Stroke rehabilitation using noninvasive cortical stimulation: aphasia

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Stroke rehabilitation using noninvasive cortical stimulation: aphasia Expert Rev. Neurother. 12(8), 973–982 (2012)

Veit Mylius*‡1,2, Hela G Zouari‡1,3,4, Samar S Ayache1,3, Wassim H Farhat1,3 and Jean-Pascal Lefaucheur1,3 Université Paris-Est-Créteil, Faculté de Médecine, EA 4391, Créteil, France 2 Department of Neurology, Philipps University Marburg, Marburg, Germany 3 Hôpitaux de Paris, Hôpital Henri Mondor, Service de Physiologie, Explorations Fonctionnelles, Créteil, France 4 CHU Habib Bourguiba, Service d’explorations fonctionnelles, Sfax, Tunisia *Author for correspondence: Tel.: +49 642 158 65200 Fax: +49 642 158 65208 [email protected] 1

‡

Authors contributed equally.

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Poststroke aphasia results from the lesion of cortical areas involved in the motor production of speech (Broca’s aphasia) or in the semantic aspects of language comprehension (Wernicke’s aphasia). Such lesions produce an important reorganization of speech/language-specific brain networks due to an imbalance between cortical facilitation and inhibition. In fact, functional recovery is associated with changes in the excitability of the damaged neural structures and their connections. Two main mechanisms are involved in poststroke aphasia recovery: the recruitment of perilesional regions of the left hemisphere in case of small lesion and the acquisition of language processing ability in homotopic areas of the nondominant right hemisphere when left hemispheric language abilities are permanently lost. There is some evidence that noninvasive cortical stimulation, especially when combined with language therapy or other therapeutic approaches, can promote aphasia recovery. Cortical stimulation was mainly used to either increase perilesional excitability or reduce contralesional activity based on the concept of reciprocal inhibition and maladaptive plasticity. However, recent studies also showed some positive effects of the reinforcement of neural activities in the contralateral right hemisphere, based on the potential compensatory role of the nondominant hemisphere in stroke recovery. Keywords: aphasia • cortical excitability • language • neuromodulation • speech • stroke • theta burst stimulation • transcranial direct current stimulation • transcranial magnetic stimulation • treatment

Aphasia is defined as the impairment or loss of language function and can result from cerebral stroke. It concerns approximately 30% of stroke patients but clearly improves during the first 4 weeks in one-third of patients and during the first 6 months in approximately half of them [1–3]. Aphasia causes an important disability in the daily life, representing a key feature for the functional outcome of different subtypes of stroke [4] . Beyond 1 year after stroke, no spontaneous recovery can be expected, but intensive speech therapy consisting of functional and communicative training is still able to lead to further improvement [5] . In general, it is recommended to provide speech therapy for at least 5–10 h a week and to start it in early poststroke phase [6] . However, additional therapeutic approaches such as noninvasive cortical stimulation (NICS) may further ameliorate the therapeutic outcome by acting more directly on the excitability and plasticity of cortical networks [7,8] . Aphasia results from the lesion of a cortical and subcortical perisylvian network perfused by the 10.1586/ERN.12.76

middle cerebral artery and usually located in the left dominant hemisphere [9] . The occlusion of a critical artery leads to cell death in the zone that is no longer perfused and to cell dysfunction in the surrounding zone of penumbra, which has a reduced perfusion. This perilesional area is characterized by low excitability of neural structures, which can regain function gradually as they are reperfused. However, functional recovery is mostly associated with a process of reorganization and plasticity in the language network [10,11] . It concerns the stroke-damaged area but also the perilesional and connected structures in the left hemisphere as well as contralateral homotopic areas, depending on the respective localization and size of the lesion. Nonfluent aphasias can be differentiated from fluent aphasias before further subdividing in diverse aphasia subtypes. As these subtypes do not represent stable entities, especially during the acute poststroke phase, different prevalence of these subtypes can be observed between acute and chronic strokes [3] . The most common types

