This study tested whether ASC was related to an atypical pattern of hemispheric lateralization, both in terms of functional and neuroanatomical asymmetry.
Corpus Callosum Asymmetry
We found significant interactions between group and handedness for the posterior and the anterior midbody between participants with ASC and controls. Both results implied that left-handed controls were more strongly leftward lateralized than left-handed adolescents with ASC in both subregions. In the control group, but not the ASC group, this correlation between handedness and asymmetry was significant.
Luders et al. (
2006) found similar results showing stronger rightward lateralization in the anterior callosal section which projects to the motor cortices in right-handed males, concluding that stronger leftward lateralization of motor functions in right-handers reduces left interhemispheric fibres. Our findings are consistent with this and reports suggesting that motor transfer is more efficient from the right to the left hemisphere via the corpus callosum (Braun et al.
2003; Saron et al.
2003). We did not find this relationship between handedness and asymmetry in the ASC group. As the lack of an association does not necessarily imply impairment, we can just speculate that the absence of the normally occurring leftward lateralization in left-handed people with ASC might result in a less favourable distribution of commissural connections.
The corpus callosum has been found to play an important role in the neuropathology of autism. However, most studies have only looked at its size and there are no existing results on asymmetry. We therefore can only compare our findings to other groups of people with brain lesions in these callosal regions or indirectly via looking at injuries in cortical areas, which the callosal subregions carry projections to. The anterior midbody projects to the motor cortex (Hofer and Frahm
2006), while the posterior midbody projects to the posterior parietal cortex (PPC), which is a highly interconnected region integrating motor and sensory input from somatic and visual modalities (Andersen and Buneo
2002). It subserves higher cognitive functions such as early planning of sensory-guided movements (such as eye, grasp, and reach movements) and regulation of controlled behaviour in response to environmental stimuli. Studies looking at behavioural and cognitive outcomes in patients with lesions in the middle and posterior part of the corpus callosum report deficits in complex bimanual coordinative movements (Meyer et al.
1998) and interhemispheric transfer of tactile information (Bentin et al.
1984). Patients with PPC lesions display difficulties in following verbal commands, performing sequences of actions and fine-tuning eye and hand movements when grasping things (Geschwind and Damasio
1985; Goodale and Milner
1992; Perenin and Vighetto
1988). Similar problems in ASC suggests that atypical lateralization of the posterior midbody and the anterior midbody might underpin symptoms such as clumsiness (Burgoine and Wing
1983; Ghaziuddin and Butler
1998), impaired fine motor skills (Dawson and Watling
2000), difficulties in motor planning and planned sequencing of actions (Greenspan and Wieder
1997) and difficulties responding to spoken commands (Preis
2006). As one sub-region of the PPC is involved in the planning of eye-movements, the question arises whether anomalous joint attention and eye contact in autism may be related to this brain region as well.
In a case study, Dimond et al. (
1977) report behavioural, verbal and emotional deficits following section of the middle third of the corpus callosum. After surgery impairments were present in linguistic ability characterized by simplified or repetitive and stereotyped language, alongside difficulties in expressing and naming emotions, and a change in ear preference on the dichotic listening task as well as in hand-preference in favour of the left. The similarities in symptomatology to autism are striking. Also, reports of complete agenesis of the corpus callosum confirm that associated symptoms such as impaired social skills overlap with the diagnostic criteria for autism (Badaruddin et al.
2007; Paul et al.
2007). We have to be careful when deriving conclusions from these studies for our own, as we don’t know if atypical asymmetries and brain lesions are comparable on a neuroanatomical level in terms of clinical outcome. Still, morphological alterations in the same region might lead to similar cognitive deficits.
Previous studies have looked at the relationship between handedness and the corpus callosum showing that non-consistently right-handed men have a larger corpus callosum than consistently right-handed men (Witelson
1989). This consistently reported finding seems incompatible with the notion that individuals with ASC are more often reported to be left-handed and to have reduced corpus callosum volume. Taking both direction (right vs. left) and degree (consistent vs. non-consistent) of lateralization into account, the non-consistently right-handed individuals might actually represent a group of people with greater bihemispheric cognitive representation. This would be in line with findings showing that less strongly lateralized people, such as women, have a larger corpus callosum (Steinmetz et al.
1995). In the same way, Luders et al. (
2010) found that less lateralized left-handers had a larger corpus callosum than strongly lateralized right-handers and so did less lateralized right-handers in comparison to strongly lateralized left-handers.
Future studies should further explore how the direction and the degree of handedness differentially relate to callosal size and asymmetry in autism in comparison to typical individuals. It has yet to be defined whether left-handed individuals with autism compose a qualitatively different group, with possibly different degrees of lateralization. Looking at callosal asymmetries in this context can give us even more detailed information on the location of callosal size reductions or increases and shed also light on the degree of lateralization in related cortical areas.
