Brain Advance Access originally published online on December 5, 2005
Brain 2006 129(2):346-351; doi:10.1093/brain/awh694
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Left hippocampal pathology is associated with atypical language lateralization in patients with focal epilepsy
Departments of 1 Epileptology and 2 Radiology, University of Bonn and 3 Department of Diagnostic and Therapeutic Neuroradiology, Medical Center Bonn, Bonn, Germany, 4 Academic Neurology Unit, Division of Genomic Medicine, University of Sheffield, Royal Hallamshire Hospital, Sheffield, UK and 5 F.C. Donders Center for Cognitive Neuroimaging and Department of Neurology, Radboud University Nijmegen, Nijmegen, The Netherlands
Correspondence to: Dr Bernd Weber, Department of Epileptology, Sigmund Freud Street 25, 53105 Bonn, Germany E-mail: Bernd.Weber{at}ukb.uni-bonn.de
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Summary |
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It is well recognized that the incidence of atypical language lateralization is increased in patients with focal epilepsy. The hypothesis that shifts in language dominance are particularly likely when epileptic lesions are located in close vicinity to the so-called language-eloquent areas rather than in more remote brain regions such as the hippocampus has been challenged by recent studies. This study was undertaken to assess the effect of lesions in different parts of the left hemisphere, lesions present during language acquisition, on language lateralization. We investigated 84 adult patients with drug-resistant focal epilepsy with structural lesions and 45 healthy control subjects with an established functional MRI language paradigm. Out of the 84 patients 43 had left hippocampal sclerosis, 13 a left frontal lobe lesion and 28 a left temporal-lateral lesion. All these lesions were likely to have been present during the first years of life during language acquisition. To assess the lateralization of cerebral language representation globally as well as regionally, we calculated lateralization indices derived from activations in four regions of interest (i.e. global, inferior frontal, temporo-parietal and remaining prefrontal). Patients with left hippocampal sclerosis showed less left lateralized language representations than all other groups of subjects (P < 0.005). This effect was independent of the factor of region, indicating that language lateralization was generally affected by a left hippocampal sclerosis. Patients with left frontal lobe or temporal-lateral lesions displayed the same left lateralization of language-related activations as the control subjects. Thus, the hippocampus seems to play an important role in the establishment of language dominance. Possible underlying mechanisms are discussed.
Key Words: fMRI; language; epilepsy; hippocampus
Abbreviations: AVM = arteriovenous malformation; DNT = dysembryoblastic neuroepithelial tumour; FCD = focal cortical dysplasia; FFE = fast field echo; fMRI = functional MRI; ROIs = regions of interest; TSE = turbo spin echo; TSE sequence = sagittal T1-weighted 3D gradient echo sequence
Received September 1, 2005. Revised October 10, 2005. Accepted October 24, 2005.
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Introduction |
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In
94% of healthy subjects language functions are strongly lateralized to the left (Springer et al., 1999
; Knecht et al., 2000), but early damage to the left hemisphere can result in atypical, i.e. bilateral or right-lateralized, representation of language (Rasmussen and Milner, 1977; Staudt et al., 2002). The mechanism underlying the higher incidence of atypical language dominance associated with left-hemispheric pathologies is not very well understood. Furthermore, the question of whether patients with lesions near classical language-related areas, i.e. Broca's or Wernicke's area, display a higher degree of atypical dominance than patients with lesions spatially separated from these areas is under debate (Knecht, 2004; Liegeois et al., 2004).
