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New Rules to Protect Your Kid’s Noggin

May 25, 2019, Parents Magazine

 
Children bonk their head all the time when they’re wrestling with siblings, playing soccer, and just being clumsy-and it’s easy to worry that a bump could turn into something bigger. After all, more than 800,000 kids in the U.S. get a concussion every year. For the first time, the Centers for Disease Control and Prevention has released specific “return to learn” and “return to play” guidelines for head injuries, based on 25 years of research. One doctor shares the big takeaways.

ALWAYS take any injury beyond a light head bump seiously. A concussion occurs when a bump, blow, or jolt to the head or a hit to the body makes the brain bounce or twist in the skull. This creates chemical changes and can sometimes damage brain cells. “If your child complains of a headache or dizziness, is nauseous or vomiting, appears dazed, or sleeps more or less than usual, it’s time to get a doctor’s evaluation,” says Dennis Cardone, D.O., associate professor of orthopedic surgery and pediatrics and co-director of the NYU Langone Concussion Center. Even toddlers can get a concussion from a tumble, so look for changes in their behavior such as not wanting to nurse or eat or losing interest in toys.

If diagnosed with a concussion, your child will need menlal rest, says Dr. Cardone. That means taking a break from all activities for two to three days, and after that, starting with light aerobic activity. He may need to attend school for only half the day or do little to no homework (he won’t mind this rule!). However, he shouldn’t return to any sports or strenuous activities that have a high risk of falling or contact (think: field hockey, gymnastics, climbing a tree) until he’s been cleared by his doctor, which should be within a few weeks.

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Ann C. McKee, chief of neuropathology at the VA Boston Healthcare System, which houses the world’s largest brain bank devoted to CTE research, examines a brain earlier this month.(Photo: Robert Deutsch, USA TODAY)

Researchers close in on CTE diagnosis in living, one brain at a time

By Nancy Armour, August 24, 2018, USA TODAY

BOSTON – Submerged in chemicals in the stainless-steel bowl is the key to life and, researchers hope, death.

It’s a human brain. That of a man who played college football in the 1950s, to be exact. His family donated his brain to get answers for themselves, but what’s found could lead to more answers about chronic traumatic encephalopathy, the devastating neurodegenerative disease linked to concussions and repetitive head trauma from football and other contact sports.

“Our main objective, our overarching goal, is to help the people who are living. To be able to diagnose this disease during life,” says Ann McKee, chief of neuropathology at the VA Boston Healthcare System, which houses the world’s largest brain bank devoted to CTE research.

“If we can diagnose it, we can monitor it and test therapies to see if they’re effective in treating this disease,” says McKee, director of the CTE Center at Boston University’s School of Medicine. “It would really dramatically increase our ability to point out genetic susceptibilities for this. We’d be able to look at how much is too much in certain individuals or certain positions in certain sports.”

As another football season begins, it inevitably leads to questions and fears about head trauma and its long-term damage. How many hits are too many? What can parents do to protect their children or players do to protect themselves? Are athletes in certain sports more susceptible?

Most important, which athletes will develop CTE – or Parkinson’s or ALS (amyotrophic lateral sclerosis) – and why?

The answers will come from brains such as the one McKee dissected this month, when USA TODAY Sports toured the brain bank.

The brain bank has more than 500 brains, most of them donated by former athletes or their families who suspected CTE because of mood swings, behavioral changes, depression or dementia. Of those brains, more than 360 had CTE, McKee says.

SEARCHING FOR CLUES

The arrival of a brain sets two teams in motion. One set of clinicians talks to the family to find out more about the donors. Did they play any sports? If so, what and for how long? When did they start? Did they experience any other kind of head trauma, say from an automobile accident, domestic violence or military service? Did they have drug or alcohol problems? How did their mental health change, and when did that occur?

Separately, and usually without any information about the person whose brain it was, McKee and her researchers study the brain. It is cut in half, and one half is stored in a minus-80-degree freezer, so it will be available for molecular, genetic and biochemical studies.

The other half is then photographed and sectioned. After removing the brain stem, McKee uses what looks like a bread knife to cut slices of the brain about a quarter-inch thick.


