Brain Struct Funct DOI 10.1007/s00429-014-0746-4

ORIGINAL ARTICLE

Heschl’s gyrification pattern is related to speech-listening hemispheric lateralization: FMRI investigation in 281 healthy volunteers N. Tzourio-Mazoyer • D. Marie • L. Zago • G. Jobard G. Perchey • G. Leroux • E. Mellet • M. Joliot • F. Crivello • L. Petit • B. Mazoyer

•

Received: 9 September 2013 / Accepted: 28 February 2014 Ó Springer-Verlag Berlin Heidelberg 2014

Abstract This study investigates the structure–function relationships between the anatomy of Heschl’s gyri (HG) and speech hemispheric lateralization in 281 healthy volunteers (135 left-handers). Hemispheric lateralization indices (HFLIs) were calculated with Wilke’s method from the activations obtained via functional magnetic resonance imaging while listening to lists of words (LIST). The mean HFLI during LIST was rightward asymmetrical, and lefthanders displayed a trend toward decreased rightward asymmetry. The correlations between LIST BOLD contrast maps and individual HFLIs demonstrated that among the cortical areas showing significant asymmetry during LIST, only phonological regions explained HFLI variability. Significant positive correlations were present among the left HG, supramarginal gyri, and the anterior insula. Significant negative correlations occurred in the mid-part of the right superior temporal sulcus. Left HG had the largest functional activity during LIST and explained 10 % of the HFLI variance. There was a strong anatomo-functional link in the HG: duplication was associated with a decrease in

N. Tzourio-Mazoyer (&)
D. Marie
L. Zago
G. Jobard
G. Perchey
G. Leroux
E. Mellet
M. Joliot
F. Crivello
L. Petit
B. Mazoyer GIN, Groupe d’Imagerie Neurofonctionnelle UMR5296, Univ. Bordeaux, Baˆt. PQR, CHU Pellegrin, 33000 Bordeaux, France e-mail: [email protected] N. Tzourio-Mazoyer
D. Marie
L. Zago
G. Jobard
G. Perchey
G. Leroux
E. Mellet
M. Joliot
F. Crivello
L. Petit
B. Mazoyer CNRS, GIN, UMR 5296, 33000 Bordeaux, France N. Tzourio-Mazoyer
D. Marie
L. Zago
G. Jobard
G. Perchey
G. Leroux
E. Mellet
M. Joliot
F. Crivello
L. Petit
B. Mazoyer CEA, GIN, UMR 5296, 33000 Bordeaux, France

both the surface area of the anterior HG and HG functional activity. Participants with a single left HG exhibited leftward anatomical and functional asymmetry of HG, but participants with a left duplication lost either anatomical and/or functional leftward asymmetries. Finally, manual preference was related to HG anatomy, but not to HG functional asymmetries measured during LIST. The anatomical characteristics of left-handers (lower occurrence of right HG duplication and a smaller surface area of the right first HG) thus appeared to be unrelated to variations in speech lateralization with handedness. Keywords Hemispheric specialization
Speech
Heschl’s gyri
Handedness

Introduction Hemispheric specialization for speech varies with handedness, with left-handers exhibiting a larger variability in hemispheric dominance for language in neuropsychological studies (Hecaen and Sauguet 1971; Hardyck and Petrinovich 1977), Wada testing (Wada and Rasmussen 1960; Mateer et al. 1984), and, more recently, functional imaging of healthy volunteers (Tzourio et al. 1998a; Pujol et al. 1999; Knecht et al. 2000; Szaflarski et al. 2002; Tzourio-Mazoyer et al. 2004; Hund-Georgiadis et al. 2002). Although of primary focus, manual preference (MP) is not the only factor explaining inter-individual variability in speech lateralization. For instance, we previously showed that factors influencing the lateralization of either language production or language comprehension differed: while production lateralization varied with MP, speech-listening lateralization in the same individuals varied with both MP and anatomical variations of areas involved in the processing of speech

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sounds. One of these factors was the left planum temporale surface area, which is composed of the unimodal associative auditory cortex; the increase in this surface area was associated with increased leftward lateralization during story listening without any influence on the lateralization of speech production (Tzourio et al. 1998b; Josse et al. 2003). This difference may explain the existence of rare dissociations between hemispheres that dominate the comprehension and production of language in healthy individuals (TzourioMazoyer et al. 2004). These investigations of the structure–function relationships of the hemispheric lateralization of language did not consider the anatomy of the anterior (or first) gyrus of Heschl (aHG), a macroscopic marker of the primary auditory cortex (PAC) (Rademacher et al. 1993, 2001; Rivier and Clarke 1997; Clarke and Rivier 1998; Morosan et al. 2001). Previously, Zatorre questioned whether the anatomical features of auditory cortical areas predict individual patterns of the hemispheric lateralization of speech (Zatorre et al. 2002). This question relates to the question of the lateralization of sound processing, while the left auditory cortex is relatively more specialized in the temporal processing of sounds, which is mandatory for speech processing, the right auditory areas are more involved in tonal processing (Zatorre et al. 2002; Zatorre and Gandour 2008; Hickok and Poeppel 2007; Boemio et al. 2005). A structure–function relationship between the anatomy of Heschl’s gyrus and auditory cortex lateralization for sound processing was previously demonstrated; the volume of the left Heschl’s gyrus was correlated with the amount of the left auditory cortex activated during the temporal processing of sounds, while the volume of the right Heschl’s gyrus was correlated with the amount of the right auditory cortex activated during tonal processing (Warrier et al. 2009). Interestingly, a clear-cut functional lateralization of these two types of sound processing was observed only in the five individuals displaying leftward asymmetry of the volume of the aHG (Warrier et al. 2009). This observation suggests that aHG volume asymmetry may be a marker of the strength of speech functional lateralization in Heschl’s region. Moreover, expertise or proficiency in phonological processing (Wong et al. 2008; Golestani et al. 2007) and early bilingualism (Ressel et al. 2012) have also been associated with larger left aHG volume. Duplications in Heschl’s gyrus have been related to expertise; in the right hemisphere of both musicians and non-musicians, a high occurrence of Heschl’s gyrus duplications has been associated with expertise in pitch shift (Schneider et al. 2005), and left duplications were observed more frequently in individuals with phonetic expertise (Golestani et al. 2011). One difficulty in further investigating this anatomofunctional relation comes from the highly variable anatomy of Heschl’s gyrus, in terms of both gyrification pattern and