Initial evidence suggests that left temporal lobe pathology is more often associated with atypical language lateralization than left frontal pathology (Liegeois et al., 2004). This suggestion was derived from the localization of abnormalities within the left hemisphere detected by structural magnetic resonance imaging in ten children with intractable epilepsy. Five of the patients had lesions in the left inferior frontal region, while the other five patients had lesions in the left temporal lobe. None of the patients with inferior frontal lesions displayed language-related activation in the right hemisphere, while four out of the five patients with left temporal lobe lesions showed atypical language dominance leading to the hypothesis that lesions near classical language-related areas do not necessarily lead to a transhemispheric shift of language dominance but rather to a shift within the hemisphere to neighbouring regions. A different study based on 100 patients with temporal lobe epilepsy related to hippocampal sclerosis suggested that atypical language representation can not only be caused by temporal-lateral lesions adjacent to the so-called eloquent cortex (i.e. Wernicke's area), but also by damage to temporomedial structures (Janszky et al., 2003). While all 17 patients with right hippocampal lesions showed typical left-sided language dominance, 20 out of the 83 patients with left-sided lesions exhibited atypical language dominance. In that study language lateralization was determined by the intracarotid amobarbital procedure (Wada and Rasmussen, 1960). Although results of the Wada-test largely depend on the suppression of frontal functions, they cannot assess the lateralization of temporo-parietal and frontal language-related areas independently (Lehericy et al., 2000). In addition, the study by Janszky and co-workers examined patients with hippocampal sclerosis only and thus it could not reveal how its finding was specifically related to hippocampal lesions (Janszky et al., 2003).
Hence, two questions remain incompletely answered. Namely, are lesions close to classic language-related areas or are hippocampus lesions more likely to lead to a shift in language dominance and are frontal and temporo-parietal regions similarly involved in the displacement of language representations? To answer these questions we compared a group of 45 healthy control subjects and three groups of patients with epileptogenic lesions present during language acquisition in different brain regions of the left hemisphere (hippocampus, lateral temporal cortex, frontal lobe). Cortical representation of language was assessed by functional MRI (fMRI) with a behavioural paradigm with a semantic-perceptual contrast.
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Subjects and methods |
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Subjects
A total of 84 patients with drug-resistant epilepsy from our presurgical epilepsy programme and 45 healthy subjects were included in the study. All were native German speakers and had normal or fully corrected vision. Table 1 shows the lesion for each patient and Table 2 gives an overview of the demographic and clinical data. All patients in the hippocampal sclerosis group had either their first seizure or a complex febrile convulsion before the age of 2 years. The lesions in the other groups were either developmental (e.g. focal cortical dysplasias) or acquired perinatally (e.g. asphyxia during birth). Hence, all patients had neocortical lesions or hippocampus sclerosis or functional deficits of the left hippocampus leading to sclerosis during the time of language acquisition. Lesions were diagnosed by an expert neuroradiologist (H.U.). Written informed consent was obtained according to the Medical Ethics Committee of the University of Bonn in accordance with the Declaration of Helsinki (1991).
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Structural MRI
During presurgical evaluation, every patient underwent a standardized high-resolution MR-evaluation. MRI was performed on a 1.5 T scanner (Gyroscan NT-Intera, Philips Medical Systems, Best, Netherlands). The protocol included sagittal T1-weighted 3D gradient echo (FFE) sequence (slice thickness: 1 mm, repetition time (TR): 12 ms, echo time (TE): 3.6 ms), axial T2-weighted TSE sequence (slice thickness: 5 mm; interslice gap 1.0 mm; TR: 4849 ms; TE: 100 ms), axial FLAIR TSE sequence (slice thickness: 5 mm; interslice gap: 1 mm; inversion time 2000 ms; TR: 6000 ms; TE: 120 ms), coronal FLAIR TSE sequence (slice thickness: 3 mm; TI: 2000 ms; TR: 6000 ms; TE: 120 ms), coronal T2-weighted TSE sequence (slice thickness: 2 mm; TR: 4263 ms; TE: 100 ms) and coronal T1-weighted inversion recovery sequence (slice thickness: 5 mm; interslice gap: 1 mm; TI: 400 ms; TR: 3223 ms; TE: 14 ms). In patients with temporal lobe epilepsy, sequences were angulated perpendicularly or parallel to the longitudinal axis of the hippocampus.
Behavioural procedure
In the scanner, a series of item pairs, either word or consonant string pairs, were presented back-projected onto a translucent screen, which subjects viewed by way of a mirror. Both constituents of each pair were simultaneously presented for 4 s interleaved with the presentation of a central fixation cross for 0.2 s, above and below a central fixation cross. A semantic condition (synonym-judgement task) alternated with a perceptual condition (letter-matching task) every 25 s so that six item pairs were presented for each of 30 half-cycles. Hence, the behavioural experiment took 12.5 min in total.
