Autism as a disorder of prediction

Autism is characterized by many different symptoms: difficulty interacting with others, repetitive behaviors, and hypersensitivity to sound and other stimuli. MIT neuroscientists have put forth a new hypothesis that accounts for these behaviors and may provide a neurological foundation for many of the disparate features of the disorder.

The researchers suggest that autism may be rooted in an impaired ability to predict events and other people’s actions. From the perspective of the autistic child, the world appears to be a “magical” rather than an orderly place, because events seem to occur randomly and unpredictably. In this view, autism symptoms such as repetitive behavior, and an insistence on a highly structured environment, are coping strategies to help deal with this unpredictable world.

The researchers hope that this unifying theory, if validated, could offer new strategies for treating autism.

“At the moment, the treatments that have been developed are driven by the end symptoms. We’re suggesting that the deeper problem is a predictive impairment problem, so we should directly address that ability,” says Pawan Sinha, an MIT professor of brain and cognitive sciences and the lead author of a paper describing the hypothesis in the Proceedings of the National Academy of Sciences this week.

“I don’t know what techniques would be most effective for improving predictive skills, but it would at least argue for the target of a therapy being predictive skills rather than other manifestations of autism,” he adds.

The paper’s senior author is Richard Held, a professor emeritus in the Department of Brain and Cognitive Sciences. Other authors are research affiliates Margaret Kjelgaard and Sidney Diamond, postdoc Tapan Gandhi, technical associates Kleovoulos Tsourides and Annie Cardinaux, and research scientist Dimitrios Pantazis.

Dealing with an unpredictable world

Sinha and his colleagues first began thinking about prediction skills as a possible underpinning for autism based on reports from parents that their autistic children insist on a very controlled, predictable environment.

“The need for sameness is one of the most uniform characteristics of autism,” Sinha says. “It’s a short step away from that description to think that the need for sameness is another way of saying that the child with autism needs a very predictable setting.”

Most people can routinely estimate the probabilities of certain events, such as other people’s likely behavior, or the trajectory of a ball in flight. The MIT team began to think that autistic children may not have the same computational abilities when it comes to prediction.

This hypothesized deficit could produce several of the most common autism symptoms. For example, repetitive behaviors and insistence on rigid structure have been shown to soothe anxiety produced by unpredictability, even in individuals without autism.

“These may be proactive attempts on the part of the person to try to impose some structure on an environment that otherwise seems chaotic,” Sinha says.

Impaired prediction skills would also help to explain why autistic children are often hypersensitive to sensory stimuli. Most people are able to become used to ongoing sensory stimuli such as background noises, because they can predict that the noise or other stimulus will probably continue, but autistic children have much more trouble habituating.

“If we were unable to habituate to stimuli, then the world would become overwhelming very quickly. It’s like you can’t escape this cacophony that’s falling on your ears or that you’re observing,” Sinha says.

Autistic children also often have a reduced ability to understand another person’s thoughts, feelings, and motivations — a skill known as “theory of mind.” The MIT team believes this could result from an inability to predict another person’s behavior based on past interactions. People with autism have difficulty using this type of context, and tend to interpret behavior based only on what is happening in that very moment. 

Leonard Rappaport, chief of the division of developmental medicine at Boston Children’s Hospital, says he believes the new theory is “a uniting concept that could lead us to new approaches to understanding the etiology and perhaps lead to completely new treatment paradigms for this complex disorder.”

“This is not the first theory to explain the complex of symptoms we see every day in our clinical programs, but it seems to explain more of what we see than other theories that explain individual symptoms,” says Rappaport, who was not involved in the research.

Timing is everything

The researchers believe that different children may show different symptoms of autism based on the timing of the predictive impairment.

“In the millisecond range, you would expect to have more of an impairment in language,” Sinha says. “In the tens of milliseconds range, it might be more of a motor impairment, and in the range of seconds, you would expect to see more of a social and planning impairment.”

The hypothesis also predicts that some cognitive skills — those based more on rules than on prediction — should remain unharmed, or even be enhanced, in autistic individuals. This includes tasks such as math, drawing, and music, which are often strengths for autistic children.

