Functional Anatomy of Dominance for Speech Comprehension in Left Handers vs Right Handers 1

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1 NEUROIMAGE 8, 1 16 (1998) ARTICLE NO. NI Functional Anatomy of Dominance for Speech Comprehension in Left Handers vs Right Handers 1 N. Tzourio, F. Crivello, E. Mellet, B. Nkanga-Ngila, and B. Mazoyer 2 Groupe d Imagerie Neurofonctionnelle, UPRES EA 2127 Université de Caen and CEA LRC 13, Caen Cedex, France Received December 11, 1997 In order to study the functional anatomy of hemispheric dominance for language comprehension we compared the patterns of activations and deactivations with PET and H 15 2 O during a story-listening task in two groups of normal volunteers selected on the basis of their handedness. The reference task was a silent rest. The results showed asymmetrical temporal activations favoring the left hemisphere in right handers (RH) together with Broca s area and medial frontal activations. A rightward lateralization of deactivations located in the parietal and inferior temporal gyrus was also observed. In left handers (LH) the temporal activations were more symmetrical as were the parietal and inferior frontal deactivations. Broca s area and medial frontal gyrus activations were present in LH. The direct comparison of RH and LH activations revealed larger activations in the left superior temporal, in particular in the left planum temporale and temporal pole of RH, while LH activated an additional right middle temporal region. Individual analysis of LH differences images superimposed on individual MRI planes demonstrated an important variability of functional dominance, with two LH leftward lateralized, two symmetrical, and one showing a rightward lateralization of temporal activations. There was no relationship between functional dominance and handedness scores. These results are in accordance with data from aphasiology that suggest a greater participation of the right hemisphere in language processing in LH. In addition, the presence of bilateral deactivations of the dorsal route could support the assumption that LH ambilaterality concerns, in addition to language, other cognitive functions such as visuospatial processing Academic Press Key Words: PET; language; temporal cortex; dominance; handedness. 1 This work was presented in part at the Third International Conference on Functional Mapping of the Human Brain, Copenhagen, May 23 19, To whom correspondence and reprint requests should be addressed at GIP Cyceron, Boulevard Becquerel, BP 5229, Caen Cedex, France. Fax: mazoyer@cyceron.fr. INTRODUCTION Cerebral dominance is a component of cerebral organization that concerns major brain functions such as language, movement, attention, and spatial processing. But since the discovery by Broca that language functions are lateralized to the left hemisphere in right handers (RH), its origin, epigenesis, and consequences for brain organization are still under debate (Hiscock and Kinsbourne, 1995). Following his discovery that language functions were leftward lateralized in RH, Broca made the assumption that a mirror organization should be present in left handers (LH). However, aphasiology abandoned this concept which turned into the study of language area variability and its relation to handedness and gender. Indeed, while the relationship between handedness and hemispheric dominance for language appears to be quite strong in RH, it appears to be much harder to draw any conclusion in LH or ambidextrous subjects. Results of the presurgical assessment of hemispheric language dominance in patients suffering from intractable epilepsy, with the amobarbital test or Wada test (Wada and Rasmussen, 1960), have shown that 92 to 99% of dextral individuals are left-hemisphere dominant for language (for review see Loring et al., 1990), while the pattern in nondextral individuals includes leftward, but also bilateral or even rightward, dominance for language in 15% of LH without any early brain injury, rising to 19% when subjects with early brain injury are included (Rasmussen and Milner, 1977). As a matter of fact, early left-hemisphere lesions appearing before the age of 1 or 3 can produce a shift in both manual preference and cerebral dominance (Strauss and Wada, 1983; Vargha-Khadem et al., 1985). The incidence of such a phenomenon was thought to be even underestimated and a review of Wada tests performed in 237 epileptic patients showed that taking into account early brain injuries results in an absence of correlation between handedness and hemispheric dominance for language (Woods et al., 1988), although this conclusion should be taken with caution given the very small sample of nonhemiparetic LH in the study /98 $25.00 Copyright 1998 by Academic Press All rights of reproduction in any form reserved.

