Article Published in the Author Account of

Marcelo L Berthier

Recovery from Post-stroke Aphasia: Lessons from Brain Imaging and Implications for Rehabilitation and Biological Treatments

Abstract: Aphasia, a condition defined as the partial or complete loss of language function after brain damage, is one of the most devastating cognitive deficits produced by stroke lesions. Over the past decades, there have been great advances in the diagnosis and treatment of post-stroke language and communication deficits. In particular, the advent of functional brain imaging and other brain mapping methods has advanced our understanding of how the intact and lesioned brain takes over the activity of irretrievably damaged networks in aphasic patients. This review examines the contribution of these ancillary methods to elucidate the neural changes that take place to promote improvement of language function in early, late, and very late stages of recovery. Also, functional neuroimaging is helpful to identify brain areas involved in language recovery as well as to characterize the plastic reorganization of neural networks produced by scientifically-based language therapies and biological treatments (drugs, transcranial magnetic stimulation).



Introduction

Discovering the mechanisms underpinning recovery of the injured brain represents a major challenge to modern neuroscience (Cramer et al., 2008; 2011). Structural and functional magnetic resonance imaging (fMRI), positron emission tomography (PET), and other diagnostic methods of brain mapping (magnetoencephalography, MEG; event-related potentials, ERP) have increased our understanding of how the brain recovers from injury during the acute and chronic stages of stroke (Pulvermüller et al., 2005; Breier et al., 2007; Barwood et al., 2011a; Meinzer et al., 2011). In addition, these ancillary methods are unraveling the dynamic brain changes that take place in response to modern rehabilitation strategies and other biological approaches (e.g., transcranial electrical and magnetic stimulation and drugs) (Naeser et al., 2010; Berthier and Pulvermüller, 2011). One of the most impressive advances in clinical neuroscience has been elucidating some neural mechanisms underpinning recovery from post-stroke aphasia (PSA), a condition defined as the partial or complete loss of language function after vascular damage (Berthier, 2005; Hillis, 2007). Efforts to learn more about stroke-related language deficits are clearly justified because PSA is a very frequent and disabling condition (Berthier, 2005; Hillis, 2007) with an annual incidence of 43-60 per 100,000 persons (Engelter et al., 2006; Dickey et al., 2010) and of 77.5 per 100,000 persons in cases referred to rehabilitation centers and in elderly patients (Law et al., 2009). Therefore, gaining knowledge on the neural mechanisms of recovery from PSA may help to identify more reliable predictors of recovery and to design better strategies to enhance recovery. In this article, we review the contribution of modern brain imaging and related brain mapping methods to our knowledge of PSA as well as the implications of this knowledge for rehabilitation treatment. The analysis of other emerging functional techniques (e.g., near infrared spectroscopy, magnetic resonance spectroscopy) (Sakatani et al., 1998; Grachev et al., 2002) is beyond the scope of this article (for a recent review see Crosson et al., 2010).

Mechanisms of Recovery

Figure 1. Dissociated performance on repetition performance of nonwords in chronic aphasia according to the site and extent of structural damage. (A) MRI of a patient with chronic nonfluent aphasia and impaired repetition (Broca's aphasia). A large area of infarction is seen involving the left frontotemporal cortex with extension into insula, basal ganglia (white arrows) and different segments of dorsal (arcuate fasciculus) (green arrow) and ventral pathways (blue arrows) crucial for language repetition. Despite significant bilateral activation of temporal and frontal lobes and supplementary motor areas on fMRI during nonword repetition, the patient's performance on this task was severely impaired (27/104). (B) Schematic diagram depicting the area of infarction (grey triangle) which involves both the dorsal (green) and ventral (blue) pathways underlying language repetition. (C) MRI of a patient with chronic nonfluent aphasia and preserved repetition (transcortical motor aphasia). A large area of infarction is seen on the left mesial frontal cortex (white arrows) with minimal compromise of the anterior portion of the dorsal pathway (green arrow). Patient's performance on nonword repetition was preserved (95/104) and the fMRI during nonword repetition shows significant activation of a bilateral phonological language network similar to the one activated in normal control subjects. (D) Schematic diagram depicting the area of infarction (grey triangle) which minimally involves the anterior part of the dorsal pathway (green) with sparing of the ventral pathway (blue). The left side is represented on the left side of the MRI.

Figure 1. Dissociated performance on repetition performance of nonwords in chronic aphasia according to the site and extent of structural damage. (A) MRI of a patient with chronic nonfluent aphasia and impaired repetition (Broca′s aphasia). A large area of infarction is seen involving the left frontotemporal cortex with extension into insula, basal ganglia (white arrows) and different segments of dorsal (arcuate fasciculus) (green arrow) and ventral pathways (blue arrows) crucial for language repetition. Despite significant bilateral activation of temporal and frontal lobes and supplementary motor areas on fMRI during nonword repetition, the patient′s performance on this task was severely impaired (27/104). (B) Schematic diagram depicting the area of infarction (grey triangle) which involves both the dorsal (green) and ventral (blue) pathways underlying language repetition. (C) MRI of a patient with chronic nonfluent aphasia and preserved repetition (transcortical motor aphasia). A large area of infarction is seen on the left mesial frontal cortex (white arrows) with minimal compromise of the anterior portion of the dorsal pathway (green arrow). Patient′s performance on nonword repetition was preserved (95/104) and the fMRI during nonword repetition shows significant activation of a bilateral phonological language network similar to the one activated in normal control subjects. (D) Schematic diagram depicting the area of infarction (grey triangle) which minimally involves the anterior part of the dorsal pathway (green) with sparing of the ventral pathway (blue). The left side is represented on the left side of the MRI.

