1 Neuroscience Section, Information Science Division, Electrotechnical Laboratory, Tsukuba and , 2 Department of Neurological Surgery, Chiba University School of Medicine, Chiba, Japan
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Abstract |
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Introduction |
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The lesion and anatomical data emphasized the role of posterior regions in this sex difference. However, neuroimaging studies to date have provided support for differences only in the anterior perisylvian areas (Shaywitz et al., 1995; Pugh et al., 1996
; Jaeger et al., 1998
). In these studies revealing the sex difference in the anterior areas, one using past-tense generation tasks (Jaeger et al., 1998
) and the others using a rhyme-judgement task (Shaywitz et al., 1995
; Pugh et al., 1996
), semantic processing was not required.
To detect sex differences in the posterior language areas, it is important to activate the posterior language areas that appear to be involved in critical aspects of language comprehension (Damasio, 1992). One possible way to do this is to require semantic judgements about words, but this does not work well (Frost et al., 1999
). Another approach is to ask subjects to comprehend global aspects of a whole story, since this activates more areas in the posterior regions than are activated by simple word lists alone (Mazoyer et al., 1993
).
Our study focused on sex differences in the degree of language lateralization in the brain, with special focus on the posterior language areas. Functional magnetic resonance imaging (fMRI) was performed while male and female subjects listened attentively to an essay read aloud (forward condition) and to a recording of the same essay played in reverse (reverse condition). Sex differences in activation were noted in the posterior language areas.
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Materials and Methods |
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Forty-seven volunteer healthy subjects, 22 males (age 2247 years) and 25 females (age 2043 years) participated in the experiments. All the subjects were neurologically normal and strongly right-handed according to the Edinburgh Inventory (Oldfield, 1971). The subjects were university students, university graduates or college graduates. The studies received approval from the institutional human review committee. All subjects gave written informed consent according to institutional guidelines.
Task
In each experiment, the subjects were instructed to close their eyes and listen attentively to sound stimuli delivered through headphones for 380 s. The stimulus amplitude, which remained constant across subjects, had an average sound pressure level of 97 dB at the distal end of the audio system (Resonance Technology, Northridge, CA). Beforehand, the subjects were told that the sound stimuli contained a story and that several questions about the story would be asked after the experiment. Each experiment consisted of nine epochs: five control epochs alternating with four narrative epochs. The first control epoch was 60 s long and all the other epochs were 40 s long.
Three types of experiments were carried out. In experiment 1, to observe the whole extent of activation elicited by listening to a narrative, the narrative of a short essay (160 s) was delivered during the four test epochs (epochs 2, 4, 6 and 8) and no sound was delivered during the control epochs. In experiment 2, to exclude activation elicited by processing of auditory signals in general, the narrative was delivered during the test epochs and the preceding test epochs were replayed in reverse during each control epoch. In experiment 3, to eliminate activation caused by the processing of global structures in sentences, the narrative was cut into pieces of 1 s duration and the pieces were randomly presented in each test epoch (permuted stimuli), and the reverse replay of the preceding test epoch was delivered during each control epoch.
Six short essays were read aloud and the voice was digitally sampled (44.1 kHz) and recorded with a PC (Power Mac 9600/200MP, Apple Computer, Cupertino, CA). Three sound sequences for experiments 1, 2 and 3 were prepared for each essay using Matlab software (MathWorks, Natic, MA) on the PC and were re-recorded on a mini-disk. A mini-disk player (Sony, Tokyo, Japan) was used to play one of the 18 sound sequences during each experiment.
Nineteen male and 21 female subjects participated once each in experiments 1, 2 and 3, and three male and four female subjects participated once each in experiments 1 and 2. Sequences from the six essays were randomly assigned to each subject so that the subject listened to a story only once. The order of the experiments was balanced among the subjects.
Immediately after each experiment, the subject was required to respond orally to a set of questions prepared for each essay. The scores (perfect score = 10) by males were 8.4 ± 1.2 (mean ± SD, n = 17), 8.8 ± 0.9 (n = 16) and 1.0 ± 1.2 (n = 13) in experiment 1, 2 and 3, respectively. The scores by females were 8.6 ± 1.0 (n = 14), 8.4 ± 1.2 (n = 14) and 0.9 ± 1.1 (n = 10), respectively. Thus, as expected, all subjects understood little when presented with the fragmented stories and reverse replay (experiment 3). An analysis of variance showed that the number of correct answers to these questions did not depend significantly on sex (df = 1, F = 0.84, P = 0.36), the order of the experiments (df = 2, F = 2.0, P = 0.15) or the essay content (df = 5, F = 0.46, P = 0.65), but depended on the type of experiment (df = 2, F = 270, P < 0.0001).