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size (Rademacher et al. 2001; Morosan et al. 2001). Asymmetries in the Sylvian fissure appear as early as 24 weeks of gestation (Hill et al. 2010) and remain stable after birth (Li et al. 2013), suggesting that anatomical variability in Heschl’s gyrus may contribute to inter-individual variability in speech functional lateralization. We recently investigated the anatomy of Heschl’s gyrus in 430 healthy volunteers from BIL&GIN, a database of healthy volunteers dedicated to the study of hemispheric specialization; duplication of Heschl’s gyrus occurred frequently in these subjects, and the aHG surface area was smaller in the presence of duplication (Marie et al. 2013). This decrease in aHG surface area on the duplicated side was associated with strong differences in its asymmetry, with the number of gyri in the left and right hemispheres in each individual (the inter-hemispheric pattern of duplications) varying. In addition, in this population balanced for handedness, left-handers displayed a lower occurrence of duplication on the right and decreased leftward asymmetry of the aHG (Marie et al. 2013). This observation raises the question of whether such differences in Heschl’s anatomy in left-handers are related to the lower frequency of leftward speech asymmetries reported in this population. To test the hypothesis that anatomical variability in Heschl’s gyrus is related to the functional lateralization of speech perception, we studied 281 participants from the BIL&GIN. Each volunteer underwent functional resonance magnetic imaging (FMRI) while listening to a list of words (LIST), which involves all stages of the cortical processing of word listening. We first calculated the hemispheric functional lateralization index (HFLI) via Wilke’s method (Wilke and Lidzba 2007). Applying the method developed by Seghier et al. (2011), we then identified the cortical areas in each hemisphere whose BOLD variation significantly explained the variance in the HFLI of speech listening. We also investigated the relationship between the inter-individual variability of functional areas and the variations in the inter-hemispheric duplication pattern of Heschl’s gyrus. Last, we questioned whether differences in the anatomy of Heschl’s gyrus, observed in terms of subject handedness, were related to differences in lateralization during speech listening.

Materials and methods Participants The present study included 281 healthy volunteers, 135 left-handers (67 men) and 146 right-handers (72 men). All participants were recruited during the same period through announcements made in the University. They were selected as having French as their mother tongue and were free from

Brain Struct Funct

developmental problems, neurological antecedents, and psychiatric history, with the exception of past and resolved histories of depression. All participants were free of brain abnormalities on magnetic resonance imaging (MRI) as assessed by an expert neuroradiologist. This study was approved by the local ethics committee (Comite´ de Protection des Personnes Nord-Ouest). All participants provided informed written consent and received compensation for their participation. The mean (±standard deviation) subject age was 25 ± 6 years (range [18, 57]). The mean level of education (corresponding to the number of schooling years since the first grade of primary school) was 15 ± 2 years [11, 20], corresponding to 4 years at the university level. MP was self-reported by the participants, and its strength evaluated with the Edinburgh inventory (Oldfield 1971). The mean Edinburgh Score was 93 ± 12 [41; 100] for right-handers and -65 ± 40 [-100, 55] for left-handers. Right-handers were 2.5 years older (p = 0.0007, t test) and had 1.1 more years of education than left-handers (p \ 0.0001, t test). Skull perimeter (SP) was measured in each participant. The mean SP was 57 ± 2 cm, and it significantly differed by sex (men 58 ± 2 cm, women 56 ± 2 cm, p \ 0.0001, t test). Image acquisition Imaging was performed with a Philips Achieva 3 Tesla MRI scanner at the Cyceron Imaging Center between 2007 and 2011. Structural MRI protocols consisted of a localizer scan and a high-resolution 3D T1-weighted volume obtained using a 3D-FFE-TFE sequence (3T Intera Achieva, Philips Medical System, TR = 20 ms; TE = 4.6 ms; flip angle = 10°; inversion time = 800 ms; turbo field echo factor = 65; sense factor = 2; matrix size = 256 9 256 9 180 mm; 1 mm3 isotropic voxel). T2*-weighted multislice images were also acquired (T2*-weighted fast field echo, sequence parameters: TR = 3,500 ms; TE = 35 ms; flip angle = 90°; sense factor = 2; 70 axial slices; 2 mm3 isotropic voxel size) to allow registration with functional BOLD images. Functional images were acquired via whole-brain T2*weighted echo planar image acquisition (TR = 2 s; TE = 35 ms; flip angle = 80°; 31 axial slices; 3.75 mm3 isotropic voxel size) covering the same field of view as the T2*-FFE acquisition. Anatomical image analysis

defined according to the criteria of Rademacher (Rademacher et al. 1993; Penhune et al. 1996; Leonard et al. 1998) as reviewed in Abdul-Kareem and Sluming (2008); both complete and partial duplications were considered a double Heschl’s gyrus. There are two Heschl’s sulci in cases of complete duplication, the first one splitting the gyrus into two parts; in cases of partial duplication, the gyrus is partially split by the sulcus intermedius of Beck, which never reaches the internal border of the gyrus. In case of partial duplication, we considered that there was duplication when the sulcus intermedius length was at least onethird of Heschl’s gyrus length, and a complete description of our method can be found in Marie (Marie et al. 2013). The number of Heschl’s gyri in each hemisphere allowed the definition of the inter-hemispheric duplication pattern for each participant (L: left; R: right; L1R1: bilateral single Heschl’s gyrus; L1R2: single left and right duplication; L2R1: left duplication and right single; L2R2: bilateral duplication). Delineation of aHG In each participant’s native space, Heschl’s gyrus, or the aHG in cases of duplication, was manually delineated by NTM. We refer to this anatomical region as the aHG to be consistent with the previous publications (Smith et al. 2011); although there are no precise macroanatomical landmarks to define the PAC based on cytoarchitecture, the first transverse temporal gyrus remains the best macroanatomical landmark for PAC (Penhune et al. 1996; Rademacher et al. 2001). Twodimensional tracing was optimized via the knife-cut method, which is based on the reconstruction of an oblique section plane passing through the Sylvian fissure (Kulynych et al. 1993; Tzourio-Mazoyer et al. 2010) via the dedicated custom software Voxeline (Diallo et al. 1998). An oblique section plane parallel to the Sylvian fissure was generated, uncovering the superior temporal plane and passing through the point where Heschl’s gyrus was largest. Axial, coronal, sagittal, and oblique slices were displayed simultaneously for identifying duplications and the borders of Heschl’s gyrus. In cases of partial duplication, we used a virtual line corresponding to the internal extent of the sulcus intermedius of Beck corresponding to the posterior border of the aHG, while in cases of complete duplication, the posterior border of the aHG was defined as the first Heschl’s sulcus. Last, the aHG was delineated on the oblique slice in each participant’s native space, and its surface area was calculated (mm2). This methodology was fully described by Marie et al. (2013).