The mechanisms by which the brain is repaired and reorganized after stroke depend, at least in part, on the site and extent of the lesion (Crosson et al., 2005) as well as on the capacity of partially damaged and non-damaged structures that are recruited to improve inefficient language functions (Heiss and Thiel, 2006; Sharp et al., 2010; Tulkeltaub et al., 2011) (Figure 1). For example, patients with large infarctions in the left middle cerebral artery territory may display pervasive, long-lasting reduction of speech fluency if certain key structures (e.g., subcallosal fasciculus) initiating speech are damaged (Naeser et al., 1989) (Figure 2). In such cases, the additional involvement of the left temporal lobe or the right hemisphere predicts a poor response to rehabilitation procedures tailored to exploit unaffected cognitive functions (e.g., nonverbal iconic visual communication) (Naeser et al., 1988). By contrast, PSA associated with infarcts in arterial watershed areas between the left middle cerebral artery and either the anterior cerebral artery or the posterior cerebral artery territories, which spare the perisylvian language core, usually have good long-term outcome (Flamand-Roze et al., 2011).

Recovery also relies on the complex interaction between host’s characteristics (age, gender, education, handedness, pre-morbid representation of language, medical comorbidities, history of previous strokes, regional atrophy in areas participating in recovery), and environmental contingencies (occupational and leisure activities, communication partners) (McClung et al., 2010; Price et al., 2010). Hence, it seems that individual differences in a myriad of factors account for the commonly observed heterogeneous patterns of spontaneous and therapy-induced recovery across aphasic individuals. Therefore, the search for new and better measures to predict recovery from PSA is a constant preoccupation for clinicians and researchers. After decades of research, scientists have reached a consensus that variability of language recovery after first-ever stroke is the rule, and that the final outcome of language deficits cannot be reliably predicted at three months post-onset by traditional demographic variables (age, sex, handedness, etc.) and/or lesion characteristics (location and volume) (Lazar and Antoniello, 2008; Cloutman et al., 2009). This is a crucial issue because gaining further knowledge on these factors may help to achieve a successful prediction of outcome in the acute stage and to implement early rehabilitation (Cloutman et al., 2009; Price et al., 2010; Saur et al., 2010). Some initiatives in this direction are emerging, so that a few words on the promissory role of brain imaging in predicting language outcome in PSA are warranted before analyzing how the brain adapts to stroke lesions at different stages of evolution.

Figure 2. Structural MRI of a patient with chronic non-fluent aphasia (spontaneous speech limited to single, concrete words and perseverations) showing a large ischemic infarction in the left middle cerebral artery territory. The axial MRI at 3 T shows extensive damage throughout the left hemisphere involving cortical surface in fronto-temporo-parietal regions. Also, there is extensive subcortical involvement including the insula, claustrum, basal ganglia (putamen, globus pallidum, caudate) and internal capsule. Fronto-parietal pathways (arcuate fasciculus, superior longitudinal fasciculus) and other white matter tracts (uncinate fasciculus) are severely damaged. Left perinecrotic tissue seen in deep white matter (green arrow) and subcallosal fasciculus (red arrows) could account for the long-lasting deficit of speech fluency (Naeser et al., 1989). The left side is shown on the right.

Figure 2. Structural MRI of a patient with chronic non-fluent aphasia (spontaneous speech limited to single, concrete words and perseverations) showing a large ischemic infarction in the left middle cerebral artery territory. The axial MRI at 3 T shows extensive damage throughout the left hemisphere involving cortical surface in fronto-temporo-parietal regions. Also, there is extensive subcortical involvement including the insula, claustrum, basal ganglia (putamen, globus pallidum, caudate) and internal capsule. Fronto-parietal pathways (arcuate fasciculus, superior longitudinal fasciculus) and other white matter tracts (uncinate fasciculus) are severely damaged. Left perinecrotic tissue seen in deep white matter (green arrow) and subcallosal fasciculus (red arrows) could account for the long-lasting deficit of speech fluency (Naeser et al., 1989). The left side is shown on the right.

Functional MRI studies have attempted to distinguish regions of the brain that promote improvement of language deficits from those which may hinder full recovery through maladaptive reorganization of nodes and networks (Heiss and Thiel, 2006; Turkeltaub et al., 2011b). Findings from fMRI studies suggest that activation foci in the intact right hemisphere during language tasks performed very early after stroke may be related to the long-term outcome (Crinion and Price, 2005; Crinion and Leff, 2007) and even that good response to intensive behavioral therapy [constraint-induced aphasia therapy (CIAT) also termed constraint-induced language therapy (CILT)] (Pulvermüller et al., 2001) can be expected in patients with increased right hemisphere activation at baseline (Richter et al., 2008). On the basis of the pattern of fMRI activation two weeks after stroke, Saur et al. (2010) were able to predict recovery in 76% of PSA patients at 6 months follow-up. Importantly, they found that fMRI or diffusion-weighted imaging findings in the hyperacute period (2 days after stroke onset) using the same method (fMRI) could not predict outcomes at 6 months (Saur et al., 2010). A multinational study is collecting a large database of linguistic and neuroimaging recovery patterns of PSA patients that would allow predicting the evolution of a similar new case (Price et al., 2010).

