Gestures can improve understanding in language disorders

When words fail, gestures can help to get the message across -- especially for people who have a language disorder. An international research team has now shown that listeners attend the gestures of people with aphasia more often and for much longer than previously thought. This has implications for the use of gestures in speech therapy.

People who suffer from an acquired language disorder due to a brain injury -- for example after a stroke, traumatic brain injury or brain tumor -- often have difficulties communicating with others. Previous research on aphasia indicates that these patients often try to express their needs using hand gestures. It was previously assumed that conversation partners pay relatively little attention to such non-verbal forms of communication -- but this assumption was based on research involving participants without language disorders.

Communicating with gestures

A new study from the University of Zurich, carried out together with researchers from the Netherlands and Japan, looked at whether gestures receive more attention if the verbal communication is impeded by aphasia. The researchers showed healthy volunteers video clips in which people with and without speech disorders described an accident and a shopping experience. As the participants watched the video clips, their eye movements were recorded.

Focus of attention shifts

"Our results show that when people have very severe speaking difficulties and produce less informative speech, their conversation partner is more likely to pay attention to their hand movements and to look longer at their gestures," says Basil Preisig of the Department of Comparative Language Science at UZH. In people who have no limitations in verbal production, hand gestures are granted less attention. Thus, it seems that listeners shift their attention when the speaker has a speech impediment and focus more on the speaker's nonverbal information provided through gestures. "For people with aphasia, it may be worth using gestures more in order to be better understood by the other person," says Preisig.

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'Resetting' the injured brain offers clues for concussion treatment

New research in mice raises the prospects for development of post-concussion therapies that could ward off cognitive decline and depression, two common conditions among people who have experienced a moderate traumatic brain injury.

The study in mice clarified the role of specific immune cells in the brain that contribute to chronic inflammation. Using a technique called forced cell turnover, researchers eliminated these cells in the injured brains of mice for a week and then let them repopulate for two weeks.

"It's almost like hitting the reset button," said senior study author Jonathan Godbout, professor of neuroscience in The Ohio State University College of Medicine.

Compared to brain-injured mice recovering naturally, mice that were given the intervention showed less inflammation in the brain and fewer signs of thinking problems 30 days after the injury.

Though temporarily clearing away these cells, called microglia, in humans isn't feasible, the findings shed light on pathways to target that could lower the brain's overall inflammatory profile after a concussion, potentially reducing the risk for behavioral and cognitive problems long after the injury.

"In a moderate brain injury, if the CT scan doesn't show damage, patients go home with a concussion protocol. Sometimes people come back weeks, months later with neuropsychiatric issues. It's a huge problem affecting millions of people," said Godbout, faculty director of Ohio State's Chronic Brain Injury Program and assistant director of basic science in the Institute for Behavioral Medicine Research.

"How do you treat that? At least in mice, by turning over the microglia in the brain we had a very positive effect on their behavior, cognitive status and level of inflammation in the brain. Now we can focus on cellular pathways that generate chronic inflammation as a target."

The research is published online in the Journal of Neuroscience.

About 85% of traumatic brain injuries are similar to the type of concussion examined in this study, involving dispersed impact to the head that causes brain tissue to bump against the skull. Previous research suggests that at least 75% of people who experience a moderate brain injury have long-term mental health and cognitive complications.

Godbout's lab previously linked depressive symptoms in mice to microglia's sustained "high alert" status after a head injury, which causes the cells to overreact to later challenges to the immune system and become excessively inflammatory. In a more recent study in mice, his team showed that forced turnover of microglia before a head injury could reduce later neuropsychiatric complications.

"That was a proof of principle to show that a lot of the inflammation, especially in the long term, is mediated by microglia," he said. "But there is an acute phase of inflammation -- you want to initiate that repair process. There's a positive to that early inflammatory response in the brain or spinal cord. If it lasts a long time and doesn't fully resolve, that's when it's dangerous."

In this new study, researchers waited for seven days after the brain injury to force the turnover of microglia, giving the cells time to carry out their work promoting initial healing. An experimental drug that inhibits a protein that microglia in mice need for survival was added to their food for a week, resulting in depletion of over 95% of microglia in their brains.