Handedness
We did not find an overall difference in handedness between the three groups. Participants with ASC did not differ from controls in handedness, in contrast to previous studies which have documented greater functional right-lateralization. However, some studies have failed to establish significant differences in handedness between people with ASC and controls (Barry and James
1978) or also found significant differences between people with ASC and their siblings or parents (Boucher
1977; Tsai
1982). Incongruity in results might partly be due to methodological limitations. There are many discrepancies in handedness assessment across different studies, with some only asking subjects to specify their writing hand (Vuoksimaa et al.
2010), while others ask them to fill in different questionnaires (Annett
1970; Crovitz and Zener
1962; Oldfield
1971) or perform manual tasks (Hand Preference Demonstration Task; Soper et al.
1986). Also, studies differ in the way handedness is classified, and where cut-off points for categories are set, resulting in classifications such as “left- versus right-handedness”, “right- versus non-right-handedness”, and “mixed handedness”. Many report neither IQ nor age, which is important to specify the level of cognitive functioning and to assess the possibility of whether mixed-handedness reflects an age-related developmental lag.
Due to the small number of available handedness measures in the sibling (n = 10) and control group (n = 19), the power to detect handedness differences might have been limited. In fact, the effect sizes for the handedness difference between the ASC and sibling group (r = −.27) and the ASC and control group (r = −0.15) both are very small. Additionally, non-parametric tests are known to be less powerful than parametric tests. The trend in the data in the expected direction suggests that with additional numbers the between group differences may reach significance, consistent with previous reports.
In view of the large number of consistent reports, it seems that there is a shift in the handedness distribution towards non-right-handedness in ASC. The question remaining is what these elevated rates tells us. In contrast to neuroanatomical asymmetries, handedness appears to be a more global marker of lateralization and due to the lack of a neurobiological substrate, it is less straightforward to interpret. In order to be able to derive conclusions, it is important to look at it in association with other traits with known brain structural correlates such as language or cognitive function, which can be impaired in autism. Accordingly, as we did not find a marked difference between our overall sample of adolescents with ASC and controls, the question arises, whether there are differences in lateralization between certain subgroups within people with ASC based on their level of functioning. DeLong (
1978), for example, argues that there are different handedness subtypes in autism comprising a “bihemispheric autistic syndrome” which is related to lower levels of functioning and mixed handedness and a “left hemisphere autistic syndrome” which is less severe and linked to high-functioning autism. In line with this, several studies report that lower functioning individuals may be more likely to display mixed-handedness (Fein et al.
1984; Tsai
1983).
Our ASC group seemed to be less strongly lateralized compared to the two other groups. The EHI score is not sensitive to differentiate between ambiguous and ambidextrous handedness patterns, so that this less strongly lateralized pattern in the autism group could mean that they use different hands for different tasks (ambidextrous) or different hands for same tasks (ambiguous). The latter would reflect that they are unable to establish a normal pattern of lateralization, which makes them switch hands within tasks. However, as ambiguous handedness has been linked to low functioning autism and as we only included individuals with IQ scores higher than 70, it is less likely that this applies to our participants. Future research would benefit from using tests that distinguish between these two patterns and from comparing low-functioning with high-functioning individuals to establish the relationship between handedness and the level of cognitive functioning.
Also, Escalante-Mead et al. (
2003) consider diagnostic sub-groups separately. They reported reduced rates of established lateral preference in individuals with autism with delayed language development compared to individuals with autism with typical early language acquisition. We did not distinguish between different subgroups, as we did not look at Asperger Syndrome and HFA separately in our analyses.
These considerations are consistent with the idea that atypical handedness is a marker of different etiologic subgroups within ASC. Future studies should differentiate between subtypes within ASC, and include measures such as age and IQ, alongside consistent handedness classifications, to establish whether different patterns of lateralization manifest at different degrees of impairment.
Cognitive Function and Symptom Severity
Strikingly, we found a significant correlation between leftward asymmetry of the isthmus and worse performance on stage eight of the ID/ED task in individuals with autism. Based on Bradshaw’s fronto-striatal model (2001), we would have expected that rightward asymmetry of regions projecting to the frontal lobe, such as the rostral body, genu or rostrum would show an association with poorer executive function. An association with one of these regions has been found by Just et al. (
2007) showing that size reductions in the genu were associated with functional underconnectivity between frontal and parietal areas during the Tower of London task. Still, also Keary et al. (
2009) report that worse performance in participants with autism on the Tower of Hanoi and Wisconsin card sorting test was associated with smaller isthmus size. As this region projects to the tempo-parietal cortex, which is involved in language and complex cognitive functions, its role in executive function has yet to be established. Since this was the only result for the ID/ED task and there were no results for the SOC task, we assume that atypical lateralization might play a less crucial role for executive function deficits. Nonetheless, further research is needed to confirm this.
Rightward asymmetry of several callosal subregions such as the splenium, the rostral body and the posterior midbody were associated with increased symptom severity. The splenium has projections to the occipital and inferior temporal lobe that are crucial for face and object processing. Schultz (
2005) has shown unusually greater activity in the inferior temporal gyrus and less activity in the fusiform face area (FFA) during face processing in autism compared to controls. Difficulties with face processing in autism constitute an underlying precursor of social interaction difficulties and might also provide a potential explanation for why alterations in the splenium region are associated with social interaction difficulties as measured by the ADOS subdomain-B.
