Development of the Corpus Callosum & Its Relationship to Autism
For those who are unfamiliar, the corpus callosum is a large bundle of communicative fibers that connects the two cerebral hemispheres, allowing crosstalk between them. Below are some DTI images singling out the corpus callosum (orange). To the left is a sidewards or sagittal view, and to the right shows a frontal view of the tract (minus the lower right branch) bridging the divide between the hemispheres.
The corpus callosum is largely comprised of fibers arising from Layer III of the neocortex. The axons grow tangentially towards the hemispheric midline, then downwards, and finally are guided across the divide by what is known as the glial wedge, two sets of glial cells that act as repulsive bodies for the axons to push between, as shown in the image below borrowed from Shu et al. (2001).
Above in red is the developing corpus callosum in embryonic mouse. You can see that the fibers have been guided between the glia, shown in green. The two arrows indicate the two components of the “glial wedge”.
It has been found, perhaps a bit unsurprisingly, that axons from one hemisphere largely project to equivalent sections of cortex on the contralateral (opposite) side. Interestingly, once the fibers reach the midline of what is the developing corpus callosum, their positions therein determine where in the opposite hemisphere they will project to; therefore, appropriate guidance to their places at the midline is vital .
As you might imagine, appropriate maturation of the cells which make these callosal projections is also vital to appropriate development of this bundle of fibers. When that goes awry, you might expect to see changes in– and in rare instances usually associated with some sort of syndrome, underdevelopment or even complete agenesis of– the structure itself. Autism is certainly no exception.
There have been many structural MRI and DTI studies on the corpus callosum in autism. And while there have been some conflicting reports (possibly due to variations in method or differences between their autistic groups), a meta-analysis by Frazier and Hardan (2009) concluded that most studies reported a general reduction in size of the corpus callosum in autism. It’s interesting to note, however, that there may be some heterogeneity present in these autism groups, and that substantial differences in a handful of subjects may be tipping the scales. For example, Alexander et al. (2007) found that the largest differences in corpus callosal size were due to a subgroup within his larger autism grouping. Not only did these subjects have smaller overall callosal size, they also had significantly lower Performance IQ (PIQ), suggesting that those who are more severely affected cognitively may exhibit greater reduction in corpus callosum size.
Although most cases of autism do not seem to exhibit severe malformation in the corpus callosum, there is however some overlap in symptomotology between individuals with complete agenesis (lack of development) of the corpus callosum and autism. Two separate studies, one by Booth et al. (2011) and another by Badaruddin et al. (2007), reported that a subset of those children with agenesis of the corpus callosum (ACC) also displayed some of the social deficits found in kids with autism, although the latter study reported fewer issues with repetitive and restrictive behaviors. And although it’s been a continual debate over the years, there has been discussion that the great memory savant, Kim Peek, who had ACC may have also fulfilled criteria for autism, although he was never officially diagnosed. In general, Peek’s ACC plus unique facial features, including macrocephaly, have suggested to some that he probably had FG Syndrome, otherwise known as Opitz-Kaveggia Syndrome. Several of the genes, including CASK and MED12, which cause variants of the condition are strongly linked with autism.
The incredible Kim Peek.
In humans, it has been shown that maturation of the corpus callosum, as reflected by overall size, continues throughout childhood and into adulthood . Therefore, it is difficult to determine whether differences in size of the corpus callosum between autistics and controls is something which occurs prenatally, e.g., fewer fibers manage to cross into the contralateral hemisphere, or whether it’s a postnatal effect in which there are discernible differences in fiber size (i.e., smaller fiber diameters would lead to a reduction in CC size) or heavier pruning through childhood and into adulthood, all of which are feasible. Hopefully, future MRI studies involving young siblings at higher risk for autism may help to answer that question, prenatal vs. postnatal. I for one will be eager to know when that difference arises, because if it’s embryonic, that gives an important clue as to how the cells in Layer III of the neocortex developed in the first place, and may give greater insight into the etiology of heterogeneous autism.
This post is dedicated to the amazing Kim Peek, who passed away in 2009, as well as to his ever-dedicated father, Fran, who recently passed away this last April. Requiescat In Pace.