Three ways neuroscience can advance the concussion debate

While concussion awareness has improved over the past decade, understanding the nuances of these sports injuries, their severity, symptoms, and treatment, is still a work in progress. In the June 21 issue of Neuron, UCLA neurologists and neurotraumatologists review the science of concussions and outline several areas where neuroscience and clinical research can help create consensus in the field: definitions of what acute and chronic concussions are, diagnostics, and management and treatment.

“For patients, you have to be able to provide the best care even if you don’t have the exact research study to prove what you’re doing, and you also have to address the information that the patients and their families are getting through the media,” says Christopher C. Giza (@griz1), Director of the UCLA Steve Tisch BrainSPORT program and Professor of Pediatrics, Neurology, and Neurosurgery at the University of California Los Angeles. “That’s a discussion that’s hard to have because people naturally look for very short answers and sound biytes, and it’s far more complex than that.”

1. Let’s Agree on the Definition of a “Concussion,” both Acute and Chronic

The Centers for Disease Control and Prevention reported about 2.8 million traumatic-brain-injury-related emergency department visits, hospitalizations, and deaths in the United States in 2013. However, researchers disagree about whether all concussions and traumatic brain injuries are equal. A concussion may be characterized by wooziness, disorientation, incoordination, headache, and other “typical” symptoms after a hit to the head and may occur even with only rapid back-and-forth motion of the head and neck. Some have postulated that subconcussive injuries with repetitive head impacts in the absence of symptoms may result in cumulative problems.

Giza says that although a concussion and a more severe traumatic brain injury may sound similar, and although they may share some symptoms, the overlap between the two is not clear. Additionally, the determination of whether someone has a concussion or a mild traumatic brain injury or something else is largely subjective and often relies heavily on symptom reporting from the patient.

“One of the things that will help us on the acute diagnosis of concussion would be if we moved away from the current understanding of concussion as a black-or-white, yes-or-no answer,” Giza says. “There are scenarios when we can be more certain, clinically, that we’re making the correct diagnosis. If there’s a clear impact event, there’s a typical constellation of symptoms that occurs in temporal relationship to the impact, and that symptom pattern has a time course consistent with what we see in concussion in terms of peaking early followed by gradual improvement, then we can diagnose confidently.”

Giza notes that not every symptom that occurs after a hit to the head is related to a concussion, which is why formal diagnosis requires an experienced clinician. Similarly, not all chronic symptoms are referable to a distant concussion or head impact. Understanding the physiological mechanisms underlying concussions and concussive symptoms (both acute and chronic) can lead to better diagnostic tests and potentially point the way to individualized treatment plans.

2. Realize that Diagnosis Is Critical to Treatment

Some concussion patients experience atypical symptoms, or usual symptoms that get worse later on instead of improving. One potential pitfall of concussion diagnosis is that some symptoms may appear to be concussion related but could actually be a symptom of something else, like migraine, dehydration, hyperthermia, neck strain, or more severe brain injury.

“We need to prioritize what we think sounds like a definite concussion vs. probable vs. possible, and even recognize that there are syndromes with neurological symptoms that occur after impact that are something more than a concussion,” Giza says. “There are rare patients who have cerebral edema — sometimes, we call it second impact syndrome, which is another ambiguous term — but that’s not a concussion. Patients who very rarely get a subdural hematoma as a consequence of a sports injury sometimes are portrayed as having had a concussion, but a subdural hematoma or an epidural hematoma is something much more than what we would diagnose clinically as a concussion.”

There are also computerized tests, and soon, hopefully blood tests, brain imaging, and electrical tests that can help diagnose concussion or follow recovery, but because concussions are “the most complex injury to the most complex organ” in the human body, there is not necessarily a magic bullet, catch-all, perfect method for diagnosing concussions.

3. Focus on Animal Research to Discover Better Treatment Plans

“In the clinical concussion world, many of the research protocols are observational, but I think laboratory neuroscience can inform in terms of how important is the time between injuries and how much cognitive or physical activity should there be during the recovery period,” Giza says. Focusing on animal models is one way neuroscience can help accelerate concussion and traumatic brain injury research, particularly in the investigation of how consequences of repetitive injury differ when they occur very close in time versus when they are spaced out, and in determining when the brain is physiologically ready to return to activity.

“Animal models are also well suited for looking at long-term processes set into play by the acute injury.” Giza says. “So animals can be subjected to repetitive injuries when they’re relatively young — at least in rodent models, within a year or two, those animals become ‘old’ animals, and we can look to see along that time course whether mechanisms of neurodegeneration have been activated, and whether that leads to deficits over time. Those studies can be done in the time course of months to years rather than decades, as would be necessary for clinical studies. If we do things right in the coming years, we can really change the game in our understanding about concussion and brain injuries.”

New technique makes brain scans better

People who suffer a stroke often undergo a brain scan at the hospital, allowing doctors to determine the location and extent of the damage. Researchers who study the effects of strokes would love to be able to analyze these images, but the resolution is often too low for many analyses.

To help scientists take advantage of this untapped wealth of data from hospital scans, a team of MIT researchers, working with doctors at Massachusetts General Hospital and many other institutions, has devised a way to boost the quality of these scans so they can be used for large-scale studies of how strokes affect different people and how they respond to treatment.

“These images are quite unique because they are acquired in routine clinical practice when a patient comes in with a stroke,” says Polina Golland, an MIT professor of electrical engineering and computer science. “You couldn’t stage a study like that.”

Using these scans, researchers could study how genetic factors influence stroke survival or how people respond to different treatments. They could also use this approach to study other disorders such as Alzheimer’s disease.

