5 August 2014 - Amazon Web Services

Autism research news and opinion
29 July 2014 - 5 August 2014
For the latest news, visit SFARI.org on the Web
Suicidal thoughts alarmingly common in people with autism
Sarah DeWeerdt
31 July 2014
Julia Yellow
As a teenager, Bianca Marshack often flew into rages over seemingly minor problems — as when her
mother, Kathy, didn’t bring her favorite chicken dinner home from the grocery store. Her anger would
quickly spiral out of control, and she would threaten to kill herself.
“I would try to just hold her, to calm her down and say, ‘I’m here, I’m here for you,’” recalls Kathy
Marshack, a Portland, Oregon-area psychologist.
Bianca had been diagnosed at age 13 with a high-functioning form of autism called Asperger
syndrome, and as she got older her moods could be explosive. “Sometimes she would say, ‘If you
would just kill me, then we would both not have to suffer anymore,’” Kathy remembers.
Bianca’s behavior reflects the striking paradox of emotional turmoil in autism, an aspect of the
disorder that has received attention only in the past few years. Often, people with the disorder can
seem emotionless, with a flat affect and little interest in talking about feelings — their own or anyone
else’s. But they may also have outbursts in which they make dramatic, shocking threats to end their
lives.
Experienced clinicians have long had a sense that people with autism are at increased risk of
‘suicidality,’ which encompasses thoughts, plans and attempts to kill oneself. Their suspicions have
been borne out in recent years: Several large studies of adolescents and adults with autism reveal that
bleak moods and suicidal despair are alarmingly common, particularly among those on the milder end
of the spectrum with so-called high-functioning autism or Asperger syndrome.
At the same time, this suicidality may be difficult to recognize, because people with autism don’t talk
about their emotions in typical ways — for example, they may report feeling suicidal without
describing themselves as depressed.
In the most recent study, published in June in The Lancet Psychiatry, two-thirds of a group of adults
diagnosed with Asperger syndrome said they had thought about committing suicide at some point,
and 35 percent had made specific plans or actually made an attempt1.
“These are individuals who have been struggling all their lives to fit in,” says study leader Simon
Baron-Cohen, professor of developmental psychopathology at the University of Cambridge in the U.K.
“Along the way, they have really been suffering.”
In fact, researchers say, some of the cognitive patterns seen in people with autism, such as the
tendency to perseverate or get stuck on a particular line of thought, may make these individuals
particularly vulnerable to suicidality. With this new evidence, they are starting to look for ways to
identify suicidality and prevent it in this population.
“This is a community in distress,” says Katherine Gotham, assistant professor of psychiatry at
Vanderbilt University in Nashville, Tennessee, who studies depression in autism. “This is something
we need to know more about and do something about, and the faster the better.”
Hidden epidemic:
For a long time, suicide was largely ignored by autism researchers. “When I got started taking care of
people with autism, there was this belief that it’s not possible for them to have depression,” says Janet
Lainhart, professor of psychiatry at the University of Wisconsin in Madison. People with autism were
thought to have little experience of emotion, let alone of suicidal despair.
Through the 1990s and 2000s, even as knowledge and awareness of autism rapidly accelerated, few
rigorous studies investigated the topic2. One of the earliest, in 2007, involved just a few people but
offered a strong suggestion that persistent, serious thoughts of suicide are common. In that study, ten
adolescents with Asperger syndrome answered a detailed questionnaire about how frequently they
had had various suicidal thoughts over the previous month. Half scored in a range that indicates high
risk for suicide3.
Although Asperger syndrome is no longer an official diagnosis in the Diagnostic and Statistical
Manual of Mental Disorders, the term is still in use in the U.K. and elsewhere, and many individuals
still identify with it.
In the past couple of years, larger studies have confirmed that suicidality is common among young
people with autism. Last year, researchers reported that among 791 children with autism younger than
age 16, 14 percent had either talked about or attempted suicide, compared with just 0.5 percent of
children without autism4. Another study of 102 children aged 7 to 16 with anxiety and
high-functioning autism found that 11 percent had suicidal thoughts and behaviors5.
