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Handedness and corpus callosum morphology
Psychiatry Research Neuroimaging 116 (2002) 33–42
Handedness and corpus callosum morphology Ulrich W. Preussa, Eva M. Meisenzahla,*, Thomas Frodla, Thomas Zetzschea, Jan Holdera, ¨ a ¨ Gerda Leinsingerb, Ulrich Hegerla, Klaus Hahnb, Hans-Jurgen Moller a
¨ Munchen ¨ Department of Psychiatry, Ludwig-Maximilians-Universitat (LMU), Nussbaumstr. 7, D-80336 Munich, Germany ¨ Munchen ¨ Department of Radiology, Ludwig-Maximilians-Universitat (LMU), Nussbaumstr. 7, D-80336 Munich, Germany
b
Received 28 May 2001; received in revised form 27 December 2001; accepted 28 January 2002
Abstract Investigations of a relationship between callosal size and functional behavioral lateralization lead to the hypothesis that, as the size of the corpus callosum (CC) increases, interhemispheric information transfer is facilitated and behavioral laterality effects become smaller. The aim of our in vivo study was to investigate the relationship between functional asymmetry of handedness and CC size in healthy subjects. Magnetic resonance images of the CC and five CC subregions were obtained with a 1.5-T Magnetom using a three-dimensional T1 sequence in 46 healthy men. Handedness was determined using the ‘handedness dominance test’ (HDT). According to the HDT values, 32 consistent and 14 non-consistent right-handers were identified. No significant difference between handedness subgroups in CC regions and no significant correlations between HDT values and CC areas were detected. 䊚 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Corpus callosum; Functional asymmetry; Hand preference; Hand dominance test
1. Introduction The corpus callosum (CC) is the largest fiber tract in primate brains. It connects cortical association areas of the left and right cerebral hemispheres (Steinmetz et al., 1996), and its ratio to total brain volume is two–three times smaller in humans than in other primates (Hopkis and Rilling, 2000), probably due to brain enlargement, functional lateralization and facilitated processing of information in humans. The CC consists of myelinated axons of large pyramidal neurons that are *Corresponding author. Tel.: q49-89-5160-5772; fax: q49421-218-4600. E-mail address: [email protected] (E.M. Meisenzahl).
localized in neocortical layers II and III. The projection targets of these neurons are localized mainly in the same cortical layers of the contralateral hemisphere (Diao and So, 1991). The CC fibers show a somatotopic arrangement: fibers from the inferior frontal and anterior inferior parietal regions course through the rostrum and the genu of the CC; temporo-parieto-occipital junction regions and occipital areas traverse the CC splenium (de Lacoste et al., 1985; Witelson, 1989). Research on the CC, including the examination of split-brain patients, indicates that callosal fibers play an important role in interhemispheric communication by facilitating the interhemispheric exchange of sensory, motor and higher-order cerebral information (Gazzaniga, 2000). Somatosen-
0925-4927/02/$ - see front matter 䊚 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 9 2 5 - 4 9 2 7 Ž 0 2 . 0 0 0 6 4 - 1
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Table 1 Sample characteristics of healthy subjects (ns46) Right-handed: ns32
Age (years) Body height (cm) Body weight (kg) Daily alcohol intake (gyday) Nicotine use (cigarettesyday) WST IQ
Mixed-handed: ns14
Mean
S.D.
Minimum
Maximum
Mean
S.D.
Minimum
Maximum
29.6 180 75.1 18.0 7.9 110.3
"8.7 "6.3 "10.4 "16.5 "8.8 "14.2
18.0 168 57.0 0.0 0.0 66.0
45.0 190 92.0 60.0 30.0 139.0
32.2 180 76.1 9.0 1.2 113.0
"8.6 "7.4 "7.6 "8.0 "3.1 "14.9
20.0 170 60.0 0.0 0.0 92.0
44.0 190 105.0 20.0 10.0 139.0
sory and motor fibers are localized in the central portion of the CC, whereas fibers connecting higher-order processing areas are concentrated in the genu and the isthmus (Aboitiz, 1992), as was also reported from animal research (Pandya and Seltzer, 1986). It has been suggested that the CC exerts an inhibitory action on the non-dominant hemisphere, thereby suppressing potentially conflicting motor programs (Gazzaniga, 2000). There is evidence that ontogenetic development and the maintenance of cerebral dominance may be tightly associated with the development and extension of the CC (Galaburda et al., 1990). An inverse relationship has been suggested between the magnitude of cerebral anatomic asymmetry and the extent of commissural connectivity between cortical areas. This relationship may be specific to Homo sapiens amongst extant primates (McGrew and Marchant, 1997; Buxhoeveden and Casanova, 2000). This asymmetry might be correlated with relatively gross morphological hemispheric differences, such as the size of the planum temporale (Galaburda, 1993) and Broca’s area (Witelson and Kigar, 1992). On the basis of pioneering post-mortem studies, Witelson reported that non-consistent right-handed men show a larger posterior CC area than consistent right-handed men. It was concluded therefore that laterality and callosal size might be related (Witelson, 1985, 1989; Witelson and Goldsmith, 1991). The aim of our quantitative MRI study was to determine the in vivo size of the CC in healthy male subjects in order to examine a possible correlation between CC size and handedness.
2. Methods 2.1. Sample Forty-six male right-handed healthy subjects were recruited from the local community. They showed a normal age distribution. Demographic information, past and current personal history, and family history of all subjects were obtained using a semistructured interview that included a variety of measures relevant to the study. Exclusion criteria were history of head trauma, positive family history for psychiatric disease, and treatment with corticosteroids within the last 3 months. Detailed sample characteristics are given in Table 1. 2.2. Assessment of handedness Handedness was determined using the ‘handedness dominance test’ (HDT) (Steingrueber and Lienert, 1971). The HDT, modified for use with adult samples, shows high reliability and validity ¨ (Jancke, 1996). It is a paper-and-pencil test that encompasses three dexterity tasks, each to be performed with speed and precision over 15 s, separately for the right and the left hand. The tasks were to trace lines, dot circles and squares, and performance was scored for each hand. For all hand-skill tasks, the raw value of each hand’s performance and the widely-used laterality coefficient (RyL)y(RqL) were calculated to obtain hand-skill asymmetry scores independent of overall performance. To compare subgroups with regard to handedness, HDT asymmetry scores higher than 0.1 were
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considered to indicate consistent right-handers, whereas scores lower than 0.1 defined non-consistent right-handers (including mixed-handers as ¨ suggested by previous research; Jancke, 1996). There were 32 consistent right-handers (HDT asymmetry value: 0.16"0.039) and 14 non-consistent right-handers (HDT asymmetry mean: 0.08"0.015). Fig. 2 depicts the distribution of a symmetry scores in the two subgroups. 2.3. Ethical standards Written informed consent was obtained by all participants after complete description of the study. The study was approved by the ethical committee of the Ludwig-Maximilians-University of Munich according to the ethical standards of the Helsinki Declaration, 1964. 2.4. MRI procedures Imaging was obtained using a 1.5-T Magnetom Vision (Siemens, Erlangen). Three-dimensional T1-weighted images using a magnetization-prepared rapid gradient echo sequence (MPRAGE) were acquired with the following parameters: echo time (TE)s4.9 ms; repetition time (TR)s11.6 ms; number of acquisitionss1; field of view (FOV)s230=230=190; slice thicknesss1.5 mm; matrixs512=512=126. 2.5. Image processing For further image processing with size reduction from 16 to 8 bits (transformation to a uniform matrix of 256=256=126 of 1.5-mm slice thickness), the software package Analyze was used (Biomedical Imaging Resource, Mayo Foundation, Rochester, MN). MR data were processed on Silicon graphics workstations (SGI). All MRI data sets were spatially normalized using the software BRAINS (Andreasen et al., 1992). For each data set three-dimensional spatial realignment was performed. In a first step, the interhemispheric fissure was aligned on the coordinate axes. In a second step, realignment was performed according to the anterior–posterior commissure (AC–PC) line.
