Causes of Neurodevelopmental Challenge

There are three main categories of causes or “etiologies” that we know contribute to neurodevelopmental disorders. These categories include genetic conditions that affect brain development or function, brain injury/environmental exposures, and toxic stress. We believe that a comprehensive evaluation begins with trying to understand the “why” of the challenge as in some, but not all cases, this changes our treatment approach. Over the years, our SNAP team has seen families greatly benefit by knowing contributing causes – even if it does not change the treatment recommendation. It often opens doors for families to find a community of parents who are “in the same place” and can inform risk of developing other challenges over a lifetime. It can give families a starting point and a sense of what is NOT causing the problem— ending the exhausting search and cycle of self-blame that is often associated with neurodevelopmental disorders. We always think of identified “causes” as contributors rather than the singular cause as we know that humans are complex and who we end up being is always an interplay between our complex genetic coding, our nervous system health, our practice, and our life experiences. In our clinics, we strive to find contributing causes of developmental differences so that we can best personalize treatment recommendations. In our research, we strive to inform the search and push the boundaries of our treatments.

Genetic Conditions that Affect the Brain

We often begin our search for contributing causes of neurodevelopmental disorders with a genetics screening approach. Thanks to the pioneering work done by the Hagerman’s at UC Davis, and Fragile X sensory investigations done by Randi Hagerman and Lucy Miller, we have known for decades that Fragile X syndrome leads to neurodevelopmental challenges with an estimated 1% of children with Autism Spectrum Disorders (ASD) having Fragile X.  Drs. Miller and Hagerman showed that children with Fragile X show more robust and prolonged responses than neurotypical children on sensory challenges.

We have known since the early 2000’s that individuals have losses or gains of chunks of DNA across their 23 pairs of chromosomes.  We call these losses (deletions) and gains (duplications) “copy number variations or CNVs” and can test for copy number variations with a genetic test called a chromosome microarray or SNP array.  One of the most common CNVs occurs on chromosome 16 (16p11.2) and there are developmental challenges associated with both the loss and gain of DNA at this location.  We estimate that in general, 10% of individuals with ASD will have a CNV as a contributing cause with 1% of individuals with ASD having a 16p11.2 deletion or duplication.  UCSF researchers Elliott Sherr, Pratik Mukherjee, Srikantan Nagarajan, Elysa Marco, and Joaquin Anguera have contributed to our understanding of this condition in association with the Simons Research Foundation and our collaborators across the country.

Our technology has advanced in the last decade to allow for the search of genetic variation in our DNA by looking at the letter by letter code.  While we are looking at the “whole genome” in our research labs, in our clinic we are only routinely testing the exons—which are the regions that ultimately code for proteins and comprise an estimated 10% of our total DNA.  By looking at the exon sequence, we are beginning to be able to determine if an individual has a new or inherited genetic change in a single gene that may affect their neurodevelopment and behavior.  In our SNAP research, we have identified sensory related gene changes in a gene long known to be related to neurodevelopment, called ARHGEF9 which leads to auditory hypersensitivity due to a dysregulated GABA receptor.  We are now finding that up to 18% of children with sensory processing dysfunction, who do not meet criteria for ASD, will have important changes in single neurodevelopment related genes.  We are also actively investigating the role of accumulated small changes that are inherited from their parents.  More work needs to be done in this realm to guide our therapeutic treatments for affected children and adults. This genetics work has been supported by the Wallace Research Foundation, the James Gates Family Foundation, the Brody Mickelson Family Foundation, the Gretsch Family, and the SNAP Crowdfunding community. You can check out what we are doing at UCSF, by clicking here.

Brain Injury, Miswiring, and Malformation

When we think about brain injury, we often think about conditions that affect adults but the truth is that brain injury can and does affect children both while they are in the womb and throughout development.  We know that brain injury and brain malformations (atypical formation of the brain) can affect neurodevelopment in gross motor, fine motor, language, social, sensory, and attention domains.  The behavior outcome is determined by the neural networks affected by the injury, miswiring, or malformation. 

At UCSF SNAP research lab and in Dr. Marco's neurodevelopment clinics at Cortica Healthcare, we generally find that individuals with one domain of development affected often have a second or third that is not working well or may be miswired.  We think this is because we each have only one brain and if one area is not formed or functioning efficiently, it stands to reason that others might also be affected.  Drs. Mukherjee and Marco have shown that boys and girls with SPD have measurable differences in their brain connections that are most prominent in the back part of the brain. Click here to learn more.

In research published in 2017, we show that 40% children with Sensory Processing Dysfunction (SPD) will have challenges with fine motor control (handwriting) and 40% will also have challenges with cognitive control (attention).  We are now delineating the neural mechanisms underlying the sensory over-responsivity, fine motor control, and cognitive control to better understand what the networks are and how to reliably measure them.

With a good measure of the network, we can determine whether we are making real brain changes with our targeted interventions.  This work continues with our collaboration with UCSF Neuroscape's Adam Gazzaley and Joaquin Anguera. We have published our ability to make brain changes in children with SPD and attention challenges using a 4-week video game-like brain-training (Project: EVO™). This digital brain training, now called Endeavor, has now gotten FDA approval as the first prescription based digital device for children with ADHD. For more information on our brain training project, check out our pediBBT project.

There are many known causes of brain injury and malformation in children.  Unfortunately, one of the most common is injury related to premature delivery.  We have shown that children born prematurely have a much greater risk of sensory processing dysfunction. This challenge is most common in the auditory domain which we know can lead to communication and social challenges. We are actively researching how children process sounds and touch information using structural and functional neuroimaging. 

At UCSF, under the direction of Dr. Sherr in the Brain Development Research Program (BDRP), we also have an active research program investigating a significant condition of brain malformation or disconnection called Agenesis of the Corpus Callosum (AgCC).  In this condition, the connections that should be formed between the right and left hemispheres (sides) of the brain are not formed properly.  Thus, the right and left sides of the brain are not talking to each other efficiently.  We know from our research that this leads to SLOW processing and also differences in auditory information processing.  It is no wonder that the most famous person with AgCC is Kim Peek who was the real-life character from the movie Rainman which brought autism into our public awareness.  In addition to injury related to prematurity and brain malformations of all kinds, we know that children can sustain brain injury from chemical exposures while in the womb (in utero) and following delivery.  We know that in utero exposure to alcohol and certain drugs can have lifelong consequences and we are learning about the effects of exposure to pesticides and other introduced chemicals.  This remains a key concern and an area with great promise for prevention!

Toxic Stress

Another area of great importance and emerging awareness is the effect of toxic stress or adversity on the developing brain and behavior.  We have long known that poverty and violence changes our children’s ability to succeed as adults but we are only now starting to really understand how these exposures change the brain and the brain function.  At UCSF, Drs. Tom Boyce, Nicki Bush, and Danielle Roubinov are investigating how adversity affects our nervous system across the lifespan and how to change the way we practice primary care to help affected children from the beginning.