Post-stroke plastic reorganisation in the adult brain

Review

Post-stroke plastic reorganisation

Post-stroke plastic reorganisation in the adult brain

Paolo M Rossini, Cinzia Calautti, Flavia Pauri, and Jean-Claude Baron Recovery of function after a stroke is attributable to several factors, including events in the first few days (eg, reabsorption of perilesional oedema, tissue reperfusion). However, consistent reorganisation and recovery after a stroke takes weeks or months. In the early stages, recovery from stroke can vary greatly among patients with identical clinical symptoms. Neuroimaging techniques that enable us to assess baseline and task-related functions, and neurophysiological techniques that measure brain function in “real time”, can be used to study the recovery of brain lesions after a stroke. In this review, we discuss important neuroimaging and neurophysiological studies of post-stroke brain reorganisation. Lancet Neurology 2003; 2: 493–502

Stroke is the third most common cause of death and the commonest cause of chronic disability; it affects many activities of daily life and brain functions, such as sensorimotor integration, movement, walking, language, vision, balance, mood, and sensory perception. Acute stroke lesions consist of a core of dead neurons surrounded by an ischaemic penumbra, in which the neurons are still alive but are dysfunctional because of suboptimal blood flow in arterioles, capillaries, and collateral vessels. The penumbra contributes significantly to the severity of the early clinical deficit. If blood flow does not return to normal, the neurons in the penumbra can only survive for a short time, after which necrosis leads to stabilisation of the clinical deficits. Delayed neuronal death can cause secondary transynaptic axonal degeneration. Neurological deficits typically improve in the first few weeks or months after a stroke.1 Recovery can vary greatly, even among patients with identical clinical severity in the acute phase. Several explanations for these differences have been proposed: reabsorption of perilesional oedema; variability in the perfusion territory (ie, the extent to which collateral vessels from adjacent arteries supply blood to the perilesional neurons); multiple representations of the same function in different cortical areas; and the presence and number of alternative neural routes.2 Our understanding of the mechanisms that promote or prevent recovery is fundamental to the design of novel therapies for acute stroke. Despite extensive research,3–12 the mechanism of post-stroke recovery was not understood until recently because of the lack of techniques available for the investigation of this process in human beings.13 The term “brain plasticity” encompasses all possible mechanisms of neuronal reorganisation: recruitment of THE LANCET Neurology Vol 2 August 2003

pathways that are functionally homologous to, but anatomically distinct from, the damaged ones (eg, nonpyramidal corticospinal pathways); synaptogenesis; dendritic arborisation; and reinforcement of existing but functionally silent synaptic connections (particularly at the periphery of the damaged core).14,15 Improved long-term synaptic potentiation in perilesional areas,16 fibre sprouting from surviving neurons, and the formation of new synapses have been shown to occur a few weeks after stroke.17 Complex interactions—such as diaschisis (an change in functional output caused by a disturbance in an area of the brain distant to, but anatomically connected with, the primary site of injury)—lead to loss of output from damaged brain areas to adjacent or distant brain areas (eg, via corticocortical connections or transcallosal connections).18 Motor activity and sensory feedback are fundamental.19,20 Patients with poor (or absent) recovery of hand motor control after a stroke have severely reduced metabolism in the sensory thalamic relay,21,22 which suggests that appropriate sensory feedback from the paretic hand is essential for motor recovery. Primary sensory and motor cortices have a symmetrical organisation, particularly for hand control, in the right and left hemispheres.23–25 Groups of neurons that are anatomically connected to the lesion site progressively adopt the functions of the damaged area.26,27 In monohemispheric stroke, reorganisation changes the interhemispheric symmetry of the somatotopic organisation of the primary sensory and motor cortices. Therefore, by use of the unaffected hemisphere as a reference, we can assess reorganisation in the affected hemisphere and relate it to clinical recovery. In this review, we discuss functional brain-imaging studies of reorganisation after stroke. Because motor function of the arms can be used to model the recovery of higher functions, such as language processing, we will focus on the recovery of sensorimotor hand and arm function.

