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.”

New learning mechanism for individual nerve cells

“This means a dramatic increase in the brain’s learning capacity. The cells we have studied control the blink reflex, but there are many cells of the same type that control entirely different processes. It is therefore likely that the timing mechanism we have discovered also exists in other parts of the brain”, said Professor of neurophysiology Germund Hesslow.

Professor Hesslow and colleagues Fredrik Johansson and Dan-Anders Jirenhed have used ‘conditioned reflexes’ for the research. The principle comes from the Russian researcher Ivan Pavlov, who, around the turn of the last century, taught dogs to associate a certain sound with food so that they began to drool on hearing the sound.

In the present experiment, the researchers studied animals that learnt to associate a sound with a puff of air in the eye that caused them to blink. If the time between the sound and the puff of air was quarter of a second, the animals blinked after quarter of a second even if the puff of air was removed. If the time was changed to half a second, the animals blinked after half a second, and so on.

The prevalent theories in brain research state that this learnt timing mechanism is a result of strengthening or weakening of the contacts – or synapses – throughout a network of nerve cells. However, using super-thin electrodes, the Lund group have now shown that no networks are needed: one single cell can learn when it is time to react.

The cells which the researchers have studied are called Purkinje cells and are located in the cerebellum. The cerebellum is the part of the brain responsible for posture, balance and movement, and the researchers focused on those cells that control blinking.

This work is basic research, but possible future applications could include rehabilitation following a stroke, which often affects a patient’s movements. The findings could also have a bearing on conditions such as autism, ADHD and language problems, in which the cerebellum is believed to play a part.

“Intelligible speech is dependent on correct timing, so that the pauses between the sounds are right”, explained Germund Hesslow.

The new findings have already attracted attention in the research community: the internationally renowned memory researcher Charles Gallistel came all the way from Rutgers University in the spring to study the group’s work. Work is now continuing to study what transmitter substance and what receptor on the surface of the cell are responsible for the newly discovered timing mechanism.

Single dose of antidepressant changes the brain

A single dose of antidepressant is enough to produce dramatic changes in the functional architecture of the human brain. Brain scans taken of people before and after an acute dose of a commonly prescribed SSRI (serotonin reuptake inhibitor) reveal changes in connectivity within three hours, say researchers who report their observations in the Cell Press journal Current Biology on September 18.

"We were not expecting the SSRI to have such a prominent effect on such a short timescale or for the resulting signal to encompass the entire brain," says Julia Sacher of the Max Planck Institute for Human Cognitive and Brain Sciences.

While SSRIs are among the most widely studied and prescribed form of antidepressants worldwide, it’s still not entirely clear how they work. The drugs are believed to change brain connectivity in important ways, but those effects had generally been thought to take place over a period of weeks, not hours.

The new findings show that changes begin to take place right away. Sacher says what they are seeing in medication-free individuals who had never taken antidepressants before may be an early marker of brain reorganization.

Study participants let their minds wander for about 15 minutes in a brain scanner that measures the oxygenation of blood flow in the brain. The researchers characterized three-dimensional images of each individual’s brain by measuring the number of connections between small blocks known as voxels (comparable to the pixels in an image) and the change in those connections with a single dose of escitalopram (trade name Lexapro).

Their whole-brain network analysis shows that one dose of the SSRI reduces the level of intrinsic connectivity in most parts of the brain. However, Sacher and her colleagues observed an increase in connectivity within two brain regions, specifically the cerebellum and thalamus.

The researchers say the new findings represent an essential first step toward clinical studies in patients suffering from depression. They also plan to compare the functional connectivity signature of brains in recovery and those of patients who fail to respond after weeks of SSRI treatment.

Understanding the differences between the brains of individuals who respond to SSRIs and those who don’t “could help to better predict who will benefit from this kind of antidepressant versus some other form of therapy,” Sacher says. “The hope that we have is that ultimately our work will help to guide better treatment decisions and tailor individualized therapy for patients suffering from depression.”

Research Shows How Brain Can Tell Magnitude of Errors

University of Pennsylvania researchers have made another advance in understanding how the brain detects errors caused by unexpected sensory events. This type of error detection is what allows the brain to learn from its mistakes, which is critical for improving fine motor control.  

Their previous work explained how the brain can distinguish true error signals from noise; their new findings show how it can tell the difference between errors of different magnitudes. Fine-tuning a tennis serve, for example, requires that the brain distinguish whether it needs to make a minor correction if the ball barely misses the target or a much bigger correction if it is way off.

