Compound protects brain cells after traumatic brain injury

A new class of compounds has now been shown to protect brain cells from the type of damage caused by blast-mediated traumatic brain injury (TBI). Mice that were treated with these compounds 24-36 hours after experiencing TBI from a blast injury were protected from the harmful effects of TBI, including problems with learning, memory, and movement.

Traumatic brain injury caused by blast injury has emerged as a common health problem among U.S. servicemen and women, with an estimated 10 to 20 percent of the more than 2 million U.S. soldiers deployed in Iraq or Afghanistan having experienced TBI. The condition is associated with many neurological complications, including cognitive and motor decline, as well as acquisition of psychiatric symptoms like anxiety and depression, and brain tissue abnormalities that resemble Alzheimer’s disease.

"The lack of neuroprotective treatments for traumatic brain injury is a serious problem in our society," says Andrew Pieper, senior study author and associate professor of psychiatry, neurology, and radiation oncology at the University of Iowa Carver College of Medicine. “Everyone involved in this work is motivated to find a way to offer hope for patients, which today include both military personnel and civilians, by establishing a basis for a new treatment to combat the deleterious neuropsychiatric outcomes after blast injury.”

It is known that TBI, as well as certain neurodegenerative diseases, damages axons—the tendril-like fibers that sprout from brains cells (neurons) and form the connections called synapses. In TBI, axon damage is followed by death of the neuron. The new study, published Sept. 11 in the journal Cell Reports, shows that a group of compounds, called the P7C3 series, blocks axon damage and preserves normal brain function following TBI.

Pieper led the team of scientists that discovered the P7C3 compound several years ago at UT Southwestern Medical Center. Subsequent studies showed that the root compound and its active analogs protect newborn neurons from cell death and also protect mature neurons in animal models of neurodegenerative diseases, including Parkinson’s disease and amyotrophic lateral sclerosis (ALS).

The researchers have also previously shown efficacy of P7C3 molecules in brain injury due to concussion, and plan to investigate whether these compounds might be applicable in stroke as well, given that there appear to be common factors mediating neuronal cell death in these conditions.

By tweaking the structure of the original P7C3 compound, Pieper and his colleagues Joseph Ready and Steven McKnight, at UT Southwestern Medical Center, have further improved its potency and drug-like properties. In the latest study, Pieper’s team at the UI Carver College of Medicine, including co-first authors graduate student Terry Yin, senior technician Jeremy Britt, and graduate student Hector De Jesus-Cortes, tested the neuroprotective effects of the newest version, (-)-P7C3-S243, which can be given orally, in mice with blast-induced TBI.

In the study, blast-induced TBI caused learning, memory, and movement problems in the mice, which resemble the problems experienced by people affected by TBI. The researchers found that (-)-P7C3-S243 prevented acute memory and learning impairment caused by TBI. The compound also prevented TBI-associated balance and coordination problems in mice exposed to blast-injury. By examining the brain tissue at a cellular level, the team also found that the protection afforded to brain functions after injury was matched by preservation of normal neuronal axon structure and synaptic neurotransmission.

Importantly, the compound still produced its protective effects even when treatment was delayed until 24 to 36 hours after the blast injury.

"Seeing protection even when the compound was given this long after injury was important because it represents a liberal window of time within which almost all patients would be expected to be able to access treatment after injury," Pieper says.

The team also found that learning, memory, and coordination problems caused by the TBI persisted in untreated mice at least eight months after the single injury occurred, suggesting that the compound actually prevented these problems rather simply speeding up a normal recovery process.

In a separate study led by Pieper’s colleagues McKnight and Ready at UT Southwestern, and also published on Sept. 11 in the journal Cell, the team has identified the biological mechanism by which P7C3 compounds act in the brain. The compounds activate the molecular pathway that preserves neuronal levels of an energy molecule known as nicotinamide adenine dinucleotide (NAD).

"Based on the well-established role of NAD in axonal degeneration, the ability of (-)-P7C3-S243 to protect mice after blast-mediated traumatic brain injury is likely related to preservation of NAD levels," Pieper explains. "Now that we understand the mechanism of action of the P7C3 class of compounds, we can see why they should have therapeutic utility in an unusually broad spectrum of neurodegenerative conditions, without impeding any of a number of other normal forms of cell death.

