Posts tagged ASD
Articles and news from the latest research reports.
Chemical Derived from Broccoli Sprouts Shows Promise in Treating Autism
Results of a small clinical trial suggest that a chemical derived from broccoli sprouts — and best known for claims that it can help prevent certain cancers — may ease classic behavioral symptoms in those with autism spectrum disorders (ASDs).
The study, a joint effort by scientists at MassGeneral Hospital for Children and the Johns Hopkins University School of Medicine, involved 40 teenage boys and young men, ages 13 to 27, with moderate to severe autism.
In a report published online in the journal Proceedings of the National Academy of Sciences during the week of Oct. 13, the researchers say that many of those who received a daily dose of the chemical sulforaphane experienced substantial improvements in their social interaction and verbal communication, along with decreases in repetitive, ritualistic behaviors, compared to those who received a placebo.
“We believe that this may be preliminary evidence for the first treatment for autism that improves symptoms by apparently correcting some of the underlying cellular problems,” says Paul Talalay, M.D., professor of pharmacology and molecular sciences, who has researched these vegetable compounds for the past 25 years.
“We are far from being able to declare a victory over autism, but this gives us important insights into what might help,” says co-investigator Andrew Zimmerman, M.D., now a professor of pediatric neurology at UMass Memorial Medical Center.
Mouse Version of an Autism Spectrum Disorder Improves When Diet Includes a Synthetic Oil
When young mice with the rodent equivalent of a rare autism spectrum disorder (ASD), called Rett syndrome, were fed a diet supplemented with the synthetic oil triheptanoin, they lived longer than mice on regular diets. Importantly, their physical and behavioral symptoms were also less severe after being on the diet, according to results of new research from The Johns Hopkins University.
(Image caption: Mitochondria (arrows) in muscle cells from mice with Rett syndrome improved in appearance after the mice were given triheptanoin oil. Top: Muscle from mice given regular food. Bottom: Muscle from mice given food supplemented with triheptanoin. Left: Healthy mice. Right: Mice with a genetic mutation that mimics Rett syndrome.)
Researchers involved in the study think that triheptanoin improved the functioning of mitochondria, energy factories common to all cells. Since mitochondrial defects are seen in other ASDs, the researchers say, the experimental results offer hope that the oil could help not just people with Rett syndrome, but also patients with other, more common ASDs.
A description of the research was published on Oct. 9 in the journal PLOS ONE.
ASDs affect an estimated one in 68 children under 8 years of age in the United States. Rett syndrome is a rare ASD caused by mutations in the MECP2 gene, which codes for methyl-CpG-binding-protein 2 (MeCP2). Rett syndrome includes autismlike signs, such as difficulty communicating, socializing and relating to others. Other hallmarks are seizures, decreased muscle tone, repetitive involuntary movements, and gastrointestinal and breathing problems. These other signs are also seen in some patients with other ASDs, suggesting underlying similarities in their causes. While the causes of most ASDs are unknown and thought to be complex, Rett syndrome is unique — and could be a source of insight for the others — because it is caused by an error in a single gene.
The research team used mice lacking the MeCP2 protein, which left them with severe Rett syndrome. In examining those mice, what stood out, according to Gabriele Ronnett, M.D., Ph.D., who led the research project at the Johns Hopkins University School of Medicine, was that they weighed the same as healthy mice but had large fat deposits accompanied by lower amounts of nonfat tissue, such as muscle. This suggested that calories were not being used to support normal tissue function but instead were being stored as fat.
This possibility led Ronnett and her research team to consider the role of mitochondria, which transform the building blocks of nutrients into a high-energy molecule, ATP. This molecule drives processes such as the building of muscle and the growth of nerve cells. Mitochondria use a series of biochemical reactions, collectively called the TCA cycle, to make this transformation possible. According to Susan Aja, Ph.D., a research associate and lead member of the research team, “If the components of the TCA cycle are low, nutrient building blocks are not processed well to create ATP. They are instead stored as fat.”
Ronnett suspected, she says, that some of Rett syndrome’s neurological symptoms could stem from metabolic deficiencies caused by faulty mitochondria and reduced energy for brain cells. “Rett syndrome becomes apparent in humans 6 to 18 months old, when the energy needs of the brain are particularly high, because a lot of new neural connections are being made,” says Ronnett. “If the mitochondria are already defective, stressed or damaged, the increased demand would be too much for them.”