Fig. 1. Corpus callosum (CC) measurement: The outer edge of the CC was traced in the midsagittal area. After that, the areas of five callosal subregions were outlined in two steps. First, a rectangle was placed over the CC. The lower side of the rectangle cut the two lowest points of the anterior and the posterior parts of the CC tangentially. In the second step, a radial divider with 10 rays equidistant from each other was placed at the midpoint on the lower side of the rectangle. Its four upper rays divided the CC into five subregions.
2.6. Corpus callosum Areas of the total CC and five callosal subregions were measured in the realigned sagittal T1weighted MRI slices that best represented the midsagittal section (Meisenzahl et al., 1999). This slice was chosen by using anatomical landmarks in a hierarchical order (Talairach and Tournoux, 1993). First, slices were selected that showed only minimal or no white matter in the cortical mantle surrounding the CC. When more than one slice fulfilled this criterion, the medial thalamic nuclei
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Fig. 2. Distribution of handedness asymmetry scores in right- and mixed-handed subjects.
served as a second anatomical landmark. The selected slice then showed the interthalamic adhesion connecting the left and the right medial thalamic nuclei, or only the smallest size of the thalamus of either one or the other side. The transparent septum and the cerebral aqueduct were used in the third step to confirm the selection when the remaining two slices showed a similar amount of thalamic substance. After the midsagittal slice was determined, the total callosal area was measured on a SGI workstation by manually tracing the outer edge of the CC on this slice using the Analyze software package. The areas of five callosal subregions were outlined in two subsequent steps. First, a rectangle was placed over the image of the CC. The lower side of the rectangle cut tangentially the two lowest points of the anterior and posterior parts of the CC. Two lines perpendicular to this lower side that cuts the most anterior and the most posterior points of the CC determine the rectangle’s length. In the second step, a radial divider with 10 rays equidistant from each other was placed at the midpoint on the lower side of the rectangle. Its four upper rays divided the CC into five subregions. The number of pixels within each region was summed
automatically and multiplied by the pixel size to obtain absolute values in millimeters squared for the areas of total CC and the five subregions (labeled C1–C5 in a rostral–occipital direction; see Fig. 1). 2.7. Interrater and intrarater reliability of CC measurements To assess interrater reliability, two independent researchers (E.M. and T.F.) measured the total callosal area in 10 randomly chosen subjects. To evaluate intrarater reliability, one researcher measured the total area of the callosal subregions twice in 10 randomly chosen subjects. The intraclass correlation coefficient for the total callosal area was 0.98 for the interrater and 0.97 for the intrarater reliability; for the regional CC measurements, interrater reliability ranged from 0.94 for the Cl subregion to 0.91 for the C5 subregion. 2.8. Statistics Statistics were performed using SPSS Software (Statistical Package for the Social Sciences, 10.0, SPSS Inc, Chicago, 2000). All continuous values were tested for normal distribution.
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Table 2 Correlation between sample characteristics and CC areas
Right-handed (ns32) Daily alcohol intake (gyday) Age (years) Wortschatz (Vocabulary) test value Mixed-handed (ns14) Daily alcohol intake (gyday) Age (years) Wortschatz (Vocabulary) test value
Total CC area
C1 area
C2 area
C3 area
C4 area
C5 area
HDT
Corr. R Sig. P Corr. R Sig. P Corr. R Sig. P
0.02 0.90 y0.35 0.06 0.20 0.29
y0.01 0.96 y0.32 0.08 0.12 0.51
y0.33 0.07 y0.21 0.26 0.10 0.59
0.07 0.72 y0.25 0.18 0.25 0.17
0.05 0.78 y0.33 0.07 0.09 0.63
0.05 0.80 y0.26 0.15 0.30 0.10
y0.35 0.06 y0.05 0.77 0.33 0.07
Corr. R Sig. P Corr. R Sig. P Corr. R Sig. P
0.10 0.77 y0.36 0.28 y0.43 0.18
0.17 0.62 y0.25 0.45 y0.25 0.46
y0.22 0.52 y0.45 0.17 y0.19 0.57
0.19 0.58 0.16 0.65 0.11 0.75
y0.03 0.92 y0.40 0.23 y0.39 0.23
0.18 0.59 y0.36 0.28 y0.38 0.22
0.50 0.12 0.26 0.44 y0.05 0.88
Differences of psychosocial characteristics and CC measurements between groups were tested with the t-test for independent samples. Relationships between handedness and CC areas were computed using Spearman rank–order correlations. A twotailed a-significance level of P-0.05 was considered statistically significant; Bonferroni’s correction for multiple testing on a-significance level was applied when necessary. 3. Results 3.1. Extension of CC (CC total and CC subregions), and handedness as measured by the HDT Table 3 shows the mean values of the CC total and CC subregions C1–C5 with regard to handedness as measured by the HDT.
schatz’ (Vocabulary) test IQ parameters, and age of the two handedness subgroups (Table 2). Thus, none of the above-mentioned variables were used as covariates in subsequent analysis. 3.3. CC total and CC subregions: differences between handedness subgroups By comparison of their values, callosal subregion C2, C3 and C5 areas tended to be larger in consistent compared with non-consistent righthanders. However, in analyses of differences between groups with t-tests for independent samples, values of CC total and CC subregions C1– C5 showed no significant differences between consistent and non-consistent right-handers (Table 3).
3.2. Correlation between CC regions, handedness and sample characteristics
3.4. Correlation between CC extension (CC total and CC subregions) and degree of handedness as measured by the HDT
To obtain possible confounders, sample properties and CC regions (CC total and CC subregions C1–C5) were correlated with several parameters: no significant correlations were found between CC, handedness and daily alcohol intake, ‘Wort-
A possible correlation between CC subregion C2 and the degree of handedness as measured by the HDT was found (Table 4). In this respect a larger degree of right-handedness was associated with a larger C2 subregion. However, this corre-
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Table 3 Comparison of CC regions between handedness groups (consistent vs. non-consistent right-handers)
CC area, total Cl area C2 area C3 area C4, area C5 area
Mixedhanders Mean"S.D.
Consistent right-handers Mean"S.D.
t-test t-value
d.f.