The verbal stimuli were 180 common German nouns (5–11 letters), forming 45 pairs of words with identical or highly similar meanings (synonyms) and 45 pairs of semantically unrelated words. The consonant strings were developed pseudorandomly to represent 45 pairs of two identical strings and 45 pairs in which one letter was different between the two constituents. Strings were matched with words with regard to the number of letters. Subjects were required to push a button with the index finger of their right hand whenever they identified a pair of two synonyms or identical letter strings.
fMRI data acquisition
Sixteen axial slices with a matrix size of 64 x 64 and a field of view of 220 x 220 mm were collected at 1.5 T (Symphony, Siemens, Erlangen, Germany). We acquired 248 T2*-weighted, gradient echo EPI-scans including eight initial scans that were discarded to achieve steady-state magnetization with the following parameters: slice thickness, 6.0 mm; interslice gap, 0.6 mm; TR, 3.125 s; TE, 50 ms. In addition, we acquired a sagittal T1-weighted 3D-FLASH sequence with 120 slices (matrix size, 256 x 256; field of view, 230 x 230 mm; slice thickness, 1.5 mm (no interslice gap); TR, 11 ms; TE: 4 ms).
fMRI data analysis
MR images were processed using SPM99 (www.fil.ion.ucl.ac.uk/spm/) and the following steps were performed: (i) Realignment with 3D motion correction. (ii) Normalization onto the MNI atlas (Montreal Neurological Institute). (iii) Spatial smoothing with a 7 mm Gaussian kernel (full width at half maximum). (iv) Modelling of the expected haemodynamic responses (box-car regressor in a general linear model, GLM). This regressor was convolved with a canonical haemodynamic response function (hrf) to represent brain physiology. (v) Temporal filtering of the acquired time-series to reduce high- and low-frequency noise attributable to scanner drifts and physiological noise. (vi) Calculation of parameter estimates for each condition covariate from the least mean squares fit of the model to the data. (vii) Definition of the pre-experimentally planned effects of interest (synonym-judgement > letter-matching and letter-matching > synonym-judgement) and generation of contrast images for each subject and each effect of interest. To estimate global and regional lateralization indices, we performed an automated quantification of global and regional activation clusters as described previously (Fernández et al., 2001, 2003). We selected three regional regions of interest (ROIs): inferior frontal region, remaining prefrontal region and a temporo-parietal region. Overlay masks were generated with the same paradigm, but in an independent sample of 12 healthy control subjects (Fernández et al., 2001) from the averaged statistical parameter map with a region-growing algorithm starting from the local activation maximum. Adding mirror images so that a corresponding negative matched each positive X-coordinate generated the symmetric masks used. For the global laterality index, we masked the whole supratentorial brain, excluding three sagittal midline planes to minimize errors due to normalization discrepancies. For the calculation of the laterality index, we had to objectively adjust individual thresholds for the identification of activated pixels because of intersubject variability in general activation levels. This approach has been used in previous studies of language lateralization (Fernández et al., 2001, 2003) and showed high test–retest reliability as well as validity as compared with results obtained by the intracarotid amobarbital procedure (Wada and Rasmussen, 1960). Individual thresholding was achieved by first calculating a mean maximum t-value defined as the mean of those 5% of voxels showing the highest level of activation in each volume of interest (VOI) of both hemispheres. The threshold for inclusion in the calculation of the laterality index was then set at 50% of this mean maximum t-value. Finally, the sum of t-values of voxels with values above this threshold was entered into the formula used to produce weighted laterality indices (Fernández et al., 2001, 2003):
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Since laterality indices were not normally distributed, we applied the Mann–Whitney U-test when comparing the four groups of subjects.
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Results |
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Structural lesions
Table 1 gives an overview of the structural lesions in the different patient groups. All patients with left hippocampal sclerosis had their first seizure within the first year of life. Seven of those patients had a history of complex febrile convulsions. Of the patients with frontal lesions, five patients had cortical dysplasias, three had dysembryoblastic neuroepithelial tumours (DNT), two had lesions due to perinatal asphyxia, one a cavernoma, one a hamartoma and one had leucomalacia. The group of patients with temporal-lateral lesions consisted of seven patients with a ganglioglioma, six with a cavernoma, eight with cortical dysplasias, three with a DNT, two with lesions due to perinatal asphyxia, one with atrophy of the temporal lobe without sclerosis of the hippocampus and one with an arteriovenous malformation (AVM). All of these lesions were either developmental or acquired before the age of 2 years.