After allowing 16 days for the microglia to repopulate, researchers compared the intervention mice to injured mice that recovered without the cell turnover treatment. The intervention mice performed better than control mice on tasks testing their memory and depressive symptoms.

Further analyses of injured brain tissue suggested the cell turnover reversed some injury-related damage to neurons, lowered overall inflammation and improved the brain's ability to adapt to change. Researchers also injected mice with a molecule that triggers an immune response to mimic an infection, and found that sickness behavior was lower in the intervention mice.

Godbout said these combined findings suggest that the repopulating microglia returned in a less "primed" state of readiness, lowering chances for a lifetime of exaggerated inflammatory responses in the brain to any challenge to the immune system -- that brain inflammation being the likely culprit behind the neuropsychiatric complications that follow a head injury.

"If microglia in the human brain don't return to normal and chronic inflammation persists after a head injury, it's not just a secondary brain injury that causes problems. Even getting a viral infection after concussion recovery can progress into a cognitive or behavioral issue or amplify some other part of behavior, like depression," Godbout said. "There is a real connection between a head injury and mental health, and the risk doesn't go away.

"Now we're looking more closely at the pathways that cause changes in microglia, and targeting something specific in that pathway. That is a way forward."

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Neuroscientists explore mysterious 'events' in the brain that open new avenues for understanding brain injuries and disorders

Using a new model of brain activity, Indiana University computational neuroscientists Maria Pope, Richard Betzel and Olaf Sporns are exploring striking bursts of activity in the human brain that have not been examined before. These bursts may have potential to serve as biomarkers for brain disease and conditions such as depression, schizophrenia, dementia, and ADHD.

While analyzing human neuroimaging data, the IU research team discovered short bursts of activity that form ongoing "events" in the brain and are always taking place no matter the activity or state of the brain. In the course of a 10-minute brain scan, these events will occur roughly 10 to 20 times, each lasting for just a few seconds, the researchers found.

"What people had not seen is that how brain regions talk to each other is punctuated by these brief moments that are just a few seconds long during which there's a lot happening," said Olaf Sporns, who is Distinguished Professor and Robert H. Shaffer Chair in the College of Arts and Sciences Department of Psychological and Brain Sciences at IU Bloomington.

"Now that we see them, we've focused on those moments to get a picture of how specific brain regions link up and talk to each other during these events."

To begin investigating the workings of these mysterious events, the team built a computational model. Led by Maria Pope, a graduate student in Sporns' lab and a dual Ph.D. candidate in neuroscience and informatics, the group used neuroimaging data of a human brain to build a model replicating its connections. The model was then simulated in a state similar to the resting brain to create synthetic MRI signals, using mathematical equations that reenact neuronal activity.

The model showed burst-like events just like those seen in human brain recordings.

The paper outlining the model and describing how it compares to the real brain was published in the November 16 issue of the Proceedings of the National Academy of Sciences.

"The model shows us that these events are guided by the brain's structural network," Pope said. "They are tied to the physical structure of brain."

More specifically, the events originate in clusters of neurons and brain regions that are densely interconnected and momentarily light up together. Sporns compared the pattern to an orchestra playing a piece of music.

"There are moments when the orchestra comes together and there's a theme. They are not just playing a single note for 10 minutes. There are brief moments in which coordinated activity dominates and at other times there might be much less," Sporns said. "This ebb and flow of coordination is something we also see in the brain, and our model can reproduce it. Clusters of brain regions combine in different ways. It's not just one pattern, but multiple variations on a theme."

The new model's outcome, Sporns suggested, is a potential game changer.

"Functional connectivity has been a strong focus in research as a potential biomarker for brain disorders and has been related to conditions such as depression, schizophrenia, dementia, and ADHD. And researchers have tried for years to use brain simulations in clinical applications for modeling lesions or diseases," Sporns said. "This new model gives us a better lens through which to look at the brain, to see more clearly what goes on under both normal and abnormal conditions."

The researchers are now delving further into why the human brain employs these brief bursts of activity.