Significance
590.5"93.5 161.6"32.6 87.5"16.9 73.2"11.9 76.4"19.8 156.4"30.1
610.6"82.4 169.5"24.6 92.4"18.1 77.9"14.5 75.2"19.7 164.2"23.5
0.67 0.84 0.80 0.98 y0.17 0.87
44 44 44 44 44 44
0.51 0.41 0.43 0.33 0.87 0.39
lation was no longer significant after Bonferroni correction of the a-significance level (three HDT values and five subregions): Ps0.54. In all other CC subregions and with respect to CC total, no significant correlation was found between degree of right-handedness and the extension of the CC. 4. Discussion The aim of our study was to investigate the in vivo size of the CC and its subregions in male subjects in order to examine the possible relationship between handedness and CC morphology. To our knowledge, this is the first study with healthy control subjects that controlled for several factors which may have contributed to the conflicting results of previous studies. After three-dimensional spatial realignment and the use of a reliable method for the determination of the midsagittal slice, we subdivided the CC into five subregions according to the anterior–posterior somatotopy of callosal connectivity (Meisenzahl et al., 1999). Important possible confounders such as age, alcohol con-
sumption, and vocabulary were considered. No relationship between handedness indices of consistent right-handers and non-consistent right-handers and CC size was detected. We could not supplement the results of Witelson (Witelson, 1989; Witelson and Goldsmith, 1991), who reported that in post-mortem brains, the isthmus of the CC was larger in non-consistent male right-handers than in consistent male right-handers. However, Witelson’s results were based on postmortem data, while our results were obtained in vivo using MRI. Furthermore, in her study, handedness measures were based on observed performance on a series of 12 unimanual and bimanual tasks taken from Annett’s hand questionnaire. Consistent right-handers were defined as showing only right-hand preferences whereas non-consistent right-handers were defined as showing left-hand preferences on at least one item. Nevertheless, the examination of severely diseased cancer patients by Witelson has obvious limitations due to possible brain changes caused by the underlying disease process and therapy, which is not comparable to the study of healthy controls. Nonetheless, this
Table 4 Relationships between CC areas and HDT scores (partial correlation coefficients, controlling for alcohol intake and age)
HDT right hand HDT left hand HDT asymmetry
R P R P R P
CC total area
Cl area
C2 area
C3 area
C4 area
C5 area
0.11 0.49 0.08 0.63 0.09 0.58
0.13 0.43 0.15 0.33 0.05 0.74
0.33 0.04* 0.24 0.13 0.12 0.45
0.05 0.76 0.02 0.90 0.07 0.66
0.09 0.57 0.12 0.45 y0.11 0.47
0.04 0.79 y0.10 0.55 0.23 0.15
R: correlation coefficient; P: significance; HDT, handedness dominance test. *Significance level after a-level correction: 0.54.
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difference in CC size between consistent and nonconsistent right-handers in post-mortem measurements (Witelson, 1989; Witelson and Goldsmith, 1991) was supported first by the in vivo study of Habib et al. (1991), who reported larger callosal regions in non-consistent right-handers defined by the Edinburgh Handedness Inventory (EHI) in 53 healthy volunteers. However, CC assessments were made from in vivo MRI data and only right- and mixed-handed subjects were included in this study whereas Witelson (1989) measured the CC in a post-mortem sample and included right-, mixedand left-handed subjects. Thus, the results can be compared only in part. Subsequent in vivo MRI studies (Cowell et al., 1993; Burke and Yeo, 1994), again with data acquisition of a single midsagittal MRI slice and use of handedness questionnaires, suggested a correlation of right-hand preference with callosal isthmus size. However, investigation of the midsagittal area of the CC in 97 subjects ranging from 56 to 90 years of age indicated that in males, the area of the posterior region of the CC was significantly correlated with increasing right-handedness (Burke and Yeo, 1994). A number of earlier in vivo studies are in line with our findings regarding an absence of a relationship between handedness and CC size. An excellent review of positive and negative findings concerning the correlation between handedness and callosal size in studies up to 1997 was presented by Beaton (1997). Kertesz et al. (1987) examined 52 right- and 52 left-handers (mean age 18–49 years). Handedness was defined on the basis of reported writing hand. Hand preference was further assessed by using a standard questionnaire (Bryden, 1982) and functional laterality tests. Strong left- and right-handers and mixed-handers were categorized on the basis of scores on hand-preference items, and a comparison with total CC and the size of the genu and the splenium was made. Callosal areas did not differ between subgroups of handedness, and no correlation with measures of lateralization for hand performance could be detected (Kertesz et al., 1987). However, a reanalysis of the same data using the hand-preference classification of Witelson revealed a larger isthmal area in non-consistent
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compared with consistent right-handed male subjects (Denenberg et al., 1991). O’Kusky et al. (1988) examined 50 patients with medically refractory seizures and 50 neurologically normal control subjects (11–57 years and 17–60 years, respectively). A subdivision into left lateral, mixed left lateral, mixed right lateral, and right lateral was made according to scores on a handedness questionnaire. The CC was divided into five subregions. No significant differences in total CC area and in CC subregions were detected between the laterality groups (O’Kusky et al., 1988). A study using in vivo MRI imaging and the EHI did not find any difference in the size of the CC or any specific callosal region as a function of handedness (Reinarz et al., 1988). In a study of 28 female subjects, MRI was used to measure callosal areas in the midsagittal plane, and subjects were subdivided into handedness groups (consistent right-handers vs. others). No effect of handedness on callosal size was found (Hines et al., 1992). Prior results reported significant sex differences in the density of fibers in the CC (Aboitiz et al., 1996). Gender differences in brain asymmetry anomalies have been shown in individuals with psychosis (e.g. Crow, 1999; Highley et al., 1999; McDonald et al., 2000). An understanding of the origin of these differences might be crucial to determine the relationship between laterality and callosal function. However, our study included male subjects only, and thus the results reported by Hines et al. (1992) are only in part comparable to ours. A subsequent study found no significant effect of handedness on CC size when subjects were categorized as left- or right-handed based on a modified version of the EHI (Clarke and Zaidel, 1994). In summary, a considerable number of studies reported that handedness and CC morphology are not related. We did not find any significant correlation between the extent of CC regions and the degree of handedness as measured by the HDT. Therefore, we failed to confirm the hypothesis that the size of CC regions might reflect handedness. Our results are supported by the findings of Steinmetz et al. (1992), who investigated different subgroups of left-, right-, and mixed-handedness in 26 males and 26 females. They did not find a relationship