Previous small clinical trials in people with a different metabolic disorder suggested that dietary intervention with triheptanoin could help. Triheptanoin is odorless, tasteless and a little thinner than olive oil. It is easily processed to produce one of the components of the TCA cycle.
When Rett syndrome mice were weaned at 4 weeks of age, they were fed a diet in which 30 percent of their calories came from triheptanoin, mixed in with their normal pelleted food. Though far from a cure, the results of the triheptanoin treatment were impressive, the researchers say. Treated mice had healthier mitochondria, improved motor function, increased social interest in other mice and lived four weeks — or 30 percent — longer than mice who did not receive the oil. The team also found that the diet normalized their body fat, glucose and fat metabolism.
“You can think of the mitochondria of the Rett syndrome model mice as damaged buckets with holes in them that allow TCA cycle components to leak out,” says Aja. “We haven’t figured out how to plug the holes, but we can keep the buckets full by providing triheptanoin to replenish the TCA cycle.”
“It is still too early to assume that this oil will work in humans with ASDs, but these results give us hope,” says Ronnett. “It’s exciting to think that we might be able to improve many ASDs without having to identify each and every contributing gene.”
According to Aja, additional mouse studies are needed to learn if female mice respond to the treatment, to perform a wider range of physiology and behavior tests, and, importantly, to assess the effects of triheptanoin treatment on the brain, which is considered the main driver of many Rett symptoms. The team would also like to provide triheptanoin at earlier ages, perhaps via the mothers’ milk, to mimic developmental ages at which most children are diagnosed with Rett syndrome.
Triheptanoin is currently made for research purposes only and is not available as a medicine or dietary supplement for humans.
(Source: hopkinsmedicine.org)
Brainwave Test Could Improve Autism Diagnosis and Classification
A new study by researchers at Albert Einstein College of Medicine of Yeshiva University suggests that measuring how fast the brain responds to sights and sounds could help in objectively classifying people on the autism spectrum and may help diagnose the condition earlier. The paper was published today in the online edition of the Journal of Autism and Developmental Disabilities.
The U.S. Centers for Disease Control and Prevention estimates that 1 in 68 children has been identified with an autism spectrum disorder (ASD). The signs and symptoms of ASD vary significantly from person to person, ranging from mild social and communication difficulties to profound cognitive impairments.
“One of the challenges in autism is that we don’t know how to classify patients into subgroups or even what those subgroups might be,” said study leader Sophie Molholm, Ph.D., associate professor in the Dominick P. Purpura Department of Neuroscience and the Muriel and Harold Block Faculty Scholar in Mental Illness in the department of pediatrics at Einstein. “This has greatly limited our understanding of the disorder and how to treat it.”
Autism is diagnosed based on a patient’s behavioral characteristics and symptoms. “These assessments can be highly subjective and require a tremendous amount of clinical expertise,” said Dr. Molholm. “We clearly need a more objective way to diagnose and classify this disorder.”
An earlier study by Dr. Molholm and colleagues suggested that brainwave electroencephalogram (EEG) recordings could potentially reveal how severely ASD individuals are affected. That study found that children with ASD process sensory information—such as sound, touch and vision—less rapidly than typically developing children do.
The current study was intended to see whether sensory processing varies along the autism spectrum. Forty-three ASD children aged 6 to 17 were presented with either a simple auditory tone, a visual image (red circle), or a tone combined with an image, and instructed to press a button as soon as possible after hearing the tone, seeing the image or seeing and hearing the two stimuli together. Continuous EEG recordings were made via 70 scalp electrodes to determine how fast the children’s brains were processing the stimuli.
The speed with which the subjects processed auditory signals strongly correlated with the severity of their symptoms: the more time required for an ASD individual to process the auditory signals, the more severe that person’s autistic symptoms. “This finding is in line with studies showing that, in people with ASD, the microarchitecture in the brain’s auditory center differs from that of typically developing children,” Dr. Molholm said.
The study also found a significant though weaker correlation between the speed of processing combined audio-visual signals and ASD severity. No link was observed between visual processing and ASD severity.