The study was led by Javier Medina, an assistant professor in the Department of Psychology in Penn’s School of Arts & Sciences, and Farzaneh Najafi, then a graduate student in the Department of Biology. They collaborated with postdoctoral fellow Andrea Giovannucci and associate professor Samuel S. H. Wang of Princeton University.

It was published in the journal eLife.

Our movements are controlled by neurons known as Purkinje cells. Each muscle receives instructions from a dedicated set of hundreds of these brain cells. The instructions sent by each set of Purkinje cells are constantly fine tuned by climbing fibers, a specialized group of neurons that alert Purkinje cells whenever an unexpected stimulus occurs.

“An unexpected stimulus is often a sign that something has gone wrong,” Medina said, “When this happens, climbing fibers send signals to their related Purkinje cells that an error has occurred. These Purkinje cells can then make changes to avoid the error in the future.”

These error signals are mixed in with random firings of the climbing fibers, however, and researchers were long mystified about how the brain tells the difference between this noise and the useful, error-related information it needs to improve motor control.

Medina and his team showed the mechanism behind this differentiation in a study published earlier this year. By using a non-invasive microscopy technique that could monitor the Purkinje cells of awake and active mice, the researchers could measure the level of calcium within these cells when they received signals from climbing fibers.

The unexpected stimuli in this experiment were random puffs of air to the face, which caused the mice to blink. The researchers located Purkinje cells that control the mice’s eyelids and saw that calcium levels necessary for neuroplasticity, i.e., the brain’s ability to learn, were greater when the mice got an error signal triggered by a puff of air than they were after a random signal.

While being able to make such a distinction is critical to the brain’s ability to improve motor control, more information is needed to fine-tune it.  

“We wanted to see if the Purkinje cells could tell the difference not just between random firings and true errors signals but between smaller and bigger errors,” Medina said.

In their new study, the researchers used the same experimental set-up, with one key difference. They used air puffs of different durations: 15 milliseconds and 30 milliseconds.

What they found was that the eyelid-associated Purkinje cells filled with different amounts of calcium depending on the length of the puff; the longer ones produced larger spikes in calcium levels.        

In addition, the researchers saw that different percentages of eyelid-related Purkinje cells respond depending on the length of the puff.  

“Though there is a large population of climbing fibers that can give error-related information to the relevant Purkinje cells when they encounter something unexpected, not all of them fire each time,” Medina said. “We saw that there is information coded in the number of climbing fibers that fire. The longer puffs corresponded to more climbing fibers sending signals to their Purkinje cells.”

Their study could help explain how practice makes perfect, even when errors are imperceptibly small.

“If you felt a short puff and a long puff, you might not be able to say which one was which, but Purkinje cells can tell the difference,” Medina said. “The difference between a ‘very good’ and an ‘awesome’ tennis serve rests on being able to distinguish errors even as tiny as that.” 

Early cerebellum injury hinders neural development, possible root of autism, theory suggests

A brain region largely known for coordinating motor control has a largely overlooked role in childhood development that could reveal information crucial to understanding the onset of autism, according to Princeton University researchers.

The cerebellum — an area located in the lower rear of the brain — is known to process external and internal information such as sensory cues that influence the development of other brain regions, the researchers report in the journal Neuron. Based on a review of existing research, the researchers offer a new theory that an injury to the cerebellum during early life potentially disrupts this process and leads to what they call “developmental diaschisis,” which is when a loss of function in one part of the brain leads to problems in another region.

The researchers specifically apply their theory to autism, though they note that it could help understand other childhood neurological conditions. Conditions within the autism spectrum present “longstanding puzzles” related to cognitive and behavioral disruptions that their ideas could help resolve, they wrote. Under their theory, cerebellar injury causes disruptions in how other areas of the brain develop an ability to interpret external stimuli and organize internal processes, explained first author Sam Wang, an associate professor of molecular biology and the Princeton Neuroscience Institute (PNI).

"It is well known that the cerebellum is an information processor. Our neocortex [the largest part of the brain, responsible for much higher processing] does not receive information unfiltered. There are critical steps that have to happen between when external information is detected by our brain and when it reaches the neural cortex," said Wang, who worked with doctoral student Alexander Kloth and postdoctoral research associate Aleksandra Badura, both in PNI.

"At some point, you learn that smiling is nice because Mom smiles at you. We have all these associations we make in early life because we don’t arrive knowing that a smile is nice," Wang said. "In autism, something in that process goes wrong and one thing could be that sensory information is not processed correctly in the cerebellum."