"Perhaps the brain has developed this type of activity because it's beneficial. Something about the structure of events may be useful to the brain," Pope said. "For example, many kinds of networked systems have to do occasional system updates or resets, taking some kind of globally useful information and communicating it to the rest of the system."

Answers to these questions may have implications not only for understanding the brain, but also for the study of neural networks and artificial intelligence.

"A clearer mapping of structure and function at the individual level could have implications for how we diagnose neurological disease and lead to personalized treatment and intervention," said Betzel, professor in the College of Arts and Sciences Department of Psychological and Brain Sciences.

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Preventing the long-term effects of traumatic brain injury

You've been in a car accident and sustained a head injury. You recovered, but years later you begin having difficulty sleeping. You also become very sensitive to noise and bright lights, and find it hard to carry out your daily activities, or perform well at your job.

This is a common situation after a traumatic brain injury -- many people experience bad side effects months or years later. These long-term effects can last a few days or the rest of a person's life.

"No therapies currently exist to prevent the disabilities that can develop after a brain trauma," says Jeanne Paz, PhD, associate investigator at Gladstone Institutes. "So, understanding how the traumatic brain injury affects the brain, especially in the long term, is a really important gap in research that could help develop new and better treatment options."

In a new study published in the journal Science, Paz and her team helped close that gap. They identified a specific molecule in a part of the brain called the thalamus that plays a key role in secondary effects of brain injury, such as sleep disruption, epileptic activity, and inflammation. In collaboration with scientists at Annexon Biosciences, a clinical-stage biopharmaceutical company, they also showed that an antibody treatment could prevent the development of these negative outcomes.

A Vulnerable Brain Region

Traumatic brain injuries, which range from a mild concussion to a severe injury, can be the result of a fall, sports injury, gunshot injury, blow to the head, explosion, or domestic violence. Often, soldiers returning from war also suffer head injuries, which commonly lead to the development of epilepsy. Traumatic brain injury affects 69 million people around the world annually, and is the leading cause of death in children and a major source of disability in adults.

"These injuries are frequent and can happen to anyone," says Paz, who is also an associate professor of neurology at UC San Francisco (UCSF) and a member of the Kavli Institute for Fundamental Neuroscience. "The goal of our study was to understand how the brain changes after traumatic brain injuries and how those changes can lead to chronic problems, such as the development of epilepsy, sleep disruption, and difficulty with sensory processing."

To do so, Paz and her team recorded the activity of different cells and circuits in the brain of mice after brain injury. The researchers monitored the mice continually and wirelessly, meaning the mice could go about their normal activities without being disrupted.

"We collected so much data, from the time of injury and over the next several months, that it actually crashed our computers," says Paz. "But it was important to capture all the different stages of sleep and wakefulness to get the whole picture."

During a trauma to the head, the region of the brain called the cerebral cortex is often the primary site of injury, because it sits directly beneath the skull.

But at later time points, the researchers discovered that another region -- the thalamus -- was even more disrupted than the cortex. In particular, they found that a molecule called C1q was present at abnormally high levels in the thalamus for months after the initial injury, and these high levels were associated with inflammation, dysfunctional brain circuits, and the death of neurons.

"The thalamus seems particularly vulnerable, even after a mild traumatic brain injury," says Stephanie Holden, PhD, first author of the study and former graduate student in Paz's lab at Gladstone. "This doesn't mean the cortex isn't affected, but simply that it might have the necessary tools to recover over time. Our findings suggest that the higher levels of C1q in the thalamus could contribute to several long-term effects of brain injury."

The Paz Lab collaborated with Eleonora Aronica, MD, PhD, a neuropathologist at the University of Amsterdam, to validate their findings in human brain tissues obtained from autopsies, in which they found high levels of the C1q molecule in the thalamus 8 days after people had sustained a traumatic brain injury. In addition, by working with fellow Gladstone Assistant Investigator Ryan Corces, PhD, they determined that C1q in the thalamus likely came from microglia, the immune cells in the brain.

"Our study answered some very big questions in the field about where and how changes are happening in the brain after a trauma, and which ones are actually important for causing deficits," says Paz.