Identification of duplications and inter-hemispheric duplication patterns

Speech-listening task (LIST)

A single expert (NTM) identified the gyrus of Heschl and its gyrification type. The number of gyri (one or two) was

Each participant completed a slow event-related speechlistening task involving list of overlearned familiar words.

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This task was designed to be sensitive to all auditory aspects of word listening, including phonological and prosodic processing at the word and list level as well as automated lexical processing. During the LIST, the participants briefly (1 s) viewed a scrambled drawing and then carefully listened to a list of months, days of the week, and/ or seasons while fixating a central cross. The mean duration of word-list auditory presentation was 4,386 ± 484 ms. At the end of the each list’s auditory presentation, the participants had to press a button. A reference task followed list presentation that consisted of the detection of the transformation of a centrally displayed cross into a square.

Fig. 1 LIST slow-event paradigm (a) and corresponding brain activation pattern averaged over 281 healthy volunteers (b). a Structure of one of the 13 slow events of LIST. After a 1-s presentation of a scrambled drawing, participants listened to a list of words while fixating a central cross; participants pressed a pad at the end of the list. Participants pressed the pad a second time when the cross was switched to a square. b Surface rendering and axial slices of the average activation map (red) superimposed on the average anatomical image of the BIL&GIN template, which included 80 participants (p \ 0.05, FWE corrected)

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When they detected this change, the participants pressed a response button. The LIST included thirteen 14-s trials (Fig. 1). The experiment was programed with the E-prime software (Psychology Software Tools, Pittsburg, PA, USA) integrated in the IFIS-SA system (MRI Devices Inc., Gainesville, FL, USA). Visual stimuli were projected onto a translucent screen and participants viewed a backlit projection coming from the rear of the magnet bore through a mirror mounted on the head coil. Subjects’ motor responses were collected using two fiber-optic response pads.

Brain Struct Funct

Functional image analysis LIST contrast maps Pre-processing was based on Statistical Parametric Mapping subroutines (SPM5, Wellcome Trust Centre for Neuroimaging, London, UK; http://www.fil.ion.ucl.ac.uk/ spm). Anatomical T1-weighted volumes were spatially normalized by aligning individual anatomical volumes to specific cerebral tissue templates built from the T1 images of 80 right-handed subjects (40 men), including 19 participants in the present study, acquired with the same scanner and acquisition parameters. Spatial normalization parameters were set to their SPM5 default values, providing a 3D, spatially normalized deformation field for each subject. The functional run was corrected for slice timing and motion and registered onto the T2*-MS volume. Combining the T2*-MS and T1-weighted registration parameters and the spatial normalization parameters, functional images were resampled into the template space and spatially smoothed (Gaussian 6 mm full width at half maximum filter). For each subject, the effect of interest was modeled by boxcar functions computed with paradigm timing and convolved with a standard hemodynamic response function (SPM5). Finally, the effect of interestrelated contrast maps, word-list listening minus minus cross change detection task, was calculated. LIST voxel-wise asymmetry contrast maps To investigate the asymmetry patterns of activation for LIST, we performed voxel-based functional asymmetry analyses by generating maps of the laterality difference at each voxel for each subject as follows: (1) contrast images from the first-level analysis (word-list listening minus cross change detection) were copied and each copy was flipped along the inter-hemispheric fissure (i.e., x axis mirror images), and (2) the resulting flipped images were then subtracted from their original (unflipped) versions to create maps of asymmetry. Voxel-based maps of asymmetry therefore code the relative difference between the activity at each voxel and at its homolog in the other hemisphere. Calculation of HFLI for LIST For each participant, the HFLI was calculated on the entire hemisphere using the lateralization index (LI) toolbox available on the SPM website (Wilke and Lidzba 2007). HFLIs were computed with a bootstrap algorithm from each participant list of words minus a reference t map thresholded at t = 0 (positive t map) with a lower bootstrap sample of five voxels and a higher sample size of 1,000 voxels, with a resample ratio of k = 0.25. Weighted HFLI

means were reported. HFLIs were calculated within the gray- and white-matter compartments of the template used for FMRI data normalization, excluding the cerebellum. This calculation yielded values between -100 and ?100, with -100 indicating purely right activation and ?100 purely left activation. Statistical analysis Statistical analyses were performed using JMP statistical software package, Version 11 pro (SAS Institute Inc., Cary, NC, USA). Anatomical analyses A descriptive analysis of the frequency of gyrification in each hemisphere and of the various inter-hemispheric gyrification patterns was completed for this sample of participants. To evaluate differences in hemispheric Heschl’s gyrus number and inter-hemispheric gyrification pattern with regard to handedness, multinomial logistic-regression models were applied, with SP, age, and educational level as covariates. To test the effect of duplication (one or two gyri) on aHG surface area, we carried out an ANCOVA for each hemisphere, including the number of gyri and MP, SP, sex, age, and educational level as covariates. To test whether asymmetry of the aHG surface area (left-minus-right surface area) varied with the inter-hemispheric gyrification pattern and MP, we completed an ANCOVA with MP and gyrification pattern as factors, and included SP, age, and educational level as covariates. The size of effects in all analyses was measured with the eta-squared value. Functional analyses Calculation of LIST mean contrast map and voxel-wise asymmetry map Individual LIST maps and asymmetry maps were entered into a group analysis with SPM5 applying a fixed-effect analysis corresponding to a one-sample t test. Statistical threshold was set at p \ 0.05, Family-Wise Error (FWE) corrected. Correlation of LIST BOLD variation with HFLI To identify the brain areas in which activity supported differences in LIST HFLI, we calculated the correlation between the BOLD contrast map and the HFLI, applying the method proposed by Seghier et al. (2011). Positive and negative correlations of LIST individual contrast maps with HFLI values (SPM5, p \ 0.05 false discovery

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rate-corrected statistical threshold) were masked inclusively by the LIST mean contrasts map (mask: p \ 0.05 uncorrected for multiple comparisons). The significant clusters obtained in this analysis, which corresponded to the areas that were either positively or negatively correlated with HFLI were used as mask to define to define a set of regions of interest that we refer to as LatROIs and are further described in the results section. Descriptive statistics in for LatROIs and quantification of each LatROI contribution to HFLI’s variability

