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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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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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CARSON, CA – AUGUST 03: Bronze medal winner Dave Mirra speaks in a press conference after the Rally Car race during the summer X Games 14 at Home Depot Center on August 3, 2008 in Carson, California. (Photo by Christian Petersen/Getty Images)

Months after committing suicide, Dave Mirra has become the first action sports athlete to be diagnosed with CTE

by Robert Silverman, vocativ.com (May 24, 2016)
 
After BMX biking legend Dave Mirra committed suicide on February 4 of this year, his wife had his brain tested for chronic traumatic encephalopathy. Sadly, the result came back positive, rife with tau proteins dotting both his temporal and frontal lobes after years of enduring an unknown amount of concussive and sub-concussive trauma. This makes Mirra the first action sports athlete to be diagnosed with CTE.

The neuropathologist went so far as to equate the condition of his brain to that of NFL players and other contact sport athletes that have been posthumously diagnosed with the disease. “I couldn’t tell the difference,” Dr. Lili-Naz Hazrati said.

In an exclusive interview with ESPN: The Magazine, Mirra’s wife Lauren describes the agonizing final weeks of his life, the transformation of his formerly vibrant personality into something different and darker, prone to wild mood swings and unprovoked crying jags or bouts of exhaustion, his mind clouded and wracked with depression.

“I remember seeing him sitting on our bed one day, in the last month of his life,” she said. “I had just gotten out of the shower and saw him hunched over with the blankest lost look. I sat down next to him and held his hand. I said, ‘What is wrong? Are you OK?’ And he just shrugged his shoulders. He couldn’t even speak. He didn’t know. He couldn’t put it into words. He was lost. He was helpless. It was completely different from who he was.”

“He was gone. I could see straight through him,” she continued. “It was the hardest thing to see, looking at someone you love, and you can’t have a conversation with them, and you can see straight through their eyes.”

Lauren Mirra doesn’t know what her exact plans might be for the future, but her overarching hope is that she’ll be able to find a forum in which to speak out, to encourage best practices and prevention measures, without coming across as an ideologue out to ban action sports altogether.

“Through him we have an opportunity to help and change,” she said. “Beauty from ashes. That’s how I will always choose to see it.”

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The Cohen family partners with USC to serve families in Los Angeles.
 
by Lynn Lipinski, tfm.USC.edu (Autumn 2016) — PEACE AFTER WAR can be elusive for combat veterans who fight painful memories long after they’ve left the battlefield. Of the more than 2.6 million men and women who have served in the U.S. military since 9/11, about 20 percent experience some form of post-traumatic stress or brain injury—but nearly half forego treatment, according to the Cohen Veterans Network.

The Steven A. Cohen Military Family Clinic at USC, made possible by a $15.7 million gift from Steven Cohen and the Cohen Veterans Network, offers veterans and their family members free outpatient mental health services and case management. Recently opened in downtown Los Angeles, the Cohen Military Family Clinic at USC is part of a national network of clinics serving veterans and is a collaboration between the USC School of Social Work and the Keck School of Medicine of USC.

Providers will also be stationed at locations throughout the county in areas that otherwise lack these types of services. The clinic will also serve veterans who are ineligible for Veterans’ Admnistration benefits, such as those who served in the National Guard or the Reserves.

“The wounds of war are serious. It is not easy to serve your country in combat overseas and then come back into society seamlessly, especially if you are suffering,” says Cohen, chairman and CEO of Point72 Asset Management. “Veterans have paid an incredible price. It’s important that this country pays back that debt.”

The Cohen Veterans Network plans to create a system of about two dozen centers across the country by 2020 as part of a $275 million initiative to improve access to behavioral health care for recent veterans. Cohen’s support of services for veterans began in part because of a personal connection: His son, Robert, deployed to Afghanistan with the Marines and is currently in the Reserves.

USC’s strong programs for veterans made it a natural fit to host the clinic. The USC School of Social Work is home to the Center for Innovation and Research on Veterans and Military Families, where researchers conducted the first comprehensive study of veterans in L.A. County. Their findings are already helping to create effective services for veterans. The school has also earned national recognition for its pioneering master’s degree in military social work—the only program of its kind offered by a civilian research university.

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By John Prybys, LAS VEGAS REVIEW-JOURNAL (August 22, 2016) — Randy Dexter and Captain are more than just dog owner and dog. That’s obvious from the way Captain looks for Dexter whenever the Army veteran leaves the room, and the way the Lab mix’s demeanor slips instantly from playful to dead serious once he’s wearing the jacket that denotes his status as a service animal.