Ann C. McKee slices the brain into segments about a quarter-inch thick as part of in-depth, time consuming research on the organ. McKee hopes the work will unlock answers to CTE. (Photo: Robert Deutsch, USA TODAY)
 
Simply by looking at the brain, McKee can tell a few things. The brain of this man, who was in his 80s when he died, has shrunk, noticeably smaller than it should be for a man who once played football. The folds of the brain, normally pressed tightly against one another, are loose and have gaps between them, some large enough that the tip of a finger could be inserted.

She points to the ventricles, chambers in the middle of his brain that are filled with fluid during life. They should be small, but these are “just gigantic.”

“As the brain shrinks, they expand. What this indicates is there’s been enormous shrinkage of the brain,” McKee says. “Those are huge.”

The hippocampus, a section in the middle of the brain that controls memory, is small but not abnormally so for a man in his 80s. If it was, that could be an indication of Alzheimer’s. But a membrane that runs from one side of the brain to the other, normally thick like a rubber band, has shrunk. In some spots, it’s almost invisible.

“This is looking more like frontal predominant atrophy, and that could mean CTE because Alzheimer’s almost always affects the hippocampus,” McKee says. “At this point, I always want to know, ‘What is it? Let’s look under the microscope.’ But you have to wait.”

CTE can’t be seen by the naked eye, and it takes at least three weeks to prepare slides of the brain tissue.


 
CTE is caused by tau, a protein in the brain released as a result of head trauma. When tau clumps together, it damages brain cells and can change the brain’s function. Though tau causes Alzheimer’s, McKee says, the tau that causes CTE looks distinctly different.

Under a microscope, it can be seen in telltale brown spots.

“CTE is very focal. In fact, in its early stages, it’s in the crevices. It just piles up. And that’s around blood vessels,” McKee says. “That’s very different. Alzheimer’s never does that.”

As CTE progresses, those clusters or clumps of tau will spread, and the disease will become more severe. That’s why, in the early stages of disease, stages 1 and 2, the symptoms usually relate to behavioral changes or mood swings. In stages 3 and 4, the disease is exhibited in memory loss.

“We think there may be more pathology in the young players than we’re appreciating just with the tau protein,” McKee says. “We think there’s maybe white matter structural changes or maybe inflammatory changes that are responsible for that loss of control, which is so difficult for the individuals.”

‘EVERY CASE IS A MYSTERY’

Once the slides have been examined, the pathologists and clinicians will come together for a conference. At this point, neither knows what the other does. The clinicians detail what they’ve learned about the brain donor’s history and suggest a diagnosis. The pathologists will then say whether the brain tissue confirms it.

“Every case is a mystery,” McKee says. “It’s not the same way you usually solve a mystery. I solve the pathology first, and then you go back and find out (the history). And then you try and put the two together.”

Some former players and their families once were reluctant to donate their brains, but that stigma largely has disappeared. So much so that McKee said brains arrive at the Boston bank almost every day.

Though that lengthens the time it takes to reach a definitive diagnosis, it will shorten the time before a living diagnosis can be found. In addition to the work done in her lab, McKee shares tissue samples with researchers around the world.

“What we want to do is establish the risk, educate people, educate parents, educate players,” McKee says. “So if they’re unwilling to risk that future self, if they’re unwilling to take that risk because it’s too high for them personally, we want to give them enough data so they can make a very sound and wise decision.”

When that day comes, it will change sports forever.

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TIAA-CREF Tuition Financing, Inc. also Oversees Treasurer’s ScholarShare Program

August 8, 2018 | Contact:Press Office, news@sto.ca.gov, 916-653-2995

SACRAMENTO – California State Treasurer John Chiang today announced the selection of TIAA-CREF Tuition Financing, Inc. (TFI) to administer the California Achieving a Better Life Experience (CalABLE) Program.

“TFI’s selection means we’re one step closer to turning on CalABLE’s ‘Open for Business’ sign,” said State Treasurer John Chiang. “TFI’s expertise and oversight are a welcome help in reaching Californian’s with disabilities and their families, who will soon be able to save up to $15,000 a year, tax free, without jeopardizing their federal and state assistance.”

