Atypical language lateralisation associated with right fronto-temporal grey matter increases — a combined fMRI and VBM study in left-sided mesial temporal lobe epilepsy patients

NeuroImage 59 (2012) 728–737

Contents lists available at ScienceDirect

NeuroImage j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / y n i m g

Atypical language lateralisation associated with right fronto-temporal grey matter increases — a combined fMRI and VBM study in left-sided mesial temporal lobe epilepsy patients Kirsten Labudda a, b, Markus Mertens a, Jozsef Janszky c, Christian G. Bien a, Friedrich G. Woermann a,⁎ a b c

Mara Hospital, Bethel Epilepsy Center, Bielefeld, Germany Department of Clinical Psychology and Psychotherapy, University of Bielefeld, Germany Department of Neurology, University of Pecs, Hungary

a r t i c l e

i n f o

Article history: Received 6 April 2011 Revised 9 June 2011 Accepted 18 July 2011 Available online 2 August 2011 Keywords: Grey matter Hippocampal sclerosis Broca's area Heschl's gyri Reorganisation

a b s t r a c t By combining language functional magnetic resonance imaging and voxel-based morphometry in patients with left-sided mesial temporal lobe epilepsy and hippocampal sclerosis, we studied whether atypical language dominance is associated with temporal and/or extratemporal cortical changes. Using verbal fluency functional magnetic resonance imaging for language lateralisation, we identified 20 patients with left-sided mesial temporal lobe epilepsy with hippocampal sclerosis and atypical language lateralisation. These patients were compared with a group of 20 matched left-sided mesial temporal lobe epilepsy patients who had typical language lateralisation. Using T1-weighted 3D images of all patients and voxel-based morphometry, we compared grey matter volumes between the groups of patients. We also correlated grey matter volumes with the degree of atypical language activation. Patients with atypical language lateralisation had increases of grey matter volumes, mainly within right-sided temporo-lateral cortex (x = 59, y = − 16, z = − 1, T = 6.36, p b .001 corrected), and less significantly within frontal brain regions compared to patients with typical language lateralisation. The degree of atypical fronto-temporal language activation (measured by lateralisation indices and relative functional magnetic resonance imaging activity) was correlated with right-sided temporal and frontal grey matter volumes. Patients with atypical language lateralisation did not differ in terms of language performance from patients with typical language dominance. Atypical language lateralisation in patients with left-sided mesial temporal lobe epilepsy was associated with increased grey matter volume within the nonepileptic right temporal and frontal lobe. Grey matter increases associated with atypical language might represent morphological changes underlying functional reorganisation of the language network. This hardwired reorganised atypical language network seems to be suitable to support language functions. © 2011 Elsevier Inc. All rights reserved.

Introduction Language lateralisation in patients with epilepsy differs from what is known in the normal population (Springer et al., 1999). Atypical, i.e. bilateral or right-sided representations of language are more frequent in patients with epilepsy and seemed to be associated with left-sided seizure origin, an early age of onset, left handedness, and a lesion in the vicinity of primary language areas of Broca and Wernicke (Woermann et al., 2003). Even the presence of an epileptogenic lesion remote from primary language areas, like hippocampal sclerosis (HS) has an impact on language dominance. Mesial temporal lobe epilepsy (TLE) patients with HS are more likely to have atypical language organisation compared to TLE patients without HS (Janszky et al., 2003; ⁎ Corresponding author at: MRI Unit, Bethel Epilepsy Center, Mara Hospital, Maraweg 21, 33517 Bielefeld, Germany. Fax: + 49 521 772 777 62. E-mail address: [email protected] (F.G. Woermann). 1053-8119/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.neuroimage.2011.07.053

Maccotta et al., 2007; Richardson et al., 2003; Weber et al., 2006). In TLE patients with HS, interictal epileptic activity propagating to the ipsilateral neocortex and measured by surface EEG, has been associated with atypical language dominance. In those patients, higher frequencies of left-sided spikes representing a more widespread epileptic network were linked to a shift of language representation from left to right (Janszky et al., 2003, 2006). A direct role of the diseased hippocampus within reorganising language networks of TLE patients has been proposed by Liégeois et al. (2004) and is also discussed by Weber et al. (2006). Studies investigating the morphological correlates of atypical language representation in epilepsy patients are rare. In a study of GM volume changes in epilepsy patients, Foundas et al. (1996) reported a rightward asymmetry of the pars triangularis of the frontal operculum in a single TLE patient with right-sided language lateralisation. Manually measuring the volume of the planum temporale, Oh and Koh (2009) showed a rightward volume asymmetry in 7/10 patients

K. Labudda et al. / NeuroImage 59 (2012) 728–737

with atypical language representation. In contrast, Dorsaint-Pierre et al. (2006) found leftward asymmetries in the planum temporale and in Heschl's gyri in patients with poorly characterised epilepsy independent of language lateralisation. It remained unclear whether atypical language lateralisation and associated morphological brain changes are a phenomenon of left-sided TLE. In the current study, we addressed the question whether in patients with left-sided TLE and HS atypical language dominance is associated with hippocampal and extrahippocampal changes in grey matter (GM) volume measured using voxel-based morphometry (VBM). We hypothesised volume changes within language-associated regions such as the inferior frontal gyrus and the lateral temporal lobe. In patients with atypical language organisation, we hypothesised fronto-temporo-lateral decreases of GM in the left hemisphere and volume increases within in the right hemisphere. Based on the results of Liégeois et al. (2004) and Weber et al. (2006), we also hypothesised that patients with left-sided TLE and atypical language dominance had more GM volumes within the right hippocampus compared to patients with typical language representation.

729

Table 1 Sociodemographic, epilepsy-related and neuropsychological data of the two patient groups. Typical (n = 20)

Atypical (n = 20)

Statistics

Mean (SD)

Mean (SD)

Sex

13 ♀, 7 ♂

11 ♀, 9 ♂

Handedness

2 left, 1 ambidextrous, 17 right 39.60 (9.37) 11.48 (9.22) 28.13 (13.50)

4 left, 16 right

Chi2 = 1.21, p = .55 Chi2 b .68, p N .40

32.75 (12.59) 10.44 (11.39) 22.31 (11.62)

t = 1.95, p = .06 t = .32, p = .75 t = 1.46, p = .15

5.35 (4.45)

5.41 (6.24)

t = −.04, p = .97

9.60 (0.94)

9.90 (1.62)

t = −.72, p = .48

95.67 (8.98) 46.25 (10.04)

92.54 (11.27) 43.55 (11.32)

t = .76, p = .45 t = .80, p = .43

− 0.51 (0.16)

0.09 (0.21)

t = − 10.20, p b .001

Age at MRI scan Age of onset Epilepsy duration (years) Seizure frequency (per month) Years of education IQ (MWT-B) Verbal Fluency (t-score) Lateralisation index