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between handedness and the area of the CC isthmus. Our study is not without limitations. Only male subjects were investigated, and therefore possible effects of sex on CC size, as reported by prior studies (e.g. Steinmetz et al., 1992), could not be tested. Furthermore, only right-handers subdivided into ‘consistent’ and ‘non-consistent’ right-handers were investigated. It might be that the exclusion of left-handers was the reason that no difference or correlation between handedness and degree of handedness with callosal size was detected. Finally, several methodological factors referring to discrepancies regarding variations of CC morphology as a function of handedness deserve discussion. First, it is difficult to compare studies that include subjects who differ considerably with regard to age, educational level, and health status. Confounding factors, e.g. medication or alcohol consumption, are rarely considered. While some prior research related CC size to fetal alcohol syndrome in humans (Clarren et al., 1978) and the effect on the CC in Marchiafava–Bignami disease (Kohler et al., 2000), using alcohol intake as a cofactor in our analysis did not change the results. Second, differences in MRI data acquisitions, slice thickness, and MRI preprocessing are often underestimated methodological aspects. Individual variations in head position in the MR scanner, in particular, may lead to great variability in the subsequent definition of the midsagittal slice and consequently to a larger variability in measurements of the CC. To our knowledge, realignment of MRI data sets to a standard position in previous reports measuring CC has not been performed. Third, a variety of methods for the determination of a ‘representative’ midsagittal slice were described which may yield different CC values in the same subject (Coffman et al., 1989). In the literature the subdivision of the CC has been made based on a variety of distinct methods. The definition of borders between the classical anatomical subregions ‘rostrum, genu, midbody, isthmus and splenium’ is highly controversial (de Lacoste et al., 1985; Witelson, 1989; Steinmetz et al., ¨ 1992; Jancke et al., 1997). Results of studies that have used different definitions of CC subregions
in the anterior, middle and posterior portions of the CC are in consequence not fully comparable. Finally, one possible reason for these differing results may be the use of different instruments to assess handedness. For instance, a number of studies (e.g. O’Kusky et al., 1988; Reinarz et al., 1988) used the EHI, which is a questionnaire based on hand use in everyday life, but not on functional testing. By contrast, the HDT, previously used by other research groups as well as our own (Steinmetz et al., 1995; Zetzsche et al., 2001), is a paper-and-pencil test that encompasses three dexterity tasks, each to be performed with speed and precision over 15 s, separately for the right and the left hand. Thus, hand dominance may be assessed more appropriately by functional tests than by a questionnaire. This point of view is supported by Crow et al. (1998), who used a simple test of manual skills in a large sample of more than 12 000 individuals to demonstrate a relationship between weak lateralization and cognition including reading difficulties. Thus, hand dominance may be assessed either by functional tests or by questionnaire. Different instruments for the determination of handedness may examine different aspects of handedness (Annett, 1985; Beaton, 1985). A study of the relationship between the HDT and the EHI by our group (Zetzsche et al., 2001) yielded low and non-significant correlations between the two tests. These two tests assess different characteristics of handedness: the EHI is based on hand preference in everyday life and the HDT on performance in a test situation using the left and right hand. The definition of a consistent and non-consistent right- or left-hander may differ according to different questionnaires or functional tests. Denenberg et al. (1991) made an important contribution concerning different instruments for handedness assessment. His group revealed in a re-analysis that even within the same study, the use of different handedness questionnaires may produce contradictory results. Our findings support earlier studies that showed no relationship between handedness and CC size in consistent and non-consistent right-handed males. Nevertheless, our findings do not necessarily contradict the assumption of Witelson and
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Nowakowski (1991), who speculated that naturally occurring axon loss during early brain development may be a mechanism involved in determining hand preference and associated hemispheric asymmetries. They proposed that the greater the loss, the smaller the CC and the greater the lateralization of function in right-handed subjects. It may be that differences in handedness present in most human subjects are based on subtle morphological differences in the CC that are not detectable with the high-resolution MRI techniques currently used in measuring the CC. Callosal anatomy is also influenced by factors so far unrelated to lateralization, such as fiber thickness, packing density or myelination (LaMantia and Rakic, 1984). The influence of these factors may be decisive. Therefore, these variables have to be taken into account in the search for structural–functional correlations based on gross anatomic measurement. For this reason, future in vivo studies of brain connectivity should include functional imaging techniques such as MR spectroscopy and may benefit from the use of the newer technique of diffusion tensor imaging, which is capable of defining important variables of long fiber tracts. Acknowledgments This work was supported by the Deutsche Forschungsgemeinschaft, Nr. 231y96. We are grateful to Prof. Nancy Andreasen and her coworkers, who provided generous support with the segmentation program BRAINS. We thank Dr W.M. Wong for English language editing. References Aboitiz, F., 1992. Brain connections: interhemispheric fiber systems and anatomical brain asymmetries in humans. Biological Research 25, 51–61. Aboitiz, F., Rodriguez, E., Olivares, R., Zaidel, E., 1996. Agerelated changes in fibre composition of the human corpus callosum: sex differences. Neuroreport 29, 1761–1764. Andreasen, N.C., Cizadlo, T., Harris, G., Swayze, V., O’Leary, D.S., Cohen, G., Ehrhardt, J., Yuh, W.T., 1992. Voxel processing techniques for the antemortem study of neuroanatomy and neuropathology using magnetic resonance imaging. Journal of Neuropsychiatry and Clinical Neuroscience 5, 121–130.
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magnetic resonance imaging. Brain and Cognition 16, 41–61. Highley, J.R., McDonald, B., Walker, M.A., Esiri, M.M., Crow, T.J., 1999. Schizophrenia and temporal lobe asymmetry. A post-mortem stereological study of tissue volume. British Journal of Psychiatry 175, 127–134. Hines, M., Chiu, L., McAdams, L.A., Bentler, P.M., Lipcamon, J., 1992. Cognition and the corpus callosum: verbal fluency, visuospatial ability, and language lateralization related to midsagittal surface areas of callosal subregions. Behavioral Neuroscience 106, 3–14. Hopkis, W.D., Rilling, J.K., 2000. A comparative MRI study of the relationship between neuroanatomical asymmetry and interhemispheric connectivity in primates: implication for the evolution of functional asymmetries. Behavioral Neuroscience 114, 739–748. ¨ Jancke, L., 1996. The Hand Performance Test with a modified time limit instruction enables the examination of hand performance asymmetries in adults. Perceptual and Motor Skills 82, 735–738. ¨ Jancke, L., Staiger, J.F., Schlaug, G., Yanxiong, H., Steinmetz, H., 1997. The relationship between corpus callosum size and forebrain volume. Cerebral Cortex 7, 48–56. Kertesz, A., Polk, M., Howell, J., Black, S.E., 1987. Cerebral dominance, sex, and callosal size in MRI. Neurology 37, 1385–1388. Kohler, C.G., Ances, B.M., Coleman, A.R., Ragland, J.D., Lazarev, M., Gur, R.C., 2000. Marchiafava–Bignami disease: literature review and case report. Neuropsychiatry, Neuropsychology and Behavioral Neurology 13, 67–76. LaMantia, A.S., Rakic, P., 1984. The number, size, myelination, and regional variation of axons in the corpus callosum and anterior commissure of the developing rhesus monkey. Society of Neuroscience Abstracts 10, 1081. McDonald, B., Highley, J.R., Walker, M.A., Herron, B.M., Cooper, S.J., Esiri, M.M., Crow, T.J., 2000. Anomalous asymmetry of fusiform and parahippocampal gyrus gray matter in schizophrenia: a postmortem study. American Journal of Psychiatry 157, 40–47. McGrew, W.C., Marchant, L.F., 1997. On the other hand: current issues in and meta-analysis of the behavioral laterality of hand function in nonhuman primates. Yearbook of Physical Anthropology 40, 201–232. Meisenzahl, E.M., Frodl, T., Greiner, J., Leinsinger, G., Maag, ¨ K.P., Heiss, D., Hahn, K., Hegerl, U., Moller, H.J., 1999. Corpus callosum size in schizophrenia—a magnetic resonance imaging analysis. European Archives of Psychiatry and Clinical Neuroscience 249, 305–312.
