What part of the body does autism generally affect?

Brain changes in autism are far more sweeping than previously known, UCLA-led study finds

Brain changes in autism are comprehensive throughout the cerebral cortex rather than just particular areas thought to affect social behavior and language, according to a new UCLA-led study that significantly refines scientists’ understanding of how autism spectrum disorder (ASD) progresses at the molecular level.

The study, published today in Nature, represents a comprehensive effort to characterize ASD at the molecular level. While neurological disorders like Alzheimer’s disease or Parkinson’s disease have well-defined pathologies, autism and other psychiatric disorders have had a lack of defining pathology, challenging efforts to develop more effective treatments.

The new study finds brain-wide changes in virtually all of the 11 cortical regions analyzed, regardless of whether they are higher critical association regions – those involved in functions such as reasoning, language, social cognition and mental flexibility – or primary sensory regions.

“This work represents the culmination of more than a decade of work of many lab members, which was necessary to perform such a comprehensive analysis of the autism brain,” said study author Dr. Daniel Geschwind, the Gordon and Virginia MacDonald Distinguished Professor of Human Genetics, Neurology and Psychiatry at UCLA. “We now finally are beginning to get a picture of the state of the brain, at the molecular level, of the brain in individuals who had a diagnosis of autism. This defines a molecular pathology, which similar to other brain disorders such as Parkinson’s, Alzheimer’s and stroke, provides a key starting point for understanding the disorder’s mechanisms, which will inform and accelerate development of disease-altering therapies.”

Just over a decade ago, Geschwind led the first effort to identify autism’s molecular pathology by focusing on two brain regions, the temporal lobe and the frontal lobe. Those regions were chosen because they are higher order association regions involved in higher cognition – especially social cognition, which is disrupted in ASD.

For the new study, researchers examined gene expression in 11 cortical regions by sequencing RNA from each of the four main cortical lobes. They compared brain tissue samples obtained after death from 49 people with ASD against 54 controls individuals.

While each profiled cortical region showed changes, the largest changes in RNA levels were in the visual cortex and the parietal cortex, which processes information like touch, pain and temperature. The researchers said this may reflect the sensory hypersensitivity that is frequently reported in people with ASD. Researchers found strong evidence that the genetic risk for autism is enriched in a specific group of genes expressed in neurons that has lower expression across the brain, indicating that these correlated RNA changes in the brain are likely the cause of ASD rather than a result of the disorder.

One of the next steps is to determine whether researchers can use computational approaches to develop therapies based on reversing gene expression changes the researchers found in ASD, Geschwind said, adding that researchers can use organoids to model the changes in order to better understand their mechanisms.

Other authors include Michael J. Gandal, Jillian R. Haney, Brie Wamsley, Chloe X. Yap, Sepideh Parhami, Prashant S. Emani, Nathan Chang, George T. Chen, Gil D. Hoftman, Diego de Alba, Gokul Ramaswami, Christopher L. Hartl, Arjun Bhattacharya, Chongyuan Luo, Ting Jin, Daifeng Wang, Riki Kawaguchi, Diana Quintero, Jing Ou, Ye Emily Wu, Neelroop N. Parikshak, Vivek Swarup, T. Grant Belgard, Mark Gerstein, and Bogdan Pasaniuc. The authors declared no competing interests.

This work was funded by grants to Geschwind (NIMHR01MH110927, U01MH115746, P50-MH106438 and R01MH109912, R01MH094714), Gandal (SFARI Bridge to Independence Award, NIMH R01-MH121521, NIMH R01-MH123922 and NICHD-P50-HD103557), and Haney (Achievement Rewards for College Scientists Foundation, Los Angeles Founder Chapter, UCLA Neuroscience Interdepartmental Program).

Neuroscience For Kids

Fred’s parents were concerned. Fred was two and a half years old, but had not begun to talk. He didn’t babble like other children his age. Fred did not make eye contact, but his vision seemed fine. He loved watching his own hands. He could sit for hours watching his hands move back and forth.

Fred was diagnosed with autism, a neurological disorder that disrupts normal development. Some children with autism can attend school with children their own age; others need special care.

