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ISRIB molecule—image by the Adam Frost lab at UCSF

Drug Reverses Age-Related Mental Decline Within Days, Suggesting Lost Cognitive Ability is Not Permanent

By Good News Network, December 27, 2020

 
Just a few doses of an experimental drug that reboots protein production in cells can reverse age-related declines in memory and mental flexibility in mice, according to a new study by UC San Francisco scientists.

The drug, called ISRIB, has already been shown in laboratory studies to restore memory function months after traumatic brain injury (TBI), reverse cognitive impairments in Down Syndrome, prevent noise-related hearing loss, fight certain types of prostate cancer, and even enhance cognition in healthy animals.

In the new study, published Dec. 1 in the open-access journal eLife, researchers showed rapid restoration of youthful cognitive abilities in aged mice, accompanied by a rejuvenation of brain and immune cells that could help explain improvements in brain function—and with no side effects observed.

“ISRIB’s extremely rapid effects show for the first time that a significant component of age-related cognitive losses may be caused by a kind of reversible physiological “blockage” rather than more permanent degradation,” said Susanna Rosi, PhD, Lewis and Ruth Cozen Chair II and professor in the departments of Neurological Surgery and of Physical Therapy and Rehabilitation Science.

“The data suggest that the aged brain has not permanently lost essential cognitive capacities, as was commonly assumed, but rather that these cognitive resources are still there but have been somehow blocked, trapped by a vicious cycle of cellular stress,” added Peter Walter, PhD, a professor in the UCSF Department of Biochemistry and Biophysics and a Howard Hughes Medical Institute investigator. “Our work with ISRIB demonstrates a way to break that cycle and restore cognitive abilities that had become walled off over time.”

Rebooting cellular protein production holds key to aging

Walter has won numerous scientific awards, including the Breakthrough, Lasker and Shaw prizes, for his decades-long studies of cellular stress responses. ISRIB, discovered in 2013 in Walter’s lab, works by rebooting cells’ protein production machinery after it gets throttled by one of these stress responses—a cellular quality control mechanism called the integrated stress response (ISR; ISRIB stands for ISR InhiBitor).

The ISR normally detects problems with protein production in a cell—a potential sign of viral infection or cancer-promoting gene mutations—and responds by putting the brakes on cell’s protein-synthesis machinery. This safety mechanism is critical for weeding out misbehaving cells, but if stuck in the ‘on’ position in a tissue like the brain, it can lead to serious problems, as cells lose the ability to perform their normal activities, according to Walter and colleagues.

In particular, their recent animal studies have implicated chronic ISR activation in the persistent cognitive and behavioral deficits seen in patients after TBI, by showing that, in mice, brief ISRIB treatment can reboot the ISR and restore normal brain function almost overnight.

The cognitive deficits in TBI patients are often likened to premature aging, which led Rosi and Walter to wonder if the ISR could also underlie purely age-related cognitive decline. Aging is well known to compromise cellular protein production across the body, as life’s many insults pile up and stressors like chronic inflammation wear away at cells, potentially leading to widespread activation of the ISR.

“We’ve seen how ISRIB restores cognition in animals with traumatic brain injury, which in many ways is like a sped-up version of age-related cognitive decline,” said Rosi, who is director of neurocognitive research in the UCSF Brain and Spinal Injury Center and a member of the UCSF Weill Institute for Neurosciences. “It may seem like a crazy idea, but asking whether the drug could reverse symptoms of aging itself was just a logical next step.”

Signature effects of aging disappeared literally overnight

In the new study, researchers led by Rosi lab postdoc Karen Krukowski, PhD, trained aged animals to escape from a watery maze by finding a hidden platform, a task that is typically hard for older animals to learn. But animals who received small daily doses of ISRIB during the three-day training process were able to accomplish the task as well as youthful mice—and much better than animals of the same age who didn’t receive the drug.

The researchers then tested how long this cognitive rejuvenation lasted and whether it could generalize to other cognitive skills. Several weeks after the initial ISRIB treatment, they trained the same mice to find their way out of a maze whose exit changed daily—a test of mental flexibility for aged mice who, like humans, tend to get increasingly stuck in their ways. The mice who had received brief ISRIB treatment three weeks before still performed at youthful levels, while untreated mice continued to struggle.

