Brain, Vol. 125, No. 12, 2710-2718,
December 2002
© 2002 Oxford University Press
Language lateralization in monozygotic twin pairs concordant and discordant for handedness
Rudolf Magnus Institute of Neuroscience, Department of Psychiatry, Neuroscience Division, University Medical Centre Utrecht, The Netherlands
Correspondence to: Iris Sommer, Department of Psychiatry, Neuroscience Division, University Medical Centre Utrecht, Heidelberglaan 100, 3584CX Utrecht, The NetherlandsE-mail: i.sommer{at}azu.nl
Received January 6, 2002. Revised April 29, 2002. Accepted July 29, 2002.
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An unexpectedly high percentage of monozygotic twin pairs is discordant for handedness. Some of these twins show mirror-imaging of several ectodermally derived features. Both features of discordant left–right asymmetry may be caused by relatively late monozygotic twinning, when the original embryo has already lost its bilateral symmetry. Language lateralization is related to handedness and may therefore also be altered during the development of embryological asymmetry in some monozygotic twins. Language lateralization was measured with functional MRI in 12 monozygotic twin pairs who were concordant for handedness and in 13 monozygotic twin pairs discordant for handedness. Lateralization indices were calculated from indi vidual language activation patterns. Correlations were calculated to test intra-pair resemblance for language lateralization. The intra-pair correlation for language lateralization was significant in the handedness-concordant group, but not in the handedness-discordant group. In the handedness-discordant group, five twin pairs were also discordant for cerebral dominance; the other twin pairs of discordant handedness exhibited remarkable similarity in language lateralization. The high intra-pair correlation for language lateralization in the handedness-concordant twins suggests a genetic basis for language lateralization. However, in monozygotic twin pairs of discordant handedness, discordance for language dominance occurs in a significant number of twins. Discordant language dominance may be caused by a relatively late time of splitting of the original embryo, which disrupts the normal development of left–right asymmetry.
Keywords: cerebral dominance; monozygotic twins; genetics
Abbreviations: fMRI = functional MRI; VOI = volume of interest
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Introduction |
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Though symmetry across the anterior–posterior axis is the basic structure for animal and human life, many structures in the human body show left–right asymmetry. Even bilaterally paired organs, such as the lungs, kidneys and testes, show consistent left–right asymmetry in anatomy or function (Fujinaga, 1997
). Left–right asymmetries of the internal (mesodermally derived) organs are generally extremely stable, though inversions of some or all internal organs do occur (Fujinaga, 1997). Complete reversal of visceral left–right asymmetry, situs inversus, is a very rare finding (approximately 1 in 10 000), but lesser degrees of disturbed visceral situs—isomerism—are more frequent (Fujinaga, 1997). Isomerism may be expressed as polysplenia or asplenia, as congenital heart disease or ectopic vein malformation (Burn, 1991; Fujinaga, 1997).
The cerebral hemispheres can also be considered as a paired organ. Unlike the mesodermally derived organs, the ectodermally derived cerebral hemispheres show normal variation in asymmetry (Geschwind et al., 1979). Cerebral asymmetry is most pronounced for language function, for which the left hemisphere is generally dominant (Geschwind et al., 1979; Knecht et al., 2000a). Handedness is correlated with language dominance, in that left-handed persons are more likely to divert from standard left cerebral dominance (Pujol et al., 1999; Knecht et al., 2000a). Whereas there are relatively few large-scale studies on language dominance, handedness has been studied extensively (Herron, 1980). Despite the abundance of studies, controversy remains about the origin of left-handedness. Several arguments favour a genetic mechanism. First, studies in singletons show that left-handedness tends to run in families; children of left-handed parents are three to ten times more likely to be left-handed than children from two right-handed parents (McManus and Bryden, 1992; Coren, 1994). Adoption studies further show that the handedness of a child is strongly related to that of the biological parents, whereas the handedness of their adoption parents is of little influence (Hicks and Kinsbourne, 1976; Carter-Saltzman, 1980). McManus (1985) introduced a genetic model for handedness in which handedness is determined by one gene with two alleles: D for dextral and C for chance. The DD genotype always leads to right-handedness but the CC genotype provides no direction to handedness, which then develops in a random fashion (i.e. left-handedness in 50% of offspring and right-handedness in 50%). The intermediate genotype, CD, is an additive type, which gives rise to right-handedness in a certain percentage (
75%) of cases. Indeed, children from two left-handed parents, who are likely to be of the CC genotype, are left-handed themselves in only 50% of cases (Annett, 1974).