"Our ultimate goal is to facilitate development of a new class of neuroprotective drugs with wide applicability to treating patients with TBI and other currently untreatable forms of neurodegeneration," he adds.

Tipping the Balance of Behavior

Humans with autism often show a reduced frequency of social interactions and an increased tendency to engage in repetitive solitary behaviors. Autism has also been linked to dysfunction of the amygdala, a brain structure involved in processing emotions. Now Caltech researchers have discovered antagonistic neuron populations in the mouse amygdala that control whether the animal engages in social behaviors or asocial repetitive self-grooming. This discovery may have implications for understanding neural circuit dysfunctions that underlie autism in humans.

This discovery, which is like a “seesaw circuit,” was led by postdoctoral scholar Weizhe Hong in the laboratory of David J. Anderson, the Seymour Benzer Professor of Biology at Caltech and an investigator with the Howard Hughes Medical Institute. The work was published online on September 11 in the journal Cell. 

"We know that there is some hierarchy of behaviors, and they interact with each other because the animal can’t exhibit both social and asocial behaviors at the same time. In this study, we wanted to figure out how the brain does that," Anderson says.

Anderson and his colleagues discovered two intermingled but distinct populations of neurons in the amygdala, a part of the brain that is involved in innate social behaviors. One population promotes social behaviors, such as mating, fighting, or social grooming, while the other population controls repetitive self-grooming—an asocial behavior.

Interestingly, these two populations are distinguished according to the most fundamental subdivision of neuron subtypes in the brain: the “social neurons” are inhibitory neurons (which release the neurotransmitter GABA, or gamma-aminobutyric acid), while the “self-grooming neurons” are excitatory neurons (which release the neurotransmitter glutamate, an amino acid).

To study the relationship between these two cell types and their associated behaviors, the researchers used a technique called optogenetics. In optogenetics, neurons are genetically altered so that they express light-sensitive proteins from microbial organisms. Then, by shining a light on these modified neurons via a tiny fiber optic cable inserted into the brain, researchers can control the activity of the cells as well as their associated behaviors.

Using this optogenetic approach, Anderson’s team was able to selectively switch on the neurons associated with social behaviors and those linked with asocial behaviors.

With the social neurons, the behavior that was elicited depended upon the intensity of the light signal. That is, when high-intensity light was used, the mice became aggressive in the presence of an intruder mouse. When lower-intensity light was used, the mice no longer attacked, although they were still socially engaged with the intruder—either initiating mating behavior or attempting to engage in social grooming.

When the neurons associated with asocial behavior were turned on, the mouse began self-grooming behaviors such as paw licking and face grooming while completely ignoring all intruders. The self-grooming behavior was repetitive and lasted for minutes even after the light was turned off.

The researchers could also use the light-activated neurons to stop the mice from engaging in particular behaviors. For example, if a lone mouse began spontaneously self-grooming, the researchers could halt this behavior through the optogenetic activation of the social neurons. Once the light was turned off and the activation stopped, the mouse would return to its self-grooming behavior.

Surprisingly, these two groups of neurons appear to interfere with each other’s function: the activation of social neurons inhibits self-grooming behavior, while the activation of self-grooming neurons inhibits social behavior. Thus these two groups of neurons seem to function like a seesaw, one that controls whether mice interact with others or instead focus on themselves. It was completely unexpected that the two groups of neurons could be distinguished by whether they were excitatory or inhibitory. “If there was ever an experiment that ‘carves nature at its joints,’” says Anderson, “this is it.”

This seesaw circuit, Anderson and his colleagues say, may have some relevance to human behavioral disorders such as autism.

"In autism," Anderson says, "there is a decrease in social interactions, and there is often an increase in repetitive, sometimes asocial or self-oriented, behaviors"—a phenomenon known as perseveration. "Here, by stimulating a particular set of neurons, we are both inhibiting social interactions and promoting these perseverative, persistent behaviors."

Studies from other laboratories have shown that disruptions in genes implicated in autism show a similar decrease in social interaction and increase in repetitive self-grooming behavior in mice, Anderson says. However, the current study helps to provide a needed link between gene activity, brain activity, and social behaviors, “and if you don’t understand the circuitry, you are never going to understand how the gene mutation affects the behavior.” Going forward, he says, such a complete understanding will be necessary for the development of future therapies.

