Breakout Session H: Prenatal Causes and Early Brain Development in Autism

Presented by Eric Courchesne, PhD, Alysson Muotri, PhD, and Karen Pierce, PhD 

This breakout session was based on studies that were/are conducted at University of California, San Diego.  The first speaker, Karen Pierce, PhD, (http://www.autism-center.ucsd.edu/about-us/Pages/team.aspx)
discussed how there were rare-to-no studies on autism in infants and children under three at the time that they started their study.  She implemented the one-year well-baby approach with a network of pediatricians in the area.  The doctors would use the CSBS test (http://firstwords.fsu.edu/pdf/checklist.pdf) at the well-baby checkup.  If the baby failed the test, they would then be referred to the autism study at UCSD. 
A big part of the study was to take a sleep FMRI of the baby's brain.  This allowed researchers to compare the brains of the children at risk for autism with typically developing children.  During the FMRI, they would play different vocalizations to determine the brain activity.  (For example, they would read a bedtime story).  There was less response to language sounds for kids with autism.  The left side of the brain was not activated.  When looked at laterally to speech, ASD babies had right-sided dominance with the left side not having a normal response to language sounds.
-Social Orienting Defects
Another part of the FMRI was to use stimuli that would normally catch a child's attention, i.e., calling out their name, saying cautionary words or using directional phrases, i.e., "Look over here!"  With the social orienting FMRIs, there was normal stimuli with the typical kids, while the children with an ASD had no stimuli with social orienting.  The same thing was done with environmental stimuli, i.e., the sound of a bell, a horn honking, etc.  Social vs nonsocial - Not much differentiation. 
By 2 years, there is a lack of functional responding to social orienting stimuli, particularly in the temporal cortex of the brain.
Why?  Overabundance of neurons and faulty long-distance connections may lead to ineffective functional architecture which can lead the ASD child to difficulty switching between rest and evoked state.

Modeling Rett Syndrome Using Human Neurons
Alysson Muotri, PhD (http://cancer.ucsd.edu/research-training/people/Pages/summary-database.aspx)

Dr. Muotri is a researcher at UCSD.  His presentation was about an exciting new development in stem cell research.  Where as before, stem cells were either taken from post-mortem brain tissue, a mouse model or embryonic stem cells, this was not effective in treating patients because the newly developed undifferentiated cell systems could be rejected by the body because they were not the patient's own cells. 
In 2007 there was a huge breakthrough in stem cell research.  It was found that they could isolate cells by skin biopsy and differentiate cells into pluripotent state (embryonic-like state) which would also reduce the chance for rejection. 
They are hoping to begin a study where they can use stem cells to study neurons derived from an autistic patient.   They have already done this using a Rett Syndrome patient biopsy (because unlike autism, Rett Syndrome is a well-characterized genetic defect).  They were able to reprogram the biopsy to become neurons.  They can compare the neurons from a typical person's biopsy to that of Rett Syndrome.    Rett Syndrome neurons are smaller (10% reduction in size).  They replicated the typical to the Rett Syndrome neurons by removing the gene that is not there in Rett Syndrome, and they got the same result as Rett's.    Reduction of density of neuronal spines (less branches).  Neurons don't have spines when very immature.  The spines are where the neurons talk to each other and how information affects the brain.  Can affect networks which can affect brain circuit which then affects behavior.
Next, they wanted to see if they could revert the process (of Rett's) by injecting cells with IGF-1 (which had previously worked in a mouse model).  Can rescue the number of synapses which means you can manipulate.  Now, with clinical trial of IGF-1, need to work on dosing because it actually over corrected the Rett's Syndrome.  IGF-1 can affect more than one cell type.  It is a big molecule that cannot filtrate the brain.  Looking for a smaller version to get into the brain.

Major Goals of UCSD Autism Center of Excellence
Eric Courchesne, PhD (http://www.autism-center.ucsd.edu/about-us/Pages/team.aspx)

Major Goals of UCSD Autism Center of Excellence
-Identify the neural and genetic defects that cause early brain overgrowth and dysfunction in ASD.
-We theorize defects in prenatal regulation of neural genesis and apoptosis (cell death).

-In the first years of life, the autistic brain grows too large too fast.  This information has been found in numerous studies on autism by MRI or head circumference.  It was assumed that the growth was found in the frontal and temporal lobes because of the social/language association.  Discovered deviantly large, but posterior region of the brain was not. 

Differences in Age-Related FA changes in ASD and typically developing.
-Significant tracts.  What pathways of the brain are abnormally growing?
-What tracts are responsible?  Every signal tract that shows abnormality is frontal lobe or frontal lobe that connects with the temporal lobe (with emotions and tracts functional for language development) higher order frontal integration tracts.
-Growth of tracts start too fast, too large and too early.  Abnormal tracts flatten out and don't mature.
-We want to know about early frontal lobal overgrowth and  abnormal fiber tracts.  What starts this?

-Studied postmortem young ASD brains.  Counted the number of brain cells.  There are 65% more neurons in frontal (compared to typical child's) and 25% more in the medial.  The brain cells are generated before born, other than the dentate gyrus.  The increase of 65% is evidence that this is definitively prenatal.

-In 2 year olds with autism, there are twice as many brain cells than typical adults. 
-Autism is a continuous disorder of removal of excess brain cells and recircuiting of neurons.

Gene Regulations
-There are 102 genes that can abnormally express themselves in ASD toddlers. 

Disregulation in Genetic Pathways that Determine Cell Numbers and Functional Integrity:
-Neurogenesis
-Cell cycle regulation
-DNA damage responses (failure to get rid of damaged DNA in autism).
-Apoptosis and survival
-Migration and axon pathfinding (genes not properly functioning).
-Down regulation of neural-patterning genes (multiple genes turned down, showing not opearating correctly (ie., language), cause for right and left asymetry found in Dr. Pierce's study mentioned above.

-Genes are messed up from the very beginning because failure of the patterning gene. 
-Humans generate bulk of neurons in the middle of the second trimester.
-Patches of cortex that fail to develop normal layers of neurons-(failure of neurons)-do 3D reconstructions.
-Dysregulation of normal migration of cells.

Could be EITHER increased number of neurons OR failure of removal of bad cells.  If you had twice as many neurons, that means 4 times as many bad connections which is why autism is found many times in conjunction with other factors, ie., GI issues or seizure disorder.