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Mechanisms of functional recovery after stroke: Insights from imaging
Cerebral plasticity; post-stroke
Pratique Neurologique – FMC 2012;3:160–166
Mechanisms of functional recovery after stroke: Insights from imaging Mécanismes et exploration de la plasticité cérébrale après AVC : données de l'imagerie J.-C. Baron a,b
a
Inserm U894, université Paris 5, Centre de Psychiatrie et Neurosciences, 2, ter rue d'Alésia, 75014 Paris, France b University of Cambridge, Department of Clinical Neurosciences, Addenbrooke's Hospital, Box 83, Cambridge, CB2 2QQ, UK
INTRODUCTION Following the acute phase of stroke where major physiological events such as salvage of the ischemic penumbra underlie rapid clinical changes and determine final tissue outcome, the subacuteto-chronic phase is characterized by functional recovery that evolves despite residual damage. This can involve two entirely different processes: developing new behavioral strategies to circumvent the deficit (e.g., using the unaffected arm after hemiparesis), a suboptimal type of spontaneous recovery seen in animals but also in humans if left unattended; genuine restoration – to a variable degree – of the lost function, which therapy aims to enhance. In the present article, primarily the latter will be addressed as it is the most useful and the one subtended by neuronal plasticity. Here we will use a broad definition of plasticity as any change in neuronal connections, circuitry and large-scale networks, be it at the molecular, cellular or functional level, that occurs subsequent to focal brain damage. The ultimate aim of studying, and hopefully understanding, the phenomenon of plasticity is to enhance adaptive plasticity, and curb maladaptive plasticity, by therapeutic means in order to improve functional outcome. 160
The present paper will focus on what insights into post-stroke plasticity mechanisms have been gained from functional imaging. Furthermore, we will focus on motor recovery, because hemiparesis, and particularly hand motor deficit, is not only the most disabling sequelae of stroke in functional terms, but also the most frequent (occurring in nearly 50% of stroke survivors) and the slowest to recover. Finally, we will focus on adultonset stroke, where the type and degree of plasticity, and hence the issues facing plasticity research, are entirely different from childhood-onset stroke, where hardwired connections have not crystallized yet, and hence major changes in brain organization can take place, such as taking-over of the damaged crossed corticospinal tract (CST) by the opposite-side uncrossed CST, clearly documented using functional imaging and single-pulse TMS (Stoeckel and Binkofski, 2010). Thus, children can enjoy very good functional outcome despite sometimes massive unilateral brain damage, although are at risk of (re)emergence of the masked paralysis in case of recurrent stroke affecting the other hemisphere. Although the bulk of recovery takes place within the first month, it usually continues at a slower pace over several months and in some patients several years. This simple clinical observation suggests that a variety of mechanisms underlie restoration of function after stroke.
Keywords Stroke Plasticity Recovery Functional imaging fMRI
Mots clés Accident vasculaire cérébral Plasticité Récupération Imagerie fonctionnelle cérébrale Imagerie par résonance magnétique
Corresponding author. J.-C. Baron, Inserm U894, université Paris 5, Centre de Psychiatrie et Neurosciences, 2, ter rue d'Alésia, 75014 Paris, France. E-mail address: [email protected]
© 2012 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.praneu.2012.01.008
Pratique Neurologique – FMC 2012;3:160–166
BRAIN PLASTICITY: A BRIEF SUMMARY OF BASIC MECHANISMS Physiological plasticity Brain plasticity is a normal process throughout development, acting to incorporate experience-based knowledge (i.e., learning) into neuronal connections in order to enhance adapted behavior. These processes are mainly based on experience-dependent glutamatergic synaptic growth and strengthening such as long-term potentiation (LTP). Synaptic pruning that occurs during adolescence stabilizes the person's own adaptative behaviors. During development, acquisition of specific skills such as motor skills, e.g. playing the violin, is therefore associated with growth of synaptic connections relevant to the particular skill, ultimately translating into enlarged cortical volume for finger representations in the primary motor cortex (M1), which is larger the younger the age at start of skill acquisition. Although synaptic plasticity is less prominent in adulthood, evidence from functional imaging of synaptic strength changes with experience is now overwhelming, as are changes in distribution of large-scale network activation during acquisition of a motor skill until it becomes nearly automatic (Karni et al., 1995). Although such plastic potential declines with aging, it remains active until very old age in man.
Brain plasticity after focal damage It was widely believed until about 30 years ago that the adult central nervous system had little or no ability for reorganization and self-repair following focal injury, i.e. is not plastic. To explain recovery of neurological deficits following e.g., stroke, processes such as vanishing of peri-lesional edema/pressure, recovery from diaschisis (an acute functional depression of neural ensembles remote from but disconnected by the damaged area), reperfusion of the affected territory, and use of alternative cortical representations of the same function and of builtin alternative pathways such as the uncrossed CST, were postulated (Baron, 2005). Of these mechanisms, only reperfusion of the affected territories, provided it occurs within a few hours of ischemic stroke onset, has a proven major role in functional recovery, by rescuing the ischemic penumbra. Delayed reperfusion does not improve clinical function, and in fact almost consistently occur spontaneously as an epiphenomenon (Baron, 2005). Pressure from vasogenic edema or mass effect from hematoma do not cause peri-lesional ischemia or fiber dysfunction except with very large lesions such as malignant MCA infarction. Diaschisis has been documented in the acute stage of stroke, but in specific cases only such as with crossed cerebellar diaschisis, which can indeed regress but seems not to carry direct functional consequences, and thalamo-cortical diaschisis, where regression of
