Neuroscience

A new study published 26th November in the open access journal PLOS Biology, identifies a new target in the search for therapeutic interventions for Huntington’s disease – a devastating late-onset neurodegenerative disorder.

The disease is genetic, affecting up to one person in 10,000, and from the age of about 35 leads to increasingly severe problems with movement, mental function, and behavior. Patients usually die within 20 years of onset, and there is to date no treatment that will modify the disease onset or progression.

Huntington’s disease is caused by an unusual type of mutation in a gene that encodes the “huntingtin” protein. These mutations create long stretches of the amino acid glutamine within the protein chain, preventing huntingtin from folding properly and making it more ‘sticky’. This causes huntingtin proteins to self-aggregate in both the nucleus and cytoplasm of cells, disrupting multiple aspects of cellular function and ultimately leading to the progressive death of nerve cells.

Nuclear huntingtin aggregates have been found to interfere with the transcription of many genes, and previous work has shown beneficial effects for Huntington’s disease of inhibiting a family of enzymes that are normally thought to regulate transcription – the histone deacetylases, or HDACs. However, humans have eleven different HDAC enzymes, and it’s been uncertain exactly which HDAC needs to be inhibited to see these benefits.

The new study from Michal Mielcarek, Gillian Bates and colleagues at King’s College London has pinpointed just one of these enzymes as the target – HDAC4 – but with an intriguing twist; everything is happening in the cytoplasm, not the nucleus, and HDAC4’s classic role in transcription has little to do with it.

The researchers noted that the HDAC4 protein naturally contains a region that, like mutant huntingtin, is rich in the amino acid glutamine. They show that HDAC4 can associate directly with huntingtin protein in a manner that depends on the length of the glutamine tracts, but that this association between HDAC4 and huntingtin occurs in the cytoplasm of nerve cells in the mouse brain, and – surprisingly – not in the nucleus, where HDAC4 is known to have its transcriptional role.

Bates and colleagues did their work in an aggressive disease mouse model of Huntington’s disease – the gold standard model for this type of study. They find that halving the levels of HDAC4 in the cells of Huntington’s disease mice can delay the aggregation of huntingtin in the cytoplasm, thereby identifying a new route to modulating the toxicity of mutant huntingtin protein. Crucially, reducing HDAC4 levels can also rescue the overall function of nerve cells and their synapses, with corresponding improvements seen in coordination of movement, neurological performance and lifespan of the mice. In agreement with the cytoplasmic association between HDAC4 and huntingtin, this all happens without any obvious improvement in the defective gene transcription in the nucleus.

There are currently no disease-modifying therapeutics available for Huntington’s disease. It is still very early days and it is important to note that the medical applications of any therapy arising from this study have not been studied in a clinical setting and are far from clear. However, one broad-brush HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA) had previously been shown to improve movement defects in preclinical tests in this mouse model. The authors have shown in a related publication that, in addition to inhibiting HDAC enzyme function, SAHA decreases levels of the HDAC4 protein. Therefore it is hoped that the development of HDAC4-targeted compounds may be a promising strategy in improving the lot of Huntington’s disease patients.

A study published recently in the Journal of Neuroscience points, for the first time, to the gene trkC as a factor in susceptibility to the disease. The researchers define the specific mechanism for the formation of fear memories which will help in the development of new pharmacological and cognitive treatments.

Five out of every 100 people* in Spain suffer from panic disorder, one of the diseases included within the anxiety disorders, and they experience frequent and sudden attacks of fear that may influence their everyday lives, sometimes even rendering them incapable of things like going to the shops, driving the car or holding down a job.

It was known that this disease had a neurobiological and genetic basis and for some time the search had been on to discover which genes were involved in its development, with certain genes being implicated without their physiopathological contribution being understood. Now, for the first time, researchers from the Centre for Genomic Regulation (CRG) have revealed that the gene NTRK3, responsible for encoding a protein essential for the formation of the brain, the survival of neurones and establishing connections between them, is a factor in genetic susceptibility to panic disorder.

"We have observed that deregulation of NTRK3 produces changes in brain development that lead to malfunctions in the fear-related memory system", explains Mara Dierssen, head of the Cellular and Systems Neurobiology group at the CRG. “In particular, this system is more efficient at processessing information to do with fear, the thing that makes a person overestimate the risk in a situation and therefore feel more frightened and, also, that stores that information in a more lasting and consistent manner".

Different regions of the human brain are responsible for processing this feeling, although the hippocampus and amygdala play crucial roles. On the one hand, the hippocampus is responsible for forming memories and processing contextual information, which means that the person may be afraid of being in places where they could suffer a panic attack; and on the other, the amygdala is crucial in converting this information into a physiological fear response.

Although these circuits are activated in everyone in warning situations, what the CRG researchers have discovered is that “in those people who suffer from panic disorder there is overactivation of the hippocampus and altered activation in the amygdala circuitry, resulting in exaggerated formation of fear memories”, explains Davide D’Amico, a PhD student at the CRG, co-author of the work and the article published in the Journal of Neuosciences, together with Dierssen and the researcher Mónica Santos.

They have also found that Tiagabine, a drug that modulates the brain’s fear inhibition system, is able to reverse the formation of panic memories. Although it had already been observed to alleviate certain symptoms in some patients, “we have discovered that it specifically helps restore the fear memory system”, points out Dierssen.

Panic disorder

Panic attacks are a key symptom of panic disorder. They can last several minutes, be sudden and repeated, and the sufferer has a physical reaction similar to the alarm response to real danger, involving palpitations, cold sweats, dizziness, shortness of breath, tingling in the body, nausea and stomach pain. On top of this, they feel continuously anxious when faced with the prospect of suffering another attack.

This study by the CRG researchers reveals that the way in which the memories resulting from a panic attack are stored is what ultimately ends up producing the disorder, which usually appears between 20 and 30 years of age. Although it has a genetic basis, it is also influenced by other environmental factors, such as accumulated stress. This is why the authors of the paper consider elevated environmental stress in Spanish society to have led to an increase in the occurrence of these disorders.

Currently, there is no cure for this disease, which is treated with medicines that block the more serious symptoms, as well as with cognitive therapy, which aims to help the person learn to survive the attacks better. “The problem is that drugs have many side effects and psychotherapy is not really aimed at specific moments in the process of forming and forgetting fear memories. In our work we have defined a specific creation mechanism for these fear memories that could help in the development of new drugs and, also, in identifying the key moments for applying cognitive therapy”, indicates D’Amico.

Scientists are a step closer to understanding how some of the brain’s 100 billion nerve cells co-ordinate their communication. The study is published in the journal Cell Reports.

