Voices may not trigger brain’s reward centers in children with autism

In autism, brain regions tailored to respond to voices are poorly connected to reward-processing circuits, according to a new study by scientists at the Stanford University School of Medicine.

The research could help explain why children with autism struggle to grasp the social and emotional aspects of human speech. “Weak brain connectivity may impede children with autism from experiencing speech as pleasurable,” said Vinod Menon, PhD, senior author of the study, published online June 17 in Proceedings of the National Academy of Sciences. Menon is a professor of psychiatry and behavioral sciences at Stanford and a member of the Child Health Research Institute at Lucile Packard Children’s Hospital.

"The human voice is a very important sound; it not only conveys meaning but also provides critical emotional information to a child," said Daniel Abrams, PhD, a postdoctoral scholar in psychiatry and behavioral sciences who was the study’s lead author. Insensitivity to the human voice is a hallmark of autism, Abrams said, adding, "We are the first to show that this insensitivity may originate from impaired reward circuitry in the brain."

The study focused on children with a high-functioning form of autism. They had IQ scores in the normal range and could speak and read, but had difficulty holding a back-and-forth conversation or understanding emotional cues in another person’s voice.

The scientists compared functional magnetic resonance imaging brain scans from 20 of these children with scans from 19 typically developing children, paying particular attention to a portion of the brain that responds selectively to the sound of human voices. Prior research has shown that adults with autism had low voice-selective cortex activity in response to speech. But until this study by Menon and his colleagues, no one had looked at connections between the voice-selective cortex and other brain regions in individuals with autism.

The new study found that in children with a high-functioning form of autism, the voice-selective cortex on the left side of the brain was weakly connected to the nucleus accumbens and the ventral tegmental area — brain structures that release dopamine in response to rewards. The voice-selective cortex on the right side of the brain, which specializes in detecting vocal cues such as intonation and pitch, was weakly connected to the amygdala, which processes emotional cues.

The weaker these connections in children with autism, the worse their communication deficits, the study showed. The researchers were able to predict the children’s scores on the verbal portion of a standard test of autism severity by looking at the degree of impairment in these brain connections.

The findings may help to validate some autism therapies already in use, said co-author Jennifer Phillips, PhD, a clinical associate professor of psychiatry and behavioral sciences at Stanford who also treats children with autism at Packard Children’s. For instance, pivotal-response training aims to increase social use of language in children who can speak some words but who usually do not talk to others.

"Pivotal-response training goes after ways to naturally motivate kids to start using language and other forms of social interaction," Phillips said. Future studies could test whether brain connections leading from voice to reward centers are strengthened by autism therapies, she added.

The findings also help resolve a long-standing debate about why individuals with autism show less-than-normal interest in human voices. The team investigated two competing theories to explain the phenomenon: that individuals with autism have a deficit in their social motivation, or, alternatively, that they have sensory-processing deficits which impair their ability to fully hear human voices. The new study found normal connections between voice-selective cortex and primary auditory brain regions in children with high-functioning autism, suggesting that these children do not have sensory-processing deficits.

The next steps for researchers include studying the consequences of the weak voice-to-reward circuit in autism. “It is likely that children with autism don’t attend to voices because they are not rewarding or emotionally interesting, impacting the development of their language and social communication skills,” Menon said. “We have discovered an aberrant brain circuit underlying a core deficit in autism; our findings may aid the development of new treatments for this disorder.”

(Image: Getty Images)

Researchers Provide the First Comprehensive and Prospective Characterization of a Genetic Subtype of Autism

In the first prospective study of its kind, Seaver Autism Center researchers at the Icahn School of Medicine at Mount Sinai provide new evidence of the severity of intellectual, motor, and speech impairments in a subtype of autism called Phelan-McDermid Syndrome (PMS). The data are published online in the June 11 issue of the journal Molecular Autism.

Mutation or deletion of a gene known as SHANK3 is one of the more common single-gene causes of autism spectrum disorders and is critical to the development of PMS, a  severe type of autism. To date, clinicians have relied on case studies and retrospective reviews of medical records to understand  the features of this disorder and how the clinical presentation relates to the extent of the genetic changes in the SHANK3 region. In the first systematic and comprehensive prospective trial, researchers led by Alex Kolevzon, MD, Clinical Director of the Seaver Autism Center, under the direction of Joseph Buxbaum, PhD, Director of the Seaver Autism Center, enrolled 32 participants with SHANK3 deletions to comprehensively assess their clinical symptoms and examine how the size of the SHANK3 deletion correlated to those symptoms.