Material and methods Subjects From our presurgical evaluation programme, we investigated 40 patients with left-sided mesial TLE. Only patients with unilateral HS and no extrahippocampal/-temporal changes on visual inspection of high resolution magnetic resonance imaging (MRI) were included. MR characteristics of unilateral HS were clear cut unilateral hippocampal atrophy and increased hippocampal T2 signal intensity; bilaterality was excluded using hippocampal T2 relaxometry (Woermann et al., 1998). Bilateral interictal and ictal EEG changes were further exclusion criteria. We consecutively included 20 patients with atypical language lateralisation (see below) who were investigated in the context of the presurgical programme of Mara hospital with a verbal fluency functional magnetic resonance imaging (fMRI) task (Woermann et al., 2003). Twenty patients with left-sided TLE with HS and with typical language lateralisation served as a matched patient control group. We used the following inclusion criteria in order to match the typical patients with the atypical patients: presence of unilateral left-sided temporal lobe epilepsy defined by unilateral EEG patterns. Presence of unilateral HS and absence of extratemporal lesions, gender and age. Outside the scanner verbal intelligence was measured using the MWT-B (Mehrfachwahl-Wortschatztest, the German version of the National Adult Reading Test, Lehrl et al., 1991) and phonematic verbal fluency performance was assessed with a German standardised word generation task (Regensburger Wortflüssigkeitstest, Aschenbrenner et al., 2000). Table 1 summarises the patient groups' characteristics and the neuropsychological performance. In this retrospective study, MRI, fMRI and neuropsychological testing were part of the approved presurgical evaluation programme. All patients gave written informed consent prior to these investigations and agreed that their data were used for research purposes. Data acquisition High-resolution anatomical images of the whole brain were obtained on a 1.5 T scanner (Siemens Magnetom Symphony, Erlangen, Germany) equipped with a standard head coil and with echo planar imaging (EPI) capability. Image analysis was performed on a Linux Workstation using Matlab 7.5 (The Mathworks Inc., Natick, MA, USA) and SPM5 software (Wellcome Trust Centre for Neuroimaging, London, UK; http://www.fil.ion.ucl.ac.uk/spm/). Subsequent statistical analyses were performed on a Windows PC using PASW Statistics 18 (SPSS Inc., Chicago, IL, USA).

fMRI To assess language lateralisation, we used a blocked verbal fluency fMRI task (see Woermann et al., 2003). This task consists of two conditions (phonematic word generation and rest) each having 10 blocks of 30 s duration. Before starting the fMRI, subjects were instructed to generate words silently (i.e. without moving the lips) beginning with the given letter for 30 s. Before scanning, a brief training session was conducted with each patient to assure compliance with the task instructions. During scanning, the letters were given verbally via the intercom at the beginning of each block. Each block ends with the spoken command “stop” signalling the subject to stop generating words and listening to the scanner's noise for the next 30 s. We contrasted 100 sets of images sampled during the 10 blocks of covert word generation with 100 sets of images from the 10 rest blocks in each patient. 16 T2*-weighted slices with a thickness of 5 mm were sampled at intervals of 3 s using a standard EPI sequence (TR = 1600 ms, TE = 50 ms, flip angle 90°, field of view [FOV] 128 mm, matrix 64 × 64). The axial T2*-weighted images were aligned to the AC-PC line. To allow for T1 saturation effects, the EPI sequence started with two images that were immediately discarded. The images of the subsequent experiment were processed using SPM5. To correct for head movements, the images were first realigned using the SPM5 default algorithm. EPI images were resampled at a resolution of 2 × 2 × 2 mm. Prior to smoothing and group comparisons, anatomical differences were compensated for by spatial normalisation and reslicing using the SPM5 default settings and the standard stereotactic space, i.e. the MNI (Montreal Neurological Institute) brain. The EPI images were realigned to the first functional image to correct for head movement. Then spatial smoothing was applied with a Gaussian kernel of 8 mm full-width at half-maximum (FWHM) to increase signal and anatomical conformity. Based on individual contrast images, a random effects analysis was conducted to reflect language associated fMRI activation (verbal fluency N rest). We conducted a one sample t-test for each group and a two sample t-test to compare differences in activation between both patient groups. All fMRI analyses were FWE corrected for multiple comparisons (p b .05, minimal cluster size k = 30) using age as covariate of no interest. Lateralisation index In order to assess individual language lateralisation, we took activated voxels within a specific region of interest (ROI) into account.

730

K. Labudda et al. / NeuroImage 59 (2012) 728–737

The ROI was defined as volume of both frontal and temporal lobes. Lateralisation indices (LI) for each subject were calculated: LI = ðactivated voxels ½right – leftÞ = ðsum of all activated voxelsÞ The LIs have been calculated with an adaptive thresholding algorithm for frontal and temporal lobes (Wilke and Lidzba, 2007). This adaptive thresholding algorithm was chosen because it provides robust calculations. The LI ranged from −1 to +1. Patients classified as having typical language organisation had LIs b − 0.2. Patients classified as having atypical lateralised language representation had LIs ≥ − 0.2 (Springer et al., 1999). We also conducted a group comparison of fMRI language activations between all patients with atypical language lateralisation and with typical lateralisation. Voxel-based morphometry A T1-weighted 3D sequence (MPRAGE, TR = 11.1 ms, TE = 4.3 ms, slice thickness 1.5 mm, FOV 201 × 230 mm, matrix 224 × 256) covering the whole brain was obtained from all subjects. The present study employed the VBM5 toolbox (Gaser, http://dbm. neuro.uni-jena.de/vbm) which utilises the unified segmentation approach implemented in SPM5 (Ashburner and Friston, 2005). The images were resampled at a resolution of 1 × 1 × 1 mm, normalised to the SPM standard template, bias field corrected, and automatically segmented. The VBM5 toolbox extends the unified segmentation approach as it increases the quality of segmentation by applying a hidden Markov Field (HMRF) on the segmented tissue. This procedure removes isolated voxels that are unlikely to belong to the tissue class to which they have been assigned initially, thereby minimising noise effects. The T1-weighted 3D-images of all subjects were segmented into GM, white matter and cerebrospinal fluid (CSF). The final tissue maps were modulated with the Jacobian determinants of the deformation parameters obtained from the normalisation to the MNI standard space to correct voxel signal intensities for the amount of volume displacement during normalisation. Modulation involves scaling by the amount of contraction, so that the total amount of GM in the modulated GM remains unchanged in comparison with the original images. The modulated images were corrected for non-linear warping. The resulting GM images were smoothed with a 12 mm FWHM Gaussian kernel and used for statistical whole brain comparison. Additionally, regions where there was an a priori hypothesis for GM changes were evaluated using a small volume correction within anatomically predefined regions of interest. Counts of supra-threshold voxels and labelling of the anatomical clusters were performed using the template-based automated anatomical labelling tool for SPM (Tzourio-Mazoyer et al., 2002; Cyceron, http:// www.cyceron.fr/web/aal__anatomical_automatic_labeling.html). All statistical analyses were performed using the default settings of SPM5 and the VBM5 toolbox. The main whole brain between-group comparison (atypical N typical) was FWE corrected for multiple comparisons (p b .05). Hypotheses-driven, we used a frontal-temporal VOI approach using a threshold of p b 0.001 uncorrected. This VOI was anatomically defined by using the WFU PickAtlas tool (http://www.fil. ion.ucl.ac.uk/spm/ext/#WFU_PickAtlas). It included cortial mesial and lateral frontal and temporal regions and excluded subcortical midline structures such as the basal ganglia. As the threshold was uncorrected, only volume differences with a cluster size of k = 240 voxel (1 × 1 × 1 mm voxel size) were reported — equivalent to the minimum cluster volume of the fMRI analyses (k = 30 with 2 × 2 × 2 mm voxel size). Age was introduced as covariate of no interest into all analyses. For the comparison of both hemispheres within each patient group, we flipped the segmented, normalised and modulated individual GM volumes of the patients vertically in the midsagittal plane (x= 0). Images were smoothed with a 12 mm FWHM Gaussian kernel. We then conducted a two-sample t-test within each group separately in order to