A few previous studies have tried to pinpoint which parts of the brain are involved in making predictions. So far, the strongest candidates are the basal ganglia, the nucleus accumbens, and the cerebellum — structures that are often structurally abnormal in autistic patients. “It’s a very tentative connection at the moment, but I think this is a fruitful line of inquiry for the future,” Sinha says.

Sinha’s team has already begun testing some elements of the prediction-deficit hypothesis. Initial results of one study suggest that autistic children do have an impairment in habituation to sensory stimuli; in another set of experiments, the researchers are testing autistic children’s ability to track moving objects, such as a ball. “The hypothesis is guiding us toward very concrete studies,” Sinha says. “We hope to enlist the participation of families and children touched by autism to help put the theory through its paces.”

The striatum acts as hub for multisensory integration

A new study from Karolinska Institutet provides insight on how the brain processes external input such as touch, vision or sound from different sources and sides of the body, in order to select and generate adequate movements. The findings, which are presented in the journal Neuron, show that the striatum acts as a sensory ‘hub’ integrating various types of sensory information, with specialised functional roles for the different neuron types.

“The striatum is the main input structure in the basal ganglia, and is typically associated with motor function”, says Principal Investigator Gilad Silberberg at the Department of Neuroscience. “Our study focuses on its role in processing sensory input. This is important knowledge, since the striatum is implicated in numerous diseases and disorders, including Parkinson’s disease, Huntington’s disease, ADHD and Tourette syndrome.”

The striatum is the largest structure in a collection of brain nuclei called the basal ganglia, which are located at the base of the forebrain. It is involved in motor learning, planning and execution as well as selecting our actions out of all possible choices, based on the expected reward by the dopamine system. Most research performed in the striatum is focused on the motor aspects of its function, largely due to the devastating motor symptoms of the related diseases.

However, in order to select the correct actions, and generate proper motor activity it is essential to continuously process sensory information, often arriving from different sources, different sides of the body and from different sensory modalities, such as tactile (touch), visual, auditory, and olfactory. This integration of sensory information is in fact a fundamental function of our nervous system.

Patch-clamp recordings

In the current study, researchers Gilad Silberberg and Ramon Reig show that individual striatal neurons integrate sensory input from both sides of the body, and that a subpopulation of these neurons process sensory input from different modalities; touch, light and vision. The team used intracellular patch-clamp recordings from single neurons in the mouse striatum to show their responses to whisker stimulation from both sides as well as responses to visual stimulation. Neurons responding to both visual and tactile stimuli were located in a specific medial region of the striatum.

“We also showed that neurons of different types integrate sensory inputs in a different manner, suggesting that they have specific roles in the processing of such sensory information in the striatal network”, says Gilad Silberberg.

(Image: Shutterstock)

Choice bias: A quirky byproduct of learning from reward

The price of learning from rewarding choices may be just a touch of self-delusion, according to a new study in Neuron.

The research by Brown University brain scientists links a fundamental problem in neuroscience called “credit assignment” — how the brain reinforces learning only in the exact circuits that caused the rewarding choice — to an oft-observed quirk of behavior called “choice bias” – we value the rewards we choose more than equivalent rewards we don’t choose. The researchers used computational modeling and behavioral and genetic experiments to discover evidence that choice bias is essentially a byproduct of credit assignment.

“We weren’t looking to explain anything about choice bias to start off with,” said lead author Jeffrey Cockburn, a graduate student in the research group of senior author Michael Frank, associate professor of cognitive, linguistic, and psychological sciences. “This just happened to be the behavioral phenomenon we thought would emerge out of this credit assignment model.”

So the next time a friend raves about the movie he chose and is less enthusiastic about the just-as-good one that you chose, you might be able to chalk it up to his basic learning circuitry and a genetic difference that affects it.