2 2 TZOURIO ET AL. The same conclusions were drawn from aphasiology. First studies showed that 60% of right handers with lesion in the left hemisphere developed aphasia, while only 32% of nondextral with lesion in the same hemisphere presented a language impairment (Benson, 1962). Further studies by Hécaen on the comparison of aphasia in right and left handers demonstrated that, although left-hemisphere lesions had the same effects on language functions in LH, albeit with more frequent troubles in comprehension in RH, lesions of the right hemisphere resulted in troubles of oral and written language in LH only (Gloning et al., 1969; Gloning, 1977; Hécaen and Sauguet, 1971). Moreover, Hécaen showed that LH with left posterior lesions had less frequent comprehension deficits but showed deficits usually encountered in right hemisphere lesions in RH such as spatial disorientation (Hécaen and Ajuriaguerra, 1963). He concluded that LH present a greater ambilaterality for language and other lateralized functions, in particular when presenting familial sinistrality (Hécaen et al., 1981). The concept of a more frequent implication of the right hemisphere in language processing in LH was challenged by Kimura, who, in a series of 520 patients, confirmed that aphasia was less severe in LH but did not find more frequent aphasia in LH with left or right lesions. He claimed that the right hemisphere had a negligible role in speech function in LH without early left hemisphere damage (Kimura, 1983). Presurgical mapping conducted with electrocortical stimulations started from this point, namely the absence of right-hemisphere lateralization of language except after early left-hemisphere brain injury, and focused on the investigations in the left hemisphere. These studies demonstrated that there was a great deal of language variability within the left hemisphere of adults with left lateralization of language (Ojemann, 1991). From these clinical data it seems very difficult to extrapolate what would be the functional lateralization for language in normal subjects, as already pointed out by others (Woods et al., 1988). Moreover, little is known about the regions supplying hemispheric dominance for language within the hemispheres, since the methods used until today were of very low resolution: the Wada test questions the whole hemisphere, while aphasia studies frequently lack anatomical analysis and, when the latter is available, are limited by the usually large size of the lesions. As for cortical mapping, it allows one to document only the exposed cortex of the altered hemisphere. With this in mind, functional imaging appears as a key tool for such investigations. The functional anatomy of language has been extensively studied over the past 10 years in RH (for review see Cabeza and Nyberg, 1997; Frackowiak, 1994), but very few studies have been devoted to the question of the cerebral dominance for language. Three functional imaging studies conducted in epileptic patients were designed to compare their results for functional dominance assessment with those of the Wada test during either verb generation (Hertz-Pannier et al., 1997; Pardo and Fox, 1993) or single-word semantic decision task (Binder et al., 1996); in the latter case, lateralization was first evaluated in normal subjects (Binder et al., 1995). These studies resulted in a good correlation between the two methods, but the effect of functional dominance in terms of its anatomofunctional organization and variability remains to be investigated. The aim of the present work was thus to investigate the anatomofunctional support of hemispheric dominance for language comprehension. Within this context LH, who constitute a heterogeneous population with an absence of clear relationship between manual preference and hemispheric dominance for language (Benton et al., 1962; Hécaen et al., 1981; Hécaen and Sauguet, 1971), represent a potential model for such an investigation. To achieve this goal we measured normalized regional cerebral blood flow (NrCBF) with positron emission tomography (PET) in five LH during a storylistening task and, in order to compare their mean activation pattern to that of RH, have reanalyzed with SPM a previously published dataset obtained in 10 RH (Mazoyer et al., 1993). Moreover, to study the support of language comprehension dominance anatomofunctional variability, we conducted an individual analysis in these five LH subjects. MATERIALS AND METHODS Data Analysis Subject Selection The subjects were 5 LH and 10 RH healthy French male graduate medical students, all having French as their mother tongue; their mean age was 24 years (SD 2.2 years). Handedness was assessed using the Edinburgh inventory (Oldfield, 1971) and we derived from the questionnaire a manual preference score (MPS) ranging from 100 to 100, plus the preferred eye and foot. The presence of familial sinistrality was also evaluated (see Table 1). The selected LH considered themselves left handers and showed a clear leftward hand preference in all but LH5, together with left foot preference for all and left eye preference for all but LH4. Familial sinistrality was present in two of the five subjects: LH4 had a lefthanded father and LH5 had numerous left-handed second-degree relatives (one uncle and two cousins); familial sinistrality was unknown in one orphan subject and absent in the remaining two subjects. All RH MPS scores were higher than 66 and their preferred foot and eye were usually right except in

3 STORY LISTENING IN RIGHT AND LEFT HANDERS 3 TABLE 1 Laterality Scores in the 15 Subjects Selected for the Study Subjects Hand Foot Eye FS RH1 75 R R RH2 100 R R RH3 75 R R RH4 100 * * RH5 100 * * RH6 81 R R RH7 81 R R RH8 100 R R RH9 100 * * RH10 66 B R LH1 50 L L * LH2 77 L L LH3 100 L L LH4 100 L R LH5 11 L L Note. Edinburgh score is given for the preferred hand and ranges from 100 (exclusive right-hand utilization) to 100 (exclusive lefthand utilization). Preferred eye and foot are given as right or left or both (R, right; L, left; B, both; FS, familial sinistrality; * missing data). subject RH10 who used both feet to shoot a ball. RH first-degree relatives were RH except for RH3 as well as RH5 who each had a brother who could be ambidextrous. The subjects were free from cerebral abnormalities as assessed by their MRI brain scans. The study was approved by the Atomic Energy Commission Ethics Committee and all subjects gave their written informed consent. Task Design We chose to study the functional anatomy of language dominance during a story-listening task because we had demonstrated in a previous report that this task elicits in RH large strongly leftward lateralized activations in the temporal cortices (Mazoyer et al., 1993), allowing individual analysis (Levrier et al., 