For the past 25 years, researchers have been hard at work, trying to localize the neuroanatomic pathways that - when perturbed - give rise to ASD. (Autism in search of a home in the brain. Rapin, I. Neurology, 52 (5), 1999 ) Thus far, however, no specific abnormality has been consistently found in the brains of persons with ASD. Instead, we find occasional abnormalities almost everywhere we look. This is consistent with the idea that ASD is a disorder of subsets, rather than a monolithic entity, but it makes unraveling the functional neuroanatomy more challenging.

The cerebral cortex: There are subtle difference in the size and thickness of various regions of the cortex in persons with ASD. A recent computer-assisted brain-imaging study that looked simultaneously at multiple regions of the cortex (Ecker C, Marquand A, Mourão-Miranda, J, et al. Describing the Brain in Autism in Five Dimensions-Magnetic Resonance Imaging-Assisted Diagnosis of Autism Spectrum Disorder Using a Multiparameter Classification Approach; The Journal of Neuroscience, August 11, 2010, 30(32):10612-10623), was able to differentiate adults with IQ>70 plus clinically diagnosed ASD from adults with Attention Deficit Hyperactivity Disorder. (The work is elegant but the authors should be taken to task for using the word "Diagnosis" in the title. The computerized MRI was able to distinguish between subjects with already diagnosed ASD and subjects with ADHD, but that's a far cry from popping someone into a scanner and coming out 15 minutes later with a diagnosis. That remains the stuff of science fiction.)

Mirror neurons: If you see a spider crawling up someone's arm, your own skin will begin to prickle, as a special set of neurons in your own brain - aptly named "mirror neurons" - start to fire. Mirror neurons enable us to "feel the pain" of the other person. One theory proposes that our ability to feel empathy is due to this mirror neuron system. It's only a short leap from there to the idea that defective mirror neurons can impair Theory of Mind, and lead to ASD, and in fact persons with ASD do appear to have defective mirror neurons. (read the book Mirroring People, by Marco Iacoboni).

Limbic System - The limbic system is made up of several structures deep within the brain, that regulate emotions (specifically, arousal and rage), and memory. The limbic system is part of our "old brain" - dating back tens of millions of years - as opposed to the cortex, which is a relatively recent development, from an evolutionary standpoint. The limbic system is responsible for assigning meaning to different scents - animals can literally "smell danger," and for humans perfume or "new car smell" can evoke powerful emotional responses. A distinct group of children with ASD are "sniffers": they smell all sorts of objects in the environment - each crayon before putting it to paper, their mother's hair, or anything else with which they come into contact. Do these children have "Limbic Autism"? We don't know, but the idea is intriguing.

The cerebellum: Cerebellum literally means "little brain." The cerebellum is tucked below the cerebral cortex, at the back of the skull. When I was in medical school, we only thought about the cerebellum when it was malfunctioning, which we'd know because the patient had jiggling eye movements (nystagmus), tremor, or an unsteady gait (ataxia). Otherwise, the function of the cerebellum was a big mystery. Now we know that the cerebellum is involved in mental activity, although we're still not sure exactly how. There are as many connections between the cerebellum and the cortex as there are between the brain itself and the rest of the body. What the information is that passes back and forth between these 2 structures, and how the disruption of these pathways might figure into ASD, is still unclear. It's intriguing to note, however, that the most commonly observed brain abnormalities in persons with ASD are in the cerebellum.

Brainstem - The brainstem is the "stalk" that attaches the brain to the spinal cord. Like a complex series of tollgates, the brainstem regulates the flow of traffic between the brain and the body. Anatomic defects in the brainstem have been identified in children with ASD following exposure to specific drugs (thalidomide and Valproate). In animal models and in human children, these anatomic abnormalities are strongly associated with autistic, or autistic-like behavioral changes.

Thus, there are many competing theories as to the region of the brain that is malfunctioning in ASD, each supported by a body of evidency. Probably, each theory is true for some children. Once we become able to identify areas of brain malfunction, we will adopt a whole new classification scheme for ASD. Rather than splitting clinical hairs (does Johnny have PDD-NOS, or AS, or NLD?), we will start classifying children with atypical development according to underlying brain region that has gone haywire: Johnny might have "cerebellar-cortical ASD" while Billy has "limbic-temporal ASD," and so on.

It may be that the real problem in ASD is not the malfunction of any one area of the brain, but the failure of all the different areas of the brain to work together in harmony. Ultimately, therefore, ASD may prove the adage "The whole is greater than the sum of the parts."

Here are some additional references:
1. Grillon, C., E. Courchesne, and N. Akshoomoff, Brainstem and middle latency auditory evoked potentials in autism and developmental language disorder. J Autism Dev Disord, 1989. 19(2): p. 255-69.
2. Fletcher, P.C., et al., Other minds in the brain: a functional imaging study of "theory of mind" in story comprehension. Cognition, 1995. 57(2): p. 109-28.
3. Rodier, P.M., et al., Embryological origin for autism: developmental anomalies of the cranial nerve motor nuclei. J Comp Neurol, 1996. 370(2): p. 247-61.
4. Baron-Cohen, S., et al., The amygdala theory of autism. Neurosci Biobehav Rev, 2000. 24(3): p. 355-64.
5. Rapin, I., Autism in search of a home in the brain. Neurology, 1999. 52(5): p. 902-4.
6. Critchley, H.D., et al., The functional neuroanatomy of social behaviour: changes in cerebral blood flow when people with autistic disorder process facial expressions. Brain, 2000. 123 ( Pt 11): p. 2203-12.
7. Hardan, A.Y., N.J. Minshew, and M.S. Keshavan, Corpus callosum size in autism. Neurology, 2000. 55(7): p. 1033-6.
8. Howard, M.A., et al., Convergent neuroanatomical and behavioural evidence of an amygdala hypothesis of autism. Neuroreport, 2000. 11(13): p. 2931-5.
9. Riva, D. and C. Giorgi, The cerebellum contributes to higher functions during development: evidence from a series of children surgically treated for posterior fossa tumours. Brain, 2000. 123 ( Pt 5): p. 1051-61.
10. Frith, C., What do imaging studies tell us about the neural basis of autism? Novartis Found Symp, 2003. 251: p. 149-66; discussion 166-76, 281-97.
11. Hendry, J., et al., White matter abnormalities in autism detected through transverse relaxation time imaging. Neuroimage, 2006. 29(4): p. 1049-57.

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