Golland is the senior author of the paper, which will be presented at the Information Processing in Medical Imaging conference during the week of June 25. The paper’s lead author is Adrian Dalca, a postdoc in MIT’s Computer Science and Artificial Intelligence Laboratory. Other authors are Katie Bouman, an MIT graduate student; William Freeman, the Thomas and Gerd Perkins Professor of Electrical Engineering at MIT; Natalia Rost, director of the acute stroke service at MGH; and Mert Sabuncu, an assistant professor of electrical and computer engineering at Cornell University.

Filling in data

Scanning the brain with magnetic resonance imaging (MRI) produces many 2-D “slices” that can be combined to form a 3-D representation of the brain.

For clinical scans of patients who have had a stroke, images are taken rapidly due to limited scanning time. As a result, the scans are very sparse, meaning that the image slices are taken about 5-7 millimeters apart. (The in-slice resolution is 1 millimeter.)

For scientific studies, researchers usually obtain much higher-resolution images, with slices only 1 millimeter apart, which requires keeping subjects in the scanner for a much longer period of time. Scientists have developed specialized computer algorithms to analyze these images, but these algorithms don’t work well on the much more plentiful but lower-quality patient scans taken in hospitals.

The MIT researchers, along with their collaborators at MGH and other hospitals, were interested in taking advantage of the vast numbers of patient scans, which would allow them to learn much more than can be gleaned from smaller studies that produce higher-quality scans.

“These research studies are very small because you need volunteers, but hospitals have hundreds of thousands of images. Our motivation was to take advantage of this huge set of data,” Dalca says.

The new approach involves essentially filling in the data that is missing from each patient scan. This can be done by taking information from the entire set of scans and using it to recreate anatomical features that are missing from other scans.

“The key idea is to generate an image that is anatomically plausible, and to an algorithm looks like one of those research scans, and is completely consistent with clinical images that were acquired,” Golland says. “Once you have that, you can apply every state-of-the-art algorithm that was developed for the beautiful research images and run the same analysis, and get the results as if these were the research images.”

Once these research-quality images are generated, researchers can then run a set of algorithms designed to help with analyzing anatomical features. These include the alignment of slices and a process called skull-stripping that eliminates everything but the brain from the images.

Throughout this process, the algorithm keeps track of which pixels came from the original scans and which were filled in afterward, so that analyses done later, such as measuring the extent of brain damage, can be performed only on information from the original scans.

“In a sense, this is a scaffold that allows us to bring the image into the collection as if it were a high-resolution image, and then make measurements only on the pixels where we have the information,” Golland says.

Higher quality

Now that the MIT team has developed this technique for enhancing low-quality images, they plan to apply it to a large set of stroke images obtained by the MGH-led consortium, which includes about 4,000 scans from 12 hospitals.

“Understanding spatial patterns of the damage that is done to the white matter promises to help us understand in more detail how the disease interacts with cognitive abilities of the person, with their ability to recover from stroke, and so on,” Golland says.

The researchers also hope to apply this technique to scans of patients with other brain disorders.

“It opens up lots of interesting directions,” Golland says. “Images acquired in routine medical practice can give anatomical insight, because we lift them up to that quality that the algorithms can analyze.”

Find the report online at: http://www.mit.edu/~adalca/files/papers/ipmi2017_patchSynthesis.pdf

Pre-clinical study suggests Parkinson's could start in gut endocrine cells

Recent research on Parkinson’s disease has focused on the gut-brain connection, examining patients’ gut bacteria, and even how severing the vagus nerve connecting the stomach and brain might protect some people from the debilitating disease.

But scientists understand little about what’s happening in the gut — the ingestion of environmental toxins or germs, perhaps — that leads to brain damage and the hallmarks of Parkinson’s such as tremors, stiffness and trouble walking.

Duke University researchers have identified a potential new mechanism in both mice and human endocrine cells that populate the small intestines. Inside these cells is a protein called alpha-synuclein, which is known to go awry and lead to damaging clumps in the brains of Parkinson’s patients, as well as those with Alzheimer’s disease.

According to findings published June 15 in the journal JCI Insight, Duke researchers and collaborators from the University of California, San Francisco, hypothesize that an agent in the gut might interfere with alpha-synuclein in gut endocrine cells, deforming the protein. The deformed or misfolded protein might then spread via the nervous system to the brain as a prion, or infectious protein, in similar fashion to mad cow disease.

“There is abundant evidence that misfolded alpha-synuclein is found in the nerves of the gut before it appears in the brain, but exactly where this misfolding occurs is unknown,” said gastroenterologist Rodger Liddle, M.D., senior author of the paper and professor of medicine at Duke. “This is another piece of evidence that supports the hypothesis that Parkinson’s arises in the gut.”

Alpha-synuclein is the subject of much ongoing research on Parkinson’s, as it’s the main component of Lewy bodies, or toxic protein deposits that take up residence in brain cells, killing them from the inside. The clumps form when alpha-synuclein develops a kink in its normally spiral structure, making it ‘sticky,’ and prone to aggregating, Liddle said.

But how would a protein go from traveling through the inner-most ‘tube’ of the intestine, where there are no nerve cells, into the nervous system? That’s a question Liddle and colleagues sought to answer in a 2015 manuscript published in the Journal of Clinical Investigation. Although the main function of gut endocrine cells is to regulate digestion, the Duke researchers found these cells also have nerve-like properties.

Rather than using hormones to communicate indirectly with the nervous system, these gut endocrine cells physically connect to nerves, providing a pathway to communicate with the brain, Liddle said. The researchers demonstrated this in a stunning time-lapse video (2015, Journal of Clinical Investigation) in which a gut endocrine cell is placed under the microscope near a neuron. In just a few hours, the endocrine cell moves toward the neuron and fibers appear between them as they establish communication.