1993; Mazoyer et al., 1993). The 15 subjects were instructed to passively but attentively listen to factual stories in French that were designed for the RH protocol (Mazoyer et al., 1993). All stories, each lasting about 2 and a half minutes, were read by a female speaker with comparable pitch, intonation, and volume (Text condition). Auditory stimuli were presented binaurally over earphones, starting 45 s before water injection. Different texts were used for the replications. The texts were emotionally rich factual stories taken from recent events. The first one describes a police misconduct during which a young person was murdered; the second concerns the harassment of a young couple, with a pregnant young woman, by a violent neighbor; the third one was about disqualification during a ski competition. After listening to stories subjects were asked questions about the texts to ensure that they understood the stories and thus paid attention to the task. A rest condition (Rest) served as a reference and consisted in resting silently, eyes closed, without any particular instruction except to relax. All examinations were performed in total darkness. Data Acquisition Using PET and oxygen-15-labeled water, NrCBF was measured six times in each subject, including two replications of the series of two conditions in the RH group (whose experimental protocol included another task not reported here) and three replications in the LH group (giving 20 and 15 pairs of measurements, respectively). The order of the presentation was determined by a Latin square design in the RH group and was randomized by block in the LH group. Two different PET cameras were used for NrCBF measurements. For the 10 RH, NrCBF was measured on a time-of-flight PET system (Mazoyer et al., 1990) giving seven brain slices of 9-mm thickness every 12 mm with an in-plane resolution of 5 mm. The images of the 5 LH were acquired on an ECAT 953B/31 PET camera giving 31 contiguous brain slices of mm thickness with an in-plane resolution of 5 mm 1 (Mazoyer et al., 1991). All emission data were acquired with septa extended. In both cases, following the intravenous bolus injection of 60 mci of 15 O-labeled water a single 80-s scan was reconstructed (including a correction for head attenuation using a measured transmission scan) with a Hanning filter of 0.5 mm 1. The interval between two injections was 15 min. Average Analysis Image Analysis Because of the difference in the z axis direction sampling of the two cameras that were used in each group, our image analysis strategy for comparing the RH and LH groups aimed at bringing the average datasets to similar final resolution in the Talairach space. Accordingly, we reanalyzed with SPM our RH dataset which was previously published with a volume of interest analysis. The t statistic corresponding to the comparison between the Text and the Rest conditions was tested with the three-dimensional version of SPM in each group of subjects (Friston et al., 1995). The original brain images were transformed into the standard stereotaxic Talairach space (Talairach and Tournoux, 1988) using the same MNI template. A 12-mm Gaussian filter was

4 4 TZOURIO ET AL. then applied on the images giving a 3D smoothness of 12.4, 13.9, and 18 mm (in the x, y, and z axes, respectively) in the RH group and of 13.4, 15.4, and 14 mm in the LH group. Global CBF differences within and between subjects were covaried out, and comparisons across conditions were made by the way of t statistics. In order to keep the larger field of view in each group, activations and deactivations during the Text compared to the Rest in each group are reported separately with a threshold set to P 0.001, uncorrected. After alignment in the stereotaxic space the number of resels was 324 and 566 for RH and LH, respectively, with a voxel size of 2 mm 3. The group comparison was performed on a common volume of 336 resels limited to slices located from 20 to 40 mm in the z direction of the stereotaxic space, with a smoothness of mm. The ANOVA design of SPM96 was used with thresholds set to for the F value and to 0.01 for post hoc t. Individual Analysis Text minus Rest difference images were averaged and interpolated for each LH subject, in order to generate isotropic voxels (size, mm 3 ). A first anisotropic tridimensional Gaussian filter was first applied in order to obtain isotropic smoothness in the x, y, and z directions. On this fully tridimensional isotropic difference volume (in terms of voxel size and resolution), a second isotropic tridimensional Gaussian filter was applied, bringing the smoothness of the final image to 9 mm. Filtered difference images were then normalized to 1 SD and thresholded at 2 SD. A 3D region growing algorithm was applied in order to isolate and quantify 3D clusters showing a significant increase of NrCBF. For each of these clusters, we computed the coordinates of its weighted center of mass, its volume expressed in voxels, and its mean NrCBF value. To proceed to the analysis of the relationships of the activated areas with individual anatomy, the significant clusters were superimposed onto individual MRI after 3D MRI to PET registration (Woods et al., 1993). The activated areas were described in each subject relative to major sulci in the temporal lobe that had been identified by an expert using a method that was described elsewhere (Tzourio et al., 1997). RESULTS Right Handers Average Analysis Activations during the Text-Listening Task in RH (Table 2) The SPM analysis of the RH confirmed the previously reported results of this dataset using an anatomical volume of interest (AVOI) analysis (Mazoyer et al., 1993). The comparison of text listening minus rest in RH showed a very large activation in terms of volume and significance that encompassed the whole left superior temporal and part of the middle temporal gyri, extending to the left planum temporale posteriorly, to TABLE 2 Foci of Significant NrCBF Increases in Text Compared to Rest in the Group of 10 Right-Handed Subjects Coordinates Region size (voxels) Anatomical location of maximum voxel x y z Z score CBF 8750 L mid temporal L mid temporal L sup temporal (BA 42) L planum temporale (post BA 22) L Heschl gyrus (BA 41) L planum temporale (post BA 22) L amygdala L temporal pole (BA 38) L inf frontal gyrus (BA 45) L inf frontal gyrus (BA 44) R planum temporale (post BA 22) R sup temporal gyrus (BA 22) R sup temporal gyrus (BA 22) R Heschl gyrus (BA 41) R temporal pole (area 38) R temporal pole (area 38) L thalamus Note. Anatomical localization of the maximum Z-score voxels is given as stereotaxic coordinates in mm. Uncorrected significance level was set at P (Z score 3.09; L, left; R, right; sup, superior; mid, middle; inf, inferior; post, posterior; BA, Brodmann s area).