© 2012 Expert Reviews Ltd

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of aphasia are Broca’s aphasia, Wernicke’s aphasia, global aphasia and anomia. Broca’s aphasia is a nonfluent, agrammatic aphasia, impairing speech production and caused by a damage to the left posterior inferior frontal gyrus (IFG), which is the Broca’s area corresponding to Brodmann areas (BAs) 44 (pars opercularis) and 45 (pars triangularis). Wernicke’s aphasia is a fluent paragrammatic aphasia, impairing language comprehension, caused by damage to the left posterior part of the superior temporal gyrus (STG), which is the Wernicke’s area corresponding to BA 22. Other areas involved in the development of aphasia are the adjacent angular gyrus (BA 39) and subramarginal gyrus (BA 40). Global aphasia is a nonfluent aphasia showing features of both previous types with speech automatisms resulting from a damage to Broca’s and Wernicke’s areas as well as to their interconnecting fibers. Patients with anomic aphasia may show temporoparietal lesions but the disturbances of anatomofunctional connections involved in language processing are less pronounced than in other types of aphasia. Less common types of aphasia consist of conduction aphasia that presents mainly with disturbed speech repetition and transcortical aphasia showing excellent speech repetition with reduced spontaneous speech. Imaging studies revealed specific correlations between the location of the brain injury and the clinical presentation of speech or language deficit or disturbance [9] . Diffusion tensor imaging (DTI) tractography, a MRI technique, showed that several pathways could be involved, according to the subtype of aphasia, one dorsal corresponding to a motor system of speech production and the other ventral corresponding to a semantic system of language comprehension [12] . Accordingly, a temporal model for the dynamics of cortical reorganization after stroke has been proposed. An initial dysfunction of the remaining functional language areas is followed by an increased activity of those areas but also of homotopic contralateral areas in the postacute phase, which finally tends to normalize in the chronic phase if the recovery is good [10] . The level of neural activity in the Broca’s area during the postacute phase (2 weeks after stroke) was found to positively correlate with clinical outcome in the long term [13] . Such activity changes in cortical structures are reflected by perfusion changes in imaging studies and by excitability changes in neurophysiological studies. The concept of interhemispheric rivalry implicates that stroke not only results into a reduced excitability of the damaged cortical region but induces a hyperexcitability of homologous regions in the unaffected contralesional hemisphere, which are released from inhibitory influences of the lesioned area [14] . Furthermore, unilateral injury can also lead to disinhibition in the neighboring ipsilesional cortical areas that may play an important role in poststroke cortical plasticity. However, some controversies exist on the respective involvement of ipsilesional and contralesional reorganization of brain activities for the poststroke recovery process regarding aphasia, in contrast to what has been demonstrated regarding sensory-motor deficit or visuospatial neglect [15,16] . Brain imaging data, including DTI, gave evidence for the existence of homologies of anatomical and functional connections between the language areas of the left and right hemispheres [11,17] . When the dominant hemisphere 974

is damaged, there is a relief of the inhibition of the language areas in the right hemisphere. Thus, specific language therapies like the melody intonation therapy (MIT) or the Crosson’s naming task have been designed to enhance language abilities in nonfluent aphasia by this way [18,19] . MIT improves speech by combining the intoning (singing) of simple phrases with left hand tapping, based on the right lateralization of music-related brain activation and on the improvement of speech-related motor functions [20] . The Crossons’s naming task involves complex lefthand movements followed by a picture-naming task to increase right-lateralized attention processes, which in turn can improve picture naming [19] . Because NICS can modulate the excitability, activity or plasticity of specifically targeted cortical regions [21,22] , this approach is of particular interest for the treatment of stroke. The purpose of NICS application in the neurorehabilitation of aphasic patients is to act on specific networks involved in the pathophysiology of language processing and to promote adaptative cortical reorganization after stroke [7,8,23] . This review presents the data published to date that were obtained by using NICS in stroke patients with aphasia. NICS techniques are mainly represented by repetitive transcranial magnetic stimulation (rTMS), including conventional paradigms (tonic low-frequency stimulation and phasic high-frequency stimulation) and new paradigms, such as theta burst stimulation (TBS). These techniques aim to produce long-term synaptic changes. By contrast, transcranial direct current stimulation (tDCS) rather produces neuromodulatory effects. Principles, mechanisms of action and methodological aspects of the different NICS techniques are described elsewhere [24,25] and will not be detailed. Clinical applications of NICS techniques in stroke patients with aphasia

