Peripheral vision reaction time assessment to diagnose mild traumatic brain injury patients

A new test using peripheral vision reaction time could lead to earlier diagnosis and more effective treatment of mild traumatic brain injury, often referred to as a concussion, according to Peter J. Bergold, PhD, professor of physiology and pharmacology at SUNY Downstate Medical Center and corresponding author of a study published by the Journal of Neurotrauma.

While most patients with mild traumatic brain injury or concussion fully recover, a significant number do not, and earlier diagnosis could lead to better management of patients at risk for developing persistent symptoms, according to Dr. Bergold and his co-authors. Lingering symptoms may include loss of concentration and/or memory, confusion, anxiety, headaches, irritability, noise and light sensitivity, dizziness, and fatigue.

“Mild traumatic brain injury is currently diagnosed with subjective clinical assessments,” says Dr. Bergold. “The potential utility of the peripheral vision reaction test is clear because it is an objective, inexpensive, and rapid test that identifies mild traumatic brain injury patients who have a more severe underlying injury.”

Reference: Womack, Kyle B., Christopher Paliotta, Jeremy F. Strain, Johnson S. Ho, Yosef Skolnick, William W. Lytton, L. Christine Turtzo, Roderick Mccoll, Ramon Diaz-Arrastia, and Peter J. Bergold. “Measurement of Peripheral Vision Reaction Time Identifies White Matter Disruption in Patients with Mild Traumatic Brain Injury.” Journal of Neurotrauma, 2017. doi:10.1089/neu.2016.4670.
Research funding: United States Army Medical Research and Materiel Command, Center for Neuroscience and Regenerative Medicine.
Adapted from press release by SUNY Downstate Medical Center.

Research shows positive outcome for early epilepsy surgery

There are important, long-term gains from hastening the processes around surgical interventions against epilepsy, before the disease has had too much negative impact on brain functions and patients’ lives. These are some of the findings of a thesis for which more than 500 patients were studied and followed up.

“Around one third of those undergoing surgery today are children and the percentage is growing, which is encouraging. But the average time until operation for adults is still 20 years, and that’s a very long time. There’s a major lack of knowledge among the treating neurologists about which patients may benefit from epilepsy surgery,” says Anna Edelvik, researcher at Sahlgrenska Academy and Senior Physician on the Sahlgrenska University Hospital epilepsy team.

Around 60,000 people have epilepsy in Sweden, making it our most common chronic neurological disease. Around one out of three patients do not become seizure free from medication and it is primarily here that surgery comes in. If the epilepsy is focal, which implies that seizure onset is clearly delimited in the brain, surgery may be possible.

“We try to locate the origin of the seizures as precisely as possible, and determine the proximity to areas of vital functional importance. It’s important to be able to give good information to the patients about possible risks and benefits before making a decision to operate or not,” says Anna Edelvik.

Her research shows that 58 percent of those who underwent surgery were seizure-free after five to ten years compared with 17 percent in the group of those who were not operated. The longer the individuals had had epilepsy, the fewer were seizure-free on the long term.

The importance of acting faster is also apparent from the study concerning how many of those who underwent epilepsy surgery who were gainfully employed at long-term.

“The highest number of persons in full-time employment at long-term was found among those who worked full-time before surgery, but even if they dropped out of the labor market before surgery, about one third of the persons who were seizure-free had full-time employment after ten to 15 years. It’s important to identify the patients as early as possible before the epilepsy has had too large of an impact,” says Anna Edelvik.

In another study, when non-surgical patients rated their health-related quality of life, it was considerably lower than among comparable individuals without epilepsy. The group who underwent surgery scored higher and was more like the age- and gender-matched reference group, but still had lower ratings for social function and mental health.  

“They want to have a job and a family like everyone else, but that doesn’t happen just by becoming seizure-free. Even if the whole lifestyle situation doesn’t change, many would in any case benefit from being examined or evaluated for epilepsy surgery earlier than today,” says Anna Edelvik.