“This is a first step toward developing a biomarker of autism severity—an objective way to assess someone’s place on the ASD spectrum,” said Dr. Molholm. “Using EEG recordings in this way might also prove useful for objectively evaluating the effectiveness of ASD therapies.”
In addition, EEG recordings might help diagnose ASD earlier. “Early diagnosis allows for earlier treatment—which we know increases the likelihood of a better outcome,” said Dr. Molholm. “But currently, fewer than 15 percent of children with ASD are diagnosed before age 4. We might be able to adapt this technology to allow for early ASD detection and therapy for a much larger percentage of children.”
Estrogen receptor expression may help explain why more males have autism
The same sex hormone that helps protect females from stroke may also reduce their risk of autism, scientists say.
In the first look at a potential role of the female sex hormone in autism, researchers at the Medical College of Georgia at Georgia Regents University have found expression of estrogen receptor beta – which enables estrogen’s potent brain protection – is significantly decreased in autistic brains. The receptor also plays a role in locomotion as well as behavior, including anxiety, depression, memory, and learning.
"If you ask any psychiatrist seeing patients with autistic behavior their most striking observation from the clinic, they will say there are more males compared to females," said Dr. Anilkumar Pillai, MCG neuroscientist and corresponding author of the study in Molecular Autism.
Estrogen is known to help protect premenopausal women from maladies such as stroke and impaired cognition. Exposure to high levels of the male hormone testosterone during early development has been linked to autism, which is five times more common in males than females.
The new findings of reduced expression of estrogen receptor beta as well as that of an enzyme that converts testosterone to estrogen could help explain the high testosterone levels in autistic individuals and higher autism rates in males, Pillai said.
It was the 5-to-1 male-to-female ratio along with the testosterone hypothesis that led Pillai and his colleagues to pursue whether estrogen might help explain the significant gender disparity and possibly point toward a new treatment.
"The testosterone hypothesis is already there, but nobody had investigated whether it had anything to do with the female hormone in the brain," Pillai said. "Estrogen is known to be neuroprotective, but nobody has looked at whether its function is impaired in the brain of individuals with autism. We found that the children with autism didn’t have sufficient estrogen receptor beta expression to mediate the protective benefits of estrogen."
Comparing the brains of 13 children with and 13 children without autism spectrum disorder, the researchers found a 35 percent decrease in estrogen receptor beta expression as well as a 38 percent reduction in the amount of aromatase, the enzyme that converts testosterone to estrogen.
Levels of estrogen receptor beta proteins, the active molecules that result from gene expression and enable functions like brain protection, were similarly low. There was no discernable change in expression levels of estrogen receptor alpha, which mediates sexual behavior.
The study focused on the brain’s prefrontal cortex, which is involved in social behavior and cognition. Brain tissue from both autistic and healthy subjects was obtained from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Brain and Tissue Bank for Developmental Disorders at the University of Maryland. The children died at an average age of 11 from drowning, other accidents, or suicide. All the brain tissue was from male children except for one control.
While much work remains, estrogen receptor beta agonists, which are already known to improve brain plasticity and memory in animals, might one day help reverse autism’s behavioral deficits, such as reclusiveness and repetitive behavior, Pillai said.
The scientists already are moving to animal studies to see what happens when they reduce estrogen receptor beta expression in mice. They also plan to give an estrogen receptor beta agonist – which should increase receptor function – to a mouse with generalized inflammation and signs of autism to see if it mitigates those signs. Inflammation is a factor in many diseases of the brain and body, and estrogen receptor beta agonists already are in clinical trials for schizophrenia
Larger, follow-up studies should also include comparing expression of testosterone receptor levels in healthy and autistic children, Pillai said. MCG scientists also want to know more about why the reduced beta receptor expression occurs.
Studies published in the journal Molecular Psychiatry earlier this year by scientists at the University of Cambridge and Denmark’s Statens Serum Institute showed that male children who develop autism were exposed to higher levels of steroid hormones, including testosterone and progesterone, during development than their healthy peers.
The incidence of autism has increased about 30 percent in the past two years in the United States, to the current rate of about 1 in 68 children, according to the Centers for Disease Control and Prevention. Most children are diagnosed at about age 4, although the disorder can be diagnosed by about age 2, according to the CDC. Diagnosis is made through extensive behavioral and psychological testing.
(Source: eurekalert.org)
Are Three Brain Imaging Techniques Better than One?