Teenagers are already at a higher risk of suicide because of the emotional and social turmoil of
adolescence. Having autism intensifies these difficulties, says Oren Shtayermman, associate professor
in the School of Health Professions at the New York Institute of Technology, who conducted the 2007
study. “As they become adolescents, they become more and more ostracized from their peer groups,”
he says. “They become more and more isolated from society.”
Age may not offer any relief from this sense of isolation. An unpublished analysis of medical records of
more than 2,000 California adults with autism found that 1.8 percent of these individuals attempted
suicide between 2008 and 2012, compared with 0.3 percent of controls.
Rehan Siddiqui became severely depressed in early 2001, during his second semester of college. “I had
no friends, really. I went to class, I attended lectures, but had no one to hang out with.” During that
period, he sometimes thought about ending his life, but was too deeply depressed to take any action.
“I said I wish I would die, I wish I would die in a car crash, stuff like that,” he recalls. When he was
diagnosed with Asperger syndrome nearly two years later, it came as a great relief, he says: “Finally
there was a reason for why I’m so different.”
“These are individuals who have been
struggling all their lives to fit in. Along
the way, they have really been
suffering.”
Some researchers say people like Siddiqui may be even more vulnerable to suicidality than those
diagnosed as children, having spent years to decades without an explanation for their struggles — and
without access to help. The 374 participants in Baron-Cohen’s, study, for example, were diagnosed at
an average age of 31. They were nine times more likely than people in the general population to
experience suicidal thoughts.
The adults with autism in the California study were more than five times more likely than controls to
attempt suicide. “I think this is the tip of the iceberg in terms of the bigger picture of suicidal
ideation,” says Lisa Croen, director of the Autism Research Program at Kaiser Permanente, a
nonprofit health care system based in California.
For many people with the disorder, the longing for social and romantic relationships, independence
and meaningful work is intense, but there are few programs to help them fulfill these basic human
desires.
Siddiqui says his hope is “to live a nice, independent life.” He lives with a roommate and is excited
that he recently got a car, because it will help him stay more socially engaged. But bouts of depression
— winter is especially difficult — have sometimes prevented him from working. “I’ve had my ups and
downs,” he says. “Ideally, I would love to have a job where I can support myself without any
government support.”
Depression’s new face:
Among the general population, most people who become suicidal are depressed. That’s true among
people with autism too4. And because people with autism have high rates of depression, it’s not
surprising that they are frequently suicidal.
Still, traditional screens for depression may miss the emotional experience of people with autism. In
Baron-Cohen’s study, suicidality was far more common than depression as it is usually diagnosed.
Although 66 percent of the participants reported having suicidal thoughts, less than half as many
reported feelings of depression.
That’s not because they don't have those feelings, however. “They may not be able to access or have
the vocabulary to describe their emotional state,” says Baron-Cohen. This condition, called
alexithymia, is common in people with autism.
Yet if clinicians listen closely, they may hear clues — albeit not the usual ones. People with autism may
be unlikely to describe themselves as depressed, but “they will explain their emotional pain in
idiosyncratic ways,” says Lainhart.
One clinician recalls an individual with autism who was so deeply sad and hopeless that he described
himself as “now darkness.” Another said she constantly thought that the time had come for her leave
this planet, in search of another galaxy where she would fit in better and find a friend.
The way people with autism think may itself make them more vulnerable to suicidality. For example,
they often don’t think to reach out to others when they are upset: Asking for help is, after all, a social
skill.
They also tend to have rigid, inflexible thinking, so once suicide enters their mind, it may stay there.
Gotham and her colleagues have found that patterns of repetitive thought contribute to depression in
people with autism. “I think that there could be something similar going on with suicidality,” she says.
People with autism often struggle to imagine the thoughts and feelings of others, including their own
future selves. As a result, they may have trouble believing they will ever feel better. They can also
easily become overwhelmed by the small but complex problems of everyday life and respond with
extreme thoughts or statements.
In the study of children with anxiety and high-functioning autism, researchers found that the children
sometimes made suicidal threats for attention or to escape from an unpleasant situation. “Often it was
a reaction to some limit being set or placed on the child,” says study leader Eric Storch, professor of
pediatrics, psychology and psychiatry at the University of South Florida in Tampa. For example, a
parent might announce that it’s time to stop playing video games, and a child might throw a tantrum,
lose control and say that he is going to kill himself.