Citation: Edelvik, Anna. “Long-term outcomes of epilepsy surgery-prospective studies regarding seizures, employment and quality of life.” (2016).University of Gothenburg, Sahlgrenska Academy Doctoral thesis.
Link: hdl.handle.net/2077/48660
Adapted from press release by University of Gothenburg.

Tau protein as biomarker for predicting recovery time after concussion

Elevated levels of the brain protein tau following a sport-related concussion are associated with a longer recovery period and delayed return to play for athletes, according to a study published in Journal Neurology. The findings suggest that tau, which can be measured in the blood, may serve as a marker to help physicians determine an athlete’s readiness to return to the game.

Brain. Credit: Ashton University.

A team led by Jessica Gill, R.N., Ph.D. of the National Institute of Nursing Research at the National Institutes of Health and Jeffrey Bazarian, M.D., M.P.H. of the University of Rochester Medical Center evaluated changes in tau in 46 Division I and III college athletes who experienced a concussion. Tau, which plays a role in the development of chronic traumatic encephalopathy or CTE, frontotemporal dementia and Alzheimer’s disease was measured in preseason blood samples and again within 6 hours following concussion using an ultra-sensitive technology that allows researchers to detect single protein molecules.

The athletes – a mix of soccer, football, basketball, hockey and lacrosse players from the University of Rochester and Rochester Institute of Technology – were divided into two groups based on recovery time. Athletes in the “long return to play” group took more than 10 days to recover following concussion, while athletes in the “short return to play” group took less than 10 days to return to their sport.

Individuals in the long return to play group had higher levels of tau in their blood 6 hours after concussion compared to those in the short return to play group. Long return to play athletes also exhibited a jump in tau from preseason levels compared to their short return to play counterparts. Statistical analyses showed that higher blood tau concentrations 6 hours post-concussion consistently predicted that an athlete would take more than 10 days to resume play.

The study included both male and female athletes and showed that tau-related changes occurred in both genders across a variety of sports. The team found significant differences based on sex: women made up 61 percent of the long return to play group, but only 28 percent of the short return to play group. Bazarian says this isn’t surprising; it’s well established that females take longer to recover following concussion than males.

Bazarian and Gill acknowledge that the study is limited by its small size and that more research is needed to establish tau as a biomarker of concussion severity. Next steps include getting blood samples from athletes immediately following a concussion to see if the relationship between tau and return to play holds true on the sideline in the first few minutes following a head hit.

Citation: Gill,Jessica,  Kian Merchant-Borna, Andreas Jeromin,  Whitney Livingston, and Jeffrey Bazarian. Acute plasma tau relates to prolonged return to play after concussion. Neurology 2017. DOI: 10.1212/WNL.0000000000003587
Research funding: NIH/Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH/National Institute of Nursing Research.
Adapted from press release by The University of Rochester Medical Center.

Deep brain magnetic stimulation provides precise and reliable activation of target neurons

Massachusetts General Hospital (MGH) researchers have developed what appears to be a significant improvement in the technology behind brain implants used to activate neural circuits responsible for vision, hearing or movement. The investigators, who are also affiliated with the Boston VA Healthcare System, describe their development of tiny magnetic coils capable of selectively activating target neurons in journal Science Advances.

“Neural stimulation systems based on electrodes are currently being used to restore senses such as vision and hearing; to treat neurological disorders such as Parkinson’s disease, and for brain-computer interfaces that can give paralyzed patients the ability to communicate or move objects,” explains lead author Seung Woo Lee, PhD, of the MGH Department of Neurosurgery. “But electrode-based neural stimulation devices, especially those that target the cortex, have several significant limitations. The environment within the brain can erode a metal electrode over time, and the brain’s natural foreign-body response can lead to scarring, which can impede passage of electrical fields.”