“Previous studies have not utilized prospective assessments to understand Phelan-McDermid Syndrome, and the prevalence of autism spectrum disorder has never been examined using gold-standard instruments” said Dr. Kolevzon. “There is no established standard for assessing  this type of autism, and our study provides important guidance in developing such a standard.”

Of the 32 patients enrolled, 84 percent met criteria for an autism spectrum disorder. Seventy-seven percent of patients exhibited severe to profound intellectual disability, with 19 percent using some form of verbal communication. Other common features included low muscle tone, gait disturbance, and seizures. The researchers also found that patients who had larger SHANK3 deletions had more severe disease.

“Our findings provide additional evidence of the significant impairment associated with SHANK3 deficiency,” said Dr. Kolevzon. “Also, knowing how large the deletion of the  SHANK3 gene is may have important implications for medical monitoring and individualizing treatment plans. Results  also provide much-needed guidance in developing a standardized methodology for evaluating the features of this disorder.”

Many of the patients who participated in this study were next enrolled in a clinical trial at Mount Sinai evaluating Insulin-Like Growth Factor-1 (IGF-1), a  commercially available compound for growth deficiency that is known to promote nerve cell survival as well as synaptic maturation and plasticity.  The primary aim of the study is to target core features of PMS, including social withdrawal and language impairment, which will be measured using both behavioral and objective assessments. The clinical studies with IGF-1 were supported by studies in a genetically modified mouse with a mutation in SHANK3. These studies, carried out by Dr. Ozlem Bozdagi of the Seaver Autism Center, carefully examined brain function in the mice when SHANK3 was mutated, and provided preclinical evidence for a beneficial effect of IGF-1. These studies were reported the April 27th issue of Molecular Autism (1, 2).

“The Seaver Autism Center has the unique capacity to evaluate autism spectrum disorders on both the molecular level and the clinical level,” said Dr. Buxbaum. “This capability puts us in a unique position to see the entire picture—the connection between genetics and behavior in these disorders—and to develop new treatments and better tailor existing ones for these children.”

Alzheimer’s, Schizophrenia, and Autism Now Can Be Studied With Mature Brain Cells Reprogrammed from Skin Cells

Difficult-to-study diseases such as Alzheimer’s, schizophrenia, and autism now can be probed more safely and effectively thanks to an innovative new method for obtaining mature brain cells called neurons from reprogrammed skin cells. According to Gong Chen, the Verne M. Willaman Chair in Life Sciences and professor of biology at Penn State University and the leader of the research team, “the most exciting part of this research is that it offers the promise of direct disease modeling, allowing for the creation, in a Petri dish, of mature human neurons that behave a lot like neurons that grow naturally in the human brain.” Chen added that the method could lead to customized treatments for individual patients based on their own genetic and cellular information. The research will be published in the journal Stem Cell Research.

"Obviously, we don’t want to remove someone’s brain cells to experiment on, so recreating the patient’s brain cells in a Petri dish is the next best thing for research purposes and drug screening," Chen said. Chen explained that, in earlier work, scientists had found a way to reprogram skin cells from patients to become unspecialized or undifferentiated pluripotent stem cells (iPSCs). "A pluripotent stem cell is a kind of blank slate," Chen explained. "During development, such stem cells differentiate into many diverse, specialized cell types, such as a muscle cell, a brain cell, or a blood cell. So, after generating iPSCs from skin cells, researchers then can culture them to become brain cells, or neurons, which can be studied safely in a Petri dish."

Now, in their new research, Chen and his team have found a way to differentiate iPSCs into mature human neurons much more effectively, generating cells that behave similarly to neurons in the brain. Chen explained that, in their natural environment, neurons are always found in close proximity to star-shaped cells called astrocytes, which are abundant in the brain and help neurons to function properly. “Because neurons are adjacent to astrocytes in the brain, we predicted that this direct physical contact might be an integral part of neuronal growth and health,” Chen explained.