Liddle and other scientists were astonished at the video, he said, because the endocrine cells — which are not nerves — were behaving like them. This suggests they are able to communicate directly with the nervous system and brain.

With the new finding of alpha-synuclein in endocrine cells, Liddle and colleagues now have a working explanation of how malformed proteins can spread from the inside of the intestines to the nervous system, using a non-nerve cell that acts like a nerve.

Liddle and colleagues plan to gather and examine the gut endocrine cells from people with Parkinson’s to see if they contain misfolded or otherwise abnormal alpha-synuclein. New clues about this protein could help scientists develop a biomarker that could diagnose Parkinson’s disease earlier, Liddle said.

New leads on alpha-synuclein could also aid the development of therapies targeting the protein. Scientists have been investigating treatments that could prevent alpha-synuclein from becoming malformed, but much of the research is still in its early stages, Liddle said.

“Unfortunately, there aren’t great treatments for Parkinson’s disease right now,” he said. “It’s conceivable down the road that there could be ways to prevent alpha-synuclein misfolding, if you can make the diagnosis early.”

Scientists try to crack the brain's memory codes

In a pair of studies, scientists at the National Institutes of Health explored how the human brain stores and retrieves memories. One study suggests that the brain etches each memory into unique firing patterns of individual neurons. Meanwhile, the second study suggests that the brain replays memories faster than they are stored.

The studies were led by Kareem Zaghloul, M.D., Ph.D., a neurosurgeon-researcher at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS). Persons with drug resistant epilepsy in protocols studying surgical resection of their seizure focus at the NIH’s Clinical Center enrolled in this study. To help locate the source of the seizures, Dr. Zaghloul’s team surgically implanted a grid of electrodes into the patients’ brains and monitored electrical activity for several days.

“The primary goal of these recordings is to understand how to stop the seizures. However, it’s also a powerful opportunity to learn how the brain works,” said Dr. Zaghloul.

For both studies, the researchers monitored brain electrical activity while testing the patients’ memories. The patients were shown hundreds of pairs of words, like “pencil and bishop” or “orange and navy,” and later were shown one of the words and asked to remember its pair.

In one study, published in the Journal of Neuroscience, the patients correctly remembered 38 percent of the word pairs they were shown. Electrical recordings showed that the brain waves the patients experienced when they correctly stored and remembered a word pair often occurred in the temporal lobe and prefrontal cortex regions. Nevertheless, the researchers showed that the waves that appeared when recalling the words happened faster than the waves that were present when they initially stored them as memories.

“Our results suggest the brain replays memories on fast forward,” said Dr. Zaghloul.

In the second study, published in Current Biology, the researchers used a new type of grid, called a high density microelectrode array, to monitor the activity of dozens of individual neurons during the memory tests. The arrays were implanted into the middle temporal gyrus, a part of the brain thought to control word, face and distance recognition.

In this study, the patients correctly remembered 23 percent of the word pairs. When the researchers looked at the electrical recordings, they found that the pattern of neurons that fired when the patients correctly recalled a word pair appeared to be similar to the pattern of neurons that fired when they first learned the pair. Moreover, the results showed that the overall activity of the neurons was specific to each individual word pair and was quietest when the patients correctly remembered a pair, suggesting that the brain only uses a small proportion of neurons to represent each memory.

“These results support the idea that each memory is encoded by a unique firing pattern of individual neurons in the brain,” concluded Dr. Zaghloul.

In the future, Dr. Zaghloul’s team plans to continue exploring the neural mechanisms that underlie how the brain forms and retrieves memories and whether they can use similar techniques to understand the electrical codes underlying the epilepsies.

Unexpected mechanism behind chronic nerve pain

It has long been assumed that chronic nerve pain is caused by hypersensitivity in the neurons that transmit pain. Researchers at Karolinska Institutet in Sweden now show that another kind of neuron that normally allows us to feel pleasant touch sensation can switch function and instead signal pain after nerve damage. The results, which are presented in the journal Science, can eventually lead to more effective pain treatments.

Severe, treatment-demanding chronic nerve pain is a common condition but the drugs available have, at best, only some efficacy. Since the mechanisms behind nerve pain are largely unknown, the pharmaceutical industry has encountered major setbacks in the development of new drugs.

It was previously assumed that certain sensory neurons only transmit pleasant tactile sensations, while other specializes to transmit pain. During chronic nerve pain, normal touch can cause pain, but how this happens has remained a mystery. Scientists at Karolinska Institutet have now discovered that a small RNA molecule (microRNA) in sensory neurons regulates how touch is perceived. Upon nerve damage, levels of this molecule drop in the sensory neurons, which results in raised levels of a specific ion channel that makes the nerve cells sensitive to pain.

“Our study shows that touch-sensitive nerves switch function and start producing pain, which can explain how hypersensitivity arises,” says Professor Patrik Ernfors at Karolinska Institutet’s Department of Medical Biochemistry and Biophysics. “MicroRNA regulation could also explain why people have such different pain thresholds.”

The drug substance gabapentin is often used to treat nerve pain, even though the mechanism of action has not been known. The new study shows that gabapentin operates in the touch-sensitive neurons and blocks the ion channel that increases when microRNA levels decrease. Yet it is still around only half of all patients who respond positively to the treatment.

“Nerve pain is a complex condition with several underlying mechanisms,” says Professor Ernfors. “What’s interesting about our study is that we can show that the RNA molecule controls the regulation of 80 per cent of the genes that are known to be involved in nerve pain. My hope, therefore, is that microRNA-based drugs will one day be a possibility.”

