519-525. This study relates the findings from 10 patients recovering from stroke. The electromagnetic stimulation of the unaffected hemisphere failed to produce short-latency depolarization of ipsilateral biceps motoneurons. 13.
No difference of activation of motor cortices was observed when right-handed volunteers performed a motor task with their right or with their left fingers. When the task was performed at high rate and amplitude, contralateral motor cortex, SMA and ipsilateral cerebellum were activated, whereas at low rate and amplitude, only SMA was activated. Contralateral motor cotfex and ipsikateral cerebellum appear highly dependent on the execution of the task.
SABATINIU, CHOLLI~’F, RAXOL 0, CELSIS1: RAXOL A, LENZI G, MARC-VERGNES JP: Effect of Side and Rate of Stimulation
on Cerebral Blood Flow Changes in IMotor Areas During Finger Movements in Humans. J Cereb Blood Flow Metab 1993, 13:639-645.
lsl,
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18. ..
FIXIFSW, DANEK A, SCHEIDTMANNK, HAMBURGERC: Motor Recovery Following Capsular Stroke. Role of Descending Pathways from Multiple Motor Areas. Brain 1993, 116:369-382. The authors correlate clinical outcome of hemiplegic patients to the precise site of lesions. Lesions strictly located to the internal capsule are associated with a severe initial motor deficit and with a good recovery. Further experiments in macaque monkeys showed different anatomical pathways through the internal capsule. The three subsystems might act in parallel, compensating partially or totally for the lesion of the other.
F Chollet, Department of Neurology and INSERM U230, HBpital Purpan, Place du Docteur Bay&, 31059 Toulouse Cedex, FIXICe. C Weiller, Neurologische
Universitatklinik,
Essen 45122, Germany.
past years
have seen significant
recovery of function of sophisticated
after brain
methods
by using positron
for exploring
emission
tomography
appears that two main mechanisms recruitment
advances
lesions.
This
in our
results
the human
understanding
living
especially it
in the recovery process:
of cortical areas in the undamaged hemisphere specialized
brain,
scans. From the recent literature,
may participate
of
from the development
and extension
of
areas adjacent to the lesioned site.
Current Opinion
in Neurobiology
Introduction Recovery is very often observed after brain injury. It is well known by neurologists that traumatic, inflammatory and vascular lesions of the human brain produce acute neurological deficits that may recover in the days, weeks or months following the insult. This phenomenon is particularly true in patients who have suffered a stroke, as in some cases recovery is listed as one of the diagnostic criteria. On the other hand, recovery of neurological functions remains unpredictable and poorly understood. Sometimes recovery occurs late after the stroke and in a very limited fashion, whereas at other times it may be observed soon after the stroke and there may be complete or nearly complete recovery of the motor, sensory, visual or linguistic function affected. It is becoming increasingly important for physicians (and for patients) to be aware of these differences because it could help determine which pharmacological therapy would best accelerate recovery and because it would assist making more rational decisions about the methods of rehabilitation. Until recently, the mechanisms responsible for recovery were largely unknown. Dramatic improvement in non-invasive imaging techniques have recently allowed for insights into the changes occurring in the damaged human brain during the recovery period. In particular, positron emission tomography (PET) scanning, with the emergence of new highly sensitive cameras and with the improvement of image analysis software, now allows for the study of individuals (instead of groups) and for comparisons of individual patterns of reactivity to controls. Recently, important data about normal human brains have been obtained using the activation technique, which gives quantitative images of the brain during the performance of tasks and contributes information on the functional architecture of
1994,
4:226-230
the brain 11-61. One can also foresee that in the near future, functional magnetic resonance imaging (MRI) 1731 will allow for complementary approaches to the mapping of the human brain functions, as will electrophysiology and magnetoencephalography, with their main advantage: good time resolution. Most of the studies published until now in the literature have focused on recovery of motor function in patients presenting with lesions to the cortocospinal tract and other major descending motor pathways from the cortex to the brainstem and spinal cord [9,10”,11**,12*1. Recovery of other neurological functions is starting to be studied with these new techniques 1131. Stroke represents an appropriate model for the study of recovery of function after acute brain injury. Nevertheless, it may be that the adaptative processes in the brain are somewhat different in cases of chronic or non-vascular damage. Degenerative disorders such as amyotrophic lateral sclerosis (ALS) offer a possibility to investigate adaptative processes to progressive neuronal degeneration or loss 114.1. In this review, we will discuss the two main mechanisms involved in brain recovery, namely recruitment of remote cortical areas and extension of areas adjacent to the lesion site.
