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Autism Coach

LC Theory of Autism

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A theory, published in the March 2009 issue of Brain Research Reviews, hypothesizes that autism is a developmental disorder caused by impaired regulation of the locus coeruleus (LC), a bundle of neurons in the brain stem that processes sensory signals from all areas of the body and also regulates fever.  Children within the autism spectrum often function at a higher level when they are running a fever.  Emotional and physiological stress during and after pregnancy may be lead to impairment of the LC.

Researchers at the Albert Einstein College of Medicine in New York believe 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.  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.

The locus coeruleus (Latin for "the blue spot" because it is has a dark bluish pigment) is the region of the brain that controls fever.  The LC is involved in the fight-or-flight, activation response, post-traumatic stress disorders, neurodegenerative diseases and depression.  The LC is the major location of norepinephrine in the brain, and is composed of mostly medium-sized neurons.  The LC's operation is acted on by opiates. 


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.

There are numerous anecdotal observations by parents that symptoms of ASD abate during infection-related fevers. A detailed study published in Pediatrics, comparing behavior changes associated with fevers in children with and without ASD, provided evidence that fever normalizes behavior in children with ASD. This effect was notable for irritability, hyperactivity, and inappropriate speech. In each case, the onset of fever initiated a window of more normal behavior that continued temporarily after the fever abated.  The complexity of the LC makes it particularly vulnerable to immunological stress of inflammation and as contributing to ASD. This is also consistent with the reported prevention of ASD by omega-3 oils taken prenatally.

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."  An epigentic therapy would most likely involve the turning off and on off genes to normalize function and research into creating epigentic treatments is in its infancy.

"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."