Twin studies partly support a genetic basis for handedness. Several large twin studies on handedness did not find increased concordance in monozygotic twin pairs compared with dizygotic pairs (McManus, 1980; Derom et al., 1996; Orlebeke et al., 1996; Ross et al., 1999), although a large meta-analysis of 9969 twin pairs from 28 studies found slightly but significantly higher concordance for handedness in monozygotic than in dizygotic twin pairs (Sicotte et al., 1999). This discrepancy between family and twin studies may indicate the presence of another, non-genetic factor in determining handedness in twins (Derom et al., 1996; Sicotte et al., 1999).
In contrast to the abundance of studies on handedness in twins, only two studies assessed cerebral dominance for language in twins (Springer and Searleman, 1978; Jancke and Steinmetz, 1994). Both of these studies reported no significant intra-pair resemblance in monozygotic twin pairs in the dichotic listening paradigm, suggesting non-genetic influences on cerebral dominance for language.
An obvious explanation for the low concordance for handedness and language lateralization in twin pairs is that twin birth is more complicated and more frequently preterm than singleton birth, which could cause pathological left-handedness, i.e. left-handedness as a result of left hemispheric brain injury, and deviant language dominance (Annett, 1974; van den Daele, 1974; Annett and Ockwell, 1980). However, this cannot be the only explanation, as brain lesions resulting from perinatal asphyxia are almost completely confined to the second-born twin (Bulmer, 1970; Arnold et al., 1987; Prins, 1994), but left-handedness in twins is not more frequent in second-born than in first-born twins (Christian et al., 1979; Nachshon and Denno, 1986, 1987; Orlebeke et al., 1996). Another possible explanation for the low concordance for language dominance in monozygotic twin pairs is that the twinning process itself can sometimes disrupt the normal development of asymmetry of the embryo (Boklage, 1987; Levin, 1999; Sommer et al., 1999). This process may increase discordance for language lateralization and handedness only in monozygotic twin pairs, thereby reducing the difference in concordance between monozygotic and dizygotic twin pairs.
In the chicken, mouse and frog, a cascade of genes has been discovered that regulates left–right orientation at a very early stage (Levin and Mercola, 1998a). Without asymmetrical expression of these genes, left–right asymmetry develops in a random fashion (Levin, 1998). A similar genetic cascade probably also determines the development of asymmetry in the human embryo (Levin and Mercola, 1998b; Schneider and Brueckner, 2000).
The time of splitting of a human embryo into monozygotic twin pairs is variable. On the basis of the anatomy of the placenta, monozygotic twins can be divided into two groups: approximately one-third of monozygotic twins are dichorionic and two-thirds are monochorionic (Bryan, 1992). The twinning process of dichorionic monozygotic twins probably occurs before blastocyst formation, whereas monochorionic twin pairs split after formation of the chorion, at least 4 days after fertilization (Bulmer, 1970; Derom et al., 1995). Only 4% of monochorionic twins are monoamniotic (Bulmer, 1970). These monoamniotic twins are thought to arise still later, at least 8 days after fertilization (Bryan, 1992; Derom et al., 1995). Inactivation of one X chromosome in female embryos is closely associated in time with monozygotic twinning, and occurs when the embryo consists of 20 cells (Puck et al., 1998). By studying the similarity of X-inactivation patterns in female monozygotic twin pairs, these periods for the formation of dichorionic (Monteiro et al., 1998), monochorionic (Monteiro et al., 1998) and monoamniotic (Chitnis et al., 1999) twins have been confirmed.
When monozygotic twinning occurs relatively late, as in monochorionic twins, the cascade of asymmetrically expressed genes regulating left–right asymmetry may already have been initiated. Splitting of this asymmetrical embryo may leave one side with inappropriate information on left–right orientation. In the individual that develops from this side, left–right asymmetry may become deviant, which would increase the discordance rate for asymmetrical traits, such as handedness and cerebral dominance, in monozygotic twin pairs.