Dexter is a retired U.S. Army staff sergeant who did two tours of duty in Iraq. He was diagnosed with both post-traumatic stress disorder and a mild traumatic brain injury, and the story of Dexter and Captain is featured in a new awareness campaign urging veterans and military service people to seek help for traumatic brain injury if they need it.

The campaign, “A Head for the Future,” is sponsored by the Defense and Veterans Brain Injury Center. In his video, Dexter shares the struggles he has experienced coping with his injuries and the reluctance he felt at first to seek help for it.

But, he says, “I was lucky, because when I was in the Army and had my head injury, I was kind of forced to get help.”

Dexter, 34, is a graduate of Green Valley High School who served in the Army for 11 years and had two tours of duty in Iraq. In 2005, Dexter, a combat medic, and his squad were hit by an IED, prompting a long, and continuing, struggle with post-traumatic stress disorder.

Then, after returning home and while still being treated for PTSD and training soldiers bound for Iraq and Afghanistan, Dexter suffered a brain injury during a recreational football game. He’s not sure, even now, what happened. All he knows is that he lost the memory of about 24 hours’ time and, even, of going to the game at all.

X-rays and imaging studies revealed no skull fractures or apparent injuries. But, afterward, Dexter experienced a worsening of already existing problems with his memory, concentration and equilibrium, and began to suffer migraines and severe, debilitating headaches that eventually compounded his PTSD and caused severe depression.

Dr. Scott Livingston, director of education for the Defense and Veterans Brain Injury Center in Silver Springs, Maryland, says symptoms of PTSD and brain injury often can overlap, making diagnosis a challenge. And when a brain injury does occur, he says, it often presents with no obvious symptoms that can be detected by X-ray or imaging scans.

In such cases, the problem likely is “more of a microscopic type of injury within the brain,” Livingston says.

Most civilians probably assume that brain injuries among service people are caused mostly by blasts and blunt-force trauma to the head. Yet, Livingston says, most are caused by motor vehicle collisions, training-related accidents, falls and sports and recreational activities.

Whatever the cause, military personnel are reluctant to report an injury or seek care for it. The current campaign is designed to raise awareness of brain injuries among service people, promote ways to prevent it when possible, and encourage men and women to report it and get it checked out, Livingston says.

“It’s well-known in scientific literature that the earlier someone reports a mild traumatic brain injury and goes to seek help, the better the chances are for better and more complete recovery,” he says.

During his treatment, Dexter participated in a program that paired injured veterans with service dogs. His experience with a dog named Ricochet was so good that he later welcomed the chance to be paired with Captain.

Dexter and Captain are a great team. Dexter says the dog can detect impending anxiety attacks even before he does, and that the dog can serve as a physical shield and protector in such public places as big-box retail stores, which can be particularly unnerving places for those with PTSD.

The true test of Captain’s effectiveness is that the dog has allowed Dexter to significantly reduce the medications he has to take. Today, it would be difficult for someone who doesn’t know the back story to detect Dexter’s struggles with traumatic brain injury, and it was his own previous interest in speaking out publicly about his conditions that led to his participation in the new awareness campaign.

Dexter now attends UNLV, where he’s majoring in communication studies and Spanish. He has been active on the debate teams, will be a peer adviser for other veterans, and hopes to kick off a music show on the university’s HD/internet radio station.

Dexter hopes his video and his story will help to persuade other veterans and active service people to seek out help for PTSD and brain injury. That can be difficult, he notes, because the standard soldier’s stance is that, whatever is happening, “you just deal with it, and that’s true across the whole military culture.”

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By Alyssa Navarro, Tech Times (August 23, 2016) — Federal health regulators in the United States approved on Monday the use of two new computer softwares as cognitive screening tests for traumatic head injury patients.

Known as ImPACT or the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT), the new testing device, as well as a similar test designed for children, can be used by doctors to evaluate signs and symptoms of head injuries that could indicate concussion.

ImPACT is designed for patients aged 12 to 59 years old, while ImPACT Pediatric is intended for children aged 5 to 11 years old, officials said. Licensed health care professionals are the only ones allowed to perform the analysis and interpret the results.

The software can be accessed easily because it runs on both desktop computers and laptops, according to the U.S. Food and Drug Administration (FDA). Both tests the first ever devices permitted by the FDA to assess cognitive function after experiencing a possible concussion. They are designed to be part of medical evaluations in hospitals.

Although ImPACT and ImPACT Pediatric will definitely be useful for doctors, both tests are not meant to diagnose concussions or determine treatments that are appropriate for such cases, the FDA said.

Instead, both devices are only designed to test cognitive skills such as reaction time, memory and word recognition. All of these can be impacted by head injuries. Afterwards, the results are compared to a patient’s pre-injury baseline scores or an age-matched control database, the FDA said.