Modeled mechanism

The model, developed by Frank, Cockburn, and co-author Anne Collins, a postdoctoral researcher, was based on prior research on the function of the striatum, a part of the brain’s basal ganglia (BG) that is principally involved in representing reward values of actions and picking one. “An interaction between three key BG regions moderates that decision-making process. When a rewarding choice has been made, the substantia nigra pars compacta (SNc) releases dopamine into the striatum to reinforce connections between cortex and striatum, so that rewarded actions are more likely to be repeated. But how does the SNc reinforce just the circuits that made the right call? The authors proposed a mechanism by which another part of the subtantia nigra, the SNr, detects when actions are worth choosing and then simultaneously amplifies any dopamine signal coming from the SNc.”

“The novel part here is that we have proposed a mechanism by which the BG can detect when it has selected an action and should therefore amplify the dopamine reinforcing event specifically at that time,” Frank said. “When the SNr decides that striatal valuation signals are strong enough for one action, it releases the brakes not only on downstream structures that allow actions to be executed, but also on the SNc dopamine system, so any unexpected rewards are amplified.”

Specifically, dopamine provides reinforcement by enhancing the responsiveness of connections between cells so that a circuit can more easily repeat its rewarding behavior in the future. But along with that process of reinforcing the action of choosing, the value placed on the resulting reward becomes elevated compared to rewards not experienced this way.

Experimental evidence

That prediction seemed intriguing, but it still had to be tested. The authors identified both behavioral and genetic tests that would be telling.

They recruited 80 people at Brown and elsewhere in Providence to play a behavioral game and to donate some saliva for genetic testing.

The game first presented the subjects pictures of arbitrary Japanese characters that would have different probabilities of rewards if chosen ranging from a 20 percent to 80 percent chance of winning a point or losing a point. For some characters, the player could choose a character to discover its resulting reward or penalty, whereas for others, its result was simply given to them. After that learning phase, the subjects were then presented the characters in pairs and instructed to pick the one they thought had the highest chance of winning based on what they had learned.

The researchers built the game so that for every character a player could choose, there was an equally rewarding one that had merely been given to them. On average, players showed a clear choice bias in that they were more likely to prefer rewarding characters that they had chosen over equally rewarding characters they had been given.

Notably, they exhibited no choice bias between unrewarding characters suggesting that choice bias emerges only in relation to reward, one of the key predictions of their model. But they wanted to test further whether the impact of reward on choice bias was related to the proposed biological mechanism, that striatal dopaminergic learning is enhanced to chosen rewards.

The genetic tests focused on single-letter differences in a gene called DARPP-32, which governs how well cells in the striatum respond to the reinforcing influence of dopamine.

People with one version of the gene have been shown in previous research to be less able to learn from rewards, while people with other versions were less driven by reward in learning.

“The reason why this gene is interesting is because we know something about the biology of what it does and where it is expressed in the brain,” Frank said. “It’s predominant in the striatum and specifically affects synaptic plasticity induced by dopamine signaling. It’s related to the imbalance by which you learn from really good things or not so good things.

“The logic was if the mechanism that we think describes this choice bias and credit assignment problem is accurate then that gene should predict the impact of how good something was on this choice bias phenomenon,” he said.

Indeed, that’s what the data showed. People with the form of the gene that predisposed them to be responsive to big rewards also showed more choice bias from the most strongly rewarded characters. Interestingly, the other people also showed choice bias, but more strongly for those characters that were more mediocre. This pattern was mirrored by the authors’ model when it simulated the effects of DARPP-32 on reward learning imbalances from positive vs. negative outcomes.

For some people, the plums are sweeter if they picked them.

MRI brain scans detect people with early Parkinson’s

The new MRI approach can detect people who have early-stage Parkinson’s disease with 85% accuracy, according to research published in Neurology, the medical journal of the American Academy of Neurology.

'At the moment we have no way to predict who is at risk of Parkinson's disease in the vast majority of cases,' says Dr Clare Mackay of the Department of Psychiatry at Oxford University, one of the joint lead researchers. 'We are excited that this MRI technique might prove to be a good marker for the earliest signs of Parkinson's. The results are very promising.'

