Thursday, August 21, 2014

Children with autism have extra synapses in brain

In a study of brains from children with autism, researchers found that autistic brains did not undergo normal pruning during childhood and adolescence. 

The images show representative neurons from autistic (left) and control (right) brains; the spines on the neurons indicate the location of synapses.

Credit: Guomei Tang, PhD and Mark S. Sonders, PhD/Columbia University Medical Center

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 behaviours 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 behaviour 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.

David Sulzer
During normal brain development, a burst of synapse formation occurs in infancy, particularly in the cortex, a region involved in autistic behaviours; 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 behaviours."

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 behaviour, 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."

Journal Reference: 
Guomei Tang, Kathryn Gudsnuk, Sheng-Han Kuo, Marisa L. Cotrina, Gorazd Rosoklija, Alexander Sosunov, Mark S. Sonders, Ellen Kanter, Candace Castagna, Ai Yamamoto, Zhenyu Yue, Ottavio Arancio, Bradley S. Peterson, Frances Champagne, Andrew J. Dwork, James Goldman, David Sulzer. "Loss of mTOR-Dependent Macroautophagy Causes Autistic-like Synaptic Pruning Deficits." Neuron, 2014; DOI: 10.1016/j.neuron.2014.07.040

ADHD children make poor decisions due to less differentiated learning processes

Attention-Deficit/Hyperactivity Disorder (ADHD) is one of the most common psychiatric disorders among school children. Pupils with ADHD often make poorer decisions than their unaffected classmates.

Researchers from the University of Zurich now discovered that different learning and decision-making mechanisms are responsible for these behaviors, and localized the underlying impairments in the brain.

Which shirt do we put on in the morning? Do we drive to work or take the train? From which takeaway joint do we want to buy lunch?

We make hundreds of different decisions every day. Even if these often only have a minimal impact, it is extremely important for our long-term personal development to make decisions that are as optimal as possible.

People with ADHD often find this difficult, however. They are known to make impulsive decisions, often choosing options which bring a prompt but smaller reward instead of making a choice that yields a greater reward later on down the line.

Researchers from the University Clinics for Child and Adolescent Psychiatry, University of Zurich, now reveal that different decision-making processes are responsible for such suboptimal choices and that these take place in the middle of the frontal lobe.

Mathematical models help to understand the decision-making processes
In the study, the decision-making processes in 40 young people with and without ADHD were examined.

Lying in a functional magnetic resonance imaging (fMRI) scanner to record the brain activity, the participants played a game where they had to learn which of two images carried more frequent rewards.

To understand the impaired mechanisms of participants with ADHD better, learning algorithms which originally stemmed from the field of artificial intelligence were used to evaluate the data.

These mathematical models help to understand the precise learning and decision-making mechanisms better.

"We were able to demonstrate that young people with ADHD do not inherently have difficulties in learning new information; instead, they evidently use less differentiated learning patterns, which is presumably why sub-optimal decisions are often made", says first author Tobias Hauser.

Multimodal imaging affords glimpses inside the brain
To study the brain processes that triggered these impairments, the authors used multimodal imaging methods, where the participants were examined using a combined measurement of functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) to record the electrical activity and the blood flow in the brain.

It became apparent that participants with ADHD exhibit an altered functioning in the medial prefrontal cortex, a region in the middle of the frontal lobe.

This part of the brain is heavily involved in decision-making processes, especially if you have to choose between several options, and in learning from errors.

Although a change in activity in this region was already discovered in other contexts for ADHD, the Zurich researchers were now also able to pinpoint the precise moment of this impairment, which already occurred less than half a second after a feedback, i.e. at a very early stage.

Psychologist Tobias Hauser, who is now researching at the Wellcome Trust Centre for Neuroimaging, University College London, is convinced that the results fundamentally improve our understanding of the mechanisms of impaired decision-making behaviour in people with ADHD.

The next step will be to study the brain messenger substances. "If our findings are confirmed, they will provide key clues as to how we might be able to design therapeutic interventions in future," explains Hauser.