To test this hypothesis, Chen and his colleagues began by culturing iPSC-derived neural stem cells, which are stem cells that have the potential to become neurons. These cells were cultured on top of a one-cell-thick layer of astrocytes so that the two cell types were physically touching each other.

"We found that these neural stem cells cultured on astrocytes differentiated into mature neurons much more effectively," Chen said, contrasting them with other neural stem cells that were cultured alone in a Petri dish. "It was almost as if the astrocytes were cheering the stem cells on, telling them what to do, and helping them fulfill their destiny to become neurons."

To demonstrate the superiority of the neurons grown next to astrocytes, Chen and his co-authors used an electrophysiology recording technique to show that the cells grown on astrocytes had many more synaptic events — signals sent out from one nerve cell to the others. In another experiment, after growing the neural stem cells next to astrocytes for just one week, the researchers showed that the newly differentiated neurons start to fire action potentials — the rapid electrical excitation signal that occurs in all neurons in the brain. In a final test, the team members added human neural stem cells to a mixture with mouse neurons. “We found that, after just one week, there was a lot of ‘cross-talk’ between the mouse neurons and the human neurons,” Chen said. He explained that “cross-talk” occurs when one neuron contacts its neighbors and releases a chemical called a neurotransmitter to modulate its neighbor’s activity.

"Previous researchers could only obtain brain cells from deceased patients who had suffered from diseases such as Alzheimer’s, schizophrenia, and autism," Chen said. "Now, researchers can take skin cells from living patients — a safe and minimally invasive procedure — and convert them into brain cells that mimic the activity of the patient’s own brain cells." Chen added that, by using this method, researchers also can figure out how a particular drug will affect a particular patient’s own brain cells, without needing the patient to try the drug — eliminating the risk of serious side effects. "The patient can be his or her own guinea pig for the design of his or her own treatment, without having to be experimented on directly," Chen said.

Researchers Discover How Brain Circuits Can Become Miswired During Development

Researchers at Weill Cornell Medical College have uncovered a mechanism that guides the exquisite wiring of neural circuits in a developing brain — gaining unprecedented insight into the faulty circuits that may lead to brain disorders ranging from autism to mental retardation.

In the journal Cell, the researchers describe, for the first time, that faulty wiring occurs when RNA molecules embedded in a growing axon are not degraded after they give instructions that help steer the nerve cell. So, for example, the signal that tells the axon to turn — which should disappear after the turn is made — remains active, interfering with new signals meant to guide the axon in other directions.

The scientists say that there may be a way to use this new knowledge to fix the circuits.

"Understanding the basis of brain miswiring can help scientists come up with new therapies and strategies to correct the problem," says the study’s senior author, Dr. Samie Jaffrey, a professor in the Department of Pharmacology.

"The brain is quite ‘plastic’ and changeable in the very young, and if we know why circuits are miswired, it may be possible to correct those pathways, allowing the brain to build new, functional wiring," he says.

Disorders associated with faulty neuronal circuits include epilepsy, autism, schizophrenia, mental retardation and spasticity and movement disorders, among others.

In their study, the scientists describe a process of brain wiring that is much more dynamic than was previously known — and thus more prone to error.

Proteins Sense the Environment to Steer the Axon

During brain development, neurons have to connect to each other, which they do by extending their long axons to touch one another. Ultimately, these neurons form a circuit between the brain and the target tissue through which chemical and electrical signals are relayed. In this study, researchers investigated neurons that travel up the spinal cord into the brain. “It is very critical that axons are precisely positioned in the spinal cord,” Dr. Jaffrey says. “If they are improperly positioned, they will form the wrong connections, which can lead to signals being sent to the wrong target cells in the brain.”

The way that an axon guides and finds its proper target is through so-called growth cones located at the tips of axons. “These growth cones have the ability to sense the environment, determine where the targets are and navigate toward them. The question has always been — how do they know how to do this? Where do the instructions come from that tell them how to find their proper target?” Dr. Jaffrey says. The team found that RNA molecules embedded in the growth cone are responsible for instructing the axon to move left or right, up or down. These RNAs are translated in growth cones to produce antenna-like proteins that steer the axon like a self-guided missile.