Monochorionic monozygotic twins, who result from a late twinning process, would be especially prone to this process. Two studies assessed concordance for handedness in monochorionic and dichorionic monozygotic twin pairs. Derom and colleagues studied handedness in 750 monozygotic twins and found no difference in handedness concordance between monochorionic and dichorionic monozygotic twin pairs (Derom et al., 1996). However, the failure to find a difference could be an artefact. In this study, handedness was scored as ‘unknown’ in cases of ambidexterity. Among the monochorionic monozygotic twins there were 19 cases of unknown handedness against only four among the dichorionic monozygotic twins. If discordance for handedness had been defined as ambidexterity and left-handedness (non-right-handedness) in one twin and right-handedness in the co-twin, the prevalence of handedness discordance would have been significantly higher in monochorionic than in dichorionic twins. Carlier and colleagues reported four handedness-discordant twin pairs among 20 monochorionic monozygotic twin pairs against two among 20 dichorionic monozygotic twin pairs (Carlier et al., 1995).
Since handedness is related to cerebral language representation, discordance in monozygotic twin pairs may also be expected for cerebral dominance. In this study, language lateralization was assessed in monozygotic twin pairs. By assessing functional language lateralization patterns in monozygotic twin pairs, we tried to differentiate between genetically defined discordant handedness (as a result of the CC or CD genotype) and discordant handedness as a component of disrupted embryological development of laterality.
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Subjects
Twelve monozygotic twin pairs were included who were concordant for handedness (both were right-handed). Another 13 monozygotic twin pairs were included who were discordant for handedness (one right-handed, one left-handed). Twelve twin pairs were male and 13 were female. Monozygosity was confirmed by genotyping. Handedness was assessed using the Edinburgh Handedness Inventory (Oldfield, 1971
). Familial left-handedness was defined as occurring when one or more first-degree relatives, apart from the left-handed twin, were left-handed. Three handedness-concordant twin pairs and five handedness-discordant twin pairs had familial left-handedness.
To decrease the chance of including a subject with pathological left-handedness (Coren, 1994) the following exclusion criteria were used: born before the 35th week of pregnancy, birth weight <2 kg and paediatric admission due to perinatal complications.
Information on chorion type could be retrieved for 20 twin pairs. From these, 13 twin pairs (five handedness-concordant and eight handedness-discordant pairs) were monochorionic and seven (four handedness-concordant and three handedness-discordant pairs) were dichorionic.
After the subjects had been given a complete description of the study, written informed consent was obtained according to the Declaration of Helsinki and the study was approved by the Ethical Committee of our hospital.
Scanning protocol
The functional MRI (fMRI) technique, the language activation tasks and the statistical analysis of the individual scans are described in detail elsewhere (Ramsey et al., 2001). Briefly, functional scans were acquired with a Philips ACS-NT 1.5 tesla clinical scanner, using the blood oxygen level-dependent-sensitive, navigated 3D PRESTO pulse sequence (Ramsey et al., 1998), with the following parameter settings: TE (echo time) 35 ms, TR (repetition time) 24 ms, flip angle 9°, FOV (field of view) 180 x 225 x 91 mm, matrix 52 x 64 x 26, voxel size 3.51 mm isotropic, scan time per fMRI volume 2.4 s.
Following the fMRI procedure an anatomical scan was acquired (3d-FFE, TE 4.6 s, TR 30 ms, flip angle 30°, FOV 256 x 256 x 180 mm, matrix 128 x 128 x 150, slice thickness 1.2 mm).
Language tasks
Two word tasks were used: a verb-generation task and a semantic decision task. For both tasks, words were presented visually, one every 3 s.
Silent vocalization was used to avoid head motion. All tasks were presented for ten blocks of 30 s each, alternated with periods of 30 s in the baseline condition.
For the semantic decision task, answers were given by pushing an air-mediated button and recorded by a computer.
Analyses
Functional images were analysed for each subject separately, on a voxel-by-voxel basis, using multiple regression analysis (Worsley and Friston, 1995). Voxels were considered active if the task-related t-value exceeded 4.0 [corresponding to P < 0.05 Bonferroni-corrected for the total number of voxels in all volumes of interest (VOIs)]. Brain activity maps were obtained by analysing the fMRI scans acquired during the two tasks together. Advantages of this combined task analysis are discussed elsewhere (Ramsey et al., 2001).