Dr. Carlos Peña, director of the neurological and physical medicine division at the Center for Devices and Radiological Health, acknowledges that the two testing devices can provide useful information that can aid doctors in the evaluation of people who are experiencing potential signs of concussion.

However, Peña says that clinicians should not completely depend on the tests alone to rule out concussion or to decide whether a player with a head injury should return to a game.

Statistics from the Centers for Disease Control and Prevention (CDC) reveal that traumatic brain injuries are responsible for more than 2 million visits to the emergency room in the country annually. Traumatic brain injuries also account for more than 50,000 deaths in America every year.

Cases of head injury among kids have been increasing. In May, a CDC report showed that from January 2001 to December 2013, approximately 214,883 children aged 14 years old and below were brought to emergency departments due to head injuries.

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UCSF Researchers Advocate Prioritizing Teens for Education and Prevention

by Scott Maier (August 17, 2016) — The number of Americans diagnosed with concussions is growing, most significantly in adolescents, according to researchers at UC San Francisco. They recommend that adolescents be prioritized for ongoing work in concussion education, diagnosis, treatment and prevention.

The findings appear online August 16, 2016, in the Orthopaedic Journal of Sports Medicine.

“Our study evaluated a large cross-section of the U.S. population,” said lead author Alan Zhang, MD, UCSF Health orthopaedic surgeon. “We were surprised to see that the increase in concussion cases over the past few years mainly were from adolescent patients aged 10 to 19.”

Concussions are a form of mild traumatic brain injury resulting in transient functional and biochemical changes in the brain. They can lead to time lost from sports, work and school, as well as significant medical costs.

Though symptoms resolve in most concussion patients within weeks, some patients’ symptoms last for months, including depression, headache, dizziness and fogginess. Neuroimaging and neuropathological studies also suggest there may be chronic structural abnormalities in the brain following multiple concussions.

Recent studies have shown an increase in traumatic brain injuries diagnosed in many U.S. emergency departments. Smaller cohort studies of pediatric and high school athletes also have indicated a rise in concussions for certain sports, such as football and girls’ soccer. However, this is the first study to assess trends in concussion diagnoses across the general U.S. population in various age groups.

In this study, Zhang and his colleagues evaluated the health records of 8,828,248 members of Humana Inc., a large private payer insurance group. Patients under age 65 who were diagnosed with a concussion between 2007-2014 were categorized by year of diagnosis, age group, sex, concussion classification, and health care setting of diagnosis (emergency department or physician’s office).

Overall, 43,884 patients were diagnosed with a concussion, with 55 percent being male. The highest incidence was in the 15-19 age group at 16.5 concussions per 1,000 patients, followed by ages 10-14 at 10.5, 20-24 at 5.2 and 5-9 at 3.5.

The study found that 56 percent of concussions were diagnosed in the emergency department, 29 percent in a physician’s office, and the remainder in urgent care or inpatient settings. As such, outpatient clinicians should have the same confidence and competence to manage concussion cases as emergency physicians, Zhang said.

A 60 percent increase in concussions occurred from 2007 to 2014 (3,529 to 8,217), with the largest growth in ages 10-14 at 143 percent and 15-19 at 87 percent. Based on classification, 29 percent of concussions were associated with some loss of consciousness.

A possible explanation for the significant number of adolescent concussions is increased participation in sports, said Zhang, MD, who is also assistant professor of orthopaedic surgery at UCSF. It also may be reflective of an improved awareness for the injury by patients, parents, coaches, sports medical staff and treating physicians.

For example, the U.S. Centers for Disease Control and Prevention “HEADS UP” initiative has caused numerous states such as California to alter guidelines for youth concussion treatment.

Many medical centers also are establishing specialty clinics to address this, which could be contributing to the increased awareness. At UCSF, the Sports Concussion Program evaluates and treats athletes who have suffered a sports-related concussion. The team includes experts from sports medicine, physical medicine and rehabilitation, neuropsychology and neurology. Their combined expertise allows for evaluation, diagnosis and management of athletes with sports concussions, helping them safely recover and return to sports.

Other UCSF orthopaedic surgery contributors to the Orthopaedic Journal of Sports Medicine study were senior author Carlin Senter, MD, associate professor; Brian Feeley, MD, associate professor; Caitlin Rugg, MD, resident; and David Sing, clinical research associate.

UC San Francisco (UCSF) is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with nationally renowned programs in basic, biomedical, translational and population sciences; and a preeminent biomedical research enterprise. It also includes UCSF Health, which comprises two top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children’s Hospital San Francisco, and other partner and affiliated hospitals and healthcare providers throughout the Bay Area.

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