The research was primarily conducted on mice but also verified in tests on human tissue, where low microRNA levels could be linked to high levels of the specific ion channel and vice versa, suggesting that the mechanism is the same in humans.

“It’s vital that we understand the mechanisms that lead to chronic nerve pain so that we can discover new methods of treatment,” says Professor Ernfors. “The pharmaceutical companies have concentrated heavily on substances that target ion channels and receptors in pain neurons, but our results show that they might have been focusing on the wrong type of neuron.”

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Phagocytes in the brain: Good or bad?

The precise impact of the microglia in neurodegenerative diseases such as Alzheimer’s and Parkinson’s remains unclear. In the brain, microglial cells migrate to sites of neural damage in response to neuro-inflammatory signals, and dispose of dying cells and insoluble cell debris by engulfing and enzymatically digesting them. The microglia therefore perform essentially the same role as that carried out by the immune cells known as macrophages in other tissues. However, neuro-inflammatory responses may also contribute to the pathogenesis of neurodegeneration, as microglia are known to be activated in virtually all types of dementia. This may simply relate to their role as phagocytic cells in the degradation of the extracellular protein deposits (amyloid plaques) that are a hallmark of Alzheimer’s. But it is also possible that activated microglia promote disease progression by secreting molecular signals that exacerbate inflammatory responses which are ultimately deleterious to healthy nerve cells.

The new study was carried out by an interdisciplinary German-Swiss team of cell biologists, radiologists and neuropathologists led by Professor Christian Haass, who holds the Chair of Metabolic Biochemistry at LMU and is Speaker of the German Center for Neurodegenerative Diseases (DZNE) in Munich. To clarify whether the microglia are the good guys or the bad guys, the researchers focused on the function of the gene TREM2. In the brain, this gene is expressed predominantly in microglia. Furthermore, mutations that impair its expression or the function of its protein product are associated with increased risk for neurodegenerative conditions such as Alzheimer’s, Parkinson’s and frontotemporal dementia (FTD).

With the aid of the CRISPR/Cas9 gene-editing system, Haass and his colleagues altered a single subunit (base-pair) in the coding sequence of the TREM2 gene of mice, which directs the synthesis of the TREM2 protein. In humans, this same mutation is associated with increased risk for a form of FTD. In earlier studies, it had been demonstrated that the normal TREM2 protein is transported to the cell membrane in order to perform its biological function. The mutation introduced by the CRISPR system disrupts this process, such that very little of the protein is expressed on the surface of microglial cells. In mice, this genetic alteration leads to a drastic impairment of microglial function, as evidenced by a variety of tests. For example, the mutant strain no longer activates its microglial cells in response to neuronal loss in the brain. As a result, the cells fail to migrate to sites of cell damage — and dead cells, insoluble debris and plaques cannot be disposed of. In addition, the mutation has catastrophic consequences for energy metabolism. The normal brain is totally dependent on glucose as an energy source, but loss of the TREM2 function leads to a significant fall in glucose consumption in the mutant brain. Moreover, the blood supply to the brain in a whole is markedly curtailed. Similar phenomena are observed in patients who carry loss-of-function mutations in the TREM2 gene. Taken together, these observations argue that microglial activation is indispensable for normal brain function.

Christian Haass summarizes the wider implications of the study as follows: “Our findings underline the significance of microglia for homeostasis in the brain, and they imply that these cells have an immunoprotective function, at least in the early stages of the pathogenesis of neurodegenerative diseases. We believe that our data provide the rationale for a new approach to the development of effective therapies, based on boosting the defense response of the microglia. If we succeed in enhancing this function, either by pharmacological or other means, it might be possible to delay the onset of dementias.”

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In multiple sclerosis, problems reading social cues may be tied to brain changes

For people with multiple sclerosis (MS), an impaired ability to understand how others feel and think may be linked to subtle brain changes, according to a study published in the May 31, 2017, online issue of Neurology®, the medical journal of the American Academy of Neurology.

“Understanding how MS affects the ‘social brain’ has not been well studied, but the ability to interpret other people’s feelings and intentions may influence people’s ability to maintain a job and their relationships with family and friends,” said Sonia Batista, MD, of the University of Coimbra in Coimbra, Portugal. “These skills are very important for people with MS since having good support is one of the main factors in whether people have a good quality of life.”

The study involved 60 people with MS and 60 healthy people of the same age and education level. The people with MS had been diagnosed with the disease for an average of 11 years; 50 had the relapsing-remitting form of the disease and the rest had secondary progressive MS.

All of the participants took tests to measure their Theory of Mind skills, or their ability to infer other peoples’ beliefs, desires and intentions to explain and predict behavior. In one test, people are shown photographs of peoples’ eyes along with four words describing mental states such as “anxious” or “embarrassed” and are asked to select the word that best describes the feelings of the person in the photo. In another test, participants are shown silent video clips of people interacting along with two words describing the interaction and are asked to choose the best word.

The participants also had MRI brain scans and advanced MRI scans called diffusion tensor imaging to look for changes in the brain’s white matter. The scans are based on the movement of water molecules in brain tissue and measure microstructural changes in white matter, which connects different brain regions.

The people with MS had lower scores on both Theory of Mind tests, with an average score of 59 percent on the photo test, compared to an average of 82 percent for the healthy participants. On the video test, the people with MS had an average of 75 percent compared to 88 percent for the healthy controls.

The results for the people with MS were not related to how long they had had MS or how disabled they were, but they were related to the total volume of lesions called T1 and T2 lesions, which are areas of damage in the brain.

On the brain scans, compared to the healthy people, those with MS had widespread abnormalities in their white matter, with the most extensive damage in areas including the uncinate fasciculus, fornix and corpus callosum, which play an important role in the brain’s social network. The more damage people had in these areas of the brain, the more likely they were to also have low scores on the social tests.