O’Kusky, J., Strauss, E., Kosaka, B., Wada, J., Li, D., Dmhan, M., Petrie, P., 1988. The corpus callosum is larger with right-hemisphere cerebral speech dominance. Annals of Neurology 24, 379–383. Pandya, D.N., Seltzer, B., 1986. The topography of commisural fibers. In: Lepore, F., Ptito, M., Jasper, H.H. (Eds.), Two Hemispheres—One Brain: Functions of the Corpus Callosum. Alan R. Liss, New York,. Reinarz, S.J., Coffman, C.E., Smokere, W.R., Godersky, J.C., 1988. MR imaging of the corpus callosum: normal and pathologic findings and correlation with CT. American Journal of Roentgenology 151, 791–798. Steingrueber, H.J., Lienert, G.A. 1971. Hand-Dominanz-Test. Hogrefe, Goettingen. ¨ Steinmetz, H., Jancke, L., Kleinschmidt, A., Schlaug, G., Volkmann, J., Huang, Y., 1992. Sex but no hand difference in the isthmus of the corpus callosum. Neurology 42, 749–752. ¨ Steinmetz, H., Staiger, J.F., Schlaug, G., Huang, Y., Jancke, L., 1995. Corpus callosum and brain volume in women and men. Neuroreport 6, 1002–1004. Steinmetz, H., Staiger, J.F., Schlaug, G., Yanxioung, H., 1996. Inverse relationship between brain size and callosal volume. Naturwissenschaften 83, 221. Talairach, J., Tournoux, P., 1993. Referencial Orientated Cerebral MRI Anatomy: Atlas of Stereotaxic Anatomical Correlations for Grey and White Matter. Thieme Medical Publishers, Stuttgart. Witelson, S.F., 1985. The brain connection: the corpus callosum is larger in left handers. Science 229, 665–668. Witelson, S.F., 1989. Hand and sex differences in the isthmus and genu of the human corpus callosum. A postmortem morphological study. Brain 112, 799–835. Witelson, S., Kigar, D.L., 1992. Broca’s region: anatomical and function asymmetries. Society of Neuroscience Abstracts 18, 331. Witelson, S.F., Goldsmith, C.H., 1991. The relationship of hand preference to anatomy of the corpus callosum in men. Brain Research 545, 175–182. Witelson, S.F., Nowakowski, R.S., 1991. Left out axons make men right: a hypothesis for the origin of handedness and functional asymmetry. Neuropsychologia 29, 327–333. Zetzsche, T., Meisenzahl, E.M., Preuss, U.W., Holder, J.J., ¨ Leinsinger, G., Hahn, K., Hegerl, U., Moller, H.J., 2001. Invivo analysis of the human planum temporale: does the definition of PT borders influence the results with regard to cerebral asymmetry and correlation with handedness? Psychiatry Research: Neuroimaging 107, 99–115.
Handedness and corpus callosum morphology Ulrich W. Preussa, Eva M. Meisenzahla,*, Thomas Frodla, Thomas Zetzschea, Jan Holdera, ¨ a ¨ Gerda Leinsingerb, Ulrich Hegerla, Klaus Hahnb, Hans-Jurgen Moller a
¨ Munchen ¨ Department of Psychiatry, Ludwig-Maximilians-Universitat (LMU), Nussbaumstr. 7, D-80336 Munich, Germany ¨ Munchen ¨ Department of Radiology, Ludwig-Maximilians-Universitat (LMU), Nussbaumstr. 7, D-80336 Munich, Germany
b
Received 28 May 2001; received in revised form 27 December 2001; accepted 28 January 2002
Abstract Investigations of a relationship between callosal size and functional behavioral lateralization lead to the hypothesis that, as the size of the corpus callosum (CC) increases, interhemispheric information transfer is facilitated and behavioral laterality effects become smaller. The aim of our in vivo study was to investigate the relationship between functional asymmetry of handedness and CC size in healthy subjects. Magnetic resonance images of the CC and five CC subregions were obtained with a 1.5-T Magnetom using a three-dimensional T1 sequence in 46 healthy men. Handedness was determined using the ‘handedness dominance test’ (HDT). According to the HDT values, 32 consistent and 14 non-consistent right-handers were identified. No significant difference between handedness subgroups in CC regions and no significant correlations between HDT values and CC areas were detected. 䊚 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Corpus callosum; Functional asymmetry; Hand preference; Hand dominance test
1. Introduction The corpus callosum (CC) is the largest fiber tract in primate brains. It connects cortical association areas of the left and right cerebral hemispheres (Steinmetz et al., 1996), and its ratio to total brain volume is two–three times smaller in humans than in other primates (Hopkis and Rilling, 2000), probably due to brain enlargement, functional lateralization and facilitated processing of information in humans. The CC consists of myelinated axons of large pyramidal neurons that are *Corresponding author. Tel.: q49-89-5160-5772; fax: q49421-218-4600. E-mail address: [email protected] (E.M. Meisenzahl).
localized in neocortical layers II and III. The projection targets of these neurons are localized mainly in the same cortical layers of the contralateral hemisphere (Diao and So, 1991). The CC fibers show a somatotopic arrangement: fibers from the inferior frontal and anterior inferior parietal regions course through the rostrum and the genu of the CC; temporo-parieto-occipital junction regions and occipital areas traverse the CC splenium (de Lacoste et al., 1985; Witelson, 1989). Research on the CC, including the examination of split-brain patients, indicates that callosal fibers play an important role in interhemispheric communication by facilitating the interhemispheric exchange of sensory, motor and higher-order cerebral information (Gazzaniga, 2000). Somatosen-
0925-4927/02/$ - see front matter 䊚 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 9 2 5 - 4 9 2 7 Ž 0 2 . 0 0 0 6 4 - 1
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Table 1 Sample characteristics of healthy subjects (ns46) Right-handed: ns32
Age (years) Body height (cm) Body weight (kg) Daily alcohol intake (gyday) Nicotine use (cigarettesyday) WST IQ
Mixed-handed: ns14
Mean
S.D.
Minimum
Maximum
Mean
S.D.
Minimum
Maximum
29.6 180 75.1 18.0 7.9 110.3
"8.7 "6.3 "10.4 "16.5 "8.8 "14.2
18.0 168 57.0 0.0 0.0 66.0
45.0 190 92.0 60.0 30.0 139.0
32.2 180 76.1 9.0 1.2 113.0
"8.6 "7.4 "7.6 "8.0 "3.1 "14.9
20.0 170 60.0 0.0 0.0 92.0
44.0 190 105.0 20.0 10.0 139.0
sory and motor fibers are localized in the central portion of the CC, whereas fibers connecting higher-order processing areas are concentrated in the genu and the isthmus (Aboitiz, 1992), as was also reported from animal research (Pandya and Seltzer, 1986). It has been suggested that the CC exerts an inhibitory action on the non-dominant hemisphere, thereby suppressing potentially conflicting motor programs (Gazzaniga, 2000). There is evidence that ontogenetic development and the maintenance of cerebral dominance may be tightly associated with the development and extension of the CC (Galaburda et al., 1990). An inverse relationship has been suggested between the magnitude of cerebral anatomic asymmetry and the extent of commissural connectivity between cortical areas. This relationship may be specific to Homo sapiens amongst extant primates (McGrew and Marchant, 1997; Buxhoeveden and Casanova, 2000). This asymmetry might be correlated with relatively gross morphological hemispheric differences, such as the size of the planum temporale (Galaburda, 1993) and Broca’s area (Witelson and Kigar, 1992). On the basis of pioneering post-mortem studies, Witelson reported that non-consistent right-handed men show a larger posterior CC area than consistent right-handed men. It was concluded therefore that laterality and callosal size might be related (Witelson, 1985, 1989; Witelson and Goldsmith, 1991). The aim of our quantitative MRI study was to determine the in vivo size of the CC in healthy male subjects in order to examine a possible correlation between CC size and handedness.