But could this concept ever actually be used to modify a human behavior?

"All of this is very far away, but if you found the right population of neurons, it might be possible to override the genetic component of a behavioral disorder like autism, by just changing the activity of the circuits—tipping the balance of the see-saw in the other direction," he says.

Speech processing while unconscious: Sleep inhibits action but not preparation and meaning

In a team effort between the Medical Research Council Cognition and Brain Sciences Unit (Cambridge, UK) and the Laboratory of Cognitive and Psycholinguistics Sciences, Ecole Normale Superiore (Paris), part of what we are capable of while sleeping has been unravelled.

People were asked to classify words belonging to one of two categories – animals or objects – by pressing buttons with the left or the right hand, and continued to do so until they have fallen asleep. Their brain activity indicated that they were able to decode the meaning of the words and intended to act but the unconscious state during sleep prevented them from responding (no movement of the fingers).

This result indicates that once a rule (animals press left/objects press right) is established during wakefulness it can still be implemented even during sleep. This means that the decoding networks in the brain process the spoken words and that information (if it is an animal or an object for instance) is passed to a motor plan signaling the intention and subsequent action. During sleep that action is inhibited (we do not purposefully move during sleep) but this study has found that the meaning extraction and subsequent action preparation remained but was slower and lasted longer.

To confirm this result a second study tested whether people could classify word or nonwords (like boat or foat). A similar pattern emerged, showing appropriate brain preparation activity for left or right button presses even if responses were inhibited by the sleep mechanisms.

New Study Examines Impact of Violent Media on the Brain

With the longstanding debate over whether violent movies cause real world violence as a backstop, a study published today in PLOS One found that each person’s reaction to violent images depends on that individual’s brain circuitry, and on how aggressive they were to begin with.

The study, which was led by researchers at the Icahn School of Medicine at Mount Sinai and the NIH Intramural Program, featured brain scans which revealed that both watching and not watching violent images caused different brain activity in people with different aggression levels. The findings may have implications for intervention programs that seek to reduce aggressive behavior starting in childhood.

“Our aim was to investigate what is going on in the brains of people when they watch violent movies,” said lead investigator Nelly Alia-Klein, PhD, Associate Professor of Neuroscience and Psychiatry at the Friedman Brain Institute and Icahn School of Medicine at Mount Sinai. “We hypothesized that if people have aggressive traits to begin with, they will process violent media in a very different way as compared to non-aggressive people, a theory supported by these findings.”

After answering a questionnaire, a group of 54 men were split by the research team into two groups—one with individuals possessing aggressive traits, including a history of physical assault, and a second group without these tendencies. The participants’ brains were then scanned as they watched a succession of violent scenes (shootings and street fights) on day one, emotional, but non-violent scenes (people interacting during a natural disaster) on day two, and nothing on day three.

The scans measured the subjects’ brain metabolic activity, a marker of brain function. Participants also had their blood pressure taken every 5 minutes, and were asked how they were feeling at 15 minute intervals.

Investigators discovered that during mind wandering, when no movies were presented, the participants with aggressive traits had unusually high brain activity in a network of regions that are known to be active when not doing anything in particular. This suggests that participants with aggressive traits have a different brain function map than non-aggressive participants, researchers said.

Interestingly, while watching scenes from violent movies, the aggressive group had less brain activity than the non-aggressive group in the orbitofrontal cortex, a brain region associated by past studies with emotion-related decision making and self-control. The aggressive subjects described feeling more inspired and determined and less upset or nervous than non-aggressive participants when watching violent (day 1) versus just emotional (day 2) media. In line with these responses, while watching the violent media, aggressive participants’ blood pressure went down progressively with time while the non-aggressive participants experienced a rise in blood pressure.

“How an individual responds to their environment depends on the brain of the beholder,” said Dr. Alia-Klein. “Aggression is a trait that develops together with the nervous system over time starting from childhood; patterns of behavior become solidified and the nervous system prepares to continue the behavior patterns into adulthood when they become increasingly coached in personality. This could be at the root of the differences in people who are aggressive and not aggressive, and how media motivates them to do certain things. Hopefully these results will give educators an opportunity to identify children with aggressive traits and teach them to be more aware of how aggressive material activates them specifically.”