PMR is at the University Campus Bio-Medico, Rome; AFaR Department of Neuroscience, Hospital Fatebenefratelli, Isola Tiberina, Rome; and the IRCCS Centro S Giovanni di Dio, Brescia, Italy. FP is at the Neurology and Otorhinolaryngology Department, La Sapienza University and the AFaR Department of Neuroscience, Hospital Fatebenefratelli, Isola Tiberina, Rome, Italy. CC and J-CB are at the Department of Neurology, University of Cambridge, UK. Correspondence: Paolo Maria Rossini, Ospedale Fatebenefratelli, Isola Tiberina, Rome, Italy. Tel + 39 06 6837300; fax +39 06 6837360; email [email protected]

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areas enables restorative as well as maladaptive plasticity (eg, phantom limb pain, tinnitus, or musician’s cramp).36 The adoption of a related dysfunctional area by cooperating areas is commonly seen in response to a peripheral lesion.

External information: Three-dimensional space Target position (dynamics) Target feature Planning Posterior parietal cortex

Premotor cortical areas Basal ganglia

Physiology of motor plasticity

The extent to which neuronal sprouting—or the unmasking of existing, but functionally silent, synapses—is involved in reshaping SpinoBody information: motor output during learning or cerebellum Schema Sensoriafter a lesion is debatable. Changes in (vermis and Postion (dynamics) motor intermediate Muscle contraction synaptic efficiency, such as long-term feedback zone) depression and long-term potentiation, significantly affect the extent of inhibition or excitation. These basic mechanisms underlie learning and Figure 1. Sensory perception, and its role in motor planning, involves large brain areas, including primary somatosensory, visual, and motor cortices and secondary sensorimotor areas. Basal ganglia memory as well as cortical plasticity. and thalamic relays contribute significantly to motor planning, sensory perception, and sensorimotor Long-term potentiation is the protointegration. Supplementary motor and premotor cortices have an important role in motor type of modified synaptic efficacy;37 it preparation and execution, via corticospinal fibres from the primary motor cortex under the parallel explains how converging inputs from control of other descending systems. Cerebellar relays constantly monitor the motor output and motor execution. various sources, including intracortical and thalamocortical connections, Physiology of sensorimotor brain areas and of interact to reshape cortical input-output somatotopy.38–42 related plasticity Long-term potentiation is mediated by glutamate receptors The primary sensory and motor cortices, visual cortices, and and typically involves the downregulation of local inhibitory secondary sensorimotor areas are all involved in sensory circuits.43 In adult rat brains, experience-dependent cortical perception. The basal ganglia and thalamic-relay circuits plasticity is accompanied by increased synapse turnover (ie, contribute to motor planning, perception, and sensorimotor turnover of dendritic spines).44–54 integration. The supplementary motor and premotor cortices are essential for motor preparation and execution, the latter Neurophysiology of post-stroke recovery being implemented by corticospinal fibres from the primary Several factors may contribute to brain reorganisation after motor cortex under the parallel control of other descending stroke—eg, changes in neuronal-membrane excitability, systems. Cerebellar relays monitor motor output and removal of inhibition, improved synaptic transmission execution (figure 1). The primary sensory cortex is a major (possibly due to long-term potentiation), loss of source of somatosensory input to the primary motor cortex28 perilesional GABAergic inhibition (possibly associated with because it is also the only primary sensory area that has direct downregulation of GABAA receptors), and increased connections with it. The primary motor cortex is strongly glutamatergic activity.45,46,55 After partial damage of the modulated by sensory flow. The existence of multiple, discrete, primary motor cortex in animal models,3 or after partial efferent zones in the primary motor cortex is a peculiarity of infarction of primary sensory and motor cortices in human this area. In fact, selective stimulation of different regions of beings, activation of perilesional areas has been reported.47,48 the primary motor cortex can produce the same These findings suggest that pre-existing, functionally silent movement.29–34 The cortical areas that control digit, wrist, synapses around the lesion are unmasked or disinhibited, or elbow, and shoulder movements are connected over distances that neural networks that are not normally involved are of up to 10 mm by dense, bidirectional projections. Individual progressively activated. Recovery from partial damage can movements are, therefore, controlled by a network of neurons be mediated by adaptation of existing synapses; however, that are distributed throughout the primary motor cortex. recovery after a complete lesion necessitates the activation This network enables the convergence of overlapping cortical of related systems that can adopt the function of the territories on to single muscles as well as divergence from one damaged circuitry.52 Survival of around a fifth of pyramidal cortical site to multiple muscles and extensive cells is sufficient to maintain or reinstate fractionated finger interconnections.34,35 In addition, limb joints (eg, shoulder, movement; hence, recovery of motor function can be elbow, wrist) are represented in the cortex more than once, achieved by reorganisation of the pyramidal system.24,53–62 but with different contiguity (shoulder to wrist, shoulder to The role of non-pyramidal, cortical efferents (ie, the elbow, etc) to enable a large repetoire of target-muscle bilateral premotor reticulospinal projection) is unclear. In activation. As a result, the system can sustain various fact, large-scale reorganisation outside of the primary movement combinations. Cooperation of multiple cortical motor cortex is a long process that never results in a full Cerebrocerebellum (lateral zone)

