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.”

2-D or 3-D? That is the Question

The increased visual realism of 3-D films is believed to offer viewers a more vivid and lifelike experience—more thrilling and intense than 2-D because it more closely approximates real life. However, psychology researchers at the University of Utah, among those who use film clips routinely in the lab to study patients’ emotional conditions, have found that there is no significant difference between the two formats. The results were published recently in PLOS ONE.

The study aimed to validate the effectiveness of 3-D film, a newer technology, as compared to 2-D film that is currently widely used as a research tool. Film clips are used in psychological and neuroscience studies as a standardized method for assessing emotional development. Because it is less invasive than other methods, it is especially useful when studying the emotional responses of young people for whom emotional well-being is critical to healthy development.

Author Sheila Crowell, assistant professor of psychology at the U, says that results of the large and tightly controlled study also suggest that as an entertainment medium, 3-D may not provide a different experience from 2-D, insofar as evoking emotional responses go.

“We set out to learn whether technological advances like 3-D enhance the study of emotion, especially for young patients who are routinely exposed to high-tech devices and mediums in their daily lives,” says Crowell. “Both 2-D and 3-D are equally effective at eliciting emotional responses, which also may mean that the expense involved in producing 3-D films is not creating much more than novelty. Further studies are of course warranted, but our findings should be encouraging to researchers who cannot now afford 3-D technologies.”

How the study was conducted

Researchers looked at several measures of emotional state in 408 subjects, including palm sweat, breathing and cardiovascular responses, such as heart rate. These measures are commonly used to gauge emotional responses.

Four film clips were chosen because each prompted one discrete emotion intensely and in context without viewing the entire film. Study participants viewed a 3-D and 2-D clip of approximately five minutes of each film: “My Bloody Valentine” (fear), “Despicable Me” (amusement), “Tangled” (sadness) and “The Polar Express” (thrill or excitement). Participants were randomized to view the films in a design that balanced the pairs of films watched, in which format, and order of presentation. The complex configurations allowed the researchers to compare not only emotional responses, but effects of format and viewing order on the results.

Taken as a whole, the results showed few significant differences between physiological reactions to the films. When accounting for the large number of statistical tests, only one difference was seen between the formats—the number of electrodermal responses (palm sweat) during a thrilling scene from “The Polar Express” 3-D clip. The researchers believe that could be because the 3-D content of the film is of especially high quality, with more and a larger variety of 3-D effects than the others.

Supporting the overall finding is that participants’ individual differences in anxiety, inability to control emotional responses or “thrill seeking” did not alter the psychological or physiological responses to 3-D viewing. In other words, personality differences did not change the results: 2-D is still equally effective for emotion elicitation. According to Crowell, “this could be good news for people who would rather not wear 3-D glasses or pay the extra money to see these types of films.”

Beneath the Surface: What Zebrafish Can Tell Us About Anxiety

The right tool for the job is important. A surgeon wouldn’t use a chainsaw when a scalpel offers more control. But sometimes the best treatments available aren’t precise. For example, anxiety medications available today are too blunt in how they target the brain, according to Ian Woods, assistant professor of biochemistry at Ithaca College.

“If you look at current treatments for anxiety disorders, the approach is a bit like taking a sledgehammer to a mosquito,” he said. “The treatments may work for anxiety, but they can have a lot of side effects.”

Woods researches how genetics influence responses to stimuli that can trigger anxiety, and he’s using zebrafish — a tropical member of the minnow family named for the black stripes on their bodies — to do so. He and his team of student researchers examine how fish with tweaked genes respond to different triggers compared to unmodified fish. The work could someday lead to better, more nuanced medications for anxiety disorders.

Zebrafish make ideal test subjects for several reasons. The embryos are transparent and develop outside the mother’s body, making it easy for Woods and his team to observe their growth under a microscope. They develop rapidly, are easy to care for and easy to breed in large quantities.

Specifically, Woods is looking at neuropeptides, which are the chemical messengers between brain cells. Different neuropeptides deliver different messages, which in turn produce different behaviors.

“Fish have the same neuropeptides as humans, and they mostly do the same things in the brain,” Woods said. “We can never faithfully model a complex human behavior like anxiety, but when we’re trying to figure out how the brain works, it’s useful to see inside a fish.”

Woods and his team isolate specific genes to disrupt, amplify, alter or replace, then analyze the movements of the modified fish with the aid of a computerized camera system. They examine responses to stimuli such as slight changes in water temperature, decreases in light intensity, or mild chemical irritants such as mustard oil.

“By observing the ensuing behavioral changes in the fish, we know how that replaced gene changed the message in the brain,” Woods explained. For example, fish exhibiting anxiety-like behaviors might hug the walls of the tank, while the rest will swim toward the middle. It’s not unlike social experiments in which the room temperature is raised gradually to see how human occupants will react.