Cerebral plasticity; post-stroke cortical glucose and oxygen hypometabolism may underlie part of the observed cognitive recovery (Baron, 2005). Marked reductions in glucose/oxygen metabolism do occur bilaterally after hemispheric stroke, but develop only after a few days and in proportion to the volume of the infarct, have no clear clinical counterpart and probably simply reflect extensive Wallerian degeneration. Regarding the opposite-hemisphere uncrossed CST, it does not appear to play any significant role in adult post-stroke hand recovery, as documented by single-pulse TMS (Gerloff et al., 2006). However, unmasking of (latent) cortical representations is an interesting possibility following cortical damage (see below). Brain plasticity after focal stroke encompasses innumerable mechanisms that can affect essentially the entire brain, i.e., not only the peri-lesional areas but also remote areas within the same hemisphere, contralateral hemisphere (via trans-hemispheric connections), cerebellum and spinal cord (Cramer, 2008; Rossini et al., 2003). These include: at the molecular level, changes such as with gene regulation and expression, release of neurotransmitters, membrane components, receptor density and affinity, excitatory/inhibitory (i.e., GABA/glutamate) balance; at the cellular level, such as axonal sprouting from remaining fibres of a partly damaged pathway, synaptic growth or loss, experience-dependent changes in synaptic strength, dendritic arborization, and cell proliferation (neurogenesis, angiogenesis) with morphological and functional changes (e.g., microglial and astroglial activation with consequent release of cell signaling molecules); at the neural circuitry level, such as unmasking of latent connections, re-distribution of strength of connections and of activation within a pre-existing pathway, and recruitment of alternative pathways functionally homologous but anatomically distinct from the damaged ones (e.g., non-pyramidal corticospinal pathways, so-called vicariation). Of note, individual factors, including genetic build-up (such as BDNF polymorphism), age, development (education) and environment-dependent, and co-morbidities such as previous stroke, white matter ischemic damage and depression, play a key role in plasticity, accounting for a large part of the observed variance in individual functional outcome despite same damage. Importantly, although the above plastic changes can be adaptative, i.e., serving to restore lost function, they can also be maladaptive, i.e., hindering restoration of function (Cramer, 2008). Distinguishing these two types of plasticity is obviously paramount with regards to therapeutic implications. The role of rehabilitation in modulating some of these changes is crucial. For instance, by driving experience-dependent synaptic mechanisms, active rehabilitation of the affected arm such as 161
Cerebral plasticity; post-stroke constraint-induced therapy (CIT), has been shown in the monkey with experimental infarction of the M1 hand area to prevent or even reverse "learned non-use'', i. e., a maladaptive plasticity such that the spontaneous exclusive use of the unaffected arm causes regression of hand area connections in the affected side M1 homonculus (Nudo et al., 1996).
BRAIN PLASTICITY AFTER STROKE AND RECOVERY OF HAND MOTOR DEFICIT: GENERAL NOTIONS Functional organization of the motor system: brief overview Although moving the fingers may appear a simple function, the motor system has extreme organizational complexity. It is organized as a network involving not only M1, but also the premotor cortex (PM) and the supplementary motor area (SMA), which all share somatotopic representation. These areas all have functionally distinct subdivisions, such as the anterior and posterior M1 (BA4a and 4p), the dorsal and ventral PM (PMd and PMv), the rostral and caudal SMA (pre-SMA and SMAproper). The motor system can be considered "cognitive'' inasmuch as it has extensive connections with the prefrontal, parietal and cingulate cortices and the insula (Calautti and Baron, 2003). The SMA is connected with higher order areas, mainly the prefrontal cortex, and is involved in motor act programming, while the PM is involved in bimanual motor coordination. M1 contributes only part of the CST fibres, which also originate from the PM and the post-central cortex (S1). However, distal upper limb function is subtended only by the pyramidal tract, and lesions of the PM result in proximal movement disturbance only, mainly of an apraxic type. There are considerable connections between M1 and S1, contributing to sensori-motor integration, as well as transcallosal (mainly inhibitory), contributing to bimanual coordination and proximal limb automatic movements. Other motor systems exist, such as the reticulospinal tract, which is bilaterally organized. In addition, the motor cortices have strong connections with the ipsilateral basal ganglia and thalamus as well as the contralateral cerebellum. Within M1, there is a mosaic-like representation of upper limb muscles with extensive intracortical connectivity for fine movement coordination. Functional imaging has demonstrated plasticity of the M1 representations in normal adults as they perform – and therefore learn – complex motor tasks (Karni et al., 1995), and this physiological cortical plasticity has considerable importance in recovery from focal injury (see below). The uncrossed CST has only marginal physiological function, as shown by TMS studies in normal subjects where only proximal responses are seen with intense stimuli only. 162
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Influence of corticospinal tract damage in post-stroke motor recovery One of the most important factors influencing poststroke motor recovery is integrity of the pyramidal motor output system. In both animals and man, extensive/ complete lesions of the precentral gyrus induce permanent loss of prehension, while good recovery generally takes place after partial lesions. Accordingly, the absence of evoked motor potentials (MEPs) on single-pulse TMS of ipsilesional M1 in the subacute stage after stroke is predictive of poor motor recovery (Rossini et al., 2003). Conversely, detection of MEPs is a marker of recovery, while the severity of CST damage predicts the response to rehabilitation therapy (Riley et al., 2011). It is estimated that the survival of at least 1/5 of the pyramidal fibers following M1 or CST stroke is necessary, though not sufficient, to ultimately ensure restitution of fractionated hand finger movement. Recent diffusion tensor imaging studies of CST Wallerian degeneration following cortical or subcortical stroke have strengthened these notions (Riley et al., 2011). Hence, within-CST reorganization is a major candidate for functional recovery of motor control. However, the extent of CST damage accounts for only a fraction of the variance in motor recovery (Riley et al., 2011), indicating that additional factors have a major role in this process, i. e. for the same degree of CST damage the outcome will differ from subject to subject as a function of individual factors (see above). The role of externally- or self-delivered rehabilitation, as well as its type and intensity, also play an important role. Understanding these factors may lead to new strategies for individualized therapy and hence better stroke outcome for a given damage.
BRAIN PLASTICITY AND MOTOR RECOVERY AFTER STROKE: INSIGHTS FROM FUNCTIONAL IMAGING Thanks to the advent of functional imaging, i.e. brain activity mapping during behavioral tasks, the biological basis of human post-stroke motor recovery has made considerable progress (Baron et al., 2004; Calautti and Baron, 2003; Cramer, 2008; Dimyan and Cohen, 2011; Rossini et al., 2003). These techniques mainly include Positron Emission Tomography (PET), and more recently functional Magnetic Resonance Imaging (fMRI), transcranial magnetic stimulation (TMS) and magneto-encephalography (MEG).