Behavioural performance
Reaction times and the number of correct trials are listed in Table 3. Patients and control subjects were able to solve the semantic task clearly above chance level (t = 16.96, P < 0.001). A MANOVA revealed significant differences in reaction times and performance (number of correct responses) for both the semantic and the perceptual control task between the control group and the patient groups (max P < 0.001; F = 10.273). However, we did not find any significant difference between the patient groups (min P = 0.153).
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Influences of lesion site on lateralization of language-related cortical activity
The mean laterality indices of patients with hippocampal sclerosis were significantly lower in all four regions of interest (i.e. less left lateralized) than of the patients with frontal or temporal-lateral lesions or the control group (Fig. 1). The mean global laterality index in the hippocampal sclerosis group was 0.36, and ranged in the other groups between 0.61 and 0.81, displaying a decrease in the mean laterality index of at least 0.25. Moreover, patients with a fully right-lateralized activation pattern (i.e. laterality index < –0.7) were only found in the hippocampal sclerosis group. Even after excluding these five extreme cases, the hippocampal group showed a significantly larger variance of the laterality indices than all other groups (inferior frontal: Z = 1.630, P < 0.05; temporo-parietal: Z = 1.446, P < 0.05; remaining prefrontal: Z = 1.389, P < 0.05; global: Z = 1.389, P = 0.052). The other patient groups and the control group did not differ significantly in their laterality indices in any of the regions of interest (min P = 0.212).
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A two-way ANOVA on lateralization indices with the within-subject factor region (inferior frontal region, remaining prefrontal region, temporo-parietal region, hemisphere) and the across-subject factor of group (hippocampal sclerosis, temporal-lateral lesion, frontal lobe lesion and control group) did not reveal a significant interaction between the factors region and group (F = 0.494, n.s.), indicating that frontal as well as temporo-parietal activations related to the semantic task were uniformly less left lateralized in the hippocampal sclerosis group than in the other groups.
Influences of clinical and demographic factors on laterality indices
A stepwise regression analysis was performed to determine the influence of clinical and demographic factors on the laterality indices in each region of interest. Only handedness displayed an influence on the laterality index in all four ROIs (standard coefficient: inferior frontal, 0.180; P < 0.05; temporo-parietal, 0.280; P < 0.005; remaining prefrontal, 0.314; P < 0.001; global, 0.252; P < 0.005). However, this effect cannot explain the differences in laterality indices between groups, because the groups did not differ significantly with respect to their handedness-scores (F = 1.546, P = 0.206, see Table 2). Moreover, the gender did not show any effect on the laterality indices in either of the ROIs (P = 0.311; 0.583; 0.224 and 0.382), nor age (P = 0.281; 0.337; 0.181 and 0.180).
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Discussion |
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Our results show that lesions of the left hippocampus are associated more frequently with atypical language dominance in inferior frontal as well as temporo-parietal language areas than neocortical lesions in left frontal or left temporal lobes. While our findings are in line with previous research (Janszky et al., 2003
; Liegeois et al., 2004) they provide new insights, because they show that the hippocampus but not the temporal lobe in general is the critical structure for language lateralization and that lateralization of both frontal and temporal aspects of cortical language representations are affected by left hippocampal lesions.
Liegeois and co-workers showed in a study of 10 children that interhemispheric shifts in language dominance are not so much associated with lesions found in close proximity to classical language-related areas but in the temporal lobe (Liegeois et al., 2004). However, the small sample size makes it difficult to generalize these findings, especially since the lesions outside language-related areas were spatially distributed and not due to a single type of pathology. The large group of adult patients with well-described lesions examined here enables us to confirm and extend the results of previous studies in that it identifies left hippocampal lesions as particularly relevant to atypical language dominance. This observation is in keeping with a study by Janszky and co-workers who showed in patients with left hippocampal sclerosis that epileptic activity, i.e. the quantity of seizures and count of epileptic discharges in the EEG, corresponded to a higher degree of atypical language dominance as measured by the Wada-test (Janszky et al., 2003). An important constraint of the Wada-test is, however, that it can only examine the function of a whole hemisphere, which makes it impossible to discern the localization of different language-related areas, whose laterality may be affected in different ways by pathological processes in the dominant hemisphere. Our fMRI study confirms that hippocampal sclerosis is associated with an increase in the displacement of all language-related areas to the right hemisphere and demonstrates that this displacement is not seen with temporal-lateral or frontal lesions, which were not included in the previous study.