Claire Bale, research communications manager at Parkinson’s UK, which funded the work, explains: ‘This new research takes us one step closer to diagnosing Parkinson’s at a much earlier stage – one of the biggest challenges facing research into the condition. By using a new, simple scanning technique the team at Oxford University have been able to study levels of activity in the brain which may suggest that Parkinson’s is present. One person every hour is diagnosed with Parkinson’s in the UK, and we hope that the researchers are able to continue to refine their test so that it can one day be part of clinical practice.’

Parkinson’s disease is characterised by tremor, slow movement, and stiff and inflexible muscles. It’s thought to affect around 1 in 500 people, meaning there are an estimated 127,000 people in the UK with the condition. There is currently no cure for the disease, although there are treatments that can reduce symptoms and maintain quality of life for as long as possible.

Parkinson’s disease is caused by the progressive loss of a particular set of nerve cells in the brain, but this damage to nerve cells will have been going on for a long time before symptoms become apparent.

If treatments are to be developed that can slow or halt the progression of the disease before it affects people significantly, the researchers say, we need methods to be able to identify people at risk before symptoms take hold.

Conventional MRI cannot detect early signs of Parkinson’s, so the Oxford researchers used an MRI technique, called resting-state fMRI, in which people are simply required to stay still in the scanner. They used the MRI data to look at the ‘connectivity’, or strength of brain networks, in the basal ganglia – part of the brain known to be involved in Parkinson’s disease.

The team compared 19 people with early-stage Parkinson’s disease while not on medication with 19 healthy people, matched for age and gender. They found that the Parkinson’s patients had much lower connectivity in the basal ganglia.

The researchers were able to define a cut-off or threshold level of connectivity. Falling below this level was able to predict who had Parkinson’s disease with 100% sensitivity (it picked up everyone with Parkinson’s) and 89.5% specificity (it picked up few people without Parkinson’s – there were few false positives).

Dr Mackay explains: ‘Our MRI approach showed a very strong difference in connectivity between those who had Parkinson’s disease and those that did not. So much so, that we wondered if it was too good to be true and carried out a validation test in a second group of patients. We got a similar result the second time.’

The scientists applied their MRI test to a second group of 13 early-stage Parkinson’s patients as a validation of the approach. They correctly identified 11 out of the 13 patients (85% accuracy).

'We think that our MRI test will be relevant for diagnosis of Parkinson's,' says joint lead researcher Dr Michele Hu of the Nuffield Department of Clinical Neurosciences at Oxford University and the Oxford University Hospitals NHS Trust. 'We tested it in people with early-stage Parkinson's. But because it is so sensitive in these patients, we hope it will be able to predict who is at risk of disease before any symptoms have developed. However, this is something that we still have to show in further research.'

To see if this is the case, the Oxford University researchers are now carrying out further studies of their MRI technique with people who are at increased risk of Parkinson’s.

Did standing up change our brains?

Although lots of animals are smart, humans are even smarter. How and why do we think and act so differently from other species?

A young boy’s efforts while learning to walk have suggested a new explanation, in a new journal paper jointly authored by his father and grandfather, both academics at the University of Sydney.

In the latest issue of the scientific journal, Frontiers in Neuroscience, the son-and-father team Mac and Rick Shine suggest that the big difference between humans and other species may lie in how we use our brains for routine tasks.

They advance the idea that the key to exploiting the awesome processing power of our brain’s most distinctive feature - the cortex - may have been to liberate it from the drudgery of controlling routine activities.

And that’s where young Tyler Shine, now two years old, comes into the story. When Tyler was first learning to walk, his doting father and grandfather noticed that every step took Tyler’s full attention.

But before too long, walking became routine, and Tyler was able to start noticing other things around him. He was better at maintaining his balance, which freed up his attention to focus on more interesting tasks, like trying to get into mischief.

How did Tyler improve? His father and grandfather suggest that he did so by transferring the control of his balance to ‘lower’ parts of the brain, freeing up the powerful cortex to focus on unpredictable challenges, such as a bumpy floor covered in stray toys.