Mustafa Sahin, a neurologist at Boston’s Children Hospital and associate professor of neurology at Harvard Medical School, said that Wang and his co-authors build upon known links between cerebellar damage and autism to suggest that the cerebellum is essential to healthy neural development. Numerous studies — including from his own lab — support their theory, said Sahin, who is familiar with the work but was not involved in it.

"The association between cerebellar deficits and autism has been around for a while," Sahin said. "What Sam Wang and colleagues do in this perspective article is to synthesize these two themes and hypothesize that in a critical period of development, cerebellar dysfunction may disrupt the maturation of distant neocortical circuits, leading to cognitive and behavioral symptoms including autism."

Traditionally, the cerebellum has been studied in relation to motor movement and coordination in adults. Recent studies, however, strongly suggest that it also influences childhood cognition, Wang said. Several studies also have found a correlation between cerebellar injury and the development of a disorder in the autism spectrum, the researchers report. For instance, the researchers cite a 2007 paper in the journal Pediatrics that found that individuals who experienced cerebellum damage at birth were 40 times more likely to score highly on autism screening tests. They also reference studies in 2004 and 2005 that found that the cerebellum is the most frequently disrupted brain region in people with autism.

"What we realized from looking at the literature is that these two problems — autism and cerebellar injury — might be related to each other" via the cerebellum’s influence on wider neural development, Wang said. "We hope to get people and scientists thinking differently about the cerebellum or about autism so that the whole field can move forward."

The researchers conclude by suggesting methods for testing their theory. First, by inactivating brain-cell electrical activity, it should be possible to pinpoint the developmental stage in which injury to one part of the brain affects the maturation of another. A second, more advanced method is to reconstruct the neural connections between the cerebellum and other brain regions; the federal BRAIN Initiative announced in 2013 aims to map the activity of all the brain’s neurons. Finally, mouse brains can be used to disable and restore brain-region function to observe the “upstream” effect in other areas.

(Image caption: These scans show atrophy of the cerebellum in a boy with Christianson Syndrome. This symptom was observed in some, but not all boys, with the condition. Credit: Eric Morrow/Brown University)

Diagnostic criteria for Christianson Syndrome

Because the severe autism-like condition Christianson Syndrome was only first reported in 1999 and some symptoms take more than a decade to appear, families and doctors urgently need fundamental information about it. A new study that doubles the number of cases now documented in the scientific literature provides the most definitive characterization of CS to date. The authors therefore propose the first diagnostic criteria for the condition.

"We’re hoping that clinicians will use these criteria and that there will be more awareness among clinicians and the community about Christianson Syndrome," said Brown University biology and psychiatry Assistant Professor Dr. Eric Morrow, senior author of the study in press in the Annals of Neurology. “We’re also hoping this study will impart an opportunity for families to predict what to expect for their child and what’s a part of the syndrome.”

In conducting their study, which includes detailed behavioral, medical and genetic observations of 14 boys with CS from 12 families, the team of scientists and physicians worked closely with families of the small but fast-growing Christianson Syndrome Association , including hosting the group’s inaugural conference at Brown’s Alpert Medical School last summer.

In their study, Morrow’s team was able to quantify the most frequent symptoms specific to CS. These include moderate to severe intellectual disability, epilepsy, difficulty or inability walking and talking, attenuated head and brain growth, and hyperactivity. Boys sometimes exhibit other specific symptoms – including autism-like behaviors, low height and weight, acid reflux, and regressions in speech and motor skills after age 10 – that the researchers include as secondary proposed diagnostic criteria. A third of the boys also had potentially neurodegenerative problems such as atrophy of the cerebellum.

What’s still not clear is whether the disease limits the eventual lifespan of patients.

Distinct genetic cause

Many CS traits, including a very happy disposition, appear similar to those of another autism-like condition, Angelman Syndrome, but the study defines important differences.

Among the most important ones is that the two syndromes have distinct genetic underpinnings. In all CS cases, said Morrow who treats autism patients at the E. P. Bradley Hospital in East Providence, boys have a mutation on the SLC9A6 gene on the X chromosome that disables production of a protein called NHE6 that is important for neurological development.

Girls, who have two X chromosomes, can also be carriers of CS mutations, but they appear to be affected differently and less severely or not at all, the study reports.

The connection to the SLC9A6 gene was first discovered in 2008. In analyzing the genomes of each patient and their parents in the new study, lead authors Matthew Pescosolido, a graduate student, and David Stein, a former undergraduate, found that each boy had only one mutation, but there were many different ones across the entire group. More often than not, they determined, the mutation was not inherited, but an unlucky “de novo” change that occurred in the affected boy. In two situations, boys in unrelated families happened to share the same mutation. These recurrent mutations suggest that there may be hotspots in the DNA for mutation at these sites, Morrow said, although further research will be necessary to sort this out.