Table 1 Inter-hemispheric gyrification pattern of Heschl’s gyri Left Heschl’s gyrus number, % (N) Right Heschl’s gyrus number, % (N)

L1

L2

Total

R1

41.6 (117)

15.3 (43)

56.9 (160)

R2

22.1 (62)

21 (59)

43.1 (121)

Total

63.7 (179)

36.3 (102)

100 (281)

Contingency table of the left (L) and right (R) Heschl’s gyrus configurations (1: single Heschl’s gyrus; 2: duplication of Heschl’s gyrus)

Results

The distribution of the inter-hemispheric gyrification patterns is detailed in Table 1. A trend toward a significant difference in inter-hemispheric gyrification pattern according to MP was observed (multinomial regression, Chi squared = 23.86, p = 0.06, eta squared = 0.02), with the L1R1 pattern occurring more frequently in left-handers than right-handers (49.0 and 34.9 %, respectively). When considering the hemispheres separately, right duplication occurred more frequently in right-handers than in lefthanders (48.7 vs. 39.4 %, Chi squared = 3.61, p = 0.057), while there was no difference in left Heschl’s gyrus anatomy according to MP. The presence of duplication led to a significant decrease in aHG area (left hemisphere: 281 mm2 with duplication vs. 358 mm2 without duplication; F(1,275) = 66, p \ 0.0001, eta squared = 0.18; right hemisphere: 290 mm2 with duplication vs. 339 mm2 without duplication; F(1,275) = 33.7, p \ 0.0001, eta squared = 0.09. Heschl’s gyri inter-hemispheric gyrification patterns had a highly significant effect on aHG asymmetry [F(3,273) = 16.8, p \ 10-4, eta squared = 0.16]. aHG was leftward asymmetrical for the L1R1 (14 ± 93 mm2) and L1R2 (77 ± 97 mm2) configurations, but rightward asymmetrical for the L2R1 (-54 ± 104 mm2) and L2R2 configurations (-8 ± 76 mm2). A significant main effect of MP on aHG surface area was also present [F(1,274) = 9.03, p = 0.003, eta squared = 0.026]. The residuals of an ANCOVA of aHG surface area, which included inter-hemispheric gyrification pattern, sex, SP, age, and educational level, showed that right-handers were leftward asymmetrical (left–right aHG = 15 ± 88 mm2, t = 2.04, p = 0.04), whereas lefthanders were rightward asymmetrical (left–right aHG = -16 ± 92 mm2, t = -2.02, p = 0.04).

Anatomical results

Functional results

The macroscopical anatomy of Heschl’s gyri in the present sample did not differ from that observed in the larger population they were selected from (Marie et al. 2013). There was a high occurrence of duplication, with 58 % of participants exhibiting duplication in at least one hemisphere (Table 1).

Group average LIST activation and asymmetry maps

We first measured the BOLD hemispheric values and asymmetry of each LatROI. To quantify the relative contribution of each left and right LatROI to the variability of the HFLI, we performed an ANCOVA on the HFLI values that included the ten LatROIs as factors in the model and we measured the contribution of each LatROI to the HFLI with the eta-squared value. Variations of speech asymmetries with Heschl’s gyrus inter-hemispheric gyrification pattern and MP Statistical analysis of the BOLD values associated with LatROIs was completed via two-factor MANCOVA with repeated measures of the LatROIs (five levels) and hemispheric side (two levels: left and right) main effects. This MANCOVA model also included a LatROI 9 Side interaction. Heschl’s gyri inter-hemispheric gyrification pattern and MP were entered as between-subject factors. Age, sex, educational level and SP were included as confounding variables. Post hoc analysis included a second MANCOVA to characterize the main effect of Side and Side 9 LatROI interaction on LatROI asymmetry values. In this MANCOVA, LatROI was a five-level within-subject factor, and Heschl’s gyri inter-hemispheric gyrification pattern and handedness were four- and two-level between-subject factors, respectively. Age, sex, educational level and SP were included as confounding variables. These analyses were refined using simple ANOVAs on each LatROI as additional post hoc analyses.

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The LIST activated bilateral cortical areas including the superior temporal gyri reaching the temporal pole anteriorly, the inferior frontal gyri, the inferior two-thirds of the precentral gyrus, the supplementary motor area in the frontal

Brain Struct Funct Table 2 Clusters of significant BOLD increase during LIST Cluster size