Functional imaging in normal subjects Functional imaging studies in normal subjects have elucidated the functions of the different motor areas by varying the experimental conditions, e.g. rate, force, modality of execution (i.e., motor preparation, initiation,
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execution, learning, mental imagery, internally generated vs. externally paced movement, active vs. passive), and established the somatotopy within M1, PM and SMA (Calautti and Baron, 2003). While a simple dominant hand task typically involves the contralateral SM1, PMd and SMA-proper and ipsilateral cerebellum, it will tend to involve the same areas bilaterally if performed by the non-dominant hand, as do also forceful or complex tasks which in addition may also involve parietal, prefrontal and striatal areas. Even healthy aging is associated with significant, albeit minor, changes in network activation pattern during simple motor tasks.
Findings in stroke patients Summarizing across over a hundred functional imaging studies of post-stroke hand motor recovery, most crosssectional and some longitudinal, a number of consistent major findings have emerged (Buma et al., 2010; Calautti and Baron, 2003; Cramer, 2008).
General pattern The main observation from both cross-sectional and longitudinal studies is that, regardless of the stroke location, motor recovery is best if the normal pattern of network activation for the particular task studied is reestablished (Calautti and Baron, 2003). However, even in the situation of fully recovered normal pattern, significant changes in connection strength between the main cortical motor areas can be found as ultimate evidence of underlying plasticity (Grefkes and Fink, 2011; Sharma et al., 2009). The magnitude of these connectivity changes correlates with residual motor deficit, such as assessed by maximal index-thumb tapping rate or other indices of dexterity (Sharma et al., 2009), indicating these changes are adaptative.
Ipsilesional motor cortex The changes observed in ipsilesional M1 activation, together with their therapeutic implications, differ whether the infarct directly involves M1 or not. After partial damage to M1, peri-infarct activation is a consistent observation (Cramer et al., 1997; Jaillard et al., 2005), in agreement with the above-described monkey studies (Nudo et al., 1996). This peri-infarct activation increases over time and probably underlies clinical improvement, further highlighting the key role of penumbral salvage in the acute stage. This phenomenon likely reflects disinhibition/unmasking of pre-existing but normally "silent'' representations in the surround of the lesion (redundancy), and/or progressive activation of motor representations normally not devoted to the lost function, i.e. supporting more proximal muscles (vicariation).
Cerebral plasticity; post-stroke After subcortical stroke affecting the CST (hence resulting in M1 de-efferentation), a constant observation in the early stages after stroke is overactivation of ipsilesional M1 (Chollet et al., 1991), which tends to return towards normal levels over time as motor performance improves (Calautti et al., 2001a). Regardless whether ipsilesional M1 over-recruitment reflects redundancy or vicariation, it should result in increased output down the remaining CST fibers and hence help to produce the intended movement. In turn, neuronal hyperactivity may inherently drive plastic changes through experience-dependent synaptic strengthening, which would account for the gradual return of M1 activation towards normal as recovery proceeds. Congruent with this, consistent displacement of activation peak within M1 has been reported, suggesting reorganization of the motor representations within the homonculus (Calautti and Baron, 2003). It logically follows that stimulating ipsilesional M1 after stroke should further enhance motor recovery. Accordingly, intensive affected arm training and excitatory repetitive TMS (rTMS) onto ipsilesional M1 have been applied with significant benefit. In the early stages post-stroke, the higher ipsilesional M1 activation is, the greater the gains from ipsilesional rTMS (Ameli et al., 2009). However, in the chronic stage ipsilesional M1 activation does not correlate with performance (Calautti et al., 2007), and the lower it is, the higher the chance that stimulatory therapy is effective and results in the intended increases in M1 activation. Thus, increasing ipsilesional M1 activation is an aim of, and a marker for, effective therapy in the chronic stage. As will be seen below, maladaptive overactivation of contralesional M1 may be the culprit, through transcallosal inhibition of ipsilesional M1.
Non-primary motor areas In both cortical and subcortical strokes, overactivation of the non-primary motor network bilaterally is another consistent finding in the early stage. This tends to abate as recovery proceeds, returning to normal in those who recover best but remaining abnormally elevated, particularly in contralesional M1 and PMd, in those with worse recovery (Calautti et al., 2001a). Overactivation of PMd and SMA probably represents enhanced input down non-pyramidal CST fibers, driven by higher order areas, and contributing to CST as well as non-CST systems output. In addition, contralesional PMd activation may subtend recovery of/compensation by non-force components of dexterity such as speed and rythmicity and coordination of complex movement, as suggested by both fMRI (Calautti et al., 2010a) and rTMS studies (Johansen-Berg et al., 2002).
Contralesional motor cortex Overactivation of contralesional M1 following hemispheric stroke is an intriguing phenomenon that has 163
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Cerebral plasticity; post-stroke attracted considerable interest because of both its elusive pathophysiology and its potential therapeutic implications (Calautti et al., 2007; Stoeckel and Binkofski, 2010). In recovering strokes, it is present initially but tends to abate over time, with "refocusing'' of activation towards the ipsilesional M1 (Calautti et al., 2001b; Gerloff et al., 2006). Importantly, this temporal pattern has also been observed in fMRI studies of rats subjected to cortical M1 stroke, showing early contralesional S1 activation with affected side median nerve stimulation, with subsequent refocusing towards the affected side. Clearly, contralesional M1 activation after stroke does not represent activity of the contralesional uncrossed CST, as: the higher this activation the worse the hand recovery (Calautti et al., 2007; Johansen-Berg et al., 2002); all direct functional connections to hand muscles after recovered stroke originate from ipsilesional M1, as shown by EEG-EMG coherence (Gerloff et al., 2006); and as indicated above, single-pulse TMS of contralesional M1 does not evoke any affected hand response (Gerloff et al., 2006). Likewise, contralesional M1 activation is not significantly associated with the presence of contralateral synkinesiae (i.e., mirror movements). One possible interpretation is that it represents loss of inhibition from damaged ipsilesional M1. However, although this phenomenon is well documented using TMS (Rossini et al., 2003), it would be inconsistent with the situation in subcortical stroke where ipsilesional M1 is not only present but often overactive. A different hypothesis is that it reflects the patient's effort to execute the required task, in analogy with normal subjects executing complex tasks (Calautti and Baron, 2003; Gerloff et al., 2006). In this scenario, contralesional M1 activation would result from increased drive from upstream PM and SMA and in turn from higher order prefrontal cortex, aiming to send sufficient output down the damaged CST. This hypothesis is supported by reports of significant correlation between the degree of CST damage and the magnitude of contralesional M1 activation. Not mutually exclusive, contralesional M1 overactivation likely also reflects maladaptive plasticity. This is supported not only by its negative correlation with affected hand performance (Calautti et al., 2007; Johansen-Berg et al., 2002), but also by the fact that contralesional M1 inhibition by means of rTMS tends to improve affected hand motor functions (Lindenberg et al., 2010). This aberrant maladaptive activity would exert its functional effects via transcallosal inhibition of ipsilesional M1 (Rossini et al., 2003).