compare the original images with the newly created flipped images (original N flipped images). All interhemispheric comparisons were conducted within the whole brain using a threshold of p b .05 FWE corrected. Results Patient groups did not differ according to sociodemographic and epilepsy related variables, but the patients with typical language lateralisation were slightly (although not significantly) older than the patients with atypical language lateralisation. Consequently, we introduced age as a covariate of no interest into the VBM and fMRI analyses. The patient groups did not differ according to school education, verbal intelligence and phonological verbal fluency and mean performances of both groups were within the unimpaired range (see Table 1). fMRI For the group level analysis, we used the random effects model available in SPM5 to determine significant activation in the two subject groups (one sample t-test) and to test for activation differences between the atypical and typical patients (two sample t-test). Those patients with typical language lateralisation had typical fluencyrelated activation comprising of the left inferior frontal gyrus (maximum at x = − 44, y = 16, z = 20, extent k = 4919 voxels, T = 10.58, p b .001 corrected, see Fig. 1a). Patients with atypical language dominance exhibited a cluster of activation within the right-sided inferior frontal gyrus (x = 32, y = 24, z = − 10, k = 1642, T = 6.49, p b .001 corrected, see Fig. 1b), but also in a smaller frontolateral cluster within the left inferior frontal gyrus (x = −42, y = 14, z = − 8, k = 314, T = 5.21, p = .002 corrected). In the group comparison, subjects with typical language dominance had stronger left-sided fronto-lateral activation comprising of the left middle frontal gyrus (x = − 46, y = 26, z = 24, k = 390, T = 4.67, p = .002 corrected) compared to those with atypical language representation. The inverted contrast showed that the atypical patients exhibited stronger right-sided fronto-lateral (inferior frontal gyrus, x = 44, y = 16, z = 28, k = 846, T = 5.70, p b .001 corrected) and right-sided fronto-polar (medial frontal gyrus, x = 12, y = 56, z = 18, k = 474, T = 4.62, p = .001 corrected) activations compared to those with typical language dominance (see Fig. 2b). VBM There were clusters of GM increases in patients with atypical language lateralisation compared to those with typical language representation. When using a corrected threshold (FWE, p b .05), the main increase of GM was found in the right superior temporal gyrus including Heschl's gyri (x = 56, y = −16, z = −1, k = 695, T = 6.36, p b .001, Fig. 2a). When exploring GM volume differences at a more liberal threshold (p b 0.001, uncorrected) increases were also present in the right superior and middle temporal gyrus, the right superior and medial frontal gyrus, the right middle frontal gyrus, and the right cingulate gyrus. Although to a lesser degree, volume increases were also found within the left fronto-mesial and fronto-polar region within the atypical patients (Table 2, Fig. 2b). Fig. 2b shows overlapping areas of GM increases (yellow) and fMRI activations associated with atypical language (red). There were no increases of GM volumes in patients with typical language lateralisation compared to patients with atypical language dominance, neither at a conservative threshold of p b .05 FWE corrected nor at a more liberal threshold of p b .001 uncorrected. To test whether the above mentioned volume differences within right Heschl's gyri merely represent the most common largest difference across groups, we conducted an explorative analysis of

K. Labudda et al. / NeuroImage 59 (2012) 728–737

731

Fig. 1. (a) Language associated fMRI activation within the group of patients with typical language lateralisation (one-sample t-test, verbal fluency N rest, FEW corrected; according to the neurological convention left side of all images corresponds to left side of the brain). (b) Language associated fMRI activation within the group of patients with atypical language lateralisation (one-sample t-test, verbal fluency N rest, FWE corrected).

this region in individual cases. We created a spheric volume of interest (VOI) of 15 mm radius around the peak voxel which differentiated both groups best (x = 56, y = − 16, z = −1), thus covering the right Heschl's gyri. We than analysed whether each single patient of the atypical group showed a volume increase within this VOI compared to the group of typical patients (at a threshold of p N .01 uncorrected). 14 of 20 patients showed significant volume increases in this region (mean cluster size k = 915 voxel, SD = 731.28). To test whether volume increases within the group of atypical patients were specific (i.e. did not occur in typically lateralised patients), we also compared each of the typical patients with the rest of the typical group. Only 4 of the 20 typically lateralised patients showed slight volume increases (mean cluster size k = 42 voxels, SD = 46.73). The number of individual patients with volume increases differed significantly

between the two groups (14 of the atypical patients versus 4 of the typical patients, chi 2 = 10.1, p = .002).

Correlation analyses LIs and VBM When correlating individual fMRI LIs with GM volume using VBM in all patients using a whole brain regression analysis, we found increases of GM associated with positive LIs; i.e. more atypical LIs were associated with larger GM volumes within right Heschl's gyri (superior temporal gyrus, x = 58, y = −22, z = 4, k = 3307, T = 4.80, p = .03). Further subtle increases of GM volumes associated with atypical LIs were found in a cluster within the right medial frontal gyrus; but this correlation did

Fig. 2. (a) VBM results reflecting GM volume increases within the group of atypical patients (two-sample t-test atypical N typical at p b .05, FEW corrected). (b) Overlaps of GM increases (yellow) in patients with atypical language compared to patients with typical language at the liberal threshold (p b .001 uncorrected) and fMRI activations (red) associated with atypical language (atypical patients N typical patients, p b .05, corrected).

732

K. Labudda et al. / NeuroImage 59 (2012) 728–737

Table 2 VBM results of the group comparison (controlled for age at surgery, whole brain analysis, threshold p b .001 uncorrected). Each grey line indicates a cluster of a significant increase of GM in patients with atypical compared to typical language lateralisation with its respective peak voxel coordinates. Each white line indicates a local maximum within the above cluster. r = right; l = left; k = cluster size.

Region

VBM results: atypical > typical MNI coordinates k x, y, z

Superior and middle temporal gyrus Postcentral gyrus Claustrum Superior and medial frontal gyrus Superior frontal gyrus Middle frontal gyrus Middle frontal gyrus Cingulate gyrus Cingulate gyrus Cingulate gyrus Posterior cingulate gyrus Medial frontal gyrus Medial frontal gyrus Superior frontal gyrus Cingulate gyrus Superior frontal gyrus Middle frontal gyrus

r r r r r r r r r r l l l l l l l

56, -16, -1 48, -18, 24 32, 11, 12 17, 52, -12 16, 57, 1 36, 46, -11 18, 4, 54 15, 15, 41 14, -39, 43 8, -50, 24 -9, -49, 20 -13, 56, -8 -9, 40, -14 -16, 48, -10 -14, 27, 32 -24, 41, 27 -33, 44, 18

t

16,804

11,717

4400

2744 6696

3916

p

6.36 <.001 6.07 5.99 5.50 <.001 5.14 4.81 5.29 .008 4.60 4.56 5.17 .047 4.88 5.14 .001 4.72 01.04.64 4.70 .007 4.57 3.98

not survive correction for multiple comparisons (x= 24, y = 44, z = 18, k = 999, T = 4.42, p N .05). Results are displayed in Fig. 3a. Language associated fMRI activation and VBM The language associated activation within the right-sided frontolateral cluster that differentiated best between atypical and typical patients (Fig. 2b) was used to analyse the relationship between fMRI activation and GM volumes. Therefore, the average β parameter of each patient (indicating individual activation strength) of this cluster was extracted and used as regressor in a regression analysis with GM volumes as dependent variable. Higher activation strength of the right fronto-lateral activation cluster was significantly correlated with GM volume increases within a right fronto-polar cluster (right medial frontal gyrus: x = 15, y = 54, z = 4, T = 5.71, k = 6666, p = .001 corrected) and – to a lesser extent – with a left fronto-polar area (left