“Genes typically don’t cause the anxiety,” Woods said. “But they can make organisms more susceptible to environmental triggers that might elicit what we’d call an anxious behavior.”

Anxiety disorders are the most common mental illness in the United States; over 40 million Americans suffer from some type in their lifetimes. But medications can be overprescribed and abused. For example, emergency room visits related to the use of Xanax and related drugs doubled from 2005 to 2011, according to the U.S. Substance Abuse and Mental Health Services Administration.

Anxiety in invertebrates opens research avenues

For the first time, CNRS researchers and the Université de Bordeaux have produced and observed anxiety-like behavior in crayfish, which disappears when a dose of anxiolytic is injected. This work, published in Science on June 13, 2014, shows that the neuronal mechanisms related to anxiety have been preserved throughout evolution. This analysis of ancestral behavior in a simple animal model opens up new avenues for studying the neuronal bases for this emotion.

Anxiety can be defined as a behavioral response to stress, consisting in lasting apprehension of future events. It prepares individuals to detect threats and anticipate them appropriately so as to increase their chances of survival. However, when stress is chronic, anxiety becomes pathological and may lead to depression.

Until now, non-pathological anxiety had only been described in humans and a few vertebrates. For the first time, it has been observed in an invertebrate. To achieve this, researchers at the Institut de Neurosciences Cognitives et Intégratives d’Aquitaine (CNRS/Université de Bordeaux) and the Institut des Maladies Neurodégénératives (CNRS/Université de Bordeaux) repeatedly exposed crayfish to an electric field for thirty minutes. They then placed the crayfish in an aquatic cross-shaped maze. Two arms of the maze were lit up (which repels the crustaceans) and two were dark—which they find reassuring.

The researchers analyzed the exploratory behavior of the crayfish. Those made anxious tended to remain in the dark areas of the maze, by contrast to control crayfish, which explored the entire maze. This behavior is an adaptive response to a felt stress: the animal aims to minimize the risk of meeting an attacker. This emotional state wore itself out after about one hour.

Anxiety in crayfish is correlated to increased serotonin concentration in their brains. Neurotransmitter serotonin is involved in regulating many physiological processes in both invertebrates and humans. It is released when stress is experienced and regulates several responses related to anxiety, such as increasing blood glucose levels. The researchers have also highlighted that injecting an anxiolytic commonly used in humans (benzodiazepine) stops the prevention behavior in crayfish. This shows how early neural mechanisms that trigger or inhibit anxiety-like behavior appeared in the evolutionary process and that they have been well preserved over time.

This work provides researchers specializing in stress and anxiety with a unique animal model. Crayfish have a simple nervous system whose neurons are easy to record, so they may shed light on the neuronal mechanisms at work when stress is experienced, as well as on the role of neurotransmitters such as serotonin or GABA. The team now plans to study anxiety in crayfish subject to social stress and the neuronal changes that occur when the anxiety is prolonged for several days.

Dealing with negative thinking

Is it ‘normal’ to think about pushing someone in front of a train or to fantasise about driving your car into oncoming traffic?

The answer is yes says Victoria University of Wellington researcher Dr Kirsty Fraser who graduated with a PhD in Psychology last week.

“It’s common for people to occasionally have those kind of negative thoughts, but then most of us realise it’s a bit ridiculous and move on,” says Dr Fraser.

For some people, however, those negative thoughts may persist, leading to anxiety and depression.

“It’s how we react to, and process, those negative intrusions that can make the difference between brushing them off and developing obsessive compulsive symptoms, such as severe anxiety and depression.

“For example, some people could be so anxious about those kind of thoughts that they go out of their way to avoid catching a train or driving.”

Dr Fraser’s thesis focused on two ways of processing negative thoughts—inflated responsibility (IR) and thought action fusion (TAF), and the way each relates to mental disorders.

“TAF is when you believe that thinking about an action is equivalent to actually carrying out that action, while IR is one of the driving forces behind obsessive compulsive disorder (OCD), where you believe you can prevent something happening by what you do or don’t do.

“My research demonstrates that both types of beliefs play important roles in the development and maintenance of psychological symptoms related to anxiety, depression and OCD.”

Dr Fraser’s research also looked at how childhood experiences, critical events in one’s life and religious beliefs could impact upon thoughts.

She surveyed more than 1,000 people and divided them into four groups: undergraduate students, so called ‘normal’ citizens, patients from an anxiety clinic and those with religious and atheist beliefs.

“Overall,” she says, “my research provided strong support for existing theories about the role of cognitive processes in the maintenance of symptoms and distress.”

When Kirsty arrived at Victoria in 2002, she began studying human resources. She took a psychology paper out of interest and “never left”.

