many tight connections in frontal-lobe circuits and too few
long-distance links between the frontal lobe and the rest of the brain
may cause some of the language, social problems and repetitive behavior
seen in autism spectrum disorders, according to a new study published
in Science Translational Medicine. The research links a variant of the CNTNAP2 gene to this particular type of rewiring in the brain.
The new findings, which used functional magnetic resonance imaging
(fMRI) to measure the types and strength of connections between brain
regions, could provide autism experts with some important clues for
early intervention and treatment. (More on Time.com: Special Report: Kids and Mental Health)
"I think it is quite a beautiful study," says Kamila Markram,
director of the Autism Project at the Brain Mind Institute of the École
Polytechnique Fédérale de Lausanne in Switzerland, who was not
associated with the current research. "What's new is that it brings the
genetic data together with the functional brain activity and that is
usually not done. Either people look at gene expression or they look at
functional brain activity. To bring them together and relate them to
say, 'That particular gene is responsible for the different connection
pattern that one observes,' that's a unique research area and that's the
beauty of the study."
The gene produces a protein called CASPR1 and is active during brain
development — mostly during frontal-lobe development. "During early
development, it is localized to parts of brain that are 'more evolved' —
areas where learning and language happen, the frontal lobes where
really complex thinking takes place," says Ashlee Scott-van Zeeland, a
postdoctoral fellow at the Scripps Translational Science Institute in La
Jolla, Calif., and lead author of the study. "[It is] thought to help
structure the brain." The gene also influences the development of reward
regions of the brain, which are involved in motivation, pleasure and
learning. (More on TIME.com: Is Picky Eating an Early Sign of Autism?)
For the new study, researchers compared 32 autistic and typically
developing children, aged 11 to 13. Some had an autism-risk variant of
CNTNAP2, while others had a non-risk variant. In the sample, the
non-autistic children were just as likely to have the risk variant as
the autistic children. Indeed the CNTNAP2 gene, which 1 in 3 people in
the general population carry, doesn't guarantee autism — the gene is
only one of many risk factors involved in the disorder. "In autism,
there are many roads to Rome," explains Scott-van Zeeland. "You can have
some of the common risk variants and they all stack up. [Only] if you
have enough of them [will you] fall over edge."
All the kids underwent an fMRI scan. While in the scanner, the kids
played a learning-related game that gave them monetary rewards for
correct answers. The task was chosen because it activated many of the
brain regions affected by CNTNAP2, including those involved in reward. (More on Time.com: 1 in 5 Kids With an Autistic Sibling Show Subtle Symptoms Too).
Regardless of autism diagnosis, the children with autism-risk
variants showed different patterns of activity within the frontal lobe
and between the frontal lobe and the rest of the brain. During the task,
they showed more activity throughout the frontal cortex. For example,
they had increased activity in the medial prefrontal cortex, which
normally tends to be active when the brain is not engaged in a
task; carriers of the risk variant showed less decrease in activity
during the game than those without the risk variant. (More on TIME.com:Genetic Testing for Autism)
In children with the non-risk variant of CNTNAP2, brain pathways more
strongly linked the frontal regions to parts of the left side of the
brain, areas that typically specialize in language. In risk-variant
carriers, the frontal lobe was connected more diffusely to both sides of
the brain, which may help explain why the variant can be associated
with delays in speech.
In addition, children without the risk variant had better long-range
connections between brain regions — from the front to the back of the
brain, for example. There were no differences in IQ associated with the
risk variant alone.
CNTNAP2 — pronounced catnap two — is "a really interesting gene,"
says Scott-van Zeeland. It was first discovered in a family whose
members suffered from obsessive-compulsive disorder and Tourette's
syndrome (symptoms of both disorders are also frequently seen in
autism). The same gene has also been linked to ADHD, schizophrenia and a
language disorder known as Specific Language Impairment. (More on Time.com:A Five-Minute Brain Scan Tracks Kids' Development and May Spot Disorders).
"Genes do not code for diagnoses. They code for proteins, which then
go about creating an effect," says Nancy Minshew, professor of
psychiatry and neurology at the University of Pittsburgh, who has done
prior research on brain connectivity in autism but was not associated
with the current research. "Hence the same genes may be seen in
clinically related disorders." All of the related disorders involve
problems with directing attention and controlling behavior.
The new findings lend support to the "intenseworld"
theory of autism, which has posited that patterns of brain circuitry
that result in excessive functioning in some regions may lead to
extremes in attention and perception, which can produce both the
deficits — and the sometimes extraordinary intellectual talents — that
characterize some people with autism. (More on TIME.com:Is Anorexia a 'Female' Form of Autism?)
In a brain wired with hyper-local connections, those regions would be
prone to hyperactivity; in turn, the excess activity leads to
hyper-responsiveness to incoming information and quick learning. "They
react more to stimulation than normal circuits. And not only do they
react too much, they also learn too much," says Markram, an author of
the intense world theory.
Although that sounds like it could be a good thing — it may well
explain the abilities of autistic savants, who are extremely gifted in
mathematics, computer science or music — in the context of decreased
long-term connections between brain regions, the end result can be
overwhelming. Indeed, many people with autism describe being
incapacitated by sensory experiences — whether they are bright lights,
loud noises or social interactions.
"At a psychological level, basically, it would mean that the autistic
person could feel, perceive and learn too much. That could lead to
sensory overload, as well as consequences like social avoidance or
withdrawal and repetitive behavior," says Markram. Autistic people tend
to use these behaviors to keeping their world the same, and to keep an
overly intense world at bay.
"If you have too much noise — all that talking that's going on in the
frontal lobes — it might be hard to figure out what sources of
information to pay attention to," says Scott-van Zeeland. "To figure out
what's going on requires these long-term connections."
Still, in the absence of other genes or environmental risk factors
that lead to full blown autism, the pattern of brain connections
associated with the risk variant of CNTNAP2 may carry certain
advantages. "It would be really exciting to see what would be the
strengths of this kind of connectivity pattern," says Scott-van Zeeland.
"A lot of people carry this variation — if it weren't beneficial in
some way, you would expect it to disappear."
Going forward, researchers may focus on using the new information to
improve early autism interventions. Early brain development is complex
and shaped by environmental signals, but a brain that is paralyzed by
sensory overload misses early social cues, which may change the entire
course of its development. So autistic children may have social problems
not because their social brains are defective, but because sensory
overload and the methods children use to cope with it prevent them from
absorbing and understanding the information they need to develop
Early social intervention could help prevent — or at least
significantly mitigate — the disability associated with autism. "If you
can identify these early brain signals and know what the problem is, you
can do more intensive therapy," Scott van-Zeeland says. "A child's
brain is so flexible. So instead of letting a child obsess over trains,
you could spend a lot more time teaching them to pay attention to mom's
face and trying to get that be rewarding. Once we find out what circuits
are not automatically doing what they should, if you can explicitly
tell them what they should do, that would go a really long way.”
As autism researcher David Mandell told the New York Times this week in a story on early autism intervention:
you ultimately might be doing is preventing a certain proportion of
autism from ever emerging ... I'm not saying you're curing these kids,
but you may be changing their developmental trajectory enough by
intervening early enough that they never go on to meet criteria for the
disorder. And you can't do that if you keep waiting for the full
disorder to emerge.