This work constitutes the first study to investigate language lateralization in patients with TSC. We used a lexico-semantic decision task during MEG recording that allowed measurement of strong language cerebral activation in language-related areas that was expected from prior studies [24
]. Cerebral activation starts with an occipital activation measured around 115 ms, which is followed by a fusiform gyrus activation around 130 ms reflecting basic visual feature analysis. At this stage, written words are clearly distinguished from geometrical forms, faces or other objects, but there is no discrimination between words/nonwords and random consonant strings [26
]. At 175 ms post-stimuli presentation, a strong cerebral activation is measured in the basal temporal language area that would reflect the letter-string analysis. Some authors suggest that this region may support the transformation of written words into sounds, possibly involving phonological working memory [27
]. Finally, cerebral activations are consistently measured in Wernicke’s area (between 220 and 620 ms) and then in Broca’s area (between 250 and 620 ms). Wernicke’s area activation is associated with reading comprehension, including lexico-semantic aspects as well as phonological processing [28
]. Broca’s area activation is associated with semantic processing as well as graphophonological conversion of words that might reflect subvocal articulatory processes of the written word [29
Interestingly, we found decreased language laterality in our TSC patient sample. Data show that, among the 15 patients involved in this study, 11 patients (73.3%) with TSC have a left-hemisphere language dominance whereas the remaining four patients (26.7%) have a bilateral language representation. In the healthy adult population, 94–96% of individuals present left-hemisphere language dominance [30
]. However, when the left hemisphere has been injured or exposed to chronic deleterious episodes such as seizures, language function reorganization is likely to occur, especially when these events occur at a young age. Language functions can then be taken over by the right hemisphere or both hemispheres. There is an increase of aberrant brain circuits that support language functions in patients with cortical pathology [31
]. Consistent with this view, individuals with epilepsy show greater language dominance variety than healthy individuals characterized by higher percentages of non left-hemisphere language dominance in epileptic than non-epileptic populations [33
]. Atypical language patterns in lesional patients (for instance, brain tumor, vascular lesions) have also been reported [24
]. In the present study, atypical language representations are associated with the clinical presentation of TSC. Investigation of the relationships between language lateralization patterns in patients with TSC and tuber cerebral location as well as a history of epilepsy showed that patients with a bilateral language pattern tend to have more tubers in language-related areas than those with a left-hemisphere language dominance, and that TSC patients with history of epilepsy are significantly more prone to present a bilateral language pattern than TSC patients with no history of epilepsy. These results show that multiple factors, including cerebral abnormalities and history of epilepsy, may contribute to the inter-hemispheric cerebral language reorganization predisposing to a decrease of left-hemispheric language dominance in patients with TSC. In the present study, the sample size is small; a research project including more patients would confirm these findings. In future studies, a comparison with control groups including patients without epilepsy with other developmental lesions (e.g., tumors, vascular lesions) or non-lesional patients with epilepsy would help to better specify respective influence of cortical tubers and epileptogenic activity on functional language dominance in patients with TSC.
Previous studies showed that right-handed patients with epilepsy present left-hemisphere language dominance in 63 to 96% of cases, whereas only 48 to 75% of left-handed or ambidextrous patients with epilepsy present a left-hemisphere language dominance [35
]. In the present study, three out of fifteen participants (patients # 7, 11 and 13 in ) present a left-or bilateral-handedness, presuming a presence of abnormal language dominance in our sample. However, there is no clear correlation between atypical manual dominance and abnormal language pattern in our group. Anomalous manual and language dominances may have been induced by multiple causes, including cortical tubers and epileptogenic activity, which may have affected independently both functional representations. White matter abnormalities are often found in patients with TSC and may have also influenced anatomo-functional networks. A study including fiber tractography may help to explain the relationship between manual and language dominances in patients with TSC. For instance, tractography would allow for investigation of the intra-hemispheric language representation in patients presenting left-hemisphere language dominance and an atypical manual dominance. Our research group is currently analyzing diffusion tensor imaging data acquired in these patients in order to investigate the relationship between fiber track anomalies and tuber location, epilepsy history as well as language and manual dominances. We hope to publish these data in the near future.
Language laterality index calculation is threshold-dependent; therefore some would consider this a limitation [34
]. There is no consensus of procedures for determining the threshold. Here, we propose an objective method to obtain an appropriate threshold. A source amplitude threshold was set in each subject at half of the maximal source amplitude extracted from all ROIs. Thus, all sources with an amplitude equivalent or higher to the half of the maximal amplitude source value were included in the LI calculation. This provided an objective method for setting the detection threshold, which renders the laterality index calculation statistically robust.
In the present study, the sample of patients was small, and no comparison with standard invasive techniques such as intracarotid amobarbital injection (the Wada Test) or cortical electrostimulation mapping was made for validation of language dominance pattern. In further studies, using a protocol including multiple tasks would be helpful in order to assess multiple aspects of language functions, such as receptive and expressive language. Magnetoencephalography may also be used to better understand functional reorganization in patients with different cerebral pathologies such as epilepsy and TSC. Factors influencing atypical language representation have theoretical importance in understanding the organization and reorganization of higher cognitive functions and the underlying pathology as well as practical implications in some patients such as cognitive and language rehabilitation in individuals with acquired lesions (e.g., traumatic brain injury, tumors or strokes) as well as presurgical assessment of language function in candidates for epilepsy surgery. Functional connectivity measures using MEG and fMRI, both at rest and during activation, also are a new way to characterize the integrity of cortex. Combining functional connectivity and structural connectivity, or the human connectome, will in future studies lead to a better understanding of how tubers affect functional networks [37
]. In addition to language mapping, MEG has also been shown to be helpful for the localization of epileptic activity in patients with TSC who are candidates for epilepsy surgery [8
]. Inclusion of a MEG recording for localization and lateralization of epileptogenic zone as well as language functions in the presurgical assessment protocol of patients with TSC who are epilepsy surgery candidates may diminish the need for invasive procedures or at least help in choosing stimulation sites and reduce the number of intracranial electrodes used during invasive mapping.