Currently, savings for individuals receiving Supplemental Security Income (SSI) or other public benefits have a $2,000 resource limit. Once a beneficiary is determined to have more than this $2,000, their benefits may be suspended until savings fall below that level. CalABLE — the state’s version of the federal ABLE Act — allows people with disabilities to establish a tax-advantaged savings account in which they can save up to $15,000 per year, up to a total of $100,000, without jeopardizing their ability to continue to receive existing public benefits. Earnings into CalABLE accounts are not subject to federal income tax or California state income tax, so long as the earnings are spent on a broad range of disability related expenses.

“We are excited to see the CalABLE program move forward in providing people with disabilities the opportunity to build their futures,” added Christina Mills, executive director of the California Foundation for Independent Living Centers. “There are very few ways for people in our community to save money without penalties. Opening a CalABLE account will be a game-changer for individuals with disabilities, and parents of children with disabilities, who have been limited by programs and services that prevent us from saving and becoming more independent.”

TFI was selected to manage the new CalABLE program by a vote on Tuesday by the CalABLE Act Board, based on the firm’s low costs, proposed investment portfolio that offered simple choices for enrollees with clear preferences, and the simplicity of its program for those new to such a savings program.
TFI is a national leader in providing program management services for college savings plans and currently serves as the manager for California’s successful ScholarShare 529 college savings program.

Any individual whose disability occurred before age 26 is eligible to open a CalABLE account so long as they receive benefits based on disability, such as SSI or Social Security Disability Insurance, or if they have disability certification (including a copy of a diagnosis signed by a physician).

CalABLE participants can:
• Make automatic contributions from a bank account
• Invite family and friends to contribute directly to an account
• Deposit online or by check
• Select from easy to understand investment options

Chiang added, “No one should have to fear losing their disability benefits because they decided to save wisely and invest in their future. This program will help ensure no Californian with a disability will be penalized for thinking ahead.”
CalABLE will launch by the end of 2018.

For more information about CalABLE visit https://www.treasurer.ca.gov/able or call 916-653-1728.

For more news, please follow the Treasurer on Twitter at @CalTreasurer, and on Facebook at California State Treasurer’s Office

Traumatic brain injury causes widespread damage to neurons, leading to deficits in learning and memory. Cypin activators restore neuronal survival and function in mice, allowing for normal learning and memory. Credit: Mihir Patel/Rutgers University-New Brunswick

Traumatic brain injury: Discovery of two molecules could lead to new drug treatments

By Todd B. Bates, July 27, 2018, Rutgers University

After 10 years of research, a Rutgers-led team of scientists has identified two molecules that protect nerve cells after a traumatic brain injury and could lead to new drug treatments.

The molecules promote full recovery after traumatic brain injury (TBI) in mice, according to the study published online in Neurobiology of Disease. Traumatic brain injury is the leading cause of death for people under 45 years old in the United States and is associated with disability, early-onset dementia, cognitive disorders, mental illness and epilepsy.

Nearly all approaches for treating TBI focus on trying to prevent neurons, or nerve cells, from degenerating or on attempting to promote their survival, the study notes. TBI typically alters neural circuits within injured brain regions.

“The big issue with treatment after TBI is that there are no drugs that work well on patients to restore memory, and we’re targeting reconnectivity of neural circuitry,” said Bonnie L. Firestein, senior author of the study and a professor in the Department of Cell Biology and Neuroscience at Rutgers University-New Brunswick. “That means we want our neurons to function properly and connect with other neurons. We want to allow people to retain their cognition and ability to remember and learn, so our angle is novel.”

The researchers studied the protein cypin, an enzyme that breaks down guanine, which is an important building block for DNA and RNA in cells. The scientists previously showed that cypin is involved in promoting the proper shape in neurons and “keeping them happy,” Firestein said. This study found that speeding the breakdown of guanine protects neurons from injury and retains brain functioning.

Scientists at Rutgers-New Brunswick, University of Pennsylvania, Fox Chase Chemical Diversity Center Inc. and Columbia University want to develop drugs from the molecules for further studies.