Recruitment
of cortical
areas in undamaged
hemispheres Several neurobiological mechanisms can be evoked to account for recovery from insults to the brain; apart from the resolution of the initial shock and edema, bilateral representation of function, creation of new connections, release of inhibition and synaptic sprouting are the most common proposed mechanisms. In a
Abbreviations ALS-amyotrophic lateral sclerosis; EMC-electromyography; PET-positron emission tomography; rCBF-regional
226
0 Current
Biology
GABA-yaminobutyric acid; MRI-magnetic resonance imaging; cerebral blood flow; WA-supplementary motor area.
Ltd ISSN 0959-4388
Imaging recovery of function following brain injury Chollet and Weiller
series of three articles 19,10..,11**1, starting from 1991, the group from the Hammersmith Hospital in London describe their work using PET to identify two main brain mechanisms that compensate for a motor deficit and contribute to the functional reorganization of the brain. Firstly, uncrossed ipsilateral motor pathways from the undamaged hemisphere may be accessed to channel signals coding for movements down to the spinal cord, and, secondly, cortical areas in the damaged hemisphere may contain representations of movement and these may access the spinal cord via alternative pathways that bypass the lesioned pyramidal tract. In the first paper, Chollet et al. [91 reported on a study of six patients recovering from their first hemiplegic stroke. The authors noticed that when the patients’ affected hand was performing a finger to thumb opposition task, there was bilateral activation of the motor cortices, whereas movements of the unaffected hand were accompanied only by activation of the contralatera1 motor cortices. No contralateral-associated movements were observed when the affected hand was moving. The results from this paper strongly suggest that ipsilateral cortices play a role in the recovery processes. In this first work of the series, the contralateral unaffected hand served as a control for the recovered hand [91. In the second paper of the series llO”l, the pattern of activation elicited by movement of the affected (recovered), as well as the contralateral, hand was compared with the pattern of activation measured in 10 healthy controls. The recording of regional cerebral blood flow (rCBF) in patients and controls, at rest, showed‘a basic functional reorganization of the brain [lo”]. Some areas showed lower rCBF in patients than in controls; this was not only true for the site of the lesion but also for remote areas of the cortex (insula, premotor cortex) and the brainstem, all corresponding to functional disconnection of these areas. Conversely, measurements of rCBF in other cortical areas (mainly in the undamaged hemisphere) was found to be higher in patients than in controls, demonstrating a positive effect, probably related to the release of cortico-cortical inhibitions. When patterns of motor activation in patients were compared with those of normals, a signihcantly greater activation was found in the ipsilateral premotor cortices and in the contralateral cerebellum of patients, as well as strong bilateral activation in other areas in the lower parietal cortices (BA40) and in the insula near to the frontal operculum. Those changes of rCBF pattern at rest and during motor activation were observed several weeks after the stroke, and at the time of the PET study, the recovery of motor function was complete or nearly complete. So, one can assume that these changes are related to the recovery processes. Nevertheless, we must admit that, until now, no longitudinal data support this hypothesis. This paper [lO**l confirms that functional reorganization occurs in a damaged brain and supports the idea that cortical areas ipsilateral to the deficit participate in the recovery processes.
These conclusions were challenged in a recent article by Palmer et al. 112.1. They studied 10 patients, recovering from a single cerebral or brainstem infarct and with an Initial severe hemiplegia, who were able to maintain a contraction of their hemiplegic biceps muscle at the time of the study. When the subjects’ unaffected hemispheres were electromagnetically stimulated, no short-latency depolarization of their ipsilateral biceps motoneurons was detected, whereas short-latency depolarization of their contralateral biceps was easily recorded. The authors concluded that fast Torticospinal ipsilateral pathways do not develop after stroke. Apart from the fact that short-latency depolarization of ipsilateral neurons may not have been detected because of too high thresholds for magnetic stimulation or too small evoked postsynaptic potentials, it appears that ipsilateral pathways, if they participate in motor recovery, may be mediated by slowly conducting or polysynaptic ipsilateral pathways. In fact, stimulation of the unaffected hemisphere resulted in late (50 msec) facilitation in 30% of the contralateral biceps motor units and in 20% of the ipsilateral biceps motor units.