Hemispheric balance of motor cortex activation Based on the above, a further conceptual shift is that, rather than considering each side separately, it is the hemispheric balance within this transcallosally 164
connected system that controls performance. This can be conveniently studied using the Laterality Index (LI), a mathematical formula whereby +1 reflects exclusively ipsilesional (i.e., physiological for simple finger movement) and -1 exclusively contralesional activation (Cramer et al., 1997). Studies have shown that the lower the LI (i.e., the more unphysiological), the worse the clinical outcome (Calautti et al., 2007; Johansen-Berg et al., 2002). Accordingly, the LI returns towards more physiological values as performance improves over time (Calautti et al., 2010b). The logical speculation then is that interventions aiming to restore this balance towards more physiological levels, either by stimulation of ipsilesional M1 or via inhibition of contralesional M1, or both, should result in improved motor performance. There is accumulating evidence supporting this notion, from studies for instance involving CIT, rehab – or robot – driven active arm training, rTMS (Lindenberg et al., 2010) or pharmacological agents such as fluoxetine (Pariente et al., 2001). Crucially, this effect can take place even in the chronic stage of stroke, months or years after the motor deficit has stabilized, indicating that the balance between adaptive and maladaptive plasticity can reach a plateau which is functionally suboptimal but can be shifted towards better outcome by appropriate interventions. Another key point is that to work optimally, such interventions must be associated with active motor training/rehabilitation probably because these induce effective use-dependent plasticity, therefrom enhanced by other means.
Other cortical areas Another interesting finding regards the recruitment of areas normally not engaged in task execution, such as prefrontal, posterior parietal, anterior cingulate and insular. This involvement might reflect compensatory cognitive strategies, e.g. attentional or visuo-spatial, whatever `simple' the task may seem. The decreasing recruitment over time of some of these areas (Calautti et al., 2001a) suggests that recourse to such strategies gradually becomes less necessary to produce the motor behavior.
CONCLUDING COMMENT Despite the above major breakthroughs afforded by functional brain imaging in understanding plasticity after stroke and how it underpins functional recovery, much remains to be done to clarify the exact time-course of changes from the acute to the chronic stage, the fine mechanisms underlying recovery of the various aspects of motor behavior and dexterity, and their intimate underlying processes at the neuronal ensemble, single-cell, synaptic and molecular levels. This effort will be necessary to fulfill the ultimate goal to deliver to each stroke victim the best possible care, and hence reach optimal functional outcome given each person's brain damage.
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Points essentiels Il existe un énorme potentiel de plasticité céré
brale après accident vasculaire cérébral (AVC) chez l'adulte. Mieux comprendre les mécanismes biologiques qui sous-tendent la plasticité cérébrale, et plus particulièrement pourquoi la récupération fonctionnelle après AVC est si variable d'un patient à l'autre, permettra de développer de nouvelles approches thérapeutiques visant à garantir la meilleure récupération possible. La plasticité cérébrale est un phénomène physiologique qui emprunte de multiples processus depuis le niveau moléculaire jusqu'au niveau des cartes neuronales. Ces processus sont exacerbés après un AVC, mais peuvent être adaptatifs ou maladaptatifs. L'imagerie fonctionnelle cérébrale a mis en évidence un certain nombre de cibles pour des interventions visant à améliorer la récupération motrice, y compris au stade chronique. Les futures études devront affiner ces connaissances et mettre en oeuvre des essais cliniques de façon à transposer celles-ci dans la pratique quotidienne.
DISCLOSURE OF INTEREST The author declares that he has no conflicts of interest concerning this article.