To understand how ISRIB might be improving brain function, the researchers studied the activity and anatomy of cells in the hippocampus, a brain region with a key role in learning and memory, just one day after giving animals a single dose of ISRIB. They found that common signatures of neuronal aging disappeared literally overnight: neurons’ electrical activity became more sprightly and responsive to stimulation, and cells showed more robust connectivity with cells around them while also showing an ability to form stable connections with one another usually only seen in younger mice.

The researchers are continuing to study exactly how the ISR disrupts cognition in aging and other conditions and to understand how long ISRIB’s cognitive benefits may last. Among other puzzles raised by the new findings is the discovery that ISRIB also alters the function of the immune system’s T cells, which also are prone to age-related dysfunction. The findings suggest another path by which the drug could be improving cognition in aged animals, and could have implications for diseases from Alzheimer’s to diabetes that have been linked to heightened inflammation caused by an aging immune system.

“This was very exciting to me because we know that aging has a profound and persistent effect on T cells and that these changes can affect brain function in the hippocampus,” said Rosi. “At the moment, this is just an interesting observation, but it gives us a very exciting set of biological puzzles to solve.”

Success shows the ‘serendipity’ of basic research

Rosi and Walter were introduced by neuroscientist Regis Kelly, PhD, executive director of the University of California’s QB3 biotech innovation hub, following Walter’s 2013 study showing that the drug seemed to instantly enhance cognitive abilities in healthy mice. To Rosi, the results from that study implied some walled-off cognitive potential in the brain that the molecule was somehow unlocking, and she wondered if this extra cognitive boost might benefit patients with neurological damage from traumatic brain injury.

The labs joined forces to study the question in mice, and were astounded by what they found. ISRIB didn’t just make up for some of the cognitive deficits in mice with traumatic brain injury—it erased them. “This had never been seen before,” Rosi said. “The mantra in the field was that brain damage is permanent—irreversible. How could a single treatment with a small molecule make them disappear overnight?”

Further studies demonstrated that neurons throughout the brains of animals with traumatic brain injury are thoroughly jammed up by the ISR. Using ISRIB to release those brakes lets brain cells immediately get back to their normal business. More recently, studies in animals with very mild repetitive brain injury—akin to pro athletes who experience many mild concussions over many years—showed that ISRIB could reverse increased risk-taking behavior associated with damage to self-control circuits in the frontal cortex.

“It’s not often that you find a drug candidate that shows so much potential and promise,” Walter says, calling it “just amazing”.

No side effects

One might think that interfering with the ISR, a critical cellular safety mechanism, would be sure to have serious side effects, but so far in all their studies, the researchers have observed none. This is likely due to two factors. First, it takes just a few doses of ISRIB to reset unhealthy, chronic ISR activation back to a healthier state. Second, ISRIB has virtually no effect when applied to cells actively employing the ISR in its most powerful form—against an aggressive viral infection, for example.

ISRIB has been licensed by Calico, a South San Francisco, Calif. company exploring the biology of aging, and the idea of targeting the ISR to treat disease has been picked up by many other pharmaceutical companies, Walter says.

“It almost seems too good to be true, but with ISRIB we seem to have hit a sweet spot for manipulating the ISR with an ideal therapeutic window,” Walter said.

Get more links to background studies from original article from UCSF News.
 

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Pictured is a high-fidelity map of physician-scientist Nico Dosenbach’s brain while his dominant arm was in a cast for two weeks. The red and yellow areas of the MRI image represent previously undetected brain pulses. Dosenbach and colleagues at Washington University School of Medicine in St. Louis found that disuse of an arm causes the affected brain region to disconnect from the rest of the brain’s motor system within two days. However, spontaneous pulses maintain activity in the disused circuits until the region becomes active again when mobility is regained.

 

Previously undetected brain pulses may help circuits survive disuse, injury

Research may lead to treatment advances for patients with immobilizing illness, injury

By Washington University in St. Louis, June 15, 2020

 

To study brain activity, Nico Dosenbach, MD, PhD, an assistant professor of neurology at Washington University School of Medicine in St. Louis, wore a fiberglass cast for two weeks.