Mostly based on the theory of interhemispheric rivalry [14] , similar paradigms and concepts of NICS have been employed in the rehabilitation of stroke patients with motor deficit, hemispatial neglect or aphasia [7,26,27] . More precisely, the rehabilitation of poststroke aphasia refers to two different strategies: the recruitment of perilesional cortical regions in the dominant (left) hemisphere on one hand and the development of language ability in the nondominant (right) hemisphere on the other hand using either rTMS (Table 1) or tDCS (Table 2) . Although in some patients with poststroke Broca’s aphasia, right IFG activation was found to be at the origin of language function recovery [28] , the compensatory potential of the nondominant hemisphere is probably limited and the recovery from poststroke aphasia seems to be more effective in patients who recover left hemisphere networks and left IFG function [29] . Therefore, the majority of NICS trials in poststroke aphasia aimed to reinforce the activity of brain regions in the left hemisphere. This goal can be achieved by using an excitatory NICS protocol (either intermittent TBS [iTBS] [30] or anodal tDCS [31–34]) to reactivate the lesioned area or an inhibitory NICS protocol (either lowfrequency rTMS [35–41] or cathodal tDCS [42]) to reduce activities in the contralesional homologous area. Expert Rev. Neurother. 12(8), (2012)

Number and type of patients

Control condition


One chronic stroke: nonfluent aphasia

Four chronic stroke: nonfluent aphasia

Two chronic stroke: nonfluent aphasia

One chronic stroke: nonfluent aphasia

One chronic stroke (7 years after stroke): nonfluent aphasia

Eight chronic stroke: nonfluent aphasia

12 chronic stroke (2–6 years Right pars triangularis Sham after stroke): nonfluent of IFG (BA 45; apical stimulation (parallel group aphasia part), F8 design)

Naeser et al. (2005)


Martin et al. (2009)


Hamilton et al. (2010)


Barwood et al. (2011)

None

1 Hz, 90% RMT

1 Hz, 90% RMT

1 Hz, 90% RMT

1 Hz, 90% RMT

1 Hz, 90% RMT

1 Hz, 90% RMT

1 Hz, 90% RMT

1 Hz, 90% RMT

Results

1200 pulses, 10 sessions Improvement in speech/language performance (BDAE) lasting up to 2 months

1200 pulses, 10 sessions Inhibition of right pars opercularis led to significant increase in RT, but no change in number of pictures named. Inhibition of right pars triangularis led to significant increase in pictures named, and significant decrease in RT

1200 pulses, 10 sessions Improvement in speech/language performance (both information content and fluency scale of the WAB), lasting up to 10 months

1200 pulses, 10 sessions Improvement in speech/language performance (BDAE)

1200 pulses, 10 sessions Improvement in speech/language performance (BNT) up to 46 months after rTMS. Reported concomitant brain activation changes in fMRI exam (regarding sensorimotor cortex, IFG and SMA, bilaterally)

1200 pulses, 10 sessions Improvement in speech/language performance (BNT and BDAE) up to 8 months after rTMS



Stimulation Number of pulses frequency per session and and intensity number of sessions

[40]

[56]

[39]

[23]

[38]

[37]

[36]

[35]

Ref.

AAT: Aachen aphasia test; BA: Brodmann area; BDAE: Boston diagnostic aphasia exam; BNT: Boston naming test; DLPFC: Dorsolateral prefrontal cortex; F8: Figure-of-eight coil; fMRI: Functional MRI; IFG: Inferior frontal gyrus; iTBS: Intermittent theta burst stimulation; RMT: Resting motor threshold; RT: Reaction time; rTMS: Repetitive transcranial magnetic stimulation; SLTA: Standard language test of aphasia; SMA: Supplementary motor area; STG: Superior temporal gyrus; WAB: Western aphasia battery.

Right pars opercularis None or triangularis of IFG (BA 44 or 45), F8

Right IFG, F8

Right pars triangularis None of IFG (BA 45; anterior or posterior part), F8

Right pars triangularis None of IFG (BA 45), F8





Target, coil type


Right frontal inhibition

Study (year)

Table 1. Therapeutic studies using repetitive transcranial magnetic stimulation and theta burst stimulation in stroke patients with aphasia.