Regardless of the intent, parents and clinicians should take threats of suicide from people with autism
seriously. “It’s their best attempt to raise a red flag saying that they need help,” says Lainhart.
Storch and his colleagues are developing a program for suicidal teens with autism based on a similar
one for those with Tourette syndrome. The next step for Baron-Cohen’s group is simple but unusual:
The researchers plan to ask people from the Asperger syndrome clinic what would help them.
“We just have to be a little bit cautious not to jump to solutions that are off-the-shelf,” Baron-Cohen
says. For example, telephone crisis lines are often recommended for suicidally depressed people — but
because of their social deficits, people with autism may be unlikely to call.
Since her daughter’s diagnosis, Kathy Marshack has oriented her psychotherapy practice to help
families who have a child or parent on the autism spectrum.
“At the time, it was frightening to me that Bianca was suicidal,” Marshack says. But looking back, she
says, her daughter probably lacked the empathy to recognize the effect her pleas about wanting to die
would have on her mother. “She was in such pain,” Marshack says. “She was trying to say, ‘I feel
helpless.’”
News and Opinion articles on SFARI.org are editorially independent of the Simons
Foundation.
References:
1: Cassidy S. et al. The Lancet Psychiatry 1, 142-147 (2014) Abstract
2: Hannon G. and E.P. Taylor Clin. Psychol. Rev. 33, 1197-1204 (2013) PubMed
3: Shtayermman O. Issues Compr. Pediatr. Nurs. 30, 87-107 (2007) PubMed
4: Mayes S.D. et al. Res. Autism Spect. Disord. 7, 109-119 (2013) Abstract
5: Storch E.A. et al. J. Autism Dev. Disord. 43, 2450-2459 (2013) PubMed
Mutant protein causes reversible autism-like behaviors
Alla Katsnelson
4 August 2014
Mice that begin expressing a mutant
version of a protein called neurexin at 2
weeks of age develop autism-like behaviors
that researchers can erase weeks or months
later. The report, published 24 July in Cell
Reports, suggests that it may be possible to
treat autism symptoms even in adulthood1.
In particular, the animals’ social behavior,
such as self-grooming and interaction with
other mice, returned to normal.
Julia Yellow
“I think this is good news for the autism
field because it shows that reversion even
in old animals can be possible,” says lead
researcher Francisco G. Scholl, professor of
medical physiology and biophysics at the
University of Seville in Spain.
The neurexin family of proteins helps neurons send signals across a synapse — the point at which two
neurons connect. From their position on one side of the synapse, they bind to another family of
proteins called neuroligins on the other side to facilitate the release of chemical messengers2.
Mutations in neurexins and other synaptic proteins have been linked to autism.
Several studies over the past few years have successfully reversed symptoms in mouse models of
autism and related conditions such as Rett syndrome, tuberous sclerosis and fragile X syndrome. Last
year, for example, researchers administered gene therapy to correct behavioral and other deficits in
adult mice modeling Rett syndrome, and another study used a drug for sleeping sickness to reverse
social and other deficits in a mouse model of severe autism.
“It does give people hope that some aspects of autism can be improved in adulthood,” says Gavin
Rumbaugh, associate professor of neuroscience at the Scripps Research Institute in Jupiter, Florida,
who was not involved in the study.
Research so far suggests that social deficits may be especially amenable to reversal in adulthood.
Rumbaugh says this may be because the mutations associated with social behavior disrupt the
functioning of individual neurons, rather than affecting overall brain structure or circuits.
Reversal of fate:
In the new study, Scholl and his colleagues engineered mice that develop normally for the first two
weeks of life and then express a mutant fragment of one type of neurexin — called neurexin1β — in
certain neurons of the forebrain. This mutant fragment blocks the normal protein from binding to its
partner neuroligin, and prevents the movement of chemical messengers between neurons.
Weeks later, the mice develop behavioral abnormalities: Compared with controls, they groom
themselves compulsively, display repetitive behaviors, and show less interest in other mice and in
social odors such as urine, and more in nonsocial odors such as vanilla and orange blossoms.