Diffusion tensor imaging (DTI) offers a fine-grained study of white matter tract architecture in the living human brain (Geva et al., 2011). Recent studies using this technique revealed variability in the hemispheric lateralization of long white matter pathways (e.g., arcuate fasciculus) (Catani et al., 2007; Vernooij et al., 2007; Catani and Mesulam, 2008; Thiebaut de Schotten et al., 2011) that play a role in the clinical profile, prognosis, and recovery patterns of PSA (Hosomi et al., 2009; Berthier et al., 2011a). Furthermore, DTI may also assist rehabilitation by identifying preserved structures crucial to mediate recovery as well as morphological changes in white matter pathways triggered by intensive rehabilitation (Schlaug et al., 2009; 2011). Intensive rehabilitation strategies exploiting residual rhythm, melodic and repetition ability related to right hemisphere activity, are associated with remodeling (e.g., increases in the number of fibers) of the right arcuate fasciculus (Schlaug et al., 2009; 2011).

There is consistent evidence that the mechanisms operating to promote recovery from PSA vary throughout its longitudinal course (Cloutman et al., 2009). Therefore, in this review we distinguish recovery mechanisms taking place in early post-stroke stages from those seen in the chronic phases of this condition.

Early recovery

Brain imaging provides a window into the recovery process from PSA because it allows the identification of the gross radiological expression of underlying pathophysiological mechanisms occurring at cellular levels, including removal of inhibition, unmasking of pre-existing connections, activity-dependent synaptic changes, and changes in neurotransmitter activity (Johansson, 2000). Until now, relatively few brain imaging studies have examined the neural mechanisms responsible for the early recovery from PSA (Cappa et al., 1997; Hillis and Heidler, 2002; Price and Crinion, 2005; Saur et al., 2006). Collectively, these studies suggest that recovery of language function in acute stroke depends on three basic mechanisms: (i) reperfusion of incompletely damaged, but highly vulnerable perilesional tissue (ischemic penumbra) (Lee et al., 2006; Hillis et al., 2008), (ii) resolution of focal edema and reversal of reduced metabolism in cortical and subcortical regions distant from the site of the infarct, and (iii) reorganization of the relationship between structure and function (Hillis and Heidler, 2002). These restorative mechanisms occur spontaneously and can be enhanced by implementing therapeutic strategies aimed to improve tissue reperfusion (thrombolysis, stenting, endarterectomy, pharmacologically-induced blood pressure elevation) (Hillis, 2006; Lee et al., 2006). Furthermore, these therapeutic procedures are being increasingly combined with drugs that potentiate language function through re-establishment of neurotransmitter activity (Cheng et al., 2010; Barrett et al., 2011). Future studies should use multimodal brain imaging (e.g., fMRI, PET with donepezil binding) to detect whether more rapid and efficient neural reorganization and compensation can be achieved with combination treatments.

Modern brain imaging permits to move a step forward at elucidating the relative contribution of the left and right cerebral hemispheres to early recovery from aphasia (Saur et al., 2006). Studies in acute PSA showed that the restoration of perilesional networks of the left hemisphere, which have escaped from being irretrievably damaged, is the main mechanism underlying recovery, although there is contribution of right hemisphere areas as well (Heiss and Thiel, 2006). A H215O-PET study of patients with various clinical types of aphasia and heterogeneous lesion locations (subcortical, temporal and frontal) used a word repetition activation paradigm at 2 and 8 weeks following stroke. This study found better recovery of language deficits when language eloquent left temporal areas were spared by the lesions and could be re-engaged in the service of language function (Heiss and Thiel, 2006). By contrast, the role of the right hemisphere was viewed as subsidiary, because it was recruited only when more efficient left hemisphere language networks were severely damaged (Heiss and Thiel, 2006). These results were confirmed by the same research group in another longitudinal study combining low frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) and H215O-PET (Winhuisen et al., 2005; 2007). The main finding was that more patients in the initial assessment (2 weeks post-onset) than in the follow-up examination (8 weeks post-onset) worsened the performance in a verbal semantic task when the functional activity of the right inferior frontal gyrus was inhibited with rTMS. These findings suggest that although the right hemisphere contributed to early recovery of language function (Winhuisen et al., 2005), its role vanished over time in favor of more efficient left hemisphere networks (Winhuisen et al., 2007). Another longitudinal study evaluated the recovery of language function using fMRI on three separate occasions in patients with non-fluent and fluent aphasias associated to left hemisphere infarctions of heterogeneous location (Saur et al., 2006). All patients showed language improvement of variable degree. In the hyperacute phase (0-4 days post-onset) an auditory comprehension activation task elicited little activation in two small perilesional frontal areas (pars orbitalis and pars triangularis), which had escaped from being structurally damaged in most patients, while no activation of homologous areas in the right hemisphere was observed (Saur et al., 2006). In the subacute stage (~2 weeks post-onset) a strong task-related activity was observed in a bilateral cortical network, but improvement of language function only correlated with activation of the right inferior frontal gyrus and adjacent insula (Saur et al., 2006). Further improvement in language function was observed in the chronic stage (~4-12 months post-stroke onset) and it coincided with the re-engagement of left hemisphere cortical areas (inferior frontal and temporal cortices, supplementary motor area) and persistence of right inferior frontal gyrus activity (Saur et al., 2006). In summary, all these results vindicate the “normal” supremacy of the left over the right hemisphere as the likely mechanism underlying recovery from PSA. However, in light of the variable localization of structural lesions in the left hemisphere and the altered inter-hemispheric balance, it is also possible that during the early evolution of PSA the brain implements other alternative functional mechanisms (Hillis, 2006) and patterns of cortical rearrangement to optimize effective recovery (Cappa et al., 1997; Thompson and den Ouden, 2008; Hamilton et al., 2011).