Many recent imaging studies have shown that in children with autism, different parts of the brain do not connect with each other in typical ways. Initially, most researchers thought that the autistic brain has fewer connections between key regions. The most recent studies, however, point to an opposite conclusion: The brains of people with autism exhibit overconnectivity.
To date, almost all studies of autism in children have used a single imaging technique to explore connectivity. None has been able to capture a robust picture of the brain abnormalities associated with autism—until now.
Two new grants from the National Institute of Mental Health (NIMH) will allow San Diego State University Psychology Professor Ralph-Axel Müller to combine three imaging techniques and harness the best of each one in his study of autism.
Techniques in tandem
Although the term “brain imaging” gets thrown around a lot when describing the latest advances in neuroscience and psychology, there are dozens of different brain imaging techniques. Each gives scientists a different view of the inner workings of the brain, and each comes with its own strengths and limitations.
For example, the frequently cited technique of fMRI, or functional magnetic resonance imaging, measures blood flow in different areas of the brain at specific snapshots in time, based on the knowledge that increased blood flow indicates increased activity of nerve cells in that area of the brain. The technique is powerful, but has limitations when it comes to detecting dynamic changes in brain activity that occur very fast, within milliseconds.
EEG (electroencephalography), a much older technique, is actually better at detecting such dynamic changes, although it cannot pinpoint exactly where in the brain the activity occurs. A powerful and more recent technique is MEG, or magnetoencephalography, which can detect dynamic changes in brain activity that happen within a few milliseconds.
Müller looks for disorganized patterns of brain activity that could be responsible for some of the telltale characteristics of autism spectrum disorder, such as inattention to social cues and repetitive and obsessive behaviors. For example, last year, Müller and his colleagues discovered that in children with autism, connectivity was impaired between the cerebral cortex and the thalamus, a deep brain structure that is important for sensorimotor functions and attention.
With $4.2 million in new funding from NIH, Müller—together with collaborators Ksenija Marinkovic at SDSU and Thomas Liu at the University of California, San Diego—will apply fMRI, EEG, and MEG to study both autistic and non-autistic, or typically-developing, children and adolescents during a variety of tests, including language tests designed to tease out activity in various parts of the brain.
Defining the differences
One component of the project will concern the visual system. Previous research has shown that people with autism rely on their visual cortex more than typically- developing people during thought processes, for example, when making a semantic distinction, such as deciding whether a truck is a vehicle. Using the one-two punch of fMRI and MEG together, Müller and his team will be able to determine the dynamic processes in how brain regions work together to come up with a response, and how these processes differ in autism.
The study will also examine brain function during its resting state in order to identify abnormalities in brain network organization. The combined use of EEG and MEG, together with fMRI techniques that reveal brain anatomy, will produce a much more complete picture of abnormal brain organization in autism.
Ultimately, Müller and his colleagues hope to identify biomarkers in the brain that can reliably indicate whether the participant falls on the autism spectrum.
“Autism is a brain-based disorder, but its diagnosis is still based entirely on behavioral observation,” Müller said. “This is inadequate. We need to find brain biomarkers for autism.”
Another goal of the researchers is to find brain biomarkers that can distinguish different subtypes of autism. It is generally suspected that the term “autism” actually covers several different disorders, each of which may be caused by different genetic and environmental risk factors. Eventually, brain biomarkers might be tied to genetic data, giving scientists a better understanding of the origins of autism, as well as new leads for treatment.
“For decades, research teams studying autism have specialized in one or another scientific technique, often without understanding well what other techniques can reveal. Our study combining several of the major imaging techniques will be one step toward a more comprehensive account of how the autistic brain differs from the typically developing one – and what may be done about it,” Müller said.
(Image caption: In a study of brains from children with autism, neurons in brains from autistic patients did not undergo normal pruning during childhood and adolescence. The images show representative neurons from unaffected brains (left) and brains from autistic patients (right); the spines on the neurons indicate the location of synapses. Credit: Guomei Tang, PhD and Mark S. Sonders, PhD/Columbia University Medical Center)
Children with Autism Have Extra Synapses in Brain
Children and adolescents with autism have a surplus of synapses in the brain, and this excess is due to a slowdown in a normal brain “pruning” process during development, according to a study by neuroscientists at Columbia University Medical Center (CUMC). Because synapses are the points where neurons connect and communicate with each other, the excessive synapses may have profound effects on how the brain functions. The study was published in the August 21 online issue of the journal Neuron.
