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Study Finds New Evidence that Autism Begins During Pregnancy
Researchers at the University of California, San Diego School of Medicine
and the Allen Institute for Brain Science have published a study that gives
clear and direct new evidence that autism begins during pregnancy.
The study will be published in the March 27 online edition of the New
England Journal of Medicine.
The researchers – Eric Courchesne, PhD, professor of neurosciences and
director of the Autism Center of Excellence at UC San Diego, Ed S. Lein, PhD
, of the Allen Institute for Brain Science in Seattle, and first author Rich
Stoner, PhD, of the UC San Diego Autism Center of Excellence – analyzed 25
genes in post-mortem brain tissue of children with and without autism.
These included genes that serve as biomarkers for brain cell types in
different layers of the cortex, genes implicated in autism and several
control genes.
“Building a baby’s brain during pregnancy involves creating a cortex that
contains six layers,” Courchesne said. “We discovered focal patches of
disrupted development of these cortical layers in the majority of children
with autism.” Stoner created the first three-dimensional model visualizing
brain locations where patches of cortex had failed to develop the normal
cell-layering pattern.
“The most surprising finding was the similar early developmental pathology
across nearly all of the autistic brains, especially given the diversity of
symptoms in patients with autism, as well as the extremely complex genetics
behind the disorder,” explained Lein.
During early brain development, each cortical layer develops its own
specific types of brain cells, each with specific patterns of brain
connectivity that perform unique and important roles in processing
information. As a brain cell develops into a specific type in a specific
layer with specific connections, it acquires a distinct genetic signature or
“marker” that can be observed.
The study found that in the brains of children with autism, key genetic
markers were absent in brain cells in multiple layers. “This defect,”
Courchesne said, “indicates that the crucial early developmental step of
creating six distinct layers with specific types of brain cells – something
that begins in prenatal life – had been disrupted.”
Equally important, said the scientists, these early developmental defects
were present in focal patches of cortex, suggesting the defect is not
uniform throughout the cortex. The brain regions most affected by focal
patches of absent gene markers were the frontal and the temporal cortex,
possibly illuminating why different functional systems are impacted across
individuals with the disorder.
The frontal cortex is associated with higher-order brain function, such as
complex communication and comprehension of social cues. The temporal cortex
is associated with language. The disruptions of frontal and temporal
cortical layers seen in the study may underlie symptoms most often displayed
in autistic spectrum disorders. The visual cortex – an area of the brain
associated with perception that tends to be spared in autism – displayed no
abnormalities.
“The fact that we were able to find these patches is remarkable, given that
the cortex is roughly the size of the surface of a basketball, and we only
examined pieces of tissue the size of a pencil eraser,” said Lein. “This
suggests that these abnormalities are quite pervasive across the surface of
the cortex.”
Data collected for the Allen Brain Atlas, as well as the BrainSpan Atlas of
the Developing Human Brain was developed by a consortium of partners and
funded by the National Institute of Mental Health. It allowed scientists to
identify specific genes in the developing human brain that could be used as
biomarkers for the different layer cell types.
Researching the origins of autism is challenging because it typically relies
upon studying adult brains and attempting to extrapolate backwards. “In
this case,” Lein noted, “we were able to study autistic and control cases
at a young age, giving us a unique insight into how autism presents in the
developing brain.”
“The finding that these defects occur in patches rather than across the
entirety of cortex gives hope as well as insight about the nature of autism,
” added Courchesne.
According to the scientists, such patchy defects, as opposed to uniform
cortical pathology, may help explain why many toddlers with autism show
clinical improvement with early treatment and over time. The findings
support the idea that in children with autism the brain can sometimes rewire
connections to circumvent early focal defects, raising hope that
understanding these patches may eventually open new avenues to explore how
that improvement occurs.
Additional contributors to the study include Maggie L. Chow, PhD, and
Subhojit Roy, MD, PhD, UC San Diego; Maureen P. Boyle, PhD, UC San Diego and
Allen Institute; Peter R. Mouton, PhD, University of South Florida School
of Medicine; Anthony Wynshaw-Boris, MD, PhD, Case Western Reserve University
School of Medicine; and Sophia A. Colamarino, PhD, Stanford University
School of Medicine.
This research was supported by funds from the Simons Foundation, the Peter
Emch Family Foundation, Cure Autism Now/Autism Speaks, the Thursday Club
Juniors, the UC San Diego Autism Center of Excellence (NIMH grant P50-
MH081755), and the Allen Institute for Brain Science (NIMH grant RC2MH089921
).