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Movement

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Post-stroke plastic reorganisation

recovery. The ipsilateral primary motor cortex may contribute to recovery of function via interhemispheric, corticoreticular, or direct corticospinal connections.

PET

Blood flow Resting

Techniques for functional brain imaging

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Activated

Various imaging techniques are currently available; they either map regional blood flow and metabolic changes linked with neuronal firing Haemoglobin Radiolabelled H2O Oxygen (eg, PET and functional MRI [fMRI]) or analyse electromagnetic brain activity (eg, electroencephalography, magnetoencephalography, and transcranial magnetic stimulation [TMS]). PET and fMRI are three dimensional imaging techniques that allow reconstruction of data according to tomographic slices.63 PET measures regional cerebral blood flow as a marker of synaptic activity (figure 2). At present, PET can only detect areas of activation but these maps can be superimposed on to anatomic MRI from the same Figure 2. Generation of fMRI and PET signals. The fMRI signal (left) is dependent on changes in the individual to improve anatomical concentration of deoxyhaemoglobin. When neurons become active, they require more oxygen and resolution. glucose, but their oxygen consumption increases less than the increase in perfusion; this results in a FMRI measures the blood oxygen- relative decrease in local deoxyhaemoglobin concentration, the blood oxygen-level dependent level dependent signal. Changes in signal. The magnetic-resonance scanner detects this signal change, even if it is very small. For PET (right), regional cerebral blood flow is measured by use of various radioisotopes, which enable deoxyhaemoglobin concentration are detection of activation within individuals and allow mapping of these changes on to anatomic MRI dependent on blood flow, blood from the same individual. volume, and blood oxygen saturation. When neurons are active, they need more oxygen and glucose synchronously firing, either spontaneously or in response to so blood flow increases. However, the increase in perfusion an external stimulus, in restricted cortical areas. Externally overcompensates for the increase in oxygen consumption, recorded magnetic fields, produced by groups of neurons thus causing a decrease in local deoxyhaemoglobin firing, can be modelled as current dipoles72 (figure 3). Such concentration (figure 2).64 The temporal resolution of fMRI is dipoles not only characterise the position of the firing determined by the haemodynamic response and can detect neurons but also their strength (ie, their number and differences in peak activation time between brain regions in orientation). A decrease or increase in the responsive area the order of 1–2 s.65 Together PET and fMRI give a caused by recruitment or loss of neurons surrounding the comprehensive view of the distributed network that governs a central core, causes a corresponding increase or decrease in particular brain function and provide a detailed analysis of the the dipole strength. relation between function and anatomy. However, both techniques have several limitations: the sequence of activation PET and fMRI events can be too quick to be accurately recorded; the inability Cross-sectional studies to differentiate excitation from inhibition; and lack of Cross-sectional PET and fMRI studies of paretic-hand discrimination between motor output and sensory feedback.66 movement after full clinical recovery have shown that TMS of scalp regions that overlie the motor cortex is a patterns of activation after stroke are significantly different safe, non-invasive, and painless technique67 that triggers to those of normal individuals.26,47,48,74–76 In patients with transient electromyographic responses (motor evoked striatocapsular infarction, the following responses were potentials) in the target muscles. Because TMS excites consistently seen: increased bilateral activation of motor discrete brain regions, it can be used to map the motor pathways not due to mirror movements (symmetrical, cortex.67–71 identical, contralateral involuntary movements that Magnetoencephalography is another non-invasive accompany voluntary movements on one side); recruitment technique that detects the electromagnetic fields produced of additional sensory and secondary motor structures by active neurons. It can identify and provide a precise (predominantly in the unaffected premotor cortex)77 that are three-dimensional location of neurons that are not normally involved; extension of primary sensorimotor THE LANCET Neurology Vol 2 August 2003