A drug that restores normal synaptic pruning can improve autistic-like behaviors in mice, the researchers found, even when the drug is given after the behaviors have appeared.
“This is an important finding that could lead to a novel and much-needed therapeutic strategy for autism,” said Jeffrey Lieberman, MD, Lawrence C. Kolb Professor and Chair of Psychiatry at CUMC and director of New York State Psychiatric Institute, who was not involved in the study.
Although the drug, rapamycin, has side effects that may preclude its use in people with autism, “the fact that we can see changes in behavior suggests that autism may still be treatable after a child is diagnosed, if we can find a better drug,” said the study’s senior investigator, David Sulzer, PhD, professor of neurobiology in the Departments of Psychiatry, Neurology, and Pharmacology at CUMC.
During normal brain development, a burst of synapse formation occurs in infancy, particularly in the cortex, a region involved in autistic behaviors; pruning eliminates about half of these cortical synapses by late adolescence. Synapses are known to be affected by many genes linked to autism, and some researchers have hypothesized that people with autism may have more synapses.
To test this hypothesis, co-author Guomei Tang, PhD, assistant professor of neurology at CUMC, examined brains from children with autism who had died from other causes. Thirteen brains came from children ages two to 9, and thirteen brains came from children ages 13 to 20. Twenty-two brains from children without autism were also examined for comparison.
Dr. Tang measured synapse density in a small section of tissue in each brain by counting the number of tiny spines that branch from these cortical neurons; each spine connects with another neuron via a synapse.
By late childhood, she found, spine density had dropped by about half in the control brains, but by only 16 percent in the brains from autism patients.
“It’s the first time that anyone has looked for, and seen, a lack of pruning during development of children with autism,” Dr. Sulzer said, “although lower numbers of synapses in some brain areas have been detected in brains from older patients and in mice with autistic-like behaviors.”
Clues to what caused the pruning defect were also found in the patients’ brains; the autistic children’s brain cells were filled with old and damaged parts and were very deficient in a degradation pathway known as “autophagy.” Cells use autophagy (a term from the Greek for self-eating) to degrade their own components.
Using mouse models of autism, the researchers traced the pruning defect to a protein called mTOR. When mTOR is overactive, they found, brain cells lose much of their “self-eating” ability. And without this ability, the brains of the mice were pruned poorly and contained excess synapses. “While people usually think of learning as requiring formation of new synapses, “Dr. Sulzer says, “the removal of inappropriate synapses may be just as important.”
The researchers could restore normal autophagy and synaptic pruning—and reverse autistic-like behaviors in the mice—by administering rapamycin, a drug that inhibits mTOR. The drug was effective even when administered to the mice after they developed the behaviors, suggesting that such an approach may be used to treat patients even after the disorder has been diagnosed.
Because large amounts of overactive mTOR were also found in almost all of the brains of the autism patients, the same processes may occur in children with autism.
“What’s remarkable about the findings,” said Dr. Sulzer, “is that hundreds of genes have been linked to autism, but almost all of our human subjects had overactive mTOR and decreased autophagy, and all appear to have a lack of normal synaptic pruning. This says that many, perhaps the majority, of genes may converge onto this mTOR/autophagy pathway, the same way that many tributaries all lead into the Mississippi River. Overactive mTOR and reduced autophagy, by blocking normal synaptic pruning that may underlie learning appropriate behavior, may be a unifying feature of autism.”
Alan Packer, PhD, senior scientist at the Simons Foundation, which funded the research, said the study is an important step forward in understanding what’s happening in the brains of people with autism.
“The current view is that autism is heterogeneous, with potentially hundreds of genes that can contribute. That’s a very wide spectrum, so the goal now is to understand how those hundreds of genes cluster together into a smaller number of pathways; that will give us better clues to potential treatments,” he said.
“The mTOR pathway certainly looks like one of these pathways. It is possible that screening for mTOR and autophagic activity will provide a means to diagnose some features of autism, and normalizing these pathways might help to treat synaptic dysfunction and treat the disease.”