Noninvasive cortical stimulation in aphasia

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Kakuda et al. (2011)

Eight (chronic stroke [more than 1 year after stroke]: nonfluent aphasia)

Szaflarski et al. (2011)

Four chronic stroke (5–28 years after stroke): nonfluent aphasia

Two chronic stroke (7–8 months after stroke): fluent aphasia

Control condition

Left STG (TP5), F8

Right (n = 2) or left (n = 2) frontal cortex (contralateral to fMRI maximal region of activation in a naming task), F8

Left Broca’s area (according to fMRI-guided neuronavigation), F8

Left DLPFC, F8

Right frontal cortex, F8

None

None

None

Placebo stimulation (parallel group design)

None

Right pars triangularis Vertex of IFG (BA 45), F8 stimulation (parallel group design)

Target, coil type

1 Hz, 90% RMT

1 Hz, 90% RMT

iTBS train (3 pulses at 50 Hz every 200 ms), 80% RMT

20 Hz, 90% RMT

1 Hz, 90% RMT

1 Hz, 90% RMT

Improvement in speech/language performance (AAT) for 2 weeks without concomitant brain activation changes in PET exam (activation shift toward the right hemisphere in the control group only)

Results

Improvement in speech/language performance (semantic fluency) with concomitant brain activation changes in fMRI exam (left-hemispheric shift)

1200 pulses, 10 sessions Improvement in speech/language performance (Token test, SLTA), lasting up to 3 months

1200 pulses, 10 sessions Mild-to-moderate improvement in speech/language performance

600 pulses (iTBS trains of 2 s repeated every 10 s for 190 s), 10 sessions

Improvement in object naming lasting 2000 pulses, up to 48 weeks 20 sessions (combined with speech therapy after each rTMS session)

1200 pulses, 18 sessions Improvement in speech/language performance (SLTA, WAB) primed by 6-Hz rTMS (combined with speech therapy)

1200 pulses, 10 sessions (combined with speech therapy after each rTMS session)

Stimulation Number of pulses frequency per session and and intensity number of sessions

[53]

[52]

[30]

[44]

[58]

[41]

Ref.

AAT: Aachen aphasia test; BA: Brodmann area; BDAE: Boston diagnostic aphasia exam; BNT: Boston naming test; DLPFC: Dorsolateral prefrontal cortex; F8: Figure-of-eight coil; fMRI: Functional MRI; IFG: Inferior frontal gyrus; iTBS: Intermittent theta burst stimulation; RMT: Resting motor threshold; RT: Reaction time; rTMS: Repetitive transcranial magnetic stimulation; SLTA: Standard language test of aphasia; SMA: Supplementary motor area; STG: Superior temporal gyrus; WAB: Western aphasia battery.


Left temporal inhibition


Right or left frontal inhibition

Three (chronic stroke: nonfluent aphasia)

Cotelli et al. (2011)

Left frontal excitation

Ten (postacute stroke [16 weeks]: five Wernicke’s aphasia, two Broca’s aphasia, one amnestic)

Weiduschat et al. (2011)

Right frontal inhibition (cont.)

Study (year)

Table 1. Therapeutic studies using repetitive transcranial magnetic stimulation and theta burst stimulation in stroke patients with aphasia (cont.).

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Left IFG Three chronic stroke (7 months to 4 years after stroke): nonfluent aphasia with apraxia of speech

Marangolo et al. (2011)

Eight chronic stroke (1–12 years after stroke): mildly fluent aphasia

Fridriksson et al. (2011)

Eight chronic stroke (2–8 years after stroke): nonfluent aphasia

Right posterior IFG Six chronic stroke (1.3–10 years after stroke): nonfluent aphasia

Left Broca’s area (crossing point between T3-Fz and F7-Cz); occipital area

12 chronic stroke: anomia Right temporo parietal area

Sham tDCS (cross-over Cathodal or design) anodal, 1 mA

20 min during language training, six sessions

20 min, series of three sessions coupled with MIT

10 min, one session

fMRI: Functional MRI; IFG: Inferior frontal gyrus; MIT: Melodic intonation therapy; tDCS: Transcranial direct current stimulation.

