My previous blog served to introduce the possibility of a defect in brain development that could explain many of the observed pathological features of autism (see http://bit.ly/1aM5KFu ). In it I tried to explain the concept of a locus minoris resistentiae (or path of least resistance) as guiding my research efforts towards finding a commonality among the neurpathological findings associated with  autism.  I stated that, “My own research has led me to believe that there is a locus minoris resistentiae in autism, this being the germinal cells that give rise to both the cerebral cortex and different nuclei of the brainstem. It is my belief that in genetically susceptible individuals these cells are prompted to divide by an environmental exigency. Because these cells are forced to divide at an inopportune time, the structures that they are meant to generate (e.g., cerebral cortex) are malformed (also called dysplastic). Cells migrating to affected areas are therefore uncoordinated in their maturation with those already inhabiting the same thus providing for symptomatology. Variability in the genetic susceptibility of the individual and timing/severity of the environmental exigency (time during brain development) could all account for variability in expression of symptoms”.

Figure: The idea that there are many prerequisites for an autism phenotype was dealt in a previous blog on the Triple Hit Hypothesis of autism (http://bit.ly/1bWA6TI ). The figure illustrates that variability in the contribution of environmental exigencies, genetic susceptibility and timing during brain development may all account for the clinical heterogeneity observed in autism.

At this point it may useful to review how the cortex is formed and to clarify some terms. This may be the most abstruse aspect of my blogs dealing with this theme, so please bear with me. Within the core of the brain are fluid filled cavities called ventricles. During brain development the ventricles are surrounded by blood-rich tissue that is extremely cell dense (see figure below).  Under the microscope this tissue, also called germinal matrix, provides a cadre of stem cells divided by septa into well-demarcated columns. These stem cells have the basic ability of dividing and transforming into diverse specialized cell types. The germinal/stem cells begin dividing before the 6th week of gestation in the human fetal brain with a limited series of so-called “symmetrical” divisions. The initial division provides for copies of each other and prevents this cell resource from being rapidly depleted. Cell divisions are performed through regular mitosis with resultant daughter cells having an equal lineage to each other. This is followed by a wave of “asymmetric” germinal cells divisions where generated daughter cells have more restricted developmental capacities. Thus, while mother cells retain their original characteristics daughter cells commit to a pathway of differentiation with restricted choices. These daughter cells are now known as multipotent and will give rise to different cell types found in the brain, i.e., neurons, oligodendrocytes, and astrocytes.

Figure: A) Germinal cells surrounding the ventricular cavities (hence called periventricular germinal cells), and B) Minicolumns during the formation of the cerebral cortex (more on this in the next paragraph). The immature neurons or neuroblasts in the primitive cerebral cortex are the precursors of excitatory cells called pyramidal neurons. These neurons acquire a rectilinear apposition to each other by migrating along a radial projection leading from the germinal matrix into the cortical plate. In this regard, positioning of neuroblasts (future pyramidal cells) antedates cellular and cortical specialization, e.g., synaptic contacts and laminar development. Taken from Casanova MF (editor) Imaging the Brain in Autism, Springer, 2013.

After the asymmetrical division of germinal cells, daughter cells that are going to become pyramidal neurons settle in a radial inside-out configuration within the cortical plate. In humans, the symmetrical phase of cell division ends at about the 17th week of gestation. The end result is a cortex comprised of multiple minicolumns each having a core of pyramidal cells surrounded by a peripheral cell sparse space rich in dendrite arborizations, synapses, and GABAergic (inhibitory) interneurons.  As you may imagine, the whole process is a highly coordinated ballet that can break down at several different levels. We propose that the basic mechanism underlying germinal cell divisions and migration is at fault in autism.

How do we recognize abnormalities in the above-related mechanism of germinal cell divisions and subsequent migration? We do so by examining the region surrounding the ventricles (periventricular region), the white matter, and the structural organization of the cerebral cortex (see the figure below).

Figure: A slice of the brain.  Early during brain development its surface is relatively simplified. At the center of the figure are the ventricles.  Surrounding the ventricles are germinal cells (labeled as #1).  Germinal cells divide asymmetrically and migrate through the white matter (labeled as #2) to reach the cerebral cortex (labeled as #3). In autism, multiple researchers have found abnormalities at each of these locations.

Abnormalities at location 1 in autism: Sometimes daughter cells produced by the asymmetric divisions of germinal cells do not migrate out of the ventricular zone. These cells remain behind in clusters usually first discovered as nodules in symptomatic individuals who undergo Magnetic Resonance Imaging (MRI). Individuals with nodular heterotopias may suffer from seizures, developmental delays, and learning deficits such as dyslexia. The pathology of two genetic conditions that manifest significant autistic symptomatology, Ehlers-Danlos syndrome and tuberous sclerosis, is characterized by periventricular heterotopias. The figure below was taken from the Autism Brain Atlas collection of the Autism Tissue Program. The individual had  idiopathic autism.