5 STORY LISTENING IN RIGHT AND LEFT HANDERS 5 the left amygdala internally, and to the temporal pole anteriorly. This volume of activated pixels included Broca s area, with two maxima, one in the pars triangularis and the other in the pars opercularis of the left inferior frontal gyrus (see Fig. 1). In the right temporal cortex, a large area was activated but was less than half of the volume of the corresponding left-hemisphere temporal cortex activation. It included the whole superior temporal gyrus with the temporal pole and the planum temporale but without any extension toward the right middle temporal gyrus nor toward the right inferior frontal gyrus. A significant activation was observed in the left thalamus. Deactivations during the Text-Listening Task in RH (Table 3) Also, we were able to describe deactivations that were not previously reported. Deactivations during Text in right handers were asymmetrical, favoring the right hemisphere, with two main locations: frontal and parietal. The main frontal deactivations were observed in the right middle frontal gyrus and in the middle frontal sulcus in front of the inferior frontal gyrus. In the posterior part of the brain, deactivations were located in the right posterior cingulate and the right intraparietal sulcus extending to the superior occipital, in the right inferior temporal cortex, near the occipitotemporal junction and extending to the fusiform gyrus, and in the precuneus. In the left hemisphere a small deactivation was located in the supramarginalis gyrus. Left Handers Average Analysis Activations during the Text-Listening Task in LH (Table 4) Subtracting the Rest condition from the text-listening task in the LH group showed almost symmetrical activations in the temporal cortex (see Fig. 2). The largest activation was, as in RH, located in the left superior temporal and included the whole superior temporal gyrus with the left temporal pole, with the middle temporal gyrus, and extending toward the left inferior frontal gyrus including Broca s area and the pars orbitaris of this gyrus. The second set of activated voxels was of similar volume and covered the whole right superior temporal gyrus extending toward the right superior temporal sulcus and the middle temporal and included the temporal pole. The Z scores for the two first maxima were similar to that for the left corresponding voxels which were located in the homologous regions of the right superior temporal gyrus (BA 22). FIG. 1. Statistical parametric maps of the 10 right handers (N pairs 5 20) corresponding to the story-listening versus rest comparison activations (top) and deactivations (bottom). Z volumes were projected in three orthogonal directions, sagittal, coronal, and axial, and thresholded at Z (P, 0.001, uncorrected for multiple comparisons). Stereotactic coordinates of local maxima within the activated areas are given in Tables 2 and 3.

6 6 TZOURIO ET AL. TABLE 3 Foci of Significant NrCBF Decreases in Text Compared to Rest in the 10 Right-Handed Subjects Region size (voxels) Anatomical location of maximum voxel Coordinates x y z Z score CBF 1100 R mid frontal sulcus R mid frontal gyrus R mid frontal gyrus R post cingulate R intraparietal sulcus R sup occipital gyrus R mid temporal sulcus R fusiform gyrus R fusiform gyrus R supramarginalis gyrus L precuneus R precuneus R sup frontal gyrus (area 10) L supramarginalis gyrus Note. Anatomical localization of maximum Z-score voxels is given as stereotaxic coordinates in mm. Uncorrected significance level was set at P (Z score 3.09; L, left; R, right; sup, superior; mid, middle; inf, inferior; post, posterior). The left medial frontal gyrus (BA 9) was activated and a second medial frontal spot was observed in the orbital part of the frontal gyrus. Deactivations during the Text-Listening Task in LH (Table 5) In the LH group deactivations were located, as in the RH group, in middle frontal and parietal regions and inferior temporal gyrus but appeared symmetrically in both hemispheres. In the posterior part of the brain, the pattern of deactivations involved bilaterally the supramarginalis gyri and medially, the precuneus and the cingulate gyrus. In the temporal lobe, bilateral inferior temporal gyri NrCBF decreases were present. In the frontal lobe, bilateral superior frontal sulci and middle frontal gyri were deactivated with, on the left, a deactivation of the middle frontal sulcus following the sulcus route, just in front of Broca s area. In other words, the deactivation patterns were very TABLE 4 Foci of Significant NrCBF Increases in Text Compared to Rest in Five Left Handers Region size (voxels) Anatomical location of maximum voxel Coordinates x y z Z score CBF 6203 L sup temporal (BA 22) L sup temporal (BA 22) L temporal pole (BA 38) L temporal pole (BA 38) L inf frontal gyrus (BA 45) L mid temporal gyrus L inf frontal gyrus (BA 47) L inf parietal R sup temporal (BA 22) R sup temporal (BA 22) R sup temporal sulcus/middle temporal gyrus R temporal pole (BA 38) R temporal pole (BA 38) R Heschl gyrus (BA 41) L orbital frontal Left medial frontal gyrus Note. Anatomical localization of maximum Z-score voxels is given as stereotaxic coordinates in mm. Uncorrected significance level was set at P (Z score 3.09; L, left; R, right; sup, superior; mid, middle; inf, inferior).