"Any complicated task - like driving a car or playing a musical instrument - starts out consuming all our attention, but eventually becomes routine," Mac Shine says.

"Studies of brain function suggest that we shift the control of these routine tasks down to ‘lower’ areas of the brain, such as the basal ganglia and the cerebellum.

"So, humans are smart because we have automated the routine tasks; and thus, can devote our most potent mental faculties to deal with new, unpredictable challenges.

"What event in the early history of humans made us change the way we use our brains?

Watching Tyler learn to walk suggested that it was the evolutionary shift from walking on all fours, to walking on two legs.

"Suddenly our brains were overwhelmed with the complicated challenge of keeping our balance - and the best kind of brain to have, was one that didn’t waste its most powerful functions on controlling routine tasks."

So, the Shines believe, those first pre-humans who began to stand upright faced a new evolutionary pressure not just on their bodies, but on their brains as well.

"New technologies are allowing us to look inside the brain while it works, and we are learning an enormous amount," Mac Shine says.

"But in order to interpret those results, we need new ideas as well. I’m delighted that my son has played a role in suggesting one of those ideas."

"Hopefully, by the time he is watching his own son learn to walk, we will be much closer to truly understanding the greatest mystery of human existence: how our brains work."

Brain imaging reveals clues about chronic fatigue syndrome

A brain imaging study shows that patients with chronic fatigue syndrome may have reduced responses, compared with healthy controls, in a region of the brain connected with fatigue. The findings suggest that chronic fatigue syndrome is associated with changes in the brain involving brain circuits that regulate motor activity and motivation.

Compared with healthy controls, patients with chronic fatigue syndrome had less activation of the basal ganglia, as measured by fMRI (functional magnetic resonance imaging). This reduction of basal ganglia activity was also linked with the severity of fatigue symptoms.

According to the Centers for Disease Control and Prevention, chronic fatigue syndrome is a debilitating and complex disorder characterized by intense fatigue that is not improved by bed rest and that may be worsened by exercise or mental stress.

The results are scheduled for publication in the journal PLOS One.

"We chose the basal ganglia because they are primary targets of inflammation in the brain," says lead author Andrew Miller, MD. "Results from a number of previous studies suggest that increased inflammation may be a contributing factor to fatigue in CFS patients, and may even be the cause in some patients."

Miller is William P. Timmie professor of psychiatry and behavioral sciences at Emory University School of Medicine. The study was a collaboration among researchers at Emory University School of Medicine, the CDC’s Chronic Viral Diseases Branch, and the University of Modena and Reggio Emilia in Italy. The study was funded by the CDC.

The basal ganglia are structures deep within the brain, thought to be responsible for control of movements and responses to rewards as well as cognitive functions. Several neurological disorders involve dysfunction of the basal ganglia, including Parkinson’s disease and Huntington’s disease, for example.

In previous published studies by Emory researchers, people taking interferon alpha as a treatment for hepatitis C, which can induce severe fatigue, also show reduced activity in the basal ganglia. Interferon alpha is a protein naturally produced by the body, as part of the inflammatory response to viral infection. Inflammation has also been linked to fatigue in other groups such as breast cancer survivors.

"A number of previous studies have suggested that responses to viruses may underlie some cases of CFS," Miller says. "Our data supports the idea that the body’s immune response to viruses could be associated with fatigue by affecting the brain through inflammation. We are continuing to study how inflammation affects the basal ganglia and what effects that has on other brain regions and brain function. These future studies could help inform new treatments."

Treatment implications might include the potential utility of medications to alter the body’s immune response by blocking inflammation, or providing drugs that enhance basal ganglia function, he says.

The researchers compared 18 patients diagnosed with chronic fatigue syndrome with 41 healthy volunteers. The 18 patients were recruited [not referred] based on an initial telephone survey followed by extensive clinical evaluations. The clinical evaluations, which came in two phases, were completed by hundreds of Georgia residents. People with major depression or who were taking antidepressants were excluded from the imaging study, although those with anxiety disorders were not.