“It appears that there is a disconnect in the social brain network,” said Batista.

One limitation of the study is that the tests and scans were conducted once, so any changes over time in social test scores or areas of brain damage could not be assessed.

Batista said more research is needed to better understand these social problems in MS, such as whether different types of MS are affected differently, how these problems affect people with MS in their daily lives and whether the social problems are linked to or separate from other problems with thinking and memory skills that occur in MS.

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Virtual reality eases phantom limb pain

Virtual Reality can relieve the sensation of phantom limb pain. A new test devised by researchers at Aalborg University shows that VR technology can trick the amputee’s brain into thinking that it is still in control of a missing limb.

If a hand, an arm or a leg is amputated due to accident or disease, eight out of ten amputees experience a feeling of discomfort in the limb that is no longer there. The phenomenon is called phantom limb pain. Even though science has yet to come up with an unambiguous explanation, the most discussed theory concerns the sudden lack of input from the severed neural cords.

“The tactile representation of different body parts are arranged in the brain in a sort of map,” explains Bo Geng, Postdoc at the Faculty of Medicine at Aalborg University in Denmark.

“If the brain no longer receives feedback from an area, it tries to reprogram its signal reception map. That is the most common conception of how phantom limb pain occurs,” she says.

Tricking the brain

Tests have shown that phantom limb pain can be relieved if the brain is tricked into thinking that the amputated limb is still attached to the body. By placing a mirror at an angle in front of the chest you can create the visual illusion that the body is symmetrical.

If you then pretend to do the same movements simultaneously with both hands, the brain in many cases can be convinced that it is in contact with an amputated hand.

The method has proven effective in a number of amputees and is the foundation for a new method that has been developed by Bo Geng in collaboration with Dr. Martin Kraus and Master’s students Bartal Henriksen and Ronni Nedergaard Nielsen from Medialogy at Aalborg University.

Through the looking glass

By using Virtual Reality it is possible to create an experience of being present in a three dimensional world where you can move around freely, grab things and interact with them.

“The mirror therapy has some limitations because you have to physically sit down in front of a mirror, do the same movement in a confined space with both hands at the same time and keep your eyes on the mirror. The illusion can easily be broken,” Bo Geng explains. “With Virtual Reality there is a much better chance of creating a convincing alternative reality.”

In the new method the patients have to put on VR goggles and a glove. At the same time, small electrodes are placed on the residual limb, known as the stump.

By stimulating the stump with tiny electrical impulses, researchers try to recreate the sensation of the phantom hand.

The amputee plays a number of different VR games that involve doing the same thing with both hands such as grabbing a pole that has to be twisted into different shapes or pushing different virtual buttons.

In the virtual reality it feels exactly as if you were using both hands.

A convincing reality

“Even though a person who has had a hand amputated can no longer see it, in many cases he or she can still feel it. This sensory conflict may be interpreted by the brain as pain. With this new method we try to overcome that conflict by providing an artificial visual and tactile feedback and in that way suppress the pain,” says Bo Geng.

The new approach underwent its first clinical test at the China Rehabilitation Research in Beijing last fall. Here, two out of three amputees felt their phantom limb pain ease whereas the third one experienced a decrease in the frequency of phantom limb pain attacks.

“Of course we need to do more tests, but the results so far look promising,” Bo Geng says.

At the moment the system only works with upper body amputees, but students at Aalborg University are developing a version for people who have had a foot or a leg amputated as well.

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How the injured brain tells the body it’s hurt

Johns Hopkins researchers say they have identified a new way that cells in the brain alert the rest of the body to recruit immune cells when the brain is injured. The work was completed in mouse models that mimic infection, stroke or trauma in humans.

Investigators already knew there was a communication highway between the brain and the immune system but have been unclear about how exactly how the brain sends signals to the immune system. While immune system cells’ purpose is to defend and protect the body, ironically the brain’s “call to arms” may cause more harm than good when it instructs immune cells to enter into the brain. The persistence of these cells can cause chronic inflammation and damage the brain.

In their new study, described in Science Signaling April 13, Johns Hopkins researchers say there is evidence that vesicles or small (about the size of a virus), fat-like molecules and protein-filled sacks released from a type of immune cell in the brain called astrocytes travel through the bloodstream to the liver. The liver then instructs white blood cells to go to the site of injury in the brain.

“This work describes an entirely new way that the brain talks with the body,” says Norman Haughey, Ph.D., professor of neurology at the Johns Hopkins University School of Medicine. “Identifying this pathway has helped us pinpoint ways to impede this process and reduce brain damage brought on by the body’s own excessive immune response.”

Because of the work of several other collaborators, Haughey says, his team knew that some sort of inflammation-promoting molecule was released from brain and targeted to the liver after brain injury to send immune system cells to the damaged area, but the identity of this go-between had been elusive for years.

The questions remained of what the signal was, and how, exactly, the signal got all the way to the liver from the brain, particularly since the blood-brain barrier prevents many molecules in the brain from crossing over into the rest of the body, just as it prevents molecules from getting into the brain. The team focused on an enzyme called neutral sphingomyelinase, known as nSMase2, which they knew from a separate project was turned on by an immune system chemical messenger, a cytokine interleukin 1-beta (IL-1b) that promotes inflammation. Sphingomyelinases like nSMase2 play a normal role in the cell’s metabolism by breaking down fatty molecules into smaller components that cells use for every day functions.