The use of magnetic rather than electrical fields to stimulate neurons presents several advantages, including the ability to penetrate scar tissue. Since the magnetic signal can pass through the biocompatible insulating material, direct contact between neural tissue and the metal coil is eliminated, further reducing the potential for damage to the coil. But it had been believed that magnetic coils strong enough to activate neurons would be too large to be implanted within the brain’s cortex. The device developed by Lee and senior author Shelley Fried, Ph.D., of MGH Neurosurgery — in collaboration with scientists at the Palo Alto Research Center – takes advantage of the fact that the passage of electric current through a bent wire will induce a magnetic field. The novel coil they designed, while similar to the size of electrodes used for brain stimulation, was able to generate magnetic fields in excess of the thresholds required to activate neurons.

Testing these microcoils in brain tissue samples from mice revealed not only that they were capable of activating neurons but also that they did so more selectively than would be possible with metal electrodes. Electric fields most effectively activate neurons when they are oriented along the length of nerve cells, but most implantable electrodes generate fields that spread uniformly in all directions. In contrast, magnetic fields extend in specific directions, allowing selective targeting of neurons with the same orientation while simultaneously avoiding the activation of other neurons. The ability to avoid activation of passing nerve fibers prevents the spread of activation that typically occurs with electrodes, which can lead, for example, to the blurring of a visual image generated in response to stimulation of the visual cortex.

The MGH team proceeded to show that these microcoils could safely be implanted into the brains of anesthetized mice. Stimulation of coils inserted into the portion of the motor cortex that controls the animals’ whiskers resulted in whisker motion, with the direction depending on the frequency of the signal. Stimulating coils placed in the whisker sensory cortex caused whisker retraction. These experiments proved that implanted coils can be used to drive responses associated with the targeted neurons.

“Our next steps will be to continue improving coil design to reduce power and enhance selectivity, to confirm that the enhanced effectiveness of these coils will persist over time, and to determine whether stimulation of the visual cortex does elicit a visual signal,” says Fried, who is an associate professor of Neurosurgery at Harvard Medical School. “More stable long-term performance of these microcoils and the high-resolution signals produced by ever greater selectivity in neuron activation would significantly improve currently available neural prostheses and open up many new applications.”

Citation: Lee, Seung Woo,  Florian Fallegger, Bernard D. F. Casse and Shelley I. Fried. “Implantable microcoils for intracortical magnetic stimulation.” Science Advances 2016 vol: 2 (12).
DOI: 10.1126/sciadv.1600889
Research funding: Veterans Administration-Rehabilitation Research and Development Service, NIH/National Eye Institute, NIH/National Institute for Neurological Disease and Stroke, Rappaport Foundation.
Adapted from press release by Massachusetts General Hospital.

Magnetoencephalography and computational analysis to accurately diagnose concussions

Simon Fraser University researchers have found that high-resolution brain scans, coupled with computational analysis, could play a critical role in helping to detect concussions that conventional scans might miss.

In a study published in PLOS Computational Biology, Vasily Vakorin and Sam Doesburg show how magnetoencephalography (MEG), which maps interactions between regions of the brain, could detect greater levels of neural changes than typical clinical imaging tools such as MRI or CAT scans.
Qualified clinicians typically use those tools, along with other self-reporting measures such as headache or fatigue, to diagnose concussion. They also note that related conditions such as mild traumatic brain injury, often associated with football player collisions, don’t appear on conventional scans.

“Changes in communication between brain areas, as detected by MEG, allowed us to detect concussion from individual scans, in situations where MRI or CT failed,” says Vakorin. The researchers are scientists with the Behavioral and Cognitive Neuroscience Institute based at SFU, and SFU’s ImageTech Lab, a new facility at Surrey Memorial Hospital. Its research-dedicated magnetoencephalography (MEG) and MRI scanners make the lab unique in western Canada.

The researchers took magnetoencephalography (MEG) scans of 41 men between 20-44 years of age. Half had been diagnosed with concussions within the past three months.