A neuroscientist’s neon pink arm cast led him and fellow researchers at Washington University School of Medicine in St. Louis to discover previously undetected neuronal pulses in the human brain that activate after an immobilizing illness or injury.

The pulses appeared on MRI scans used to measure brain activity of the neuroscientist and, later, two additional adults whose arms were in casts. The researchers compared those MRI images with scans of the scientists before and after their arms were put in casts.

The scans showed that the brain’s main circuits responsible for movement in specific areas of the body disconnected within 48 hours of a person wearing a cast that encumbered movement in such an area. Also during this time, “disuse pulses” emerged to maintain neural activity and allow the main motor circuits to reactivate if and when mobility was restored through physical therapy.

The findings, published online June 16 in Neuron, offer clues to how the brain’s billions of neurons — cells that transmit nerve impulses — can rewire and restore pathways after injury or illness. Understanding just what is behind this resiliency may lead to new therapies for people with broken limbs or recovering from strokes or other immobilizing conditions.

“Many scenarios exist in neurology in which a person doesn’t use an arm or a leg and, consequently, related brain circuits for an extended period of time,” said senior author Nico Dosenbach, MD, PhD, an assistant professor of neurology. “In offering the best care to patients, it’s important to understand specifically what changes occur in brain function. Accurate understanding and mapping of these circuits may lead to advancements in treating patients who have lost use of their limbs.”

In 2015, Dosenbach — also an assistant professor of occupational therapy, of pediatrics, of radiology and of biomedical engineering — wore the pink cast for two weeks despite the fact he had no injury requiring one. He aimed to collect high-quality data using brain-imaging techniques to evaluate neural networks that control movement.

Many of the patients Dosenbach treats at St. Louis Children’s Hospital suffer from conditions that limit mobility and cause them to favor one side of the body. A common treatment is constraint-induced movement therapy, also known as forced-use therapy, which immobilizes the dominant arm with a cast, forcing the child to use the impaired arm.

“My goal was a better understanding of what my patients experience during therapy, although I acknowledge it’s more difficult for them because of their disabilities,” Dosenbach said.

He also wanted to pinpoint a timeline of when individual neural changes occur. Commonly, scientists gather MRI data from dozens of people and average it. “But I did not want to do that because everyone’s brain is anatomically different, and when MRI data are averaged, it all blurs together,” Dosenbach said.

So Dosenbach decided to wear a fiberglass cast on his dominant, right arm. It stretched from his fingertips to just below his shoulder. It was pink, the favorite color of his daughter, Maike, then age 2.

He wore it during the hot, humid summer. It itched. It was awkward. He had to learn how to change a diaper with one hand. 

Every day, he arose predawn to lie stiffly for 30 minutes for a resting-state functional MRI. He did this for the two weeks his arm was in the cast, as well as for the two weeks before and after.

During the six weeks, Dosenbach also wore accelerometers on both wrists to track the motor strength of his arms while performing basic tasks such as writing and moving objects.

“It wasn’t terrible, just unpleasant,” Dosenbach recalled. “But immediately, I noticed my right arm got worse, and my left hand got stronger. It was much faster than any of us expected.”

The MRI data showed that brain changes occurred within 48 hours. Additionally, the researchers measured a decrease in grip strength in his right arm — from 124 pounds of force to 90 during the two weeks he wore the cast.

“Once my cast was removed, my right hand began to grow stronger,” Dosenbach said. “My left returned to its former role, too.”

Surprised by such resiliency, Dosenbach and the study’s first author, Dillan Newbold, a MD, PhD student, conducted the same experiment on two “crazy-in-a-good-way” scientists — one who wore a fluorescent yellow cast decorated in doodles, the other a forest green cast that recalled childhood memories of camping.

Using a resting-state functional MRI scan, the researchers identified and measured the precise regions in each individual’s brain that controlled each casted arm, examining more than 20 hours of recordings for each person. These techniques allowed the researchers to discover and characterize the pulses.