The University of Bristol research team investigated some of the chemical processes that underpin how brain cells co-ordinate their communication. Defects in this communication are associated with disorders such as epilepsy, autism and schizophrenia, and therefore these findings could lead to the development of novel neurological therapies.

Neurons in the brain communicate with each other using chemicals called neurotransmitters. This release of neurotransmitter from neurons is tightly controlled by many different proteins inside the neuron. These proteins interact with each other to ensure that neurotransmitter is only released when necessary. Although the mechanisms that control this release have been extensively studied, the processes that co-ordinate how and when the component proteins interact is not fully understood.

The School of Biochemistry researchers have now discovered that one of these proteins called ‘RIM1α’ is modified by a small protein named ‘SUMO’ which attaches to a specific region in RIM1α. This process acts as a ‘molecular switch’ which is required for normal neurotransmitter release.

Jeremy Henley, Professor of Molecular Neuroscience in the University’s Faculty of Medical and Veterinary Sciences and the study’s lead author, said: “These findings are important as they show that SUMO modification plays a vital and previously unsuspected role in normal brain function.”

The research builds on the team’s earlier work that identified a group of proteins in the brain responsible for protecting nerve cells from damage and could be used in future for therapies for stroke and other brain diseases.

Scientists have moved a step closer to understanding genetic changes that permitted humans and other mammals to develop such big brains.

During evolution, different mammal species have experienced variable degrees of expansion in brain size. An important goal of neurobiology is to understand the genetic changes underlying these extraordinary adaptations.

The process by which some species evolved larger brains – called encephalization – is not well understood by scientists. The puzzle is made more complex because evolving large brains comes at a very high cost.

Dr Humberto Gutierrez, from the School of Life Sciences, University of Lincoln, UK, led research which examined the genomes of 39 species of mammals with the aim of better understanding how brains became larger and more complex in mammals.

To do this, the scientists focussed on the size of gene families across these species. Gene families are groups of related genes which share similar characteristics, often linked with common or related biological functions. It is believed that large changes in the size of gene families can help to explain why related species evolved along different paths.

The researchers found a clear link between increased brain size and the expansion of gene families related to certain biological functions.

Dr Gutierrez said: “We found that brain size variations are associated with changes in gene number in a large proportion of families of closely related genes. These gene families are preferentially involved in cell communication and cell movement as well as immune functions and are prominently expressed in the human brain. Our results suggest that changes in gene family size may have contributed to the evolution of larger brains in mammals.”

Mammalian species in general tend to have large brains compared to their body size which represent an evolutionary costly adaptation as they require large amounts of energy to function.

Dr Gutierrez explained: “The brain is an extremely expensive organ consuming a large amount of energy in proportion to its volume, so large brains place severe metabolic demands on animals. Larger brains also demand higher parental investment. For example, humans require many years of nurturing and care before their brains are fully matured.”

Dr Gutierrez’s research concluded that variations in the size of gene families associated with encephalization provided an evolutionary support for the specific physiological demands associated with increased brain size in mammals.

Establishing links between genes, the brain and human behavior is a central issue in cognitive neuroscience research, but studying how genes influence cognitive abilities and behavior as the brain develops from childhood to adulthood has proven difficult.

Now, an international team of scientists has made inroads to understanding how genes influence brain structure and cognitive abilities and how neural circuits produce language.

The team studied individuals with a rare disorder known as Williams syndrome. By measuring neural activity in the brain associated with the distinct language skills and facial recognition abilities that are typical of the syndrome, they showed that Williams is due not to a single gene but to distinct subsets of genes, hinting that the syndrome is more complex than originally thought.

"Solutions to understanding the connections between genes, neural circuits and behavior are now emerging from a unique union of genetics and neuroscience," says Julie Korenberg, a University of Utah professor and an adjunct professor at the Salk Institute, who led the genetics aspects on the new study.

The study was led by Debra Mills, a professor of cognitive neuroscience at Bangor University in Wales. Ursula Bellugi, a professor at the Salk Institute for Biological Studies in La Jolla, was also integrally involved in the research.

Korenberg was convinced that with Mills’ approach of directly measuring the brain’s electrical firing they could solve the puzzle of precisely which genes were responsible for building the brain wiring underlying the different reaction to human faces in Williams syndrome.

"We also discovered," says Mills, "that in those with Williams syndrome, the brain processes language and faces abnormally from early childhood through middle age. This was a surprise because previous studies had suggested that part of the Williams brain functions normally in adulthood, with little understanding about how it developed."

The results of the study were published November 12, 2013 in Developmental Neuropsychology.

Williams syndrome is caused by the deletion of one of the two usual copies of approximately 25 genes from chromosome 7, resulting in mental impairment. Nearly everyone with the condition is missing these same genes, although a few rare individuals retain one or more genes that most people with Williams have lost. Korenberg was the early pioneer of studying these individuals with partial gene deletions as a way of gathering clues to the specific function of those genes and gene networks. The syndrome affects approximately 1 in 10,000 people around the world, including an estimated 20,000 to 30,000 individuals in the United States.

Although individuals with Williams experience developmental delays and learning disabilities, they are exceptionally sociable and possess remarkable verbal abilities and facial recognition skills in relation to their lower IQ. Bellugi has long observed that sociability also seems to drive language and has spent much of her career studying those with Williams syndrome.

"Williams offers us a window into how the brain works at many different levels," says Bellugi. "We have the tools to measure the different cognitive abilities associated with the syndrome, and thanks to Julie and Debbie we are now able to combine this with studies of the underlying genetic and neurological aspects."

Suspecting that specific genes might lie at the origins of brain plasticity, functional changes in the brain that occur with new knowledge or experiences, and that these genes might be linked to the unusual proficiencies of those with Williams, the team enrolled individuals of various ages in their study. They drew from children, adolescents and adults who all had the full genetic deletion for Williams syndrome and compared them with their non-affected peers. Their study is additionally significant for being one of the first to examine the brain structure and its functioning in children with Williams. And, as Korenberg predicted, a critical piece of the puzzle came from including in their study two adults with partial genetic deletions for Williams.

Using highly sensitive sensors to measure brain activity, the researchers, led by Mills, presented their study participants with both visual and auditory stimuli in the form of unfamiliar faces and spoken sentences. They charted the small changes in voltage generated by the areas of the brain responding to these stimuli, a process known as event-related potentials (ERPs). Mills was the first to publish studies on Williams syndrome using ERPs, developed the ERP markers for this study, and oversaw its design and analysis.

Mills identified ERP markers of brain plasticity in Williams syndrome in children and adults of varying ages and developmental stages. These findings are important because the brains of people with Williams are structured differently than those of people without the syndrome. In the Williams brain, the dorsal areas (along the back and top), which help control vision and spatial understanding, are undersized. The ventral areas (at the front and the bottom), which influence language, facial recognition, emotion and social drive, are relatively normal in size.