More information: Tobias U. Hauser, Reto Iannaccone, Juliane Ball, Christoph Mathys, Daniel Brandeis, Susanne Walitza & Silvia Brem: Role of Medial Prefrontal "Cortex in Impaired Decision Making in Juvenile Attention-Deficit/Hyperactivity Disorder," in: JAMA Psychiatry, DOI: 10.1001/jamapsychiatry.2014.1093

Wednesday, August 20, 2014

Autism: ASU experts follow gut reaction in digestion treatment study

Clostridium difficile in the gut. The overgrowth of this dangerous bacteria can cause serious, life-threatening infections. 

About half of all children and adults with autism suffer from chronic gastrointestinal problems, causing frequent pain, discomfort and irritability.

Research out of Arizona State University suggests these gastrointestinal (GI) complications may be due, in part, to abnormal gut bacteria.

A new study approved by the U.S. Food and Drug Administration and led by Arizona State University will examine a novel treatment, called fecal microbiota transplant (FMT), for GI problems in children with autism.

The treatment involves transferring about 1,000 different species of live gut bacteria from a healthy donor that then act like a broad-spectrum probiotic treatment to restore normal gut bacteria.

FMT has been used to treat serious Clostrium difficle infections that kill up to 15,000 people each year in the United States.

Determining the safety and tolerability of using FMT to treat GI problems in children with autism is driving the study.

The FDA has approved a pilot treatment study of 20 children with autism, ages 7 to 17 years, and moderate to severe gastrointestinal problems.

Missing bacteria
Led by professor Rosa Krajmalnik-Brown, an expert on evaluating the composition of gut bacterial communities, and professor James Adams, director of the ASU Autism/Asperger's Research Program, the ASU research team published a scientific paper last year demonstrating that children with autism were missing several hundred species of gut bacteria compared to typical children.

"Our initial work found major differences in the gut bacteria of children with autism compared to typical children, and our subsequent work has confirmed those findings," said Krajmalnik-Brown.

"Children with autism seem to be missing hundreds of beneficial gut bacteria."

"Many children and adults with autism have chronic gut problems, sometimes lasting for many years and seriously affecting their quality of life," said Adams. "We think this treatment may be helpful."

The team's hypothesis is that FMT will "reseed" the gut with beneficial bacteria that will help diminish GI problems and possibly reduce autistic symptoms.

Several studies show that FMT may also be helpful in treating other GI problems, such as ulcerative colitis, Crohn's disease, inflammatory bowel disease, irritable bowel syndrome and chronic constipation.

Beneficial versus harmful
The human gut typically contains more than 1,000 different species of bacteria – most of them beneficial.

These bacteria help with digesting food, making certain vitamins, improving GI function and protecting against pathogenic bacteria.

However, there are a few dangerous bacteria, such as Clostidium difficile (C. difficile), which can cause serious, life-threatening infections.

C. difficile kills about 15,000 people per year in the U.S., but a single dose of FMT has been shown to cure C. difficile with 92 percent effectiveness, usually within a few days.

Collaborating with Northern Arizona University and University of Arizona, the ASU team will lead the treatment portion of the study, with the help of Sharon McDonough-Means, a developmental pediatrician involved in the care of children with autism and previous research studies.

Greg Caporaso at NAU, an expert in computational and statistical methods for studying communities of microorganisms, will analyze the effect of FMT on gut bacterial communities, and Matthew Sullivan at UA will investigate the viruses that infect gut bacteria, and thereby affect bacterial populations in the gut.

The new initiative is a follow-up to a previous study that demonstrated that treatment with a powerful oral antibiotic, vancomycin, led to a temporary improvement in both gut symptoms and symptoms of autism, presumably because it killed off harmful bacteria in the gut.

However, when the treatment was stopped, the benefits were lost, presumably because there was insufficient "reseeding" of the gut with beneficial bacteria.

Monday, August 18, 2014

The boundaries of reading apps for children

A series of binary discussions has been plaguing early reading instruction for quite some time now: phonics versus whole language, reading for pleasure versus reading for learning, digital versus paper books and it seems that there is a new tug-of-war on the educational horizon: spritzing versus slow reading.

