The new neurobiology of autism: cortex, connectivity, and neuronal organization

Abstract

This review covers a fraction of the new research developments in autism but establishes the basic elements of the new neurobiologic understanding of autism. Autism is a polygenetic developmental neurobiologic disorder with multiorgan system involvement, though it predominantly involves central nervous system dysfunction. The evidence supports autism as a disorder of the association cortex, both its neurons and their projections. In particular, it is a disorder of connectivity, which appears, from current evidence, to primarily involve intrahemispheric connectivity. The focus of connectivity studies thus far has been on white matter, but alterations in functional magnetic resonance imaging activation suggest that intracortical connectivity is also likely to be disturbed. Furthermore, the disorder has a broad impact on cognitive and neurologic functioning. Deficits in high-functioning individuals occur in processing that places high demands on integration of information and coordination of multiple neural systems. Intact or enhanced abilities share a dependence on low information-processing demands and local neural connections. This multidomain model with shared characteristics predicts an underlying pathophysiologic mechanism that impacts the brain broadly, according to a common neurobiologic principle. The multiorgan system involvement and diversity of central nervous system findings suggest an epigenetic mechanism.

Figure 1

Graphical representation of nonuniform growth patterns in autistic brain. Yellow areas indicate the outer radiate white matter white zone, which are larger in volume in this study of children with autism than in the controls. The white area represents bridging and sagittal components, which did not differ in volume from controls. The volumes of areas in blue were absolutely but not relatively different. Image courtesy of Martha Herbert, MD, PhD.

Figure 2

Micrographs of Brodmann area 4, lamina III, from a patient with autism (A) and from an age-matched control (B). Insets highlight the cores of minicolumn fragments identified by a software program, illustrating the reduction in minicolumnar width in autism. Scale bars measure 200 μm in the full images and 50 μm in the insets. Image courtesy of Manuel Casanova, MD.

Figure 3

Cognitive pathway involved in face processing in typical adult subject (A) and in an adult with autism (B).

Figure 4

A, Brain activation of autism and control groups during sentence comprehension (sentence vs fixation contrast). Participants with autism show less activation in the left inferior frontal gyrus (LIFG) than the control group, but more activation in the left posterior superior temporal gyrus (LSTG) than the control group. Scale is t test values. B, Functional connectivity for autism and control participants in the 10 region of interest (ROI) pairs with a reliable (P<.05) difference between autism and control participants (presented in descending order of mean connectivity). The pattern of functional connectivities across these 10 ROI pairs is very similar for the 2 groups (r=0.98). Error bars represent the standard error of the mean. CALC indicates calcarine fissure; DLPFC, dorsolateral prefrontal cortex; FEF, frontal eye field; IES, inferior extrastriate; IFG, inferior frontal gyrus; IPL, inferior parietal lobe; IPS, intraparietal sulcus; IT, inferior temporal; OP, occipital pole; SMFP, superior medial frontal paracingulate; and TRIA, triangularis. Image courtesy of Oxford University Press.