Brief communicationA proposed regional hierarchy in recovery of post-stroke aphasia
Introduction
Functional recovery after focal brain lesions is dependent on the adaptive plasticity of the cerebral cortex and of the non-affected elements of the functional network. For the motor system it has been convincingly demonstrated that after cortical injury the adjacent spared cortical tissue as well as more remote cortical areas are altered resulting in a functionally modified network (Nudo, 1999). Small lesions in the somatosensory cortex lead to changes of excitability due to downregulation of GABAA-receptors and upregistration of NMDA-receptors (Qü, Mittmann, Luhmann, Schleicher, & Zilles, 1998) in remote brain areas and these changes in both excitatory and inhibitory neurotransmission may be part of an adaptive process involved in functional reorganization (Witte et al., 1997). As a consequence, newly learned movements after focal cortical injury are represented over larger cortical territories (Fridman et al., 2004, Nudo and Milliken, 1996), an effect which is dependent on the intensity of rehabilitative training (Nudo, Wise, SiFuentes, & Milliken, 1996). Along with these changes in excitatory and inhibitory neurotransmitter systems,widespread structural changes with dendritic sprouting and synapse formation take place not only in spared regions of the damaged hemisphere, but also in the sensorimotor cortex of the hemisphere contralateral to the injury (Carmichael and Chesselet, 2002, Kozlowski and Schallert, 1998, Stroemer et al., 1995).
One could speculate that the change in excitability in adjacent and contralateral homotopic regions of a cortical lesion is a consequence of reduced collateral (i.e., in ipsilateral perilesional regions) and transcallosal (i.e., in contralateral homotopic regions) inhibition. For the specialization of different brain areas for definite functions and for the lateralization of higher functions, the neurons involved in the special tasks must inhibit neurons in neighbouring areas and those parts of the bilateral network which are not participating in this performance (Netz, Ziemann, & Homberg, 1995). These mechanisms may play a role in the development of localized and asymmetric lateralized function: anatomical studies in human brains (Aboitiz, 1992) and comparative studies in the developing rat and human brain (Galaburda, Rosen, & Sherman, 1990) have indicated a reduction of neurons and in callosal fibres. The loss of nerve cells could be caused by selective neuronal degeneration (apoptosis) adapting the neuronal population to the functional requirements of the projection field (Cowan, Fawcett, O’Leary, & Stanfield, 1984). It was also convincingly demonstrated by functional studies in healthy volunteers, that these specialized areas inhibit neighbouring regions and (even contralateral) brain regions connected by fibre pathways (Chen et al., 2003, Ferbert et al., 1992, Gilio et al., 2003, Innocenti, 1994, Lang et al., 2004, Netz et al., 1995, Trompetto et al., 2004). Recent rTMS studies gave evidence that unilateral stroke lesions indeed reduce transcallosal inhibition (Shimizu et al., 2002). The unaffected hemisphere may actually inhibit the generation of a voluntary movement by the paretic hand (Duque et al., 2005, Murase et al., 2004): the abnormally high interhemispheric inhibitory drive from the intact to the lesioned hemisphere may lead to improved motor performance of the affected limb after stimulation of the intact M1 region.
In contrast to the motor system, where our knowledge on the interaction of various brain regions mainly is based on animal experiments, studies on the functional network for language cannot rely on findings in animal models but must be based on studies in healthy volunteers or in patients with defined brain lesion. However, this may change in the future, since new evidence, both from research in non-human primates and from functional imaging studies in man, indicates a distributed system with two functionally different projections responsible for auditory processing in animals and speech perception in man (Wise, 2003). The mechanisms controlling recovery might therefore depend not only on the specifics of function (i.e., language or motor performance) but also on the underlying anatomical connectivity. Compared to the motor system, where function is symmetrically represented in both hemispheres—with a dominance for handedness and skills in a high percentage of the population in the left—language function is extremely lateralized in the majority of adults regardless of hand preference to the left hemisphere. It is still a matter of dispute if hemispheric language lateralization (Selnes, 2000) is predefined or evolves gradually during the early years of development. In any instance it seems to be advantageous to suppress mirror activity in the contralateral hemisphere during language production, and studies in humans have provided evidence of an inhibitory role of the corpus callosum in language relevant cortical areas (Karbe, Herholz, Halber, & Heiss, 1998). A further topological specialization represents the various components of language comprehension and production, with the classical core regions (Broca’s and Wernicke’s areas) defined over a century ago as well as many other ipsi- and contralateral areas including the cerebellum, all contributing to the complex function of language (Price, 2000, Stowe et al., 2005).