Spritz is a recently developed programme that brings speed-reading to the untrained eye. Its makers claim that users can ultimately read 1,000 words per minute.

Their goal is to have 15% of the world's texts available in Spritz format by 2016.

But a message is coming from the other direction too. Those who revere and often romanticise printed books argue that we need to slow down.

They warn that the digital age has made us shallow readers who flit from text to text without taking anything in.

We have a clear conflict here. On one hand, lots of people want to read faster, especially now that there is more to read out there than at any other time in human history.

On the other hand, we hear that children in the digital age do not read in depth and the often cited culprit is the device in their hand – the technology that distracts them from picking up a good book.

Is a middle ground possible?

Reading and writing always come hand-in-hand. If readers whizz through rather than engage with texts, this will ultimately be reflected in the type of texts made available to them.

Spritz certainly responds to the zeitgeist to read fast in order to cope in a text-saturated era. You can also see this tendency in the proliferation of listicles on news websites and contents pages that tell you how long it will take you to read an article.

Some say that the only way to cope with large email volumes, is to binge-read our inboxes. Spritz could be thus seen as another invention that panders to our growing tendency to read more but in less depth.

At the same time, readers, be they young or old,need to be given time to pause and think with the author of a text.

Slow reading is, for many, synonymous with deep reading and reading for learning and there are in fact technological developments happening to help readers improve their deep reading, almost the antidote to Spritz.

There are reading annotation systems with built-in interactive discussion to help readers, students in particular, to better understand what they are reading.

These slow them down in their reading by asking them questions or prompting them to pause and take notes.

Similarly for younger readers, there are read-to-learn apps that explain vocabulary and thus help with reading comprehension.

So which approach is better for the contemporary reader? We can now whizz through every page on the internet by installing Spritzlet on our web browser.

It may not be long until slow reading widgets will become available to help us highlight information in onscreen texts, underline unfamiliar words, unpick abstract metaphors and provide links to facts.

In thinking about how to teach children to read effectively in digital age, we need to stop thinking in terms of slow and fast.

There is a difference between reading an email or a chemistry textbook or a novel. We use different reading formats for different contents, and different contents & formats for different purposes.

These different purposes come with different personal investments and hence different reading techniques.

There is already a disturbing disconnect between the content and format of reading happening in schools and outside the classrooms. Let's not increase this gap with another fictitious dichotomy.

Tuesday, August 5, 2014

Children with Autism: Blood-oxytocin levels in normal range

Spacefilling model of oxytocin. Created using ACD/ChemSketch 8.0, ACD/3D Viewer and The GIMP. 

Credit: Wikipedia.

Autism does not appear to be solely caused by a deficiency of oxytocin, but the hormone's universal ability to boost social function may prove useful in treating a subset of children with the developmental disorder, according to new findings from the Stanford University School of Medicine and Lucile Packard Children's Hospital Stanford.

Low levels of oxytocin, a hormone involved in social functioning, have for years been suspected of causing autism. Prior research seeking a link has produced mixed results.

Now, in the largest-ever study to test the purported connection, the range of blood oxytocin levels has been shown to be the same in children with autism as that observed in two comparison groups: children with autistic siblings and children without autistic siblings.

In other words, similar numbers of children with low, medium and high oxytocin levels were found in all three groups.

A paper describing the new findings will be published online Aug. 4 in Proceedings of the National Academy of Sciences (PNAS).

Although autism was not directly linked to oxytocin deficiency, the Stanford team found that higher oxytocin levels were linked to better social functioning in all groups.

All children with autism have social deficits, but in the study these deficits were worst in those with the lowest blood oxytocin and mildest in those with the highest oxytocin.

In the comparison groups, children's social skills also fell across a range that correlated to their oxytocin levels.

"Oxytocin appears to be a universal regulator of social functioning in humans," said Karen Parker, PhD, assistant professor of psychiatry and behavioural sciences and the lead author of the study.

"That encompasses both typically developing children as well as those with the severe social deficits we see in children with autism."

Autism is a developmental disorder that affects 1 of every 68 children in the United States. It is characterised by social and communication deficits, repetitive behaviours and sensory problems.