For the brain imaging portion of the study, participants were told they’d win a dollar if they correctly guessed whether a preselected card was red or black. After they made a guess, the color of the card was revealed, and at that point researchers measured blood flow to the basal ganglia.

The key measurement was: how big is the difference in activity between a win or a loss? Participants’ scores on a survey gauging their levels of fatigue were tied to the difference in basal ganglia activity between winning and losing. Those with the most fatigue had the smallest changes, especially in the right caudate and the right globus pallidus, both parts of the basal ganglia.

Ongoing studies at Emory are further investigating the impact of inflammation on the basal ganglia, including studies using anti-inflammatory treatments to reduce fatigue and loss of motivation in patients with depression and other disorders with inflammation including cancer.

Common links between neurodegenerative diseases identified

Diseases of the central nervous system are a big burden to society. According to estimates, they cost €800 billion per year in Europe. And for most of them, there is no definitive cure. This is true, for example, for Parkinson disease. Although good treatments exist to manage its symptoms, they become more and more ineffective as the disease progresses. Now, the EU-funded REPLACES project, completed in 2013, which associated scientists with clinicians, has shed light on the abnormal working of a particular brain circuitry related to Parkinson’s disease. The results of the project suggest that these same circuits are implicated in different forms of pathologies. And this gives important insights into the possible common links between neurodegenerative diseases such as Parkinson and intellective disabilities or autism.

Existing treatments for Parkinson are very effective at the beginning. When the disease progresses, however, drugs, such as levodopa and so-called dopamine agonists, produce side effects that are sometimes even worse than the initial symptoms of the condition. In particular, they cause a complication called dyskinesia, characterised by abnormal involuntary movements. Therapies are therefore sought that allow better management of symptoms.

The project focused on the study of a highly plastic brain circuitry, which connects regions of the cerebral cortex with the basal ganglia. It is involved in very important functions such as learning and memory. “This system, based onglutamate as a mean of signalling between neurons, has also been discovered to be damaged in Parkinson disease,” says Monica Di Luca, professor of neuropharmacology at the University of Milan, Italy, and the project coordinator. She adds: “Parkinson’s more well-known and characteristic trait is the selective loss of cells producers of neurotransmitter dopamine.”

Researchers involved into the project studied the function and plasticity of this circuit in different animal models of Parkinson disease, from mice to non-human primates. They found that exactly the same alterations were present and conserved. This makes it an interesting and alternative target for trying to re-establish the correct functioning and reverse the symptoms of the disease.

One expert agrees with the need to target alternative target systems. “What researchers are trying to do is to intervene to modulate other systems that do not involve dopamine and obtain a better symptoms management,” explains Erwan Bezard, a researcher at the Neurodenerative Diseases Institute at the University of Bordeaux, in France. He also works on alternative targets in Parkinson disease. In monkeys, compounds that target glutamate receptors, used in combination with traditional drugs, have previously shown to improve some deficits in voluntary motor control.

But the research has also shed some light into apparently unrelated diseases. It is becoming more and more obvious that the same alterations in the working of the communication systems among neurons are shared among different diseases. “This is why we speak about ‘synaptopathies’: there are common players among Parkinson disease, autism and other forms of intellectual disabilities and even schizophrenia. Several of the mutated genes are the same, and affect the signalling systems through common molecules,” says Claudia Bagni, who works on synaptic plasticity in the context of intellectual disabilities at the University of Leuven, in Belgium and University of Rome Tor Vergata, in Italy. “For example, the glutamatergic system is also affected in the X-fragile syndrome, the most common form of inherited intellectual disability.”

Progress is in sight thanks to a much better understanding of the working of the abnormal synapses in Parkinson disease, and experiments performed in monkeys showing encouraging results. Indeed, “the team studied human primates, the model system closest to humans, and therefore their findings are relevant to human health.” says Bagni. Project researchers hope the door is now opened for the first clinical trials in humans. “We have identified a potential new target for treatment, and tested a couple of molecules in animals,” says Di Luca, the “next step would be to find a partnership with pharmaceutical industries interested in pursuing this research.”