It was previously believed that in individuals with Williams, the ventral portion of the brain operated normally. What the team discovered, however, was that this area of the brain also processed information differently than those without the syndrome, and did so throughout development, from childhood to the adult years. This suggests that the brain was compensating in order to analyze information; in other words, it was exhibiting plasticity. Of additional importance, the distinct ERP markers identified by Mills are so characteristic of the different brain organization in Williams that this information alone is approximately 90 percent accurate when analyzing brain activity to identify someone with Williams syndrome.

Other key findings of the study resulted from comparing the ERPs of participants with full Williams deletion with those with partial genetic deletions. While psychological tests focused on facial recognition show no difference between these groups, the scientists found differences in these recognition abilities on the ERP measurements, which look directly at neural activity. Thus, the scientists were able to see how very slight genetic differences affected brain activity, which will allow them identify the roles of sub-sets of Williams genes in brain development and in adult facial recognition abilities.

By combining these one-in-a-million people with tools capable of directly measuring brain activity, the scientists now have the unprecedented opportunity to study the genetic underpinnings of mental disorders. The results of this study not only advance science’s understanding of the links between genes, the brain and behavior, but may lead to new insight into such disorders as autism, Down syndrome and schizophrenia.

"By greatly narrowing the specific genes involved in social disorders, our findings will help uncover targets for treatment and provide measures by which these and other treatments are successful in alleviating the desperation of autism, anxiety and other disorders," says Korenberg.

Our sense of smell is often the first response to environmental stimuli. Odors trigger neurons in the brain that alert us to take action. However, there is often more than one odor in the environment, such as in coffee shops or grocery stores. How does our brain process multiple odors received simultaneously?

Barani Raman, PhD, of the School of Engineering & Applied Science at Washington University in St. Louis, set out to find an answer. Using locusts, which have a relatively simple sensory system ideal for studying brain activity, he found the odors prompted neural activity in the brain that allowed the locust to correctly identify the stimulus, even with other odors present.

The results were published in Nature Neuroscience as the cover story of the December 2013 print issue.

The team uses a computer-controlled pneumatic pump to administer an odor puff to the locust, which has olfactory receptor neurons in its antennae, similar to sensory neurons in our nose. A few seconds after the odor puff is given, the locust gets a piece of grass as a reward, as a form of Pavlovian conditioning. As with Pavlov’s dog, which salivated when it heard a bell ring, trained locusts anticipate the reward when the odor used for training is delivered. Instead of salivating, they open their palps, or finger-like projections close to the mouthparts, when they predict the reward. Their response was less than half of a second. The locusts could recognize the trained odors even when another odor meant to distract them was introduced prior to the target cue.

“We were expecting this result, but the speed with which it was done was surprising,” says Raman, assistant professor of biomedical engineering. “It took only a few hundred milliseconds for the locust’s brain to begin tracking a novel odor introduced in its surrounding. The locusts are processing chemical cues in an extremely rapid fashion.”

“There were some interesting cues in the odors we chose,” Raman says. “Geraniol, which smells like rose to us, was an attractant to the locusts, but citral, which smells like lemon to us, is a repellant to them. This helped us identify principles that are common to the odor processing.

Raman has spent a decade learning how the human brain and olfactory system operate to process scent and odor signals. His research seeks to take inspiration from the biological olfactory system to develop a device for noninvasive chemical sensing. Such a device could be used in homeland security applications to detect volatile chemicals and in medical diagnostics, such as a device to test blood-alcohol level.

This study is the first in a series seeking to understand the principles of olfactory computation, Raman says.

“There is a precursory cue that could tell the brain there is a predator in the environment, and it has to predict what will happen next,” Raman says. “We want to determine what kinds of computations have to be done to make those predictions.”

In addition, the team is looking to answer other questions.

“Neural activity in the early processing centers does not terminate until you stop the odor pulse,” he says. “If you have a lengthy pulse – 5 or 10 seconds long – what is the role of neural activity that persists throughout the stimulus duration and often even after you terminate the stimulus? What are the roles of the neural activity generated at different points in time, and how do they help the system adapt to the environment? Those questions are still not clear.”

To flexibly deal with our ever-changing world, we need to learn from both the negative and positive consequences of our behaviour. In other words, from punishment and reward. Hanneke den Ouden from the Donders Institute in Nijmegen demonstrated that serotonin and dopamine related genes influence how we base our choices on past punishments or rewards. This influence depends on which gene variant you inherited from your parents. These results were published in Neuron on 20 November.

The brain chemicals dopamine and serotonin partly determine our sensitivity to reward and punishment. At least, this was a common assumption. Hanneke den Ouden and Roshan Cools investigated this assumption together with colleagues from the Donders Institute and New York University. Den Ouden explains: ‘We used a simple computer game to test the genetic influence of the genes DAT1 and SERT, as these genes influence dopamine and serotonin. We discovered that the dopamine gene affects how we learn from the long-term consequences of our choices, while the serotonin gene affects our choices in the short term.’

Online game

‘In nearly 700 people we analysed which variant of the SERT and the DAT1 genes they had’, Den Ouden describes. ‘Using an online game, we investigated how well people are able to adjust their choice strategy after receiving a reward or a punishment.’ The players would repeatedly choose one of two symbols. Symbol A usually resulted in a reward whereas symbol B usually resulted in punishment. Halfway through the game, these rules were reversed. The game allowed the researchers to measure how flexible people are in adjusting their choices when the rules change. But it also showed whether people impulsively change their choice when the computer happened to give misleading feedback.

Different genes, different strategies

Den Ouden: ‘Different players use different strategies, which depend on their genetic material. People’s tendency to change their choice immediately after receiving a punishment depends on which serotonin gene variant they inherited from their parents. The dopamine gene variant, on the other hand, exerts influence on whether people can stop themselves making the choice that was previously rewarded, but no longer is.’

This study shows that dopamine and serotonin are important for different forms of flexibility associated with receiving reward and punishment. Many neuropsychiatric disorders caused by abnormal dopamine and/or serotonin levels are associated with forms of inflexibility, for example addiction, anxiety, or Parkinson’s disease. So this study not only tells us more about the heritability of our choice behaviour; a better understanding of the relationship between brain chemicals and behaviour in healthy people will ultimately help to provide us with better insight into these neuropsychiatric disorders.

Alexander disease is a devastating brain disease that almost nobody has heard of — unless someone in the family is afflicted with it. Alexander disease strikes young or old, and in children destroys white matter in the front of the brain. Many patients, especially those with early onset, have significant intellectual disabilities.