They found that concussions were associated with alterations in the interactions between different brain areas–in other words, there were observable changes in how areas of the brain communicate with one another.

The researchers say magnetoencephalography (MEG) offers an unprecedented combination of “excellent temporal and spatial resolution” for reading brain activity to better diagnose concussion where other methods fail.

Relationships between symptom severity and magnetoencephalography (MEG) based classification also show that these methods may provide important measurements of changes in the brain during concussion recovery.

The researchers hope to refine their understanding of specific neural changes associated with concussions to further improve detection, treatment and recovery processes.

Citation:  “Detecting Mild Traumatic Brain Injury Using Resting State Magnetoencephalographic Connectivity.” Vakorin, Vasily A., Sam M. Doesburg, Leodante da Costa, Rakesh Jetly, Elizabeth W. Pang, and Margot J. Taylor. PLOS Computational Biology 12, no. 12 (2016): e1004914.
DOI: 10.1371/journal.pcbi.1004914
Research funding: Defense Research and Development Canada.
Adapted from press release by Simon Fraser University.

New biomarker based on expression of SHOX2 gene for predicting survival in Gliomas

Researchers at UT Southwestern Medical Center have found a new biomarker for glioma, a common type of brain cancer, that can help doctors determine how aggressive a cancer is and that could eventually help determine the best course of treatment. The findings are published in EBiomedicine.

Researchers from the Harold C. Simmons Comprehensive Cancer Center found that high expression of a gene called SHOX2 predicted poor survival in intermediate-grade gliomas.  “As an independent biomarker, SHOX2 expression is as potent as the currently best and widely used marker known as IDH mutations,” said Dr. Adi Gazdar, Professor of Pathology in the Nancy B. and Jake L. Hamon Center for Therapeutic Oncology and a member of the Simmons Cancer Center.

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According to the National Cancer Institute, cancers of the brain and nervous system affect nearly 24,000 people annually. In 2013, there were an estimated 152,751 people living with brain and other nervous system cancer in the United States. The overall 5-year survival rate is 33.8 percent.
Knowing the probable survival status of an individual patient may help physicians choose the best treatment. In combination with IDH mutations or several other biomarkers, SHOX2 expression helped to identify subgroups of patients with a good prognosis even though other biomarkers had predicted a bad prognosis.

“Our findings are based on analysis of previously published studies. They will have to be confirmed in prospective studies, and their clinical contribution and method of use remain to be determined,” said Dr. Gazdar, who holds the W. Ray Wallace Distinguished Chair in Molecular Oncology Research.

Citation: “SHOX2 is a Potent Independent Biomarker to Predict Survival of WHO Grade II–III Diffuse Gliomas”. Yu-An Zhang1, Yunyun Zhou1, Xin Luo, Kai Song, Xiaotu Ma, Adwait Sathe, Luc Girard, Guanghua Xiao and Adi F Gazdar. EBioMedicine 2016 vol: 13 pp: 80-89.
DOI: 10.1016/j.ebiom.2016.10.040
Research funding: NIH
Adapted from press release by UT Southwestern Medical Center.

NeuroVascular Unit on a chip created to mimic functions of Blood-brain barrier

The blood-brain barrier is a network of specialized cells that surrounds the arteries and veins within the brain. It forms a unique gateway that both provides brain cells with the nutrients they require and protects them from potentially harmful compounds.

This is an illustration of the neurovascular unit on a chip.
Credit: Dominic Doyle, Vanderbilt University

An interdisciplinary team of researchers from the Vanderbilt Institute for Integrative Biosystems Research and Education (VIIBRE) headed by Gordon A. Cain University Professor John Wikswo report that they have developed a microfluidic device that overcomes the limitations of previous models of this key system and have used it to study brain inflammation, dubbed the “silent killer” because it doesn’t cause pain but contributes to neurodegenerative conditions such as Alzheimer’s and Parkinson’s diseases. Recent research also suggests that it may underlie a wider range of problems from impaired cognition to depression and even schizophrenia.