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Cerebral plasticity; post-stroke Calautti C, Baron JC. Functional neuroimaging studies of motor recovery after stroke in adults: a review. Stroke 2003;34:1553–66. Calautti C, Jones PS, Guincestre JY, Naccarato M, Sharma N, Day DJ, et al. The neural substrates of impaired finger tapping regularity after stroke. Neuroimage 2010a;50:1–6. Calautti C, Jones PS, Naccarato M, Sharma N, Day DJ, Bullmore ET, et al. The relationship between motor deficit and primary motor cortex hemispheric activation balance after stroke: longitudinal fMRI study. J Neurol Neurosurg Psychiatry 2010b;81:788–92. Calautti C, Leroy F, Guincestre JY, Baron JC. Dynamics of motor network overactivation after striatocapsular stroke: a longitudinal PET study using a fixed-performance paradigm. Stroke 2001a;32: 2534–42. Calautti C, Leroy F, Guincestre JY, Marie RM, Baron JC. Sequential activation brain mapping after subcortical stroke: changes in hemispheric balance and recovery. Neuroreport 2001b;12:3883–6. Calautti C, Naccarato M, Jones PS, Sharma N, Day DD, Carpenter AT, et al. The relationship between motor deficit and hemisphere activation balance after stroke: A 3 T fMRI study. Neuroimage 2007;34:322–31. Chollet F, DiPiero V, Wise RJ, Brooks DJ, Dolan RJ, Frackowiak RS. The functional anatomy of motor recovery after stroke in humans: a study with positron emission tomography. Ann Neurol 1991;29:63–71. Cramer SC. Repairing the human brain after stroke: I. Mechanisms of spontaneous recovery. Ann Neurol 2008;63:272–87. Cramer SC, Nelles G, Benson RR, Kaplan JD, Parker RA, Kwong KK, et al. A functional MRI study of subjects recovered from hemiparetic stroke. Stroke 1997;28:2518–27. Dimyan MA, Cohen LG. Neuroplasticity in the context of motor rehabilitation after stroke. Nat Rev Neurol 2011;7:76–85. Gerloff C, Bushara K, Sailer A, Wassermann EM, Chen R, Matsuoka T, et al. Multimodal imaging of brain reorganization in motor areas of the contralesional hemisphere of well recovered patients after capsular stroke. Brain 2006;129:791–808. Grefkes C, Fink GR. Reorganization of cerebral networks after stroke: new insights from neuroimaging with connectivity approaches. Brain 2011;134:1264–76. Jaillard A, Martin CD, Garambois K, Lebas JF, Hommel M. Vicarious function within the human primary motor cortex? A longitudinal fMRI stroke study Brain 2005;128:1122–38. Johansen-Berg H, Rushworth MF, Bogdanovic MD, Kischka U, Wimalaratna S, Matthews PM. The role of ipsilateral premotor cortex in hand movement after stroke. Proc Natl Acad Sci U S A 2002;99:14518–23. Karni A, Meyer G, Jezzard P, Adams MM, Turner R, Ungerleider LG. Functional MRI evidence for adult motor cortex plasticity during motor skill learning. Nature 1995;377:155–8. Lindenberg R, Renga V, Zhu LL, Nair D, Schlaug G. Bihemispheric brain stimulation facilitates motor recovery in chronic stroke patients. Neurology 2010;75:2176–84. Nudo RJ, Wise BM, SiFuentes F, Milliken GW. Neural substrates for the effects of rehabilitative training on motor recovery after ischemic infarct. Science 1996;272:1791–4. Pariente J, Loubinoux I, Carel C, Albucher JF, Leger A, Manelfe C, et al. Fluoxetine modulates motor performance and cerebral activation of patients recovering from stroke. Ann Neurol 2001;50: 718–29.
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Mechanisms of functional recovery after stroke: Insights from imaging Mécanismes et exploration de la plasticité cérébrale après AVC : données de l'imagerie J.-C. Baron a,b
a
Inserm U894, université Paris 5, Centre de Psychiatrie et Neurosciences, 2, ter rue d'Alésia, 75014 Paris, France b University of Cambridge, Department of Clinical Neurosciences, Addenbrooke's Hospital, Box 83, Cambridge, CB2 2QQ, UK
INTRODUCTION Following the acute phase of stroke where major physiological events such as salvage of the ischemic penumbra underlie rapid clinical changes and determine final tissue outcome, the subacuteto-chronic phase is characterized by functional recovery that evolves despite residual damage. This can involve two entirely different processes: developing new behavioral strategies to circumvent the deficit (e.g., using the unaffected arm after hemiparesis), a suboptimal type of spontaneous recovery seen in animals but also in humans if left unattended; genuine restoration – to a variable degree – of the lost function, which therapy aims to enhance. In the present article, primarily the latter will be addressed as it is the most useful and the one subtended by neuronal plasticity. Here we will use a broad definition of plasticity as any change in neuronal connections, circuitry and large-scale networks, be it at the molecular, cellular or functional level, that occurs subsequent to focal brain damage. The ultimate aim of studying, and hopefully understanding, the phenomenon of plasticity is to enhance adaptive plasticity, and curb maladaptive plasticity, by therapeutic means in order to improve functional outcome. 160
The present paper will focus on what insights into post-stroke plasticity mechanisms have been gained from functional imaging. Furthermore, we will focus on motor recovery, because hemiparesis, and particularly hand motor deficit, is not only the most disabling sequelae of stroke in functional terms, but also the most frequent (occurring in nearly 50% of stroke survivors) and the slowest to recover. Finally, we will focus on adultonset stroke, where the type and degree of plasticity, and hence the issues facing plasticity research, are entirely different from childhood-onset stroke, where hardwired connections have not crystallized yet, and hence major changes in brain organization can take place, such as taking-over of the damaged crossed corticospinal tract (CST) by the opposite-side uncrossed CST, clearly documented using functional imaging and single-pulse TMS (Stoeckel and Binkofski, 2010). Thus, children can enjoy very good functional outcome despite sometimes massive unilateral brain damage, although are at risk of (re)emergence of the masked paralysis in case of recurrent stroke affecting the other hemisphere. Although the bulk of recovery takes place within the first month, it usually continues at a slower pace over several months and in some patients several years. This simple clinical observation suggests that a variety of mechanisms underlie restoration of function after stroke.
Keywords Stroke Plasticity Recovery Functional imaging fMRI
Mots clés Accident vasculaire cérébral Plasticité Récupération Imagerie fonctionnelle cérébrale Imagerie par résonance magnétique
Corresponding author. J.-C. Baron, Inserm U894, université Paris 5, Centre de Psychiatrie et Neurosciences, 2, ter rue d'Alésia, 75014 Paris, France. E-mail address: [email protected]
© 2012 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.praneu.2012.01.008
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BRAIN PLASTICITY: A BRIEF SUMMARY OF BASIC MECHANISMS Physiological plasticity Brain plasticity is a normal process throughout development, acting to incorporate experience-based knowledge (i.e., learning) into neuronal connections in order to enhance adapted behavior. These processes are mainly based on experience-dependent glutamatergic synaptic growth and strengthening such as long-term potentiation (LTP). Synaptic pruning that occurs during adolescence stabilizes the person's own adaptative behaviors. During development, acquisition of specific skills such as motor skills, e.g. playing the violin, is therefore associated with growth of synaptic connections relevant to the particular skill, ultimately translating into enlarged cortical volume for finger representations in the primary motor cortex (M1), which is larger the younger the age at start of skill acquisition. Although synaptic plasticity is less prominent in adulthood, evidence from functional imaging of synaptic strength changes with experience is now overwhelming, as are changes in distribution of large-scale network activation during acquisition of a motor skill until it becomes nearly automatic (Karni et al., 1995). Although such plastic potential declines with aging, it remains active until very old age in man.