(Image credit)

Device to help people with Parkinson’s disease communicate better now available

SpeechVive Inc. announced Wednesday (Sept. 10) the commercial launch of the SpeechVive device intended to help people with a soft voice due to Parkinson’s disease speak more loudly and communicate more effectively.

The device is now available to try as a demo through the National Parkinson’s Disease Foundation’s Centers of Excellence prior to purchasing. People who suffer from a soft voice due to Parkinson’s disease can make an appointment at any of these centers: the Muhammad Ali Parkinson Center at Barrow Neurological Institute in Phoenix; the University of Florida, Gainesville, Florida; University of North Carolina, Chapel Hill, North Carolina; Struthers Parkinson’s Center, Minneapolis, Minnesota; and Baylor College of Medicine, Waco, Texas.

"We are providing demo units and training at no cost to as many of the National Parkinson’s Centers of Excellence as are interested in offering SpeechVive in conjunction with or as an alternative to speech therapy," said Steve Mogensen, president and CEO of SpeechVive. "We also are offering the SpeechVive units and training to professionals at Veterans Administration Medical Centers across the country. The first VAMC to offer SpeechVive is in Cincinnati, Ohio."

The SpeechVive device also is available to try at the M.D. Steer Speech and Hearing Clinic at Purdue University in West Lafayette, Indiana.

The technology was developed over the past decade by Jessica Huber, associate professor in Purdue’s Department of Speech, Language and Hearing Sciences and licensed through the Purdue Office of Technology Commercialization. The focus of Huber’s research is the development and testing of behavioral treatments to improve communication and quality of life in older adults and people with degenerative motor diseases.

SpeechVive reduces the speech impairments associated with Parkinson’s disease, which cause people with the disease to speak in a hushed, whispery voice and to have mumbled speech. People with Parkinson’s disease are commonly affected in their ability to communicate effectively.

"The clinical data we have collected over the past four years demonstrates that SpeechVive is effective in 90 percent of the people using the device," Huber said. "I am proud of the improvements in communication and quality of life demonstrated in our clinical studies. I look forward to seeing the device on the market so that more people with Parkinson’s disease will have access to it."

More than 1.5 million people in the United States are diagnosed with Parkinson’s disease, and it is one of the most common degenerative neurological diseases. About 89 percent of those with the disease have voice-related change affecting how loudly they speak, and at least 45 percent have speech-related change affecting how clearly they speak.

Neuroscientists decode brain maps to discover how we take aim

Serena Williams won her third consecutive US Open title a few days ago, thanks to reasons including obvious ones like physical strength and endurance. But how much did her brain and its egocentric and allocentric functions help the American tennis star retain the cup?

Quite significantly, according to York University neuroscience researchers whose recent study shows that different regions of the brain help to visually locate objects relative to one’s own body (self-centred or egocentric) and those relative to external visual landmarks (world-centred or allocentric).

“The current study shows how the brain encodes allocentric and egocentric space in different ways during activities that involve manual aiming,” explains Distinguished Research Professor Doug Crawford, in the Department of Psychology. “Take tennis for example. Allocentric brain areas could help aim the ball toward the opponent’s weak side of play, whereas the egocentric areas would make sure your muscles return the serve in the right direction.”

The study finding will help healthcare providers to develop therapeutic treatment for patients with brain damage in these two areas, according to the neuroscientists at York Centre for Vision Research.
“As a neurologist, I am excited by the finding because it provides clues for doctors and therapists how they might design different therapeutic approaches,” says Ying Chen, lead researcher and PhD candidate in the School of Kinesiology and Health Science.

The study, Allocentric versus Egocentric Representation of Remembered Reach Targets in Human Cortex, published in the Journal of Neuroscience, was conducted using the state-of-the-art fMRI scanner at York U’s Sherman Health Science Research Centre. A dozen participants were tested using the scanner, which Chen modified to distinguish brain areas relating to these two functions.

The participants were given three different tasks to complete when viewing remembered visual targets: egocentric reach (remembering absolute target location), allocentric reach (remembering target location relative to a visual landmark) and a nonspatial control, colour report (reporting color of target).

When participants remembered egocentric targets’ locations, areas in the upper occipital lobe (at the back of the brain) encoded visual direction. In contrast, lower areas of the occipital and temporal lobes encoded object direction relative to other visual landmarks. In both cases, the parietal and frontal cortex (near the top of the brain) coded reach direction during the movement.