The project is part of a $70 million “Tissue Chip for Drug Testing Program” funded by the National Institutes of Health’s National Center for Advancing Translational Sciences. Its purpose is to develop human organ-on-a-chip technology in order to assess the safety and efficacy of new drugs in a faster, cheaper, more effective and more reliable fashion.

The importance of understanding how the blood-brain barrier works have increased in recent years as medical researchers have found that this critical structure is implicated in a widening range of brain disorders, extending from stroke to Alzheimer’s and Parkinson’s disease to blunt force trauma and brain inflammation.

Despite its importance, scientists have had considerable difficulty creating faithful laboratory models of the complex biological system that protects the brain. Previous models have either been static and so have not reproduced critical blood flow effects or they have not supported all the cell types found in human blood-brain barriers.

The new device, which the researchers call a NeuroVascular Unit (NVU) on a chip, overcomes these problems. It consists of a small cavity that is one-fifth of an inch long, one-tenth of an inch wide and three-hundredths of an inch thick – giving it a total volume of about one-millionth of a human brain. The cavity is divided by a thin, porous membrane into an upper chamber that acts as the brain side of the barrier and a lower chamber that acts as the blood or vascular side. Both chambers are connected to separate microchannels hooked to micropumps that allow them to be independently perfused and sampled.

To create an artificial blood-brain barrier, the researchers first flip the device over so the vascular chamber is on top and inject specialized human endothelial cells. They found that if they maintain a steady fluid flow through the chamber during this period, the endothelial cells, which left to themselves form shapeless blobs, consistently orient themselves parallel to the direction of flow. This orientation, which is a characteristic of the endothelial cells in human blood-brain barrier, has been lacking in many previous models.

After a day or two, when the endothelial cells have attached themselves to the membrane, the researchers flip the device and inject the two other human cell types that form the barrier — star-shaped astrocytes and pericytes that wrap around endothelial cells — as well as excitatory neurons that may regulate the barrier. These all go into the brain chamber that is now on top. The porous membrane allows the new cells to make physical and chemical contact with the endothelial cells just as they do in the brain.

The researchers were able to purchase the human endothelial cells, astrocytes and pericytes that they need from commercial sources. For the excitatory neurons required, they turned to Vanderbilt University Medical Center collaborators M. Diana Neely, research associate professor of pediatrics, and Aaron Bowman, associate professor of pediatrics, neurology and biochemistry. Starting with human induced pluripotent stem cells that are generated directly from adult cells they were able to produce the specialized neurons that the project needed.

“This is one of the most exciting projects I’m involved with,” said Neely. “Although it’s still in its infancy, it has tremendous potential.” According to Bowman, one potential application is to develop tissue chips that contain cells from individual patients, making it possible to predict their personal reactions to different drugs.

“Once we had successfully created the artificial barrier, we subjected it to a series of basic tests and it passed them all with flying colors. This gives us the confidence to state that we have developed a fully functional model of the human blood-brain barrier,” said VIIBRE staff scientist Jacquelyn Brown, who is first author of the paper “Recreating blood-brain barrier physiology and structure on chip: A novel neurovascular microfluidic bioreactor” that described this achievement in the journal Biomicrofluidics.

“The NeuroVascular Unit (NVU) on a chip has reached the point where we can begin using it to test different drugs and compounds,” observed team member Donna Webb, associate professor of biological sciences who is interested in studying how different substances affect synapses — the junctions between neurons. “There is an urgent need for us to understand how various substances affect cognitive processes. When we do, we will be in for a number of surprises!

Already, the VIBRE team has used the NeuroVascular Unit (NVU) on a chip to overcome a basic limitation of existing studies of brain inflammation, which have only produced snapshots of the process at various stages. Because the NeuroVascular Unit (NVU) on a chip can be continuously monitored, it has provided the first dynamic view of how the brain and blood-brain barrier respond to systemic inflammation.