rTMS is a non-invasive procedure to create electric currents in discrete brain areas (Pascual-Leone, Davey, Wassermann, Rothwell, & Puri, 2002) which depending on frequency, intensity, and duration can lead to transient increases and decreases in excitability of the affected cortex. Low frequencies of rTMS (below 5 Hz) can suppress excitability of the cortex, while higher frequency stimulation (5–20 Hz) leads to an increase in cortical excitability (Kobayashi & Pascual-Leone, 2003). As in the motor system (Chen et al., 1997) it can also be applied to identify the various areas involved in language processing and production by a selective disturbance of partial function with low frequency rTMS. Most frequently rTMS is used in the so-called “lesion mode” to interfere with normal brain function. In our studies cited below rTMS was applied with 4 Hz at resting motor threshold for 10–30 s. These parameter settings were chosen because Wassermann (2002) has shown that 4 Hz is the lowest frequency which consistently interferes with language function and simultaneously minimizes the risk of inducing seizures.
Increases in relative cerebral blood volume in contralateral homologous language regions during overt propositional speech fMRI in chronic, non-fluent aphasia patients indicated overactivation of right language homologues (Naeser et al., 2004). This right hemisphere overactivation may represent a maladaptive strategy, as suggested previously by Belin et al. (1996) and Rosen et al. (2000) in their studies with chronic, non-fluent aphasia patients. This overactivation in the right hemisphere homologous language areas during overt propositional speech can be interpreted as a result of decreased transcallosal inhibition due to damage of the specialized and lateralized speech areas. Recent TMS studies by Martin et al. (2004) and Naeser et al. (2005) have reported improved picture naming ability in chronic non-fluent aphasia patients following a series of 10, 20-min, 1 Hz rTMS sessions to suppress a portion of the right pars triangularis area in the right Broca’s area. Picture naming ability was significantly improved at 2 months following 10, 20-min rTMS sessions (90% of motor threshold). The authors hypothesized that suppression of the right pars triangularis modulated the bi-hemispheric neural network for naming, resulting in improved picture naming after the rTMS treatment series.
Both types of inhibition—collateral ipsilateral and transcallosal contralateral—can be demonstrated by simultaneous rTMS and PET activation studies (Thiel, Schumacher, et al., xxxx). In six normal male volunteers the Broca area, as defined by maximal activation during verb generation in the left inferior frontal gyrus was stimulated by rTMS (4 Hz at resting motor threshold for 30 s) to interfere with normal language function. Interference with language function (positive TMS-effect) is usually classified into three types on the behavioural level: (1) No response to the stimulus (e.g., no verb generated to a presented noun). (2) Wrong response to the stimulus (e.g., a verb is generated which is not semantically related to the presented noun). (3) The reaction time latency to the stimulus is changed (e.g., faster response means facilitation, slower response means inhibition). At rest, rTMS decreased blood flow ipsilateral and contralateral. During verb generation, rCBF was decreased during rTMS ipsilateral under the coil, but increased ipsilateral outside the coil and in the contralateral homologous area. The effect of rTMS was accompanied by a prolongation of reaction time latencies to verbal stimuli.
Section snippets
Recovery of post-stroke aphasia
Changes in the interaction within the functional network of language are important for the recovery from aphasia after stroke. Stroke is the most frequent cause of aphasia (Wade, Hewer, David, & Enderby, 1986), and its prognosis depends mainly on the localization and the extent of the ischemic lesion in the dominant hemisphere (Naeser & Palumbo, 1994). However, clinical and neuroimaging studies of non-fluent aphasic patients suggest that quality of improvement is dependent on undamaged portions
Language function in brain tumours
The speed of the development of a brain lesion may have an effect on the functional impairment and on the mechanisms of compensation and reorganization of the involved networks. In a study on 61 patients with tumours in the dominant left hemisphere (Thiel et al., 2001) a verb generation paradigm not only increased flow in the left IFG (Brodman 44 and 55), both superior temporal gyri and the cerebellum (the pattern observed in the control group), but additionally in the left frontal medial gyrus
Hierarchical organization for recovery?
The different dynamics of recovery of language function observed in patients after stroke and with tumours in the left hemisphere suggest various mechanisms for compensation of the lesion within the functional network. Despite the limited number of longitudinal studies, the heterogeneity with respect to type of aphasia in the patients included and the differences among the activation and stimulation paradigms, a hierarchy for effective recovery might be deduced from these data:
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Acknowledgments
This study was supported by the Marga and Walter Boll-Foundation.
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