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Cannabinoids may help limit secondary damage of TBIs

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In the hours and days after a traumatic brain injury, inflammation inside the brain can accelerate to the point that more brain damage occurs, says a scientist working to better understand the acceleration and whether interventions like cannabinoids can improve patient outcomes.

While some TBI patients do well, most would benefit from therapy to create a better balance between the vigorous inflammation needed in the immediate injury aftermath to clean up the site and the deceleration needed to complete healing and avoid more brain damage, says Dr. Kumar Vaibhav, translational neuroscientist in the Department of Neurosurgery at the Medical College of Georgia.

“You cannot suppress the entire pro-inflammatory process otherwise it would be difficult to recover from your injury,” Vaibhav says. But in this case, there is too much inflammation, a major factor in the reality that one-third of hospitalized patients with a TBI die from damage that continues after their acute injury.

The aftermath of concussions, essentially a closed-head injury, in football players is another case. Immediate problems might include a headache, dizziness and fogginess but ongoing memory and sleep problems, depression, as well as epilepsy, Alzheimer’s and Parkinson’s also can later occur.

Neither surgical nor medical intervention typically enable control of inflammation to limit the secondary destruction, and better understanding inflammation in the brain is a major barrier to successful treatment, the scientist says.

Vaibhav is principal investigator on a new $1.8 million grant (1RO1NS114560) from the National Institute of Neurological Disorders and Stroke further exploring the role of the body’s endocannabinoid system — identified by researchers studying the mind-altering effects of THC, and now known to play a role in immunity, sleep, memory and even reproduction. Its involvement appears to start with the physical injury that happens to our brains.

With a TBI, the injured brain cells’ plasma membrane, which helps contain the cell’s contents, ruptures, releasing lipids, or fats, a major component of the membrane, throughout the body. Two key endocannabinoids, 2-AG and AEA, which are also lipid molecules, also get released from the damaged membrane where they are made. These molecules are supposed to bind with endocannabinoid receptors and activate the endocannabinoid system to help regulate the immune response. The two main endocannabinoid receptors are CB1 and CB2, and in this case, the 2-AG’s target appears to be CB2 receptors, which are found on immune cells and known to reduce inflammation and related problems like swelling and blood vessel dysfunction.

“Within 24 hours after an injury, we see CB2 receptor activation and expression go up with 2-AG secreted in the blood,” Vaibhav says. “It’s a very quick response.” Trouble is, the injured cells also release an enzyme called MAGL and the now-free-floating lipids further activate it.

MAGL, or endocannabinoid-metabolizing enzyme monoacylglycerol lipase, as its long name implies is an enzyme whose job includes degrading 2-AG once it has done its job. Activation of MAGL is known to worsen TBI outcomes but exactly what it does after TBI is not well understood, Vaibhav says.

Vaibhav and his colleagues think the problem is that high MAGL appears to degrade 2-AG before it can play out its important anti-inflammatory role. He theorizes that high MAGL levels become instead a switch that turns up inflammation after TBI. He also has some evidence that reducing MAGL levels can help restore a healthy synergy between MAGL, 2-AG and the cannabinoid receptor CB2, making it a key point for intervention.

His research team is using both a research drug that inhibits MAGL and the cannabinoid CBD, which they have early evidence also inhibits MAGL, to see if they are correct.

His team has found reduced 2-AG in the cerebrospinal fluid of people with TBIs, but exactly why it was happening was unclear. In their laboratory model of a TBI, they have also found that MAGL levels are high while 2-AG levels are low, suggesting a link. And, that when they selectively activate the CB2 receptor early after a TBI, immune cells like macrophages are less inclined to promote inflammation, that swelling and blood flow are improved, and so are outcomes. Conversely, immune cells that are very inflammatory have high levels of MAGL inside, more evidence for their reasoning that when MAGL is high, it’s degrading too much 2-AG before it can go bind with the CB2 receptor and calm inflammation.

When they have reduced MAGL levels with the research drug, 2-AG concentrations went up, so did its binding to CB2 receptors, and immune cells began to favor reducing inflammation, findings which they published in 2018 in the journal Brain, Behavior and Immunity. “It’s actually polarizing macrophages into anti-inflammatory,” he says.

A major focus of the new grant is to look at what early inhibition of MAGL in immune cells — with the research drug, cannabinoids as well as commercially produced versions of the endocannabinoids 2-AG and AEA — does to the enzyme’s apparent natural predisposition to accelerate inflammation following a TBI.

“If we inhibit MAGL or over activate it, what happens?” Vaibhav says, of answers he is pursuing to better define MAGL’s role. He and his team are looking again to see if reduced activation of the CB2 receptor by 2-AG in the face of high MAGL is key to injury progression. And, whether progression includes affecting the white matter — brain tissue full of nerve fibers that enable connections between different parts of the brain and the spinal cord — and worsening problems like dementia.

He is inhibiting MAGL to also see how that plays out, and wants to learn more about why MAGL levels don’t just return to normal on their own. He also wants to connect the dots with yet another lipid, prostaglandins, which are made at the site of an injury, and whose many roles include promoting inflammation, because when MAGL degrades 2-AG, it enables more prostaglandin production.