These results are summarized in a paper titled “Metabolic consequences of inflammatory disruption of the blood-brain barrier in an organ-on-chip model of the human neurovascular unit” accepted for publication in the Journal of Neuroinflammation.

The scientists exposed the NeuroVascular Unit (NVU) on a chip to two different compounds known to induce brain inflammation: a large molecule found on the surface of certain bacteria called lipopolysaccharide and a “cocktail” of small proteins called cytokines that play an important role in immune response to inflammation.

“One of our biggest surprises was the discovery that a critical component in the blood-brain barrier’s response to these compounds was to begin increasing protein synthesis,” said Brown. “Next will be to find out which proteins it is making and what they do.”

The researchers also found that the blood vessels in the barrier respond to inflammation by pumping up their metabolic rate while the metabolism of the brain cells slows down. According to Brown, “It might be that the vasculature is trying to respond while the brain is trying to protect itself.”

Citation: “Metabolic consequences of inflammatory disruption of the blood-brain barrier in an organ-on-chip model of the human neurovascular unit” accepted in Journal of Neuroinflammation.
Research funding: NIH

Adapted from press release by Vanderbilt University.

Treating traumatic nerve injury with 4-aminopyridine

Researchers at the University of Rochester Medical Center believe they have identified a new means of enhancing the body’s ability to repair its own cells, which they hope will lead to better diagnosis and treatment of traumatic nerve injuries, like those sustained in car accidents, sports injuries, or in combat. The research team showed that a drug previously approved for chronic nerve disease, multiple sclerosis can ‘wake up’ damaged peripheral nerves and speed repair and functional recovery after injury.

Structure of 4-amionpyridine (4AP) molecule
credit: Wikipedia user Yikrazuul
The study appearing in EMBO Molecular Medicine demonstrates for the first time that 4-aminopyridine (4AP), a drug currently used to treat patients with the chronic nerve disease, multiple sclerosis, has the unexpected property of promoting recovery from acute nerve damage. Although this drug has been studied for over 30 years for its ability to treat chronic diseases, this is the first demonstration of 4-aminopyridine’s benefit in treating acute nerve injury and the first time those benefits were shown to persist after treatment was stopped.
Study authors, John Elfar, M.D., associate professor of Orthopaedics, and Mark Noble, Ph.D., Martha M. Freeman, M.D., Professor of Biomedical Genetics, and their laboratory team, found that daily treatment with 4-aminopyridine promotes repair of myelin, the insulating material that normally surrounds nerve fibers. When this insulation is damaged, as occurs in traumatic peripheral nerve injury, nerve cell function is impaired. These researchers found that 4-aminopyridine treatment accelerates repair of myelin damage and improvement in nerve function.

These findings advance an area of research that has been stagnant for nearly 30 years and may address unmet needs of traumatically injured patients in the future. The current standard of care for traumatic peripheral nerve injury is “watchful waiting” to determine whether a nerve has the ability to spontaneously recover, or if it will require surgery.

The problem, says Elfar, a Sports Medicine surgeon specializing in hand, wrist, elbow and shoulder repairs, is that “the patient who may recover is recovering so slowly that nerve-dependent tissues are in jeopardy, and the patient who needs surgery has to wait for weeks for the diagnosis that surgery is appropriate. That delay means that surgery is less effective.”

Elfar’s and Noble’s team, which includes Kuang-Ching Tseng, Ph.D., former graduate student in the Center for Musculoskeletal Research at the University of Rochester Medical Center and first author of the study, also found that treating mice with a single dose of 4-aminopyridine one day after nerve crush injury improved muscle function within an hour. In this model, nerves are damaged, but not completely severed. The team believes this finding may suggest that 4-aminopyridine could be used immediately after an injury to diagnose whether a nerve is severed, however, further studies are required to determine if this will work in humans.