Autism rates steady for two decades
A University of Queensland study has found no evidence of an increase in autism in the past 20 years, countering reports that the rates of autism spectrum disorders (ASDs) are on the rise.
The study, led by Dr Amanda Baxter from UQ’s Queensland Centre for Mental Health Research at the School of Population Health, was a first-of-its-kind analysis of research data from 1990 to 2010.
Dr Baxter said she and her colleagues found that rates had remained steady, despite reports that the prevalence of ASDs was increasing.
“We found that the prevalence of ASDs in 2010 was one in 132 people, which represents no change from 1990,” Dr Baxter said.
“We found that better recognition of the disorders and improved diagnostic criteria explain much of the difference in study findings over time.”
Part of the Global Burden of Disease project, this is the largest study to systematically assess rates and disability caused by ASDs in the community, using data collected from global research findings in the past 20 years.
ASDs are chronic, disabling disorders that stem from problems with brain development.
They affect people from a young age and are among the world’s 20 most disabling childhood conditions.
The study shows that about 52 million children and adults around the globe meet diagnostic criteria for an ASD.
Dr Baxter said researchers hoped the study would help guide health policy and improve support for those with ASD and their families.
“As ASDs cause substantial lifelong health issues, an accurate understanding of the burden of these disorders can inform public health policy as well as help allocate necessary resources for education, housing and employment,” she said.
The study, a collaboration with the University of Leicester and the University of Washington’s Institute for Health Metrics and Evaluation, is published in Psychological Medicine journal.
(Source: uq.edu.au)
Study Links Autistic Behaviors to Enzyme
Fragile X syndrome (FXS) is a genetic disorder that causes obsessive-compulsive and repetitive behaviors, and other behaviors on the autistic spectrum, as well as cognitive deficits. It is the most common inherited cause of mental impairment and the most common cause of autism.
Now biomedical scientists at the University of California, Riverside have published a study that sheds light on the cause of autistic behaviors in FXS. Appearing online today (July 23) in the Journal of Neuroscience, and highlighted also on the cover in this week’s print issue of the journal, the study describes how MMP-9, an enzyme, plays a critical role in the development of autistic behaviors and synapse irregularities, with potential implications for other autistic spectrum disorders.
MMP-9 is produced by brain cells. Inactive, it is secreted into the spaces between cells of the brain, where it awaits activation. Normal brains have quite a bit of inactive MMP-9, and the activation of small amounts has significant effects on the connections between neurons, called synapses. Too much MMP-9 activity causes synapses in the brain to become unstable, leading to functional deficits.
“Our study targets MMP-9 as a potential therapeutic target in Fragile X and shows that genetic deletion of MMP-9 favorably impacts key aspects of FXS-associated anatomical alterations and behaviors in a mouse model of Fragile X,” said Iryna Ethell, a professor of biomedical sciences in the UC Riverside School of Medicine, who co-led the study. “We found that too much MMP-9 activity causes synapses to become unstable, which leads to functional deficits that depend on where in the brain that occurs.”
Ethell explained that mutations in FMR1, a gene, have been known for more than a decade to cause FXS, but until now it has been unclear how these mutations cause unstable synapses and characteristic physical features of this disorder. The new findings expand on earlier work by the research group that showed that an MMP-9 inhibitor, minocycline, can reduce behavioral aspects of FXS, which then led to its use to treat FXS.
To further establish a causative role for MMP-9 in the development of FXS-associated features, including autistic behaviors, the authors generated mice that were missing both FMR1 and MMP-9. They found that while mice with a single FMR1 mutation showed autistic behaviors and macroorchidism (abnormally large testes), mice that also lacked MMP-9 showed no autistic behaviors.
“Our work points directly to MMP-9 over-activation as a cause for synaptic irregularities in FXS, with potential implications for other autistic spectrum disorders and perhaps Alzheimer’s disease,” said Doug Ethell, the head of Molecular Neurobiology at the Western University of Health Sciences, Pomona, Calif., and a coauthor on the study.
The research paper represents many years of bench work and effort by a dedicated team led by the Ethells. The work was primarily done in mice, but human tissue samples were also analyzed, with findings found to be consistent. Specifically, the work involved assessing behaviors, biochemistry, activity and anatomy of synaptic connections in the brain of a mouse model of FXS, as well as the creation of a new mouse line that lacked both the FXS gene and MMP-9.