“The lecturer was John McDowall, who introduced me to how interesting the subject is. He ended up being my supervisor for my PhD.”

For the past three years, Kirsty has combined doctoral study with teaching a second year psychology paper at Victoria, marking for another tertiary institution and being a full-time mother.

“Now I’m starting to think about other challenges, including possible research positions. I’d like to publish my PhD research and continue lecturing.”

How the gut feeling shapes fear

An unlit, deserted car park at night, footsteps in the gloom. The heart beats faster and the stomach ties itself in knots. We often feel threatening situations in our stomachs. While the brain has long been viewed as the centre of all emotions, researchers are increasingly trying to get to the bottom of this proverbial gut instinct.

It is not only the brain that controls processes in our abdominal cavity; our stomach also sends signals back to the brain. At the heart of this dialogue between the brain and abdomen is the vagus nerve, which transmits signals in both directions – from the brain to our internal organs (via the so called efferent nerves) and from the stomach back to our brain (via the afferent nerves). By cutting the afferent nerve fibres in rats, a team of scientists led by Urs Meyer, a researcher in the group of ETH Zurich professor Wolfgang Langhans, turned this two-way communication into a one-way street, enabling the researchers to get to the bottom of the role played by gut instinct. In the test animals, the brain was still able to control processes in the abdomen, but no longer received any signals from the other direction.

Less fear without gut instinct

In the behavioural studies, the researchers determined that the rats were less wary of open spaces and bright lights compared with controlled rats with an intact vagus nerve. “The innate response to fear appears to be influenced significantly by signals sent from the stomach to the brain,” says Meyer.

Nevertheless, the loss of their gut instinct did not make the rats completely fearless: the situation for learned fear behaviour looked different. In a conditioning experiment, the rats learned to link a neutral acoustic stimulus – a sound – to an unpleasant experience. Here, the signal path between the stomach and brain appeared to play no role, with the test animals learning the association as well as the control animals. If, however, the researchers switched from a negative to a neutral stimulus, the rats without gut instinct required significantly longer to associate the sound with the new, neutral situation. This also fits with the results of a recently published study conducted by other researchers, which found that stimulation of the vagus nerve facilitates relearning, says Meyer.

These findings are also of interest to the field of psychiatry, as post-traumatic stress disorder (PTSD), for example, is linked to the association of neutral stimuli with fear triggered by extreme experiences. Stimulation of the vagus nerve could help people with PTSD to once more associate the triggering stimuli with neutral experiences. Vagus nerve stimulation is already used today to treat epilepsy and, in some cases, depression.

Stomach influences signalling in the brain

“A lower level of innate fear, but a longer retention of learned fear – this may sound contradictory,” says Meyer. However, innate and conditioned fear are two different behavioural domains in which different signalling systems in the brain are involved. On closer investigation of the rats’ brains, the researchers found that the loss of signals from the abdomen changes the production of certain signalling substances, so called neurotransmitters, in the brain.

“We were able to show for the first time that the selective interruption of the signal path from the stomach to the brain changed complex behavioural patterns. This has traditionally been attributed to the brain alone,” says Meyer. The study shows clearly that the stomach also has a say in how we respond to fear; however, what it says, i.e. precisely what it signals, is not yet clear. The researchers hope, however, that they will be able to further clarify the role of the vagus nerve and the dialogue between brain and body in future studies.

Switching off anxiety with light

G protein coupled receptors play an important role in medicine and health

One receptor, which is important for the regulation of serotonin levels in the brain, is the 5-HT_1A receptor. It belongs to a protein family called G protein coupled receptors (GPCRs). These receptors can activate different signalling pathways in cells to support or suppress various signalling events. “About 30 per cent of the current drugs target specifically GPCRs”, says Prof Dr Stefan Herlitze from the Department of General Zoology and Neurobiology at the RUB. Due to the lack of tools to control intracellular signalling pathways with high temporal and spatial accuracy, it was so far difficult to analyse these pathways precisely.

Coupling of visual pigments to serotonin receptors

Applying optogenetic methods the scientists in Bochum used cone opsins from the mouse and human eye to control specifically serotonin signalling pathways either with blue or red light. Prof Dr Stefan Herlitze has been working with optogenetic techniques since 2005 and is one of the pioneers in the field. The light-activated serotonin receptors can be switched on within milliseconds, are extremely light sensitive in comparison to other optogenetic tools and can be repetitively activated. “We hope that with the help of these optogenetic tools, we will be able to gain a better understanding about how anxiety and depression originate”, states RUB neuroscientist Dr Olivia Masseck.

Successful behavioural tests

The scientists also demonstrated that they were able to modulate mouse emotional behaviour using the light-activated receptors. When they switched on the serotonergic signals by light in a certain brain area, the mice became less anxious.