Their MRI data nearly mirrored Dosenbach’s. The findings indicated that disuse of each arm caused affected neurons to disconnect from the rest of the brain’s motor system within two days. Newbold’s analysis revealed that throughout the time the casts were worn, spontaneous pulses maintained activity in the disused circuits until the neurons began firing again when mobility was regained.

“Finding the spontaneous pulses was incredible,” Newbold said. “People can be motionless, but their neurons seem to protect the brain from completely disengaging when it’s not being used. More research is needed, but this was the most exciting part of the study because of the clinical implications.”

 

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Computer Vision Syndrome

 

Caring for Your Vision with So Much Screen-Time!

Avoid “Computer Vision Syndrome”

By Carl Hillier, OD FCOVD

 
Most of us are engaged in “screen time” more than ever before—using Zoom/Skype/FaceTime as a tele-therapy platform. For many, this can be very successful, but also potentially very visually stressful.

We recommend the following guidelines to help minimize the following problems associated with excess screen-time—collectively known as “Computer Vision Syndrome”:

  • Cognitive Fatigue
  • Visual Fatigue/Eye Strain
  • Dry Eye Symptoms
  • Blurred Distance Vision
  • Headache
  • Neck and Shoulder Pain
  • Poor-Quality Sleep

 

Things to do to alleviate the symptoms above:

  • Take scheduled breaks from screen time at least every 30 minutes, walking away from the computer for at least 2 minutes.
  • During these 2 minutes, stand or sit in a very relaxed way and rotate your body without moving your feet—try to look behind you one way, then back to the other way as far as you are able.
  • Check each eye individually during these 2-minute breaks to ensure you are not losing distance vision from either eye.
  • Acquire optical quality lenses that deflect the harmful blue light that emanates from screens. Your optometrist can get the proper protective lenses for you.
  • Research-proven nutritional supplementation solutions:
    • Lutein (10 mg), Zeaxanthin (2 mg) and Mesozeaxanthin (10 mg)—to improve visual performance, sleep quality and decrease adverse physical symptoms
    • Omega-3—Minimum EPA: 400 mg; Minimum DHA: 960 mg
  • Stop screen time 2 hours before going to sleep.
  • Get outside as much as possible!

If you would like more advice on how to establish a strong visual foundation for the demands of online learning, just let us know. We can provide activities for you to do off-line that will help you maintain good vision while you are on-line!

Carl G. Hillier, OD FCOVD
Melissa C. Hillier, OD FCOVD
San Diego Center For Vision Care
SanDiegoCenterForVisionCare.com

CLICK HERE to download the original article
 

 

What’s the difference between all the different head scans (X-Ray, CT, MRI, MRA, PET scan)? And what do they show in the head?

Michael S. Tehrani, M.D.Follow Founder & CEO at MedWell Medical

 
Ever wonder what’s the difference between all the different head scans (xray, CT, MRI, MRA, PET scan) and what they show in the head. Well wonder no more. The Dr. T easy to understand version…

X-Ray: shows bone/skull only. Does not show the brain. Best used to detect if there are bone fractures.

CT: a quick test. Shows brain but detail not great. Shows if any larger bleed, stroke, lesions, or masses.

MRI: a long test. Shows brain and detail is great. Shows smaller bleeds, stroke, lesions, or masses.

MRA:
shows the flow of blood in the vasculature system of the brain. If there is vessel narrowing or blockage this test would show it.

PET scan: shows how active different parts of the brain is. An active brain uses sugar as energy and pet scan detects how much sugar is being used by lighting up and turning different colors. The more sugar being used the more that area will light up and be different in colors. Cancer cells use the most sugar so cancer cells light up the most. PET scan is used to see if there are cancer cells. (Cancer cells replicate at a very fast and uncontrolled rate hence use a lot of sugar to allow that replication hence why they light up so much).

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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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Junior Seau, shown at his beloved Pacific Ocean in the ESPN Films “30 for 30” documentary “Seau,” which premieres Thursday. (ESPN Films)

ESPN hits the mark with documentary ‘Seau’

By Tom Krasovic, September 20, 2018, San Diego Union Tribune

An aerial view of the Oceanside coast, in full sparkle and splendor below, grandly eases viewers into “Seau,” an ESPN Films documentary in the “30 for 30” series that debuts Thursday on the streaming service ESPN+.