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With better devices, science can get closer to a more complete picture of how neurons interact for cognitive functionality. (Photo/iStock)

Are we getting closer to a complete brain mapping? New devices explore more regions safely

By Breanne Grady, April 13, 2018, viterbischool.usc.edu

Researchers have developed thin, flexible polymer-based materials that record activity in more subregions of the brain with safer, more specific placement.

Science has yet to unravel a complete understanding of the brain and all its intricate workings. It’s not for lack of effort.

Over many decades, multiple research studies have sought to understand the dizzying “talk,” or interconnectivity, between thousands of microscopic entities in the brain, in particular neurons. The goal: to one day arrive at a complete brain “mapping” — a feat that could unlock tremendous therapeutic potential.

Researchers at the USC Viterbi School of Engineering have developed thin, flexible polymer-based materials for use in microelectrode arrays that record activity more deeply in the brain and with more specific placement than ever before. What’s more is that each microelectrode array is made up of eight “tines,” each with eight microelectrodes which can record from a total 64 subregions of the brain at once.

Same Quality, More Safety

In addition, the polymer-based material, called Parylene C, is less invasive and damaging to surrounding cells and tissue than previous devices comprised of silicon or microwires. However, the long and thin probes can easily buckle upon insertion, making it necessary to add a dissolvable brace made up of polyethylene glycol (PEG) that prevents it from bending.

Professor Ellis Meng of the USC Viterbi Department of Biomedical Engineering said that the performance of the new polymer-based material is on par with microwires in terms of recording fidelity and sensitivity. “The information that we can get out is equivalent, but the damage is much less,” Meng said. “Polymers are gentler on the brain, and because of that, these devices get recordings of neuronal communication over long periods of time.”

As with any prosthetic implant, caution must be exercised in terms of the body’s natural immune response to a foreign element. In addition to inflammation, previous microelectrode brain implants made of silicon or microwires have caused neuronal death and glial scarring, which is damage to connective tissue in the nervous system. However, Parylene C is biocompatible and can be microfabricated in extremely thin form to mold well to specific subregions of the brain, allowing for exploration with minimal damage.

Listening In

So far, these arrays have been used to record synaptic responses of individual neurons within the hippocampus, a part of the brain responsible for memory formation. If injured, the hippocampus may be compromised, resulting in a patient’s inability to form new memories. Meng, a faculty member of the Michelson Center for Convergent Bioscience, said that the polymer-based material can conform to a specific location in the hippocampus and “listen in on a conversation” between neurons. Because there are many such “eavesdroppers” (the microelectrodes), much more information about their interconnectivity can be gleaned.

“I can pick where I want my electrodes to be, so I can match up to the anatomy of the brain,” Meng, the Dwight C. and Hildagarde E. Baum Chair, said. “Along the length of a tine, I can put a group of electrodes here and a group of electrodes there, so if we plant to a certain depth, it’s going to be near the neurons I want to record from.”

Up Next

Future research will determine the recording lifetime of polymer-based arrays and their long-term “signal-to-noise” (SNR) stability. Also, the team plans to create devices with even higher density, including a double-sided microelectrode array with 64 electrodes per tine instead of eight — making for a total of around 4,000 electrodes placed in the brain at once.

In addition to Meng, Professor Ted Berger, the David Packard Chair in Engineering, and Research Professor Dong Song (both of the USC Viterbi School of Engineering) were co-authors along with Ph.D. students Huijing Xu and Ahuva Weltman Hirschberg and post-doctoral scholar Kee Scholten. Funding was provided be the National Science Foundation (NSF) and the National Institutes of Health (NIH). The study titled “Acute in vivo testing of a conformal polymer microelectrode array for multi-region hippocampal recordings” now published in the Journal of Neural Engineering.

About the Michelson Center

The USC Michelson Center for Convergent Bioscience brings together a diverse network of premier scientists and engineers under one roof, thanks to a generous $50 million gift from orthopedic spinal surgeon, inventor and philanthropist Gary K. Michelson, and his wife, Alya Michelson. At the Michelson Center, scientists and engineers from the USC Dornsife College of Letters, Arts and Sciences, USC Viterbi School of Engineering and Keck School of Medicine of USC are working to solve some of the greatest intractable problems of the 21st century in biomedical science, including a fundamentally new understanding of the cell and new approaches for cancer, neurological and cardiovascular disease.