Five VOIs were delineated manually in each hemisphere of all anatomical scans, blind to statistical results. The VOIs comprised Broca’s area and its contralateral homologue [Brodmann areas (BA) 44 and 45], the middle temporal gyrus (BA 21), the superior temporal gyrus (BA 22, 38, 41, 42 and 52), the supramarginal gyrus (BA 40) and the angular gyrus (BA 39). Activation maps were superimposed on the anatomical scan.
A lateralization index was calculated for each subject using the formula: lateralization index = (number of active voxels in all VOIs of the left hemisphere – number of active voxels in all VOIs of the right hemisphere)/sum of activated voxels in all VOIs of both hemispheres.
Correlations were calculated between the lateralization indices of the first and the second twin of a pair for the concordant and the discordant group in order to test intra-pair resemblance.
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All subjects performed well on the semantic decision task (<10% mistakes). Significant activation of the language areas could be demonstrated in all subjects.
The mean lateralization index of the handedness-concordant twins (n = 24) was 0.62 (SD 0.32) and the mean lateralization index of the handedness-discordant group (n = 26) was 0.38 (0.43); the difference was significant (t = –2.3, P < 0.05). Within the handedness-discordant group, the mean lateralization index of the right-handed subjects was 0.48 (0.3) and that of the left-handed subjects was 0.27 (0.51); this difference was not significant (t = 1.7, P = 0.1). The correlation between the lateralization indices of the first and second twins of a pair was significant in the handedness-concordant group (
= 0.74, P < 0.01) (Fig. 1). The correlation between the lateralization index of the twins in the handedness-discordant pairs was not significant ( = 0.18) (Fig. 1). Lateralization indices and demographic data of the twin pairs are given in Tables 1 and 2.
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Examples of language activation patterns of a handedness-discordant twin pair with discordant lateralization and a handedness-discordant twin pair with similar language lateralization are shown in Fig. 2.
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Discussion |
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Language lateralization was studied in 12 monozygotic twin pairs of concordant handedness and 13 pairs of discordant handedness. In the handedness-concordant twins, the intra-pair correlation was 0.74, which is high if we take into account the reproducibility of this language activation method (test–retest correlation 0.79) (Rutten et al., 2002
). The high intra-pair resemblance in the handedness-concordant twins suggests a genetic component in language lateralization. In the handedness-discordant twin pairs, some pairs had a high degree of resemblance for language lateralization, while other pairs showed opposite patterns of lateralization.
Though this is the first study to assess language lateralization in monozygotic twins with fMRI, language lateralization was previously estimated in monozygotic twins with the dichotic listening paradigm. Springer and Searleman (1978) applied this technique to examine a large sample of 75 monozygotic twin pairs, of which 19 pairs were discordant for handedness. However, the data were only analysed group-wise, which prevents the distinction between twin pairs with similar and discordant perceptual asymmetry. Jancke and Steinmetz (1994) also applied the dichotic listening paradigm to study language lateralization in 20 monozygotic twin pairs, of which 10 were handedness-discordant. From the low intra-pair correlation of the whole group, Jancke and Steinmetz concluded that language lateralization is non-genetic in origin. A non-genetic origin of language lateralization would indeed explain their findings. However, language lateralization is correlated to handedness, which is known to be strongly determined by the handedness of the biological parents but not by the handedness of adoption parents (Hicks and Kinsbourne, 1976; Carter-Saltzman, 1980). It therefore appears likely that language lateralization will also be genetic in origin. To our knowledge, only one study has addressed language lateralization directly in families and found more similar language lateralization among family members (Bryden, 1975).