Neurons in the somatosensory cortex — a region with an especially high amount of mutant neurexin
— send fewer messages than normal.
Neurexin is expressed in the mouse throughout development and into adulthood. Scholl’s team chose
to block its function at 2 weeks of age to show that this is enough to trigger autism-like behaviors.
They turned off the expression of the mutant protein at 2 to 4 months of age in one group of mice and
at 9 to 11 months in another. Within two weeks of the treatment, the mice show no signs of their
previous symptoms and behave like controls do.
“This clearly shows that neurexin dysfunction in
postnatal neurons is sufficient to trigger autism
symptoms and that correct neurexin function is
needed throughout life,” Scholl says.
It would be interesting to know whether the same
reversal would be possible if the mutant protein
were introduced earlier — for example, around
the first week, when brain development is at its
peak, notes Catherine Fernandes, lecturer in
social genetic and developmental psychiatry at
Kings College London, who was not involved in
the study. “[Scholl’s team is] almost implying that
if there was a prenatal effect, it would have been
reversed, but of course they haven’t done that,”
she says.
Gone awry: Neurons with a mutant neurexin form
healthy synapses, but information doesn't travel across
them as it should.
Another question left unaddressed is whether
turning the mutant protein off in adulthood also
restores normal signaling, says Lucas PozzoMiller, professor of neurobiology at the University
of Alabama at Birmingham, who was not involved in the study. “They didn’t go back and check to see
if the synapses got better after they stopped the production of mutant proteins, like the behaviors
did,” he says.
Perhaps a bigger issue is that the link between the behavioral symptoms in mice and those of people
with autism is unclear. Many genes affect social behavior, but not all those genes are necessarily
involved in autism.
The same is true at the circuit level, notes Rumbaugh. “We don’t understand how similar the circuitry
and the function that drives behavior in the mouse brain is to that in the human brain,” he says. “Can
we reasonably say that those are the circuits that are disrupted in an autistic child’s brain?”
News and Opinion articles on SFARI.org are editorially independent of the Simons
Foundation.
References:
1. Rabaneda L.G. et al. Cell Reports 8, 338-346 (2014) PubMed
2. Südhof T.C. Nature 455,903-911 (2008) PubMed
Induced stem cells retain traces of their former state
Marissa Fessenden
30 July 2014
Reprogrammed stem cells carry
remnants of their previous cell states
in the form of chemical cues that alter
gene expression, reports a paper
published 10 July in Nature1. An
alternative method that creates
so-called nuclear transfer embryonic
stem cells produces fewer errors.
Working with stem cells offers
tantalizing opportunities to study the
genetic basis of complex diseases such
as autism. Stem cells that are
pluripotent, meaning that they can
develop into any cell type, can come
from several different sources.
Fresh start: Stem cells created through nuclear transfer — a technique
that replaces the nucleus of an egg cell with a nucleus from an adult cell
— carry fewer reprogramming errors.
Embryonic stem cells are harvested
directly from an embryo created
through in vitro fertilization. Induced
pluripotent stem cells, or iPS cells, are
adult cells reprogrammed to an
undeveloped state through chemical manipulation. Nuclear transfer embryonic stem cells (NT ES
cells) are created by replacing the nucleus of an egg cell with the nucleus of an adult cell.
NT ES and iPS cells both retain the unique genetic signature of the adult cell donor, so they can be
used to study diseases such as autism and to test therapies. iPS cells also skirt the ethical challenges of
using embryos.
Some earlier research indicated that iPS cells sometimes carry large deletions or duplications of DNA
called copy number variations. It was unclear whether those variations are introduced during the
reprogramming process or represent an incomplete reversion to an undeveloped cell.
The new study directly compared NT ES cells and iPS cells with embryonic cells with the same genetic
background, produced through in vitro fertilization. The three cell types all carry small numbers of
copy number variants. However, when the researchers examined chemical tags on the DNA —
epigenetic marks — they found that iPS cells retain tags harking back to their previous state.