FXS affects both males and females, with females often having milder symptoms than males. It is estimated that about 1 in 5,000 males are born with the disorder.
The Ethells were joined in the study by UCR’s Harpreet Sidhu (first author of the research paper), Lorraine E. Dansie, and Peter Hickmott. Sidhu and Dansie are neuroscience graduate students; Hickmott is an associate professor of psychology.
Next, the researchers plan to understand how MMP-9 regulates synapse stability inside the neurons. They also plan to find drugs that specifically target MMP-9 without side effects such as new tetracycline derivatives that are potent inhibitors of MMP-9 but lack antibiotic properties.
“Although minocycline was successfully used in clinical trial in FXS, it has some side effects associated with its antibiotic properties, such gastrointestinal irritation,” Iryna Ethell said. “We, therefore, plan to test new non-antibiotic minocycline derivatives. These compounds lack antibiotic activity but still act as non-competitive inhibitors of MMP-9 similar to minocycline.”
Study finds association between maternal exposure to agricultural pesticides, autism in offspring
Pregnant women who lived in close proximity to fields and farms where chemical pesticides were applied experienced a two-thirds increased risk of having a child with autism spectrum disorder or other developmental delay, a study by researchers with the UC Davis MIND Institute has found. The associations were stronger when the exposures occurred during the second and third trimesters of the women’s pregnancies.
The large, multisite California-based study examined associations between specific classes of pesticides, including organophosphates, pyrethroids and carbamates, applied during the study participants’ pregnancies and later diagnoses of autism and developmental delay in their offspring. It is published online today in Environmental Health Perspectives.
“This study validates the results of earlier research that has reported associations between having a child with autism and prenatal exposure to agricultural chemicals in California,” said lead study author Janie F. Shelton, a UC Davis graduate student who now consults with the United Nations. “While we still must investigate whether certain sub-groups are more vulnerable to exposures to these compounds than others, the message is very clear: Women who are pregnant should take special care to avoid contact with agricultural chemicals whenever possible.”
California is the top agricultural producing state in the nation, grossing $38 billion in revenue from farm crops in 2010. Statewide, approximately 200 million pounds of active pesticides are applied each year, most of it in the Central Valley, north to the Sacramento Valley and south to the Imperial Valley on the California-Mexico border. While pesticides are critical for the modern agriculture industry, certain commonly used pesticides are neurotoxic and may pose threats to brain development during gestation, potentially resulting in developmental delay or autism.
The study was conducted by examining commercial pesticide application using the California Pesticide Use Report and linking the data to the residential addresses of approximately 1,000 participants in the Northern California-based Childhood Risk of Autism from Genetics and the Environment (CHARGE) Study. The study includes families with children between 2 and 5 diagnosed with autism or developmental delay or with typical development. It is led by principal investigator Irva Hertz-Picciotto, a MIND Institute researcher and professor and vice chair of the Department of Public Health Sciences at UC Davis. The majority of study participants live in the Sacramento Valley, Central Valley and the greater San Francisco Bay Area.
Twenty-one chemical compounds were identified in the organophosphate class, including chlorpyrifos, acephate and diazinon. The second most commonly applied class of pesticides was pyrethroids, one quarter of which was esfenvalerate, followed by lambda-cyhalothrin permethrin, cypermethrin and tau-fluvalinate. Eighty percent of the carbamates were methomyl and carbaryl.
For the study, researchers used questionnaires to obtain study participants’ residential addresses during the pre-conception and pregnancy periods. The addresses then were overlaid on maps with the locations of agricultural chemical application sites based on the pesticide-use reports to determine residential proximity. The study also examined which participants were exposed to which agricultural chemicals.
“We mapped where our study participants’ lived during pregnancy and around the time of birth. In California, pesticide applicators must report what they’re applying, where they’re applying it, dates when the applications were made and how much was applied,” Hertz-Picciotto said. “What we saw were several classes of pesticides more commonly applied near residences of mothers whose children developed autism or had delayed cognitive or other skills.”
The researchers found that during the study period approximately one-third of CHARGE Study participants lived in close proximity – within 1.25 to 1.75 kilometers – of commercial pesticide application sites. Some associations were greater among mothers living closer to application sites and lower as residential proximity to the application sites decreased, the researchers found.