A further contribution of brain imaging during the early recovery stages results from the identification of dysfunctional cortical areas which, if rapidly reperfused, can mediate the recovery of specific language functions (word comprehension, verbal production, naming) (Hillis and Heidler, 2002; Hillis et al., 2006; 2008; Davis et al., 2008). Studies using DWI/PWI showed that the restoration of normal blood flow in the left temporoparietal cortex (Brodmann’s area 22) was accompanied by immediate recovery of lexical-semantic function (spoken word comprehension) (Hillis and Heidler, 2002) and reperfusion of the left Broca’s area (Brodmann’s areas 44/45) correlated with improvement of verbal production (Davis et al., 2008). DWI/PWI studies also showed that the site of ischemic penumbra (hypoperfused but salvageable tissue) may predict the recovery of the language domain (naming) dependent on the function of this area (Brodmann’s area 37) (Hillis et al., 2008). Taken together, DWI/PWI studies have provided compelling evidence that immediate improvement of language deficits in acute stroke can be accounted mainly for reperfusion of cortical areas and not to reestablishment of structure-function relationships or brain plasticity (Hillis et al., 2006). Preliminary studies with diffusion tensor imaging (DTI) tractography have also shown promise in examining the role of major white matter pathways in PSA. In acute PSA damage to the left arcuate fasciculus, a key structure for language repetition (Catani and Mesulam, 2008) correlated with abnormal repetition performance (Breier et al., 2008) and its involvement was a predictor of poor recovery from language deficits (Hosomi et al., 2009).

Late recovery

The majority of modern brain imaging studies examining the neural processes underlying recovery from PSA have been conducted in chronic patients (for recent reviews see Geva et al., 2011; Meinzer et al., 2011). Overall, these studies show that adaptive brain changes promoting recovery from PSA occur not exclusively in the acute and subacute phases (Saur et al., 2006; 2010; Hillis, 2007), but fast compensatory plasticity can also occur during chronic periods in response to intensive SLT (Musso et al., 1999; Pulvermüller et al., 2005; Menke et al., 2009; Warren et al., 2009; Meinzer et al., 2010) and biological treatments (Kessler et al., 2000; Cohen et al., 2004). These results demonstrate that the temporal window for improvement in PSA is much wider than previously estimated (Lazar and Antoniello, 2008). In consequence, the dogmatic position claiming that no further benefits can be expected after one year of evolution has succumbed in light of recent data showing that recovery of language function could occur well beyond this period (Basso and Caporali, 2001; Stark, 2010).