These altered epigenetic patterns also affect how the marked genes are transcribed into RNA. The
differences indicate that iPS cells are incompletely reprogrammed, the researchers suggest, whereas
the chemical environment of the egg, even in vitro, reprograms NT ES cells more faithfully. Further
work with NT ES cells may reveal what kind of chemical cues the egg relies on and whether scientists
could use them to create better iPS cells.
News and Opinion articles on SFARI.org are editorially independent of the Simons
Foundation.
References:
1. Ma H. et al. Nature 511, 177-183 (2014) PubMed
Remembering Paul Patterson (1944-2014)
Sarkis Mazmanian
29 July 2014
Paul H. Patterson, a transformative figure in autism research,
died on 25 June. He was 70.
We deeply mourn the loss of this true innovator and
iconoclast, whose discoveries remain ahead of their time. As
the Anne P. and Benjamin F. Biaggini Professor of Biological
Sciences at the California Institute of Technology (Caltech),
Paul influenced the thinking and research of dozens of
scientists. His groundbreaking discoveries advanced novel
paradigms in neuroscience and immunology, and introduced
concepts that will continue to be developed by researchers
worldwide.
Paul had a dynamic career that led him to study the immune
system’s effect on animal behavior, a concept that is still very
much emerging. He also helped lead some of the first studies
linking environmental factors to neurologic development and
function.
Paul Patterson
As research in these areas grows, Paul’s discoveries will be
even more appreciated. His research was preclinical, but it
was heavily influenced by the epidemiologic and clinical
studies of others. He used animal models of behavioral and
neurodegenerative disorders to understand fundamental
disease mechanisms, and his work was poised to test
therapies for clinical use.
Paul spent much time of his time engaged in community outreach, from his constant appearances to
meet with families of children with autism, to his avid blogging and his recent book, Infectious
Behavior. He was naturally inspired to help others, which is likely why he told many of us, shortly
after his diagnosis of glioblastoma multiforme, that he wished he had just three more years.
He and I were in the early planning stages of a clinical trial for a possible probiotic therapy to address
gastrointestinal issues in autism. I should have reminded him that he has already helped so many
people: He enriched the careers and lives of many trainees and colleagues.
Interrelated fields:
Paul completed his Ph.D. with William Lennarz at Johns Hopkins University in 1970, continued his
training at Harvard Medical School as a postdoctoral fellow, and eventually became a faculty member
there in the very first department of neurobiology established in the U.S. In this unique environment,
he pioneered the primary culture of peripheral neurons and used this to discover that developing
sympathetic neurons can switch their neurotransmitter phenotype from noradrenergic to cholinergic
in response to environmental factors.
This was a fundamental discovery in neuroscience, as it violated the ‘one neuron, one transmitter’
concept. It showed that neurotransmitter identity is not genetically determined and immutable, but
subject to regulation by the environment. Paul's quest to purify and characterize the factor that
controls this switch culminated in 1989, five years after his move to Caltech, with the purification and
microsequencing of the ‘cholinergic differentiation factor.’
The sequence of this factor revealed, astonishingly, that it was identical to leukemia inhibitory factor,
a cytokine previously identified based on its immunological function. This discovery, along with his
early adoption of monoclonal antibodies as a tool to query the nervous system, marked the beginning
of Paul's transformation into a ‘neuroimmunologist’ and the start of his thinking that factors outside
the nervous system affect neurologic function.
Paul continued his work on the effects of cytokines on the developing and diseased nervous system,
deploying antibodies both as tools and therapeutic candidates. In the early 2000s, these lines of
research led him to become increasingly interested in the interplay between the biology of
inflammation and its impact on the developing brain and behavior.
Emboldened by his unique perspective, Paul expanded on the link between the immune system and
behavior by establishing a mouse model of autism, based on epidemiologic studies showing that
infection during pregnancy increases the child’s risk of the disorder. He showed that stimulation of
the immune system in pregnant mice results in pups with altered behaviors consistent with the three
core deficits of autism, and characterized the immune pathways that promoted these outcomes.
His discovery served to increase awareness of environmental influences on neurodevelopmental
conditions; studies by other investigators corroborated his observations in people. Gastrointestinal
disturbances have also been linked to children with autism. In one of his most recent studies, Paul
demonstrated that the gut microbiome, the diverse collection of intestinal bacteria, regulates
behaviors in mouse models of autism, and that probiotic treatment leads to improvements in
behavioral deficits.