superior frontal gyrus: x = −12, y = −51, z = −10, T = 5.05, k = 3940, p = .015 corrected, see Fig. 3b). VBM and verbal fluency We correlated verbal fluency performance with GM volumes within each patient subgroup and within the whole group (using the SPM regression approach). There was no significant association between verbal fluency and GM volumes in theses three analyses. In a second step, independent of language lateralisation we compared GM volumes of those patients with impaired verbal performance (according to the clinical criterion defined as Tscores b 40) with GM volumes of patients with unimpaired verbal fluency. Four patients of the typical group and 8 patients of the atypical group had T-scores b 40. Frequencies of impaired (Chi 2 = 6.75, p = .35) and unimpaired (Chi 2 = 23.24, p = .18) patients in both groups did not differ significantly. We also analysed whether those 8 atypical patients with reduced verbal fluency performance differed according to GM volumes from those 12 atypical patients with intact verbal fluency performance. The two-sample t-tests (impaired atypical patients N intact atypical patients; intact atypical patients N impaired atypical patients) did not reflect any volume differences, neither at the conservative threshold (p b .05 FWE corrected) nor at the more liberal threshold (p b .001 uncorrected) within the fronto-temporal VOI. Additional results In order to test whether the GM volume group differences were a result of normalisation artefacts or differing extent of atrophy between the groups of patients, we compared volumes of cerebrospinal fluid (CSF) segmented by SPM5 and did not find significant group differences. Using a VOI analysis, we compared the two groups to detect potential volume differences in the hippocampus and parahippocampal gyrus. Patients with atypical language lateralisation had GM increase in this mesiotemporal VOI on the right side. However, this result did not survive correction for multiple comparisons (x = 34, y = −40, z = −13, T = 4.01, k = 308, p = .07). Within the whole patient group and within the two separate patient samples, we calculated regression analyses in order to test whether the age of onset was correlated with GM volumes. Within the whole patient group early age of onset was correlated with

Fig. 3. (a) Regions of GM volumes that were correlated with the individual LIs within the whole sample of patients. (b) Regions of GM that were associated with the strength of activation within the right-sided frontal activation cluster that differentiated best between the two groups (x = 32, y = 24, z = − 10; see Fig. 2b).

K. Labudda et al. / NeuroImage 59 (2012) 728–737

733

see Fig. 4). Within the typical patient group, we did not find correlations between age of onset and GM volume. Interhemispheric comparison When comparing the original and the flipped images separately within each group (whole brain two-sample t-test, contrast: original N flipped images, threshold p b .05, FWE corrected), we found significant GM volume increases within the right hippocampus (due to the left-sided HS) in both groups (cluster's peak for the atypical patients: x = 27, y = − 31, z = 2; cluster's peak for the typical patients: x = 27, y = − 31, z = −2, all p b .001 corrected). We further found widely distributed GM increases within the lateral frontotemporal region within the right hemisphere compared to the left hemisphere, also within both groups (Fig. 5a and b). Beyond this general rightward GM asymmetry, we found a region of leftward asymmetry. Both patient groups had more GM volume within the left superior temporal gyrus including Heschl's gyri (cluster's peak within the atypical patients: x = −41, y = −34, z = 14; cluster's peak within the typical patients: x = −40, y = −32, z = 13, all p b .001).

Fig. 4. Result of the regression analysis in patients with atypical language dominance using age of onset as independent variable and GM increases as dependent variable. Early ages of onset were significantly associated with GM increases within the right inferior frontal gyrus (x = 58, y = 19, z = 4), the right inferior temporal gyrus (x = 63, y = − 6, z = − 20), a right-sided mesio-frontal/fronto-polar cluster (x = 52, y = 28, z = 32) and within the left precentral gyrus (x = − 49, y = − 8, z = 9; all p ≤ .04 corrected).

widespread areas of GM volume increases within the left- and right fronto-temporal region (peaks of significant [all p ≤ .006, corrected] cluster peaks: right superior frontal gyrus, x = 22, y = 66, z = 7; right superior temporal gyrus, x = 59, y = −29, z = 9; left precental gyrus, x = − 49, y = − 8, z = 9). Within the patients with atypical language dominance early ages of onset were associated with GM volume increases mainly within the right frontal lobe and the right temporolateral cortex (see Fig. 4). The strongest correlation between early age of onset with GM increases was observed within the right-sided area which is homologous to Broca's region (right inferior frontal gyrus,

Discussion We demonstrated that patients with left-sided mesial TLE with atypical language representation had increases of GM volumes in rightsided temporal and frontal lobes, compared to left-sided TLE patients with typical language dominance. These regions included right-sided Heschl's gyri and the right frontal operculum, i.e. contralateral homologues of the primary language areas. When correlating the individual LIs from language fMRI with GM volumes using VBM, there was an association of more atypical LIs with more GM volume in temporo- and fronto-lateral areas on the right side, incorporating the contralateral homologues of the temporo-lateral primary language area (see Fig. 3a). This direct linear association indicated that the GM changes between the two patient groups originated from increased GM in the group with atypical language lateralisation (instead of being the result of right-sided decreases stemming from the typical group). To further explore the relationship between atypical function and atypical morphology, we used the individual fMRI activations within the right

Fig. 5. Results of the interhemispheric comparison (two-sample t-test, original N flipped images; threshold p b .05 FWE corrected) in (a) patients with atypical language dominance and (b) in patients with typical language dominance.