It’s a sunny scene, the Pacific Ocean’s turquoise waves illuminated as they roll toward the white beach. The late Junior Seau told friends he found peace paddling on these waters, deep into his life alongside the town where he’d grown up.

Up at dawn with a yellow long-board and oar in hand, Seau had only a short walk from his beachfront home to the water.

Yet the former Chargers linebacker, role model and local philanthropist was then also writing in a journal of bouts with depression, memory loss and perceived guilt. There were headaches, too, and nights plagued by insomnia. “Buddy,” he’d told a friend and professional soccer player who’d suffered a brain injury from heading a ball, “I’ve had a concussion since I was 15.”

Diary entries also revealed feelings of humiliation and embarrassment over not living up to expectations of others and himself, and of feeling used by others.

“The world has nothing for me,” Seau pens in one entry, the cursive words all too legible.

One of Seau’s surviving adult children, after reading the grim line aloud, wonders why his father didn’t regard his family as something in this apparent world of nothing.

Why couldn’t they have been a lifeline for him to reach out and grasp?

“Seau,” produced and directed by Kirby Bradley, lets viewers draw their own conclusions about a complicated life that ended one May morning six years ago, at age 43, with a self-inflicted gunshot wound to the chest, but not before we hear from an array of family members, friends and experts in football and brain science.

At the end of the 90-minute film, themes of redemption and hope are raised.

“Let’s all walk from here being better for having known Junior Seau and the impact he had on our lives,” NFL quarterback Drew Brees, a former Chargers teammate of the Hall of Fame linebacker, concludes near the film’s end.

Former Chargers lineman Aaron Taylor notes that in death, Seau drew extraordinary attention to the link between head trauma and a degenerative brain disease, CTE, revealed in a tissue sample sent to a brain scientists at the family’s request.

Exciting beginnings and success are a thread to the film, followed often by bitter detours or hurtful endings.

Seau took to sports at Oceanside High with a passion that rivaled his stunning blend of size, speed and agility. If he was slamming into football ball-carriers or catching passes, scoring baskets or throwing the discus and shot, he was a “force of nature” for the green-and-white-clad Pirates, observers said.

A flood of football scholarship offers came to the small home where Seau and his brothers slept in a tiny garage.

Jubilation ensued when Seau chose USC, keeping him close to his parents and siblings and the tight-knit Samoan-American community in Oceanside. A similar celebration arose in 1990 when the Chargers drafted him fifth overall. “I’m a real momma’s boy,” Seau said, pulling on a blue team cap.

Playing for his beloved “Diego,” he led the long-struggling Chargers to the playoffs in just his third season, and their first Super Bowl two years later. “Now the world is gonna know the San Diego Chargers,” he told some 70,000 celebrants in Mission Valley after the team returned from claiming the 1994 AFC title in Pittsburgh.

The flip side?

If Oceanside lost a game in which he played, Junior lost his lunch money. It was the price his father exacted.

The thrill of signing with USC gave way to humiliation when a failed admittance test made him ineligible as a freshman. His father refused to talk to him in response, deeming the failure an embarrassment to the family. After a dominant junior year with USC, there would be no senior year. Making money was the next step, in no small part because he wanted to support his parents and other family members.

The Chargers couldn’t build upon their Super Bowl season, and the team’s constant losing wore on Seau.

When the Chargers traded him in the spring of 2003, after 13 seasons with the club, Seau was hurt that the team — Stay Unclassy, San Diego? — called not him but his agent to tell him the news. “I know that was hard on him,” said the agent, Steve Feldman.

Gina Seau was working for the Chargers in marketing when she first met Seau early in his NFL career.

She recalled “very kind eyes” and a “very soft voice” that almost “didn’t match the size and stature.”

The two would marry, but erratic behavior that Gina Seau linked to numerous football-related head injuries — “My head is on fire,” he told her — led to a divorce in 2002. The two remained friends. Believing that driving off a steep coastal cliff in October 2010 wasn’t an accident, Gina pleaded with her former husband to get help.

Here’s hoping that if there’s a “Seau II,” events yet to transpire bring more developments of redemption. Say, a cure for CTE.

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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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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 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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