You Took the Words Right Out of My Brain

Our brain activity is more similar to that of speakers we are listening to when we can predict what they are going to say, a team of neuroscientists has found. The study, which appears in the Journal of Neuroscience, provides fresh evidence on the brain’s role in communication.

“Our findings show that the brains of both speakers and listeners take language predictability into account, resulting in more similar brain activity patterns between the two,” says Suzanne Dikker, the study’s lead author and a post-doctoral researcher in New York University’s Department of Psychology and Utrecht University. “Crucially, this happens even before a sentence is spoken and heard.”

“A lot of what we’ve learned about language and the brain has been from controlled laboratory tests that tend to look at language in the abstract—you get a string of words or you hear one word at a time,” adds Jason Zevin, an associate professor of psychology and linguistics at the University of Southern California and one of the study’s co-authors. “They’re not so much about communication, but about the structure of language. The current experiment is really about how we use language to express common ground or share our understanding of an event with someone else.”

The study’s other authors were Lauren Silbert, a recent PhD graduate from Princeton University, and Uri Hasson, an assistant professor in Princeton’s Department of Psychology.

Traditionally, it was thought that our brains always process the world around us from the “bottom up”—when we hear someone speak, our auditory cortex first processes the sounds, and then other areas in the brain put those sounds together into words and then sentences and larger discourse units. From here, we derive meaning and an understanding of the content of what is said to us.

However, in recent years, many neuroscientists have shifted to a “top-down” view of the brain, which they now see as a “prediction machine”: We are constantly anticipating events in the world around us so that we can respond to them quickly and accurately. For example, we can predict words and sounds based on context—and our brain takes advantage of this. For instance, when we hear “Grass is…” we can easily predict “green.”

What’s less understood is how this predictability might affect the speaker’s brain, or even the interaction between speakers and listeners.

In the Journal of Neuroscience study, the researchers collected brain responses from a speaker while she described images that she had viewed. These images varied in terms of likely predictability for a specific description. For instance, one image showed a penguin hugging a star (a relatively easy image in which to predict a speaker’s description). However, another image depicted a guitar stirring a bicycle tire submerged in a boiling pot of water—a picture that is much less likely to yield a predictable description: Is it “a guitar cooking a tire,” “a guitar boiling a wheel,” or “a guitar stirring a bike”?

Then, another group of subjects listened to those descriptions while viewing the same images. During this period, the researchers monitored the subjects’ brain activity.

When comparing the speaker’s brain responses directly to the listeners’ brain responses, they found that activity patterns in brain areas where spoken words are processed were more similar between the listeners and the speaker when the listeners could predict what the speaker was going to say.

When listeners can predict what a speaker is going to say, the authors suggest, their brains take advantage of this by sending a signal to their auditory cortex that it can expect sound patterns corresponding to predicted words (e.g., “green” while hearing “grass is…”). Interestingly, they add, the speaker’s brain is showing a similar effect as she is planning what she will say: brain activity in her auditory language areas is affected by how predictable her utterance will be for her listeners.

“In addition to facilitating rapid and accurate processing of the world around us, the predictive power of our brains might play an important role in human communication,” notes Dikker, who conducted some of the research as a post-doctoral fellow at Weill Cornell Medical College’s Sackler Institute for Developmental Psychobiology. “During conversation, we adapt our speech rate and word choices to each other—for example, when explaining science to a child as opposed to a fellow scientist—and these processes are governed by our brains, which correspondingly align to each other.”

Research in the News: Brain at rest yields clues to origins of mental illness

While at rest, multiple regions of the brain remain engaged in a highly heritable, stable pattern of activity called the default mode network. Researchers have found that this network is often disrupted in people with schizophrenia and bipolar disorder, which appear to share underlying genetic causes. This network is often abnormal in their unaffected close relatives, suggesting common genetic roots.

Now researchers at the Yale University School of Medicine and the Institute of Living in Hartford have devised a method to simultaneously identify many genes that play a role in disrupting this network. “Previous studies have identified small numbers of different genes which each contribute in a small way to schizophrenia and bipolar disorder but tell us little overall about the development of psychosis in an individual,” said Godfrey Pearlson, professor of psychiatry and neurobiology and senior author of the study. “Now we have begun to identify markers for these conditions that consist of hundreds of such genes acting simultaneously in recognized pathways that will eventually help in our designing novel ways to intervene in the disease process.”

The study was published April 28 in the Proceedings of the National Academy of Sciences.

Depression is detectable in the blood

Researchers at the MedUni Vienna have demonstrated the possibility of using a blood test to detect depression. While blood tests for mental illnesses have until recently been regarded as impossible, a recent study clearly indicates that, in principle, depression can in fact be diagnosed in this way and this could become reality in the not too distant future.