"As a circuit is being built, RNAs in the neuron’s growth cones are mostly silent. We found that specific RNAs are only read at precise stages in order to produce the right protein needed to steer the axon at the right time. After the protein is produced, we saw that the RNA instruction is degraded and disappears," he says.

"If these RNAs do not disappear when they should, the axon does not position itself properly — it may go right instead of left — and the wiring will be incorrect and the circuit may be faulty," Dr. Jaffrey says.

RNAs have Tremendous Power over Brain Development

The research finding answers a long-standing puzzle in the quest to understand brain wiring, says Dr. Dilek Colak, a postdoctoral associate in Dr. Jaffrey’s laboratory.

"There have been a series of discoveries over the last five years showing that proteins that control RNA degradation are very important for brain development and, when they are mutated, you can have spasticity or other movement disorders," Dr. Colak says. "That has raised a major question — why would RNA degradation pathways be so critical for properly creating brain circuits?

"What we show here is that not only does RNA need to be present in growth cones to give instructions, it then also needs to be removed from the growth cones to take away those instructions at the right time," she says. "Both those processes are critical and it may explain why there are so many different brain disorders associated with ineffective RNA regulation."

"The idea that control of brain wiring is located in these RNA molecules that are constantly being dynamically turned over is something that we didn’t anticipate," Dr. Jaffrey adds. "This tells us that regulating these RNA degradation pathways could have a tremendous impact on brain development. Now we know where to look to tease apart this process when it goes awry, and to think about how we can repair it."

(Image: Chad Baker)

Positive Feedback: Researchers have found a new role for mTOR in autism-related disorders

Researchers have found a novel role for a protein that has been implicated in an autism-related disorder known as tuberous sclerosis complex (TSC).

The disease, which affects 1 in about 8,000 children, manifests itself in the form of mental retardation in addition to severe epileptic episodes. The disease is caused by mutations in two tumor-suppressing proteins, TSC1 and TSC2.

“Kids with this condition have benign tumors that grow all over the body,” said Bernardo Sabatini, the Takeda Professor of Neurobiology at Harvard Medical School and senior author of the study, “but we wanted to know what happened in the brain.”

The researchers found that when mutations in TSC1 and TSC2 adversely affected a third protein, mTOR, this mutation increased brain activity, which can result in epileptic seizures.

The findings were published in the May 8 issue of Neuron.

A protein kinase, mTOR is responsible for controlling cell growth in many parts of the body and has been widely implicated in epilepsy and autism. TSC1 and TSC2 normally repress the activity of mTOR to keep cell growth in check. In the case of TSC, there are mutations in TSC1 or TSC2, and mTOR’s ability to promote cell growth goes unchecked, resulting in tumors in regularly dividing cells.

“But neurons don’t divide,” said Sabatini. “So it was important to note the changes in these non-dividing cells.”  

The researchers hypothesized that mTOR’s function in the brain related to homeostasis, the brain’s ability to maintain a controlled level of electrical activity. When there’s a lot of electrical activity, a negative feedback system switches on to suppress activity. Conversely, when levels are too low, other positive feedback pathways are engaged that bring the activity level back up.

“We went into this study with the specific hypothesis that mTOR would be part of the homeostatic loop in the brain,” explained Sabatini.  

In the case of TSC patients, they thought that mTOR was incapable of maintaining homeostasis and kept adding to the level of electrical activity, leading to seizures. 

“But we were wrong,” he added.

“What we actually found was that mTOR is part of a positive feedback pathway,” said Helen Bateup, HMS research fellow in neurobiology and first author on the study. “When a cell is active, mTOR gets turned on more frequently and makes the cell even more active by reducing the amount of inhibition that the neuron receives.”

In cells where TSC proteins are mutated, this positive feedback gets out of control, and the neuronal circuit remains overactive despite all the pathways that normally shut down activity being turned on.

“It’s like the circuit is trying to keep itself quiet, but it can’t,” said Sabatini. “The out-of-control mTOR causes some cells to loss all inhibition, something that can’t be compensated for by turning down excitation.”                                        

The researchers think this key difference in how mTOR operates, in working to promote electrical activity, is important for the disease because patients end up with high levels of dysfunctional mTOR that makes for highly active circuits prone to epileptic fits. Furthermore, “we know that once a person has one seizure, they’re much more likely to have more, a concept known as kindling,” said Sabatini.

