more brain research

April 1, 2009 — (BRONX, NY) — Scientists at Albert Einstein College of
Medicine of Yeshiva University have proposed a sweeping new theory of autism
that suggests that the brains of people with autism are structurally normal
but dysregulated, meaning symptoms of the disorder might be reversible.

The central tenet of the theory, published in the March issue of Brain
Research Reviews, is that autism is a developmental disorder caused by
impaired regulation of a bundle of neurons in the brain stem that processes
sensory signals from all areas of the body.

Dominick Purpura, M.D. | Mark Mehler, M.D.The new theory stems from
decades of anecdotal observations that some autistic children seem to
improve when they have a fever, only to regress when the fever ebbs. A 2007
study in the journal Pediatrics took a more rigorous look at fever and
autism, observing autistic children during and after fever episodes and
comparing their behavior with autistic children who didn’t have fevers. This
study documented that autistic children experience behavior changes during
fever.

“On a positive note, we are talking about a brain region that is not
irrevocably altered. It gives us hope that, with novel therapies, we will
eventually be able to help people with autism,” says theory co-author Mark
F. Mehler, M.D., chairman of neurology and director of the Institute for
Brain Disorders and Neural Regeneration at Einstein.

Autism is a complex developmental disability that affects a person’s ability
to communicate and interact with others. It usually appears during the first
three years of life. Autism is called a “spectrum disorder” since it affects
individuals differently and to varying degrees. It is estimated that one in
every 150 American children has some degree of autism.

Einstein researchers contend that scientific evidence directly points to the
locus coeruleus—noradrenergic (LC-NA) system as being involved in autism.
“The LC-NA system is the only brain system involved both in producing fever
and controlling behavior,” says co-author Dominick P. Purpura, M.D., dean
emeritus and distinguished professor of neuroscience at Einstein.

The locus coeruleus has widespread connections to brain regions that process
sensory information. It secretes most of the brain’s noradrenaline, a
neurotransmitter that plays a key role in arousal mechanisms, such as the
“fight or flight” response. It is also involved in a variety of complex
behaviors, such as attentional focusing (the ability to concentrate
attention on environmental cues relevant to the task in hand, or to switch
attention from one task to another). Poor attentional focusing is a defining
characteristic of autism.

“What is unique about the locus coeruleus is that it activates almost all
higher-order brain centers that are involved in complex cognitive tasks,”
says Dr. Mehler.

Drs. Purpura and Mehler hypothesize that in autism, the LC-NA system is
dysregulated by the interplay of environment, genetic, and epigenetic
factors (chemical substances both within as well as outside the genome that
regulate the expression of genes). They believe that stress plays a central
role in dysregulation of the LC-NA system, especially in the latter stages
of prenatal development when the fetal brain is particularly vulnerable.

As evidence, the researchers point to a 2008 study, published in the Journal
of Autism and Developmental Disorders, that found a higher incidence of
autism among children whose mothers had been exposed to hurricanes and
tropical storms during pregnancy. Maternal exposure to severe storms at
mid-gestation resulted in the highest prevalence of autism.

Drs. Purpura and Mehler believe that, in autistic children, fever stimulates
the LC-NA system, temporarily restoring its normal regulatory function.
“This could not happen if autism was caused by a lesion or some structural
abnormality of the brain,” says Dr. Purpura.

“This gives us hope that we will eventually be able to do something for
people with autism,” he adds.

The researchers do not advocate fever therapy (fever induced by artificial
means), which would be an overly broad, and perhaps even dangerous, remedy.
Instead, they say, the future of autism treatment probably lies in drugs
that selectively target certain types of noradrenergic brain receptors or,
more likely, in epigenetic therapies targeting genes of the LC-NA system.

“If the locus coeruleus is impaired in autism, it is probably because tens
or hundreds, maybe even thousands, of genes are dysregulated in subtle and
complex ways,” says Dr. Mehler. “The only way you can reverse this process
is with epigenetic therapies, which, we are beginning to learn, have the
ability to coordinate very large integrated gene networks.”

“The message here is one of hope but also one of caution,” Dr. Mehler adds.
“You can’t take a complex neuropsychiatric disease that has escaped our
understanding for 50 years and in one fell swoop have a therapy that is
going to reverse it — that’s folly. On the other hand, we now have clues to
the neurobiology, the genetics, and the epigenetics of autism. To move
forward, we need to invest more money in basic science to look at the genome
and the epigenome in a more focused way.”

The paper by Drs. Mehler and Purpura, “Autism, fever, epigenetics and the
locus coeruleus,” was published in the March issue of Brain Research
Reviews.

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