It seems that the mechanisms promoting later recovery from PSA are different from those operating in early stages (Hillis et al., 2002; 2006). As aforementioned, rapid reperfusion has been invoked as the key mechanism for improvement of language deficits in the acute period (Hillis et al., 2006; Cloutman et al., 2009). Compensation (recruitment of additional brain areas to assist in language processing) and reorganization (displacement of a primary language area), which often occur too late to be causally related with the initial restorative changes, may be the likely mechanisms of late recovery from PSA (Thompson, 2000; Kleim and Jones, 2008). The potential capability of the brain to compensate for lesions is known as “neural plasticity” (Johansson, 2000; Kleim and Jones, 2008). Remodeling of neural circuits through plasticity can occur spontaneously or triggered by intensive training (e.g., experience-dependent plasticity) and biological treatments (pharmacological agents, rTMS). It is believed that neural plasticity is the basis of learning in the intact brain and in the lesioned brain (Kleim and Jones, 2008). In the later, the success of neural plasticity depends on the availability of spared or incompletely damaged neural networks that can be recruited in the service of recovery. A recent meta-analysis of functional neuroimaging studies of chronic PSA found a consistent pattern of network reorganization in chronic PSA that is mediated by both cerebral hemispheres (Turkeltabub et al., 2011a). However, on the basis of the great variability in lesion sizes and sites, the putative role of the left and right hemispheres and recruitment mechanisms to the recovery process is more difficult to ascertain. Overall, better recovery from PSA has been associated with left hemisphere lesions of small and medium sizes, than with larger ones. Mechanisms operating in cases with left hemisphere lesions of small and medium sizes include functional remodeling of perilesional brain areas partially deprived from input (Meinzer et al., 2008), increased integration of spared components of the language network critical to language control (Sharp et al., 2010), cortical map expansion (enlargement of a functional brain region) (Grafman, 2000; Fridriksson et al., 2007; Fridriksson, 2010), and recruitment of spared cortical areas unrelated to language, but participating in language-related cognitive functions (memory, attention, executive function) (Menke et al., 2009, Fridriksson et al., 2011). In cases with large lesions encompassing the whole left perisylvian language area, there is less room for recovery because it relies on activation of small islets of preserved tissue of the left hemisphere or on the compensatory capacity of the right hemisphere (Heiss and Thiel, 2006). In the latter circumstance, the contribution of the right hemisphere has been considered subsidiary (Heiss and Thiel, 2006; Winhuisen et al., 2005, 2007) as it does not host the neural machinery necessary to process language as efficiently as the left hemisphere does (Winhuisen et al., 2005; Vigneau et al., 2011). Therefore, increments of right hemisphere activity during language tasks measured with PET and fMRI are considered maladaptive and impeding recovery of language deficits (Naeser et al., 2005; Heiss and Thiel, 2006; Postman-Caucheteux et al., 2010; Richter et al., 2008) or are alternatively viewed as reflecting the implementation of other cognitive strategies (Vigneau et al., 2011). Increased activity on the right frontal cortex during language tasks has been interpreted as resulting from left-to-right functional release due to faulty control of the damaged dominant (left) hemisphere, a condition known as “transcallosal disinhibition” (Heiss and Thiel, 2006; Thiel et al., 2006). To further complicate matters, overactive areas in the right hemisphere areas can detrimentally influence the remnant activity of spared left hemisphere areas through inhibitory inter-hemispheric connections (Heiss and Thiel, 2006). The elucidation of disrupted inter-hemispheric balance in PSA is important, because it represents the theoretical foundation behind the use of rTMS as a therapeutic tool (Naeser et al., 2005). Repetitive TMS (1 Hz) suppresses over-activity in right frontal regions, thus facilitating the reorganization of neural networks within the right hemisphere and eventually restoring the balance between hemispheres (Naeser et al., 2010; Barwood et al., 2011b). While rTMS intervention over the right frontal cortex can accelerate recovery of language deficits in patients with severe and long-lasting PSA (Martin et al., 2009; Naeser et al., 2010; Barwood et al., 2011b), it should be noted that not all cortical areas of the right frontal lobe exert a deleterious effect on language performance (Martin et al., 2009a; Hamilton et al., 2010; 2011; Turkeltaub et al., 2011a). Intriguingly, two adjoining areas of the right frontal cortex (pars triangularis and pars opercularis) may play opposing roles in language performance (word retrieval) and their paradoxical activity apparently relies on the location of the lesions in the left hemisphere (Martin et al., 2009b); over-activity of the right pars triangularis interferes with language function, whereas the pars opercularis participates in recovery (Hamilton et al., 2011; Turkeltaub et al., 2011a). Although this complex balance between cerebral hemispheres in PSA require further analysis (Turkeltaub et al., 2011a) evidence from specific rehabilitation techniques indicates that, in some cases, increased reliance on the right hemisphere activity may contribute to recovery (Crosson et al., 2009; Schlaug et al., 2009). In addition, there seem to be different degrees of right-hemispheric participation in language functions in different people (Catani et al., 2007). Recent DTI studies have contributed to the demonstration that healthy individuals actually have more inter-hemispheric variability of white matter tracts (arcuate fasciculus) than previously anticipated (Catani and Mesulam, 2008) and that individuals having a symmetrical pattern show superior verbal recall (repetition) in memory tasks than those having an extreme leftward lateralization, perhaps because individuals of the former group additionally recruit the right white matter tracts during word recall (Catani et al., 2007). Although there is not a clear-cut correspondence between structural cerebral asymmetry and functional hemispheric lateralization of language (Wada, 2009), individual variability might explain not only different patterns of aphasia in patients having similar left hemisphere lesions (Berthier et al., 2011a), but the presence of variability in structural cerebral asymmetry raises the possibility that exploiting the residual activity of the right hemisphere in some gifted individuals may favor rapid and better recovery (Schlaug et al., 2009; 2011).

In summary, taken together the results of brain imaging clearly indicate that activity in the perilesional left hemisphere areas is crucial for functional recovery of language and functional communication after stroke, and that the right hemisphere also participates in the recovery of language deficits induced by rehabilitation and biological treatments (Crosson et al., 2007; Berthier and Pulvermüller, 2011). In this regard, some authors have rightly pointed out that the “left” and “right” mechanisms of recovery from PSA are not mutually exclusive (Crosson et al., 2007); rather both mechanisms may be operative with different timetables (Saur et al., 2006) or both hemispheres may simultaneously contribute to recovery (Crosson et al., 2007; Pulvermüller et al., 2005).