Peak anatomical location

x

y

12179

L Heschl’s gyrus

-48

-16

L Heschl’s gyrus

-46

-20

6

43.2

L Heschl’s suclus

-50

-24

6

14.4

L Heschl’s gyrus

-54

-8

-4

40.8

L intra-occipital sulcus

-32

-74

26

14.3

L superior temporal gyrus pole

-50

6 -12

36.7

L inferior temporal gyrus

-48

-62

-8

16.6

L superior temporal gyrus

-56

-18

-2

34.5

L inferior occipital gyrus

-48

-64

6

10.6

L planum temporale

-62

-32

6

33.1

L temporal pole

-40

-4

-20

10.2

L anterior insula L posterior superior temporal gyrus

-34 -56

24 -50

2 8

27.2 24.7

L parahippocampal gyrus L posterior STS

-22 -50

38 -50

-12 4

10.1 9.9

L fusiform gyrus

L precentral gyrus

-52

-6

48

24.1

L pars opercularis of the inferior frontal gyrus

-50

12

2

22.6

L pars triangularis of the inferior frontal gyrus

-56

14

14

21.1

L superior temporal gyrus L pars opercularis of the inferior frontal gyrus 14289

-48 -50

z

Table 3 Clusters of significant BOLD asymmetry during LIST

-42 16

4

46 26

t

Cluster size

Peak anatomical location

x

y

43.5

5693

L Heschl’s gyrus

-38

-34

2630

20.6 20.4

L inferior parietal

-40

-44

42

18.4

t

12

27.7

-30

-48

-10

R STS

50

-32

0

18.1

R posterior insula

36

-16

6

12.3

R Heschl’s gyrus

34

-18

10

11.6

R STS

52

-26

18

16.7

R planum polare

60

-6

8

9.90

R temporal pole

48

14

-26

9.14

R STS 2028

z

L rolandic genu

9.75

52

-26

-4

17.44

-32

-26

56

16.7

R Heschl’s gyrus

50

-10

2

41.4

L rolandic sulcus

-50

-10

48

16

R superior temporal gyrus pole

54

0

-8

40.8

L precentral gyrus

-44

-4

54

12.3

R planum temporale

52

-26

6

40.3

L SMA

-6

-8

54

14.9

L pre-SMA

-6

0

56

13.4

R intra-occipital sulcus R cuneus

22 2

-48 -88

20 16

13.7 11.5

R Heschl’s gyrus

46

-22

10

38.8

R Heschl’s gyrus

48

-18

8

37.9

R Heschl’s gyrus

54

-14

6

37.7

R pre-SMA R pars opercularis of the inferior frontal gyrus

-2 50

4 14

62 24

30.4 25.2

R insula

36

24

0

24.8

R pars triangularis of the inferior frontal gyrus

50

18

4

22.3

R pars triangularis of the inferior frontal gyrus

46

R precentral gyrus

54

-2

44

20.9

R precentral gyrus

50

6

50

20.8

R inferior parietal

50

-38

48

20.2

R inferior parietal

42

-44

44

20.2

R precentral gyrus

50

12

42

19.4

22

2

21.9

567

L thalamus

-12

-26

2

21.3

653

R thalamus

12

-24

-2

20.4

544

Cuneus and precuneus

8 -74

48

17.1

160

L hand motor area

54

14.8

-34

-24

1400

x, y, and z values are stereotaxic coordinates (in mm) of cluster peak anatomical locations (cluster size is in number of voxels). Peak coordinates are reported for t [ 11 only L left, R right, SMA supplementary motor area

lobe, and the inferior parietal cortices (Fig. 1b). Subcortical areas were also involved, including the head of the caudate nuclei, the putamen, and the thalami (Table 2, Fig. 1b).

2333

R cuneus 810

10

-94

22

11.4

L pars opercularis

-60

2

26

12.02

L precentral gyrus/pars opercularis

-44

4

26

7.9

177

R thalamus

1255

R medial superior frontal

8

-10

12

10.4

14

52

36

505

9.7

L middle frontal gyrus

-44

52

6

234

8.8

R intra-occipital sulcus

40

-70

38

8.5

x, y, and z values are stereotaxic coordinates (in mm) of cluster peak anatomical locations (cluster size is in number of voxels). p \ 0.05, Family-Wise Error (FWE) corrected L left, R right, SMA supplementary motor area, STS superior temporal sulcus

The voxel-wise asymmetry map revealed leftward asymmetries in the precentral gyrus at the level of hand motor representation and in its lower third, corresponding to the lip and tongue representation (Takai et al. 2010), in the supplementary motor area, and in the pre-supplementary motor area, in the head of the caudate (Table 3). Leftward asymmetry was also significant in Heschl’s gyrus, the anterior insula, the posterior superior temporal and middle temporal gyri, and the anterior occipital sulcus area. Note that a leftward asymmetry was also present in the fusiform gyrus (Fig. 2a). Rightward asymmetries overlapped the superior parietal and frontal eye field areas,

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Brain Struct Funct Fig. 2 Correlation between HFLI and voxel-based BOLD signal variations during LIST superimposed on the 80-participant anatomical template of the BIL&GIN. a Surface rendering of the positive (red) and negative (cyan, p \ 0.05 false discovery rate-corrected) correlations between HFLI and BOLD variations and of the asymmetry map calculated by computing the voxel-wise difference in mirrored voxels, left minus right in the left hemisphere and right minus left in the right hemisphere (yellow). L left, R right; p \ 0.05 FWE corrected for multiple comparisons for LIST asymmetry contrasts maps. Numbers are the stereotaxic zcoordinates of each slice. b Axial view of the two clusters used to define the LatROIs. Clusters with positive correlation with LIST HFLI are located in Heschl’s gyrus (HG), the supramarginalis gyrus (SMG), and anterior insula (INS), while clusters with negative correlation overlap the anterior and posterior superior temporal sulcus (STSa and STSp, respectively)

the thalamus, and the lingual gyrus. In the temporal lobe, a rightward asymmetry was located along the anterior twothirds of the superior temporal sulcus (STS; Fig. 2a). Descriptive statistics of LIST HFLI The mean hemispheric functional asymmetry of BOLD variations during LIST was significantly rightward asymmetrical (-4.88 ± 33, p = 0.007). The inter-individual variability of the HFLI was important, with values varying from -70 to ?80, with a non-Gaussian distribution. ANOVA revealed a significant effect of age [F(1,275) = 4.82, eta squared = 0.01, p \ 0.04], with a slight decrease in asymmetry with increasing age. The effect of MP on HFLI did not reach significance, although there was a trend for a loss of rightward asymmetry in left-handers [right-handers: -9.1 ± 32; left-handers -0.31 ± 35; p = 0.07, F(1,275) = 4.08, eta squared = 0.1]. There was no effect of SP or sex on LIST HFLI.

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Correlation of LIST BOLD variation with HFLI and definition of LatROIs Positive correlations encompassed the left Heschl’s gyrus from its medial to lateral parts, spreading along the Heschl’s gyrus posterior area and extending to the supramarginalis gyrus (SMG, Table 4, Fig. 2). A cluster of significant negative correlation was located in the mid-part of the right STS. These clusters served at defining the LatROIs, and, to calculate BOLD values of each LatROI in each hemisphere, we defined the symmetrical of each LatROI by flipping it along the x axis. The first cluster, which included 838 voxels overlapping Heschl’s gyrus and SMG was split into two ROIs: Heschl’s gyrus (HG-ROI) and SMG (SMGROI), the left anterior insula significant cluster served as a mask to define INS-ROI. The right STS cluster was split into two by cutting through a small connection between its two parts, resulting in the definition of STSa-ROI and STSp-ROI (Table 4, Fig. 2).