(Image: A mutant gene that causes the deadly Alexander disease creates an overgrowth of the protein GFAP in mouse brain cells called astrocytes (right) compared to normal brain cells (left))

Regardless of the age when it begins, Alexander disease is always fatal. It typically results from mutations in a gene known as GFAP (glial fibrillary acidic protein), leading to the formation of fibrous clumps of protein inside brain cells called astrocytes.

Classically, astrocytes and other glial cells were considered “helpers” that nourish and protect the neurons that do the actual communication. But in recent years, it’s become clear that glial cells are much more than passive bystanders, and may be active culprits in many neurological diseases.

Now, in a report in the Journal of Neuroscience, researchers at UW-Madison show that Alexander disease also affects neurons, and in a way that impacts several measures of learning and memory.

Mice were engineered to contain the same mutation in GFAP that is found in human patients. Their astrocytes spontaneously increased production of GFAP, the same response found after many types of injury or disease in the brain. In Alexander disease, the result is an increase in mutant GFAP that is “toxic to the cell, and unfortunately astrocytes respond by making more GFAP,” says first author Tracy Hagemann, an associate scientist with the university’s Waisman Center.

While GFAP is usually found in astrocytes, it also occurs in neural stem cells, a population of cells that persist in some areas of the brain to continually spawn new neurons throughout adulthood. In the mouse versions of Alexander disease, neural stem cells are present, but they fail to develop into neurons, Hagemann says. “Think of a garden where your green beans never sprouted. Was it too cold for them to sprout, or was there another problem? Something similar is happening with these neural stem cells. They are present, but inert, and we’re not sure why.”

The shortage of new neurons could explain why the mice with excess GFAP failed a test that required them to remember the location of a submerged platform in a tub of water.

The report is “the first to suggest that the problems in Alexander disease extend beyond just the white matter and astrocytes, and may provide a clue to the problems with learning and memory that are such prominent features in the human disease,” says lab leader Albee Messing, a professor of comparative biosciences in the UW School of Veterinary Medicine.

One immediate question that the team will try to answer is whether the same defect in stem cells can be found in autopsy samples stored over many years to allow just this kind of investigation.

Still to be clarified is whether the mutation affects the neural stem cells directly, or whether it acts through other astrocytes that are nearby. “We do know that the astrocytes become activated with this GFAP mutation,” Hagemann says. “That activation — a kind of inflammation — could be making the environment hostile to young neurons. Or the mutation could be changing the neural stem cells themselves in some other way.

"Medicine advances by teasing things apart," says Hagemann. "A single mutation can work in different ways — through different chains of cause and effect leading to different symptoms of a disease. In this case it’s like the old question of nature versus nurture. Was the stem cell born bad — was it genetically doomed? Or were the reactive astrocytes in the neighborhood a toxic influence? Or both? This is an important question for Alexander disease and other brain deteriorating disorders, especially with the current focus on stem cells as a source for new neurons and therapy."

Already, the Waisman group is screening drugs that might slow GFAP production. Eventually, Hagemann says, the work may illuminate the role of astrocyte dysfunction in other neural diseases featuring aggregates of misformed proteins, including ALS, Parkinson’s, and Alzheimer’s disease.

Studies have shown that resveratrol, a natural compound found in colored vegetables, fruits and especially grapes, may minimize the impact of Parkinson’s disease, stroke and Alzheimer’s disease in those who maintain healthy diets or who regularly take resveratrol supplements. Now, researchers at the University of Missouri have found that resveratrol may also block the effects of the highly addictive drug, methamphetamine.

(Image: Wikipedia)

Dennis Miller, associate professor in the Department of Psychological Sciences in the College of Arts & Science and an investigator with the Bond Life Sciences Center, and researchers in the Center for Translational Neuroscience at MU, study therapies for drug addiction and neurodegenerative disorders. Their research targets treatments for methamphetamine abuse and has focused on the role of the neurotransmitter dopamine in drug addiction. Dopamine levels in the brain surge after methamphetamine use; this increase is associated with the motivation to continue using the drug, despite its adverse consequences. However, with repeated methamphetamine use, dopamine neurons may degenerate causing neurological and behavioral impairments, similar to those observed in people with Parkinson’s disease.

“Dopamine is critical to the development of methamphetamine addiction—the transition from using a drug because one likes or enjoys it to using the drug because one craves or compulsively uses it,” Miller said. “Resveratrol has been shown to regulate these dopamine neurons and to be protective in Parkinson’s disease, a disorder where dopamine neurons degenerate; therefore, we sought to determine if resveratrol could affect methamphetamine-induced changes in the brain.”

Using procedures established by Parkinson’s and Alzheimer’s disease research, rats received resveratrol once a day for seven days in about the same concentration as a human would receive from a healthy diet. After a week of resveratrol, researchers measured how much dopamine was released by methamphetamine. Researchers found that resveratrol significantly diminished methamphetamine’s ability to increase dopamine levels in the brain. Furthermore, resveratrol diminished methamphetamine’s ability to increase activity in mice, a behavior that models the hyperactivity observed in people that use the stimulant.

“People are encouraged by physicians and dieticians to include resveratrol-containing products in their diet and protection against methamphetamine’s harmful effects may be an added bonus,” Miller said. “Additionally, there are no consistently effective treatments to help people who are dependent on methamphetamine. Our initial research suggests that resveratrol could be included in a treatment regimen for those addicted to methamphetamine and it has potential to decrease the craving and desire for the drug. Resveratrol is found in good, colorful foods, and has few side effects. We all ought to consume resveratrol for good brain health; our research suggests it may also prevent the changes in the brain that occur with the development of drug addiction.”

A vision is to implant nerve precursor cells in the diseased brains of patients with Parkinson’s and Huntington’s diseases, whereby these cells are to assume the function of the cells that have died off. However, the implanted nerve cells frequently do not migrate as hoped, rather they hardly move from the site. Scientists at the Institute for Reconstructive Neurobiology at Bonn University have now discovered an important cause of this: Attractants secreted by the precursor cells prevent the maturing nerve cells from migrating into the brain. The results are presented in the journal “Nature Neuroscience.”

One approach for treating patients with Parkinson’s or Huntington’s disease is to replace defective brain cells with fresh cells. To do this, immature precursor cells from neurons are implanted into the diseased brains; these cells are to then mature on-site and take over the function of the defective cells. “However, it has been shown again and again that the nerve cells generated by the transplant barely migrate into the brain but remain largely confined to the implant site,” says Prof. Dr. Oliver Brüstle, Director of the Institute for Reconstructive Neurobiology at Bonn University. Scientists have believed for a long time that this effect is associated with the fact that in the mature brain, there are unfavorable conditions for the uptake of additional nerve cells.