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New app designed to help survivors of traumatic brain injury recognize and regulate emotions

Indiana University School of Medicine, May 8, 2018

A new app developed by an Indiana University School of Medicine faculty member is designed to help survivors of traumatic brain injuries recognize and regulate their emotions— skills that are critical to maintaining relationships and quality of life but that are often compromised in patients who have endured head traumas.

The app, called My Emotional Compass, is the result of years of research led by Dawn M. Neumann, PhD, associate professor of physical medicine and rehabilitation at IU School of Medicine and research director at the Rehabilitation Hospital of Indiana. It is available on the Apple App Store and the Google Play Store.

Patients with TBI frequently experience damage to regions of the brain and neural networks involved with processing emotions. As a result, many survivors have trouble identifying, labeling and expressing their emotions, a condition known as alexithymia. For example, patients may be unable to articulate that receiving a surprise gift made them feel happy and appreciative, or that being passed over for a promotion left them feeling frustrated and ashamed.

As many as 60 percent of individuals with moderate to severe TBI experience alexithymia, making it challenging to display empathy and respond in a socially appropriate manner in personal and professional relationships. Patients with mild TBI also experience this challenge.

There are no standard, evidenced-based interventions to treat these issues. The app and related research studies led by Neumann aim to begin filling this gap. My Emotional Compass is specifically designed to address alexithymia by helping patients interpret and put words to their own feelings.

“We need to re-teach individuals who have experienced a traumatic brain injury about emotions and give them an emotional vocabulary,” Neumann said. “It might sound simplistic, but the very act of labeling an emotion can help control it.”

In addition to problems with recognizing and labeling personal emotions, many patients with TBI also have difficulty recognizing others’ emotions, interpreting tone of voice, reading facial and physical cues, and responding empathetically to these cues. “You can’t understand what it means that someone else is feeling sad or angry if you don’t recognize those emotions in yourself,” Neumann said.

Because there is an association between recognizing self-emotions and recognizing and responding to others’ emotions, there is a possibility treatments aimed at reducing alexithymia may also improve these other related skills as well.

The app takes users through a series of questions and helps them identify how they are feeling in response to certain scenarios. For example, a user is asked to think of a situation that occurred earlier in the day, then to identify if the experience was pleasant or unpleasant, and to further refine the emotional response in terms of level of emotional charge. (Did the event elicit a strong, moderate or mild emotional arousal?) This ultimately guides the individual to understand the nuances between feelings of anxiety, fear, disgust or anger, for instance.

The app is based on a pilot study led by Neumann at the Rehabilitation Hospital of Indiana that employed the same techniques. It involved patients who, on average, had experienced a traumatic brain injury at least eight years prior. They underwent eight, one-hour emotional awareness training sessions with a research therapist. The results were promising. “We have patients who benefitted tremendously, and the benefits were lasting,” Neumann said.

After the trial, patients were given a laminated piece of paper that reinforced what they learned and served as their Emotional Compass. Neumann sought to make the tool available to a broader audience in a user-friendly format. She selected CreateAbility Concepts, Inc. to help develop the app because of the company’s understanding of this population. It helped transfer Neumann’s manual compass into a highly interactive app through an elaborate series of interviews and mock-ups.

CreateAbility Concepts licensed Neumann’s work through the IU Innovation and Commercialization Office, which protects, markets and licenses intellectual property developed at Indiana University so it can be commercialized by industry.

“This license agreement is a perfect marriage of Dawn Neumann’s outstanding content and CreateAbility Concept’s superior technical know-how,” said David Wilhite, director at ICO. “We are glad to license this intellectual property to an Indiana-based company to bring it to the market.”

Patients are encouraged to use My Emotional Compass in collaboration with a clinician, such as a psychologist or speech language pathologist.

“The inability to recognize and interpret emotions puts a significant strain on relationships and impedes a person’s quality of life, but it is a problem that is often overlooked as clinicians focus on immediate and long-term physical complications of the injury,” Neumann said. “My hope is that this app continues to shine a light on the importance of treating alexithymia and other related conditions and empowers patients by giving them access to an effective, easy-to-use tool.”