734

K. Labudda et al. / NeuroImage 59 (2012) 728–737

fronto-lateral brain region that was activated significantly stronger in the atypical patients. Stronger right fronto-lateral language fMRI activations were associated with increased GM volumes in a similar distribution compared to the above mentioned group comparison and correlation (Fig. 3b). In the atypical group, there were additional GM increases within the left mesial frontal lobe, although smaller in extent and weaker in effect. Methodological considerations By using VBM, we objectified group differences of GM volumes in specific brain areas. In this retrospective study using data from presurgical evaluation of epilepsy patients, we did not compare the two patient groups with a group of healthy subjects. Therefore, we cannot decide whether the pattern of GM increases observed in the group of atypical language compared to the typical patients represented absolute increases of GM (i.e. more than in healthy subjects) or relative GM increases (i.e. compared to patients with typical language representation). To identify not only disease associated aspects, the most specific comparison using a control population would be a comparison with healthy subjects and atypical language dominance; these cases are scarce (b5%). We chose to compare groups with left-sided TLE because this patient group contained a relatively high percentage of cases with atypical language. Comparing groups of epilepsy patients with the same syndrome, also allowed us to control for factors leading up to global and local GM changes. Hippocampal and extratemporal atrophy has been described in TLE patients (see reviews by Keller and Roberts, 2008 and Yasuda et al., 2010). Keller and Roberts (2008) who reviewed 18 VBM studies in TLE patients reported GM decreases of GM volumes in 26 brain regions compared to healthy controls. Volume decreases have been found amongst others within temporolateral areas, the temporal pole, almost all regions of the frontal lobe and within subcortical structures. Volume decreases can be seen in both hemispheres but are more pronounced within the epileptogenic hemisphere. Only few VBM studies reported GM increases in TLE patients (Kaaden et al., 2011). In the review by Keller and Roberts, there was no study showing substantial GM increases outside of the temporal lobes, but VBM changes representing “blurring of the greywhite-matter-interface” known to affect the temporal lobe anterior to HS (Keller et al., 2002; Woermann et al., 1999). In our current study, fronto-temporo-lateral GM increases in the atypical patients compared to the typical patients resulted from a tight comparison representing relative increases compared to patients with typical language dominance. We also did not find CSF volume differences between the groups. More marked atrophy in one patient group could have led to GM differences. Decreases of GM have been reported to be accompanied by CSF increases in groups of patients with more atrophy (Good et al., 2001; Smith et al., 2007). In our study, the lack of CSF group differences makes it furthermore unlikely that the observed GM differences were the result of a normalisation artefact. VBM is said to be sensitive to systematic shape differences resulting from misregistration in the spatial normalisation step. We used the optimised VBM approach proposed by Gaser (http://dbm.neuro.uni-jena.de/vbm/) that includes a Hidden Markov Random Field model to reduce tissue misclassification. We used a larger FWHM (12 mm) in order to further reduce the unlikely effect of misregistration, increasing the accuracy of our VBM analysis (for a detailed discussion of methodological aspects of VBM such as potential normalisation errors in VBM see e.g. Ashburner, 2009; Ashburner and Friston, 2001; Bookstein, 2001). An alternative morphological method is the measurement of cortical thickness. This method is said to be less prone to local inaccuracies (including normalisation artefacts) as the extraction of the cortex follows the GM surface (Hutton et al., 2009; Kim et al., 2005; MacDonald et al., 2000). However, studies combining VBM

and measures of cortical thickness found convergent main results regarding identification and localisation of morphological changes (Chee et al., 2011; Hyde et al., 2010; Koolschijn et al., 2010; Lehmann et al., 2009). For the future, the combination of both methods might be promising to enlarge the understanding of morphological changes underlying reorganisation phenomena. Another methodological issue might be the use of only one fMRI language task to determine language lateralisation. Using a battery of verbal fMRI tasks to assess different verbal functions (such as listening to verbal stimuli, rhyming, semantic decisions, tone discrimination) might have resulted in a more reliable reflection of the language network in each patient. However, we investigated a clinical cohort of patients. In this context, fMRI tasks need to be easy and short enough to be tolerated by the patients. We assume that the fMRI task used is appropriate to lateralise language functions, specifically in TLE patients, as a high concordance between Wada test language lateralisation and fMRI lateralisation based on our paradigm has been shown in a large epilepsy patient sample (Woermann et al. 2003). In further studies, fMRI LI determination was also based on voxel activated within the frontal and temporal lobe (instead of using Broca's activation only; Janszky et al., 2006). We adapted this procedure in the current study. We did not solely use language activations in Broca's area for the LI determination because this would have neglected the fact that verbal fluency task is associated with some extra-fronto-lateral activations, e.g. within the temporo-lateral cortex, the anterior cingulate gyrus or the hippocampus (Gauthier et al. 2009; Senhorini et al., 2011; Whitney et al., 2009). We not only correlated fMRI and VBM-based estimates of GM volume, but also a measure of functional integrity with VBM results. On average, there was no difference in verbal fluency between patient groups and no correlation between verbal fluency and GM volumes. This indicates that atypical language lateralisation and the described morphological changes were not dysfunctional regarding verbal fluency. However, 8 of 20 patients within the atypical group had reduced verbal fluency performance (4/20 in the typical group). To further explore whether the GM increases within the atypical patients were specific for those with reduced verbal performance (and thus reflect a dysfunctional mechanism), we compared GM volumes of the impaired patients with those of the unimpaired. We did not find a group difference in this analysis. Thus, we assume that GM increases in the atypical patients were not specifically associated with verbal impairments. Biological considerations Increased GM has been linked to learning and reorganisation. It has been shown that function-specific training can lead to circumscribed increases of GM e.g. induced by extensive motor practise, by growing visuo-spatial experience, and by extensive learning (Ceccarelli et al., 2009; Draganski et al., 2004, 2006; Maguire et al., 2000). In neurological patients with acute and chronic brain lesions, there is some evidence of functional plasticity, i.e. a shift of functions to adjacent or even contralateral undamaged cortical areas (Labudda et al., 2010; Rosenberger et al., 2009; Voets et al., 2009; for an overview in the context of epilepsy see Labudda and Woermann, 2011; Janszky et al., 2006). Representing reorganisation, atypical language dominance is a frequent phenomenon especially in patient with left-sided TLE with HS (Janszky et al., 2003, 2006; Möddel et al., 2009; Weber et al., 2006). Studies investigating the morphological correlates of atypical language representation in epilepsy patients are rare and small (see Introduction). Dorsaint-Pierre et al. (2006) found leftward asymmetries in the planum temporale and in Heschl's gyri in patients with poorly characterised epilepsy. In only three of eleven patients with right-sided language dominance, they reported rightward asymmetries in Heschl's gyri. Using VBM in addition, they produced interhemispheric difference maps to compare patients with

K. Labudda et al. / NeuroImage 59 (2012) 728–737

left- and right-sided language dominance. Not reaching significance, they described patients with left-sided language dominance to have more GM within the left inferior frontal gyrus (corresponding to Broca's area) and patients with right-sided language dominance to have more GM in this frontal region within the right hemisphere. The authors concluded that temporo-lateral volume differences were not directly related to language lateralisation, whereas the frontal asymmetries might be a morphological substrate of language lateralisation. Our results of the direct interhemispheric GM comparisons within the two patient groups are in accordance with those of Dorsaint-Pierre and colleagues. In both groups, we also found a cluster of GM increases within the left superior temporal gyrus including Heschl's gyri (compared to the right hemisphere). This implies that this lateral temporal region (anatomically associated with language functions) had greater cortical volume in the left than in the right hemisphere. As proposed by Dorsaint-Pierre et al. (2006), this asymmetry might be independent of language lateralisation, i.e. seems not to be reversed by reorganisation towards atypical language dominance. In our study, the volume of the right-sided Heschl's gyri was increased in the atypical compared to the typical patients and was further correlated with the degree of language lateralisation. Thus, the right-sided volume increase found in the direct group comparison was in fact associated with atypical language lateralisation. The interhemispheric comparison within both groups separately further showed widespread fronto-temporal GM increases within the right hemisphere compared to the left hemisphere. This rightward asymmetry in both patient groups is most likely due to the fact that left-sided HS is not only associated with hippocampal atrophy but with additional, widespread extrahippocampal GM decreases more pronounced within the epileptogenic hemisphere (Keller and Roberts, 2008). When comparing the left and right hemisphere within patients suspected to have unilateral atrophy, it is likely to detect changes due to atrophy, which will mask the effect of GM changes associated with language lateralisation. This was the rationale why we decided to compare two patients groups closely matched according to brain pathology but different in language lateralisation. In healthy subjects with typical language lateralisation, structural leftward asymmetries have been described for the primary language areas, i.e. the planum temporale, Heschl's gyri and the frontal operculum (Abdul-Kareem and Sluming, 2008; Amunts et al., 2003; Josse et al., 2003). However, it is unclear whether or not there are structural brain differences between healthy subjects with typical and atypical language representation. There are two studies investigating morphological brain alterations, each in 10 healthy subjects with atypical (i.e. right-sided) language dominance compared to subjects with typical language dominance (Jansen et al., 2010; Keller et al., 2010). Healthy subjects with atypical language representation had a rightward asymmetry of insular volumes using manual stereological MR volumetry (Keller et al., 2010). Volume asymmetries were not restricted to a specific portion of the insula along its anterior–posterior axis. In their VBM study, Jansen et al. (2010) reported larger volumes within the left-sided superior temporal gyrus/Heschl's gyri in both, left and right lateralised healthy subjects when comparing the left and the right hemisphere separately for both groups. This is in concordance with the results of leftward GM asymmetry within this region found in both patient groups in the interhemispheric comparison of the current study (see above). When comparing both groups directly with each other, Jansen et al. reported a tendency towards volume increases within the right hippocampus in healthy subjects with atypical language representation compared to subjects with typical language dominance (also using a more permissive threshold of p b .001 uncorrected). This result is also in line with the tendency towards increased right hippocampal volumes in patients with atypical language lateralisation in our study. In the direct comparison of both groups in our study, significant GM increases in a contralateral homologue of Wernicke's area (not