Immature and more mature nerve cells attract each other like magnets

The researchers from the Institute for Reconstructive Neurobiology of Bonn University have now discovered a fully unexpected mechanism to which the deficient migratory behavior of the graft-derived neurons can be attributed. The implanted cells mature at different rates and thus there is a mixture of the two stages. “Like magnets, the precursor cells which are still largely immature attract the nerve cells which have already matured further, which is why there is a sort of agglomeration,” says lead author Dr. Julia Ladewig, who was recently awarded a research prize of 1.25 million Euro by the North Rhine-Westphalian Stem Cell Network, which is supported by State Ministry of Science and Research.

The cause of the attractive force which has remained hidden to date involves chemical attractants which are secreted by the precursor cells. “In this way, the nerve precursor cells prevent the mature brain cells from penetrating further into the tissue,” says Dr. Philipp Koch, who performed the primary work for the study as an additional lead author, together with Dr. Ladewig.

The scientists had initially observed that, the more precursor cells contained in the transplant, the worse the migration of nerve cells is. In a second step, the researchers from the Institute for Reconstructive Neurobiology at Bonn University were able to decode and inactivate the attractants responsible for the agglomeration of mature and immature neurons. When the scientists deactivated the receptor tyrosine kinase ligands FGF2 and VEGF with inhibitors, mature nerve cells migrated better into the animal brains and dispersed over much larger areas.

Promising universal approach for transplants

“This is a promising new approach to solve an old problem in neurotransplantation,” Prof. Brüstle summarizes. Through the inhibition of attractants, the migration of implanted nerve precursor cells into the brain can be significantly improved. As the researchers have shown in various models with precursor cells from animals and humans, the mechanism is a fundamental principle which also functions across species. “However, more research is still needed to transfer the principle into clinical application,” says Prof. Brüstle.

A computer program called the Never Ending Image Learner (NEIL) is running 24 hours a day at Carnegie Mellon University, searching the Web for images, doing its best to understand them on its own and, as it builds a growing visual database, gathering common sense on a massive scale.

NEIL leverages recent advances in computer vision that enable computer programs to identify and label objects in images, to characterize scenes and to recognize attributes, such as colors, lighting and materials, all with a minimum of human supervision. In turn, the data it generates will further enhance the ability of computers to understand the visual world.

But NEIL also makes associations between these things to obtain common sense information that people just seem to know without ever saying — that cars often are found on roads, that buildings tend to be vertical and that ducks look sort of like geese. Based on text references, it might seem that the color associated with sheep is black, but people — and NEIL — nevertheless know that sheep typically are white.

"Images are the best way to learn visual properties," said Abhinav Gupta, assistant research professor in Carnegie Mellon’s Robotics Institute. "Images also include a lot of common sense information about the world. People learn this by themselves and, with NEIL, we hope that computers will do so as well."

A computer cluster has been running the NEIL program since late July and already has analyzed three million images, identifying 1,500 types of objects in half a million images and 1,200 types of scenes in hundreds of thousands of images. It has connected the dots to learn 2,500 associations from thousands of instances.

The public can now view NEIL’s findings at the project website, www.neil-kb.com.

The research team, including Xinlei Chen, a Ph.D. student in CMU’s Language Technologies Institute, and Abhinav Shrivastava, a Ph.D. student in robotics, will present its findings on Dec. 4 at the IEEE International Conference on Computer Vision in Sydney, Australia.

One motivation for the NEIL project is to create the world’s largest visual structured knowledge base, where objects, scenes, actions, attributes and contextual relationships are labeled and catalogued.

"What we have learned in the last 5-10 years of computer vision research is that the more data you have, the better computer vision becomes," Gupta said.

Some projects, such as ImageNet and Visipedia, have tried to compile this structured data with human assistance. But the scale of the Internet is so vast — Facebook alone holds more than 200 billion images — that the only hope to analyze it all is to teach computers to do it largely by themselves.

Shrivastava said NEIL can sometimes make erroneous assumptions that compound mistakes, so people need to be part of the process. A Google Image search, for instance, might convince NEIL that “pink” is just the name of a singer, rather than a color.

"People don’t always know how or what to teach computers," he observed. "But humans are good at telling computers when they are wrong."

People also tell NEIL what categories of objects, scenes, etc., to search and analyze. But sometimes, what NEIL finds can surprise even the researchers. It can be anticipated, for instance, that a search for “apple” might return images of fruit as well as laptop computers. But Gupta and his landlubbing team had no idea that a search for F-18 would identify not only images of a fighter jet, but also of F18-class catamarans.

As its search proceeds, NEIL develops subcategories of objects — tricycles can be for kids, for adults and can be motorized, or cars come in a variety of brands and models. And it begins to notice associations — that zebras tend to be found in savannahs, for instance, and that stock trading floors are typically crowded.

NEIL is computationally intensive, the research team noted. The program runs on two clusters of computers that include 200 processing cores.

This research is supported by the Office of Naval Research and Google Inc.

A genetic defect that profoundly affects speech in humans also disrupts the ability of songbirds to sing effective courtship tunes. This defect in a gene called FoxP2 renders the brain circuitry insensitive to feel-good chemicals that serve as a reward for speaking the correct syllable or hitting the right note, a recent study shows. 

The research, which was conducted in adult zebrafinches, gives insight into how this genetic mutation impairs a network of nerve cells to cause the stuttering and stammering typical of people with FoxP2 mutations. It appears Nov. 21 in an early online edition of the journal Neuron.

"Our results integrate a lot of different observations that have accrued on the FoxP2 mutation and cast a different perspective on what this mutation is doing," said Richard Mooney, Ph.D., the George Barth Geller professor of neurobiology at Duke University School of Medicine and a member of the Duke Institute for Brain Sciences. "FoxP2 mutations do not simply result in a cognitive or learning deficit, but also produce an ongoing motor deficit. Individuals with these mutations can still learn and can still improve; it is just harder for them to reliably hit the right mark." 

About 15 years ago, researchers discovered a British family with many members suffering from severe speech and language deficits. Geneticists eventually pinned down the culprit — a gene called forkhead box transcription factor or FoxP2 — that was mutated in all the affected individuals. The discovery led many to believe FoxP2 was a “language gene” that granted humans the ability to speak. But further studies showed that the gene wasn’t unique to humans, and in fact was conserved among all vertebrates, including songbirds. 

Though the gene is present in every cell, it is “active,” or turned on, mostly in brain cells, particularly ones residing in a region deep within the brain known as the basal ganglia. This region is dysfunctional in Tourette syndrome, known for its vocal tics and outbursts, and is also shrunk in individuals with FoxP2 mutations. 