To see if possibly nSMase2 was also involved in alerting the immune system during brain injury, the researchers mimicked brain injury in mice by injecting cytokine IL-1b into the striatum, a structure found in the deep center of the brain. As a comparison group, they injected saline (saltwater) in the same brain area of other mice. They also injected the mouse brains with both the cytokine IL-1b and a drug called altenusin that blocks the nSMase enzyme from working.

Twenty-four hours after the injection, the researchers saw large numbers of immune system white blood cells in tissue samples of the rodent brains near the site of injury of those mice injected with the cytokine IL-1b, but not in the brain tissue of the control group of mice. In addition, they no longer saw the same large influx of white blood cells into the brain when they used the drug that inhibited nSMase, with the number of white blood cells in the brain dropping by about 90 percent. This finding told the researchers of nSMase2’s involvement but still didn’t tell them about the signal sent from the brain to activate the body’s immune response. According to Haughey, after many failed experiments to determine the brain’s messenger, he visited his colleague and collaborator Daniel Anthony at Oxford University, who introduced him to the concept of “exosomes” — miniature vesicles released from cells.

“That conversation was the ‘Ah-ha’ moment when it all began to make sense,” says Haughey.

He read earlier studies showing that the enzyme nSMase2 was required for forming and releasing exosomes. Exosomes form inside cell compartments and release outside the cell when these compartments fuse with the cell’s surrounding membrane. Exosomes are surrounded by bits of cell membrane and filled with proteins and different types of the genetic material RNA.

To test that exosomes were the source of this brain to body communication, Haughey’s research team isolated exosomes from the blood of mice four hours after injecting the cytokine IL-1b into brain and then injected the exosomes into the tail veins of different mice that had the cytokine and the nSMase-blocking drug altenusin already in their brains.

The researchers found that white blood cells in healthy mice who received exosomes from the blood of the mice with brain damage traveled to the site of brain injury, which the researchers say demonstrates that exosomes released from brain in response to damage alert the immune system to send the immune cell sentinels to the brain.

When they stripped the vesicles of protein and their genetic cargo and injected them back into mice, the blood cells no longer went to the site of brain injury.

Finally, the researchers analyzed the protein and genetic material contents of the exosomes in an effort to identify the molecules inside that alerted the immune system to brain damage. They found 10 unique proteins and 23 microRNAs — short bits of RNA that don’t code for genes — at increased levels in the vesicles. Several of these components had connections to a specific mechanism used by the liver to activate inflammation.

“Given the therapeutic potential of the nSMase target, we’re now working closely with Drs. Barbara Slusher, Camilo Rojas, Ajit Thomas and colleagues at the Johns Hopkins Drug Discovery facility to identify potent inhibitors of the nSMase enzyme which can be developed for clinical use,” says Haughey.

 

Worsening outcomes in service members five years after mild blast-induced concussion

According to a new study in JAMA Neurology, U.S. military service members who endured a mild concussion after blast injury while deployed in Iraq or Afghanistan may continue to experience mental health symptoms as well as decreases in quality of life for at least five years after their injury. The study was supported by the National Institute of Neurological Disorders and Stroke (NINDS) and the Department of Defense. NINDS is part of the National Institutes of Health.

“This is one of the first studies to connect the dots from injury to longer-term outcomes and it shows that even mild concussions can lead to long-term impairment and continued decline in satisfaction with life,” said lead author Christine L. Mac Donald, Ph.D., an associate professor in the Department of Neurological Surgery at the University of Washington School of Medicine in Seattle. “Most physicians believe that patients will stabilize 6-12 months post-injury, but this study challenges that, showing progression of post-concussive symptoms well after this time frame.”

Dr. Mac Donald’s team studied five-year outcomes in 50 service members who experienced mild traumatic brain injury (mTBI) in Iraq or Afghanistan and compared the findings to 44 controls who were deployed but not injured. The researchers have been studying the service members with mTBI since their injury and examined changes in their symptoms from one year to five years after injury. The service members underwent a battery of neurological and neuropsychological assessments as well as tests of their overall functional ability to return to work and live independently.

According to the results, 72 percent of service members in the head injury group experienced a decline in disability scores, compared to 11 percent of the combat-deployed controls. Worsening of post-traumatic stress and depression symptoms, between one and five years following injury was also more common in the blast-injured service members. The injured service members also experienced more headaches and disrupted sleep compared to controls. There were no differences in cognitive performance between service members who had experienced a concussion and those in the control group.

The study also showed that a combination of factors, including neurobehavioral symptom severity, walking ability, and verbal fluency at one year after injury, was highly predictive of poor outcomes five years later.

“We need to identify effective, long-term treatment strategies that will help these brave men and women enjoy the highest quality of life possible following their service to our country,” said Walter Koroshetz, M.D., director of NINDS. “This unique academic-military partnership highlights the power of data sharing and cutting across traditional boundaries to advance research that will help improve the lives of our military members.”

Blast injury due to improvised explosive devices was the representative injury of the wars in Iraq and Afghanistan. Approximately 20 percent of deployed service members in Iraq and Afghanistan experienced head injury. While the majority of those injuries were considered mild, the long-term effects are unknown.

Dr. Mac Donald’s group also found that while 80 percent of service members with concussions had sought treatment from mental health providers, only 19 percent reported that those programs were helpful. The authors note that this suggests the need for more targeted treatment options with longer-lasting benefits.

Dr. Mac Donald and her colleagues are currently examining a larger group of service members in order to validate these findings and are looking at how injured service members are doing beyond five years.

Possible reasons for loss of smell

Studies have shown that loss of the sense of smell can be among the first warning signs of diseases such as Alzheimer’s and Parkinson’s. Now a researcher at the Perelman School of Medicine at the University of Pennsylvania wants to shift the search for clues about this process back even further, to find out if there is a common factor responsible for the loss of smell that may also serve as an early warning signal for a number of neurodegenerative diseases. In a review published online in Lancet Neurology, Richard L. Doty, PhD, a professor of Otorhinolaryngology and director of the Smell and Taste Center, cites evidence that the common link could be damage to neurotransmitter and neuromodulator receptors in the forebrain — the front part of the brain.