735

observed in the between group analysis by Jansen et al. in healthy subjects) but also a tendency towards changes in right-sided frontal lobe and hippocampus have been shown in patients with atypical compared to typical language lateralisation. In the context of subtle but quantifiable morphometric changes underlying reorganisation processes, it might be possible to assume that these increases result from changes in neuropil, neuronal size or shape, dendritic or axonal arborisation or synaptic connections (see Mechelli et al., 2005). Addressing subcortical connectivity and in keeping with our results, the MR tractography study by Powell et al. (2007) implied that structural and functional plasticity of the language network can include both, frontal and temporal language areas. By combining language fMRI and diffusion tensor imaging, they demonstrated a pattern of bilateral connections extending posteriorly from the inferior frontal gyrus with greater temporal lobe and supramarginal gyrus connections on the right than on the left in patients with leftsided TLE. The patients also had extensive and consistent connections bilaterally to the superior and middle temporal gyri, extending anteriorly into the temporal lobe. Taken together, their and our result suggests that structural reorganisation of language networks following left-sided mesiotemporal pathology comprises of volume changes of functional GM and connecting white matter. Functional and structural reorganisation of the language network in patients with left-sided TLE might result from more widespread disruption of normal neurophysiological activity in the epileptic hemisphere, even in the presence of a circumscribed mesiotemporal brain lesion. In TLE patients with left-sided HS, a higher frequency of interictal epileptic discharges propagating to the lateral left temporal lobe was associated with atypical language lateralisation. This propagating epileptic activity was directly linked to the degree of atypical language representation (Janszky et al., 2003, 2006). Some studies suggested that atypical language organisation in epilepsy patients was associated with an early onset of seizures (e.g. Brazdil et al., 2003; Pataraia et al., 2004; Springer et al., 1999). It is assumed that the brain in general is more plastic at younger ages and the language network is less lateralised in children. Gaillard et al. (2000) reported that healthy children aged 8–12 years showed significantly more right-sided language activation compared to adults. Although there are some case reports of patients with functional language shifts in the age range of 9–15 years due to chronic progressive brain diseases such as Rasmussen's encephalitis (e.g. Loddenkemper et al., 2003), there are no reports of a fully functional language shift in adults with acute neurological disorders. It is reasonable to assume that functional and structural language reorganisation is a result of chronic brain dysfunctions starting at an early age, i.e. within the period of high brain plasticity. A developmental process that might even be involved in normal structural asymmetries of language related fronto-temporal brain regions in healthy subjects is synaptic pruning. Pruning is a regulatory mechanism that facilitates adaptive neural changes by reducing the number of overproduced and dispensable synaptic connections resulting in efficient GM reductions. In terms of synaptogenesis and pruning, maturation seems to be finished at the age of 7 years in Heschl's gyri (Devous et al., 2006). The lateral prefrontal cortex (including Broca's area) is most plastic at the age of 5–11 years (Sowell et al., 2002, 2004). During this time period increasing intrinsic network connectivity of language related frontal and temporal brain regions has been reported, including a tighter correlation of cortical thickness between Broca's area and the superior temporal gyrus (Lerch et al., 2006; Zielinski et al., 2010). In healthy subjects with typically leftward lateralised speech functions, leftward morphological asymmetries can be explained by this early pruning process leading to a reduction of redundant right-sided frontal and temporal GM. In a very recent study Porter et al. (2011) reported a significant correlation between increases of verbal fluency and decreases of cortical thickness in left- and right-sided temporal and frontal

736

K. Labudda et al. / NeuroImage 59 (2012) 728–737

language areas in healthy adolescents with left-sided language lateralisation. They concluded that the reduction of cortical thickness reflects the developmental shift from overabundant neuropil to efficient cortical networks underlying language functions. Based on our results, we argue that in patients, ongoing chronic seizure activity caused by early brain pathology in the hemisphere normally specialised for language functions might affect this pruning process. In patients with structural and functional disturbances in the left hemisphere, the absence or reduction of pruning might constitute the basis of functional and structural language reorganisation representing a reserve capacity to be hard wired. Results of the regression analyses using age of onset as covariate supported this pruning hypothesis: the whole group analysis reflected that younger age at seizure onset is associated with increases of GM volumes within the left and right fronto-temporal region. This might indicate that in the event of early functional or structural brain changes (causing epileptic seizures) the pruning process is reduced (see also Kaaden et al., 2011). We argue that this might reflect a potentially protective mechanism. In those patients with atypical language representation early age of onset is associated with more GM mainly within the right frontotemporal region (with its peak in the right frontal operculum). Future studies have to show whether VBM or other quantitative MRI measures might be helpful to lateralise language functions in individual patients (Foundas et al., 1996; Keller et al., 2010; Oh and Koh, 2009). Such morphological methods might have advantages over methods depending on activity and interaction (as fMRI or Wada test) in some epilepsy patients. Quantitative structural MRI might allow language lateralisation in patients with non-compliance or reduced cognitive abilities exploiting examinations in sedation. Conclusion In the current study, we aimed to investigate whether frequently observed atypical language dominance patterns in patients with leftsided mesial TLE were accompanied by morphological brain differences. Mainly within right-sided temporo-lateral, but also in frontal areas, we demonstrated a relative increase of GM volumes in left-sided mesial TLE patients with atypical language dominance compared to mesial TLE patients with typical language representations. These increases of rightsided GM volume were correlated with the individual strength of atypical fMRI activations. In patients with left-sided TLE and atypical language dominance, GM increases within right-sided fronto-temporal brain regions seemed to represent hard-wired reorganisation resulting in sufficient functionality. Acknowledgment We thank Dr. Simone Horstmann and Joerg Aengenendt for conducting the neuropsychological investigation of the patients. References Abdul-Kareem, I.A., Sluming, V., 2008. Heschl gyrus and its included primary auditory cortex: structural MRI studies in healthy and diseased subjects. J. Magn. Reson. Imaging 28, 287–299. Amunts, K., Schleicher, A., Ditterich, A., Zilles, K., 2003. Broca's region: cytoarchitectonic asymmetry and developmental changes. J. Comp. Neurol. 465, 72–89. Aschenbrenner, A., Tucha, O., Lange, K., 2000. RWT Regensburger Wortflüssigkeits-Test. Handanweisung. Hogrefe, Göttingen. Ashburner, J., 2009. Computational anatomy with the SPM software. Magn. Reson. Imaging 27, 1163–1174. Ashburner, J., Friston, K.J., 2001. Why voxel-based morphometry should be used. Neuroimage 14, 1238–1243. Ashburner, J., Friston, K.J., 2005. Unified segmentation. Neuroimage 26, 839–851. Bookstein, F.L., 2001. “Voxel-based morphometry” should not be used with imperfectly registered images. Neuroimage 14, 1454–1462. Brazdil, M., Zakopcan, J., Kuba, R., Fanfrdlova, Z., Rektor, I., 2003. Atypical hemispheric language dominance in left temporal lobe epilepsy as a result of the reorganization of language functions. Epilepsy Behav. 4, 414–419.