The Right Window to Treat Chronic Effects After Traumatic Brain Injury

The C1q molecule, which is part of an immune pathway, has well-documented roles in brain development and normal brain functions. For instance, it protects the central nervous system from infection and helps the brain forget memories -- a process needed to store new memories. The accumulation of C1q in the brain has also been studied in various neurological and psychiatric disorders and is associated, for example, with Alzheimer's disease and schizophrenia.

"C1q can be both good and bad," says Paz. "We wanted to find a way to prevent this molecule's detrimental effect, but without impacting its beneficial role. This is an example of what makes neuroscience a really hard field these days, but it's also what makes it exciting."

She and her group decided to leverage the "latent phase" after a traumatic brain injury, during which changes are occurring in the brain but before long-term symptoms appear.

"My cousin, for example, was hit in the head when he was 10 years old, and the impact broke his skull and damaged his brain," says Paz. "But it wasn't until he was 20 that he developed epilepsy. This latent phase presents a window of opportunity for us to intervene in hopes of modifying the disease and preventing any complications."

Paz reached out to her collaborators at Annexon Biosciences, who produce a clinical antibody that can block the activity of the C1q molecule. Then, her team treated the mice who sustained brain injury with this antibody to see if it might have beneficial effects.

When the researchers studied mice genetically engineered to lack C1q at the time of the trauma, the brain injury appeared much worse. However, when they selectively blocked C1q with the antibody during the latent phase, they prevented chronic inflammation and the loss of neurons in the thalamus.

"This indicates that the C1q molecule shouldn't be blocked at the time of injury, because it's likely very important at this stage for protecting the brain and helping prevent cell death," says Holden. "But at later time points, blocking C1q can actually reduce harmful inflammatory responses. It's a way of telling the brain, 'It's okay, you've done the protective part and you can now turn off the inflammation.'"

"There is a paucity of treatments for patients who have suffered from an acute brain injury," says Ted Yednock, PhD, executive vice president and chief scientific officer at Annexon Biosciences, and an author of the study. "This result is exciting because it suggests that we could treat patients in the hours to days after an acute injury like traumatic brain injury to protect against secondary neuronal damage and provide significant functional benefit."

Path to a Potential Treatment

In addition to chronic inflammation, Paz and her team also uncovered abnormal brain activity in the mice with traumatic brain injury.

First, the researchers noticed disruptions in sleep spindles, which are normal brain rhythms that occur during sleep. These are important for memory consolidation, among other things. The scientists also found epileptic spikes, or abnormal fluctuations in brain activity. These spikes can be disruptive to cognition and normal behavior, and are also indicative of a greater susceptibility to seizures.

The scientists observed that the anti-C1q antibody treatment not only helped restore the sleep spindles, but also prevented the development of epileptic activities.

"Overall, our study indicates that targeting the C1q molecule after injury could avoid some of the most devastating, long-term consequences of traumatic brain injury," says Holden. "We hope this could eventually lead to the development of treatments for traumatic brain injury."

Annexon's anti-C1q inhibitors are designed to treat multiple autoimmune and neurological disorders, and are already being examined in clinical trials, including for an autoimmune disorder known as Guillain-Barré syndrome, where the drug has been shown to be safe in humans.

"The fact that the drug is already in clinical trials may speed the pace at which a treatment could eventually be made available to patients," says Yednock. "We already understand doses of drug that are safe and effective in patients for blocking C1q in the brain, and could move directly into studies that ameliorate the chronic effects after traumatic brain injury."

For Holden, who previously worked with individuals who experienced brain injury and heard many of their personal stories, the impact of this study is particularly meaningful.

"Brain injury is a hidden disability for many of the people I met," she says. "The side effects they experience can be difficult to diagnose and their physicians often can't provide any medical treatment. Being able to contribute to finding ways to treat the detrimental consequences of the injury after it happens is really inspiring."

Paz and her lab are continuing to expand their understanding of what happens in the brain after injury. Next, they will focus on studying whether they can help prevent convulsive seizures, which are often reported by people with severe traumatic brain injuries.

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