Autistic brain

The following section explores the five areas most consistently found to be abnormal in postmortem studies of autistic brains - amygdala, septal nucleus, hippocampus, anterior cingulate cortex, and cerebellum - and discusses their hypothetical relationship to emotional and interpersonal psychopathology in autism. Note that other brain areas, which are inconsistently abnormal in neuropathological studies, may express inconsistent associated symptoms, variations in psychopathological subtypes, or inconsequential anomalies and are not discussed in this section. 

Whitney ER, Kemper TL, Bauman ML, Rosene DL, Blatt GJ (2008) Cerebellar Purkinje cells are reduced in a subpopulation of autistic brains a stereological experiment using calbindin-D28k. 

Casanova et al. (2002) have compared the brains from autistic individuals with normal brains and found that in Nissl stained vertical sections taken from Brodmann s areas 9, 21, and 22, the minicolumns in the normal and autistic brains have a somewhat different structure. In the autistic brains, the minicolumns are smaller in width, and the neurons within the vertical strings are less tightly packed, leading the authors to conclude that per unit volume of cerebral cortex, the minicolumns are more numerous in the cortices of autistic individuals. Since studies by earlier authors have shown that there is no abnormality in cell density in the cortices of autistic individuals compared to controls (Coleman et al., 1985 Bailey et al., 1993), Casanova et al. (2002) suggest that autism is the consequence of a defect in migration of cells into the cortex during development. 

In a recent review article on the anatomy of autism Amaral et al. (2008) point out that in these studies by Casanova and his colleagues, only 14 cases of autism, 9 of which had seizures and at least 10 with mental retardation, have been examined for minicolumn pathology. Consequently, more studies using a greater number of autistic brains with fewer other complications need to be carried out before any definite conclusions can be reached about changes that can only be attributed to autism. It would also be appropriate to examine brains in which the apical dendritic clusters and myelinated axon bundles have been stained to confirm the sizes of the minicolumns as detected in digitized images from autistic brains. 

Courschesne E, Redcay E, Kennedy DP (2004) The autistic brain birth through adulthood. Curr Opin Neurol 17 489 96. 

The earliest of these developmental abnormalities involve the brain stem. In a unique case, Rodier et al. (1996) reported the nearly complete absence of the superior olive and facial nerve nucleus, with shortening of the brain stem between facial nerve nucleus and the trapezoid body. They concluded that the initiating injury in this autistic brain occurred around the time of neural tube closure, which occurs at about 4 weeks of fetal development (O Rahilly and Muller, 1994). This timing also corresponds to an increased incidence of autism following exposure to the drug thalidomide during pregnancy (Rodier and Hyman, 1998 Miller et al., 2005). 

In the cerebellar cortex, the most frequently noted pathology is a decreased number of Purkinje cells (Kemper and Bauman, 1998 Palmen et al., 2004 Bauman and Kemper, 2005 Whitney et al., 2008). This pathology is most marked in the posterior lateral part of the cerebellar hemispheres and the adjacent archicerebellar cortex and occurs without evidence of loss of neurons in the inferior olive in the brain stem (Kemper and Bauman, 1998 Bauman and Kemper, 2005). The Purkinje cells have an intimate relationship with the axons of the inferior olivary neurons in the brain stem, such that loss of Purkinje cells at any time after birth leads to loss of neurons in the inferior olive (Holmes and Stewart, 1908 Norman, 1940 Sakai et al., 1994). Since this intimate relationship between the Purkinje cell and the inferior olive is established in the human brain sometime after 29-30 weeks of gestation (Rakic and Sidman, 1970), it is likely that the decrease in number of Purkinje cells occurred before this time. In those brains with a marked decrease in the number of Purkinje cells, there appears to be a concomitant decrease in the number of granule cells (Bauman and Kemper, 2005). The relationship between the number of granule cells and the number of Purkinje cells noted in the autistic brain has been elucidated in rat studies. With prenatal loss of Purkinje cells the number of granule cells is adjusted such that the ratio of Purkinje cells to the number of granule cells is maintained (Chen and Hilman, 1989). 

Rakic, 1990). It has been shown to play an essential, transient role in the development of definitive cerebral cortical circuits (Shatz et al 1998 Super et al., 1998 Okhotin and Kalinichenko, 2003). The presence of both an excess number of neurons in layer I and in the subcortical white matter in the autistic brain suggests a lack of proper resolution of this transient zone. 

Another possibility is that the frequently noted cerebrocortical malformations in the autistic brain may be associated with aberrant, increased connectivity. Evidence for this comes from studies of focal cerebrocortical malformations in experimental animal models. Rosen et al. (2000) explored the connectivity of experimentally induced polymicrogyria and showed that there was an enhancement of ipsilateral cerebrocortical projections, projections to cortical regions not normally innervated in the adult brain, and a decreased callosal connectivity. Jenner et al. (2000) studied... 

In autism, a decrease in GAD67 protein levels as measured in whole cerebellar homogenates was initially reported (Fatemi et al., 2002), suggesting a decrease in GABAergic neurotransmission in the cerebellum. More recently, anatomical studies with in situ hybridization histochemistry have shown that GAD67 mRNA levels are also markedly decreased in Purkinje cells of autistic brains (Yip et al., 2007) (Fig. 2 /t<0.0001, two tailed f-test). 

In contrast to Purkinje cells, cerebellar basket cells (BC) had a higher mean level of GAD67 mRNA (Yip et al., 2008 p<0.0001, independent Mest) in the autism group compared to the control group. GAD67 mRNA levels in stellate cells were not significantly different between controls and autistic brains but did show a trend for significance for an increased level. 

Fig. 4 Location of cholinergic deficits in the autistic brain (BDNF brain-derived neurotrophic...

Baron-Cohen S, Ring HA, Wheelwright S, BuUmore ET, Brammer MJ, Simmons A, WiUiams SC (1999) Social inteUigence in the normal and autistic brain an fMRI study. Eur J Neurosci 11 1891-1898. 

With these tools in hand, further definition of a cognitive dynamics analysis and its insights into the normative flow of information will provide a window into the cognitive dynamics of ASD. The plausible conclusion that autistic behaviors can emerge from non-autistic brains will be briefly explored. 

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