Diffuse cerebral language representation in tuberous sclerosis complex

Abstract

Introduction: Tuberous sclerosis complex (TSC) is a multisystem genetic disorder affecting multiple organs, including the brain, and very often associated with epileptic activity. Language acquisition and development seems to be altered in a significant proportion of patients with TSC. In the present study, we used magnetoencephalography (MEG) to investigate spatiotemporal cerebral language processing in subjects with TSC and epilepsy during a reading semantic decision task, compared to healthy control participants.

Methods: Fifteen patients with TSC and 31 healthy subjects performed a lexico-semantic decision task during MEG recording. Minimum-norm estimates (MNE) were computed allowing identification of cerebral generators of language evoked fields (EF) in each subject.

Results: Source analysis of the language EF demonstrated early bilateral medial occipital activation (125ms) followed by a fusiform gyrus activation around 135ms. At 270ms post stimuli presentation, a strong cerebral activation was recorded in the left basal temporal language area. Finally, cerebral activations were measured in Wernicke's area followed by Broca's area. The healthy control group showed larger and earlier language activations in Broca and Wernicke's areas compared to TSC patients. Moreover, cerebral activation from Broca's area was greater than activation from Wernicke's area in both groups, but this difference between anterior and posterior regions was smaller in the TSC group. Finally, the activation latency difference between Broca and Wernicke's areas was greater in healthy controls than in TSC patients, which shows that activations in these areas are more serial in control subjects compared to TSC patients in whom activations occur more simultaneously.

Conclusions: This is the first study to investigate cerebral language pattern in patients with TSC. Compared to healthy controls, atypical neuromagnetic language responses may reflect cerebral reorganization in these patients in response to early epileptogenic activity or presence at birth of multiple brain lesions.

Figure 1

Diagram of the expected brain sequence of language processing during a reading semantic decision task in healthy adults. A primary visual activity is recorded over bilateral median occipital regions (between 100 and 125ms) followed by a fusiform gyrus activation (around 200ms). A basal temporal language area response is then recorded around 270ms) likely reflecting letter-string analysis and pre-lexical processing. Finally, Wernicke’s and Broca’s Areas activations appears (from 300ms until 450–500ms), showing specific language processing. The rending of the brain shows the regions of interest of the anterior (Broca’s area) and posterior (Wernicke’s area) language areas involved in language processing. We used these regions of interest in our analysis described in this paper.

Figure 2

Waveforms recorded through time from a gradiometer, each located over a region of interest (occipital cortex, basal temporal language area (BTLA), Wernicke’s and Broca’s areas), in a healthy control participant. Subject’s left hemisphere, scalp (in gray) and MEG helmet (in blue) 3D reconstructions are shown. Cerebral response starts with (a) an occipital activation measured around 125ms after words onset, followed by (b) a left BTLA activation occurring around 270ms post stimulus onset. Subsequent activation appears in (c) Wernicke’s Area around 325ms, and is later accompanied by (d) a Broca’s Area activation (around 365ms). These time points were selected in order to correspond to the dSPM statistic maps shown on Figure 3.

Figure 3

dSPM statistic maps of typical cerebral activations through time in a healthy control participant (same subject than shown on Figure 2) in response to a visual semantic decision task. Cerebral response starts with (a) a bilateral median occipital activation measured around 125ms after words onset, followed by (b) a strong left basal temporal language area activation occurring around 270ms post stimulus onset. Subsequent activation appears in (c) Wernicke’s Area between 310 and 430ms, and is later accompanied by (d) a Broca’s Area activation (between 330 and 440ms). Two regions of interest (ROIs) were manually defined on each hemisphere, including posterior (Wernicke’s) and anterior (Broca’s) areas, and are shown in green under these areas’ labels (top left). Scalp topographies corresponding to the four cerebral activation time points are also shown below cerebral maps.

Figure 4

Grand averaged MNE waveforms measured in left (red line) and right (blue line) anterior ROIs of (a) TSC and (b) control groups as well as in left (red line) and right (blue line) posterior ROIs of (c) TSC and (d) control groups between 0 and 2000ms. On each graph, the green horizontal line labeled “Stimulus ON” shows stimulus duration. The amplitude scale is not equal between both groups, in order to preserve dynamic range in each group. For both groups, a strong cerebral response to words is recorded in both ROIs and hemispheres. Healthy control group showed larger and more sustained language activation in both ROIs and hemispheres compared to TSC group.