Very late recovery

Less is known about the neural mechanisms promoting very late recovery of PSA (e.g., decades after stroke onset). Paucity of data on this topic may result from several reasons. First, late recovery is viewed as unpredictable and non-linear, with periods of positive change and others of regression. Second, many aphasic patients with chronic PSA are lost for follow-up after being discharged from rehabilitation services because their therapists judge that language performance has reached a ”plateau” and no further gains can be expected (Hersh, 2011). Third, elderly aphasic patients may develop vascular dementia that interfere with long-term evaluation of recovery, or die. However, progressive recovery of language and related deficits after interrupting rehabilitation (Smania et al., 2010), or rapid recovery of aphasia with intensive rehabilitation and drug treatment (case 26 in Berthier et al., 2009) have been reported more than two decades after aphasia onset.

This would imply that plastic changes may be differentiated by the speed at which they occur. Using brain imaging and other brain mapping techniques (MEG, ERP) in longitudinal studies of individual patients with well-defined lesions may be a fruitful approach to disentangle the unexplored neural mechanisms underpinning very late recovery. Furthermore, this effort may allow rehabilitation of chronic patients with novel, scientifically-based strategies (Naeser et al., 2005; 2010; Berthier et al., 2011b). A recent single case study (Smania et al., 2010) offer some clues of how some brain areas of the uninjured hemisphere gradually take over the role of the damaged homologous counterparts many years after stroke onset, through a mechanism referred to as — homologous area adaptation — (Grafman, 2000). In the acute period, the patient had a global aphasia (loss of virtually all language functions) associated with a massive infarction involving the whole language area represented in the left cerebral hemisphere, so that there was only room for recovery at the expense of compensatory activity of the right hemisphere. Three main periods of recovery were documented in this case (Smania et al., 2010). During the first year post-onset, recovery was limited to verbal comprehension and repetition; improvement in naming and reading was slower and occurred between years 1 and 3. Further improvement in all the abovementioned language functions was seen from 3 to 25 years after stroke and this happened in parallel with the partial re-emergence of spontaneous speech (Smania et al., 2010). The recovery of comprehension in this patient is not totally unexpected as auditory-phonological and semantic processing required for language comprehension are pre-morbidly represented in different sectors of both temporal lobes (Warren et al., 2009; Buchsbaum et al., 2011; Hickok et al., 2011) and damage to one temporal lobe can be lately compensated by the other one (Musso et al., 1999). In the same vein, the recovery of repetition might have resulted from the bilateral representation of the arcuate fasciculus with the left and right engaging repetition pre-morbidly (Catani et al., 2007; Berthier et al., 2011a) and the right arcuate fasciculus gradually assuming repetition duties after vascular damage of its homologous counterpart (Pulvermüller and Schönle, 1993). Even though the mechanisms underlying slower recovery of naming and reading than other language functions are unknown, some instructive lessons can be learned from this single case (Smania et al., 2010). Right hemisphere activity in some chronic aphasic patients with extensive left hemisphere damage is not always maladaptive as recently suggested (Naeser et al., 2005; Price and Crinion, 2005; Postman-Caucheteux et al., 2011) and can profit from intensive therapy (Harnish et al., 2008). Integration of neural networks to eliciting language recovery may be gradual with different schedules for different language domains. The late recovery of other cognitive functions (motivation) could further contribute to recovery of communication (Smania et al., 2010).

Recovery Induced by Rehabilitation and Biological Treatments

Speech and language therapy

At the present time, few imaging studies have examined which brain regions mediate successful recovery from PSA in response to intense training. However, several important findings have emerged using several ancillary techniques (for reviews see Meinzer and Breitenstein, 2008; Pulvermüller and Berthier, 2008; Thompson and den Ouden, 2008). First, successful brief, intensive training induces very rapid functional plastic brain changes in normal subjects (Shtyrov et al., 2010) and in chronic aphasic patients (Musso et al., 1999). Second, aphasic patients may use different compensatory strategies before and after therapy, and training-induced network remapping may be different according to lesion site and extent (Vitali et al., 2007; 2010). Third, different brain areas may mediate language improvement induced by training after immediate versus long-term (8 months post-training) recovery (Menke et al., 2009). Functional MRI evaluation immediately after ending intensive training shows activation of brain areas implicated in processing attention, memory encoding and multimodal integration (hippocampus, fusiform gyrus, precuneus gyrus and cingulate gyrus). The long-term evaluation reveals a major contribution of the right temporal lobe (Wernicke’s area), thus implying a prominent role of both cerebral hemispheres to language recovery (Menke et al., 2009). Third, functional imaging (fMRI and PET) suggests not only that cerebral cortex is important for mediating recovery, but also that the right basal ganglia may contribute to improving language deficits (Crosson et al., 2005; Harnish et al., 2008; de Boissezon et al., 2008).

Pharmacotherapy

Pharmacotherapy is emerging as a promissory strategy to enhance cognitive function in healthy subjects and in brain-damaged individuals (Husain and Mehta, 2011). Moreover, accumulating evidence indicates that medications can also augment benefits provided by speech and language therapy in patients with PSA (Floel and Cohen, 2010; Berthier and Pulvermüller, 2011; Berthier et al., 2011b). Clinical improvement in language and communication domains is considered the primary efficacy measure (Berthier and Pulvermüller, 2011), yet there is a growing interest in studying dynamic brain changes accompanying recovery from PSA promoted by intensive rehabilitation (Meinzer et al., 2011), drugs (Crinion and Leff, 2007; Small and Llano, 2009; Berthier and Pulvermüller, 2011) and other biological methods (Martin et al., 2009; Meinzer et al., 2008; Cherney et al., 2010). One way to increase understanding on the neural correlates of recovery can be achieved using pharmacological MRI (the combination of MRI studies with the application of drugs) (Salmeron and Stein, 2002; Wise and Tracey, 2006) and other techniques such as ERP (Pulvermüller et al., 2005).