Extension
of specialized
areas
In the third paper of the series from Hammersmith [9,10**,11~~1, Weiller et al. [ll”l studied eight patients with a lesion of their internal capsule, who also suffered from acute hemiplegia and made a complete recovery from their motor deficit. A similar motor task (to the one described above) was used and the patients had to perform a finger to thumb opposition in turn during the time of data recording. A technical advance is developed in this article. The authors describe a statistical method that allows for a comparison of the rCBF changes recorded during the execution of a motor task of each individual to the pattern of motor activation of a group of 10 controls. This method consists of generating maps of 2 score, comparing for each image voxel, rCBF change of individuals to mean rCBF change of 10 healthy controls. Thus, using this method, individual patterns of brain re-organization underlying recovery may be identified. One of the main results of this article is that very different patterns of activation exist. This may result from an underlying variability in neuronal hard-wiring, the functional anatomy, the lesion site, or the extent and the time course of the process of recovery. Greater activation than in normal subjects was recorded in variable combinations of the supplementary motor area (SMA), insula, frontal operculum and parietal cortex. Ipsilateral motor pathways were also found to be more activated than in controls. Activation of ipsilateral sensori-motor cortex was found in four subjects who exhibited associated movements of the unaffected hand when the recovered (affected) hand performed the task So, the role of ipsilateral motor pathways in the recovery of motor function remains controversial, and it is
.227
228
Cognitive neuroscience
difficult to know if they correspond to the recruitment of cortico-spinal pathways or if they represent only an epiphenomenon related to artefactual mirror movements. An argument against the latter hypothesis is the symmetrical activation of cerebellar hemispheres during recovered hand movement, as shown by Chollet et al. 191 in their original paper. In that study, no ipsilateral-associated movements of the unaffected hand were detected by the authors, but then again, EMG (electromyography) recordings were not made. So, infraclinical-associated movements cannot be dismissed. In the original study 191, a 10% rCBF increase was observed in both cerebellar hemispheres of patients when their affected hand was moving. Primary sensor&motor cortices were also bilaterally activated during movements of the affected hand, but the magnitude of activation was very different in contralatera1 and in ipsilateral sensori-motor cortices (23 % rCBF increase in contralateral primary sensori-motor cortex and 10.1% rCBF increase in ipsilateral primary sensorimotor cortex). Sabatini and Chollet and colleagues [15*1 in a further motor activation study on normals have shown that, as in the sensori-motor cortex, the magnitude of activation in the cerebellar hemispheres appears to be dependent of the way the movement was executed (rate and amplitude of finger movements). According to these experimental data, one can say that it appears unlikely that small mirror movements can account for a high magnitude activation of the contralateral cerebellar hemisphere. The second important idea developed in this paper [ll**l is the detection of a large ventral extension of the hand field of the contralateral sensori-motor cortex in four patients with lesions of the posterior limb of the internal capsule. In these patients, the cortical motor field associated with finger movements appears to have enlarged significantly into that area normally associated with the face. Interestingly,
similar findings were published by Kew
et al. [14*f a few weeks later. Using PET, they studied the motor function of 12 patients with ALS, a degenerative disease characterized by a progressive loss of pyramidal cells and of motoneurones. They compared these patients with six age-matched controls. Scans were performed at rest and while subjects moved a joystick with their right hand. The authors showed that in patients at rest, ICBF was significantly reduced in primary and secondary motor areas (primary sensori-motor cortex, premotor cortex, SMA, paracentral lobule, anterior cingulate cortex, and superior and inferior parietal cortex). This reduction in rCBF has to be related to the generalized neuronal loss and with the loss of synaptic connections in all areas that project through the cortico-spinal tract. During motor activation, AIS patients have greater activation than normals in the ventral third (face area; 28 mm instead of 44 mm above the AC-PC bicommissural line) of the contralateral primary sensori-motor cortex and in the adjacent contralateral ventral premotor and parietal cortices [I4**]. The authors suggest that the recruitment
of the face area may represent a cortical adaptation to pyramidal tract disruption. In the literature, evidence is accumulating that cortical maps may undergo plastic changes in adult animals as the result of various peripheral injuries. Pons et al. [161, for example, demonstrated a 10 mm to 14mm extension of the face area into the area of the upper limb in the primary sensory cortex of adult macaques after upper limb deafferentiation. Magnetic brain stimulation studies in man have shown that following upper limb amputation, surviving limb muscles may be excited from a larger number of scalp position than in normal subjects 1171. Similar findings have been reported in patients with paraplegia and quadriplegia. To our knowledge, this is the first time that such phenomena can be directly illustrated in humans. The cellular mechanisms underlying the extension of the motor area remain to be elucidated. Its rapid occurrence after stroke (less than three months) suggests that a reinforcement of existing circuits is more probable than the growth of new connections. This is not the case in ALS patients, where the neuronal loss is progressive and no recovery is observed. Axons of sensorimotor cortex pyramidal cells have up to five collateral axons that synapse at a distance of up to 6 mm with inhibitory interneurons that are thought to connect to adjacent Betz cells. In animals, GABA antagonists placed in the sensor&motor cortex results in the evocation of more widespread movements in response to local stimulation than normal. GABA-mediated inhibitory activity modified by a lesion could facilitate the cortical spread of activation. Another explanation for the extension of the motor map could be that an alteration in sensory input may induce a reorganization of the motor cortex. This is suggested by Kew et al. 114’.1, who suspect that in patients with ALS, the deep sensory input is somewhat different from that of controls, as the execution of the motor task was not strictly similar. The four patients with posterior limb capsular ischaemic lesions studied by Weiller et al. [ll**l, however, all recovered, all executed motor tasks normally and all showed similar ventral extensions of their motor maps. It is interesting to note that the precise site of the lesion in these four patients was located in the posterior part of the posterior limb of the internal capsule, and that the sparing of the genu (classically reported as the location of the face fibres into the internal capsule) was associated with the ventral extension of the arm area into the face area. The authors suggest that this finding corresponds to a somatotopic organization of cortico-spinal fibres in the internal capsule. Acceptance for such an organization remains controversial. In a recent clinical and experimental study, Fries et al. 118”l performed an assessement of motor function in twenty-three patients with capsular or striatocapsular stroke. They found that selective lesions of basal ganglia do not affect voluntary movements of the extremities. Lesions of the anterior limb and of the posterior limb of the internal capsule lead to an initially severe motor impairment of the extremities followed by an ex-
Imaging recovery of function following brain injury Chollet and Weiller
cellent recovery. In contrast, lesions of the posterior limb, in combination with damage to the lateral thalamus, compromise motor outcome. It is shown once more in this paper [18**1 that lesions of the anterior limb of the internal capsule (believed to be free of corticospinal motor fibres) can induce severe paralysis, and that an impairment of sensory feedback may compromise recovery. In a second part of this study [IS**], using experimental tracing of the internal capsule in macaque monkeys, the authors showed that fibres coming from primary motor cortex passed through the middle third of the posterior limb of the internal capsule. Fibres coming from the SMA pass through the anterior part of the posterior limb. Fibres coming from premotor cortex are located first in the anterior limb of the internal capsule then around the genu. These results look very interesting as they contribute to modifying our hierarchical view of the organization of the motor system. It might be that primary motor cortex, premotor cortex and SMA (which all contain pyramidal cells) participate in a parallel, rather than in a sequential, way to the motricity, with each of the three subsystems (primary motor cortex, premotor cortex and SMA) being able to compensate partially or totally for deficits in the other. If it is obvious that the study of recovery of motor function with appropriate imaging tools will allow significant advances in our comprehension of the motor system, in the same way, the study of recovery of other neurological functions will give us insights into their physiology. This is becoming apparent in the area of language and aphasia. Several studies of language in normals have been published in the last few years Pi-61. Weiller et al. 1131studied six right-handed male patients recovering from Wernicke’s aphasia. They all had an infarction of the posterior part of the superior temporal gyrus and were making good recovery. Six right-handed males were used as controls. Using PET, brain activation was measured during three conditions: rest, performance of a semantic task (internal generation of verbs) and silent repetition of non-words. Both tasks induced an increase of rCBF in premotor cortex, putamen, superior temporal gyrus on the left hemisphere, and an activation of homologous regions in the right hemisphere. Significant activation was found in the right superior temporal gyrus, in the right BA44 and in lateral prefrontal cortex of patients. Right-sided activations were significantly higher in patients. Conversely, no obvious compensating processes were detected in the left hemisphere, with no extension of language areas comparable to those found in the recovery of motor function. The authors assume that in these patients there is a radical reorganization of activity within pre-exising bilateral language networks.
Conclusions Participation of ipsilateral motor pathways and anatomical extension of specialized cortical areas are two
mechanisms by which reoganization of the human brain occurs after a lesion. Recent experimental data lend support to such conclusions. One can speculate that further developments in techniques and of experimental paradigms will contribute in the near future to a better understanding of individual patterns of recovery and what determines them.
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F Chollet, Department of Neurology and INSERM U230, HBpital Purpan, Place du Docteur Bay&, 31059 Toulouse Cedex, FIXICe. C Weiller, Neurologische
Universitatklinik,
Essen 45122, Germany.