Figure: Tammy Movsas visiting our laboratory (8/26/13).

Recently I wrote a blog for my fiancee Emily Williams. The same appeared on her web site «Science over a Cuppa» (see http://bit.ly/12Flp3T ). Emily is away for a couple of weeks spending time in England presently enjoying the countryside. I was trying to reblog my original post but couldn’t (I am computer inept). In this regard I am posting the whole thing on my web site.  My reason for doing so is twofold: 1) Tammy Movsas visited us today at the laboratory (and her article was the impetus for my blog), and 2) the blog revolves around our recent emphasis at explaining the neuropathology of autism.

By training Tammy is  a Pediatric Neurophthalmologist and was in clinical practice for about 10 years.  However, she went back to college to obtain additional training in epidemiology and presently runs a research institute. Autism is one of her interests and she has written 3 or 4 articles on the subject. In one of her better cited studies she showed that gestational age influences the expression of ASD symptomatology. This appears to be the case for both infants <37 weeks and >42 weeks of gestation (JADD 42:2431-9, 2012).

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++

Sometime in July an article appeared in the Journal of Pediatrics establishing an association between ventricular enlargement in low birth weight infants and autism (Movsas et al., 2013).  I would like to expand on several of the points made by the authors as I believe that the same may provide insight into causative mechanisms to autism spectrum disorders (ASD). In this regard we have previously suggested that many conditions associated with autism (so-called syndromic autism) are the result of brain damage during fetal development.  The responsible lesion, in genetically susceptible individuals, causes abnormalities in the way cells migrate from the area surrounding the cavities at the center of the brain to the cortex. For those wishing some background material as to brain abnormalities in autism, please see my previous blogs http://bit.ly/1aM5KFu and http://bit.ly/136db0t

The study by Movsas et al. in the Journal of Pediatrics is a secondary analysis of data derived from a longitudinal study (The Neonatal Brain Hemorrhage Study) that followed the outcome of 1,105 babies that weighed less than 4 pound and 7 ounces at birth (Pinto-Martin et al., 2011).  Screening at age 16 years of roughly half of their original patient population (n=623) revealed that roughly 19% of them complied with a broad definition of ASD.  A fraction of these patients (n=189) followed-up for diagnostic assessment at age 21 years revealing 14 cases with an autism spectrum disorder diagnosis. The estimate of ASD in this sample population, close to 7%, is several times higher than recent prevalence estimates for ASD by the Centers for Disease Control and Prevention (CDC).

Figure: Neuroimaging of an extreme premature infant. The ventricles are dilated (ventriculomegaly) and there is diffuse cortical and cerebellar atrophy.

Approximately 3% of all new births fall in the range of low birth weights, defined as 2,000 grams or less.  These low birth weight babies are at risk for motor abnormalities of which cerebral palsy is the most severe form. Neuropsychiatric findings (e.g., verbal comprehension, perceptual organization, distractability) may not be evident until approximately 3 years of age.

The initial longitudinal study (Pinto-Martin et al., 2011) underlined the importance of early screening of low birth weight infants for neurodevelopmental abnormalities as early intervention can substantially improve outcome.  However, the study did not discern what medical complications or type of brain damage led to the ASD diagnosis. This was left to the follow-up study by Movsas et al. (2013).

The Movsas et al. (2013) study analyzed the cranial ultrasound of the above-described patient population.  Three cranial ultrasounds (at 4 hours, 24 hours, and 7 days after birth) were obtained by aiming the probe through the anterior fontanelle (the soft spot at the front of the skull in a baby). The researchers concluded that expansion of the ventricular cavities was a predictor for subsequent development of ASD. Otherwise isolated germinal matrix/intraventricular hemorrhages did not increase the risk for ASD. The findings are not specific to ASD as similar damage has been reported in other neuropsychiatric conditions such as attention deficit-hyperactivity disorder and obsessive compulsive disorders.

The brain exists within the confined space of the skull.  Whenever brain tissue is damage and reabsorbed the cavities at the center of the brain (called ventricles) tend to dilate in order to compensate for the tissue deficit.  It is almost as if the brain abhors a vacuum and decides to fill reabsorbed tissue by forming a cavity and/or expanding the  ventricles.  In this regard ventricular expansion remains as a tombstone of earlier brain damage.

Low birth weight infants that die shortly post-term show evidence of hemorrhages, re-absorption of the white matter surrounding the ventricles, and ventricular enlargement. Those that survive and are examined later on in life may show evidence of a malformed cerebral cortex (e.g., many small gyrifications, convolutions that take the form of mushrooms).

The germinal matrix provides the immature cells that will ultimately give rise to cortical neurons by migrating from their location surrounding the ventricle and into the cortical plate. According to the Movsas study germinal hemorrhages per se are not associated to ASD. However, lesions surrounding the ventricle that interfere with the migration of these cells on their way to the cortex did correlate to a diagnosis of ASD. The findings strengthen our thesis that a desynchronization of  radially migrating neuroblasts (future cortical excitatory cells) from those that tangentially migrate to the cortex (future interneurons, inhibitory cells) provide the genesis of ASD.

References

Movsas TZ, et al. Autism spectrum disorder is associated with ventricular enlargement in a low birth weight population. The Journal of Pediatrics 163(1):73-78, 2013.

Pinto-Martin JA, Levy SE, Feldman JF, Lorenz JM, Paneth N, Whitaker AH. Prevalence of autism spectrum disorders in adolescents born weighing <2000 grams. Pediatrics 128(5):883-91, 2011.