That makes autism a clear
brain development issue and a nasty one as well. We also now know where to look for
unexplained seizures. It has always been
suspected that we would find evidence of physical disturbance, but the lack of
such evidence has promoted other less fruitful lines of inquiry. Thus this is very good news in quite the same
way that the discovery of damaged proteins in the brain allowed Alzheimer’s to
be tackled directly.
Now we need to figure out
how this happens and it is clear that pathology will help us.
Better yet it is clearly a
developmental issue that may be trackable to something like a low level
infection. We now know where to look and
also when to look.
03.26.14 |
Nobody knows what causes autism, a condition that varies so
widely in severity that some people on the spectrum achieve enviable fame and
success while others require lifelong assistance due to severe problems with
communication, cognition, and behavior. Scientists have found countless clues,
but so far they don’t quite add up. The genetics is complicated. The
neuroscience is conflicted.
Now, a new study adds an
intriguing, unexpected, and sure-to-be controversial finding to the mix: It
suggests the brains of children with autism contain small patches where the
normally ordered arrangement of neurons in the cerebral cortex is disrupted.
“We’ve found locations where there appears to be a failure of normal development,” said Eric Courchesne, a
neuroscientist at the University of California, San Diego and an author of the
study, which appears today in
the New England Journal of
Medicine.
“It’s been really
difficult to identify a lesion or anything in the brain that’s specific and
diagnostic of autism,” said Thomas Insel, director of the National Institute of
Mental Health, one of several agencies that funded the project. The new study
is notable because it applies sophisticated molecular labeling methods to
postmortem tissue from people with autism who died as children, which is
incredibly hard to come by, Insel says.
“If it’s real, if it’s replicated and it’s a consistent finding,
it’s more evidence that autism starts prenatally and only manifests itself
when kids start to have trouble with language or social behavior around age two
or three,” Insel said. “These kinds of changes in cellular architecture
would happen during brain development,
probably around the first part of the second trimester.”
The cortex is the thin sheet of tissue on the surface of the
brain. We humans have so much of it that it’s folded up to fit inside our
skulls, giving our brains their wrinkly appearance. The cortex plays an
important role in everything from basic functions like planning movements and
making sense of information from our eyes and ears, to more advanced stuff like
language and abstract thought.
If you cut a cross-section through the cortex and looked at it
under a microscope, you’d see that it has a consistent cellular
architecture, with six distinct layers, each inhabited by certain types of
neurons with a certain pattern of connections with other neurons. This uniform
organization, many neuroscientists think, is what makes the cortex such a
powerful and flexible computer.
But that organization appears to be messed up in spots in many
children with autism, according to the new study.
Courchesne and colleagues examined post-mortem brain tissue from
22 children who died between the ages of 2 and 15 — half had autism, half did
not. The symptoms of those who had it varied from mild to severe. With help
from Ed Lein and other scientists at the Allen Brain Institute, the team
applied genetic markers that label specific cell types and specific layers of
cortex.
In 10 of 11 of the autistic brains, they found patches of cortex
that didn’t follow the normal rules. The patches were a few millimeters
across (roughly a quarter to half an inch). In some patches, a specific layer
was missing. In others, certain cells weren’t there. The details varied
from case to case.
The researchers found these abnormalities in the temporal and
prefrontal cortex, areas with roles in language and cognition that are — in a
very broad and hand-wavey sort of way — relevant to the symptoms of autism.
They did not see them in the occipital cortex, a region primarily associated
with vision, which isn’t typically disrupted in autism. Nor did they see them
in the brains of 10 of the 11 children without autism. (The one child in
this group without autism who had patches of scrambled cortex also had a
history of severe seizures, which doesn’t exactly explain that finding, but
might be relevant, Courchesne says).
“It’s intriguing to find something consistent like this,” said
Helen Barbas, a neuroscientist at Boston University who wasn’t involved in the
new study. But she’s less sure about what it means.
One popular hypothesis is that autism results from altered
connections within or between regions of the cortex. “The cortex is a huge
communication system,” Barbas said. “If you have an abnormality in the
structure of cortex, it’s going to affect connectivity.” At this point though,
it’s not possible to connect the dots between the scrambled bits of cortex
described in the new study and the type of altered connectivity Barbas and
others have found previously. “It raises a lot of questions, and that’s good.”
Courchesne acknowledges the new study is just a start. The
researchers only had access to small chunks of brain tissue, so they can’t say
how widespread the disordered patches were in any given person, let alone how
common they are overall in the brains of people with autism (or without it, for
that matter). For the same reason, it’s not clear yet whether there’s any
relationship between the severity — or the type — of autism symptoms and the
number or location of scrambled patches of cortex.
What could cause these abnormalities isn’t clear, but Courchesne
thinks genetics and environment could both play a role. The trigger could be
some relatively common (but currently unknown) thing encountered by pregnant
mothers, Courchesne suggests, but different individuals might vary in their
genetic susceptibility to it — and in their genetic potential to compensate for
it.
The findings might also be consistent with spontaneous gene
mutations, which have been implicated by several teams of autism researchers in
recent years, says Robert Hevner, a neuropathologist and neuroscientist at the
University of Washington. Unlike the inherited gene mutations passed down from
parent to offspring, spontaneous mutations occur later, during development.
“As billions of cells in our body and brain are dividing,
mistakes get made,” Hevner said. Because those mistakes affect some cells and
not others, they can create a mosaic-like pattern of abnormalities. “If there
are mutations occurring on a small scale during brain development, we might see
some changes like they’re showing here.”
Still, Hevner sees several reasons to be skeptical about the
findings. Chief among them is that the researchers haven’t directly shown that
the brains of people with autism have cellular abnormalities — they’ve inferred
that from their molecular labeling, which targets RNA. That could be
problematic in postmortem tissue, Hevner says. “The brain after death is just
sitting there stewing in its own juices, and RNA is a highly unstable molecule
that’s easily degraded.”
An alternative interpretation for the new findings, Hevner says,
is that the patches with missing molecular markers simply correspond to areas
where RNA degraded more quickly than in the surrounding tissue. Courchesne and
colleagues did experiments to try to rule this out, but Hevner says he’s still
not convinced. “I’ve developed a habit of being cautious,” he said.
When it comes to autism
research, that’s probably a healthy habit for everyone.
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