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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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Magnetic sensor could detect early signs of TBI

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Signs of traumatic brain injury, dementia and schizophrenia could be detected at an earlier stage as a result of the development of a new sensor which measures weak magnetic signals in the brain.

Through the development of the new Optically Pumped Magnetometer (OPM) sensor, scientists are hopeful of enabling a greater understanding of connectivity in the brain, which could have significant benefits in the chances of early diagnosis.

The device, developed by teams of scientists at the University of Birmingham, is currently in trail stage and clinicians at the Queen Elizabeth Hospital Birmingham are involved in its use in pinpointing the site of TBIs.

Its potential to increase diagnostics for neurological injury, neurological disorders such as dementia, and psychiatric disorders such as schizophrenia, has been widely recognised, and the team are now seeking commercial and research partnerships to help advance its development further.

The new sensor has enabled advances in detecting brain signals and distinguishing them from background magnetic noise, when compared to commercially available sensors. By using polarised light, the device can detect changes in the orientation of spin atoms when exposed to a magnetic field.

The team was also able to reduce the sensor size by removing the laser from the sensor head, and made further adjustments to decrease the number of electronic components, in a move that will reduce interference between sensors.

Benchmarking tests have taken place at the University’s Centre for Human Brain Health, and has reported “good” performance in environmental conditions where other sensors do not work.

Specifically, the researchers showed that the new sensor is able to detect brain signals against background magnetic noise, raising the possibility of magnetoencephalography (MEG) testing outside a specialised unit or in a hospital ward.

The research – published in the ‘Detection of human auditory evoked brain signals with a resilient non linear optically pumped magnetometer’ report, Kowalczyk et al (2020) – was led by physicist Dr Anna Kowalczyk.

“Existing MEG sensors need to be at a constant, cool temperature and this requires a bulky helium-cooling system, which means they have to be arranged in a rigid helmet that will not fit every head size and shape,” she says.

“They also require a zero-magnetic field environment to pick up the brain signals. The testing demonstrated that our stand-alone sensor does not require these conditions.

“Its performance surpasses existing sensors, and it can discriminate between background magnetic fields and brain activity.”

The researchers expect these more robust sensors will extend the use of MEG for diagnosis and treatment, and they are working with other institutes at the University to determine which therapeutic areas will benefit most from this new approach.

Neuroscientist Professor Ole Jensen, who is co-director of the Centre for Human Brain Health (CHBH), highlighted the potential of the sensor.

“We know that early diagnosis improves outcomes and this technology could provide the sensitivity to detect the earliest changes in brain activity in conditions like schizophrenia, dementia and ADHD,” he says.

“It also has immediate clinical relevance, and we are already working with clinicians at the Queen Elizabeth Hospital to investigate its use in pinpointing the site of traumatic brain injuries.”

The team at the CHBH has also recently been awarded Partnership Resource Funding from the UK Quantum Technology Hub Sensors and Timing to further develop new OPM sensors.

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Management during a pandemic: what we’ve learned

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As the country faces the second wave of the coronavirus pandemic, the management team at Richardson Care reflect on their experiences so far. Richardson Care has six specialist residential care homes – three for adults with acquired brain injury and three for adults with learning disabilities. Caring for up to 78 people, many of whom are vulnerable brings added responsibilities and pressures, as well as additional skills.

Our experience in supporting people who are rebuilding their lives after brain injury or living with learning disabilities means that we are problem solvers. We support people to overcome challenges every day. Never has this been more important and we’re proud of the way that our management team and staff have responded.

We asked our Homes Managers for their personal views and experiences of the pandemic – from their initial reactions to plans for the future. We discover what we’ve learnt, and how we can change things for the better.

Resilience
‘The capacity to recover quickly from difficulties; toughness’ has been demonstrated by our team throughout the pandemic. Jane Payne, Operational & Clinical Officer at Richardson Care, takes us back to the beginning of the year: “On February 18th 2020 we informed staff that there was a new virus, and preventative measures were put into place; including hourly touch point cleaning, increase in hand washing and an increase in awareness. Ahead of government guidance on March 12th 2020, we took the very tough, necessary decision to close our doors to family and friends to protect service users. We made sure that all staff worked only in one home, so in the event of an infection, it would not be transferred from one home to another by our staff.”

“The management team have become incredibly solid; working as one in supporting each other, as and when each has needed, as we live and work through the rollercoaster that is Covid-19. I am proud to lead; and be part of such a strong group of individuals displaying a sole purpose of ensuring the care, welfare, safety and security of our service users and staff. Richardson Care has shown we are more than resilient, we have become stronger through experience. Care: it’s in our DNA.”