Flöel et al. (2011)

Cathodal or anodal, 2 mA

Sham tDCS (cross-over Anodal, design) 1.2 mA

Sham tDCS (parallel design of cathodal or anodal tDCS vs sham tDCS) or occipital cathodal tDCS

Improvement in language training outcome after anodal tDCS up to 2 weeks; weaker effect after cathodal tDCS

Improvement in verbal fluency

Improvement in speech/language performance (naming accuracy) after cathodal tDCS applied to the left Broca’s area, but not after anodal tDCS applied to the left Broca’s area or after occipital cathodal tDCS

[43]

[51]

[46]

[34]

Perilesional region in the left posterior temporal cortex

20 min, five sessions Improvement in speech/language performance (reaction time) up to 3 weeks after (coupled with anomia treatment) anodal tDCS

[42]

[32]

Sham tDCS (cross-over Anodal, 1 mA design)

30 min, ten sessions Improvement in auditory verbal comprehension after cathodal tDCS (coupled with applied to the right superior temporal area conventional language therapy)

20 min, five sessions Improvement in language performance with training task (response accurancy) up to 2 months

[31]

Ref.

[33]

Cathodal or Sham tDCS (parallel group design: cathodal anodal, 2 mA [CP6] vs anodal [CP5] vs sham tDCS)


Results

20 min, five sessions Improvement in speech/language performance (naming accuracy) for 1 week (coupled with anomia treatment) after anodal tDCS.

Duration and number of sessions

20 min, five sessions Improvement in speech/language performance (naming accuracy and reaction time) up to 3 weeks after anodal tDCS

Right temporal excitation or inhibition

Vines et al. (2011)

Right frontal excitation

Monti et al. (2008)

Left frontal inhibition or excitation

Three chronic stroke (2–6 years after stroke): fluent aphasia

Fiori et al. (2011)

Stimulation polarity and intensity


Control condition

Left Wernicke’s area Sham tDCS (cross-over Anodal, 1 mA (TP5) design)

21 subacute stroke: global Left or right superior temporal aphasia area (CP5/CP6)

Left temporal excitation

You et al. (2011)

Right temporal inhibition or left temporal excitation

Ten chronic stroke (1–20 years after stroke): six fluent and four nonfluent aphasia

Left frontal cortex (according to fMRI maximal region of activation in a naming task)

Target

Baker et al. (2010)

Left frontal excitation

Study (year)

Table 2. Therapeutic studies using transcranial direct current stimulation in stroke patients with aphasia.


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Restoring the left hemisphere networks

In Broca’s aphasia, most conventional rTMS studies employed an inhibitory paradigm (low-frequency stimulation) for the stimulation of the contralesional right IFG (pars triangularis, BA 45) aiming to reduce right hemisphere hyperactivity and transcallosal inhibition exerted on the left Broca’s area [23,35–41] . The choice of this target has been corroborated by the stimulation of multiple nearby targets and the determination of the optimal site of stimulation to produce the best therapeutic response [23,37,39] . However, most studies concerned isolated clinical cases (up to six patients), largely redundant and issued from the same team, without any control condition [23,35–39] . These studies reported a beneficial effect of low-frequency rTMS delivered to the right equivalent of Broca’s area. Improvement of speech performance mainly consists of enhanced fluency in various naming tests and was found to last for several months beyond the time of stimulation. Two recent controlled rTMS trials gave further evidence of potential therapeutic benefit of low-frequency rTMS delivered to the right IFG in aphasic patients [40,41] . They enrolled at least ten patients and included a control condition, which was either a placebo stimulation with a sham coil [40] or an active stimulation delivered to a nonrelevant site (vertex) [41] . The first study showed improvement in speech/language performance on the picture-naming subtest of the Boston diagnostic aphasia exam (BDAE) and on picturenaming accuracy and latency in a standardized inventory test [40] . These effects were significant for at least 2 months following ten daily sessions of low-frequency 1 Hz inhibitory rTMS applied over the apical part of the right BA 45 in patients suffering from chronic nonfluent aphasia. The second study enrolled patients with different subtypes of aphasia (fluent, nonfluent and anomic aphasia) in the postacute phase [41] . The same rTMS protocol was used (ten daily sessions of low-frequency 1 Hz inhibitory rTMS applied over the apical part of the right BA 45), but according to an add-on design, in combination with speech therapy after each rTMS session. It showed positive effects on the Aachen aphasia test (AAT) that lasted for at least 2 weeks. A concomitant PET study revealed an activation shift toward the right hemisphere in the control group, but not in the study group, without any clear relationship between the extent of laterality shift and clinical improvement. These observations clearly open exciting perspectives for the use of inhibitory rTMS protocols delivered to the right IFG in the therapeutic m anagement of poststroke Broca’s aphasia. Two tDCS trials have used the same concept of inhibitory stimulation applied over the nondominant language hemisphere in patients suffering from global aphasia and anomia but their findings were not as consistent as those reported in rTMS st udies [42,43] . Instead of inhibiting the right hemisphere, two rTMS studies attempted to restore the left hemisphere networks and perilesional neuronal activity in the injured Broca’s area by applying excitatory rTMS protocols (either iTBS or high-frequency rTMS) on the left IFG of aphasic patients [30,44] . They showed favorable effects in patients with nonfluent aphasia. In the first study, iTBS trains were delivered under image-guided navigation to 978