“We need to retrace the steps of the development of these diseases,” Doty said. “We know loss of smell is an early sign of their onset, so finding common factors associated with the smell loss could provide clues as to the pre-existing processes that initiate the first stages of a number of neurodegenerative diseases. An understanding of such processes could provide novel approaches to their treatment, including ways to slow down or stop their development before irreversible damage has occurred.”

Currently, it’s is generally believed that the smell loss of various neurodegenerative diseases is caused by disease-specific pathology. In other words, different diseases can bring about the same loss of smell for different reasons. Doty’s review — the first of its kind — looked at many neurodegenerative diseases with varying degrees of smell loss and sought to find a common link that may explain such losses. He considered physiological factors as well as environmental factors like air pollution, viruses, and exposure to pesticides.

“Ultimately, as each possibility was evaluated, there were cases where these factors didn’t show up, which ruled them out as potential universal biomarkers.”

Doty did find compelling evidence for a neurological solution: Damage to the neurotransmitter and neuromodulator receptors in the forebrain — most notably, a system employing the neurochemical acetylcholine. Neurotransmitters are the chemicals that send signals throughout the brain. Neuromodulators influence the activity of neurons in the brain. The receptors receive the signals, and if they are damaged, it hurts the brain’s ability to process smells normally.

“The good news is we can assess damage to some of the systems by evaluating their function in living humans using radioactive neurochemicals and brain imaging processes such as positron emission tomography (PET),” Doty said. “Unfortunately, few data are currently available, and the historical data of damage to neurotransmitter/neuromodulator systems, including cell counts from autopsy studies, are limited to just a few diseases. Moreover, quantitative data on a patient’s olfactory status is rarely available, especially prior to disease diagnosis.”

Doty said the lack of early data is a problem across the board in the search for factors that may explain smell loss.

“Smell testing isn’t part of a standard check-up, and people don’t recognize a smell problem themselves until it’s already severe,” Doty said. “Research now starting in Japan will be testing thousands of people over the course of the next few years that will better define associations between changes in smell and a wide variety of physiological measures in older populations.”

“If a universal factor does exist, the benefits for patients would be obvious,” Doty said. “Damage to the neurotransmitter and neuromodulator receptors shows promise as one possibility, but we need more research in this area to truly answer the question. It could be the key to unlocking better understanding of neurological disease.”

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Materials provided by University of Pennsylvania School of Medicine. Note: Content may be edited for style and length.

Brain injury causes impulse control problems in rats

New research from the University of British Columbia confirms for the first time that even mild brain injury can result in impulse control problems in rats.

The study, published in the Journal of Neurotrauma, also found that the impulsivity problems may be linked to levels of an inflammatory molecule in the brain, and suggest that targeting the molecule could be helpful for treatment.

“Few studies have looked at whether traumatic brain injuries cause impulse control problems,” said the study’s lead author, Cole Vonder Haar, a former postdoctoral research fellow in the UBC department of psychology who is now an assistant professor at West Virginia University. “This is partly because people who experience a brain injury are sometimes risk-takers, making it difficult to know if impulsivity preceded the brain injury or was caused by it. But our study confirms for the first time that even a mild brain injury can cause impulse control problems.”

For the study, researchers gave rats with brain injuries a reward test to measure impulsivity.

Rats that were unable to wait for the delivery of a large reward, and instead preferred an immediate, but small reward, were considered more impulsive.

The researchers found that impulsivity in the rats increased regardless of the severity of the brain injury. The impulsivity also persisted eight weeks after injury in animals with a mild injury, even after memory and motor function returned.

“These findings have implications for how brain injury patients are treated and their progress is measured,” said Vonder Haar. “If physicians are only looking at memory or motor function, they wouldn’t notice that the patient is still being affected by the injury in terms of impulsivity.”

After analyzing samples of frontal cortex brain tissue, the researchers also found a substantial increase in levels of an inflammatory molecule, known as interleukin-12, that correlated with levels of impulsivity. Interleukins are groups of proteins and molecules responsible for regulating the body’s immune system.

The study builds on the researchers’ previous findings about the link between interleukin-12 and impulsivity.

Catharine Winstanley, the study’s senior author and associate professor in the UBC department of psychology, said the findings are important because impulsivity is linked to addiction vulnerability.

“Addiction can be a big problem for patients with traumatic brain injuries,” she said. “If we can target levels of interleukin-12, however, that could potentially provide a new treatment target to address impulsivity in these patients.”

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Materials provided by University of British Columbia. Note: Content may be edited for style and length.

Gauging 5-year outcomes after concussive blast traumatic brain injury

Most wartime traumatic brain injuries (TBIs) are mild but the long-term clinical effects of these injuries have not been well described. A new article published by JAMA Neurology identifies potential predictors of poor outcomes in service members diagnosed with concussive blast TBI.

The study by Christine L. Mac Donald, Ph.D., of the University of Washington School of Medicine, Seattle, and coauthors included 50 active-duty U.S. military service members with concussive blast TBI and 44 service members who were combat-deployed but had no TBI. They were enrolled from November 2008 until July 2013 either in Afghanistan or after evacuation to a medical center in Germany. Clinical evaluations in the United States were done after one and five years.

Overall, 36 of the 50 patients with concussive blast TBI (72 percent) had a decline in an overall measure of disability from the one- to five-year evaluations, according to the results.