Figure: The fluid fill cavity (ventricle) at the posterior end of the brain (occipital lobe) is surrounded by clumps of cells that never left the periventricular zone to attain their normal position at the cerebral cortex. Instead, they remain behind as nodules extrusions of clumped neurons with irregular connectivity among themselves.

Abnormalities at location 2 in autism: Misplaced neurons, when found in large clusters, can be detected by Magnetic Resonance Imaging. The cell clusters were initially named «unidentified white objects (UBO)» when the basic pathology underlying the imaging signal was not known. The few MRI studies that have screened for UBO’s in autism have a found a higher prevalence as compared to neurotypicals (Nowell et al. 1990).

Few magnetic resonance imaging (MRI) reports have indicated the presence of unidentified bright objects. Anthony Bailey was probably the first person to emphasize the presence of a migrational abnormality in autism in postmortem studies. Two of Bailey’s et al. (1998) patients had neuronal ectopias and an increased number of individual neurons within the white matter, i.e., neurons not clustering into patches. Postmortem studies indicate their presence within the white matter and germinal zone. All brain regions appear to be affected (Wegiel et al. 2010). The findings are suggestive of so-called epigenetic heterotopias as opposed to a genetically dictated heterotopias. Previous authors have suggested that the presence of heterotopias in autism may help explain the link to seizures and tuberous sclerosis.

Hutsler et al., (2007), described supernumerary cells within the subcortical white matter. These cells were never arranged in islands or clusters as described by Bailey et al., (1998). Hutsler et al. (2007) attributed the difference between the studies as due to the non-universality of the findings and the limited white matter sampling in their own study. All nine autistic cases reported by Bauman and Kemper (2005) showed abnormal clustering of neurons in the inferior olive and in one case an ectopic cluster adjacent to the inferior peduncle.

Figure: Computer generated binary images. Each black dot represents the position of a cell within the cerebral cortex. The upper panel is that of an autistic individual and the one at the bottom for a neurotypical person. The sigmoid function generated by a computer demarcates the boundary in-between the grey and white matter of the brain.  The white matter immediately beneath the cortex of autistic individuals contain many more neurons than that of neurotypicals. This appears to be a universal finding among examined postmortem samples.

Abnormalities at location 3 in autism: In autism migrational abnormalities are suggested from accounts of cortical dysplasias, thickening of the cortex, variations in neuronal density, minicolumnar alterations, the presence of neurons in the molecular layer as well as in the white matter, irregular laminar patters, poor gray-white matter differentiation, and ectopic foci of cells (Schmitz and Rezaie, 2008). Neuronal migratory defects have been linked to abnormalities in brain growth and cortical organization both of which are closely tied to gyrification.

This blog describes the presence of migrational abnormalities in the brains of autistic individuals.  The same happens during brain development and antedates the birth of the patient.  These findings need to be taken into consideration when discussing possible risk factors for autism. In future blogs I will discuss how a variety of conditions may act through the above related mechanism in cases of syndromic autism.

References

Bailey, A., Luthert, P., Dean, A., Harding, B., Janota, I., Montgomery, M., Rutter, M., & Lantos, P. (1998). A clinicopathological study of autism. Brain, 121, 889–905.

Bauman, M. L., & Kemper, T. L. (2005). Structural brain anatomy in autism: What is the evidence? In M. L. Bauman & T. L. Kemper (Eds.), The neurobiology of autism, 2^nd ed. (pp. 121–135). Baltimore: Johns Hopkins University Press.

Hutsler, J. J., Love, T., & Zhang, H. (2007). Histologic and magnetic resonance imaging assessment of cortical layering and thickness in autism spectrum disorders. Biological Psychiatry, 61, 449–457.

Schmitz, C., & Rezaie, P. (2008). The neuropathology of autism: Where do we stand? Neuropathology and Applied Neurobiology, 34, 4–11.

Wegiel, J., Kuchna, I., Nowicki, K., Imaki, H., Wegiel, J., Marchi, E., Ma, S. Y., Chauhan, A., Chauhan, V., Bobrowicz, T. W., De Leon, M., Louis, L. A., Cohen, I. L., London, E., Brown, W. T., & Wisnieski, T. (2010). The neuropathology of autism: Defects of neurogenesis and neuronal migration, and dysplastic changes. Acta Neuropathologica, 119, 755–770.