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activation in the unaffected hemisphere whereas controls have a preserved interhemispheric balance. 21 ms 21 ms As the patient recovers, activation shifts towards the affected hemisphere. Few studies have assessed the relation between activation maps and y y motor recovery, and in all of these 21 ms –1500 studies, only a few patients were 100 ms Magnetoencephalography analysis assessed so the results should be interpreted with caution. Seitz and colleagues80 and Cao and co-workers48 did not find any relation between residual motor deficit and the volume of activation in the unaffected primary sensorimotor cortex. However, in both of these cross-sectional studies, either different tasks were used to assess motor function or clinical outcome was estimated by use of a 21 ms task different to that used for imaging. Integration of magnetoencephalography and MRI In addition, it is better to relate changes in brain activation patterns Figure 3. Top: the main steps of the magnetoencephalographical analysis to spatially identify the neurons activated in response to an external stimulus (eg, contralateral median-nerve stimulation). (ie, plasticity) to parallel changes in The line graph (left) shows the recording from 25 channels in a 100 ms time interval starting from the motor function (ie, recovery) than to stimulus onset. The magnetic field distribution 21 ms after the stimulus is characterised by the relate them to final outcome (end“dipolar shape” (middle). When this field distribution appears, the source can be modelled by an observation motor ability); plasticity equivalent current dipole (ECD). The spatial position identification of the activated source is has an influence on recovery whereas expressed in a coordinate system defined by anatomical landmarks (indicated by the black dots; right). Bottom: by definition of a reference system common to magnetoencephalography spatial final outcome is influenced by lesion identification and MRI (left), it is possible to identify the anatomical features of the functionally size and site. activated area (right). Reproduced with permission from Neuroscience News. In a longitudinal PET study, Calautti and colleagues84 assessed the cortex activation towards the face area;74–76,78 and, a posterior association of changes in motor ability with changes in the shift of primary sensorimotor cortex activation peak.59 laterality index in patients with subcortical stroke. FixedSimilarly, overactivation of bilateral non-infarcted motor- rate, audiocued thumb-index tapping was used to study related and non-motor areas has been reported in patients activation during PET scanning, and motor ability was with cortical infarcts.47,48,79 This overactivation is sometimes assessed as the maximum frequency of thumb–index associated with strong activation of areas around the infarct47 tapping. The laterality index was significantly correlated or of the premotor cortex in the same hemisphere as the with motor recovery: the more activation was shifted toward lesion.80 A bilateral increase in activation of the motor the unaffected hemisphere, the poorer the recovery. Thus, a network may represent increased recruitment of neuronal shift of activation towards the unaffected hemisphere is less networks—ie, improved attention, will, and effort. The effective in terms of clinical outcome in the long run. This posterior shift and inferior extension of primary-motor- observation is consistent with several descriptive reports of cortex activation seen both in cortical and in subcortical recovery from aphasia88 and neglect.89 In addition, a strokes might be due to synaptic unmasking within the longitudinal fMRI study in a rat model of stroke showed that functional recovery may be related to the gradual restoration corticospinal tract. of neuronal networks and recruitment of neurons from Longitudinal studies and clinical association around the lesion.90 Recently, Small and co-workers86 Despite the use different experimental designs, longitudinal reported a weak, but significant, non-linear relation between imaging studies report changes in the degree and pattern of shift of activation back towards the affected hemisphere activation with recovery.78,81–86 In general, repetition of the (including the cerebellum) and improved recovery.84 same task was associated with decreased overactivation in Although the laterality index is useful as a representation of both hemispheres (figure 4). The shift of motor activation the balance of activation between the affected and unaffected towards the unaffected hemisphere can be expressed as the hemispheres, it does not give any information about the laterality index (ranging from –1 to 1).47,81,84,87 In the late stages actual level of activation, or about its significance in the of recovery after a subcortical stroke, the variability of the activated clusters. Fernandez and colleagues91 recently used a laterality index, of either the whole hemisphere or just the weighted laterality index in a study of language. Application primary sensorimotor cortex, is larger in patients than in of this method to the assessment of motor recovery after controls. This reflects the fact that patients have prominent stroke may be worthwhile. z

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Post-stroke plastic reorganisation