Brain Struct Funct Table 4 Clusters exhibiting positive (top) or negative (bottom) correlations between HFLI and BOLD signal variations during LIST. Statistical threshold for the correlation analysis was set at p \ 0.05 false discovery rate, retaining only clusters larger than 30 voxels

Cluster size

x

y

z

p

t

LIST positive correlation with HFLI 838

115 The correlation map was masked inclusively by the LIST mean activation after applying a p \ 0.05 threshold (uncorrected for multiple comparisons)

Peak anatomical location

L Heschl’s sulcus

-52

-24

2

0.0004

6.0

L supramarginal gyrus

-42

-40

24

0.0007

5.5

L lateral edge of Heschl’s sulcus

-66

-16

6

0.0007

5.3

L supramarginal gyrus

-48

-38

26

0.0007

5.3

L supramarginal gyrus

-50

-44

34

0.002

4.9

L lateral edge of Heschl’s gyrus

-64

-6

6

0.04

3.6

L insula

-30

26

8

0.001

3.9

R superior temporal sulcus

60

-28

0

0.005

4.9

R superior temporal sulcus R superior temporal sulcus

56 54

-14 -14

4 -8

0.02 0.021

4.4 4.3

LIST negative correlation with HFLI 146

R right; L left

Table 5 BOLD signal variations during LIST and corresponding contributions to HFLI in the five functional volumes of interest (LatROIs) LatROIs (N voxels)

HG (278)

SMG (380)

INS (170)

STSa (99)

STSp (39)

BOLD signal variations (mean ± standard deviation) Left

2.86 ± 1.00

0.75 ± 0.64

0.33 ± 0.29

1.42 ± 0.65

1.75 ± 0.82

Right

2.34 ± 0.84

0.28 ± 0.30

0.32 ± 0.30

1.87 ± 0.89

2.78 ± 1.31

Asymmetry (left–right)

0.51 ± 0.91*

0.47 ± 0.64*

0.01 ± 0.25

-0.44 ± 0.82*

-1.03 ± 1.28*

Left

0.11

0.04

0.02

0.00

0.01

Right Asymmetry (left–right)

0.05 0.12

0.00 0.08

0.00 0.01

0.02 0.02

0.02 0.02

Size of effect (eta squared)

BOLD signal variations are given in standardized units. The size of the effect of each LatROI on LIST HFLI was measured with the eta-squared value HG Heschl’s gyrus, SMG supramarginalis gyrus, INS anterior insula, STSa anterior part of the superior temporal sulcus, STSp posterior part of the superior temporal sulcus * p \ 0.0001

To define homotopic regions to calculate asymmetries, each Lat-ROI was flipped along the x axis. Because the HG-ROI and the mirrored STSp-ROI partially overlapped, the last step of their definition consisted of excluding the overlapping voxels, which led to final volumes of 278 and 39 voxels, respectively (Table 5). We calculated the LIST BOLD values in each LatROI in the right and left hemispheres and their left-minus-right asymmetry (Table 5). Descriptive statistics of LatROIs and quantification of their contributions to HFLI variability The HG-ROI had the highest left BOLD increase and the largest leftward functional lateralization, while the left HG-ROI had the largest effect on LIST HFLI, explaining 11 % of its variance (Table 5). Note that the right HG-ROI explained 5 % while the HG-ROI asymmetry explained 12 % of the HFLI variance.

The left SMG-ROI exhibited moderate BOLD increase with a strong leftward asymmetry. The left SMG-ROI explained 4 % of HFLI variance; the right SMG-ROI explained none of the LIST HFLI variance, but its asymmetry explained 8 % of it. The INS-ROI was the only region that did not exhibit any asymmetry, and only the left INS-ROI explained 2 % of the LIST HFLI variance. The STSp-ROI showed the strongest right hemisphere BOLD increase and the strongest rightward lateralization, and explained the same amount of HFLI variance as the right STSa-ROI (2 %). This last region had bilateral activation that was significantly rightward lateralized. Structure–function relationships in right- and left-handers: variation of asymmetries with Heschl’s gyrus anatomy MANCOVA with repeated measure applied to BOLD variations in LatROIs revealed a significant Side 9 MP

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interaction [F(1,272) = 5.89, p = 0.016], a significant ROI 9 Inter-hemispheric duplication pattern interaction (Hottling–Lawley, approximated F = 1.85, p = 0.037), and a significant Side 9 ROI 9 Inter-hemispheric duplication pattern interaction (Hottling–Lawley, approximated F = 2.43, p = 0.004). Post hoc analyses indicated that the Side 9 ROI 9 Inter-hemispheric duplication pattern interaction occurred because only the HG-ROI asymmetry varied with the inter-hemispheric duplication pattern (Fig. 3). Post hoc ANOVA demonstrated that the interhemispheric duplication pattern explained nearly 8 % of HG-ROI asymmetry variability [F(3, 272) = 7.8, eta squared = 0.78]. The L1R2 pattern had the largest leftward functional asymmetry, which was significantly larger than that of the L2R2 duplication pattern (HG-ROI asymmetry L1R2: 0.84 ± 0.99, L2R2: 0.41 ± 0.75, p = 0.024), although this asymmetry did not differ from that of the L1R1 pattern (HG-ROI asymmetry = 0.59 ± 0.93). The L2R1 pattern was associated with symmetrical BOLD activity and was significantly different from the three other

configurations (L2R1 HG-ROI asymmetry = 0.003 ± 0.65; Fig. 3). Further post hoc testing of the left HG-ROI (via ANOVA) showed that when a duplication was present, there was a decreased BOLD variation as compared to that accompanying a single gyrus (single left: mean BOLD in the left HG-ROI = 3.04 ± 1.04, left duplication = 2.55 ± 0.84, F(1, 274) = 17.1, p \ 0.0001, eta squared = 0.060). The same reduction was observed on the right (single right gyrus: mean BOLD in the right HG-ROI = 2.46 ± 0.85, right duplication = 2.18 ± 0.80, F(1, 274) = -2.99, p = 0.003, eta squared = 0.033). Exploration of the Side 9 MP interaction in LatROI asymmetries indicated that right-handers had less asymmetry than left-handers in terms of mean LatROI values (Fig. 3). Post hoc analysis using an ANOVA of the LatROIs revealed that although there were systematically higher values of HFLI in left-handers, there was no significant difference between MPs in any LatROI asymmetry (in particular in the HG-ROI [F(1,272) = 0.57, p = 0.45)], except in the STSa-ROI, where right-handers displayed larger rightward asymmetry [F(1,272) = 9.80, p = 0.002, eta squared = 0.038]; however, this interaction was not significant. Summary of results Mean LIST HFLI was rightward asymmetrical with a trend toward decreased rightward asymmetry in left-handers. The inter-individual variability of LIST HFLI was explained by positive correlation with BOLD variations in the left HG-ROI, SMG-ROI, and INS-ROI, and negative correlation with BOLD variations in the right STSa-ROI and STSp-ROI. These two sets of ROIs were, respectively, leftward and rightward asymmetrical during LIST. The inter-hemispheric gyrification pattern explained parts of the variance in the aHG anatomical and HG-ROI functional asymmetries during LIST. Duplication was associated with a decrease in HG-ROI functional activity on the ipsilateral side. The same pattern was present on the aHG surface area. As compared to right-handers, lefthanders had fewer right duplications and lacked aHG surface area asymmetry, but there was no difference in MP in terms of the functional asymmetry of the HG-ROI.