To explore the complex circuitry involved in these deficits, Mooney and his former graduate student Malavika Murugan, Ph.D., decided to replicate the human mutation in this region of the brain in songbirds. Zebrafinches start learning how to sing 30 days after they hatch, listening to a male tutor and then practicing thousands of times a day until, 60 days later, they are able to make a very good copy of the tutor’s song. As good as that copy is at day 90, the male finch’s song gets even more precise when he “directs” it to a female as part of courtship. 

To investigate the role of FoxP2 in the generation of this directed song, Murugan introduced specifically targeted sequences of RNA to suppress FoxP2 activity in the basal ganglia of male zebrafinches. The birds were placed in a glass cage that revealed a female sitting on the other side. Murugan then recorded sonograms of their song to capture the subtle vocal variations indistinguishable to the human ear when they produced directed songs at the female. 

Murugan found that though the genetically manipulated males had already learned how to sing, their ability to hit the right note repeatedly in the presence of a female — a behavior critical to attracting a mate — was subpar. This indicates that in songbirds, FoxP2 has an ongoing role in vocal control separate from a role in learning, a distinction that has not been possible to make in humans with FOXP2 mutations. 

Having deduced the behavior associated with this genetic mutation, the researchers then identified underlying neural deficits by recording brain activity in birds with normal and altered FoxP2 genes. In one set of experiments, Murugan sent an electrical signal into the input side of the basal ganglia pathway and then used an electrode on the output side to measure how quickly the signal traveled from one side to the other. Surprisingly, the signal moved more quickly through the basal ganglia of FoxP2 mutant songbirds than it did in songbirds with the functional gene. 

Murugan also found that dopamine, an important brain chemical involved in brain signaling and the reinforcement of learned behaviors like singing or playing sports, could influence how fast basal ganglia signals propagated in birds with normal but not mutant forms of FoxP2.  

"This switch between undirected and directed song is actually dependent on the influx of this neurotransmitter called dopamine," said Murugan, first author of the study. "So what we think is happening is knocking down FoxP2 makes the male incapable of reducing song variability in the presence of a female. An adult male sees the female, there is an influx of dopamine, but because the system is insensitive, the dopamine has no effect and the adult male continues to sing a variable tune." In juveniles, the inability to constrain variability and to respond to dopamine could also account for poor learning.

Though the researchers are cautious not to draw too many parallels between their findings in birds and the deficits in humans, they think their study does highlight the value of songbirds in studying human behaviors and disease.

"Birds are one of the few non-human animals that learn to vocalize," said Mooney. "They produce songs for courtship that they culturally transmit from one generation to the next. Their brains might be a thousandth the size of ours, but in this one dimension, vocal learning, they are our equal."

UCL scientists have shown that there are widespread differences in how genes, the basic building blocks of the human body, are expressed in men and women’s brains.

Based on post-mortem adult human brain and spinal cord samples from over 100 individuals, scientists at the UCL Institute of Neurology were able to study the expression of every gene in 12 brain regions. The results are published today in Nature Communications.

They found that the way that the genes are expressed in the brains of men and women were different in all major brain regions and these differences involved 2.5% of all the genes expressed in the brain.

Among the many results, the researchers specifically looked at the gene NRXN3, which has been implicated in autism. The gene is transcribed into two major forms and the study results show that although one form is expressed similarly in both men and women, the other is produced at lower levels in women in the area of the brain called the thalamus. This observation could be important in understanding the higher incidence of autism in males.

Overall, the study suggests that there is a sex-bias in the way that genes are expressed and regulated, leading to different functionality and differences in susceptibility to brain diseases observed by neurologists and psychiatrists.

Dr. Mina Ryten, UCL Institute of Neurology and senior author of the paper, said: “There is strong evidence to show that men and women differ in terms of their susceptibility to neurological diseases, but up until now the basis of that difference has been unclear.

“Our study provides the most complete information so far on how the sexes differ in terms of how their genes are expressed in the brain. We have released our data so that others can assess how any gene they are interested in is expressed differently between men and women.”

Carrying a particular version of the gene for apolipoprotein E (APOE) is the major known genetic risk factor for the sporadic, late-onset form of Alzheimer’s disease, but exactly how that variant confers increased risk has been controversial among researchers. Now an animal study led by Massachusetts General Hospital (MGH) investigators shows that even low levels of the Alzheimer’s-associated APOE4 protein can increase the number and density of amyloid beta (A-beta) brain plaques, characteristic neuronal damage, and the amount of toxic soluble A-beta within the brain in mouse models of the disease. Introducing APOE2, a rare variant that has been associated with protection from developing Alzheimer’s disease, into the brains of animals with established plaques actually reduced A-beta deposition, retention and neurotoxicity, suggesting the potential for gene-therapy-based treatment.

"Using a technique developed by our collaborators at the University of Iowa, we were able to get long-term expression of these human gene variants in the fluid that bathes the entire brain," says Bradley Hyman, MD, PhD, of the MassGeneral Institute for Neurodegenerative Disease (MGH-MIND), senior author of the report in the Nov. 20 Science Translational Medicine. “Our results suggest that strategies aimed at decreasing levels of APOE4, the harmful form of the protein, and increasing concentrations of protective variant APOE2 could be helpful to patients.”

The association between the APOE4 variant and increased Alzheimer’s risk was first made more than 20 years ago. Subsequent research has established that carrying two copies of the harmful variant increases risk 12 times compared with having two copies of the more common form, APOE3. Inheriting the APOE2 variant, however, appears to cut the risk in half. The extremely rare gene variants that directly cause the familial forms of the disease all participate in the production and deposition of A-beta, but exactly how APOE variants contribute to the process has been poorly understood. 

Secreted by certain brain cells, APOE is known to regulate cholesterol metabolism within the brain and can bind to A-beta peptides, suggesting that the different forms of the protein may affect whether and how toxic A-beta plaques form. While previous investigations into the protein’s effects have used either mice in which gene expression was knocked out or transgenic animals that expressed human gene variants throughout their lifetimes, the MGH-MIND-led study used a different approach to investigate the effects of introducing the variant forms of the protein into brains in which plaque formation had already begun. They directly injected into the cerebrospinal fluid of a mouse model of Alzheimer’s – adult animals in which plaques were well established – viral vectors carrying genes for one of the three APOE variants or a control protein.

Two month after the vectors had been injected, about 10 percent of the APOE in the brains of animals that received one of the variants was found to be the introduced human version. At five months after injection, examination of brain tissue revealed that the A-beta plaques in mice that received APOE4 injections were more numerous and significantly denser than those of mice receiving APOE2. The growth of plaques in animals receiving APOE3 was intermediate between that of the other two groups and similar to what was seen in control animals. Levels of A-beta in the blood of mice that received APOE2 were higher than in the other groups, suggesting that the protective variant had increased clearance of A-beta from the brain. 