Despite these observations, region-by-region analysis suggests that there may be more subtle consequences of stroke. Previous reports have concluded that the premotor cortex is critical for the reorganisation of the motor system during recovery of lost function, not only for its role in selection and preparation of movements, but also because of its connections to the primary somatosensory motor cortex and its contribution to the corticospinal tract.78,80,83 TMS and magnetoencephalography Cross-sectional and follow-up studies

Reorganisation of primary sensory and motor cortices after hemispheric stroke has been consistently seen with TMS and magnetoencephalography.59–61,92 These techniques elicited responses from proximal and distal arm muscles in the early stages of recovery in patients who went on to fully recover control of finger movements.93–97 In addition to abnormalities of excitability and conductivity in the corticospinal tract, asymmetry between the hand motor maps in the affected and the unaffected hemispheres was seen. This “map migration” is typically seen along the mediolateral axis, although anteroposterior shifts of up to several millimetres have also been reported. The role of both hemispheres in the acute and subacute stages of recovery after stroke has been investigated.27,98–102 Transient hyperexcitability of the unaffected hemisphere51 is an important prognostic indicator linked to plastic reorganisation. TMS is also useful for testing intracortical inhibition and facilitation. In patients with stroke, inhibition in the unaffected hemisphere was decreased 2 weeks after stroke,103 possibly because of a downregulation of GABAergic activity.104,105 This may have been due to damage of transcallosal fibres leading to a loss of physiological interhemispheric inhibitory regulation103,106–108 or to increased use of the unaffected arm in daily activities.109 The concept of disinhibition in the unaffected hemisphere is supported by the observation that larger than normal motor responses were obtained when the unaffected arm was stimulated.61,110,111 Patients with little motor deficit at onset, or with rapid motor recovery, had loss of intracortical inhibition in the affected hemisphere only. The underlying mechanisms of rapid improvement by cortical disinhibition may be related to remote effects (diaschisis) or the number of ipsilateral uncrossed corticospinal fibres.2,112–115 The normalisation of intracortical inhibition in patients with longer disease duration and poor recovery does not support the functional significance of motor-cortex hyperexcitability in the unaffected hemisphere.102 Longitudinal studies

Longitudinal assessment of motor function with TMS showed that responses from the unaffected hemisphere after stroke did not differ from normal individuals, whereas responses from the affected hemisphere changed significantly during follow-up with a partial recovery underlying ongoing clinical improvement. In patients whose paretic hand responded when the unaffected hemisphere was stimulated, clinical outcome was variable; some investigators111,116 found a relation between responses from the paretic hand during THE LANCET Neurology Vol 2 August 2003

Figure 4. Overactivation in the primary and secondary motor areas in a group of five patients with stroke (group analysis) compared with normal controls 2 months (left) and 8 months (right) after left capsular stroke during right thumb–index tapping cued at 1·26 Hz. The significant voxels (p< 0·05, corrected) are projected onto a standard MRI template. The neurological convention is used (ie, the left hemisphere is shown on the left side). Overactivation was found in the bilateral primary somatosensory and sensorimotor cortices at 2 months (left), and in the affected-hemisphere primary sensorimotor cortex and unaffectedhemisphere premotor cortex at 8 months (right). There was a clear decrease and spatial redistribution of overactivation between 2 months and 8 months. These data suggest that, as recovery progresses, patients with capsular stroke need to recruit less and less of the bilateral motor networks to do the same task. Reproduced with permission from Lippincott, Williams, & Wilkins.78

TMS of the unaffected hemisphere—presumably triggered via uncrossed corticospinal fibres—and motor recovery while other investigators found the opposite.97,117–119 In general, the larger the motor response in the acute stage, the better the prognosis,73 and many researchers report that reorganisation of sensorimotor cortex in the affected hemisphere is ongoing 3–4 months after stroke. Recovery of sensory deficits can play an important part in clinical outcome because modulation of tonic sensory flow from the skin significantly affects the size of the cortical representation of the target muscle.120,121 Patients with sensory deficits caused by parietal stroke develop dystonic, pseudoathetotic hand movements.122 Sensory processing can be assessed by the recording of electromagnetic brain responses (somatosensory evoked fields) to incoming stimuli. These somatosensory evoked fields can be discriminated from background, spontaneous electromagnetic brain activity with computerised methods and their amplitude, latency, and morphology can be reliably measured. In patients with stroke, somatosensory evoked fields were recorded on the parietal area of one side of the head after stimulation of the contralateral median nerve at the wrist and stimulation of the thumb and little fingers of both hands. The most stable and reproducible brain responses were analysed and current dipoles were calculated whenever possible. It is possible to localise the source of a particular brain response. “Hand extension”— the extension of the cortical representation of the hand— was also measured by the calculation of the distance between the centres of the dipoles activated by stimulation of the thumb and little finger of the contralateral hand. A common reference system was used to define three anatomical landmarks (figure 3).