Serotonin transporter (SERT) is a protein in the cell membrane that facilitates the transport of the neurotransmitter serotonin (popularly known as the “happiness hormone”) into the cell. In the brain, serotonin transporter regulates neural depression networks. Depressive conditions can frequently be caused by a lack of serotonin. As a result, the serotonin transporter is also the point of action for the major antidepressant drugs.

The serotonin transporter, however, also occurs in large quantities in numerous other organs such as the intestines or blood. Recent studies have shown that the serotonin transporter in the blood works in exactly the same way as in the brain. In the blood, it ensures that blood platelets maintain the appropriate concentration of serotonin in the blood plasma.

Researchers at the MedUni Vienna have now used functional magnetic resonance imaging of the brain and pharmacological investigations to demonstrate that there is a close relationship between the speed of the serotonin uptake in blood platelets and the function of a depression network in the brain.

This network is termed the “default mode network” because it is primarily active at rest and processes content with strong self-reference. Findings from recent years have also demonstrated that it is actively suppressed during complex thought processes, which is essential for adequate levels of concentration. Interestingly, patients with depression find it difficult to suppress this network during thought processes, leading to negative thoughts and ruminations as well as poor concentration.

“This is the first study that has been able to predict the activity of a major depression network in the brain using a blood test. While blood tests for mental illnesses have until recently been regarded as impossible, this study clearly shows that a blood test is possible in principle for diagnosing depression and could become reality in the not too distant future,” explains study leader Lukas Pezawas from the Department of Biological Psychiatry at the University Department of Psychiatry and Psychotherapy within the MedUni Vienna. This result means that the diagnosis of depression through blood tests could become reality in the not too distant future.

Oxytocin promotes social behavior in infant rhesus monkeys

The hormone oxytocin appears to increase social behaviors in newborn rhesus monkeys, according to a study by researchers at the National Institutes of Health, the University of Parma in Italy, and the University of Massachusetts, Amherst. The findings indicate that oxytocin is a promising candidate for new treatments for developmental disorders affecting social skills and bonding.

Oxytocin, a hormone produced by the pituitary gland, is involved in labor and birth and in the production of breast milk. Studies have shown that oxytocin also plays a role in parental bonding, mating, and in social dynamics. Because of its possible involvement in social encounters, many researchers have suggested that oxytocin might be useful as a treatment for conditions affecting social behaviors, such as autism spectrum disorders. Although oxytocin has been shown to increase certain social behaviors in adults, before the current study it had not been shown to do so in primate infants of any species.

Working with infant rhesus monkeys, the NIH researchers found that oxytocin increased two facial gestures associated with social interactions— one used by the monkeys themselves in certain social situations, the other in imitation of their human caregivers.

“It was important to test whether oxytocin would promote social behaviors in infants in the same respects as it appears to promote social interaction among adults,” said the study’s first author, Elizabeth A. Simpson, Ph.D., postdoctoral fellow of the University of Parma, conducting research in the Comparative Behavioral Genetics Section of the NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development. “Our results indicate that oxytocin is a candidate for further studies on treating developmental disorders of social functioning.”

The study was published online in Proceedings of the National Academy of Sciences.

The researchers began by gauging the ability of rhesus macaques to imitate two facial gestures: lip smacking and tongue protrusion. In lip smacking, the lips are protruded and open, then smacked together repeatedly. The study authors wrote that rhesus mothers will engage in this facial gesture with their infants in the first month after giving birth. Tongue protrusion involves a brief protrusion and retraction of the tongue. Although this gesture is seen in other primates and typically not seen in macaques, macaques will imitate it when their human caregivers display it, the study authors added.

By observing the monkeys’ ability to imitate the two gestures, the researchers sought to determine if oxytocin could promote social interaction through a gesture that was natural to them as well as through a gesture not part of their normal communication sequence.

The researchers tested the infants in the first week after birth. Three times a day, every other day, the caregivers would demonstrate the facial gestures in sequence to the infant monkeys, while the animals’ responses were recorded on video. At this phase of the study, the researchers found that some of the monkeys mimicked their caregivers’ gestures more frequently than did other monkeys. The researchers referred to the monkeys who gestured more frequently as strong imitators.

Beginning in the second week of life, the researchers tested the monkeys on two separate days. The infant monkeys inhaled an aerosolized dose of oxytocin in one session, and a dose of saline in the other. In each session, the dose was delivered through an inhalation mask held gently over the animal’s face.

Overall, the monkeys were more communicative after receiving oxytocin, more frequently making facial gestures, than they were after receiving the saline. The monkeys were more likely to engage in lip smacking than tongue protrusion, but were more likely still to engage in either of these gestures after oxytocin than after the saline. There also were differences in the frequency of gesturing among the individual monkeys, with the strong imitators becoming even stronger imitators after receiving oxytocin.