Imaging
BOLD contrast image volumes (Ogawa et al., 1993) were acquired at 3.0 T (GE-ANMR system, GE-Signa Horizon LX system, Milwaukee, WI) using gradient-echo echo-planar imaging (TR/TE = 3999 ms/20 ms, FA = 90°, slice thickness/gap = 7/3 mm, FOV = 20 x 20 cm2, matrix size = 64 x 64). Eight axial slices were obtained from 19 male and 19 female subjects. Fifteen coronal slices were obtained from three male subjects and five female subjects, and 15 sagittal slices were obtained from one female subject. To overcome difficulties in observing activations in the poles, we improved magnetic field homogeneity by using not only linear but also second order shims (Spielman et al., 1998
). Accordingly, we were able to observe activations in the dorsal part of the poles although we still failed in most subjects to observe activations in the ventral part of the poles (Fig. 2
). Ninety-five sequential images of each slice were collected during each experiment. Anatomic images of the same slices were acquired using a conventional technique (heavy T2-weighted images; TR/TE = 6000 ms/180 ms). In addition, 3-D anatomic images were acquired using a 3-D spoiled gradient-echo technique (TR/TE = 33 ms/4 ms).
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Statistical parametric mapping (SPM 96, Wellcome Department of Cognitive Neurology, Institute of Neurology, University College London, London, UK) was used initially to detect head movement; data with a head movement of <0.6 mm (one-fifth of the pixel size) were used for further analysis (Kansaku et al., 1998). This criterion was met for 17 (77% of 22), 16 (73% of 22) and 13 (68% of 19) male subjects, and 14 (56% of 25), 14 (56% of 25) and 10 (48% of 21) female subjects in experiments 1, 2 and 3, respectively.
For group analyses, SPM 96 (Friston et al., 1995) was used. For each individual subject, scans were realigned to the first image, stereotactically normalized and smoothed with a Gaussian filter (10 mm full width at half maximum, FWHM). A high-pass filter with a cut-off frequency of 0.5 cycles per min was used to exclude low-frequency confounding effects in the time series. A fixed-response, boxcar model was used to characterize condition effects. The SPM {Z} was thresholded at a Z value of 3.09 (P = 0.001, uncorrected).
In addition to group analyses, the data from each subject were analyzed. Sequential data of 90 images per slice, excluding the first five images, were correlated with a boxcar function that consisted of five alternating control epochs (5 x 40 s) and four test epochs (4 x 40 s). The boxcar function was shifted by 0 and 4 s and the correlation coefficients were calculated repeatedly; the larger correlation coefficient was assigned to each voxel. The criterion for activity was taken to be any instance of two or more contiguous voxels having a correlation coefficient greater than 0.3 (P < 0.0041). These active voxels were smoothed using a 5 mm FWHM spatial filter, and then fused with a 3-D anatomic volume prepared for each subject using the iMIPS program (iMIPS, Pembroke, MA). Three contiguous sagittal slices 10 mm thick were resliced from the lateral ends of the composite 3-D volume of activation. The activated volumes in the temporal lobes, temporoparietal cortex and inferior frontal gyrus were measured on the contiguous sagittal slices using MEDx software (Sensor Systems, Sterling, VA).
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Results |
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Figure 1a shows the differential activation between the for- ward and no voice conditions (experiment 1) across female subjects. Activation was distributed bilaterally over the primary auditory cortex and the superior temporal gyrus (STG). The differential activation was also bilaterally distributed in male subjects (Fig. 1d
).
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Individual Analysis
The group analysis showed that sex differences, left dominant activation in males versus bilateral activation in females, were most apparent in experiment 2. The sex difference in experiment 2 was apparent even when the data were analyzed subject by subject (Fig. 2). Bilateral activation was apparent in three typical female subjects (Fig. 2ac
), whereas the activation was left dominant in three typical male subjects (Fig. 2df
). However, the activated areas were distributed not only over the superior and middle temporal gyri, as expected from the group analysis, but also in the inferior frontal gyrus (Fig. 2bd
) and temporoparietal cortex (Figs. 2a,b,d,f
). Accordingly, we measured the volume of activation in each subject for the three experiments for five regions of interest: the STG (1 in Fig. 2f
), MTG (2), inferior temporal gyrus (ITG, 3), temporoparietal cortex (TPC, 4) and inferior frontal gyrus (IFG, 5). The total volume of activation in the three temporal gyri (TG, 1 + 2 + 3) was also calculated. The data are summarized in Table 2
and Figure 3
.