Brain plasticity after focal damage It was widely believed until about 30 years ago that the adult central nervous system had little or no ability for reorganization and self-repair following focal injury, i.e. is not plastic. To explain recovery of neurological deficits following e.g., stroke, processes such as vanishing of peri-lesional edema/pressure, recovery from diaschisis (an acute functional depression of neural ensembles remote from but disconnected by the damaged area), reperfusion of the affected territory, and use of alternative cortical representations of the same function and of builtin alternative pathways such as the uncrossed CST, were postulated (Baron, 2005). Of these mechanisms, only reperfusion of the affected territories, provided it occurs within a few hours of ischemic stroke onset, has a proven major role in functional recovery, by rescuing the ischemic penumbra. Delayed reperfusion does not improve clinical function, and in fact almost consistently occur spontaneously as an epiphenomenon (Baron, 2005). Pressure from vasogenic edema or mass effect from hematoma do not cause peri-lesional ischemia or fiber dysfunction except with very large lesions such as malignant MCA infarction. Diaschisis has been documented in the acute stage of stroke, but in specific cases only such as with crossed cerebellar diaschisis, which can indeed regress but seems not to carry direct functional consequences, and thalamo-cortical diaschisis, where regression of
Cerebral plasticity; post-stroke cortical glucose and oxygen hypometabolism may underlie part of the observed cognitive recovery (Baron, 2005). Marked reductions in glucose/oxygen metabolism do occur bilaterally after hemispheric stroke, but develop only after a few days and in proportion to the volume of the infarct, have no clear clinical counterpart and probably simply reflect extensive Wallerian degeneration. Regarding the opposite-hemisphere uncrossed CST, it does not appear to play any significant role in adult post-stroke hand recovery, as documented by single-pulse TMS (Gerloff et al., 2006). However, unmasking of (latent) cortical representations is an interesting possibility following cortical damage (see below). Brain plasticity after focal stroke encompasses innumerable mechanisms that can affect essentially the entire brain, i.e., not only the peri-lesional areas but also remote areas within the same hemisphere, contralateral hemisphere (via trans-hemispheric connections), cerebellum and spinal cord (Cramer, 2008; Rossini et al., 2003). These include: at the molecular level, changes such as with gene regulation and expression, release of neurotransmitters, membrane components, receptor density and affinity, excitatory/inhibitory (i.e., GABA/glutamate) balance; at the cellular level, such as axonal sprouting from remaining fibres of a partly damaged pathway, synaptic growth or loss, experience-dependent changes in synaptic strength, dendritic arborization, and cell proliferation (neurogenesis, angiogenesis) with morphological and functional changes (e.g., microglial and astroglial activation with consequent release of cell signaling molecules); at the neural circuitry level, such as unmasking of latent connections, re-distribution of strength of connections and of activation within a pre-existing pathway, and recruitment of alternative pathways functionally homologous but anatomically distinct from the damaged ones (e.g., non-pyramidal corticospinal pathways, so-called vicariation). Of note, individual factors, including genetic build-up (such as BDNF polymorphism), age, development (education) and environment-dependent, and co-morbidities such as previous stroke, white matter ischemic damage and depression, play a key role in plasticity, accounting for a large part of the observed variance in individual functional outcome despite same damage. Importantly, although the above plastic changes can be adaptative, i.e., serving to restore lost function, they can also be maladaptive, i.e., hindering restoration of function (Cramer, 2008). Distinguishing these two types of plasticity is obviously paramount with regards to therapeutic implications. The role of rehabilitation in modulating some of these changes is crucial. For instance, by driving experience-dependent synaptic mechanisms, active rehabilitation of the affected arm such as 161
Cerebral plasticity; post-stroke constraint-induced therapy (CIT), has been shown in the monkey with experimental infarction of the M1 hand area to prevent or even reverse "learned non-use'', i. e., a maladaptive plasticity such that the spontaneous exclusive use of the unaffected arm causes regression of hand area connections in the affected side M1 homonculus (Nudo et al., 1996).
BRAIN PLASTICITY AFTER STROKE AND RECOVERY OF HAND MOTOR DEFICIT: GENERAL NOTIONS Functional organization of the motor system: brief overview Although moving the fingers may appear a simple function, the motor system has extreme organizational complexity. It is organized as a network involving not only M1, but also the premotor cortex (PM) and the supplementary motor area (SMA), which all share somatotopic representation. These areas all have functionally distinct subdivisions, such as the anterior and posterior M1 (BA4a and 4p), the dorsal and ventral PM (PMd and PMv), the rostral and caudal SMA (pre-SMA and SMAproper). The motor system can be considered "cognitive'' inasmuch as it has extensive connections with the prefrontal, parietal and cingulate cortices and the insula (Calautti and Baron, 2003). The SMA is connected with higher order areas, mainly the prefrontal cortex, and is involved in motor act programming, while the PM is involved in bimanual motor coordination. M1 contributes only part of the CST fibres, which also originate from the PM and the post-central cortex (S1). However, distal upper limb function is subtended only by the pyramidal tract, and lesions of the PM result in proximal movement disturbance only, mainly of an apraxic type. There are considerable connections between M1 and S1, contributing to sensori-motor integration, as well as transcallosal (mainly inhibitory), contributing to bimanual coordination and proximal limb automatic movements. Other motor systems exist, such as the reticulospinal tract, which is bilaterally organized. In addition, the motor cortices have strong connections with the ipsilateral basal ganglia and thalamus as well as the contralateral cerebellum. Within M1, there is a mosaic-like representation of upper limb muscles with extensive intracortical connectivity for fine movement coordination. Functional imaging has demonstrated plasticity of the M1 representations in normal adults as they perform – and therefore learn – complex motor tasks (Karni et al., 1995), and this physiological cortical plasticity has considerable importance in recovery from focal injury (see below). The uncrossed CST has only marginal physiological function, as shown by TMS studies in normal subjects where only proximal responses are seen with intense stimuli only. 162
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Influence of corticospinal tract damage in post-stroke motor recovery One of the most important factors influencing poststroke motor recovery is integrity of the pyramidal motor output system. In both animals and man, extensive/ complete lesions of the precentral gyrus induce permanent loss of prehension, while good recovery generally takes place after partial lesions. Accordingly, the absence of evoked motor potentials (MEPs) on single-pulse TMS of ipsilesional M1 in the subacute stage after stroke is predictive of poor motor recovery (Rossini et al., 2003). Conversely, detection of MEPs is a marker of recovery, while the severity of CST damage predicts the response to rehabilitation therapy (Riley et al., 2011). It is estimated that the survival of at least 1/5 of the pyramidal fibers following M1 or CST stroke is necessary, though not sufficient, to ultimately ensure restitution of fractionated hand finger movement. Recent diffusion tensor imaging studies of CST Wallerian degeneration following cortical or subcortical stroke have strengthened these notions (Riley et al., 2011). Hence, within-CST reorganization is a major candidate for functional recovery of motor control. However, the extent of CST damage accounts for only a fraction of the variance in motor recovery (Riley et al., 2011), indicating that additional factors have a major role in this process, i. e. for the same degree of CST damage the outcome will differ from subject to subject as a function of individual factors (see above). The role of externally- or self-delivered rehabilitation, as well as its type and intensity, also play an important role. Understanding these factors may lead to new strategies for individualized therapy and hence better stroke outcome for a given damage.