Ceccarelli, A., Rocca, M.A., Pagani, E., Falini, A., Comi, G., Filippi, M., 2009. Cognitive learning is associated with gray matter changes in healthy human individuals: a tensor-based morphometry study. Neuroimage 48, 585–589. Chee, M.W., Zheng, H., Goh, J.O., Park, D., Sutton, B.P., 2011. Brain structure in young and old East asians and westerners: comparisons of structural volume and cortical thickness. J. Cogn. Neurosci. 23, 1065–1079. Devous Sr., M.D., Altuna, D., Furl, N., Cooper, W., Gabbert, G., Ngai, W.T., Chiu, S., Scott III, J.M., Harris, T.S., Payne, J.K., Tobey, E.A., 2006. Maturation of speech and language functional neuroanatomy in pediatric normal controls. J. Speech Lang. Hear. Res. 49, 856–866. Dorsaint-Pierre, R., Penhune, V.B., Watkins, K.E., Neelin, P., Lerch, J.P., Bouffard, M., Zatorre, R.J., 2006. Asymmetries of the planum temporale and Heschl's gyrus: relationship to language lateralization. Brain 129, 1164–1176. Draganski, B., Gaser, C., Busch, V., Schuierer, G., Bogdahn, U., May, A., 2004. Neuroplasticity: changes in grey matter induced by training. Nature 427, 311–312. Draganski, B., Gaser, C., Kempermann, G., Kuhn, H.G., Winkler, J., Buchel, C., May, A., 2006. Temporal and spatial dynamics of brain structure changes during extensive learning. J. Neurosci. 26, 6314–6317. Foundas, A.L., Leonard, C.M., Gilmore, R.L., Fennell, E.B., Heilman, K.M., 1996. Pars triangularis asymmetry and language dominance. Proc. Natl. Acad. Sci. U. S. A. 93, 719–722. Gaillard, W.D., Hertz-Pannier, L., Mott, S.H., Barnett, A.S., LeBihan, D., Theodore, W.H., 2000. Functional anatomy of cognitive development: fMRI of verbal fluency in children and adults. Neurology 54, 180–185. Gauthier, C.T., Duyme, M., Zanca, M., Capron, C., 2009. Sex and performance level effects on brain activation during a verbal fluency task: a functional magnetic resonance imaging study. Cortex 45, 164–176. Good, C.D., Johnsrude, I.S., Ashburner, J., Henson, R.N., Friston, K.J., Frackowiak, R.S., 2001. A voxel-based morphometric study of ageing in 465 normal adult human brains. Neuroimage 14, 21–36. Hutton, C., Draganski, B., Ashburner, J., Weiskopf, N., 2009. A comparison between voxel-based cortical thickness and voxel-based morphometry in normal aging. Neuroimage 48, 371–380. Hyde, K.L., Samson, F., Evans, A.C., Mottron, L., 2010. Neuroanatomical differences in brain areas implicated in perceptual and other core features of autism revealed by cortical thickness analysis and voxel-based morphometry. Hum. Brain Mapp. 31, 556–566. Jansen, A., Liuzzi, G., Deppe, M., Kanowski, M., Olschlager, C., Albers, J.M., Schlaug, G., Knecht, S., 2010. Structural correlates of functional language dominance: a voxelbased morphometry study. J. Neuroimaging 20, 148–156. Janszky, J., Jokeit, H., Heinemann, D., Schulz, R., Woermann, F.G., Ebner, A., 2003. Epileptic activity influences the speech organization in medial temporal lobe epilepsy. Brain 126, 2043–2051. Janszky, J., Mertens, M., Janszky, I., Ebner, A., Woermann, F.G., 2006. Left-sided interictal epileptic activity induces shift of language lateralization in temporal lobe epilepsy: an fMRI study. Epilepsia 47, 921–927. Josse, G., Mazoyer, B., Crivello, F., Tzourio-Mazoyer, N., 2003. Left planum temporale: an anatomical marker of left hemispheric specialization for language comprehension. Brain Res. Cogn. Brain Res. 18, 1–14. Kaaden, S., Quesada, C.M., Urbach, H., Koenig, R., Weber, B., Schramm, J., Rudinger, G., Helmstaedter, C., 2011. Neurodevelopmental disruption in early-onset temporal lobe epilepsy: evidence from a voxel-based morphometry study. Epilepsy Behav. 20, 694–699. Keller, S.S., Roberts, N., 2008. Voxel-based morphometry of temporal lobe epilepsy: an introduction and review of the literature. Epilepsia 49, 741–757. Keller, S.S., Mackay, C.E., Barrick, T.R., Wieshmann, U.C., Howard, M.A., Roberts, N., 2002. Voxel-based morphometric comparison of hippocampal and extrahippocampal abnormalities in patients with left and right hippocampal atrophy. Neuroimage 16, 23–31. Keller, S.S., Roberts, N., García-Fiñana, M., Mohammadi, S., Ringelstein, E.B., Knecht, S., Deppe, M., 2010. Can the language-dominant hemisphere be predicted by brain anatomy? J. Cogn. Neurosci. (Epub). Kim, J.S., Singh, V., Lee, J.K., Lerch, J., Ad-Dab'bagh, Y., MacDonald, D., Lee, J.M., Kim, S.I., Evans, A.C., 2005. Automated 3-D extraction and evaluation of the inner and outer cortical surfaces using a Laplacian map and partial volume effect classification. Neuroimage 27, 210–221. Koolschijn, P.C., van Haren, N.E., Schnack, H.G., Janssen, J., Hulshoff Pol, H.E., Kahn, R.S., 2010. Cortical thickness and voxel-based morphometry in depressed elderly. Eur. Neuropsychopharmacol. 20, 398–404. Labudda, K., Woermann, F.G., 2011. The role of cognitive fMRI in mesial temporal lobe epilepsy. In: (editors: Rosenow, F., Lüders, H., Ryvlin, P., Kahane, P.). The mesial temporal lobe epilepsies (pp. 173–188). Montrouge: John Libbey Eurotext. Lehmann, M., Crutch, S.J., Ridgway, G.R., Ridha, B.H., Barnes, J., Warrington, E.K., Rossor, M.N., Fox, N.C., 2009. Cortical thickness and voxel-based morphometry in posterior cortical atrophy and typical Alzheimer's disease. Neurobiol. Aging (Epub). Lehrl, S., Merz, J., Burkhard, G., Fischer, S., 1991. Mehrfachwahl-Wortschatz-Intelligenztest (MWT-B). Hogrefe, Göttingen. Lerch, J.P., Worsley, K., Shaw, W.P., Greenstein, D.K., Lenroot, R.K., Giedd, J., Evans, A.C., 2006. Mapping anatomical correlations across cerebral cortex (MACACC) using cortical thickness from MRI. Neuroimage 31, 993–1003. Liégeois, F., Connelly, A., Cross, J.H., Boyd, S.G., Gadian, D.G., Vargha-Khadem, F., Baldeweg, T., 2004. Language reorganization in children with early-onset lesions of the left hemisphere: an fMRI study. Brain 127, 1229–1236. Loddenkemper, T., Wyllie, E., Lardizabal, D., Stanford, L.D., Bingaman, W., 2003. Late language transfer in patients with Rasmussen encephalitis. Epilepsia 44, 870–871. Maccotta, L., Buckner, R.L., Gilliam, F.G., Ojemann, J.G., 2007. Changing frontal contributions to memory before and after medial temporal lobectomy. Cereb. Cortex 17, 443–456.