After oxytocin exposure, the strong imitators were more likely to look at caregivers and stand close to them than they were after the saline. Looking into a caregiver’s face and remaining in close proximity to a caregiver are indicators of social interaction and social interest, Dr. Simpson said.

In another test, the researchers found that after exposure to oxytocin, monkeys had lower levels of cortisol in their saliva. Cortisol is produced by the adrenal glands in response to stress. Lower cortisol levels after oxytocin exposure indicate that oxytocin may also function to diminish anxiety, the researchers wrote.

Overlooked cells hold keys to brain organization and disease

Scientists studying brain diseases may need to look beyond nerve cells and start paying attention to the star-shaped cells known as “astrocytes,” because they play specialized roles in the development and maintenance of nerve circuits and may contribute to a wide range of disorders, according to a new study by UC San Francisco researchers.

In a study published online April 28, 2014 in Nature, the researchers report that malfunctioning astrocytes might contribute to neurodegenerative disorders such as Lou Gehrig’s disease (ALS), and perhaps even to developmental disorders such as autism and schizophrenia.

David Rowitch, MD, PhD, UCSF professor of pediatrics and neurosurgery and a Howard Hughes Medical Institute investigator, led the research.

The researchers discovered in mice that a particular form of astrocyte within the spinal cord secretes a protein needed for survival of the nerve circuitry that controls reflexive movements. This discovery is the first demonstration that different types of astrocytes exist to support development and survival of distinct nerve circuits at specific locations within the central nervous system.

Astrocytes vastly outnumber signal-conducting neurons, and make up the majority of cells in the brain. But where neuroscientists are accustomed to seeing only vanilla when it comes to astrocytes – viewing all of them as similar despite their different locations in brain and spinal cord — they now will have to imagine “31 flavors” or more.

There might even be hundreds of distinctive varieties of astrocytes performing specific functions in different locations, according to Rowitch, chief of neonatology for UCSF Benioff Children’s Hospital San Francisco.

"Our study shows roles for specialized astrocytes that function to support particular kinds of neurons in their neighborhood," Rowitch said.

Led by Rowitch lab postdoctoral fellow Anna Molofsky, MD, PhD, the researchers studied the spinal cord sensory motor circuit, which allows both mice and humans to react without thought – to jerk a limb away from something hot, for instance.

The team discovered that a protein called Sema3a is produced much more abundantly by astrocytes close to motor neurons than by astrocytes from other regions in the spinal cord. They concluded that motor neurons required this source of Sema3a from the local astrocytes, because when Sema3a production was blocked, the motor neurons failed to form normal connections, and half of them died.

Motor neurons also die in ALS, a fatal neurodegenerative disease, and in spinal muscular atrophy, a disease that can affect newborn infants. In other studies, scientists have found that abnormal astrocytes can have toxic effects on motor neurons.

Molofsky is a psychiatrist who studies how astrocytes organize nerve circuits, and how disruptions of these nerve circuits during development or disease may involve abnormal astrocyte function. Disrupted neural circuits are believed to be responsible for certain psychiatric disorders.

"The immediate implications of this study are for diseases of motor neurons, like ALS, but I think our findings might also apply more generally to diseases of neural-circuit formation in the brain such as autism, schizophrenia and epilepsy," Molofsky said. "To achieve a comprehensive understanding of how neural circuits form and are maintained, it seems important that we integrate knowledge of how astrocytes support that process."

Rowitch agrees. “To the extent that psychiatric or neurological disease is localized to a specific part of the brain, we should now be considering the potentially specialized type of astrocytes regulating nerve connections in that region and their contributions to disease,” he said.

(Image: Astrocytes surround neuronal sysnapses and form networks physically coupled by gap-junctions. Credit: Dr. Takahiro Takano)

Scientists Hunt Down Origin of Huntington’s Disease in the Brain and Provide Insights to Help Deliver Therapy

The gene mutation that causes Huntington’s disease appears in every cell in the body, yet kills only two types of brain cells. Why? UCLA scientists used a unique approach to switch the gene off in individual brain regions and zero in on those that play a role in causing the disease in mice.

Published in the April 28 online edition of Nature Medicine, the research sheds light on where Huntington’s starts in the brain. It also suggests new targets and routes for therapeutic drugs to slow the devastating disease, which strikes an estimated 35,000 Americans.

“From day one of conception, the mutant gene that causes Huntington’s appears everywhere in the body, including every cell in the brain,” explained X. William Yang, professor of psychiatry and biobehavioral sciences at the Semel Institute for Neuroscience and Human Behavior at UCLA. “Before we can develop effective strategies to treat the disorder, we need to first identify where it starts and how it ravages the brain.”

Huntington’s disease is passed from parent to child through a mutation in a gene called huntingtin. Scientists blame a genetic “stutter” — a repetitive stretch of DNA at one end of the altered gene—for the cell death and brain atrophy that progressively deprives patients of their ability to move, speak, eat and think clearly. No cure exists, and people with aggressive cases may die in as little as 10 years.