2. Methods 2.1. Sample Forty-six male right-handed healthy subjects were recruited from the local community. They showed a normal age distribution. Demographic information, past and current personal history, and family history of all subjects were obtained using a semistructured interview that included a variety of measures relevant to the study. Exclusion criteria were history of head trauma, positive family history for psychiatric disease, and treatment with corticosteroids within the last 3 months. Detailed sample characteristics are given in Table 1. 2.2. Assessment of handedness Handedness was determined using the ‘handedness dominance test’ (HDT) (Steingrueber and Lienert, 1971). The HDT, modified for use with adult samples, shows high reliability and validity ¨ (Jancke, 1996). It is a paper-and-pencil test that encompasses three dexterity tasks, each to be performed with speed and precision over 15 s, separately for the right and the left hand. The tasks were to trace lines, dot circles and squares, and performance was scored for each hand. For all hand-skill tasks, the raw value of each hand’s performance and the widely-used laterality coefficient (RyL)y(RqL) were calculated to obtain hand-skill asymmetry scores independent of overall performance. To compare subgroups with regard to handedness, HDT asymmetry scores higher than 0.1 were
U.W. Preuss et al. / Psychiatry Research Neuroimaging 116 (2002) 33–42
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considered to indicate consistent right-handers, whereas scores lower than 0.1 defined non-consistent right-handers (including mixed-handers as ¨ suggested by previous research; Jancke, 1996). There were 32 consistent right-handers (HDT asymmetry value: 0.16"0.039) and 14 non-consistent right-handers (HDT asymmetry mean: 0.08"0.015). Fig. 2 depicts the distribution of a symmetry scores in the two subgroups. 2.3. Ethical standards Written informed consent was obtained by all participants after complete description of the study. The study was approved by the ethical committee of the Ludwig-Maximilians-University of Munich according to the ethical standards of the Helsinki Declaration, 1964. 2.4. MRI procedures Imaging was obtained using a 1.5-T Magnetom Vision (Siemens, Erlangen). Three-dimensional T1-weighted images using a magnetization-prepared rapid gradient echo sequence (MPRAGE) were acquired with the following parameters: echo time (TE)s4.9 ms; repetition time (TR)s11.6 ms; number of acquisitionss1; field of view (FOV)s230=230=190; slice thicknesss1.5 mm; matrixs512=512=126. 2.5. Image processing For further image processing with size reduction from 16 to 8 bits (transformation to a uniform matrix of 256=256=126 of 1.5-mm slice thickness), the software package Analyze was used (Biomedical Imaging Resource, Mayo Foundation, Rochester, MN). MR data were processed on Silicon graphics workstations (SGI). All MRI data sets were spatially normalized using the software BRAINS (Andreasen et al., 1992). For each data set three-dimensional spatial realignment was performed. In a first step, the interhemispheric fissure was aligned on the coordinate axes. In a second step, realignment was performed according to the anterior–posterior commissure (AC–PC) line.
Fig. 1. Corpus callosum (CC) measurement: The outer edge of the CC was traced in the midsagittal area. After that, the areas of five callosal subregions were outlined in two steps. First, a rectangle was placed over the CC. The lower side of the rectangle cut the two lowest points of the anterior and the posterior parts of the CC tangentially. In the second step, a radial divider with 10 rays equidistant from each other was placed at the midpoint on the lower side of the rectangle. Its four upper rays divided the CC into five subregions.
2.6. Corpus callosum Areas of the total CC and five callosal subregions were measured in the realigned sagittal T1weighted MRI slices that best represented the midsagittal section (Meisenzahl et al., 1999). This slice was chosen by using anatomical landmarks in a hierarchical order (Talairach and Tournoux, 1993). First, slices were selected that showed only minimal or no white matter in the cortical mantle surrounding the CC. When more than one slice fulfilled this criterion, the medial thalamic nuclei
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Fig. 2. Distribution of handedness asymmetry scores in right- and mixed-handed subjects.
served as a second anatomical landmark. The selected slice then showed the interthalamic adhesion connecting the left and the right medial thalamic nuclei, or only the smallest size of the thalamus of either one or the other side. The transparent septum and the cerebral aqueduct were used in the third step to confirm the selection when the remaining two slices showed a similar amount of thalamic substance. After the midsagittal slice was determined, the total callosal area was measured on a SGI workstation by manually tracing the outer edge of the CC on this slice using the Analyze software package. The areas of five callosal subregions were outlined in two subsequent steps. First, a rectangle was placed over the image of the CC. The lower side of the rectangle cut tangentially the two lowest points of the anterior and posterior parts of the CC. Two lines perpendicular to this lower side that cuts the most anterior and the most posterior points of the CC determine the rectangle’s length. In the second step, a radial divider with 10 rays equidistant from each other was placed at the midpoint on the lower side of the rectangle. Its four upper rays divided the CC into five subregions. The number of pixels within each region was summed
automatically and multiplied by the pixel size to obtain absolute values in millimeters squared for the areas of total CC and the five subregions (labeled C1–C5 in a rostral–occipital direction; see Fig. 1). 2.7. Interrater and intrarater reliability of CC measurements To assess interrater reliability, two independent researchers (E.M. and T.F.) measured the total callosal area in 10 randomly chosen subjects. To evaluate intrarater reliability, one researcher measured the total area of the callosal subregions twice in 10 randomly chosen subjects. The intraclass correlation coefficient for the total callosal area was 0.98 for the interrater and 0.97 for the intrarater reliability; for the regional CC measurements, interrater reliability ranged from 0.94 for the Cl subregion to 0.91 for the C5 subregion. 2.8. Statistics Statistics were performed using SPSS Software (Statistical Package for the Social Sciences, 10.0, SPSS Inc, Chicago, 2000). All continuous values were tested for normal distribution.