7 STORY LISTENING IN RIGHT AND LEFT HANDERS 7 close to those of RH, but with additional involvement in the left hemisphere of middle frontal, supramarginalis, and inferior temporal gyri. Comparison of Activations during the Listening Task: RH vs LH Larger Activations in Right Handers Than in Left Handers (Fig. 3, Top, Table 6) This contrast revealed a greater left hemisphere involvement during the text-listening task in RH. A first area was detected in the left planum temporale and left superior temporal gyrus in which the betweengroup difference was due to larger activation in RH than in LH. A second region was significantly detected in the left superior temporal gyrus and was located in the anterior part of the gyrus including the temporal pole. In the temporal pole at the local maxima the NrCBF increase in RH during story listening compared to rest was double that of LH. In the left amygdala the observed between-group difference was due to the fact that while RH showed NrCBF increase in this region, LH had no activation or small NrCBF decreases. In the orbital part of the left inferior frontal gyrus (BA 47) significantly larger activations were observed in RH, with an absence of increase or even a small NrCBF decrease in LH. Larger Activations in Left Handers versus Right Handers (Fig. 3, Bottom, Table 6) This contrast revealed two right middle temporal regions with higher activations during the listening task in LH than in RH. The first one, located in the anterior and superior part of the right middle temporal gyrus, near the superior temporal sulcus, was due to a large activation in LH, while no activation or a small NrCBF decrease was observed in RH. In contrast, the second, located in the posterior and inferior part of the right middle temporal gyrus, near the inferior temporal and the occipital cortex, was due to greater deactivations in RH than in LH. Finally, the left precuneus was also more deactivated in RH than in LH. Individual Analysis in Left Handers The individual analysis of activation image in LH demonstrated that temporal regions involved during text listening were in all subjects composed of the Heschl s gyris, the planum temporale, and the temporal poles (see Fig. 4). LH1 showed a pattern close to those of RH as established with the average analysis of the 10 RH, activations favoring the left superior temporal gyrus in terms of intensity and extent, encompassing the left middle temporal gyrus and associated with a Broca activation (visible on slice 3 from the left). A left median frontal activation was also detected. LH2 presented a clear leftward asymmetry in the superior temporal gyrus including the temporal poles, extending to the left middle temporal, but an extension to the right middle temporal gyrus was also detected. A left median frontal gyrus activation was observed as well as an activation of the left inferior frontal gyrus. LH3 temporal activations were almost symmetrical together with a bilateral activation of the cerebellum. The right precentral gyrus and thalamus were also activated in this subject. LH4 showed a bilateral implication of the superior and middle temporal gyri. An activation located in the left median frontal gyrus was present. No Broca s area nor cerebellar activation could be detected. LH5 showed a clear rightward asymmetry favoring the right superior and middle temporal with bilateral inferior frontal activation and a large left cerebellum participation. In summary at the temporal level, two subjects were clearly leftward lateralized (LH1, LH2), two were symmetrical (LH3, LH4), and one showed a rightward asymmetry. In addition, inferior frontal gyrus activation was detected on the left in four subjects (LH1, LH2 upper part, LH3, LH5) with a rightward component in LH5. Right cerebellar cortex activations were observed in LH1, LH3, and LH5 together with leftward activations in LH3 and LH5, the asymmetry favoring the left in the last case. DISCUSSION Temporal Cortex Activations The pattern of activations in the LH group included the same network of regions as in the RH group but the lateralization was strikingly different: in LH the extent of the activated areas in the temporal cortex during the text-listening task were 30% higher in the left hemisphere (using the same field of view and smoothness in both groups L, 6884; R, 5002 voxels), while in RH the volume of activation was 75% larger in the left hemisphere (L, 8477; R, 4833 voxels). Amplitudes of NrCBF increases were similar in both groups. This result in RH confirms our previous AVOI study in which statistically significant leftward asymmetry was described in the temporal cortex and Broca s area (Mazoyer et al., 1993). Although a statistical direct comparison of asymmetry is not possible with SPM, the lesser asymmetry in terms of the volume of activated resels in LH indicates that LH as a group have a lesser temporal functional asymmetry than RH, which is in agreement with what had been suggested by authors studying aphasia in LH (Hécaen et al., 1981). Whatever the method used to evaluate functional dominance, there is a consensus that RH show an important leftward

8 8 TZOURIO ET AL. FIG. 2. Statistical parametric maps of the 5 left handers (N pairs 15) corresponding to the story-listening versus Rest comparison. activations (top) and deactivations (bottom). Z volumes were projected in three orthogonal directions, sagittal, coronal, and axial, and thresholded at Z (P 0.001, uncorrected for multiple comparisons). Stereotactic coordinates of local maxima within the activated areas are given in Tables 4 and 5. FIG. 3. Statistical parametric maps of the between-group activations comparison during story listening versus Rest. Right handers versus left handers comparison (top) and left handers versus right handers (bottom). After an ANOVA for group comparison with an F value set at 0.001, the Z volumes were projected in three orthogonal directions, sagittal, coronal, and axial, and thresholded at Z (P 0.01, posthoc t tests). Stereotactic coordinates of local maxima within the activated areas are given in Table 6.

9 STORY LISTENING IN RIGHT AND LEFT HANDERS 9 FIG. 4. Results of the individual detection of activation in the 5 LH. Areas of detected activation are copied onto the corresponding MRI slice after MRI to PET coregistration; all images are given with the same scale from 0 to 60% of activation. Individual identification of anatomical landmarks was conducted in each subject thanks to a 3D software (Voxtool, General Electric) that allows 3D reconstruction and reslicing of axial MRI slices that were acquired for each subject. White arrows indicate the sylvian fissure, yellow arrows the superior temporal sulcus, yellow-green arrows the middle temporal sulcus, and red arrows the Rolando sulcus. Each row corresponds to one of the LH: from LH1 (top) to LH5 (bottom). From left to right are given lower to upper slices. Left is on the left side of the image. One may observe that although the first two subjects show a leftward asymmetry, LH3 and LH4 show language comprehension ambilaterality and LH5 a rightward dominance.