(Image caption: Example axial sections of a three-dimensional MPF map (A) obtained from a 63-year old woman with SPMS disease course and results of brain tissue segmentation (B-D). Segmentation masks corresponding to white matter (WM) (B), gray matter (GM) (C), and lesi)

MRI Shows Gray Matter Myelin Loss Strongly Related to MS Disability

People with multiple sclerosis (MS) lose myelin in the gray matter of their brains and the loss is closely correlated with the severity of the disease, according to a new magnetic resonance imaging (MRI) study. Researchers said the findings could have important applications in clinical trials and treatment monitoring. The study appears online in the journal Radiology.

Loss of myelin, the fatty protective sheath around nerve fibers, is a characteristic of MS, an inflammatory disease of the central nervous system that can lead to a variety of serious neurological symptoms and disability. MS is typically considered a disease of the brain’s signal-conducting white matter, where myelin is most abundant, but myelin is also present in smaller amounts in gray matter, the brain’s information processing center that is made up primarily of nerve cell bodies. Though the myelin content in gray matter is small, it is still extremely important to proper function, as it enables protection of thin nerve fibers connecting neighboring areas of the brain cortex, according to Vasily L. Yarnykh, Ph.D., associate professor in the Department of Radiology at University of Washington in Seattle.

“The fact that MS patients lose myelin not only in white but also in gray matter has been proven by earlier post-mortem pathological studies,” he said. “However, the clinical significance of the myelin loss, or demyelination, in gray matter has not been established because of the absence of appropriate imaging methods.”

To learn more about associations between MS and demyelination in both white and gray matter, Dr. Yarnykh and colleagues used a refined MRI technique that provides information on the content of biological macromolecules – molecules present in tissues and composed of a large number of atoms, such as proteins, lipids and carbohydrates. The new method, known as macromolecular proton fraction (MPF) mapping, has been hampered in the past because of the length of time required for data collection, but improvements now allow much faster generation of whole-brain maps that reflect the macromolecular content in tissues.

“The method utilizes a standard MRI scanner and doesn’t require any special hardware—only some software modifications,” Dr. Yarnykh said. “MPF mapping allows quantitative assessment of microscopic demyelination in brain tissues that look normal on clinical images, and is the only existing method able to evaluate the myelin content in gray matter.”

The researchers looked at 30 MS patients, including 18 with relapsing-remitting MS (RRMS), the most common type of MS initially diagnosed, and 12 with the more advanced type of disease known as secondary progressive MS (SPMS). Fourteen healthy control participants were also included in the study. Each participant underwent MRI on a 3-Tesla imager, and the researchers reconstructed 3-D whole-brain MPF maps to look at normal-appearing white matter, gray matter and MS lesions. The researchers further compared the results of their imaging technique with clinical tests characterizing neurological dysfunction in MS patients.

The results showed that MPF was significantly lower in both white and gray matter in RRMS patients compared with healthy controls, and was also significantly reduced in both normal-appearing brain tissues and lesions of SPMS patients compared to RRMS patients with the largest relative decrease in gray matter. MPF in brain tissues of MS patients significantly correlated with clinical disability and the strongest associations were found for gray matter.

“The major finding of the study is that the loss of myelin in gray matter caused by MS in its relative amount is comparable to or even larger than that in white matter,” said Dr. Yarnykh. “Furthermore, gray matter demyelination is much more advanced in patients with secondary-progressive MS, and it is very strongly related to patients’ disability. As such, we believe that information about gray matter myelin damage in MS is of primary clinical relevance.”

The improved technique has potentially important applications for MS treatments targeted to protect and restore myelin.

“First, this method may provide an objective measure of the disease progression and treatment success in clinical trials,” Dr. Yarnykh said. “And second, assessment of both gray and white matter damage with this method may become an individual patient management tool in the future.”

Dr. Yarnykh and colleagues are currently conducting additional research on the new method with the support of the National Multiple Sclerosis Society and the National Institutes of Health.

“This study was done on the participants at a single point in time,” he said. “Now we want to compare MS patients with control participants to see how myelin content will evolve over time. We further plan to extend our method to the spinal cord imaging and test whether the combined assessment of demyelination in the brain and spinal cord could better explain disability progression as compared to brain demyelination alone.”