If their results can be translated into humans, it could mean earlier and more rapid diagnosis of traumatic peripheral nerve injuries, enabling earlier surgery and better outcomes for patients whose nerves have been completely severed. For patients whose nerves are still connected, 4-aminopyridine (4AP) treatment could offer a new means to speed recovery, where none has previously existed.

The Department of Defense has recognized the potential impact this could have for soldiers in combat situations and granted $1 million to Elfar and Noble to continue this research over the next three years.

“This is an ideal outcome for development of a treatment to promote tissue regeneration,” said Noble. “The drug we use to identify injuries that need repair of their insulating myelin is the same drug we use to promote the needed repair. As 4-aminopyridine (4AP) has been well-studied in chronic injuries, and is approved for treating multiple sclerosis, the new benefits we discovered can be explored rapidly and much more cheaply than is needed for developing an entirely new drug.”

Beyond nerve injuries sustained during accidents or in the line of duty, the researchers are also looking into using 4-aminopyridine to repair nerve conduction after routine surgeries. Removal of the prostate, for example, can cause nerve damage that leaves patients with incontinence and erectile dysfunction, the burden and stigma of which may contribute to prostate cancer patients refusing the surgery.

Elfar and Noble hope to begin a clinical trial to test this in the near future. The proposed trial has been approved by the Food and Drug Administration (FDA), and University of Rochester researchers and clinicians are completing the planning stages before recruiting participants.

Citation: Tseng, Kuang‐Ching, Haiyan Li, Andrew Clark, Leigh Sundem, Michael Zuscik, Mark Noble, and John Elfar. “4‐Aminopyridine promotes functional recovery and remyelination in acute peripheral nerve injury.” EMBO Molecular Medicine (2016): e201506035.
DOI: 10.15252/emmm.201506035
Research funding: National Institutes of Health, New York State Spinal Cord Injury Research Program, American Foundation for Surgery of the Hand, Friends of Nancy Lieberman Fund.
Adapted from press release by University of Rochester Medical Center.

Research shows meninges contain neural progenitor stem cells

In a cross-domain study directed by professor Peter Carmeliet, researchers discovered unexpected cells in the protective membranes that enclose the brain, the so-called meninges. These ‘neural progenitors’ – or stem cells that differentiate into different kinds of neurons – are produced during embryonic development. These findings show that the neural progenitors found in the meninges produce new neurons after birth – highlighting the importance of meningeal tissue as well as these cells’ potential in the development of new therapies for brain damage or neurodegeneration. A paper highlighting the results was published in the leading scientific journal Cell Stem Cell.

Before the discoveries of the last few decades, neurologists once thought that the brain became ‘static’ after childhood. This dogma has changed, with researchers finding more and more evidence that the brain is capable of healing and regenerating in adulthood, thanks to the presence of stem cells. However, neuronal stem cells were generally believed to only reside within the brain tissue, not in the membranes surrounding it.

Believed in the past to serve a mainly protective function to dampen mechanical shocks, the meninges have been historically underappreciated by science as having neurological importance in its own right. The data gathered by the team challenges the current idea that neural precursors – or stem cells that give rise to neurons – can only be found inside actual brain tissue.

Prof. Peter Carmeliet said “The neuronal stems cells that we discovered inside the meninges differentiate to full neurons, electrically-active and functionally integrated into the neuronal circuit. To show that the stem cells reside in the meninges, we used the extremely powerful single-cell RNA sequencing technique, a very novel top-notch technique, capable of identifying the (complex gene expression signature) nature of individual cells in a previously unsurpassed manner, a première at VIB.”