Pharmacological MRI is a broad field encompassing several techniques (fMRI, analysis of cortical thickness, diffusion tensor tractography, spectroscopy, and so forth) aimed to identify changes in brain activity and structure resulting from pharmacological manipulation (Wise and Tracey, 2006). In recent years, some studies have investigated the modulation of brain regions subserving language processing in healthy subjects under pharmacological manipulation with serotoninergic and dopaminergic compounds (Péran et al., 2008; Kim et al., 2010). Less is known, however, about the effects of drugs used to treat PSA on physiological changes measured with functional neuroimaging as only two studies of pharmacological neuroimaging have been performed up to now (Kessler et al., 2000; Cohen et al., 2004). A randomized, placebo-controlled trial evaluated the role of piracetam, a γ-aminobutyric acid derivative with action on acetylcholine and glutamate (Malykh and Sadaie, 2010), combined with intensive SLT in acute PSA. A significant improvement was found in tasks tapping spontaneous speech, comprehension, naming, written language and verbal communication which coexisted with cerebral blood flow increases during verbal repetition in eloquent regions of the left frontotemporal cortex only in the piracetam-treated group (Kessler et al., 2000). A single case study involving a patient with chronic Broca’s aphasia due to a left temporo-insular and basal ganglia infarction documented transient improvement of speech production deficits with the hypnotic agent zolpidem, a benzodiazepine agonist selective for α1 subunit-containing γ-aminobutyric acid (type A) receptors (Cohen et al., 2004). Improvements in spontaneous speech, repetition and object naming were associated with increments in cerebral perfusion in regions surrounding the damaged area and in functionally-connected frontal and parietal cortices (Cohen et al., 2004).

Preliminary data from a pharmacological MRI study shows that drugs that enhance cholinergic neurotransmission (donepezil) improve naming performance in chronic PSA, and that further gains are obtained when drug intervention is combined with intensive speech-language rehabilitation (constraint-induced aphasia therapy) (Berthier et al., in preparation). Functional MRI reveals that, in some of these patients, picture naming improvement is associated with more focussed activation of the same left cortical areas already activated in the pre-treatment testing (Figure 3). Additionally, structural MRI reveals increases in cortical thickness of areas surrounding the infarct and other areas of the right hemisphere (Figure 4). These findings suggest that treatment-induced decreases in fMRI activation might reflect decreased effort to perform the task and more efficient online processing of naming skills due to neural network optimization (functional plasticity) (Cherney et al., 2010; Berthier et al., 2011b). Focal increases in cortical thickness in regions (frontal and parietal) neighboring the cortical areas exhibiting functional plasticity, might result from structural plasticity triggered by both cholinergic stimulation with donepezil (Sarter et al., 2009) and CIAT (Berthier and Pulvermüller, 2011).

Figure 3.

Figure 3. (A) Uninflated surface of the left hemisphere (FreeSurfer reconstruction) clearly shows the area of infarction (red) in the left posterior inferior frontal gyrus. Gyri are colored green with sulci shown in red. (B-D) fMRI BOLD activations of a patient with chronic anomic aphasia during a naming task compared to rest. Activations are shown on the patient′s inflated cortical surface. FMRI data processing was carried out using FEAT (FMRI Expert Analysis Tool) Version 5.98, part of FSL (FMRIB′s Software Library, www.fmrib.ox.ac.uk/fsl). Data were first corrected for motion FSL's mcFLIRT (Jenkinson et al., 2002) and then brain extracted using FSL′s BET (Smith, 2002). Z (Gaussianised T/F) statistic images were thresholded using clusters determined by Z>4 and a (corrected) cluster significance threshold of p = 0.001 (Worsley, 2001). Cortical reconstruction and inflation was performed using FreeSurfer (http://surfer.nmr.mgh.harvard.edu/), the details of which are described in prior publications (Dale et al., 1999; Fischl et al., 1999a, 2001). (B) At baseline the patient had moderately impaired performance on picture naming (33/42 or .79) and required widespread, bilateral activation in order to perform the task. (C) After 8 weeks of treatment with donepezil (10 mg/day) naming improved (40/42, or 95) and a much more focal network was engaged, with most activation in left perilesional areas. (D) After combined donepezil and language rehabilitation with constraint-induced aphasia therapy (CIAT) naming performance was flawless (42/42, or 1.0) and a more left-hemisphere perisylvian areas were active compared to the activation pattern in C). Of note was a concurrent increase in right hemisphere frontal lobe activation in D) compared to C).

Figure 4.