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The Intrepid Spirit traumatic brain injury treatment center is slated to open April 2 at Camp Pendleton. (Courtesy Naval Hospital Camp Pendleton) (Photo/iStock)

Brain injury center to open at Marine base

By Linda McIntosh, March 27, 2018, sandiegouniontribune.com

A brain injury treatment center for military personnel will open its doors April 2 near the Naval Hospital Camp Pendleton.

The $11.5 million Intrepid Spirit center is the seventh of nine such facilities at military bases across the country. It is funded by the New York-based nonprofit Intrepid Fallen Heroes Fund founded in 2000 by Zachary Fisher, who also started the Fisher House Foundation for military families.

The center will operate as a part of Naval Hospital Camp Pendleton to treat active-duty military patients who suffer from the physical and psychological effects of brain injury. The center will also provide education and other resources on brain injury for veterans and the wider community.

The center will expand the hospital’s existing program at the Concussion Care Clinic, which has served more than 2,000 patients since 2014. An estimated 550-600 new patients are expected to be referred to the center each year.

“The facility will offer interdisciplinary, state-of-the-art evaluation of service members using clinical, laboratory and imaging resources to guide treatment,” said Cmdr. Paul Sargent, medical director of the Intrepid Spirit center, Naval Hospital Camp Pendleton.

The center’s specialty rehabilitation and therapy programs will focus on providing service members strategies to improve recovery from physical, emotional and spiritual injuries.

“We know that being able to be close to home, surrounded by loved ones, is a crucial part of the recovery process, so we are opening centers on the West Coast this spring at Camp Pendleton and also at Joint Base Lewis-McChord in Washington in order that service members who need treatment do not have to uproot themselves and their families to get it,” said David Winters, president of the Intrepid Fallen Heroes Fund.

Two teams of clinicians will serve the clinic. Their specialties range from neurology, physical medicine and rehabilitation, psychiatry, trauma psychology, neuropsychology and pain psychology to physical and occupational therapy, creative arts therapy and neuro-optometry.

“Our approach is a broadly collaborative center for preventing, treating and researching head trauma and injury to the brain,” Sargent said.

The Intrepid Spirit center includes research, education and clinical staff from the Defense and Veterans Brain Injury Center, which is part of the Department of Defense’s Health Agency.

“Teaching Marines, sailors and their commands about the risks of head injury, how to mitigate concussions and how to understand Traumatic Brain Injury signs and symptoms, along with how to improve readiness is a major goal of our TBI training,” said Regional Education Coordinator Clint Pearman, a certified brain injury specialist with the Defense and Veterans Brain Injury Center.

Pearman provides outreach, education, training and resources for medical personnel, military commands, service members, veterans and family members and civilian community groups from the Camp Pendleton area up to northern California.

The center’s design is based on the original National Intrepid Center of Excellence, which opened in 2010 at the Walter Reed National Military Medical Center in Bethesda, Md., operated by the Department of Defense.

“There are hundreds of thousands of U.S. service members who continue to suffer from traumatic brian injury and other psychological health conditions,” Winters said. “The Intrepid Fallen Heroes Fund has tried to help these brave men and women get the best care available, so we made it our mission to build nine Intrepid Spirit centers that provide comprehensive, state-of-the-art treatment.”

The clinic’s ground breaking was last May and a grand opening ceremony will be held at 11 a.m. April 4 at the Intrepid Spirit Center.

For information about base access, visit pendleton.marines.mil/About/Base-Information/Base-Access.

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The radial-arm water maze is a common test to assess working memory in rodents.

Memory-enhancing drug reverses effects of traumatic brain injury in mice

By Ryan Cross, Jul. 10, 2017, sciencemag.org

Whether caused by a car accident that slams your head into the dashboard or repeated blows to your cranium from high-contact sports, traumatic brain injury can be permanent. There are no drugs to reverse the cognitive decline and memory loss, and any surgical interventions must be carried out within hours to be effective, according to the current medical wisdom. But a compound previously used to enhance memory in mice may offer hope: Rodents who took it up to a month after a concussion had memory capabilities similar to those that had never been injured.