 When it comes to future leads for this discovery, the scientists also see possibilities for translation into clinical application, though future work is required. Prof. Peter Carmeliet said “An intriguing question is whether these neuronal stem cells in the meninges could lead to better therapies for brain damage or neurodegeneration. However, answering this question would require a better understanding of the molecular mechanisms that regulate the differentiation of these stem cells. How are these meningeal stem cells activated to become different kinds of neurons? Can we therapeutically ‘hijack’ their regeneration potential to restore dying neurons in, for example, Alzheimer’ Disease, Parkinson’s Disease, amyotrophic lateral sclerosis (ALS), and other neurodegenerative disorders? Also, can we isolate these neurogenic progenitors from the meninges at birth and use them for later transplantation? These findings open up very exciting research opportunities for the future.”

 Moving into unchartered territory is high risk, and can offer high gain, but securing funding for such type of research is challenging. However, Carmeliet’s discoveries were made possible to a large extent by funding through “Opening the Future: pioneering without boundaries”, a recently created Mecenas Funding Campaign for funding of high-risk brain research but with potential for breakthrough discoveries, started up by the KU Leuven in 2013 and unique in Flanders.

Citation: “Neurogenic Radial Glia-like Cells in Meninges Migrate and Differentiate into Functionally Integrated Neurons in the Neonatal Cortex”. Francesco Bifari1, Ilaria Decimo1, Annachiara Pino, Enric Llorens-Bobadilla, Sheng Zhao, Christian Lange, Gabriella Panuccio, Bram Boeckx, Bernard Thienpont, Stefan Vinckier, Sabine Wyns, Ann Bouché, Diether Lambrechts, Michele Giugliano, Mieke Dewerchin, Ana Martin-Villalba, Peter Carmeliet. Cell Stem Cell 2016.
DOI: http://dx.doi.org/10.1016/j.stem.2016.10.020
Research funding: Mecenas funding initiative by the KU Leuven
Adapted from press release by VIB Vlaams Instituut Voor Biotechnologie (The Flaunders institute of biotechnology)

Signaling pathway that controls blood vessel development in brain has ability stop medulloblastoma, a cerebellar tumor.

A research team at the Krembil Research Institute has discovered that a signaling pathway which controls blood vessel development in the brain has the ability to stop brain tumor formation in animal models of medulloblastoma, the most common malignant brain tumor diagnosed in children.

The findings, published in the journal eLife, are the first to show that blocking a signaling pathway called Norrin/Frizzled4 (Fzd4) drives changes in the support structures that surround pre-cancer cells and promotes medulloblastoma development in subjects that are genetically susceptible to the disease. Researchers found that blocking the Norrin/Fzd4 signal created more opportunities to form pre-cancerous growths and speed up tumour initiation. This work also suggests that an activated pathway may therefore block tumour formation.

“Our study brings a new dimension to our understanding of Medulloblastoma,” says Dr. Valerie Wallace, principal investigator of the study, Norrin/Frizzled4 Signaling in the Preneoplastic Niche Blocks Medulloblastoma Initiation, and Co-Director of the Donald K. Johnson Eye Institute.

The research, which was carried out in large part by Dr. Erin Bassett and Mr. Nicholas Tokarew, was initiated at the Ottawa Hospital Research Institute and continued at the Krembil Research Institute after Dr. Wallace relocated to Toronto. The discovery came from replication of a human condition called Gorlin Syndrome in lab experiments. People with Gorlin Syndrome have one copy of a tumour-suppressing gene instead of two, which makes them susceptible to medulloblastoma.

The team’s next step will be to investigate how the blood vessels impacted by Norrin/Fzd4 signaling communicate with pre-cancerous cells to make them more likely to become malignant.

Citation: Bassett, Erin A., Nicholas Tokarew, Ema A. Allemano, Chantal Mazerolle, Katy Morin, Alan J. Mears, Brian McNeill et al. “Norrin/Frizzled4 signalling in the preneoplastic niche blocks medulloblastoma initiation.” eLife 5 (2016): e16764.
DOI: http://dx.doi.org/10.7554/eLife.16764
Research funding: Canadian Cancer Society, Cancer Research Society
Adapted from press release by University Health Network Ca