Figure 4. (A) Uninflated surface of the left hemisphere (FreeSurfer reconstruction) clearly shows the area of infarction (red) in the left posterior inferior frontal gyrus. Gyri are colored green with sulci shown in red. (B) Figure shows the symmetrized percent increase (SPI) in cortical thickness (defined as rate of increase/average cortical thickness). (B) Image shows an increase in thickness in peri-lesional and parietal areas between baseline and after 8 weeks of treatment with donepezil (10mg/day) alone. (C) This was followed by an increase in left-sided prefrontal areas and superior temporal areas after 2 further weeks of combined donepezil (10 mg/day) and constraint-induced aphasia therapy (CIAT) compared to donepezil treatment alone. B) and C) also show right-hemisphere increase in SPI, which did not remain when considering the SPI of the three time points together as shown in D). There is an increase in prefrontal, superior temporal and parietal lobes across the entire treatment phase as shown in D). Cortical reconstruction, inflation, thickness measurement and longitudinal analysis was performed using FreeSurfer (http://surfer.nmr.mgh.harvard.edu/), according to the methods described in Dale et al., 1999; Fischl et al., 1999a, 2001, Fischl and Dale, 2000, Reuter et al., 2010, Reuter and Fischl, 2011. Cortical thickness was calculated as the closest distance from the gray/white boundary to the gray/CSF boundary at each vertex on the tessellated surface (Fischl and Dale, 2000).

Other biological treatments

Another strategy to enhance the benefits provided by intensive SLT is applying non-invasive and invasive brain stimulating techniques that either suppress the activity of cortical regions interfering with recovery or instead enhance cortical excitability promoting improvement of language function. Several studies have been performed in chronic aphasic patients with two non-invasive techniques, rTMS and transcranial direct current stimulation (tDCS) (Naeser et al., 2010; Baker et al., 2010). Treatment with rTMS and tDCS has shown positive and durable effects on naming performance in patients with chronic, non-fluent (Martin et al., 2009a) and fluent aphasias (Barker et al., 2010). Research on the neural correlates of rTMS in chronic PSA is increasing and it is being focused on the role of fMRI to detect brain remodeling induced by SLT (CILT) (Naeser et al., 2010) and on DTI studies of the left and right arcuate fasciculus to gain further knowledge on its participation in aphasia recovery (Kaplan et al., 2010). As already stated, brain changes induced by rTMS and detected with fMRI disclosed different patterns of neural activity in both cerebral hemispheres, with improvement mainly correlating with adaptive changes in perilesional areas of the left hemisphere (Martin et al., 2009b; Naeser et al., 2010; Meinzer et al., 2011).

A pilot study used invasive epidural stimulation of the ipsilesional premotor cortex in patients with nonfluent aphasia and extensive left hemisphere infarcts to improve language performance (Cherney et al., 2010). A small sample of patients with severe and long-lasting, non-fluent PSA received a simultaneous treatment with intensive SLT and epidural stimulation during 6 weeks (3 h/day). All treated patients showed significant benefits on the Aphasia Quotient (AQ) of the WAB. The AQ-WAB is a global measure of aphasia severity and patients with changes from baseline ≥5 are considered “responders” to treatment (Berthier et al., 2009; 2011b; Cherney et al., 2010) immediately post-therapy, and 6 week and 12 week follow-up. Functional MRI revealed decreases in the global and regional activation which correlated with improvement in language performance (Cherney et al., 2010). Although further studies are needed, epidural cortical stimulation seems to be safe and may be a viable option for enhancing the limited benefits provided by SLT in patients with severe non-fluent aphasia.

Conclusions

We have provided an overview of the role of neuroimaging and other brain mapping techniques on the study of the neural correlates underpinning recovery from PSA. At the present time, neuroimaging studies in the acute stroke period have identified the reperfusion mechanisms responsible for recovery and the brain areas that should regain functional activity to rapidly return language skills to normal. In chronic PSA, most neuroimaging studies have examined functional plasticity occurring spontaneously or triggered by SLT and rTMS, but studies on structural plasticity induced by rehabilitation techniques are scant. The neural changes occurring in response to combined pharmacological treatments and neuroscientifically-based rehabilitation strategies also warrant further analysis. Finally, studies combining pharmacological fMRI coupled with other techniques (DTI, cortical thickness, connectivity) are strongly needed to evaluate the full spectrum of changes that can be modelled by these interventions.

Acknowledgments

The authors thank Dr. Ricardo Jorge for comments on a draft of this paper. This research was funded in part by the Ministerio de Educación y Ciencia, Spain (grant SEJ2007-67,793) (M.L.B.) and the Medical Research Council, U.K. (grants U1055.04.003.00001.01 and MC_US_A060_0034) (F.P.).

Disclosure

M.L. Berthier declares association with the following companies: Bayer, Eisai, Eli Lilly, GlaxoSmithhKline, Janssen, Merz, Novartis, Pfizer, and Lundbeck. R. Juárez de Mier declares association with Pfizer. N. García-Casares, S. Froudist Walsh, A. Nabrozidis, C. Green, G. Dávila, A. Gutiérrez, and F. Pulvermüller declare no competing interests.

Corresponding Author

Marcelo L. Berthier, M.D., Ph.D., Unidad de Neurología Cognitiva y Afasia, Centro de Investigaciones Médico-Sanitarias, Universidad de Málaga, Campus Teatinos, C/Marques de Beccaria 3, 29010, Málaga, España.

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[Discovery Medicine; ISSN: 1539-6509; Discov Med 12(65):275-289, October 2011. Copyright © Discovery Medicine. All rights reserved.]

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