The Symptoms

Autism is classified as a pervasive developmental disorder. The «pervasive» part of the name implies that the disorder is serious, or that it affects many areas of development. Symptoms vary greatly from person to person. People with autism may appear to daydream constantly or be unaware of people around them. Most children with autism prefer to play by themselves, and treat other people like furniture. The major symptoms of autism include:

• Communication Problems: Many people with autism are uncommunicative — they will not speak, gesture, or make facial expressions. When they do speak, the speech may be in a sing-song pattern or monotone (no variation in pitch, like playing a single note on an instrument). Other people with autism may talk at length with no regard to what another person says or does.
• Repetitive Motions: Most people with autism enjoy repetitive motions, such as spinning objects, running water, or sniffing objects. A sense of routine is very important, and it can be extremely upsetting to them when part of their routine is changed. This could be something as trivial as changing the route to the grocery store or moving an item within the house.
• Problems with Social Interactions: People with autism have trouble interpreting other people’s facial expressions. Most of the time they will not make eye contact with others and have trouble making friends. Some people with autism are hypersensitive to sound and may get very upset when they hear sirens or dogs barking. Others are fascinated by faint noises such as the ticking of a watch. To some, bright lights are distressing, while others will stare at bright lights for hours. Many people with autism can not stand light touch: scratchy clothing could be unbearable. Others seem immune to pain and may hurt themselves. Mood swings are common.

The Cause of Autism is Unknown

It was once thought that poor parenting caused autism. This is definitely not true. Although the cause of autism is unclear, it is known that genetics do play a role. The disorder is seen often in identical twins: different studies have shown that if one identical twin has autism then there is a 63-98% chance that the other twin will have it. For non-identical twins (also called fraternal or dizygotic twins), the chance is between 0-10% that both twins will develop autism. The chance that siblings will be affected by autism is about 3%.

Chance that both people will develop autism:

Autism appears to be associated with other chromosomal abnormalities, such as Fragile X syndrome or brain abnormalities such as congenital rubella syndrome. A large number of people with these disorders are also diagnosed with autism. Furthermore, complicated births, such as difficult pregnancies, labor, or delivery may to contribute to the disorder.

Diagnosis

Autism is a behaviorally defined syndrome. There is no simple test for it. Usually parents notice that their child is not developing in the same way as other children the same age. A physician can perform a psychiatric exam, ruling out other disorders such as schizophrenia, selective mutism (when the child chooses not to speak but can speak if he wanted to), or cognitive disability, to name a few. Other tests examine language skills. When all test results are examined, a physician can make a diagnosis.

Treatment

Although symptoms in children may lessen with age, autism is a lifelong disorder. Some people with autism will remain in institutionalized care and approximately 50% will remain without the ability to speak. Structured programs that do not allow the child to «tune out» have proved successful at helping many children gain language and some social skills. Many times children with autism will have other disorders, such as epilepsy (seizures), hyperactivity, and attention problems. Epilepsy, in particular, appears to get worse as autistic children get older.

Drugs that inhibit the reuptake of the neurotransmitter called serotonin have some success in treating patients with autism. These drugs, such as Fluoxetine, slow the reuptake of serotonin by the neuron that releases it. Therefore, serotonin stays in the synapse for a longer time.

A Look at the Brain of a Person with Autism

Brain imaging techniques, such as magnetic resonance imaging (MRI), have been used to examine the brains of people with autism. However, results have been inconsistent. Abnormal brain areas in people with autism include the:

• Cerebellum — reduced size in parts of the cerebellum.
• Hippocampus and Amygdala — smaller volume. Also, neurons in these areas are smaller and more tightly packed (higher cell density).
• Lobes of the Cerebrum — larger size than normal.
• Ventricles — increased size.
• Caudate nucleus — reduced volume.

Quick Facts About Autism

• Autism occurs in approximately 1 out of every 59 children in the U.S. (Reference: CDC)
• Autism is the third most common developmental disorder in the U.S., affecting at least 500,000 people.
• Autism is seen more often in boys; four or five boys will have autism compared to one girl. But girls with autism are often more severely affected than boys and score lower on intelligence tests.
• Leo Kanner first described autism as the «inability to relate themselves in the ordinary way to people and situations from the beginning of life» in the 1943 paper «Autistic Disturbances of Affective Contact.»
• Autism usually is seen within the first three years of life.
• Some people with autism are gifted in certain areas such as math or music.
• Autism has also been called «early infantile autism,» «childhood autism,» «Kanner’s autism,» and «pervasive developmental disorder.»