These findings are among the first to show that contrary to scientific consensus, mTOR does not play a part in everything.

“We have shown that one of the few things that mTOR does not seem to partake in is this negative feedback pathway,” said Sabatini.

Working in both in vitro and in vivo mouse models, the researchers think the next step would be tease out the molecular pathway of mTOR’s involvement in this positive feedback loop. “It’s also important to compare how this pathway works in normal brains versus a diseased model,” added Bateup.

“A huge challenge when studying the brain is that there are so many feedback pathways that a mutation in one gene can result in a hundred other secondary changes,” said Sabatini.

Rapamycin, a drug currently used to prevent organ rejection following transplants, targets mTOR and brings activity levels back to normal.

“We could use the drug to restore this excitatory-inhibitory balance in the brain,” said Bateup. “A lot of drugs that treat epilepsy try to make inhibition more powerful but given that the primary problem here is that a group of cells has lost inhibition, that approach won’t work,” she added. “What we might need is to target the excitation side. Or find ways of changing the biochemistry of the cells to make inhibitory synapses again.” 

“For this disease, this is the right time to start looking at human cells,” said Sabatini. “We have really good data from the mouse model and it would be a really nice test to see if the mouse model is really predictive of human disorder and if it’s worth being continued.” 

Early brain responses to words predict developmental outcomes in children with autism

The pattern of brain responses to words in 2-year-old children with autism spectrum disorder predicted the youngsters’ linguistic, cognitive and adaptive skills at ages 4 and 6, according to a new study.

The findings, published May 29 in PLOS ONE, are among the first to demonstrate that a brain marker can predict future abilities in children with autism.

“We’ve shown that the brain’s indicator of word learning in 2-year-olds already diagnosed with autism predicts their eventual skills on a broad set of cognitive and linguistic abilities and adaptive behaviors,” said lead author Patricia Kuhl, co-director of the University of Washington’s Institute for Learning & Brain Sciences.

“This is true four years after the initial test, and regardless of the type of autism treatment the children received,” she said.

In the study, 2-year-olds – 24 with autism and 20 without – listened to a mix of familiar and unfamiliar words while wearing an elastic cap that held sensors in place. The sensors measured brain responses to hearing words, known as event-related potentials.

The research team then divided the children with autism into two groups based on the severity of their social impairments and took a closer look at the brain responses. Youngsters with less severe symptoms had brain responses that were similar to the typically developing children, in that both groups exhibited a strong response to known words in a language area located in the temporal parietal region on the left side of the brain.

This suggests that the brains of children with less severe symptoms can process words in ways that are similar to children without the disorder.

In contrast, children with more severe social impairments showed brain responses more broadly over the right hemisphere, which is not seen in typically developing children of any age.

“We think this measure signals that the 2-year-old’s brain has reorganized itself to process words. This reorganization depends on the child’s ability to learn from social experiences,” Kuhl said. She cautioned that identifying a neural marker that predicts future autism diagnoses with assurance is still a ways off.

The researchers also tested the children’s language skills, cognitive abilities, and social and emotional development, beginning at age 2, then again at ages 4 and 6.

The children with autism received intensive treatment and, as a group, they improved on the behavioral tests over time. But the outcome for individual children varied widely and the more their brain responses to words at age 2 were like those of typically developing children, the more improvement in skills they showed by age 6.

In other studies, Kuhl has found that social interactions accelerate language learning in babies. Infants use social cues, such as tracking adults’ eye movements to learn the names of things, and must be interested in people to learn in this way. Paying attention to people is a way for babies to sort through all that is happening around them and serves as a gate to know what is important.

But with autism, social impairments impede children’s interest in, and ability to pick up on, social cues. They find themselves paying attention to many other things, especially objects as opposed to people.

“Social learning is what most humans are about,” Kuhl said. “If your brain can learn from other people in a social context you have the capability to learn just about anything.”

She hopes that the new findings will lead to brain measures that can be used much earlier in development – at 12 months or younger – to help identify children at risk for autism.

“This line of work may lead to new interventions applied early in development, when the brain shows its highest level of neural plasticity,” Kuhl said.