Huntington’s disease targets cells in two brain regions for destruction: the cortex and the striatum. Far more neurons die in the striatum—a cerebral region named after its striped layers of gray and white matter. But it’s unclear whether cortical neurons play a role in the disease, including striatal neurons’ malfunction and death.

Yang’s team used a unique approach to uncover where the mutant gene wreaks the most damage in the brain.

In 2008, Yang collaborated with co-first author Michelle Gray, a former UCLA postdoctoral researcher now at the University of Alabama, to engineer a mouse model for Huntington’s disease. The scientists inserted the entire human huntintin gene, including the stutter, into the mouse genome. As the animals’ brains atrophied, the mice developed motor and psychiatric-like problems similar to the human patients.

In the current study, Yang and Nan Wang, co-first author and UCLA postdoctoral researcher, took the model one step further. They integrated a “genetic scissors” that snipped off the stutter and shut down the defective gene—first in the cortical neurons, then the striatal neurons and finally in both sets of cells. In each case, they measured how the mutant gene influenced disease development in the cells and affected the animals’ brain atrophy, motor and psychiatric-like symptoms.

“The genetic scissors gave us the power to study the role of any cell type in Huntington’s,” said Wang. “We were surprised to learn that cortical neurons play a key role in initiating aspects of the disease in the brain.”

The UCLA team discovered that reducing huntingtin in the cortex partially improved the animals’ symptoms. More importantly, shutting down mutant huntingtin in both the cortical and striatal neurons—while leaving it untouched in the rest of the brain— corrected every symptom they measured in the mice, including motor and psychiatric-like behavioral impairment and brain atrophy.

“We have evidence that the gene mutation highjacks communication between the cortical and striatal neurons,” explained Yang. “Reducing the defective gene in the cortex normalized this communication and helped lessen the disease’s impact on the striatum.”

“Our research helps to shed lights on an age-old question in the field,” he added. “Where does Huntington’s disease start? Equally important, our findings provide crucial insights on where to target therapies to reduce mutant gene levels in the brain—we should target both cortical and striatal neurons.”

Some of the current experimental therapies can be delivered only to limited brain areas, because their properties do not allow them to broadly spread in the brain.

The UCLA team’s next step will be to study how mutant huntingtin affects cortical and striatal neurons’ function and communication, and to identify therapeutic targets that may normalize cellular miscommunication to help slow progression of the disease.

How the Brain Decides When to Work and When to Rest: Dissociation of Implicit-Reactive from Explicit-Predictive Computational Processes

A pervasive case of cost-benefit problem is how to allocate effort over time, i.e. deciding when to work and when to rest. An economic decision perspective would suggest that duration of effort is determined beforehand, depending on expected costs and benefits. However, the literature on exercise performance emphasizes that decisions are made on the fly, depending on physiological variables. Here, we propose and validate a general model of effort allocation that integrates these two views. In this model, a single variable, termed cost evidence, accumulates during effort and dissipates during rest, triggering effort cessation and resumption when reaching bounds. We assumed that such a basic mechanism could explain implicit adaptation, whereas the latent parameters (slopes and bounds) could be amenable to explicit anticipation. A series of behavioral experiments manipulating effort duration and difficulty was conducted in a total of 121 healthy humans to dissociate implicit-reactive from explicit-predictive computations. Results show 1) that effort and rest durations are adapted on the fly to variations in cost-evidence level, 2) that the cost-evidence fluctuations driving the behavior do not match explicit ratings of exhaustion, and 3) that actual difficulty impacts effort duration whereas expected difficulty impacts rest duration. Taken together, our findings suggest that cost evidence is implicitly monitored online, with an accumulation rate proportional to actual task difficulty. In contrast, cost-evidence bounds and dissipation rate might be adjusted in anticipation, depending on explicit task difficulty.

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Extrasynaptic NMDA Receptor Involvement in Central Nervous System Disorders

NMDA receptor (NMDAR)-induced excitotoxicity is thought to contribute to the cell death associated with certain neurodegenerative diseases, stroke, epilepsy, and traumatic brain injury. Targeting NMDARs therapeutically is complicated by the fact that cell signaling downstream of their activation can promote cell survival and plasticity as well as excitotoxicity. However, research over the past decade has suggested that overactivation of NMDARs located outside of the synapse plays a major role in NMDAR toxicity, whereas physiological activation of those inside the synapse can contribute to cell survival, raising the possibility of therapeutic intervention based on NMDAR subcellular localization. Here, we review the evidence both supporting and refuting this localization hypothesis of NMDAR function and discuss the role of NMDAR localization in disorders of the nervous system. Preventing excessive extrasynaptic NMDAR activation may provide therapeutic benefit, particularly in Alzheimer disease and Huntington disease.

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