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Table 2 Correlation between sample characteristics and CC areas
Right-handed (ns32) Daily alcohol intake (gyday) Age (years) Wortschatz (Vocabulary) test value Mixed-handed (ns14) Daily alcohol intake (gyday) Age (years) Wortschatz (Vocabulary) test value
Total CC area
C1 area
C2 area
C3 area
C4 area
C5 area
HDT
Corr. R Sig. P Corr. R Sig. P Corr. R Sig. P
0.02 0.90 y0.35 0.06 0.20 0.29
y0.01 0.96 y0.32 0.08 0.12 0.51
y0.33 0.07 y0.21 0.26 0.10 0.59
0.07 0.72 y0.25 0.18 0.25 0.17
0.05 0.78 y0.33 0.07 0.09 0.63
0.05 0.80 y0.26 0.15 0.30 0.10
y0.35 0.06 y0.05 0.77 0.33 0.07
Corr. R Sig. P Corr. R Sig. P Corr. R Sig. P
0.10 0.77 y0.36 0.28 y0.43 0.18
0.17 0.62 y0.25 0.45 y0.25 0.46
y0.22 0.52 y0.45 0.17 y0.19 0.57
0.19 0.58 0.16 0.65 0.11 0.75
y0.03 0.92 y0.40 0.23 y0.39 0.23
0.18 0.59 y0.36 0.28 y0.38 0.22
0.50 0.12 0.26 0.44 y0.05 0.88
Differences of psychosocial characteristics and CC measurements between groups were tested with the t-test for independent samples. Relationships between handedness and CC areas were computed using Spearman rank–order correlations. A twotailed a-significance level of P-0.05 was considered statistically significant; Bonferroni’s correction for multiple testing on a-significance level was applied when necessary. 3. Results 3.1. Extension of CC (CC total and CC subregions), and handedness as measured by the HDT Table 3 shows the mean values of the CC total and CC subregions C1–C5 with regard to handedness as measured by the HDT.
schatz’ (Vocabulary) test IQ parameters, and age of the two handedness subgroups (Table 2). Thus, none of the above-mentioned variables were used as covariates in subsequent analysis. 3.3. CC total and CC subregions: differences between handedness subgroups By comparison of their values, callosal subregion C2, C3 and C5 areas tended to be larger in consistent compared with non-consistent righthanders. However, in analyses of differences between groups with t-tests for independent samples, values of CC total and CC subregions C1– C5 showed no significant differences between consistent and non-consistent right-handers (Table 3).
3.2. Correlation between CC regions, handedness and sample characteristics
3.4. Correlation between CC extension (CC total and CC subregions) and degree of handedness as measured by the HDT
To obtain possible confounders, sample properties and CC regions (CC total and CC subregions C1–C5) were correlated with several parameters: no significant correlations were found between CC, handedness and daily alcohol intake, ‘Wort-
A possible correlation between CC subregion C2 and the degree of handedness as measured by the HDT was found (Table 4). In this respect a larger degree of right-handedness was associated with a larger C2 subregion. However, this corre-
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Table 3 Comparison of CC regions between handedness groups (consistent vs. non-consistent right-handers)
CC area, total Cl area C2 area C3 area C4, area C5 area
Mixedhanders Mean"S.D.
Consistent right-handers Mean"S.D.
t-test t-value
d.f.
Significance
590.5"93.5 161.6"32.6 87.5"16.9 73.2"11.9 76.4"19.8 156.4"30.1
610.6"82.4 169.5"24.6 92.4"18.1 77.9"14.5 75.2"19.7 164.2"23.5
0.67 0.84 0.80 0.98 y0.17 0.87
44 44 44 44 44 44
0.51 0.41 0.43 0.33 0.87 0.39
lation was no longer significant after Bonferroni correction of the a-significance level (three HDT values and five subregions): Ps0.54. In all other CC subregions and with respect to CC total, no significant correlation was found between degree of right-handedness and the extension of the CC. 4. Discussion The aim of our study was to investigate the in vivo size of the CC and its subregions in male subjects in order to examine the possible relationship between handedness and CC morphology. To our knowledge, this is the first study with healthy control subjects that controlled for several factors which may have contributed to the conflicting results of previous studies. After three-dimensional spatial realignment and the use of a reliable method for the determination of the midsagittal slice, we subdivided the CC into five subregions according to the anterior–posterior somatotopy of callosal connectivity (Meisenzahl et al., 1999). Important possible confounders such as age, alcohol con-
sumption, and vocabulary were considered. No relationship between handedness indices of consistent right-handers and non-consistent right-handers and CC size was detected. We could not supplement the results of Witelson (Witelson, 1989; Witelson and Goldsmith, 1991), who reported that in post-mortem brains, the isthmus of the CC was larger in non-consistent male right-handers than in consistent male right-handers. However, Witelson’s results were based on postmortem data, while our results were obtained in vivo using MRI. Furthermore, in her study, handedness measures were based on observed performance on a series of 12 unimanual and bimanual tasks taken from Annett’s hand questionnaire. Consistent right-handers were defined as showing only right-hand preferences whereas non-consistent right-handers were defined as showing left-hand preferences on at least one item. Nevertheless, the examination of severely diseased cancer patients by Witelson has obvious limitations due to possible brain changes caused by the underlying disease process and therapy, which is not comparable to the study of healthy controls. Nonetheless, this
Table 4 Relationships between CC areas and HDT scores (partial correlation coefficients, controlling for alcohol intake and age)
HDT right hand HDT left hand HDT asymmetry
R P R P R P
CC total area
Cl area
C2 area
C3 area
C4 area
C5 area
0.11 0.49 0.08 0.63 0.09 0.58
0.13 0.43 0.15 0.33 0.05 0.74
0.33 0.04* 0.24 0.13 0.12 0.45
0.05 0.76 0.02 0.90 0.07 0.66
0.09 0.57 0.12 0.45 y0.11 0.47
0.04 0.79 y0.10 0.55 0.23 0.15
R: correlation coefficient; P: significance; HDT, handedness dominance test. *Significance level after a-level correction: 0.54.