In the 20 monozygotic twin pairs from the study by Jancke and Steinmetz (1994), asymmetry of the planum temporale was assessed by structural MRI (Steinmetz et al., 1995). Though intra-pair correlations for the degree of planum temporale asymmetry were low, the individual data showed similar asymmetry in some twin pairs and discordant asymmetry in others. The authors concluded that cerebral asymmetry is likely to be genetic but that its expression could be disrupted in some monozygotic twin pairs. Recently, Geschwind and colleagues assessed anatomical asymmetry of the frontal and temporal lobes in 72 monozygotic and 67 dizygotic twin pairs. They found strong intra-pair correlations in monozygotic twins who were concordant for right-handedness but loss of intra-pair correlations in monozygotic twins of discordant handedness (Geschwind et al., 2002). Interestingly, dizygotic twin pairs of discordant handedness showed no decrease in intra-pair correlations compared with handedness-concordant dizygotic twins. However, it is not clear whether the findings of Geschwind and colleagues can be compared with the results of the present study since they observed significant rightward asymmetry of the temporal and frontal lobes in the sample as a whole, and in the right-handed twins. Therefore, their asymmetry indices cannot be the anatomical substrate of left cerebral dominance for language. Discordance for handedness in monozygotic twin pairs can be explained by the genetic model of McManus (1985): if the twins were of genotype CC they would have a 50% chance of becoming discordant for handedness (25% chance for the CD genotype). However, for language lateralization this model cannot accommodate our data. Genetic models predict that monozygotic twin pairs, who have identical genes, would have similar chances of developing left, right or bilateral dominance for language (McManus, 1985). This was not the case in the 13 handedness-discordant twin pairs of this study: 11 of 13 right-handed twins had left cerebral dominance for language, against six of the 13 left-handed co-twins. We further noted that the discordant twin pairs with similar lateralization indices had familial left-handedness. In a post hoc t-test on the twin pairs of discordant handedness, pairs with familial left-handedness turned out to have significantly lower absolute intra-pair differences in lateralization than pairs without familial left-handedness (t = 3.4, P < 0.05). Thus, twin pairs with familial left-handedness, who are probably of DC or CC genotype, may both express the same genetically defined pattern of language lateralization. Furthermore, four of the five twin pairs that were discordant for both handedness and language dominance were known to be monochorionic (information lacking for the fifth twin pair), which implies that the split into monozygotic twins occurred at a relatively late stage of embryological development, at least 4 days after fertilization (Bulmer, 1970). We postulate that in these monozygotic twin pairs the splitting of the original embryo into two genetically identical twins took place at a stage when the original embryo had already lost its bilateral symmetry. In that case, the split may have disrupted the genetically defined pattern of language lateralization in one of the twins.
Though there is little knowledge on asymmetry development in the human embryo, recent animal research has yielded several new insights in this field. In non-human vertebrates, the first occurrence of left–right asymmetry is the asymmetrical expression of a cascade of patterning genes (Schneider and Brueckner, 2000). In the chicken, for example, several patterning genes, such as chicken activin receptor IIa (cAct-RIIa), sonic hedgehog (Shh) and chicken nodal-related 1 (cNR-1), are expressed asymmetrically in embryos before the first signs of morphological asymmetry become apparent. cAct-RIIa is initially expressed more strongly on the right side of the primitive streak and then exclusively in the right half of Hensen’s node (the chicken homologue of the primitive node), in ectoderm only (Levin, 1998). This asymmetrical expression occurs 18 h after conception, when the primitive streak begins to develop. At stage 5, 20 h after conception, when the head process develops, cAct-RIIa expression in ectoderm becomes symmetrical. Expression of other patterning genes, such as Shh and cNR-1, appears to be induced by the cAct-RIIa concentration, hence initiating a cascade of asymmetrically expressed genes. Shh is initially expressed symmetrically, but its expression becomes restricted to the left when cAct-RIIa is expressed at the right side of Hensen’s node, also exclusively in the ectoderm (Levin and Mercola, 1998a). The gradient thus provided by these asymmetrically expressed genes probably regulates the embryological development of left–right asymmetry, since manipulation of the asymmetrical expression of Shh results in the development of asymmetry in a random direction (50% normal, 50% inverted) (Levin, 1998). The elements of this genetic cascade are well conserved among vertebrates (Levin and Mercola, 1998b) and homologous genes have been identified in humans for most of these factors (Schneider and Brueckner, 2000). It could thus be assumed that similar patterning genes are expressed asymmetrically during early human embryogenesis. In the human, Shh maps to 7q36 and encodes a signal that is instrumental in patterning many structures of the early embryo (Placzek and Furley, 1996). Shh is necessary for the early subdivisions in the human neural plate (Kobayashi et al., 2002) and patterns the dorsoventral axis of the nervous system in combination with other factors (Robertson et al., 2001). If Shh is also expressed asymmetrically at some point during human embryogenesis, this factor could be responsible for the asymmetrical organization of the cerebral hemispheres.