the Broca’s area, which was located on functional MRI (fMRI) data [30] . Clinical improvement (increased fluency) was associated with concomitant fMRI changes showing a relative increase in the activity of the lesioned IFG, which was stimulated [30] . In the second study, a conventional excitatory high-frequency rTMS paradigm has been applied over the left dorsolateral prefrontal cortex (DLPFC), combined with speech therapy, in three nonfluent aphasic patients [44] . An improvement in object naming was observed after rTMS, which lasted over 48 weeks in two of the three patients [44] . However, the validity of DLPFC targeting, obtained without image-guided navigation, was questionable and these results may actually reflect the stimulation of Broca’s area. Indeed, the authors have shown in a depressed patient treated by rTMS using the standard procedure of left DLPFC targeting that an improvement in speech production could in fact reveal an unexpected stimulation of Broca’s area [45] . An excitatory protocol delivered on the affected left hemisphere was also produced using tDCS in three trials [31,32,46]. The method of cortical targeting and the type of enrolled patients differed between these trials, likely explaining some diverging results. First, Baker et al. defined their target according to a previous fMRI study, as the left frontal region of maximal activation during a naming task and included patients suffering from either fluent and nonfluent aphasia [31]. In their study, Marangolo et al. targeted the left IFG and included only nonfluent aphasics with apraxia of speech [32]. After five daily sessions of ipsilesional anodal tDCS coupled to language therapy, speech/language performance significantly improved for 1 week to 2 months [31,32]. By contrast, a single anodal tDCS session applied over the Broca’s area in nonfluent aphasic patients did not show significant beneficial effects [46]. According to the same concept as that used in Broca’s aphasia, four tDCS studies (but no rTMS studies) aimed to promote recovery from Wernicke’s aphasia by exciting the Wernicke’s area (left STG, TP5) [33,34,42] or inhibiting the contralesional right STG [42,43] . All of these studies concerned fluent aphasics. The studies based on an excitatory protocol delivered to the left STG supported the value of reactivating the damaged Wernicke’s area to promote functional recovery [33,34,42] . The inhibition of the right STG was found to be more effective than the excitation of the left STG in one study [42] but was ineffective in another study [43] . In their study, You et al. reported a randomized controlled tDCS trial with parallel-group design, comparing the respective effect of an excitatory protocol (anodal stimulation) delivered to the left STG versus an inhibitory protocol (cathodal stimulation) delivered to the right homologous of Wernicke’s area versus sham tDCS in a cohort of 21 global aphasic patients with subacute stroke [42] . Although all participants showed improvement in language performance and comprehension after the ten sessions coupled with conventional language therapy, cathodal tDCS applied over the right STG improved auditory comprehension better than any of the other conditions. These results support the notion that an inhibition of neural activities in the contralesional nondominant right hemisphere may reduce its transcallosal inhibition exerted on the lesioned dominant left hemisphere and thereby enhance functional recovery. Expert Rev. Neurother. 12(8), (2012)