Vaibhav also wants to know if MAGL and/or 2-AG levels right after an injury are biomarkers of whether a patient will have destructive secondary damage.

In addition to honing in on the best place to intervene and whether the research drug or CBD can do it, they also have to find the optimal time for intervention, so they don’t interfere with the initial aggressive immune response needed to clean up the injury.

“We need to find the optimal dose and time to intervene,” Vaibhav says. “You have to know how many immune cells are activated, how long they are activated and when they are going down or suppressed to help determine the optimal time for treatment, and that is one of the things we are trying to do.”

Macrophages are a type of immune cell that are early arrivers to an injury site to digest debris and stimulate tissue repair, and can both promote or deter inflammation. Vaibhav’s lab and others have shown that more than a month after a TBI, macrophages have shifted from an early role in suppressing inflammation to chronically promoting inflammation in a vicious, destructive cycle where inflammation damages neurons, which produces debris, which increases inflammation.

In fact, an accumulation of inflammation-promoting macrophages has been seen in the corpus callosum, which connects the two hemispheres of the brain and enables their communication, in more than 25% of people with TBIs, an accumulation that correlates with brain damage two decades after their injury.

Once immune cells get activated, their instinct and function is to scavenge cell debris, which is a good thing essential to healing. But when they stay activated, the cells also start digesting healthy brain tissue and the size of the damage increases, Vaibhav says. Once an enzyme like MAGL gets activated, its major focus becomes staying activated and it will for weeks, he says.

During normal times, MAGL and 2-AG levels are both relatively low inside a cell, including immune cells. MAGL degrades 2-AG if too much gets made for some reason, and 2-AG helps keep inflammation at bay.

The hydrolase FAAH metabolizes AEA, like MAGL does 2-AG. There is not substantial proof to date of the impact of high levels of MAGL on the other major endocannabinoid AEA, but it could be a similar scenario, Vaibhav says.

More than five million Americans live with disabilities resulting from a TBI, and TBIs are most common in young people. Falls are the major cause of TBIs, particularly in children and older adults, according to the Centers for Disease Control and Prevention, and account for about half of TBI-related visits to the Emergency Department.

Being struck by or against an object is the second leading cause of TBI-related visits. Falls and motor vehicle crashes are the leading cause of patients who require hospitalization for TBI and intentional self-harm was the leading cause of TBI related deaths.

Vaibhav’s collaborators on the new grant and related studies include MCG neuroscientist Dr. Krishnan Dhandapani, who also studies TBI, and Dental College of Georgia immunologist Dr. Babak Baban, who also studies the endocannabinoid system and the impact of CBD, including on the deadly cytokine storms that occur in COVID-19.

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Two major neuro events postponed due to COVID-19

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The Neuro Convention and The National Paediatric Brain Injury Conference have both been postponed

Two significant events in neuro practitioners’ calendars have been delayed until later in the year, as the effects of the COVID-19 pandemic continue to be felt.

The National Paediatric Brain Injury Conference, which was already revised from an in-person to online event, will now not go ahead as planned in February due to the continuing demands on frontline healthcare professionals as COVID-19 cases continue to rise and the country is plunged back into lockdown.

The event, organised by The Children’s Trust, is now earmarked for May 13, although that is subject to further developments in the pandemic.

The ‘Connections and Collaborations’ conference is set to attract an international audience and will hear from an array of speakers from around the world, many of whom are global leaders in the field of paediatric neuro care.

Explaining the postponement, Dalton Leong, chief executive of The Children’s Trust, says: “Over the years, a high number of attendees are from the NHS, including consultants, doctors, surgeons, nurses, and therapists.

“We know that many of these staff are being redeployed to support the Covid pandemic.

“To run a conference at this time, taking them away from delivering vital frontline services, does not seem a sensible option. We look forward to holding the conference later in the year when, hopefully, these pressures have reduced.”

As well as the conference, the Neuro Convention too has been postponed, moving from March until September to enable delegates to attend in person.

The event, held at the Birmingham NEC, typically attracts around 3,000 people from across the country, and organisers hope that by delaying the date, it will give the best chance of lockdown and social distancing measures being lifted to allow them to go ahead.

In addition to the event planned for September 15 and 16 – although that too may be subject to change – an additional digital version of Neuro Convention is set to go ahead in March, enabling neuro professionals to still receive the insight and analysis planned for the NEC event in an online format.

Neuro Convention is hailed as being Europe’s only specialist trade event for brain and spine experts, and boasts an array of internationally-respected speakers and leaders in their field.

“We have been in consultation with various Government departments and whilst the rollout of the vaccine has given the country much needed optimism, we have been advised that we will be unable to host the Neuro Convention event in the spring,” say event organisers Roar B2B.

“The safety of our visitors, customers, partners and staff is paramount. We are confident that moving the event to September will enable us to run the safe, successful event the industry demands.

“To support our exhibitors, partners and the wider industry we are delighted to announce an additional digital version of Neuro Convention. This will provide a digital meeting place, world-class speaking sessions and access to the latest products and services.”