In a group of animals in which tiny implanted windows allowed direct imaging of brain tissue, the progression of A-beta plaque deposition was fastest in animals receiving APOE4 and slowest, sometimes even appearing to regress, in mice injected with APOE2. Signs of neuronal damage around plaques also varied depending on the APOE variant the animals received, and experiments in a different Alzheimer’s model in which plaques appear more slowly showed that injection of APOE4 increased levels of free, soluble A-beta in the fluid that bathes the brain. 

"This study has allowed us to sort out, in mice, which effects of the different types of APOE were most important to variation in amyloid plaque deposition," says Eloise Hudry, PhD, of MGH-MIND, lead author of the Science Translational Medicine report. “Our results imply that APOE-based therapeutic approaches may help to alleviate the progression of Alzheimer’s disease. More study is needed to pursue that possibility and to investigate the potential use of this gene transfer technology to introduce other protective proteins into the brain.”

After a mild concussion, special brain scans show evidence of brain abnormalities four months later, when symptoms from the concussion have mostly dissipated, according to research published in the November 20, 2013, online issue of Neurology®, the medical journal of the American Academy of Neurology.

“These results suggest that there are potentially two different modes of recovery for concussion, with the memory, thinking and behavioral symptoms improving more quickly than the physiological injuries in the brain,” said study author Andrew R. Mayer, PhD, of the Mind Research Network and University of New Mexico School of Medicine in Albuquerque.

Mayer further suggests that healing from concussions may be similar to other body ailments such as recovering from a burn. “During recovery, reported symptoms like pain are greatly reduced before the body is finished healing, when the tissue scabs. These finding may have important implications about when it is truly safe to resume physical activities that could produce a second concussion, potentially further injuring an already vulnerable brain.”

Mayer noted that standard brain scans such as CT or MRI would not pick up on these subtle changes in the brain. “Unfortunately, this can lead to the common misperception that any persistent symptoms are psychological.”

The study compared 50 people who had suffered a mild concussion to 50 healthy people of similar age and education. All the participants had tests of their memory and thinking skills and other symptoms such as anxiety and depression two weeks after the concussion, as well as brain scans. Four months after the concussion, 26 of the patients and 26 controls repeated the tests and scans.

The study found that two weeks after the injury the people who had concussions had more self-reported problems with memory and thinking skills, physical problems such as headaches and dizziness, and emotional problems such as depression and anxiety than people who had not had concussions. By four months after the injury, the symptoms were significantly reduced by up to 27 percent.

The people who had concussions also had evidence of abnormalities in the gray matter in the frontal cortex area of both sides of the brain, based on the diffusion tensor imaging scans. The increase equated to about 10 percent compared to the healthy people in the study. These abnormalities were still apparent four months after the concussion. In contrast, there was no evidence of cellular loss on scans.

Mayer said possible explanations for the brain abnormalities could be cytotoxic edema, which results from changes in where fluids are located in and around brain cells, or reactive gliosis, which is the change in glial cells’ shape in response to damage to the central nervous system.

A new blood biomarker correctly predicted which concussion victims went on to have white matter tract structural damage and persistent cognitive dysfunction following a mild traumatic brain injury (mTBI). Researchers in the Perelman School of Medicine at the University of Pennsylvania, in conjunction with colleagues at Baylor College of Medicine, found that the blood levels of a protein called calpain-cleaved αII-spectrin N-terminal fragment (SNTF) were twice as high in a subset of patients following a traumatic injury. If validated in larger studies, this blood test could identify concussion patients at increased risk for persistent cognitive dysfunction or further brain damage and disability if returning to sports or military activities.

More than 1.5 million children and adults suffer concussions each year in the United States, and hundreds of thousands of military personal endure these mild traumatic brain injuries worldwide. Current tests are not capable of determining the extent of the injury or whether the injured person will be among the 15-30 percent who experience significant, persistent cognitive deficits, such as processing speed, working memory and the ability to switch or balance multiple thoughts.

"New tests that are fast, simple, and reliable are badly needed to predict who may experience long-term effects from concussions, and as new treatments are developed in the future, to identify who should be eligible for clinical trials or early interventions," said lead author Robert Siman, PhD, research professor of Neurosurgery at Penn. "Measuring the blood levels of SNTF on the day of a brain injury may help to identify the subset of concussed patients who are at risk of persistent disability." 

In a study published yesterday in Frontiers in Neurology, Penn and Baylor researchers evaluated blood samples and diffusion tensor images from a subgroup of 38 participants in a larger study of mTBI with ages ranging from 15 to 25 years old. 17 had sustained a head injury caused by blunt trauma, acceleration or deceleration forces, 13 had an orthopaedic injury, and 8 were healthy, uninjured, demographically matched controls.

In taking neuropsychological and cognitive tests over the course of three months, results within the mTBI group varied considerably, with some patients performing as well as the healthy controls throughout, while others showed impairment initially that resolved by three months, and a third group with cognitive dysfunction persisting through three months. The nine patients who had abnormally high levels of SNTF (7 mTBI and 2 orthopaedic patients) also had significant white matter damage apparent in radiological imaging.

"The blood test identified SNTF in some of the orthopaedic injury patients as well, suggesting that these injuries could also lead to abnormalities in the brain, such as a concussion, that may have been overlooked with existing tests," said Douglas Smith, MD, director of the Penn Center for Brain Injury and Repair and professor of Neurosurgery. "SNTF as a marker is consistent with our earlier research showing that calcium is dumped into neurons following a traumatic brain injury, as SNTF is a marker for neurodegeneration driven by calcium overload."

The blood test given on the day of the mild traumatic brain injury showed 100 percent sensitivity to predict concussions leading to persisting cognitive problems, and 75 percent specificity to correctly rule out those without functionally harmful concussions. If validated in larger studies, a blood test measuring levels of SNTF could be helpful in diagnosing and predicting risk of long term consequences of concussion. The Penn and Baylor researchers hope to determine the robustness of these findings with a second larger study, and determine the best time after concussion to measure SNTF in the blood in order to predict persistent brain dysfunction. The team also wants to evaluate their blood test for identifying when repetitive concussions begin to cause brain damage and persistent disability.

Are monkeys, like humans, able to ascertain where objects are located without much more than a sideways glance? Quite likely, says Lau Andersen of the Aarhus University in Denmark, lead author of a study conducted at the Yerkes National Primate Research Center of Emory University, published in Springer’s journal Animal Cognition. The study finds that monkeys are able to localize stimuli they do not perceive.

