Autism: Is it all about bigger brains?

In spite of our bipedalism, tool-making, sweat glands, and opposable thumbs, the thing we deem as the defining human characteristic is ironically something we share, to a certain extent, with many organisms and certainly all mammals: a brain. Even though humans can be a brutal, selfish, and self-absorbed species, the natural biologist in each of us can’t help but be amazed at what this small conglomerate of tissues seated within our skulls can do. Considering the elegant complexity the neocortex has reached in Homo sapiens and a handful of other species, unsurprisingly most of us spend our waking hours trying to figure out how it all works.

For tens of millions of years, primates have been on an upward trajectory of neocortical expansion (Jerison, 1979). Termed “encephalization“, it usually refers to the evolutionary increase in brain volume, especially of the neocortex. In primates especially, encephalization has involved an increase in neocortical surface area without an equaled increase in overall volume. By adding groups of cells arranged in columns (called “minicolumns” or “microcolumns”) like a picket fence, perpendicular to the surface of the brain, surface area of the brain can be quickly increased. However, if such a strict arrangement were kept, it would 1) cause a maladaptive growth in overall brain volume (imagine the character, Brain, from Pinky and the Brain, and how top-heavy he was), and 2) such an arrangement makes connectivity throughout the cortex extremely difficult to maintain due to increased conductive resistance (electricity) with expanding distances. So the brain reached a compromise: while more and more columns of cells were being added, the neocortex began to fold, bringing distant areas into direct contact with one another and simultaneously decreasing the size of the skull needed to contain all those additional cells. So with a large increase in cell numbers, only a small volumetric increase is required. These folds are the “hill and valley” arrangement, also known as gyri and sulci, which are so characteristic of the human brain:

Compared to most other species, our brains are highly gyrencephalic, gyrus coming from the Greek for “spiral”, referring to the extreme convolutions seen in the human brain (Ankel-Simons, 1999). Other species, such as mice, have considerably fewer minicolumns and therefore don’t need to develop gyri and sulci in order to maintain overall connectivity and a reasonable cranial volume. Such species are known as lissencephalic:

But what has been the driving evolutionary force of encephalization and how does this relate to autism? There does seem to be a link between increased brain size and intelligence (Deaner et al., 2007; Reader & Laland, 2002) although “intelligence” is difficult to test across species. Mammals in general have a unique quality to their cortex which differentiates them from reptiles and other classes with which they share more distant common ancestors: while the neocortex in mammals is a six-layered structure, in reptiles it is a single-layered structure (Northcutt & Kaas, 1995), indicating that somewhere in the early evolution of mammals this single layer expanded to the varieties of six we see today in modern mammals. But not only is the verticality of neocortex imporant, the lateral expansion (the addition of more minicolumns) may be foundational to intelligence (Buxhoeveden & Casanova, 2002). But an increase in minicolumn numbers has not been uniform across all areas of the neocortex. For instance, even though the overall volume differs considerably amongst higher-order primates, the visual centers of the brain, particularly the primary visual cortex, has only moderately expanded across primate species (Casanova et al., 2009). The lobes most associated with intelligence in primate species—particularly social intelligence—are the ones in which the greatest neocortical expansion seems to have occurred: the prefrontal cortex (Bush & Allman, 2004).

Perhaps unsurprisingly, given the increase in neocortical minicolumns seen within autism (Casanova et al., 2002), the increased density is most notable within the prefrontal cortex (Buxhoeveden et al., 2006; Casanova et al., 2006). And in light of the increased cranial volumn and minicolumnar density in autism, more recent studies have begun targeting certain proteins and steroids called Growth Factors, which are in part intimately involved in neocortical expansion. Vaccarino et al. (2009) have focused their attentions on Fibroblast Growth Factors (FGFs), a family of proteins which most commonly act as mitogens on a variety of different cell types. Basic Fibroblast Growth Factor (bFGF or FGF2) has particularly important implications in autism given its involvement in prolonging the period of cell division of the number of undifferentiated radial glial cells (cortical stem cells) which determine the total number of eventual minicolumns: the longer these radial glial divide, the greater the number of minicolumns, like that seen in autism.

While much research is still needed to better understand how neocortical expansion has both played pivotal roles in human evolution and autism, the research of the past two decades has brought to the forefront some tantalizing evidence that not only sheds light on the underlying neuroanatomical characteristics of autism but likewise puts autism back into the larger framework of the human continuum. It’s fascinating to think that while autism can undoubtedly provide for its share of handicap, these foundational elements may be “abnormal” only in the sense that they’re extremes of those things which make us most human.

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