10 10 TZOURIO ET AL. TABLE 5 Foci of Significant NrCBF Decreases in Text Compared to Rest in the Five Left Handers Coordinates Region size Anatomical location of maximum voxel x y z Z score CBF 605 L supramarginalis gyrus L supramarginalis gyrus L supramarginalis gyrus L inf temporal gyrus L precuneus R median cingulate L paracentral lobule L mid frontal gyrus L mid frontal sulcus L mid frontal sulcus R supramarginalis gyrus R supramarginalis gyrus R supramarginalis gyrus L sup frontal gyrus (area 6) R mid frontal gyrus (area 6) R mid frontal gyrus (area 6) R inf temporal gyrus R mid frontal sulcus Note. Anatomical localization of the maximum Z-score voxels is given as stereotaxic coordinates in mm. Uncorrected significance level was set at P (Z score 3.09; L, left; R, right; sup, superior; mid, middle; inf, inferior). language lateralization. In the present study this asymmetry is supported by a greater implication of the left temporal cortex during auditory speech comprehension. As a matter of fact, aphasia studies have shown that RH are characterized by significantly more frequent verbal comprehension disorders after lesion of the left hemisphere than LH (Hécaen and Sauguet, 1971). The comparison of RH and LH activations allowed us to characterize this functional asymmetry difference: in the temporal cortex, the RH activate the left hemisphere more, in particular the left planum temporale TABLE 6 Comparison of Right and Left Handers NrCBF Variations during Text Compared to Rest Region size (voxels) Anatomical location of maximum voxel Coordinates CBF x y z Z score RH LH NrCBF in right handers NrCBF in left handers 245 L planum temporale (post BA 22) L sup temporal (BA 42) L amygdala region L amygdala region L inf frontal orbital (BA 47) L inf frontal orbital (BA 47) L sup temporal (BA 22) L temporal pole (BA 38) NrCBF in left handers NrCBF in right handers 262 R mid/inf temporal gyrus R mid temporal gyrus L precuneus R sup temporal sulcus/mid temporal R mid temporal/sup temporal sulcus Note. Anatomical localization of the maximum Z-score voxels is given as stereotaxic coordinates in mm (F 0.001; P 0.01; RH, right handers; LH, left handers; L, left; R, right; sup, superior; inf, inferior).

11 STORY LISTENING IN RIGHT AND LEFT HANDERS 11 and the left temporal pole, while LH activate an additional right hemisphere region in the middle temporal. Planum Temporale The greater NrCBF activation of the planum temporale in RH is congruent with anatomical studies that showed a leftward asymmetry of the planum temporale in RH (Geschwind and Levitsky, 1968), which was confirmed by in vivo MRI anatomical studies (Steinmetz, 1996) together with the evidence that LH present a decrease of this asymmetry (Steinmetz et al., 1991). From these structural studies, the hypothesis was raised that planum temporale asymmetry could reflect the left hemisphere functional dominance for language. With functional MRI, Binder et al. (1996) revisited this idea by showing an absence of additional activation in the planum temporale when comparing auditory words versus tone sequences processing. However, this last result was challenged by a recent sentence-processing study, using the same technique, that showed an increase of the amount of activation in the superior temporal gyrus, including the planum temporale, with sentence complexity (Just et al., 1996). This auditoryassociative area, corresponding to the cytoarchitectonic area Tpt, encloses the posterior part of BA 22 (Galaburda and Sanides, 1980). As numerous ERP (for review see Näätänen and Picton, 1987) and MEG (Hillyard et al., 1995) studies have shown, it is implicated in the early processing of sounds (Celesia, 1976; Liégeois-Chauvel et al., 1994; Pantev et al., 1994) and selective auditory attention. The left-hemisphere dominance for speech could in part rely on this early processing of complex language sounds in the planum temporale and adjacent regions. A default in the lefthemisphere dominance for this processing could be at the origin of language developmental pathology such as dysphasia (Tallal et al., 1993, 1996) which was supported by the observation of decreased planum temporale asymmetry in dysphasics (Jerningan et al., 1991) and dyslexics (Larsen et al., 1990). The results of the present study support the idea that the larger left planum temporale could indeed reflect left-hemisphere dominance for language comprehension, since it is more activated in RH who show a high incidence of left-hemisphere functional dominance for language. As a matter of fact, we demonstrated in a conjoint study a correlation between the left planum temporale surface and the amount of left superior temporal gyrus activation during story listening (Tzourio et al., 1998). Temporal Poles We confirm here an original finding of our early RH study of story listening (Mazoyer et al., 1993), namely the implication of the temporal poles during continuous speech processing. The temporal poles putative role, if one refers to neuropsychological studies, is to be part of the memory component implicated in the grasping of the coherence of the text. Indeed, Milner has shown (Milner, 1958) that after left anterior temporalectomy patients had an impoverished recall of stories, despite intact sentence comprehension and working-memory capacities (Frisk and Milner, 1990). Further functional imaging studies have confirmed in part this hypothesis since bilateral activations of the temporal poles have been described during the free recall of novel and of practiced narratives (Andreasen et al., 1995a), as well as during the free recall of word lists (Andreasen et al., 1995c), but without any involvement during wordrecognition memory task (Andreasen et al., 1995b). The implication of temporal poles during listening to stories seems specific to the mother tongue, since no implication of the temporal poles was detected during factual story listening delivered auditorily in an unknown or acquired language (Mazoyer et al., 1993; Perani et al., 1996). The left temporal pole had also been implicated in visually presented sentence processing (Bavelier et al., 1997; Bottini et al., 1994) and could thus be part of the syntactic system. Indeed, bilateral temporal pole activation was observed during nonautobiographic