Key Players in Autism: IV. The Brainstem

In the central nervous system the brainstem links the brain to the spinal cord. This anatomical structure is usually divided into different portions, from top to bottom, these are the midbrain, pons (meaning bridge), and medulla. Though small, relative to the size of the brain, the brainstem provides a conduit to sensory and motor projections, and to the majority of cranial nerves. In terms of function, the brainstem serves to modulate vegetative aspects of the body such as breathing, sleeping, and heart rate.

brainstem-300px

Many core symptoms of autism involve the person’s ability to process thoughts (so-called higher cognitive functions) and probably stem from deficits of the cerebral cortex. However, other symptoms such as diminished facial expression, hypersensitivity to sound and touch, and sleep disturbances could have an origin within the brainstem. In effect, a rare birth defect caused by the underdevelopment or absence of cranial nerves, Moebius syndrome, is usually associated with autism in 30 to 40% of cases.

The late Patricia Rodier, a Professor within the Departments of Obstetrics and Gynecology at the University of Rochester, examined sections of the brainstem of a single autistic individual and reported a shortened distance between some anatomical landmarks (i.e., trapezoid body and the inferior olive). Both the superior olivary and facial nuclei were absent.

rodier
The late Patricia Rodier (died 2012) was an embryologist specializing in conditions of the nervous system.

Although Rodier’s work has not been reproduced by others (Thevarkunnel et al., 2004), it did serve to broaden our thinking perspective in regards to autism. Most importantly, her work served to emphasize the possibility that autism starts before a child is born. According to her findings autism starts at around the 4th week of fetal development. She gave as supporting evidence the fact that some thalidomide babies that develop an autistic phenotype have an external ear malformation and an uncommon form of strabismus (Duane syndrome) but no malformations of their limbs. The timing of these malformations was early during the first 20-24th days of gestation.

It is interesting to note that Dr. Rodier’s arguments made their way to the Omnibus Proceedings for Vaccination Safety where she acted as a witness for the government. Her own work and data collected from thalidomide and valproic acid babies suggested an insult early during brain development not consistent with the idea of mercury toxicity by vaccines. Dr. Rodier also expanded her work to report a variant of a gene (HOXA1) as an autism susceptibility gene. Defects in the HOXA1 gene in humans give rise to difficulties in eye movement, poor ventilatory movements, deafness, swallowing difficulties, paralysis of the muscles of the face, mental retardation, and developmental delay.

Following the lead offered by Rodier, other investigators examined the structure of the medial superior olivary nucleus in 5 autistic individuals and 2 neurotypicals (Kulesza and Mangunay, 2008). Each of the 5 autistic individuals showed significant differences in the morphology of the superior olivary nucleus (cell body area, cell body shape, and orientation). Unfortunately, the study had many weaknesses. Among the weaknesses in study design, both autistics and neurotypicals were not matched for age and one of the so-called autistic individuals appears with a diagnosis of Fragile X syndrome in the Autism Tissue Program database. I was also able to examine many of the brainstem sections used in the study and they were of poor quality and ultimately unreliable for the purpose of quantitation.

Another anatomical element of the brainstem that has been paid close attention is the locus coeruleus. The cluster of cells in this nucleus control, among many things, body temperature. A few years ago, based primarily on speculation, a theory arose that abnormalities in the regulation of the body’s thermostat by the locus coeruleus would lead to either improvements or exacerbations of autistic behaviors (see http://www.sciencedaily.com/releases/2009/04/090401145312.htm).

locus_coeruleus
Projections from the locus coeruleus innervate a large portion of the central nervous system.

Two of the reported cases by Bailey et al. (1998) had abnormally dispersed cells in their locus coeruleus. A few years after the study by Bailey and colleagues, Martchek et al. (2006) used stereology to examine several neuronal parameters of this nucleus. No significant findings were reported.

Studies of the brainstem in autism have been few and far between. The presence of autonomic abnormalities in autism could easily have its genesis within the brainstem of affected individuals. Data derived from animal models, genetics, and neuroimaging (e.g., Hashimoto et a. 1995) suggests abnormalities of the brainstem in autism. However, initial results from postmortem series have used a handful of patients with faulty research designs. It is a pity that research into this area of the central nervous system has not attracted the attention it deserves.

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.

Hashimoto T, Tayama M, Murakawa K, Yoshimoto T, Miyazaki M, Harada M, Kuroda Y.(1995) Development of the brainstem and cerebellum in autistic patients.J Autism Dev Disord,25(1):1-18.

Kulesza, R. J., & Mangunay, K. (2008). Morphological features of the medial superior olive in autism. Brain Research, 1200, 132–137.

Martchek, M., Thevarkunnel, S., Bauman, M., Blatt, G., & Kemper, T. (2006). Lack of evidence of neuropathology in the locus coeruleus in autism. Acta Neuropathologica, 111, 497–499.

Rodier, P. M., Ingram, J. L., Tisdale, B., Nelson, S., & Romano, J. (1996). Embryological origins for autism: Developmental abnormalities of the cranial nerve motor nuclei. Journal of Comparative Neurology, 370, 247–261.

Thevarkunnel, S., Martchek, M. A., Kemper, T. L., Bauman, M. L., & Blatt, G. J. (2004). A neuroanatomical study of the brainstem nuclei in autism. Abstracts: Society for Neuroscience, 1028.10.