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27 mm

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Leg Hip Trunk Neckd Hea lder Shou Ar m w Elboearm For t s Wri nd Ha le t Lit ng le Ri idd M dex In

Th E y um No es b Fac se e Upper li p

Foot Toes Genitals

Lower lip Teeth, gums, and jaw Tongue Pharynx Intra-abdominal

Figure 5. “Hand extension” enlargement and a reorganisation of the sensory homunculus topography after a small ischaemic lesion in the right basal ganglia in a 62-year-old man.

Interhemispheric asymmetry and clinical outcome In studies of patients with first ever, monohemispheric stroke in stable conditions, 63% of those with recordable somatosensory evoked fields in the affected hemisphere had excessive interhemispheric signal-strength asymmetry, and nearly 80% of dipole pairs (from homologous regions in the two hemispheres) were asymmetrical with increased signal strength in the affected hemisphere compared with the unaffected hemisphere after a cortical lesion. Asymmetry has been defined in control individuals.23,62 Cross-reference of magnetoencephalography with MRI showed that all the identified dipoles were outside the anatomical lesion areas; the classic homunculus somatotopy was maintained in the sensory hand areas with the thumb area lateral, the little-finger area medial, with the median-nerve area in between. However, abnormalities, such as “hand extension” with a medial shift of the little finger and the tendency of finger representations to migrate anteriorly, were observed. Reorganisation took place at the expense of the forearm area more than of the face area (figure 5). The mean extension of the sensory hand area in the abnormal cases was 39±7 mm in the subcortical lesion group and 27±7 mm in the cortical lesion group, and 16±5 mm in healthy controls. Interhemispheric differences in shape of sensory evoked fields were minimal in controls when tested via the analysis of cross-correlation coefficients. An excessive asymmetry of wave shape was found in 60% of cases, more commonly with subcortical than cortical lesions, in combination with a spatial shift of the dipoles toward an area outside the normal limits. Abnormal wave shapes were observed in 75% of patients with clinical recovery and in 50% of patients without clinical recovery.

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As a general rule, the greater the reorganisation outside the primary sensorimotor cortex—ie, the greater the interhemispheric asymmetry—the poorer the clinical recovery.59,114 This conclusion is supported by the results of longitudinal functional imaging studies; the best recovery was associated with return of activity to the cortical areas near the lesion, whereas persistent activation of the unaffected hemisphere was representative of maladaptive plasticity.88

Effect of rehabilitation procedures Plastic changes after stroke can result from passive adaptation of the brain to the lesion, spontaneous recovery of (partially) damaged brain tissue, behavioural consequences of the lesion (eg, decreased use of a formerly paretic limb), or therapeutic intervention. Reorganisation in response to therapeutic intervention can be studied in patients in the chronic stage of stroke. At this stage, the probability of any spontaneous recovery is negligible and, therefore, any recovery is likely to be the result of intervention.109,123 Different techniques have been used to assess the effects of various interventions.109,123–125 Constraint-induced movement therapy is one such intervention.126 Before constraint-induced movement therapy, the patients had abnormally high excitability thresholds and small motor output maps in the motor cortex of the affected hemisphere. After therapy, motor output maps increased in size by around 40%, whereas those in the unaffected hemisphere were consistently, even if not significantly, decreased. These changes were associated with significant clinical improvement, presumably due to increased use of the paretic arm and decreased use of the non-affected arm during training. Motor threshold was