Medial temporal lobe epilepsy due to hippocampal sclerosis is the most common diagnosis in epilepsy surgery programmes. Although patients with hippocampal sclerosis can become seizure-free with antiepileptic drug therapy, 75% of patients become medically intractable during the course of their disease (Spencer, 2002; Wieser and ILAE Commission on Neurosurgery of Epilepsy, 2004). This high degree of intractability indicates that this is a particularly severe focal epilepsy syndrome which may be more closely related to disturbances of cortical function than other forms of focal epilepsy. Interictal discharges have been shown to be correlated to neuropsychological deficits (Aldenkamp and Arends, 2004). To our knowledge a direct comparison of the amount of interictal epileptiform activity associated with different cortical lesions has not been performed. However, several studies revealed that medial temporal lobe epilepsy shows a higher frequency of interictal discharges than other focal lesions (Hamer et al., 1999; Stuve et al., 2001; Pfander et al., 2002). Since epileptic activity may lead to a stronger involvement of the otherwise non-dominant hemisphere in language functions (Regard et al., 1994), this may explain the higher degree of atypical language dominance in left medial temporal lobe epilepsy patients compared with other focal left-hemispheric epilepsies.
The hippocampus represents higher-order associative cortex and thus it is integrated into different cognitive systems by multiple reciprocal connections (Squire and Zola-Morgan, 1991; Eichenbaum et al., 1996). This means that functional disturbances originating in the hippocampus can spread readily throughout the ipsilateral hemisphere as shown e.g. by glucose-hypometabolism outside of the temporal lobe in patients with hippocampal lesions (Hammers et al., 2001). This may also explain why patients with hippocampal sclerosis show not only memory deficits but also a variety of other cognitive impairments not directly linked to the temporal lobe (Elger et al., 2004; Wieser and ILAE Commission on Neurosurgery of Epilepsy, 2004). Moreover, deficits in these cognitive functions (especially those involving the frontal lobe), tend to improve after successful epilepsy surgery suggesting a functional disturbance of the whole hemisphere due to epileptic activity originating in the hippocampus (Elger et al., 2004). Hence, our findings may be explained by a more intense and widespread effect of a hippocampal than of a neocortical focus. It could be a consequence of such remote effects that right hemispheric homologues of eloquent language areas take over certain language function in patients with left hippocampal sclerosis more than in those with left neocortical lesion.
However, there may be another explanation for our results (Knecht, 2004). To date, it remains unclear to what extent medial temporal lobe structures are involved in language acquisition. Some studies have found that hippocampal integrity is a prerequisite for the acquisition of language (DeLong and Heinz, 1997; Gross et al., 1998), and others have found evidence for a semantic memory system independent of the medial temporal lobe (Vargha-Khadem et al., 1997). A model describing the acquisition of a mental lexicon during language development has proposed a contribution of the hippocampus in this mnemonic task (Ullman, 2004). Under normal conditions the left hippocampus may interact with neocortical language areas in the left hemisphere during language development (Dehaene-Lambertz et al., 2002; Opitz and Friederici, 2003). Hence, one could hypothesize that in case of left hippocampal damage prior to or during language acquisition the right hippocampus would play a more prominent role. As a consequence of this transhemispheric shift in hippocampal contributions, right homologues of typically left-hemispheric language areas may get involved in language operations relevant for a semantic task as used here. This involvement may be true not only for the acquisition of lexical semantics but also for the development and learning of grammatical rules which have been shown to rely on intrahemispheric fronto–temporal interactions (Dehaene-Lambertz et al., 2002).
In conclusion, our data provide evidence for the critical role of the left hippocampus in the determination of language dominance. Further prospective studies are required to determine whether the hippocampus is really important for the acquisition of language thereby determining language dominance or whether the atypical language dominance observed in this study was caused by ongoing epileptic activity.
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