These studies provide the hope that microbial therapies may be able to alleviate neurodevelopmental
disorders with strong environmental influences, perhaps through balancing of the immune system.
Paul was a true scientist, and unwaveringly applied the scientific approach to everything in life,
forever asking, “What is the evidence for that?” He was also a meticulous cook who perfected exotic
dishes to satisfy his eclectic tastes. His essence as a scientist was on display in the lab announcement
in which Paul described his illness to his trainees and colleagues. He said he was going to beat the
illness through a clinical trial that, ironically, used modulation of the patient’s immune system as the
therapeutic modality.
Paul is survived by his loving wife Carolyn, son Paul Clair and the countless people whose lives he
touched — including the children with autism who may someday benefit from his pioneering
discoveries.
Sarkis Mazmanian is the Louis & Nelly Soux Professor of Microbiology at the California Institute of
Technology in Pasadena.
Editor’s note: We, the journalists at SFARI.org, deeply miss Paul Patterson. He was persistent and
passionate in his belief that the immune system is involved in autism, but whether a paper supported
his theory or refuted it, he always made time to comment on the work. He was an avid reader of the
site, and never shied away from telling us what he thought. We fondly remember his sense of humor,
too: In November, at the Society for Neuroscience conference, he was visibly ill, but joked that his
surgical scar was the result of a scuffle with a Cell editor. “You should see the other guy,” he said,
guffawing.
News and Opinion articles on SFARI.org are editorially independent of the Simons
Foundation.
Tools for autism screening must vary with language, culture
Kate Yandell
1 August 2014
At its core, autism is the same disorder worldwide.
And ideally, it should be possible to identify it
consistently and accurately everywhere. But most
screening methods for the disorder were developed in
the U.K. and U.S., and linguistic and cultural
differences can affect their performance elsewhere.
These differences can make a real difference to
diagnosis: “Yes” answers that predict an autism
diagnosis in the original screen may not do it so well
in an adaptation.
For instance, when parents in the U.S. report that
their children are not interested in their peers, it
correlates strongly with autism. In Japan, where
expectations from children are different, the same
question does poorly at predicting autism. This may
be because Japanese parents interpret their children’s
reticence as shyness or modesty, qualities valued in
their culture, and don't consider it unusual behavior.
This is one of the many cultural differences reported
in a review of autism screens published 9 July in
Cultural contrast: Parents in Japan may view
Autism. The review analyzed 21 studies published
certain autism traits as a sign that their child is
since 2004 on the adaptation of autism screening
modest or reserved, qualities prized in Japanese
culture.
questionnaires for other cultures. These
questionnaires are given to children’s caregivers,
clinicians or teachers to identify children who might
benefit from further evaluation. In all, the review covers nine tests’ performance in 20 countries
(counting Taiwan and China as separate countries) and 10 languages.
Of the 21 studies, 12 made various types of modifications to the screening questionnaires. Sometimes,
they simply noted that caregivers around the world do not universally understand specific toys, nor do
they necessarily have names for certain games. For instance, there is no single word for peekaboo in
Mexico, so researchers translating a U.S.-developed screening questionnaire for toddlers had to first
explain the game before asking parents if their children enjoy playing it.
Other changes relate to how people in different cultures categorize information. While adapting a test
for China, for instance, researchers found that on questions to which U.S. caregivers were okay with
giving “yes” and “no” answers, their Chinese counterparts were more comfortable selecting from
answers such as “never,” “seldom,” “usually” and “often.”
The review generally assessed whether the 21 adaptations followed appropriate translation and
validation guidelines. For instance, guidelines suggest that two independent people or teams translate
the questionnaire, and then another person back-translate the questionnaire into the original
language to see if any meaning was lost. Researchers should also assess how participants react to the
translated questionnaire.
None of the 21 adaptations followed all of the guidelines perfectly, and most of them missed multiple
steps. However, it is unclear whether some of the adaptations followed guidelines but just didn’t say
so in the reports.
News and Opinion articles on SFARI.org are editorially independent of the Simons
Foundation.