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unaffected and, because motor threshold is determined at the centre of the cortical map, it was concluded that enlargements of the motor output map were caused by an increase in excitability at the borders of the map by GABA dependent modulation of horizontal intracortical inhibitory circuits.127 After therapy, the centres of the motor maps shifted mediolaterally, which suggests the recruitment of additional brain areas. Similar results have also been obtained in magnetoencephalography studies in animals.3,11,128 Studies with both PET and fMRI have shown that specific rehabilitation procedures, either passive or active, induce significant changes in brain activation patterns. These findings suggest that plasticity in the lesioned adult brain, as in the normal brain, can be manipulated.129,130 In patients with subcortical stroke, 3 weeks of intensive rehabilitation— compared with 3 weeks of standard rehabilitation procedures—increased activation of sensorimotor primary cortices in the affected hemisphere.131 Similarly, in chronic stroke, intense training of the paretic arm reversed the pattern of activation: activation of the primary motor cortex in the unaffected hemisphere changed to activation in the affected hemisphere, which was associated with a significant improvement of hand and finger control.87 This finding has important clinical implications: first, passive movements seem to have a similar effect to active movements on the sensorimotor cortex in the affected hemisphere, so passive therapy in the acute stages of stroke may improve outcome; and second, active motor training can reverse maladaptive brain reorganisation in the chronic phase of stroke.

Combined imaging techniques Methods of functional brain imaging have been combined in a few studies. In a patient with aphasia and severe right paresis after stroke who showed excellent motor recovery over a period of 12 months, fMRI, TMS, and magnetoencephalography all indicated an asymmetrical enlargement and posterior shift of the sensorimotor areas in the affected hemisphere.132 In patients with asymmetrical organisation of the affected hemisphere, there is a good correlation between fMRI during median-nerve stimulation and MEG. However, in several cases with easily recorded sensory evoked fields from the affected hemisphere, no fMRI activation was found in response to median-nerve stimulation (figure 6).114 This suggests that stroke may affect the neurovascular coupling that produces the fMRI blood-oxygen level dependent signal, and that the combination of electrophysiological and blood-flow-related techniques is therefore useful.133

Conclusions The study of neuroplasticity has clearly shown the ability of the developing brain—and of the adult and ageing brain—to be shaped by environmental inputs both under normal conditions (ie, learning) and after a lesion.134 Neuronal aggregates adjacent, or distant, to a lesion in the sensorimotor area can progressively adopt the function of the lesioned area. Imaging studies indicate that recovery of motor function after stroke is associated with a progressive change of activation patterns in specific brain structures. Effective recovery is associated with a gradual normalisation THE LANCET Neurology Vol 2 August 2003

Figure 6. Magnetoencephalography and fMRI during electrical stimulation of the median nerve at the wrist in a patient with stroke. Somatosensoryevoked-field signals are identifiable in both the hemispheres. Activation asymmetry in the parietal region is evident laterally in the left hemisphere. In support of the magnetoencephalography results, fMRI shows more posterior and lateral involvement in the affected hemisphere compared with the unaffected hemisphere.

of the initially excessive intensity and extent of activation in the motor network bilaterally, as well as with a normalisation of the balance of hemispheric activation away from predominant activation in the unaffected hemisphere. However, changes of the pattern of activation and overactivation pattern over time vary between individuals.79 In some patients, for instance, activation of the dorsolateral prefrontal cortex appears late in the recovery process, which suggests the development of executive strategies to compensate for the lost function. Moreover, remodelling of sensory and motor hand somatotopy, with or without enlargement of the hand representation, is common outside the normal areas in the affected hemisphere. The unaffected hemisphere is also reorganised, although to a lesser degree. Imaging studies suggest that changed interhemispheric symmetry of the sensorimotor hand areas is a sensible index for the assessment of brain reorganisation after stroke. Increased recruitment of the affected primary motor cortex—whether from spared tissue from around the infarct or from intact but deafferented cortex of subcortical stroke—is common and it is especially pronounced in the early stages of recovery. However, a shift of activation towards the primary motor cortex of the unaffected hemisphere suggests less efficient reorganisation, possibly even maladaptive plasticity. Recruitment of direct (uncrossed) corticospinal tracts may underlie activation of the unaffected motor cortex and may, therefore, relate to mirror movements (as it does in early-childhood stroke).135,136 However, this recruitment is more likely to reflect redistribution of activity within the pre-existing