episodic memory retrieval based on listening to sentences, a study design in which both sentence processing and memory were implicated (Fink et al., 1996). One should note, however, that the right temporal pole, together with the right amygdala, was more activated when sentences referred to autobiographic memory with a greater affective charge (Braak et al., 1996). Bilateral temporal pole activations, with an asymmetry favoring the right side, were also observed during externally generated emotions whatever the media: a movie presentation (Lane et al., 1997a; Reiman et al., 1997), the view of emotional words (see Fig. 2 of Beauregard et al., 1997), or the recall of internally generated emotion (Reiman et al., 1997). It seems thus that the temporal poles, anatomically close to the amygadala and made of an archaic cortex part of the limbic system (Mesulam, 1985), could be part of the memory system for sentences and continuous speech implicated in the processing of the emotional component of language such as that embedded in the mother tongue. The temporal pole showed a leftward dominance for language as indicated by the fact that it is implicated more during text listening in RH than in LH, while the right temporal pole could be dominant for the processing of word- or story-related evoked emotions. Middle Temporal Another striking result of the present study is the activation of a region of the right middle temporal

12 12 TZOURIO ET AL. gyrus, near the superior temporal sulcus, during the language task in LH only. Although the left middle temporal gyrus has been repeatedly implicated during various language tasks (Fiez et al., 1996; Zatorre et al., 1992), the right posterior middle temporal had never been, to our knowledge, implicated during auditory language task in RH. This result indicates in LH a participation of the right hemisphere in auditory language comprehension, which reinforces the concept that their ambilaterality is particularly marked for comprehension and is consistent with previous aphasia studies showing that LH with right-hemisphere posterior lesion have more frequent language deficits than RH (Hécaen and Sauguet, 1971). A second right middle temporal region more activated in LH was located in the posterior part of the right middle temporal and inferior temporal gyrus near the occipital lobe and corresponds to a region considered a visual field belonging to the ventral route: it had been found activated in RH during the learning and recognition of colored patterns (Roland and Gulyás 1995), the processing of new versus old pictures (Tulving et al., 1996), passive perception of visual motion (Watson et al., 1993), motion form discrimination (Gulyás et al., 1994), and retrieving and encoding object features compared to object location (Owen et al., 1996). In our study, the difference between RH and LH was due to a greater deactivation in RH during story listening; a deactivation of this region during story listening tasks has also been described in a recent study (Andreasen et al., 1995a). As will be discussed in the deactivation section, this lower deactivation in LH could reflect a lesser lateralization for visual processing of objects. Broca s Area The implication of Broca s area during text listening in RH confirms what we already described in our previous report (Mazoyer et al., 1993) and is in agreement with other reports (Perani et al., 1996). This result also fits well with aphasia studies that have demonstrated that Broca s area lesions may result in both language production and comprehension deficits (Damasio, 1992). Broca s area, as was first suggested by Petersen, could be implicated in semantic processing (Petersen et al., 1988), a hypothesis that was confirmed by the fact that Broca is activated during passive listening of list of words (Mazoyer et al., 1993; Price et al., 1996) and during language search, independent of whether the search is guided by phonological or semantic cues (Klein et al., 1995). The fact that Broca is activated during visually presented complex sentence processing (Stromswold et al., 1996), as well as during text listening, indicates that it could be implicated in both semantic and syntactic processing. In the present study, no difference was observed in Broca s area activation between RH and LH. As a matter of fact, aphasia studies on LH told us that troubles in naming in LH always follow left-hemisphere lesions (Hécaen et al., 1981). This could indicate a different dominance pattern in frontal and temporal cerebral areas during language tasks. However, individual results showed that LH5, who demonstrates a clear rightward lateralization in the temporal lobe, had bilateral inferior frontal activations, which points toward a participation of the right inferior frontal gyrus which may have been overlooked by the average analysis. Medial Wall of the Hemispheres Medial Frontal and Orbital Frontal Two significant activations of the medial wall of the left frontal were noted in LH, one in the medial frontal gyrus and one in the gyrus rectus. These activations were present at lower statistical level in RH (medial frontal 10, 48, 28; Z 3.71; volume, 137 voxels; orbital frontal 0, 52, 16; Z 3.88; volume, 90 voxels), which explains why they did not show up in the LH minus RH comparison. The first activated area, corresponding to Brodmann s area 9, is little documented in functional-imaging studies. Neuropsychology assigns to the lesion of median frontal and orbitofrontal region a defect in processing of emotion (Damasio et al., 1994). As a matter of fact, its activation has been observed, together with orbital frontal, amygdala, and thalamus activations, during emotion processing (Lane et al., 1997a,b; Reiman et al., 1997), and again together with the orbital frontal, during the recall of emotional words (Beauregard et al., 1997), as well as during the recall of personal events from the past, a condition rich in emotion (Andreasen et al., 1995a). As underlined already in our study, the stories subjects listened to were rich in emotional content, which could explain the implication of a network of regions for both linguistic and emotion processing, the latter being very likely to involve these median frontal and orbitofrontal regions. The absence of difference between LH and RH for these activations indicates that they do not contribute to the lateralization of language. Amygdala In the RH group, additional regions were detected with the SPM analysis, namely the left amygdala and the left thalamus, small regions that were overlooked using the AVOI method. The activation of the left amygdala region could be related, together with the activation of the very near temporal pole, to the encoding of the factual stories relying on the processing of their emotional content. As a matter of fact, the amygdala is known to be involved in the acquisition and expression of emotional memory (for review see Phelps