Splitting into monochorionic twins has been estimated to occur at the blastocyst stage, when the inner cell mass consists of 128–256 cells (Monteiro et al., 1998), and even later for monoamniotic monochorionic twins (Chitnis et al., 1999). At the time of splitting into monochorionic diamniotic twins, the anterior–posterior axis is already defined (Gardner, 2001). The layout of the anterior–posterior axis and other early patterning of the embryo is defined largely by homeobox genes, the transcripts of which can be detected in the very first days after conception (Gardner, 2001). In the light of these recent observations, the concept that the monozygotic twinning process itself is related to the development of congenital malformations seems plausible. Splitting of the embryo can lead to unequal distribution of such homeobox-derived proteins (Flannery, 1987). Maldistribution of these essential controlling compounds could then upset the regulatory balance between these proteins and the DNA in individual cells, which may result in failure to begin or end a particular developmental task. Indeed, several studies consistently found more congenital malformations, such as macrocephaly, encephalocele, cleft lip and palate, tracheo-oesophageal fistula, malrotation of the alimentary tract and congenital heart disease, in monozygotic twins than in singletons (reviewed by Luke and Keith, 1990). Many of these malformations can be regarded as disturbances of left–right asymmetry or as a failure of the two bilateral halves to fuse in the midline (midline defects). Interestingly, among monozygotic twins, monoamniotic twins, who have the latest separation, showed the highest frequency of these congenital malformations (Boklage, 1987; Luke and Keith, 1990).
It is not known how spontaneous splitting into monochorionic twins takes place in humans (Luke and Keith, 1990; Steinman, 2001). Reorganization into two codominant growth axes (i.e. anterior–posterior axes) has been proposed (Steinman, 2001). The fused gene, which was later renamed axin, plays a critical role in the initial establishment of the embryonic anterior–posterior axis (Gardner, 2001). In mice with two mutant alleles of this gene, duplication of the anterior–posterior axis and subsequent splitting into monochorionic twins have been observed (Gluecksohn-Schoenheimer, 1949). However, it remains uncertain whether this mechanism also underlies spontaneous monochorionic monozygotic twinning events.
The most extreme case of late monozygotic twinning results in incomplete separation of the twins. When conjoined human twins have distinct hearts, the right-sided twin commonly has dextrocardia (Levin et al., 1996). In non-conjoined monozygotic twins, situs inversus is rare but is probably more frequent than in singletons (Torgersen, 1950). Several congenital heart malformations, such as tetralogy of Fallot, hypoplastic left heart and anomalous great vessel implantation, can be viewed as milder laterality disturbances (Burn and Corney, 1984). These malformations are significantly more frequent among monozygotic twins, typically affecting only one of the pair (Burn, 1991). The heart differentiates from the mesoderm, which develops in a later embryological stage, when monozygotic twinning occurs only rarely (Bulmer, 1970). This could explain why disturbances of visceral laterality are rare, even in monozygotic twins. The ectoderm develops earlier, and mirror-imaging of ectodermal features, such as the location of the hair whorl and the tooth eruption pattern, is frequently present in monozygotic twin pairs (Farber, 1981). Results from our study suggest that laterality disturbances of the cerebral hemispheres, which are also ectodermally derived, may also be rather common in monozygotic twins.
If the monozygotic twinning process can indeed alter the embryonic development of left–right asymmetry, this could also have implications for singletons. Ultrasound studies have shown that at least 70% of twin pregnancies diagnosed before the 10th week miscarry or convert to a singleton in early pregnancy (Hall and Lopez-Rangel, 1996). This implies that left-handedness and right cerebral dominance in some subjects born as singletons may also be the result of a late monozygotic twinning process from which only one twin survives.
In summary, language lateralization appears to have a genetic component, given the similarity in most monozygotic twin pairs of this sample. Discordance for handedness and language lateralization in some monozygotic twin pairs may result from disruption of normal ectodermal asymmetry development by the twinning process itself. Though the concept of laterality disturbance in human monozygotic twins is difficult to prove, it is obvious that monozygotic twinning is a very different process from dizygotic twinning and is more susceptible to malformations (Luke and Keith, 1990). This phenomenon may complicate the interpretation of twin studies on laterality-dependent traits, but could provide a window into the embryological development of left–right asymmetry in humans.
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