K. Labudda et al. / NeuroImage 59 (2012) 728–737 MacDonald, D., Kabani, N., Avis, D., Evans, A.C., 2000. Automated 3-D extraction of inner and outer surfaces of cerebral cortex from MRI. Neuroimage 12, 340–356. Maguire, E.A., Gadian, D.G., Johnsrude, I.S., Good, C.D., Ashburner, J., Frackowiak, R.S., Frith, C.D., 2000. Navigation-related structural change in the hippocampi of taxi drivers. Proc. Natl. Acad. Sci. U. S. A. 97, 4398–4403. Mechelli, A., Price, C.J., Friston, K., Ashburner, J., 2005. Voxel-based morphometry of the human brain: methods and applications. Curr. Med. Imaging Rev. 1, 105–113. Möddel, G., Lineweaver, T., Schuele, S.U., Reinholz, J., Loddenkemper, T., 2009. Atypical language lateralization in epilepsy patients. Epilepsia 50, 1506–1516. Oh, Y.M., Koh, E.J., 2009. Language lateralization in patients with temporal lobe epilepsy: a comparison between volumetric analysis and the Wada test. J. Korean Neurosur. Soc. 45, 329–335. Pataraia, E., Simos, P.G., Castillo, E.M., Billingsley-Marshall, R.L., McGregor, A.L., Breier, J.I., Sarkari, S., Papanicolaou, A.C., 2004. Reorganization of language-specific cortex in patients with lesions or mesial temporal epilepsy. Neurology 63, 1825–1832. Porter, J.N., Collins, P.F., Muetzel, R.L., Lim, K.O., Luciana, M., 2011. Associations between cortical thickness and verbal fluency in childhood, adolescence, and young adulthood. Neuroimage 55, 1865–1877. Powell, H.W., Parker, G.J., Alexander, D.C., Symms, M.R., Boulby, P.A., WheelerKingshott, C.A., Barker, G.J., Koepp, M.J., Duncan, J.S., 2007. Abnormalities of language networks in temporal lobe epilepsy. Neuroimage 36, 209–221. Richardson, M.P., Strange, B.A., Duncan, J., Dolan, R.J., 2003. Preserved verbal memory function in left medial temporal pathology involves reorganisation of function to right medial temporal lobe. Neuroimage 20, S112–S119. Rosenberger, L.R., Zeck, J., Berl, M.M., Moore, E.N., Ritzl, E.K., Shamim, S., Weinstein, S.L., Conry, J.A., Pearl, P.L., Sato, S., Vezina, L.G., Theodore, W.H., Gaillard, W.D., 2009. Interhemispheric and intrahemispheric language reorganization in complex partial epilepsy. Neurology 72, 1830–1836. Senhorini, M.C., Cerqueira, C.T., Schaufelberger, M.S., Almeida, J.C., Amaro, E., Sato, J.R., Barreiros, M.A., Ayres, A.M., Castro, C.C., Scazufca, M., Menezes, P.R., Busatto, G.F., 2011. Brain activity patterns during phonological verbal fluency performance with varying levels of difficulty: a functional magnetic resonance imaging study in Portuguese-speaking healthy individuals. J. Clin. Exp. Neuropsychol. 27, 1–10. Smith, C.D., Chebrolu, H., Wekstein, D.R., Schmitt, F.A., Markesbery, W.R., 2007. Age and gender effects on human brain anatomy: a voxel-based morphometric study in healthy elderly. Neurobiol. Aging 28, 1075–1087. Sowell, E.R., Trauner, D.A., Gamst, A., Jernigan, T.L., 2002. Development of cortical and subcortical brain structures in childhood and adolescence: a structural MRI study. Dev. Med. Child Neurol. 44, 4–16.

737

Sowell, E.R., Thompson, P.M., Leonard, C.M., Welcome, S.E., Kan, E., Toga, A.W., 2004. Longitudinal mapping of cortical thickness and brain growth in normal children. J. Neurosci. 24, 8223–8231. Springer, J.A., Binder, J.R., Hammeke, T.A., Swanson, J.M., Frost, J.A., Bellgowan, P.S., Brewer, C.C., Perry, H.M., Morris, G.L., Mueller, W.M., 1999. Language dominance in neurologically normal and epilepsy subjects: a functional MRI study. Brain 122, 2033–2046. Tzourio-Mazoyer, N., Landeau, B., Papathanassiou, D., Crivello, F., Etard, O., Delcroix, N., Mazoyer, B., Joliot, M., 2002. Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage 15, 273–289. Voets, N.L., Adcock, J.E., Stacey, R., Hart, Y., Carpenter, K., Matthews, P.M., Beckmann, C.F., 2009. Functional and structural changes in the memory network associated with left temporal lobe epilepsy. Hum. Brain Mapp. 30, 4070–4081. Weber, B., Wellmer, J., Reuber, M., Mormann, F., Weis, S., Urbach, H., Ruhlmann, J., Elger, C.E., Fernandez, G., 2006. Left hippocampal pathology is associated with atypical language lateralization in patients with focal epilepsy. Brain 129, 346–351. Whitney, C., Weis, S., Krings, T., Huber, W., Grossman, M., Kircher, T., 2009. Task dependent modulations and hippocampal activity during intrinsic word production. J. Cogn. Neurosci. 21, 697–712. Wilke, M., Lidzba, K., 2007. LI-tool: a new toolbox to assess lateralization in functional MR-data. J. Neurosci. Methods 163, 128–136. Woermann, F.G., Barker, G.J., Birnie, K.D., Meencke, H.J., Duncan, J.S., 1998. Regional changes in hippocampal T2 relaxation and volume: a quantitative magnetic resonance imaging study of hippocampal sclerosis. J. Neurol. Neurosurg. Psychiatry 65, 656–664. Woermann, F.G., Free, S.L., Koepp, M.J., Ashburner, J., Duncan, J.S., 1999. Voxel-by-voxel comparison of automatically segmented cerebral gray matter—a rater-independent comparison of structural MRI in patients with epilepsy. Neuroimage 10, 373–384. Woermann, F.G., Jokeit, H., Luerding, R., Freitag, H., Schulz, R., Guertler, S., Okujava, M., Wolf, P., Tuxhorn, I., Ebner, A., 2003. Language lateralization by Wada test and fMRI in 100 patients with epilepsy. Neurology 61, 699–701. Yasuda, C.L., Betting, L.E., Cendes, F., 2010. Voxel-based morphometry and epilepsy. Expert Rev. Neurother. 10, 975–984. Zielinski, B.A., Gennatas, E.D., Zhou, J., Seeley, W.W., 2010. Network-level structural covariance in the developing brain. Proc. Natl. Acad. Sci. U. S. A. 107, 18191–18196.