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As expected from the observations in Figure 2, the volume of activation in the right temporal gyri (TG, median = 14 ml, Fig. 3b
) was as large as that in the left TG (15 ml) in females. In males, the median volume of activation in the left TG (22 ml) was almost twice as large as that in the right TG (12 ml). The difference between the volumes of activation in the right and left TG was not significant in females (P = 0.78), but was significant in males (P = 0.0005, Wilcoxon signed rank test). In male subjects, the dominance of activation in the left TG was detected in experiments 1 (P = 0.013, Fig. 3a
) and 2, but the significant lateralization disappeared in experiment 3 (P = 0.97, Fig. 3c
). The significant lateralization disappeared because the activation in the TG decreased on the left (17 ml from 22 ml in experiment 2, Table 2
), but increased significantly on the right (19 ml from 12 ml; P = 0.023, Wilcoxon signed rank test). In females, bilateral activation in the TG occurred in experiments 1, 2 and 3; accordingly, the difference between the activation in the left and right TG was not significant in all three experiments.
As a direct measure of lateralization in the TG, we calculated the difference between the volumes activated in the left and right TG (the degree of lateralization in the TG) for each subject (Fig. 4). An analysis of variance was used to determine which of three factors (sex, the experiment and the number of correct answers to the post-experimental questions) affected the degree of lateralization. The number of correct answers was categorized into two groups (high and low) in each experiment, according to whether the score was higher or lower than the mean score for that experiment (Fig. 4df
). The analysis of variance showed that (i) the degree of lateralization did not depend on the number of correct answers (df = 1, F = 0.86, P = 0.36), but depended on sex (df = 1, F = 11.1, P = 0.0013) and the experiment (df = 2, F = 5.63, P = 0.0054); and (ii) the effects of interactions were not significant (P > 0.7), except the interaction between sex and the experiment (df = 1, F = 6.0, P = 0.0039).
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These results show that activation in the TG was more left dominant in males than in females in experiment 2. A significant sex difference was also detected in experiment 1, but the sex difference disappeared in experiment 3, when the stimuli during the test epochs lost the global structures in the narratives. These observations were similar when the activations were analyzed separately for the STG and MTG, although no significant left dominance was found in the STG of male subjects in experiment 1 (Table 2). Activation occurred in a smaller volume in the ITG than in the STG and MTG. Consequently, no significant left dominance was found in any experiments in both sexes in the ITG (Table 2
).
Activation in the IFG
Sex-dependent left dominant activation was also found in the IFG (Table 2). In experiment 2, activation in the IFG was lateralized significantly (P = 0.008) in male subjects, but not (P = 0.59) in females. In experiment 1, lateralization in the IFG was marginally significant in males (P = 0.061), but not in females (P = 0.21). In experiment 3, lateralization was not significant in either males (P = 0.22) or females (P = 0.26).
Activation in the TPC
In contrast to the sex-dependent (male-specific) left dominance in the TG and IFG, activation in the TPC was left dominant in both sexes in experiments 1 (Fig. 3d) and 2 (Fig. 3e
). In experiment 3, left dominance was not significant in either sex (Fig. 3f
). It is worth noting that in male subjects the volume of activation in the right TPC in experiment 3 (median = 5.9 ml, Table 2
) was significantly larger (P = 0.033) than that in experiment 2 (0.60 ml), although activation in the left TPC in experiment 3 was not significantly different from that in experiment 2 (P = 0.81).
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Discussion |
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Methodological Considerations
Several methodological factors in our study design were important in identifying sex differences in the posterior language areas. First, we avoided non-semantic tasks (Shaywitz et al., 1995; Pugh et al., 1996
) and a semantic judgement task of words (Frost et al., 1999
). A previous PET study (Mazoyer et al., 1993
) suggested that listening to a whole story preferentially activates the posterior language regions. Therefore we required subjects to listen attentively to whole stories. Our result also shows differential activation in the posterior regions (Mazoyer et al., 1993
) when comparing activation during stories to no sound (experiment 1); in male subjects activation was found in the left MTG and the bilateral STG. Even when we simply compared activation during stories to no sound (experiment 1) we were able to detect male-specific left dominant activation in the MTG by measuring the volume of activation in individual subjects (individual analysis), although the sex difference was not detected in the group analysis under this condition.
Second, the selection of the control stimuli was important. Significant sex differences in lateralization were revealed in both the individual and group analyses, when we used a reverse presentation of the narrative as the control stimuli (experiment 2). Since the sound stimuli under the forward and reverse conditions were identical in volume and frequency distribution, the observed differences are most likely attributable to the processing of language, not processing of auditory signals in general. To study whether the processing of global structures in the narrative, such as sentences, was responsible for inducing the sex differences, or whether the processing of local structures, such as a train of words, was sufficient, we used permuted stimuli that maintained local, but not global, structure for up to 1 s. When we did this, differential activation was found bilaterally in both sexes (experiment 3). Taking the results of these experiments together (experiments 2 and 3), we conclude that sex differences in these posterior cortical areas are probably attributable to the processing of more global structures, such as sentences, not to the processing of local structure.