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bilateral motor network. The premotor cortex (especially in the unaffected side) and the descending corticoreticular pathway both have an important role.33,76,82 Finally, activation of non-motor areas—such as the dorsolateral prefrontal cortex and the superior parietal cortex—indicate the involvement of compensatory cognitive strategies. TMS and magnetoencephalography can detect reshaping of sensorimotor areas; they have a high temporal resolution but have several limitations. TMS can only provide bidimensional scalp maps and magnetoencephalography depicts three-dimensional spatial characteristics of virtual neural generators obtained by use of a mathematical model of the head and brain. Moreover, they do not assess movement execution or sensorimotor integration in everyday life. However, this might be an advantage. Mental and physical activity, even when outwardly normal, are abnormally difficult for patients with stroke. Task performance cannot be easily controlled for effort in paretic limbs, even when the variables are carefully matched across individuals, which has itself been rare. Therefore, increases in the distribution of activation are very difficult to interpret; they could represent the formation of new connections, the recruitment of accessory muscles, or the increased mental effort needed to initiate movement or transmit signals along a reduced efferent pathway. The resolution of abnormal activation over time could be secondary to recovery. Therefore, the use of objective methods that assess brain reactivity to a physical stimulus (ie, TMS) or to a sensory input (ie, electrical stimulation to hand and fingers) can integrate information from self-paced motor tasks. fMRI and PET, on their own, have insufficient time resolution to follow the hierarchical activation of relays within a neural network; however, because of their excellent spatial resolution, they can integrate the findings of TMS and magnetoencephalography. A multitechnological combined approach constitutes, at present, the best way to assess the plasticity that underlies recovery of hand function in patients with stroke. References 1 2 3

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Twitchell TE. The restoration of motor function following hemiplegia in man. Brain 1951; 74: 443–80. Rossini PM. Brain redundancy: responsivity or plasticity? Ann Neurol 2001; 48: 128–29. Nudo RJ, Milliken GW. Reorganization of movement representations in primary motor cortex following focal ischemic infarcts in adult squirrel monkeys. J Neurophysiol 1996; 75: 2144–49. Nudo RJ. Remodeling of cortical motor representations after stroke: implications for recovery from brain damage. Mol Psychiatry 1997; 2: 188–91. Nudo RJ, Friel KM. Cortical plasticity after stroke: implications for rehabilitation. Rev Neurol (Paris) 1999; 155: 713–17. Eccles JC .The plasticity of the mammalian central nervous system with special reference to new growths in response to lesions. Naturwissenschaften 1976; 63: 8–15 Glassmann RB, Malamut BL. Does the brain actively maintain itself? Biosystems 1977; 9: 257–68. Merzenich MM, Kaas JH, Wall J, Nelson RJ, Sur M, Felleman D. Topographic reorganization of somatosensory cortical areas 3b and 1 in adult monkeys following restricted deafferentation. Neuroscience 1983; 8: 33–55. Merzenich MH, Kaas JH, Wall JT, Sur M, Nelson RJ, Felleman DJ. Progression of change following median nerve section in the cortical representation

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Search strategy and selection criteria Data for this review were identified by searches of peerreviewed journals with the terms “CNS plasticity”, “stroke”, “brain reorganisation”, “MEG”, “TMS”, “fMRI”, “PET”, “poststroke recovery”, and “stroke rehabilitation”. Relevant findings from the authors’ own studies are included.

After stroke, neurons at risk survive for only a few hours and there is limited opportunity for effective therapeutic intervention. The development of strategies to increase plasticity and improve outcome in patients with established infarcts is therefore important. Longitudinal studies of patients still in the recovery phase will assess the chronology and relation between changes in different types of functional imaging techniques and concomitant recovery of function. By increasing our knowledge of the mechanisms that regulate final outcome, we will be able to identify new therapeutic strategies for this incapacitating disease. Acknowledgments

PMR and FP acknowledge the parts played by Drs P Cicinelli, R Traversa, P Pasqualetti, F Tecchio, V Pizzella, and GL Romani who provided clinical records and data analysis. Authors’ contributions

PMR and J-CB suggested writing this review. All authors contributed to the research, development, and writing of the article. FP and CC provided some of the figures. All authors revised and contributed to the final version. Conflict of interest

We have no conflict of interest. Role of the funding source

Research was partially funded by an Italian “Ministero della Sanità” research project, for which PMR is the project coordinator and FP has been funded as a “Unità Operativa”. J-CB and CC are supported by an MRC Programme Grant (#G0001219). None of these funding sources had a role in the preparation of this review or in the decision to submit it for publication.

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