Satisfaction with life, global disability, neurobehavioral symptom severity, psychiatric symptom severity and sleep impairment were worse in patients with concussive blast TBI compared with the combat-deployed service members without TBI, although performance on cognitive measures was no different between the two groups at the evaluation after five years, according to the article.

Risk factors for poor outcomes after five years appear to be brain injury diagnosis, preinjury intelligence, motor strength, verbal fluency and neurobehavioral symptom severity at one year, the authors report.

In addition, between the one- and five-year evaluations, 18 combat-deployed service members without TBI (41 percent) and 40 patients with concussive blast TBI (80 percent) reported seeking help from a licensed mental health professional but only nine combat-deployed service members without TBI (20 percent) and nine patients with concussive blast TBI (18 percent) reported that mental health programs helped, according to the results.

The study notes some limitations, including its modest sample size.

“Together these findings indicate progression of symptom severity beyond one year after injury. Many service members with concussive blast TBI experience evolution rather than resolution of symptoms from the one- to five-year outcomes. Even a small percentage of combat-deployed controls appeared to experience worsening over time. In both groups, this finding appears to be driven more by psychiatric symptoms than by cognitive deficits. … We believe that by being informed from longitudinal studies such as this one, the medical community can be proactive in combatting the potentially negative and extremely costly effect of these wartime injuries,” the article concludes.

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Materials provided by The JAMA Network Journals. Note: Content may be edited for style and length.

Scientists surprised to discover lymphatic ‘scavenger’ brain cells

The brain has its own inbuilt processes for mopping up damaging cellular waste — and these processes may provide protection from stroke and dementia.

University of Queensland scientists discovered a new type of lymphatic brain “scavenger” cell by studying tropical freshwater zebrafish — which share many of the same cell types and organs as humans.

Lead researcher Associate Professor Ben Hogan from UQ’s Institute for Molecular Bioscience said the fundamental discovery would help scientists understand how the brain forms and functions.

“It is rare to discover a cell type in the brain that we didn’t know about previously, and particularly a cell type that we didn’t expect to be there,” he said.

“The brain is the only organ without a known lymphatic system, so the fact that these cells are lymphatic in nature and surround the brain makes this finding quite a surprise.

“These cells appear to be the zebrafish version of cells described in humans called “mato” or lipid laden cells, which clear fats and lipids from the system but were not known to be lymphatic in nature.

“When wastes such as excess fats leak out of the bloodstream, it is the job of the lymphatic system to clean them out to avoid damaging our organs.”

Dr Hogan said the study focused on the presence and development of “scavenger” cells in zebrafish, however there was good reason to believe that equivalent cells surrounded and protected the human brain from a build-up of cellular waste.

“Zebrafish are naturally transparent, which means we can use advanced light microscopes to see directly into the zebrafish brain,” Dr Hogan said.

“Examining the zebrafish brain up close allowed us to find these cells and see how they form and function in detail.

“Normally, lymphatic endothelial cells will group together to form lymphatic vessels to carry fluid, but impressively, in the adult zebrafish brain these cells exist individually, independent of vessels and collect waste that enter the brain from the bloodstream.

“Our focus now is to investigate how these cells function in humans and see if we can control them with existing drugs to promote brain health, and improve our understanding of neurological diseases such as stroke and dementia.”

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Materials provided by University of Queensland. Note: Content may be edited for style and length.

New findings from research into multiple concussions in hockey players

The relationship between head injuries suffered during contact sport and Alzheimer’s disease is now being called into question thanks to research by the Sahlgrenska Academy, which has revealed that hockey players with multiple concussions probably have other injuries in their brains.

“There seem to be two separate conditions and pathologies involved here,” says Pashtun Shahim, a doctor and researcher of neurology and physiology.

He himself has met the 28 sportspeople who were the subjects of the research, the majority of whom were elite ice hockey players from Sweden (both male and female).

All of them had experienced long-term problems after suffering concussion on multiple occasions, with complaints including sensitivity to noise and light, irritability, depression, difficulty concentrating and memory problems.

No Plaque Formation

“You can experience a lot of problems following a concussion, but these usually resolve within a few days or weeks; this group, though, experienced the problems for more than three months,” Pashtun Shahim tells us.

The research indicates that there is a general change in the metabolism or processing of a protein called amyloid precursor protein (APP), from which Alzheimer-related beta-amyloids are excreted in the nerve-cell connections (synapses)..

This effect on the amyloid protein could indicate that there is synaptic damage, even if it is not completely understood why. The research indicates that there is an element of inflammation involved also.

“At the same time, however, the results do not indicate that there is any plaque pathology like you would see in, for example, Alzheimer’s, which is a very important discovery,” says Pashtun Shahim.

The changes mainly affected the hockey players who had been suffering concussion-related complaints for a very long time, i.e. more than a year, and as such had not been able to return to the sport. The other players did not produce the same results, nor did the 19 healthy individuals who made up the control group.

Follow-Up Anticipated

Pashtun Shahim wanted to emphasize that the research was based on samples from living human beings and the fluid — CSF — found in the cavity of the brain, not on material from autopsies as was the case in previous studies, which were based on (for example) the brains of boxers who had passed away.

“These findings indicate that there is a connection between the long-term complaints suffered following a concussion and nerve cell damage — the first time that these two could be linked, with evidence found in living contact sport athletes. This means that we can follow up on these people in five or ten years’ time and see how their problems have developed. There are currently no drugs on the market to combat the complaints, we merely treat them symptomatically, but the findings of the research may help us understand better the underlying pathophysiology and hopefully render in developing better therapeutics in the future,” says Pashtun Shahim.

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Materials provided by University of Gothenburg. Note: Content may be edited for style and length.