10 responses to “Key Players in Autism: IV. The Brainstem

  1. That’s interesting because as long ago as the late 1980’s I speculated that the locus coereleus might be involved in the etiology of autism. As you probably know, the neurotransmitter norepinephrine originates in the locus coreleus and one of the two main noradrenergic tracts in the brain, the dorsal tegmental bundle, projects to a number of areas that have been implicated in th etiology of autism, i.e. the hippocampus and cerebellum. I seem to remember from my reading, albeit limited that the dorsal tegmental bundle begins in the locus coreleus and ends in the superior cerebellar peduncle. Studies have found that stimulation of the superior cerebellar peduncle is reinforcing in rats and when the dorsal tegmental bundle was severed, it did not abolish this reinforcing effect. I don’t remember which study it was, but it was in one of my books and I could look it up. I wondered if the twiddling (self-stimulatory behavior) could originate in the superior cerebellar peduncle and that in a typical human being, norepinephrine was an inhibitory neurotransmitter and that because this was lacking in persons with ASD this could be responsible for twiddling. Also, as you probably know, norepinephrine is one of the two neurotransmitters used by Purkinje cells which have been found to be diminished or lower in count in various parts of the cerebellum of autistics. But I guess GABA is also used by purkinje cells. Eric Courchesne told me the cerebellar peduncles are too small, only a few millimeters to be measured by an MRI scan. Have any postmortem studies concentrated on the superior cerebellarpenduncless? Perhaps this might be an area of worth th pursuing. I guess I’m just grasping at straws and these are speculations with holes in them, but I’d like to know what is not working right in my brain as you know.

  2. Hi,

    Thank you for your comments. I did a Google search when I was writing my blog and, not surprisingly, found some of your earlier comments regarding the locus coeruleus. I do share the same thoughts and hopefully conveyed the idea that more research into this area is needed. Unfortunately I believe that pursuing this by using postmortem tissue will never provide proper answers. I would focus on electrophysiology and measuring autonomic parameters. The literature on this is scant but also promising (e.g. GSR, heart rate, etc.). Good look with your book, I hope to read it in the near future.

  3. As always, it only showed that you have a better grasp on autism than 90% of the researchers out there. It is a pity that many researchers never venture outside their comfort zone. Geneticists know a lot about molecular biology aspects but have never seen a patient, psychologist know all about the different theories but can’t say a word about postmortem studies, etc.

  4. Patricia Rodier was the first scientist to reproduce developmental brain abnormalties in the Valproate Acid mouse model. The VPA autism mouse model has now beem reproduced by many groups. Among the findings of prenatal valproate exposure is the loss of cerebellar Purkine cells which has been the most consisent findings in autism autopsy research.

    http://www.ncbi.nlm.nih.gov/pubmed/10840175

    The first brainstem hypothesism, the reticular activating system hypothesis, was first proposed by Bernard Rimland in his book ‘Infantile Autism’ published in 1964.

  5. Thank you for the comments. Patricia’s work did cover a lot of ground. The valproic acid model is now part of the hyperconnectivity theory of Malkram. I have some remarks about Purkinje cells in a previous blog on the cerebellum. I also had Steve Edelson write a small biosketch on Bernie Rimland.

  6. The following is a comment sent to me by Margaret Creedon. We both share similar thoughts and memories regarding Patricia Rodier.

    Dear Manny,
    Thank you for honoring Patricia Rodier in your latest blog on the Brain Stem. Although, what started as I was reading was happy remembrance of conversations was soon saddened with the realization that she was gone. She actually contacted me at a conference and then in later calls after we had mutually presented at an ASA meeting. We shared each others’ passions about some findings, the trail to early diagnosis or markers-I was looking at eye movements (and still want to share that story and equipment) as well as ears , etc. We had hoped to work out some further study regarding my clinical experience and her research which just wasn’t practical at the time. We did enjoy sharing our personal stories-I had taken embryology and other life sciences and then switched to experimental psychology; she had studied psychology and then focused on anatomy and embryological studies. I had also worked with some families and did interviews with Dr. Ritvo and others to get brain donations but that’s another story.

    I did first try to respond to your comment section which didn’t link; thank you for letting me tell an old story about my fortuitous early connections.

    Margaret Creedon
    Margaret

  7. I encourage you to read our follow up paper (from 2011), with study of additional, better preserved specimens:

    Malformation of the human superior olive in autistic spectrum disorders. Kulesza RJ Jr, Lukose R, Stevens LV. Brain Res. 2011 Jan 7;1367:360-71.

  8. Reblogged this on Cortical Chauvinism and commented:

    The reaction to this blog about the role of the brainstem in autism was a complete surprise to me. It has received over 2,000 views in less than a year of its being published. The only other blog that has received more publicity relates to ultrasound. Since I wrote the blog not much has changed. Jerzy Wegiel should have an article published on the neuropathology of the brainstem in autism some time in the near future. Otherwise the only clarification that I would like to make is the fact that Patricia Rodier’s initial case history may have been one of syndromic autism rather than idiopathic autism. The fact that her patient had missing cranial nerve nuclei suggests a Moebius sequence (see http://bit.ly/1bxqNWF ).

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