13 STORY LISTENING IN RIGHT AND LEFT HANDERS 13 and Anderson, 1997). Numerous functional-imaging studies dealing with emotion have demonstrated amygdala involvement in different cognitive tasks including emotional processing: face expression (Breiter et al., 1996; Morris et al., 1996), emotion self-rating (Schneider et al., 1995), stress of a difficult cognitive task (Schneider et al., 1996), mental imagery of a stressful situation (Shin et al., 1997), and aversive olfactory stimulation (Zald and Pardo, 1997). The amygdala is considered part of the memory systems (Squire and Zola, 1996), in particular the memory of emotions (Cahill et al., 1996). The leftward lateralization of this activation in the present study would indicate the existence of a specialization for encoding of language-related emotions. In fact, the amygdala does not seem to be implicated in verbal memory free of emotion since left amygdala deactivation has been reported during practiced word recall (Andreasen et al., 1995c). Thalamus In LH, no activation of the left thalamus was observed, while an activation in its posterior part was present in the RH group. This activation could also be related to the memory-processing component of the story-listening task. Indeed, recordings from long-term electrodes have shown asymmetries of neuronal activity favoring the left thalamus during word recognition (Bechtereva et al., 1992; Bechtereva and Medvedev, 1990). Moreover, the thalamus has been involved during memorization of words (Grasby et al., 1994) and free recall of complex narratives (Andreasen et al., 1995a), albeit in a more anterior location. As a matter of fact, although thalamic lesions can conduct to aphasia, anterior nucleus damage is necessary for the appearance of aphasia (Damasio, 1992), and this posterior thalamic activation is unlikely to reflect the left thalamus involvement during language processing. One should note, however, that bilateral thalamus activations, located at coordinates very close to those of the present study, were observed during the processing of emotions together with medial and orbitofrontal and amygdala activations (Lane et al., 1997a; Reiman et al., 1997), indicating that this activation could reflect the implication of the thalamus in the emotion processing network. This does not explain, however, why no NrCBF increase was observed in this region in LH and thus needs further documentation. Deactivations In both groups deactivations were observed in the same regions: occipital, parietal, and posterior cingulate cortices; inferior temporal; and middle frontal. These deactivations can be interpreted in two different ways, either as activations during the Rest condition as suggested by N. Andreasen (Andreasen et al., 1995d) or as deactivations specific to auditory language tasks. A review of the literature in regard to the Rest condition shows, indeed, that the retrosplenial regions, namely posterior cingulate and precuneus, show systematically larger values during this condition (Andreasen et al., 1995a). This finding is probably related to the episodic memory component of the Rest condition, the retrosplenial regions having been frequently implicated during episodic memory task implicating verbal stimuli (Grasby et al., 1993) or visual, including mental images, stimuli (Fletcher et al., 1995; Kosslyn et al., 1993; Mellet et al., 1996; Petit et al., 1996; Roland and Gulyás, 1995). Regarding the inferior temporal and occipital regions, deactivations of visual cortices during auditory language tasks have already been described (Fink et al., 1996; Mellet et al., 1996) as well as deactivations of temporal language areas during visual tasks (Dupont et al., 1993; Petit et al., 1997). Such cross-modal inhibition has also been shown with somatosensory stimulations during which visual-area NrCBF decreases have been observed (Kawashima et al., 1995). The same kind of explanation could be proposed for the right supramarginalis gyrus, part of the inferior parietal, a region involved in visuospatial processing and visuospatial attention and that has already been described as particularly deactivated during language tasks (Shulman et al., 1997). The major difference between the two groups relies on the observation that deactivations are rightward lateralized in RH while they were bilateral and slightly leftward lateralized in LH. This means that the lefthemisphere dominance for language implicates righthemisphere inhibition of visuospatial areas, functions that are represented mainly in the right hemisphere in RH, while this cross-modal deactivation implicates both hemispheres in LH. This result is in accordance with the studies conducted by Hécaen that showed much smaller differences in the comparison of left- and right-hemisphere syndromes associated with hemispheric lesions in left handers than in right handers, thereby establishing the existence of cerebral ambilaterality in left handers for language that extends to spatial functions (Hécaen et al., 1981). The same author also showed that in the left posterior hemispheric syndrome in LH there were some elements usually observed in lesions of the posterior right hemispheric syndrome in RH, namely a spatial disorientation (Hécaen and Ajuriaguerra, 1963). Accordingly, the bilateral dorsal route deactivations during text listening in LH would then be a reflect of the ambilaterality of their spatial function cerebral representation. Relationship between Left Handedness and Functional Dominance We observed in the individual analysis two LH with a leftward dominance and an anatomofunctional pattern