Humans are able to locate, and even side-step, objects in their peripheral vision, sometimes before they perceive the object even being present. Andersen and colleagues therefore wanted to find out if visually guided action and visual perception also occurred independently in other primates.

The researchers trained five adult male rhesus monkeys (Macaca mulatta) to perform a short-latency, highly stereotyped localization task. Using a touchscreen computer, the animals learned to touch one of four locations where an object was briefly presented. The monkeys also learned to perform a detection task using identical stimuli, in which they had to report the presence or absence of an object by pressing one of two buttons. These techniques are similar to those used to test normal humans, and therefore make an especially direct comparison between humans and monkeys possible. A method called “visual masking” was used to systematically reduce how easily a visual target was processed.

Andersen and his colleagues found that the monkeys were still able to locate targets that they could not detect. The animals performed the tasks very accurately when the stimuli were unmasked, and their performance dropped when visual masking was employed. But monkeys could still locate targets at masking levels for which they reported that no target had been presented. While these results cannot establish the existence of phenomenal vision in monkeys, the discrepancy between visually guided action and detection parallels the dissociation of conscious and unconscious vision seen in humans.

“Knowing whether similar independent brain systems are present in humans and nonverbal species is critical to our understanding of comparative psychology and the evolution of brains,” explains Andersen.

Patients with the most common form of focal epilepsy have widespread, abnormal connections in their brains that could provide clues toward diagnosis and treatment, according to a new study published online in the journal Radiology.

(Image: MP-RAGE volumes are segmented into 83 ROIs, which are further parcellated into 1000 cortical and 15 subcortical ROIs. Whole-brain white matter tractography is performed after voxelwise tensor calculation, and the density of fibers that connect each pair of cortical ROIs is used to calculate structural connectivity. T1w = T1-weighted. Credit: Courtesy of Radiology and RSNA)

Temporal lobe epilepsy is characterized by seizures emanating from the temporal lobes, which sit on each side of the brain just above the ear. Previously, experts believed that the condition was related to isolated injuries of structures within the temporal lobe, like the hippocampus. But recent research has implicated the default mode network (DMN), the set of brain regions activated during task-free introspection and deactivated during goal-directed behavior. The DMN consists of several hubs that are more active during the resting state.

To learn more, researchers performed diffusion tensor imaging, a type of MRI that tracks the movement, or diffusion, of water in the brain’s white matter, the nerve fibers that transmit signals throughout the brain. The study group consisted of 24 patients with left temporal lobe epilepsy who were slated for surgery to remove the site from where their seizures emanated. The researchers compared them with 24 healthy controls using an MRI protocol dedicated to finding white matter tracts with diffusion imaging at high resolution. The data was analyzed with a new technique that identifies and quantifies structural connections in the brain.

Patients with left temporal lobe epilepsy exhibited a decrease in long-range connectivity of 22 percent to 45 percent among areas of the DMN when compared with the healthy controls.

"Using diffusion MRI, we found alterations in the structural connectivity beyond the medial temporal lobe, especially in the default mode network," said Steven M. Stufflebeam, M.D., from the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital in Boston.

In addition to reduced long-range connectivity, the epileptic patients had an 85 percent to 270 percent increase in local connectivity within and beyond the DMN. The researchers believe this may be an adaptation to the loss of the long-range connections.

"The increase in local connections could represent a maladaptive mechanism by which overall neural connectivity is maintained despite the loss of connections through important hub areas," Dr. Stufflebeam said.

The results are supported by prior functional MRI studies that have shown decreased functional connectivity in DMN areas in temporal lobe epilepsy. Researchers are not certain if the structural changes cause the functional changes, or vice versa.

"It’s probably a breakdown of myelin, which is the insulation of neurons, causing a slowdown in the propagation of information, but we don’t know for sure," Dr. Stufflebeam said.

Dr. Stufflebeam and colleagues plan to continue their research, using structural and functional MRI with electroencephalography and magnetoencephalography to track diffusion changes and look at real-time brain activity.

"Our long-term goal is to see if we can we predict from diffusion studies who will respond to surgery and who will not," he said.

People with autism are more likely to also have synaesthesia, suggests new research in the journal Molecular Autism.

Synaesthesia involves people experiencing a ‘mixing of the senses’, for example, seeing colours when they hear sounds, or reporting that musical notes evoke different tastes. Autism is diagnosed when a person struggles with social relationships and communication, and shows unusually narrow interests and resistance to change. The team of scientists from Cambridge University found that whereas synaesthesia only occurred in 7.2% of typical individuals, it occurred in 18.9% of people with autism.

On the face of it, this is an unlikely result, as autism and synaesthesia seem as if they should not share anything. But at the level of the brain, synaesthesia involves atypical connections between brain areas that are not usually wired together (so that a sensation in one channel automatically triggers a perception in another). Autism has also been postulated to involve over-connectivity of neurons (so that the person over-focuses on small details but struggles to keep track of the big picture).

The scientists tested – and confirmed – the prediction that if both autism and synaesthesia involve neural over-connectivity, then synaesthesia might be disproportionately common in autism.

The team, led by Professor Simon Baron-Cohen at the Autism Research Centre at Cambridge University, tested 164 adults with an autism spectrum condition and 97 adults without autism. All volunteers were screened for synaesthesia. Among the 31 people with autism who also had synaesthesia, the most common forms of the latter were ‘grapheme-colour’ (18 of them reported black and white letters being seen as coloured) and ‘sound-colour’ (21 of them reported a sound triggering a visual experience of colour). Another 18 of them reported either tastes, pains, or smells triggering a visual experience of colour.

Professor Baron-Cohen said: “I have studied both autism and synaesthesia for over 25 years and I had assumed that one had nothing to do with the other. These findings will re-focus research to examine common factors that drive brain development in these traditionally very separate conditions. An example is the mechanism ‘apoptosis,’ the natural pruning that occurs in early development, where we are programmed to lose many of our infant neural connections. In both autism and synaesthesia apoptosis may not occur at the same rate, so that these connections are retained beyond infancy.”

Professor Simon Fisher, a member of the team, and Director of the Language and Genetics Department at Nijmegen’s Max Planck Institute, added: “Genes play a substantial role in autism and scientists have begun to pinpoint some of the individual genes involved. Synaesthesia is also thought to be strongly genetic, but the specific genes underlying this are still unknown. This new research gives us an exciting new lead, encouraging us to search for genes which are shared between these two conditions, and which might play a role in how the brain forms or loses neural connections.”

Donielle Johnson, who carried out the study as part of her Master’s degree in Cambridge, said: “People with autism report high levels of sensory hyper-sensitivity. This new study goes one step further in identifying synaesthesia as a sensory issue that has been overlooked in this population. This has major implications for educators and clinicians designing autism-friendly learning environments.”