The study “offers a glimmer of hope for our traumatic brain injury patients,” says Cesario Borlongan, a neuroscientist who studies brain aging and repair at the University of South Florida in Tampa. Borlongan, who reviewed the new paper, notes that its findings are especially important in the clinic, where most rehabilitation focuses on improving motor—not cognitive—function.

Traumatic brain injuries, which cause cell death and inflammation in the brain, affect 2 million Americans each year. But the condition is difficult to study, in part because every fall, concussion, or blow to the head is different. Some result in bleeding and swelling, which must be treated immediately by drilling into the skull to relieve pressure. But under the microscope, even less severe cases appear to trigger an “integrated stress response,” which throws protein synthesis in neurons out of whack and may make long-term memory formation difficult.

In 2013, the lab of Peter Walter, a biochemist at the University of California, San Francisco (UCSF), discovered a compound—called ISRIB—that blocked the stress response in human cells in a dish. Surprisingly, when tested in healthy mice, ISRIB boosted their memory. Wondering whether the drug could also reverse memory impairment, Walter teamed up with UCSF neuroscientist Susanna Rosi to study mouse models of traumatic brain injury. First, they showed that the stress response remains active in the hippocampus, a brain region important for learning and memory, for at least 28 days in injured mice. And they wondered whether administering ISRIB would help.

Rosi and her team first used mechanical pistons to hit anesthetized mice in precise parts of their surgically exposed brains, resulting in contusive injuries, focused blows that can also result from car accidents or being hit with a heavy object. After 4 weeks of rest, Rosi trained the mice to swim through a water maze, where they used cues to remember the location of a hidden resting platform. Healthy mice got better with practice, but the injured ones didn’t improve. However, when the injured mice were given ISRIB 3 days in a row, they were able to solve the maze just as quickly as healthy mice up to a week later, the researchers report today in the Proceedings of the National Academy of Sciences.

“We kept replicating experiments, thinking maybe something went wrong,” Rosi says. So the team decided to study ISRIB in a second model of traumatic brain injury known as a closed head injury, which resembles a concussion from a fall. They again used a mechanical piston, but this time landed a broad blow to the back of the skull. Two weeks later, the mice were trained on a tougher maze, full of bright lights and loud noise. They had to scurry around a tabletop with 40 holes, looking for the one with an escape hatch. Again, while the uninjured mice improved at the task, the concussed mice never got the hang of it. But after four daily doses of ISRIB, the concussed mice performed as well as their healthy counterparts. “This is the most exciting piece of work I’ve ever done, no doubt,” Rosi says.

“Paradigm shift is not too strong a term to use,” says Ramon Diaz-Arrastia, neurologist and director of clinical traumatic brain injury research at the University of Pennsylvania. “This … shows for the first time that a therapy in the chronic period of traumatic brain injury can have pretty potent effects.” Walter agrees. “Normally you would give up on these mice and say nothing can be done here,” he says. “But ISRIB just magically brings the cognitive ability back.”

Still, Borlongan cautions that studies in animals often don’t pan out when tested in humans. He says that this drug has a leg up, though, because it was tested in two models and also readily crosses the blood-brain barrier, which prevents many drugs that look good on paper from entering the brain and having an effect.

If the therapy translates to humans, it could be a boon for soldiers returning from war, who sometimes wait weeks between leaving the battlefield and arriving home for treatment. Brian Head, a neurobiologist at the VA San Diego Healthcare System in California notes that traumatic brain injury is still hard to diagnose, especially with veterans that show up to the clinic long after the injury. “But right now nothing else is working, and giving a compound [that works] a month later is really impressive.”

In 2015, ISRIB was licensed to the secretive Google spinout company Calico, which studies the biology of aging and life span. Walter says his lab has a research agreement with Calico to pursue “basic mechanistic work” on ISRIB, but that the new study was not funded by Calico. Google declined to comment on the new research.

Although the protein target of ISRIB is known, the exact manner in which the drug restores memory is hazy. The team hypothesizes that ISRIB may work by allowing normal protein synthesis—essential for making new neuronal connections and thus forming new memories—to resume, which would otherwise be blunted by the integrated stress response. “Even if this drug doesn’t materialize, other ways of manipulating the integrated stress response may lead to an effective treatment in the future,” Walter says.

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