The new study included 79 children with autism, 52 of their unaffected siblings and 62 unrelated children without autism. All of the children were between the ages of 3 and 12.

"It didn't matter if you were a typically developing child, a sibling or an individual with autism: Your social ability was related to a certain extent to your oxytocin levels, which is very different from what people have speculated," said Antonio Hardan, MD, professor of psychiatry and behavioural sciences and the study's senior author.

Hardan is a child and adolescent psychiatrist who treats children with autism at the hospital.

"The previous hypotheses saying that low oxytocin was linked to autism were maybe a little bit simplistic," he said.

"It's much more complex: Oxytocin is a vulnerability factor that has to be accounted for, but it's not the only thing leading to the development of autism."

The researchers caution, however, that blood oxytocin measurements may be different than oxytocin levels in the cerebrospinal fluid bathing the brain, which they did not measure.

In addition to examining blood oxytocin levels, the researchers examined the importance of small variations in the gene coding for the oxytocin receptor.

Certain receptor variants were correlated to higher scores on standard tests of social ability, the study found.

The team also discovered that blood levels of oxytocin are highly heritable: The levels are influenced by inheritance to about the same degree as adult height, which is often described as being strongly influenced by genetics.

"What our study hints at is that social function may be heritable in families," Parker said.

The study will help to guide future research to determine whether oxytocin is a useful autism treatment.

The study's findings suggest that some children with autism, such as the subset of kids with autism who have naturally low oxytocin levels, or those with oxytocin receptor gene variants associated with worse social functioning, might benefit most from oxytocin-like drugs.

"Autism is so heterogeneous," Parker said. "If we can identify biomarkers that help us identify the patients most likely to benefit from a specific therapy, we expect that will be very useful."

More information: "Plasma oxytocin concentrations and OXTR polymorphisms predict social impairments in children with and without autism spectrum disorder," by Karen J. Parker et al. PNAS,

Monday, August 4, 2014

FASD: Prenatal alcohol exposure alters development of brain function

fMRI scan of working memory activation in typically-developing children. 

Credit: The Saban Research Institute

In the first study of its kind, Prapti Gautam, PhD, and colleagues from The Saban Research Institute of Children's Hospital Los Angeles found that children with fetal alcohol spectrum disorders (FASD) showed weaker brain activation during specific cognitive tasks than their unaffected counterparts.

These novel findings suggest a possible neural mechanism for the persistent attention problems seen in individuals with FASD.

The results of this study will be published in Cerebral Cortex on August 4.

"Functional magnetic resonance imaging (fMRI) has been used to observe brain activity during mental tasks in children with FASD, but we are the first to utilize these techniques to look at brain activation over time," says Gautam.

"We wanted to see if the differences in brain activation between children with FASD and their healthy peers were static, or if they changed as children got older."

FASD encompasses the broad spectrum of symptoms that are linked to in utero alcohol exposure, including cognitive impairment, deficits in intelligence and attention and central nervous system abnormalities.

These symptoms can lead to attention problems and higher societal and economic burdens common in individuals with FASD.

During the period of childhood and adolescence, brain function, working memory and attention performance all rapidly improve, suggesting that this is a crucial time for developing brain networks.

To study how prenatal alcohol exposure may alter this development, researchers observed a group of unaffected children and a group of children with FASD over two years.

They used fMRI to observe brain activation through mental tasks such as visuo-spatial attention, how we visually perceive the spatial relationships among objects in our environment, and working memory.

"We found that there were significant differences in development brain activation over time between the two groups, even though they did not differ in task performance," notes Elizabeth Sowell, PhD, director of the Developmental Cognitive Neuroimaging Laboratory at The Saban Research Institute and senior author on the manuscript.

"While the healthy control group showed an increase in signal intensity over time, the children with FASD showed a decrease in brain activation during visuo-spatial attention, especially in the frontal, temporal and parietal brain regions."

These results demonstrate that prenatal alcohol exposure can change how brain signaling develops during childhood and adolescence, long after the damaging effects of alcohol exposure in utero.

The atypical development of brain activation observed in children with FASD could explain the persistent problems in cognitive and behavioral function seen in this population as they mature.