Promoting compensatory action of the right hemisphere networks

As aforementioned, a strategy opposite to that previously described is to reinforce the compensatory action of the right hemisphere in aphasia recovery. Classically, the shift of language processing to the right hemisphere and the overactivation of right homolog structures to the areas normally involved in the left hemisphere are considered as a maladaptative response [47] or a temporary phenomenon during the poststroke recovery process [10,37,48,49]. However, the facilitating role that nondominant hemisphere areas may play in aphasia recovery has been clinically described by Barlow since the 19th century [50], especially when large parts of the dominant hemisphere are injured. This led to the concept of treating aphasia by applying either an excitatory NICS protocol (such as anodal tDCS) [43,51] on the contralesional right hemisphere or an inhibitory protocol (either low-frequency rTMS [52,53] or cathodal tDCS [46]) on the ipsilesional left hemisphere, especially in case of failure of recovery capacities in the left hemisphere. First, Kakuda et al. demonstrated the therapeutic efficacy of an inhibitory protocol (low-frequency rTMS) targeting the left or the right frontal lobe of patients with Broca’s aphasia contralateral to language-task induced fMRI activation [52] . The same team showed in two patients with fluent Wernicke’s aphasia that lowfrequency rTMS over the left STG could promote the unmasking of language abilities in the nondominant hemisphere and increase perilesional cortical activities [53] . However, the most convincing studies in favor of this theory of right-sided compensatory brain plasticity were based on tDCS trials. Two controlled studies with a crossover design have assessed an excitatory (anodal) tDCS of the right posterior IFG in six nonfluent aphasic patients [51] and of the right temporoparietal area in 12 anomic patients [43]. Vines et al. performed repeated tDCS sessions coupled to MIT [51], which is known to enhance right hemispheral processing and to promote recovery from aphasia [54], and a significant improvement in verbal fluency was observed following anodal tDCS of the right IFG. In the study of Flöel et al., the right temporoparietal cortex was targeted on the basis of fMRI activation data and tDCS was applied coupled to language training sessions [43]. The beneficial clinical impact was more pronounced for anodal (exciting) than cathodal (inhibiting) stimulation. Finally, one study showed a short-term improvement of patients with nonfluent aphasia following a single tDCS session applied to the left Broca’s area in case of inhibitory cathodal stimulation but not of excitatory anodal stimulation [46]. All of these results suggest a potential therapeutic effect of NICS in aphasia resulting from the enhancement of the compensatory action of the right hemisphere, by exciting it directly or by inhibiting the affected left hemisphere. However, the outcome of such a NICS strategy may be influenced by the size and localization of stroke lesions as also shown for conventional language therapy [23]. Further data obtained in controlled studies including larger series of patients are needed to confirm these results. Technical considerations

Differences in NICS technique may also influence the outcome and merit further discussion. Several studies used the international www.expert-reviews.com

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EEG 10–20 system to target the IFG (F7/8) in Broca’s aphasia or the STG (TP5/6) in Wernicke’s aphasia. This approach may be suitable for tDCS studies, since the stimulation area is relatively large with this technique. However, because of individual variability in cortical anatomy and the assumed importance of a focal stimulation of a dedicated target, the EEG 10–20 approach does not allow for a precise stimulation when rTMS is used [55] . Therefore, recent rTMS studies take into account the variability in brain anatomy and the data provided by fMRI in languagespecific task by using an image-guided navigation system, in particular to target different parts of the IFG [40,56] . This approach revealed that the inhibition of the pars triangularis but not of the pars opercularis of the right IFG could result in an increased picture naming in patients with chronic nonfluent aphasia [56] . In fact, the pars triangularis of the right IFG was shown to be the site providing the best rTMS response in various case series [23,37,39] . This suggests different roles of the various parts of the IFG during the cortical process of adaptation and reorganization in poststroke aphasia recovery as also suggested by a recent imaging study [11] . This latter study detailed poststroke perilesional and contralesional regions of activation in fluent and nonfluent aphasic patients compared to those observed in healthy volunteers to determine which cortical regions could be eligible as NICS targets for the treatment of aphasia [11] . Various studies employed a navigation system to target perilesional or homolog regions, based on fMRI activation induced by linguistic tasks, individual morphological MRI or brain atlas data [30,34,43,44,52] . The therapeutic benefit of such an individualized image-guided approach remains to be confirmed in large controlled studies. Expert commentary