BRAIN PLASTICITY AND MOTOR RECOVERY AFTER STROKE: INSIGHTS FROM FUNCTIONAL IMAGING Thanks to the advent of functional imaging, i.e. brain activity mapping during behavioral tasks, the biological basis of human post-stroke motor recovery has made considerable progress (Baron et al., 2004; Calautti and Baron, 2003; Cramer, 2008; Dimyan and Cohen, 2011; Rossini et al., 2003). These techniques mainly include Positron Emission Tomography (PET), and more recently functional Magnetic Resonance Imaging (fMRI), transcranial magnetic stimulation (TMS) and magneto-encephalography (MEG).
Functional imaging in normal subjects Functional imaging studies in normal subjects have elucidated the functions of the different motor areas by varying the experimental conditions, e.g. rate, force, modality of execution (i.e., motor preparation, initiation,
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execution, learning, mental imagery, internally generated vs. externally paced movement, active vs. passive), and established the somatotopy within M1, PM and SMA (Calautti and Baron, 2003). While a simple dominant hand task typically involves the contralateral SM1, PMd and SMA-proper and ipsilateral cerebellum, it will tend to involve the same areas bilaterally if performed by the non-dominant hand, as do also forceful or complex tasks which in addition may also involve parietal, prefrontal and striatal areas. Even healthy aging is associated with significant, albeit minor, changes in network activation pattern during simple motor tasks.
Findings in stroke patients Summarizing across over a hundred functional imaging studies of post-stroke hand motor recovery, most crosssectional and some longitudinal, a number of consistent major findings have emerged (Buma et al., 2010; Calautti and Baron, 2003; Cramer, 2008).
General pattern The main observation from both cross-sectional and longitudinal studies is that, regardless of the stroke location, motor recovery is best if the normal pattern of network activation for the particular task studied is reestablished (Calautti and Baron, 2003). However, even in the situation of fully recovered normal pattern, significant changes in connection strength between the main cortical motor areas can be found as ultimate evidence of underlying plasticity (Grefkes and Fink, 2011; Sharma et al., 2009). The magnitude of these connectivity changes correlates with residual motor deficit, such as assessed by maximal index-thumb tapping rate or other indices of dexterity (Sharma et al., 2009), indicating these changes are adaptative.
Ipsilesional motor cortex The changes observed in ipsilesional M1 activation, together with their therapeutic implications, differ whether the infarct directly involves M1 or not. After partial damage to M1, peri-infarct activation is a consistent observation (Cramer et al., 1997; Jaillard et al., 2005), in agreement with the above-described monkey studies (Nudo et al., 1996). This peri-infarct activation increases over time and probably underlies clinical improvement, further highlighting the key role of penumbral salvage in the acute stage. This phenomenon likely reflects disinhibition/unmasking of pre-existing but normally "silent'' representations in the surround of the lesion (redundancy), and/or progressive activation of motor representations normally not devoted to the lost function, i.e. supporting more proximal muscles (vicariation).
Cerebral plasticity; post-stroke After subcortical stroke affecting the CST (hence resulting in M1 de-efferentation), a constant observation in the early stages after stroke is overactivation of ipsilesional M1 (Chollet et al., 1991), which tends to return towards normal levels over time as motor performance improves (Calautti et al., 2001a). Regardless whether ipsilesional M1 over-recruitment reflects redundancy or vicariation, it should result in increased output down the remaining CST fibers and hence help to produce the intended movement. In turn, neuronal hyperactivity may inherently drive plastic changes through experience-dependent synaptic strengthening, which would account for the gradual return of M1 activation towards normal as recovery proceeds. Congruent with this, consistent displacement of activation peak within M1 has been reported, suggesting reorganization of the motor representations within the homonculus (Calautti and Baron, 2003). It logically follows that stimulating ipsilesional M1 after stroke should further enhance motor recovery. Accordingly, intensive affected arm training and excitatory repetitive TMS (rTMS) onto ipsilesional M1 have been applied with significant benefit. In the early stages post-stroke, the higher ipsilesional M1 activation is, the greater the gains from ipsilesional rTMS (Ameli et al., 2009). However, in the chronic stage ipsilesional M1 activation does not correlate with performance (Calautti et al., 2007), and the lower it is, the higher the chance that stimulatory therapy is effective and results in the intended increases in M1 activation. Thus, increasing ipsilesional M1 activation is an aim of, and a marker for, effective therapy in the chronic stage. As will be seen below, maladaptive overactivation of contralesional M1 may be the culprit, through transcallosal inhibition of ipsilesional M1.
Non-primary motor areas In both cortical and subcortical strokes, overactivation of the non-primary motor network bilaterally is another consistent finding in the early stage. This tends to abate as recovery proceeds, returning to normal in those who recover best but remaining abnormally elevated, particularly in contralesional M1 and PMd, in those with worse recovery (Calautti et al., 2001a). Overactivation of PMd and SMA probably represents enhanced input down non-pyramidal CST fibers, driven by higher order areas, and contributing to CST as well as non-CST systems output. In addition, contralesional PMd activation may subtend recovery of/compensation by non-force components of dexterity such as speed and rythmicity and coordination of complex movement, as suggested by both fMRI (Calautti et al., 2010a) and rTMS studies (Johansen-Berg et al., 2002).