Morrow said there is evidence that SLC9A6 mutations – and therefore CS – may be a relatively common source of X-linked intellectual disability. One study, for example found that SLC9A6 mutations in two of 200 people suspected of having X-linked ID. Another found that 1 in 19 families with a case of ID exhibited a mutation that truncated the NHE6 protein.

"If we assume that between 1-3 percent of the world’s population is diagnosed with an intellectual disability and approximately 10-20 percent of the causes are due to X-linked genes, then we can estimate that CS may affect between 1 in 16,000 to 100,000 people," Morrow and his co-authors wrote. Worldwide that frequency would add up to more than 70,000 cases.

Relevance to autism, epilepsy

In a paper published last year, Morrow’s research group found that NHE6 is underexpressed in the brains of many children with more general forms of autism. This potential connection suggests that learning about CS can help doctors and scientists learn about autism.

Similarly by studying the regression of walking and verbal skills among Christianson boys, Morrow said researchers could learn more about regressions in autism.

"Christianson syndrome, I hope will be a model," Morrow said. "If we could understand the biological mechanism that leads to that loss, and we can prevent it, by developing a treatment, then these kids will remain further ahead."

Such advances will require much more study, but Morrow said that by uncovering a variety of mutations that all lead to the disease, the study provides a wealth of new information for that work.

"We can now study these different mutations and learn how this protein works by how it gets inactivated," he said. "All the different ways it gets inactivated can actually inform us about the different components of the protein that have an important function."

How does the cerebellum work?

Nothing says “don’t mess with me” like a deeply-fissured cortex. Even the sharpest jaws and claws in the animal kingdom are worthless without some serious thought muscle under the hood. But beneath the highly convoluted membrane covering the brains of the evolutionary upper crust hides the original crumpled processor—the cerebellum. How this organ might actually work is the subject of a review published in Frontiers of Systems Neuroscience by researchers at the University of Minnesota.

Read more

Scientists find new clues to brain’s wiring

New research provides an intriguing glimpse into the processes that establish connections between nerve cells in the brain. These connections, or synapses, allow nerve cells to transmit and process information involved in thinking and moving the body.

Reporting online in Neuron, researchers at Washington University School of Medicine in St. Louis have identified a group of proteins that program a common type of brain nerve cell to connect with another type of nerve cell in the brain.

The finding is an important step forward in efforts to learn how the developing brain is built, an area of research essential to understanding the causes of intellectual disability and autism.

“We now are looking at how loss of this wiring affects brain function in mice,” said senior author Azad Bonni, MD, PhD, the Edison Professor of Neurobiology and head of the Department of Anatomy and Neurobiology at the School of Medicine.

Bonni and his colleagues are studying synapses in the cerebellum, a region of the brain that sits in the back of the head. The cerebellum plays a central role in controlling the coordination of movement and is essential for what researchers call procedural motor learning, which makes it possible to move our muscles at an unconscious level, such as when we ride a bicycle or play the piano.

“The cerebellum also regulates mental functions,” Bonni said. “So, impairment of the wiring of nerve cells in the cerebellum may contribute to movement disorders as well as cognitive problems including autism spectrum disorders.”

His new results show that a complex of proteins known as NuRD (nucleosome remodeling and deacetylase) plays a fairly high supervisory role in some aspects of the cerebellum’s construction. When the researchers blocked the NuRD complex, cells in the cerebellum called granule cells failed to form connections with other nerve cells, the Purkinje neurons. These circuits are important for the cerebellum’s control of movement coordination and learning.

Bonni and his colleagues showed that NuRD exerts influence at the epigenetic level, which means it controls factors other than DNA that affect gene activity. For example, NuRD affects the configurations of molecules that store DNA and that can open and close the coils of DNA like an accordion, making genes less or more accessible. Changing the accessibility of genes changes their activity levels. For instance, cells can’t frequently make proteins from genes in a tightly packed coil of DNA.

NuRD also alters tags on the proteins that store DNA, decreasing the chances that the gene will be used. Among the genes deactivated by NuRD are two that control the activity of other genes involved in the wiring of the cerebellum.

“This tells us that the NuRD complex is very influential—not only does it affect the activity of genes directly, it also controls other regulators of multiple genes,” Bonni said.

(Image: Courtesy of VJ Wedeen and LL Wald, Martinos Center, Harvard Medical School, Human Connectome Project)