Organophosphates applied over the course of pregnancy were associated with an elevated risk of autism spectrum disorder, particularly for chlorpyrifos applications in the second trimester. Pyrethroids were moderately associated with autism spectrum disorder immediately prior to conception and in the third trimester. Carbamates applied during pregnancy were associated with developmental delay.
Exposures to insecticides for those living near agricultural areas may be problematic, especially during gestation, because the developing fetal brain may be more vulnerable than it is in adults. Because these pesticides are neurotoxic, in utero exposures during early development may distort the complex processes of structural development and neuronal signaling, producing alterations to the excitation and inhibition mechanisms that govern mood, learning, social interactions and behavior.
“In that early developmental gestational period, the brain is developing synapses, the spaces between neurons, where electrical impulses are turned into neurotransmitting chemicals that leap from one neuron to another to pass messages along. The formation of these junctions is really important and may well be where these pesticides are operating and affecting neurotransmission,” Hertz-Picciotto said.
Research from the CHARGE Study has emphasized the importance of maternal nutrition during pregnancy, particularly the use of prenatal vitamins to reduce the risk of having a child with autism. While it’s impossible to entirely eliminate risks due to environmental exposures, Hertz-Picciotto said that finding ways to reduce exposures to chemical pesticides, particularly for the very young, is important.
“We need to open up a dialogue about how this can be done, at both a societal and individual level,” she said. “If it were my family, I wouldn’t want to live close to where heavy pesticides are being applied.”
(Source: ucdmc.ucdavis.edu)
Groundbreaking model explains how the brain learns to ignore familiar stimuli
A neuroscientist from Trinity College Dublin has proposed a new, ground-breaking explanation for the fundamental process of ‘habituation’, which has never been completely understood by neuroscientists.
Typically, our response to a stimulus is reduced over time if we are repeatedly exposed to it. This process of habituation enables organisms to identify and selectively ignore irrelevant, familiar objects and events that they encounter again and again. Habituation therefore allows the brain to selectively engage with new stimuli, or those that it ‘knows’ to be relevant. For example, the unusual sensation created by a spider walking over our skin should elicit an appropriate evasive response, but the touch of a shirt or blouse on the same skin should be functionally ignored by the nervous system. If habituation does not occur, then such unimportant stimuli become distracting, which means that complex environments can become overwhelming.
The new perspective on the way habituation occurs has implications for our understanding of neuropsychiatric conditions, because normal habituation, emotional responses and attentional abilities are altered in several of these conditions. In particular, hypersensitivity to complex environments is common in individuals on the autism spectrum.
Habituation has long been recognised as the most fundamental form of learning, but it has never been satisfactorily explained. In a Perspective article just published in the leading international journal Neuron (embargoed copy), Professor of Neurogenetics in the School of Genetics & Microbiology at Trinity, Mani Ramaswami, explains habituation through what he terms the ‘negative-image model’. The model proposes and explains how a repeated activation of any group of neurons that respond to a given stimulus results in the build-up of ‘negative activation’, which inhibits responses from this same group of cells.
For example, the first view of an unfamiliar and scary face can trigger a fearful response. However after multiple exposures, the group of neurons activated by the face is less effective at activating fear centres because of increased inhibition on this same group of neurons. Significantly, a strong response to new faces persists for much longer in people on the autism spectrum. This matched increase in inhibition (the ‘negative image’), proposed to underlie habituation, is not normally consciously perceived but it can be revealed under particular conditions (see accompanying video for a visual example here).
Professor Ramaswami said: “This Perspective outlines scalable circuit mechanisms that can account for habituation to stimuli encoded by very small or very large assemblies of neurons. Its strength is its simplicity, its basis in experimental data, and its ability to explain many features of habituation. However, more high-quality studies of habituation mechanisms will be required to establish its generality.”
Professor of Experimental Brain Research at Trinity, and Director of the Trinity College Institute for Neuroscience, Shane O’Mara, said: “The arguments and ideas expressed by Professor Ramaswami should lead to additions and changes to our current text-book sections on habituation, which is a process of great relevance to cognition, attention and psychiatric disease. It is possible that highlighting the process of negative image formation as crucial for habituation will prove useful to clinical genetic studies of autism, by helping to place diverse autism susceptibility genes in a common biological pathway.”
(Source: eurekalert.org)