Rightward asymmetry of the rostral body was related to more marked abnormalities in reciprocal social interactions as measured by the ADI subdomain-A. This is in line with Bradshaw’s fronto-striatal model (2001) stating that abnormally lateralized frontal circuits constitute the base for impairments in higher cognitive and social functions including social behaviour.
Rightward asymmetry of the posterior midbody was associated with stronger symptom severity as measured by the ADOS subdomain-D. As described previously, the PPC integrates sensory and motor input. Autism is sometimes associated with sensory processing abnormalities in terms of hypo- or hyper-responsiveness to sensory input and sensory processing abnormalities have been found to be correlated with stereotyped and repetitive behaviour (Baranek et al.
1997). We found rightward asymmetry of the posterior midbody to be associated with stronger repetitive, stereotyped behaviour, which might suggest an indirect corroboration of that association. This implies that rightward lateralization (and possibly under-connectivity) may disturb the normal process of planned movement generation and result in stereotyped patterns of behaviour and body mannerisms.
Contrary to the other results, asymmetry of the rostrum did not show rightward disadvantage. Rostral rightward asymmetry was instead associated with
higher IQ scores and
less severe communication impairment. This is particularly striking as this region is thought to connect to prefrontal areas and it has been suggested that dysfunction of the left fronto-striatal system relates to deficits in higher-order cognitive functions in autism (Bradshaw
2001). This raises the question of whether not only impairments in high functioning autism, but also strengths of the condition such as high IQ or good systemizing skills, might be related to the same atypical pattern of lateralization in the same way. Since these two domains (IQ and onset of language) set Asperger Syndrome apart from classic autism, it would be interesting to test in future research whether there is a difference in cerebral lateralization between the two diagnostic sub-groups. Even though it is plausible to suggest that as the rostrum is the smallest sub-region of the corpus callosum it may be difficult to define, remarkably high inter-rater-reliability should substantiate the accuracy of our measurement.
Broader Autism Phenotype
In terms of callosal asymmetry siblings showed an intermediate position between the two other groups for the posterior and anterior midbody in relation to hand-preference. The same pattern occurred for neuropsychological performance based on isthmus asymmetry. However, the difference between siblings and controls was not significant for either result. Also in terms of handedness, participants with ASC showed a more pronounced difference to their siblings than to controls. These findings lead us to assume that cerebral lateralisation does not appear to be a marker of familial risk for the condition implicating that either environmental factors have considerable influence on the establishment of lateralization or that individuals with autism carry genetic variants with increased vulnerability for developing the condition that are not shared by their siblings.
In accordance with these findings, a recently published study on the genetic liability for autism showed that the relative influence of shared environment in twin pairs was higher than genetic heritability (Hallmayer et al.
2011). They raise the issue that genetic factors have been overestimated in previous reports and environmental influence should be taken into account to a greater extent in future research.
Some studies corroborate that genetic influence towards left- handedness is rather limited. Tsai (
1982) found that children with autism significantly differed from their siblings and parents displaying stronger non-right-handedness. Also Boucher et al. (
1990) reported similar findings showing that parents of children with autism had an increased incidence of pure right-handedness compared to their children. In terms of heritability of callosal morphology, Scamvougeras et al. (
2003) found corpus callosum volume to be highly heritable in young typical men and women, with a genetic influence of 94 %. Nevertheless, other studies report that the corpus callosum is one of the last main fibre tracts to mature in humans and its functional maturation extends into late childhood (Rakic and Yakovlev
1968). Thus, reports on environmentally induced callosal size differences (Lee et al.
2003; Sanchez et al.
1998; Schlaug et al.
2009,
1995) suggest that certain environmental stimuli could possibly affect corpus callosum morphology and patterns of cerebral lateralization.
Underlying mechanisms causing cerebral lateralization are still poorly understood, but as genetic studies of the developmental origins of handedness have shown, only 25 % of its variability is explained by genetic influences (Medland et al.
2006). It is believed to be influenced to some extent by factors such as sex (Gilbert and Wysocki
1992), age (Ellis et al.
1998), disruptive events in pregnancy (Bakan et al.
1973) and prenatal androgen levels (Tan
1991). In particular the latter has been suggested as a potential factor in contributing to the establishment of functional brain lateralization, as handedness originates prenatally (Hepper et al.
1998; Witelson
1987), and males are more often left-handed than females (Annett
1970; Papadatou-Pastou et al.
2008). Accordingly, exposure to high levels of testosterone during critical periods of foetal brain development might lead to an unequal brain development enhancing the maturation of the right hemisphere and resulting in non-right-handedness (Geschwind and Galaburda
1985a,
b,
c). We have previously shown that prenatal testosterone is associated with rightward asymmetry of one region of the corpus callosum (Chura et al.
2010) and with asymmetry of specific grey matter regions (Lombardo et al.
2012). Future research is required to explore whether prenatal testosterone is associated with cerebral lateralization.