References and further reading:

1. American Psychiatric Association: Diagnostic Manual of Mental Disorders (DSM-IV), 4th Edition, Washington, D.C., American Psychiatric Association, 1994.
2. Griffiths, D. 5-Minute Clinical Consult, Baltimore: Williams and Wilkins, Inc., 1999.
3. Kaplan, H.I. and Sadock, B.J., Comprehensive Textbook of Psychiatry, 6th Edition, Baltimore: Williams and Wilkins, 1995.
4. Kates, W.R. et al., Neuroanatomical and neurocognitive differences in a pair of monozygous twins discordant for strictly defined autism, Ann. Neurol., 43:782-791, 1998.
5. Rapin, I. Autism in search of a home in the brain. Neurology, 52:902-904, 1999.
6. Rowland, L.P., Merritt’s Textbook of Neurology, 9th Edition, Malvern: Williams and Wilkins, 1995.
7. Autism Information from the National Institute of Child Health and Human Development
8. University of Washington Autism Center

Copyright © 1996-2020, Eric H. Chudler, University of Washington

Autism may affect not just brain but sensory nerves, mouse study suggests

A utism impacts kids and adults socially and behaviorally — but it also impacts their senses. For instance autistic individuals may dislike being touched, or be especially averse to things like scratchy wool or buzzing refrigerators.

New research, for the first time, gives a hint as to why. A study in mice finds that autism has effects not just on the brain but also on the nerves in the skin that respond to touch. And this heightened sensitivity affects not just their sensory experience of the world but also their social interactions.

David Ginty and colleagues at Harvard Medical School studied mice with genetic mutations that are associated with autism and also with a developmental syndrome called Rett syndrome that often causes autism. Mice with these mutations share some similarities to patients with autism and Rett syndrome — they’re anxious, avoid social contact, and have a hypersensitivity to touch.

Related: Is the dramatic rise in autism tapering off?

The team engineered mice with the mutation in only some of their cells, in either the brain or in touch receptor cells throughout their skin that go into the spinal cord.

When they tested the mice’s reaction to puffs of air on their backs, they found that the Rett syndrome mutation in the nerves caused them to be especially startled, which wasn’t true if the mutation was just in the brain. Looking at the cellular level, scientists saw that the touch nerves were overactive. “Everything’s coming in with the volume turned all the way up,” Ginty said.

And over time these mice don’t acclimate to touch the way that normal mice do — akin to feeling your clothes on your skin all the time, Ginty said. “We would argue that’s pretty disruptive.”

Perhaps most intriguingly, the mutation just in touch cells had dramatic effects on the mice’s social lives.

When the researchers placed the mice in cages with a strange mouse, the mice with touch sensitivity were as antisocial as mice with the gene mutation in their whole bodies.

That is one of the most fascinating questions the study raises, Ginty said: “What is it about having normal sensation that shapes the brain to give rise to normal cognitive behavior?”

Related: Is too much folic acid during pregnancy a contributor to autism?

The findings were published Thursday in Cell.

“I’m very excited about this study,” said Caroline Robertson, a postdoctoral autism researcher at Harvard University who was not involved in the study “Importantly, it demonstrates a direct link between very low level symptoms,” like touch sensation, “and higher order differences in behavior,” like antisocial behavior.

However, Robertson points out that autism in humans is more complicated than a single mouse model. “The tricky thing about autism is that everyone has their own hypersensitivities, and sometimes even hyposensitivities,” or things they have reduced sensitivity toward.

Helen Bateup, a professor of neurobiology at the University of California, Berkeley, agrees. “There are a lot of autism genes that are only expressed in the brain,” and therefore wouldn’t affect the nerves in the skin. “I don’t see how this could be a general mechanism for all of autism. [But] this might be an interesting mechanism for some kinds of causes of autism.”

Its meaning for treatment is less clear at this point. Ginty is looking into it: “Can we add back the gene in sensory neurons and reverse the tactile dysfunction — and maybe even the anxiety-like behavior?” A drug therapy could also theoretically tamp down overactive touch nerves, and maybe reduce touch sensitivity, though whether that would affect social interactions would need to be studied.