Contralesional motor cortex Overactivation of contralesional M1 following hemispheric stroke is an intriguing phenomenon that has 163
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Cerebral plasticity; post-stroke attracted considerable interest because of both its elusive pathophysiology and its potential therapeutic implications (Calautti et al., 2007; Stoeckel and Binkofski, 2010). In recovering strokes, it is present initially but tends to abate over time, with "refocusing'' of activation towards the ipsilesional M1 (Calautti et al., 2001b; Gerloff et al., 2006). Importantly, this temporal pattern has also been observed in fMRI studies of rats subjected to cortical M1 stroke, showing early contralesional S1 activation with affected side median nerve stimulation, with subsequent refocusing towards the affected side. Clearly, contralesional M1 activation after stroke does not represent activity of the contralesional uncrossed CST, as: the higher this activation the worse the hand recovery (Calautti et al., 2007; Johansen-Berg et al., 2002); all direct functional connections to hand muscles after recovered stroke originate from ipsilesional M1, as shown by EEG-EMG coherence (Gerloff et al., 2006); and as indicated above, single-pulse TMS of contralesional M1 does not evoke any affected hand response (Gerloff et al., 2006). Likewise, contralesional M1 activation is not significantly associated with the presence of contralateral synkinesiae (i.e., mirror movements). One possible interpretation is that it represents loss of inhibition from damaged ipsilesional M1. However, although this phenomenon is well documented using TMS (Rossini et al., 2003), it would be inconsistent with the situation in subcortical stroke where ipsilesional M1 is not only present but often overactive. A different hypothesis is that it reflects the patient's effort to execute the required task, in analogy with normal subjects executing complex tasks (Calautti and Baron, 2003; Gerloff et al., 2006). In this scenario, contralesional M1 activation would result from increased drive from upstream PM and SMA and in turn from higher order prefrontal cortex, aiming to send sufficient output down the damaged CST. This hypothesis is supported by reports of significant correlation between the degree of CST damage and the magnitude of contralesional M1 activation. Not mutually exclusive, contralesional M1 overactivation likely also reflects maladaptive plasticity. This is supported not only by its negative correlation with affected hand performance (Calautti et al., 2007; Johansen-Berg et al., 2002), but also by the fact that contralesional M1 inhibition by means of rTMS tends to improve affected hand motor functions (Lindenberg et al., 2010). This aberrant maladaptive activity would exert its functional effects via transcallosal inhibition of ipsilesional M1 (Rossini et al., 2003).
Hemispheric balance of motor cortex activation Based on the above, a further conceptual shift is that, rather than considering each side separately, it is the hemispheric balance within this transcallosally 164
connected system that controls performance. This can be conveniently studied using the Laterality Index (LI), a mathematical formula whereby +1 reflects exclusively ipsilesional (i.e., physiological for simple finger movement) and -1 exclusively contralesional activation (Cramer et al., 1997). Studies have shown that the lower the LI (i.e., the more unphysiological), the worse the clinical outcome (Calautti et al., 2007; Johansen-Berg et al., 2002). Accordingly, the LI returns towards more physiological values as performance improves over time (Calautti et al., 2010b). The logical speculation then is that interventions aiming to restore this balance towards more physiological levels, either by stimulation of ipsilesional M1 or via inhibition of contralesional M1, or both, should result in improved motor performance. There is accumulating evidence supporting this notion, from studies for instance involving CIT, rehab – or robot – driven active arm training, rTMS (Lindenberg et al., 2010) or pharmacological agents such as fluoxetine (Pariente et al., 2001). Crucially, this effect can take place even in the chronic stage of stroke, months or years after the motor deficit has stabilized, indicating that the balance between adaptive and maladaptive plasticity can reach a plateau which is functionally suboptimal but can be shifted towards better outcome by appropriate interventions. Another key point is that to work optimally, such interventions must be associated with active motor training/rehabilitation probably because these induce effective use-dependent plasticity, therefrom enhanced by other means.
Other cortical areas Another interesting finding regards the recruitment of areas normally not engaged in task execution, such as prefrontal, posterior parietal, anterior cingulate and insular. This involvement might reflect compensatory cognitive strategies, e.g. attentional or visuo-spatial, whatever `simple' the task may seem. The decreasing recruitment over time of some of these areas (Calautti et al., 2001a) suggests that recourse to such strategies gradually becomes less necessary to produce the motor behavior.
CONCLUDING COMMENT Despite the above major breakthroughs afforded by functional brain imaging in understanding plasticity after stroke and how it underpins functional recovery, much remains to be done to clarify the exact time-course of changes from the acute to the chronic stage, the fine mechanisms underlying recovery of the various aspects of motor behavior and dexterity, and their intimate underlying processes at the neuronal ensemble, single-cell, synaptic and molecular levels. This effort will be necessary to fulfill the ultimate goal to deliver to each stroke victim the best possible care, and hence reach optimal functional outcome given each person's brain damage.
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Points essentiels Il existe un énorme potentiel de plasticité céré
brale après accident vasculaire cérébral (AVC) chez l'adulte. Mieux comprendre les mécanismes biologiques qui sous-tendent la plasticité cérébrale, et plus particulièrement pourquoi la récupération fonctionnelle après AVC est si variable d'un patient à l'autre, permettra de développer de nouvelles approches thérapeutiques visant à garantir la meilleure récupération possible. La plasticité cérébrale est un phénomène physiologique qui emprunte de multiples processus depuis le niveau moléculaire jusqu'au niveau des cartes neuronales. Ces processus sont exacerbés après un AVC, mais peuvent être adaptatifs ou maladaptatifs. L'imagerie fonctionnelle cérébrale a mis en évidence un certain nombre de cibles pour des interventions visant à améliorer la récupération motrice, y compris au stade chronique. Les futures études devront affiner ces connaissances et mettre en oeuvre des essais cliniques de façon à transposer celles-ci dans la pratique quotidienne.
DISCLOSURE OF INTEREST The author declares that he has no conflicts of interest concerning this article.
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