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Arm and hand function could be regained following spinal cord injury through new pioneering research

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Treatment could be developed for arm and hand dysfunction in people living with spinal cord injury through a pioneering new research project.

A pilot study of new therapy for improving upper extremity function is now underway, following funding from BrainQ Technologies – an Israel-based startup which is working widely in precision medicine to reduce disability following neurodisorders – to the Kessler Foundation.

The study is titled ‘The safety and effectiveness of the use of a brain-computer interface-based electromagnetic field treatment in the management of patients with chronic spinal cord injury: A pilot study’ and is seen as a potentially significant breakthrough in researching possible treatment.

It will be led by Dr Ghaith Androwis, a research scientist in the Centre for Mobility and Rehabilitation Engineering Research at Kessler Foundation, and Dr Steven Kirshblum, senior medical officer and director of the Spinal Cord Injury Program for Kessler Institute for Rehabilitation, who received the grant to further their work in the field.

Thousands of new traumatic spinal cord injuries occur each year, with statistics showing around 17,500 of those are from the United States alone, and more than half of those people experience loss of motor function of the upper extremities which limits their independence and adversely affects their quality of life.

“To achieve the best outcomes after spinal cord injury, restoring arm and hand function must be a priority in rehabilitative care,” says Dr Kirshblum.

“This study is an important first step towards increasing the ability of individuals to function more independently at home, in their communities, and the workplace.”

During the study – which will be conducted in the US and Israel – researchers will test the safety and efficacy of noninvasive low frequency electromagnetic field stimulation delivered via the BQ System.

Individuals with spinal cord injury (duration 18-30 months) will participate in the 34-week study. Functional status will be measured at baseline and compared with status following the experimental treatment.

By quantifying gains in motor function, motor control and activities of daily living, this pilot study will provide preliminary information on the potential application of BrainQ’s therapy in rehabilitation programs for individuals with disability.

“We are very interested in testing the effectiveness of this novel and non-invasive approach in persons with spinal cord injury,” adds Dr. Androwis.

“Such interventions may improve participants’ performance of activities of daily living leading to gains in their overall quality of life. This particularly is important when an intervention can be provided simultaneously with conventional therapy.”

This multi-site study is being conducted at Kessler Foundation, The Miami Project to Cure Paralysis, Miami, and Sheba Medical Center, Israel.

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‘My brain is slipping into my spine’

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Karl Johnston suffers from a rare condition called Chiari Malformation Type 1

After years spent in pain and struggling for a diagnosis, Karl Johnston felt relief when he was confirmed as having a little-known condition where the brain effectively slips into the spine. Here, he shares his story.

“Some dads get to put their children on their shoulders, but I’ve never got to do that.”

That is just one of the day-to-day realities facing Karl Johnston, whose condition, Chiari Malformation Type 1, means his brain is effectively slipping into his spine.

For eight years, Karl had experienced a catalogue of symptoms, including intense and debilitating neck pain, light-headedness, fatigue and numbness in his arms, but without securing a diagnosis of his condition.

But now, the 35-year-old admits he feels some relief at the knowledge he has Chiari Malformation Type 1, as devastating as the diagnosis was to receive.

“A lot of people felt sorry for me when I finally got a diagnosis, but it was a relief because I’d been telling people that I was suffering for years and they hadn’t believed me,” says Karl, from Wallasey, on Merseyside.

“You start to question yourself about things. Just knowing takes a lot of the weight off you.

“Some days the pain is so much that it’s difficult to move around and all I want to do is lie down.”

The biggest difficulty emotionally, says Karl, is the impact it has on his ability to play with his daughter Seren.

“It’s devastating when she wants to play and I’m not up to it,” he says.

“Some dads get to put their children on their shoulders, but I’ve never got to do that.”

While Chiari Malformation Type 1 is most commonly diagnosed in adults, it is believed to often be present from birth.

Many people with the condition are asymptomatic, meaning it is only found if they have an MRI scan.

Karl had symptoms from when he was a teenager, but getting a diagnosis was difficult due to the lack of awareness around the condition.

He is now determined to help raise awareness of Chiari Malformation Type 1, in the hope that others may be able to secure a diagnosis quicker than his.

“There needs to be a way to make doctors and people in general more aware of these rarer conditions because otherwise people just fall through the cracks,” says Karl.

The dad-of-one has been supported by The Brain Charity, a national charity based in Liverpool that supports people with all forms of neurological conditions. Statistics show that 1 in 6 people in the UK is currently living with such a condition.

The charity recently told NR Times that demand for its services had soared by over 70 per cent since the start of lockdown in March, with predictions that the numbers of people needing support with issues including mental health, Long Covid and employment rights would grow further still.

Having turned to the charity last year, Karl is now getting the practical and emotional support he needs to get on with his life.

“The Brain Charity helped me get a better understanding of what was going on with my condition,” he says.

“It has felt like so many people haven’t taken me seriously but The Brain Charity has.

“They didn’t pity me but tried to understand what I was going through.”

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