Finally, the use of a 3 T machine, through its relatively high signal-to-noise ratio (Gati et al., 1997), probably played an important role in detection of sex differences, when present.
Cortical Areas with Lateralization in Both Sexes
Significant lateralization was found in both sexes in the temporo- parietal cortex (experiments 1 and 2). This is an interesting finding, given the possibility that the temporoparietal cortex may be involved in phonological processing of word forms (Petersen et al., 1988, 1989
), and that hemispheric specialization arises from interhemispheric conduction delay (Ringo et al., 1994
). Ringo et al. suggested that processing of phonemes is most likely to be lateralized to one hemisphere, because inter- hemispheric communication leaves little time for the auditory analysis of phonemes. Subjects can understand speech at a presentation rate of ~30 ms per phoneme, while the average myelinated fiber would have a one-way interhemispheric delay of 25 ms. Phonological processing must therefore be localized within a single hemisphere, because an interhemispheric delay of that magnitude (25 ms) would be confusing when processing phonemes that arrive every 30 ms. Our observation of lateralized activation in the TPC in both sexes agrees well with this conjecture, as well as with the suggested role of the temporoparietal cortex in phonological processing (Petersen et al., 1988
, 1989
).
Cortical Areas with Sex Differences in Lateralization
Sex differences in language lateralization were most apparent in the temporal lobe. Females showed no significant lateralization in any of the three temporal gyri, but males showed significant left hemisphere lateralization in the STG and MTG. It is probable that sentence processing is one of the main functions of these cortical areas, because the left MTG in males was activated only by meaningful stories, not by word lists, sentences with pseudo-words or semantically anomalous sentences (Mazoyer et al., 1993). Because the sex differences disappeared when global structures were removed from auditory stimuli (experiment 3), and because a recent extensive fMRI study (Frost et al., 1999
) using a semantic judgement task of words failed to detect substantive sex differences, we suggest that sex differences only become apparent when the subjects are required to process the global structures of sentences.
According to Ringo's conjecture (Ringo et al., 1994), these observed sex differences in lateralization might reflect sex differences in the interhemispheric communication between the posterior language areas, and thus might reflect sex differences in the commissural fibers connecting the posterior language areas. In fact, the isthmus of the corpus callosum, which contains commissural fibers connecting the posterior language areas (de Lacoste et al., 1985
), is larger in females relative to the total area of the corpus callosum (Witelson, 1989
; Steinmetz et al., 1992) and the forebrain volume (Steinmetz et al., 1995
, 1996
; Jäncke et al., 1997
). It is possible that the relatively larger isthmus promotes more efficient communication between the hemispheres, allowing females to represent higher and less time-critical functions, such as processing sentences bilaterally.
Male-specific lateralization was also found in the anterior language area, the inferior frontal gyrus, in experiment 2 (Table 2). The male-specific lateralization in the inferior frontal gyrus agrees with previous imaging studies (Shaywitz et al., 1995
; Pugh et al., 1996
; Jaeger et al., 1998
) that reported bilateral activation of the inferior frontal gyrus in females and lateralized activation in males.
Implications for the Function of the Right Hemisphere in Language Processing
When listening to stories, males showed activation strongly lateralized to the left temporal gyri and temporoparietal cortex (experiment 2). However, when listening to permuted story fragments lacking global structure (experiment 3), the activation in these two areas was no longer lateralized. The subjects were forced to infer the content of sound stimuli from the fragments of words and sentences that appeared in random order (experiment 3). Therefore, nonsyntactic integration mechanisms might have been fully activated under these conditions. This increased right hemisphere activation (experiment 3) is consistent with the recent idea that the right hemisphere is more involved in nonsyntactic integration mechanisms than in the syntactic mechanisms of language processes (Beeman and Chiarello, 1998).
The increased activation in the right hemisphere was found to be significant only in males, not in females, further suggesting that the function of the right hemisphere in language processing is sex-dependent. This point must be considered when examining the function of the right hemisphere in language processing, a topic of intense debate (Caplan et al., 1996; Hickok et al., 1996
; Bavelier et al., 1998
; Beeman and Chiarello, 1998
; Paulesu and Mehler, 1998
).
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Notes |
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Address correspondence to Shigeru Kitazawa, Neuroscience Section, Information Science Division, Electrotechnical Laboratory, 1-1-4 Umezono, Tsukuba 305-8568, Japan. Email: kitazawa{at}etl.go.jp.
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