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difference in CC size between consistent and nonconsistent right-handers in post-mortem measurements (Witelson, 1989; Witelson and Goldsmith, 1991) was supported first by the in vivo study of Habib et al. (1991), who reported larger callosal regions in non-consistent right-handers defined by the Edinburgh Handedness Inventory (EHI) in 53 healthy volunteers. However, CC assessments were made from in vivo MRI data and only right- and mixed-handed subjects were included in this study whereas Witelson (1989) measured the CC in a post-mortem sample and included right-, mixedand left-handed subjects. Thus, the results can be compared only in part. Subsequent in vivo MRI studies (Cowell et al., 1993; Burke and Yeo, 1994), again with data acquisition of a single midsagittal MRI slice and use of handedness questionnaires, suggested a correlation of right-hand preference with callosal isthmus size. However, investigation of the midsagittal area of the CC in 97 subjects ranging from 56 to 90 years of age indicated that in males, the area of the posterior region of the CC was significantly correlated with increasing right-handedness (Burke and Yeo, 1994). A number of earlier in vivo studies are in line with our findings regarding an absence of a relationship between handedness and CC size. An excellent review of positive and negative findings concerning the correlation between handedness and callosal size in studies up to 1997 was presented by Beaton (1997). Kertesz et al. (1987) examined 52 right- and 52 left-handers (mean age 18–49 years). Handedness was defined on the basis of reported writing hand. Hand preference was further assessed by using a standard questionnaire (Bryden, 1982) and functional laterality tests. Strong left- and right-handers and mixed-handers were categorized on the basis of scores on hand-preference items, and a comparison with total CC and the size of the genu and the splenium was made. Callosal areas did not differ between subgroups of handedness, and no correlation with measures of lateralization for hand performance could be detected (Kertesz et al., 1987). However, a reanalysis of the same data using the hand-preference classification of Witelson revealed a larger isthmal area in non-consistent
39
compared with consistent right-handed male subjects (Denenberg et al., 1991). O’Kusky et al. (1988) examined 50 patients with medically refractory seizures and 50 neurologically normal control subjects (11–57 years and 17–60 years, respectively). A subdivision into left lateral, mixed left lateral, mixed right lateral, and right lateral was made according to scores on a handedness questionnaire. The CC was divided into five subregions. No significant differences in total CC area and in CC subregions were detected between the laterality groups (O’Kusky et al., 1988). A study using in vivo MRI imaging and the EHI did not find any difference in the size of the CC or any specific callosal region as a function of handedness (Reinarz et al., 1988). In a study of 28 female subjects, MRI was used to measure callosal areas in the midsagittal plane, and subjects were subdivided into handedness groups (consistent right-handers vs. others). No effect of handedness on callosal size was found (Hines et al., 1992). Prior results reported significant sex differences in the density of fibers in the CC (Aboitiz et al., 1996). Gender differences in brain asymmetry anomalies have been shown in individuals with psychosis (e.g. Crow, 1999; Highley et al., 1999; McDonald et al., 2000). An understanding of the origin of these differences might be crucial to determine the relationship between laterality and callosal function. However, our study included male subjects only, and thus the results reported by Hines et al. (1992) are only in part comparable to ours. A subsequent study found no significant effect of handedness on CC size when subjects were categorized as left- or right-handed based on a modified version of the EHI (Clarke and Zaidel, 1994). In summary, a considerable number of studies reported that handedness and CC morphology are not related. We did not find any significant correlation between the extent of CC regions and the degree of handedness as measured by the HDT. Therefore, we failed to confirm the hypothesis that the size of CC regions might reflect handedness. Our results are supported by the findings of Steinmetz et al. (1992), who investigated different subgroups of left-, right-, and mixed-handedness in 26 males and 26 females. They did not find a relationship
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between handedness and the area of the CC isthmus. Our study is not without limitations. Only male subjects were investigated, and therefore possible effects of sex on CC size, as reported by prior studies (e.g. Steinmetz et al., 1992), could not be tested. Furthermore, only right-handers subdivided into ‘consistent’ and ‘non-consistent’ right-handers were investigated. It might be that the exclusion of left-handers was the reason that no difference or correlation between handedness and degree of handedness with callosal size was detected. Finally, several methodological factors referring to discrepancies regarding variations of CC morphology as a function of handedness deserve discussion. First, it is difficult to compare studies that include subjects who differ considerably with regard to age, educational level, and health status. Confounding factors, e.g. medication or alcohol consumption, are rarely considered. While some prior research related CC size to fetal alcohol syndrome in humans (Clarren et al., 1978) and the effect on the CC in Marchiafava–Bignami disease (Kohler et al., 2000), using alcohol intake as a cofactor in our analysis did not change the results. Second, differences in MRI data acquisitions, slice thickness, and MRI preprocessing are often underestimated methodological aspects. Individual variations in head position in the MR scanner, in particular, may lead to great variability in the subsequent definition of the midsagittal slice and consequently to a larger variability in measurements of the CC. To our knowledge, realignment of MRI data sets to a standard position in previous reports measuring CC has not been performed. Third, a variety of methods for the determination of a ‘representative’ midsagittal slice were described which may yield different CC values in the same subject (Coffman et al., 1989). In the literature the subdivision of the CC has been made based on a variety of distinct methods. The definition of borders between the classical anatomical subregions ‘rostrum, genu, midbody, isthmus and splenium’ is highly controversial (de Lacoste et al., 1985; Witelson, 1989; Steinmetz et al., ¨ 1992; Jancke et al., 1997). Results of studies that have used different definitions of CC subregions
in the anterior, middle and posterior portions of the CC are in consequence not fully comparable. Finally, one possible reason for these differing results may be the use of different instruments to assess handedness. For instance, a number of studies (e.g. O’Kusky et al., 1988; Reinarz et al., 1988) used the EHI, which is a questionnaire based on hand use in everyday life, but not on functional testing. By contrast, the HDT, previously used by other research groups as well as our own (Steinmetz et al., 1995; Zetzsche et al., 2001), is a paper-and-pencil test that encompasses three dexterity tasks, each to be performed with speed and precision over 15 s, separately for the right and the left hand. Thus, hand dominance may be assessed more appropriately by functional tests than by a questionnaire. This point of view is supported by Crow et al. (1998), who used a simple test of manual skills in a large sample of more than 12 000 individuals to demonstrate a relationship between weak lateralization and cognition including reading difficulties. Thus, hand dominance may be assessed either by functional tests or by questionnaire. Different instruments for the determination of handedness may examine different aspects of handedness (Annett, 1985; Beaton, 1985). A study of the relationship between the HDT and the EHI by our group (Zetzsche et al., 2001) yielded low and non-significant correlations between the two tests. These two tests assess different characteristics of handedness: the EHI is based on hand preference in everyday life and the HDT on performance in a test situation using the left and right hand. The definition of a consistent and non-consistent right- or left-hander may differ according to different questionnaires or functional tests. Denenberg et al. (1991) made an important contribution concerning different instruments for handedness assessment. His group revealed in a re-analysis that even within the same study, the use of different handedness questionnaires may produce contradictory results. Our findings support earlier studies that showed no relationship between handedness and CC size in consistent and non-consistent right-handed males. Nevertheless, our findings do not necessarily contradict the assumption of Witelson and
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Nowakowski (1991), who speculated that naturally occurring axon loss during early brain development may be a mechanism involved in determining hand preference and associated hemispheric asymmetries. They proposed that the greater the loss, the smaller the CC and the greater the lateralization of function in right-handed subjects. It may be that differences in handedness present in most human subjects are based on subtle morphological differences in the CC that are not detectable with the high-resolution MRI techniques currently used in measuring the CC. Callosal anatomy is also influenced by factors so far unrelated to lateralization, such as fiber thickness, packing density or myelination (LaMantia and Rakic, 1984). The influence of these factors may be decisive. Therefore, these variables have to be taken into account in the search for structural–functional correlations based on gross anatomic measurement. For this reason, future in vivo studies of brain connectivity should include functional imaging techniques such as MR spectroscopy and may benefit from the use of the newer technique of diffusion tensor imaging, which is capable of defining important variables of long fiber tracts. Acknowledgments This work was supported by the Deutsche Forschungsgemeinschaft, Nr. 231y96. We are grateful to Prof. Nancy Andreasen and her coworkers, who provided generous support with the segmentation program BRAINS. We thank Dr W.M. Wong for English language editing. References Aboitiz, F., 1992. Brain connections: interhemispheric fiber systems and anatomical brain asymmetries in humans. Biological Research 25, 51–61. Aboitiz, F., Rodriguez, E., Olivares, R., Zaidel, E., 1996. Agerelated changes in fibre composition of the human corpus callosum: sex differences. Neuroreport 29, 1761–1764. Andreasen, N.C., Cizadlo, T., Harris, G., Swayze, V., O’Leary, D.S., Cohen, G., Ehrhardt, J., Yuh, W.T., 1992. Voxel processing techniques for the antemortem study of neuroanatomy and neuropathology using magnetic resonance imaging. Journal of Neuropsychiatry and Clinical Neuroscience 5, 121–130.
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