Fig. 3 Side 9 MP and Inter-hemispheric duplication pattern 9 ROI 9 Side interaction graphs. (Top) The MP 9 Side interaction was due to a systematic, more rightward asymmetry in right-handers. (Bottom) The Inter-hemispheric gyrification pattern 9 ROI 9 Side interaction was due to variations in the BOLD asymmetries with the inter-hemispheric gyrification pattern only in the HG-ROI (L1R1 bilateral single gyrus, L1R2 left single and duplicated right gyri, L2R1 duplicated left and single right, L2R2 bilateral duplication). L left, LH left-handers, R right, RH right-handers

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Discussion The present work has demonstrated, for the first time, an association between functional asymmetries in the Heschl’s gyri hosting primary auditory areas and the interindividual variability in the inter-hemispheric gyrification pattern of Heschl’s gyrus. It also revealed that left-handedness, which was associated with lower leftward

Brain Struct Funct

asymmetry of the aHG surface area, had no impact on the functional lateralization of Heschl’s gyrus during LIST. These results show the existence of an anatomo-functional link in the lateralization of the primary auditory areas during speech listening that is independent of MP, in favor of the hypothesis that different influences act on the various regions involved in language processing, likely in relation to both their structural and functional hierarchies and the language modality that they are supporting. Methodological issues We applied the method proposed by Seghier et al. (2011), which consists of analyzing the correlation between HFLI and BOLD variation at each voxel to unravel the key areas supporting LIST hemispheric asymmetries. As emphasized by Seghier et al., ‘‘an advantage of this method is that it circumvents the challenges associated with computing regionally specific lateralization index (LI)-based ROIs. Specifically, the problem with assessing LI in multiple regions is that voxel-based analyses of FMRI data are complex, and therefore widespread heterogeneity needs to be reduced to a few manageable variables that minimize the number of regions tested.’’ In this context, it appears consistent to use regression analysis to reveal clusters in each hemisphere that significantly explain inter-individual variability in speech hemispheric asymmetries. However, because Wilke’s method is more sensitive to voxels with larger t values, it is possible that the HFLIs calculated with this method could have biased the results for these correlations (Wilke and Lidzba 2007; Wilke and Schmithorst 2006). We thus compared t values in the LIST BOLD contrast map obtained with SPM5 with the size of the effect that BOLD variations in regions had on HFLI. The largest effect on HFLI was that of the left Heschl’s gyrus; the left HG-ROI had the largest mean t value in the SPM5 statistical map (t = 32) and the largest effect as measured by the eta-squared value (0.11, corresponding to 11 % of the variance in HFLI). However, this was not the case for the other regions. The left STSp-ROI had a mean t value of 30 with a 1 % effect, the right STSp-ROI had a mean t value of 31 and a 2 % effect, the right STSa-ROI had a mean t value of 28 and a 2 % effect of 2 %, and the left STSa-ROI had a mean t value of 28 and a 0 % effect. Variations in activity and/or lateralization of phonological areas explain the inter-individual variability of speech hemispheric asymmetry Seghier et al. (2011) observed that variation in hemispheric asymmetry during a semantic task was associated with variations in activity in both the left and right hemispheres. In the present work, hemispheric lateralization of word

listening mainly depended on the activity of phonological areas that had strong and opposite asymmetries. Lower rightward hemispheric asymmetry was associated with stronger activation of the left Heschl’s gyrus, the adjacent SMG, and the left anterior insula, while larger rightward asymmetry was associated with larger activity in the midpart of the right STS. It is important to emphasize that of the significant regional asymmetries reflected by voxel-wise asymmetry, several were out of the territory of the language areas. For example, leftward asymmetry was present in hand motor regions and in the fusiform area, which is involved in visual processing. Rightward asymmetries were present in areas of the dorsal attentional network, including the frontal eye fields and superior parietal gyrus (Corbetta and Shulman 2011; Petit et al. 2009). These very significant asymmetries were not related to the variability of LIST HFLI, as demonstrated by our voxel-wise correlation analysis between LIST contrast maps and HFLI (Fig. 2). The cortical areas that were associated with inter-individual differences in global hemispheric asymmetries of speech listening were limited to regions involved in phonological processing. Of these areas, the left Heschl’s gyrus BOLD variation and its strong leftward asymmetry explained the largest part of the variance in LIST HFLI. Such leftward asymmetry in the depth of the Sylvian fissure had recently been described in 104 participants engaging in dichotic listening to syllables (Westerhausen et al. 2013). As in the present study, the leftward asymmetry of Heschl’s area activity is likely related to the preferential involvement of the left Heschl’s gyrus in the temporal processing of speech sounds (Zatorre and Gandour 2008; Warrier et al. 2009). The temporal processing preferentially operated in the left Heschl’s gyrus has been shown to be characteristic of speech processing (Zatorre et al. 2002), and is thus necessary to decode syllables and words. The two other areas that exhibited leftward activity in relation to hemispheric asymmetry were the SMG and the anterior part of the insula. These two regions are known to support the phonological loop (Vigneau et al. 2006) triggered by LIST. The left SMG has been described as the storage area, while the left anterior insula supports executive functions and is involved in rehearsal (Zago and Tzourio-Mazoyer 2002). Decreases in HFLI corresponding to increased rightward hemispheric asymmetry during LIST were associated with greater involvement of the right STS, which is preferentially involved in spectral or tonal processing (Zatorre and Belin 2001), including the prosodic processing of speech (Beaucousin et al. 2007). In the present investigation, word lists were spoken with their specific prosody, a particular rhythm of the enunciation of words. As reviewed by Glasser and Rilling (2008), this rightward-lateralized