Repetitive daily sessions of either inhibitory low-frequency rTMS of the contralesional right IFG or excitatory anodal tDCS of the perilesioned left IFG are promising techniques that may add to conventional speech therapy for promoting poststroke recovery from aphasia, more specifically the nonfluent type. These results support the concept of interhemispheric rivalry also for speech production – that is, the inhibition of the contralesional homolog region to Broca’s area can release the damaged area from inhibitory influences of the unaffected hemisphere. This can contribute to poststroke recovery by reactivating the networks of speech production in the dominant hemisphere. On the other hand, there is an increasing amount of data suggesting that the development of language abilities in the right nondominant hemisphere could have a compensatory action. This action can be promoted by excitatory NICS protocols applied on the unaffected right hemisphere. New developments in NICS techniques should allow the use of NICS, especially coupled to language therapy, to be c onsidered in the rehabilitation of aphasic patients in the near future. Five-year view

Dynamics of cortical plasticity and reorganization after brain injury in individuals are increasingly accessible to neuroimaging techniques. This is especially interesting to improve the reliability of image-guided NICS protocols, such as neuronavigated rTMS, 979

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for the recovery of aphasic patients. Other technical advances that could increase the efficacy of NICS protocols in stroke rehabilitation include the current development of focal procedures of transcranial electrical stimulation (high-definition tDCS) [57] and various protocols of priming [24,25]. Recently, in four patients with poststroke aphasia, a ‘priming’ procedure of high-frequency rTMS (6 Hz) has been applied to modulate the initial state of cortical excitability in order to enhance the effects of a subsequent lowfrequency rTMS applied to the right frontal lobe [58]. Another research perspective should be to perform comparative studies for determining whether it is better to reactivate the cortex in the perilesional area or to inhibit the overactive homolog region in the contralesional hemisphere, or on the contrary to promote this contralesional overactivity as a compensatory mechanism if there is no possibility of recovery in the left hemisphere. To address this

issue, it is necessary to take into account the localization of the lesion, and the different stages of cortical reorganization in the acute and postacute phases of stroke, according to the different types of aphasia. Finally, it will be important to consider a combined use of speech therapy or other rehabilitation methods with NICS as an add-on technique for future therapeutic applications in this disabling clinical condition. ‍Financial & competing interests disclosure

This review was supported by a research grant from the Prof. Schmidtmann Foundation in Marburg, Germany. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was used in the production of this manuscript.

Key issues • Repeated daily sessions (applied for 10 days) of focal inhibitory repetitive transcranial magnetic stimulation (rTMS; low-frequency stimulation around 1 Hz) delivered to the right inferior frontal gyrus (homolog to the lesioned left Broca’s area) provide significant improvement of speech performance in chronic stroke patients with nonfluent aphasia. • Such improvement can last for several weeks or months beyond the time of stimulation, opening perspectives for therapeutic applications in routine practice. • Similar improvement can be obtained by anodal transcranial direct current stimulation (tDCS) delivered to the perilesional area in the affected hemisphere. • Comparative studies are needed to assess the respective therapeutic effects on speech/language performance of excitatory protocols (anodal tDCS or high-frequency rTMS) delivered to perilesional Broca’s or Wernicke’s area or inhibitory protocols (low-frequency rTMS or cathodal tDCS) delivered to contralesional homolog regions. • Comparative studies are needed to assess the respective therapeutic effects on speech/language performance of reactivating the lesioned Broca’s or Wernicke’s area or promoting the compensatory action of the contralesional homologue regions. • The use of noninvasive cortical stimulation to promote the recovery of poststroke aphasia is feasible but will require further placebo-controlled studies in large cohorts of aphasic patients prior to being considered as a valuable technique in the therapeutic armamentarium for this disabling condition. J. Speech Hear. Res. 39(5), S27–S36 (1996).

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