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Brain Struct Funct

region is involved in prosodic processing, linguistic (Wildgruber et al. 2005) or not (Riecker et al. 2002), and overlaps the location of the human voice area (Belin et al. 2000). Recently, Rosen et al. (2011) showed that the STSa has a right-dominant response to voice-like stimuli, regardless of sound intelligibility, and its activity is driven by the low-level acoustic properties of the sounds. Structure/function relationships in Heschl’s gyrus: the inter-hemispheric pattern of gyrification explains variability in lateralization during LIST A major finding of the present study is our observation of a strong structure–function relationship at the level of the Heschl’s gyrus. We found that the inter-hemispheric gyrification pattern has a comparable impact on the anatomical asymmetries of the aHG surface area and on the functional asymmetry observed in the HG-ROI during speech listening. Considering that the aHG hosts most of the PAC (Rademacher et al. 1993; Rivier and Clarke 1997; Clarke and Rivier 1998; Morosan et al. 2001; Rademacher et al. 2001), the observed anatomo-functional relationship suggests that the setting-up of PAC anatomical and functional asymmetries depends in part of the inter-hemispheric gyrification pattern. The common underlying phenomenon was the combination across hemispheres of the decrease in aHG surface area and BOLD activation in the presence of duplication. Note that the Heschl’s gyrus inter-hemispheric gyrification effect on HG-ROI asymmetry variability remained significant when aHG asymmetry was added as a factor in the model; the aHG asymmetry effect was not significant (p = 0.40). Gyrification patterns impact on HGROI functional asymmetry was thus not simply related to the differences in surface’s area and gray matter asymmetries. The two gyrification patterns including a single left gyrus (L1R2 and L1R1) occurred most frequently in our population (64 % of subjects) and were associated with a leftward anatomical and functional asymmetry of Heschl’s gyri. In contrast, in cases of left duplication, either anatomical or functional leftward asymmetry was lacking. The 43 participants with a left duplication associated with a single right gyrus displayed significant anatomical rightward asymmetry and an absence of functional asymmetry, while the group with bilateral duplications was leftward lateralized functionally but symmetrical in anatomical terms. These observations must be integrated with a previous report of an association of left Heschl’s duplication with language developmental pathologies (Leonard et al. 2001), since they indicate that the presence of a left duplication is associated with lower leftward asymmetry during speech listening. This observation favors the hypothesis that a decreased lateralization in auditory areas is associated with language developmental pathologies.

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We detected strong leftward asymmetry in Heschl’s gyrus, the first relay point for the cortical processing of speech sounds, during LIST. Heschl’s gyrus variability in functional asymmetry during LIST was explained in part by differences in the Heschl’s gyrus inter-hemispheric duplication patterns. This anatomo-functional relationship was local, since the asymmetry in other cortical areas that explained the variance in hemispheric lateralization of speech listening did not vary with gyrification pattern. Setting-up hemispheric lateralization appears to be complex, since different regions appear to be influenced by different factors in the same subject, within a set of regions involved in the processing of the same stimulus. The present results confirm that functional lateralization ‘‘develops as the outcome of several, relatively independent local asymmetries that are summed together yielding an overall lateralized effect’’ (Ide et al. 1999). Handedness is associated with differences in Heschl’s anatomy that are not related to differences in Heschl’s gyrus functional asymmetries during speech listening This complexity in the setting-up of speech-listening lateralization is confirmed by our observation that the functional asymmetry of Heschl’s gyri did not differ with handedness. In left-handers, the higher occurrence of the L1R1 pattern together with a lower occurrence of right duplication, which was significant given our large sample size, had no impact on the functional lateralization of Heschl’s gyrus. The between-group difference was not significant (t = -0.84, p = 0.40) when we tested the effect of MP on HG-ROI functional asymmetry without including the duplication pattern in the analysis. This result underlines the danger in inferring differences in functional lateralization in auditory cortices from MP. It also shows that MP can have different relationships with anatomical and functional asymmetries; thus, differences in Heschl’s gyri anatomy according to MP cannot be explained by differences in the functional lateralization supporting hemispheric specialization. Surface area of the left planum temporale has been shown to correlate with speech asymmetries (Josse et al. 2003), while a study of a large sample of individuals failed to uncover any impact of MP on planum temporale surface area asymmetry (Tzourio-Mazoyer et al. 2010). The observation that the Heschl’s gyri inter-hemispheric duplication pattern exerted only a local impact suggests that early developing anatomical asymmetries in primary auditory areas account for a small part of the inter-individual variability in the lateralization of language areas. It is likely that this variability would be better explained by other factors related to the rise of asymmetries in language

Brain Struct Funct

networks during their development (Perani et al. 2011; Friederici et al. 2011). Finally, the very small variation along with different MP observed in this investigation must be highlighted. The present study design included a large sample of individuals balanced for MP, and thus contained sufficient power to detect small differences between groups. One might have expected a stronger impact of left-handedness on speechlistening asymmetries than the trend toward a lower (rightward) asymmetry that was observed in left-handers at the hemispheric level. In addition, at the regional level, left-handers did not display any decrease in the leftward asymmetry of the HG-ROI, INS-ROI, or SMG-ROI, but rather exhibited less rightward-lateralized activation in STS voice/prosodic areas. We observed that only the rightward asymmetrical LatROIs exhibited a slight decreased in rightward asymmetry in left-handers; although this observation is consistent with the general trend of decreased lateralization in this population, it suggests that MP had no or little influence on the functional lateralization of primary areas. This finding needs to be further explored because it suggests that the PAC may behave differently from highorder language areas, the lateralization of which is known to vary greatly in left-handers. This notion is in line with the observation that asymmetries best correlate with hemispheric dominance when they are computed from high-level contrasts of language tasks in which the bilateral activities of primary cortices cancel out (Hund-Georgiadis et al. 2001; Binder 2011). Previous investigations that compared the lateralization of groups with varying MP reported decreased lateralization of language areas in lefthanders during generation tasks (Pujol et al. 1999; Vingerhoets et al. 2011; Hund-Georgiadis et al. 2002; Szaflarski et al. 2011) and during semantic tasks (Springer et al. 1999; Szaflarski et al. 2002). Differences in language lateralization with differences in MP has been shown to be more pronounced during generation tasks (Josse et al. 2006; Razafimandimby et al. 2011). Differences in the lateralization of language comprehension can be absent from groups displaying differences in the lateralization of language production (Tzourio-Mazoyer et al. 2004). When present, these differences are located in regions in outer auditory areas, as shown by positron emission tomography conducted in the absence of environmental noise (Tzourio et al. 1998a). Acknowledgments The authors are deeply indebted to Mathieu Vigneau and Nicolas Delcroix for their help in data acquisition and pre-processing and to the Aquitaine Regional Council for its funding of Damien Marie PhD. They are also very grateful to two anonymous reviewers whose fruitful comments allowed us to provide a more elaborated version of the manuscript and to Isabelle Hesling for her thoughtful comments on the revised version of the manuscript.

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