Jacky Johnson, Registered Manager at our Boughton Green Road home for adults with acquired brain injury talks about the realities of dealing with something that no one had ever experienced before. She says: “We were dealing with real disease: a real virus, in real time with real people…The guidance received from various governing and public bodies changed before the ink could dry…The initial fear demonstrated by some staff left others having to broaden their shoulders… taking on extra activities within their daily routines…The expectation on myself as a Manager weighed heavily, it felt like I should know all the answers to the questions they asked… I was clear of my expectations from my team and them of me… Resilience: it’s not about how many times you fall… it’s about how many times you stand up and face another day.”

Teamwork
It was important to create a positive spirit as we knew our response would impact our service users. Central staff were redeployed so each home had enough admin and maintenance support in their team. This means they have been able to form closer relationships with the service users, some have been helping out with maintenance jobs – developing their skills and feeling valued while completing meaningful activities.

The teams within each home became closer, bonding more as they faced challenges together. No job was too big.

Weekly management meetings moved online in February. The Managers have worked more closely together while being socially distanced. Helen Petrie, Manager at The Richardson Mews adds: “No-one has ever been in this position before. We’re all learning together and supporting each other. We’re there to boost morale when it’s needed, sharing experiences and insight to keep our service users and staff happy and safe.”

Resourceful
We’ve found more efficient ways of operating – reducing risk while continuing to help our service users develop their daily living skills. For example, instead of going out to the shops several times a day, there’s just one trip per day. This means planning ahead, so service users have been helping to plan the menus, write shopping lists and prepare for their daily needs. These all require cognitive skills.

We have all become much more tech-savvy, using the internet, apps, photos and video calls as well as phone calls and letters to keep in touch with service users’ family and friends. We’ve also been checking in with each other more too.

Wendy Coleman, Registered Manager at our Duston Road home adds: “For service users, routine is a major part of their life. When their usual activities are no longer possible – no home visits, day services, community activities – staff have shown how well they have supported service users, reassuring them throughout all this. They have also been dealing with more challenging behaviours due to service users’ complex needs and lack of understanding of what is happening. We have created different routines and activities, promoting health and exercise.”

At The Richardson Mews (inspired by Joe Wicks) the day now starts with ‘Morning Motivation’ – exercising to music every day to improve fitness, flexibility and well-being. We’re also making more use of our in-house gym equipment. One service user who has a brain injury thrived during lockdown: he was in a wheelchair in February and now he can walk 70 lengths of the parallel bars.

Although the service users have missed going out, we have had plenty of scope and opportunity to develop in-house activities. Our large gardens and outdoor spaces have been used for gardening, ‘coffee shops’, sports and games, trampolining and treasure hunts. Our indoor communal spaces have hosted quizzes, craft activities, music and karaoke sessions. We’ve celebrated birthdays with gifts, parties and barbecues. We’ve maintained structure when needed, providing mental stimulation, social interaction and fun, while supporting well-being and skills development.

Appreciating each other
“The new normal is valuing and appreciating the simple things in life and each other, focusing on the positives,” adds Wendy Coleman. As we have gone through the months, we’ve noticed positive changes in service users – improved bonding with staff due to them having much more 1-1 time. Individual service user’s communication skills have also improved.

“Staff have done all this whilst dealing with the impact on their own lives. I feel through all this we all have changed our priorities, we have learnt different coping skills, adapted to change, and have gained new skills.

“It is important to show how we value, support and appreciate each other, talk more, respect and most importantly listen to each other. Learning that showing praise and valuing people is so important in these difficult times.”

Never has the responsibility of managing specialist care services been so great. As we prepare for the next phase of the Coronavirus pandemic, we know that we have the experience, skills and resilience to face the challenges ahead.

Richardson Care provides specialist residential care and rehabilitation for adults with acquired brain injury and learning disabilities. An independent family business with a 30-year track record, it has six residential care homes in Northampton. Find out more at www.richardsoncares.co.uk

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The danger of Z-drugs for dementia patients

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Strong sleeping pills known as ‘Z-drugs’ are linked with an increased risk of falls, fractures and stroke among people with dementia – according to research from the University of East Anglia.

Sleep disturbance is common among people with dementia and the impact for patients and their families is significant.

To date there are no proven effective treatments available, however people with dementia are often prescribed Z-drugs (zopiclone, zaleplon, and zolpidem).

But a new study published today reveals that stronger doses of these drugs are linked with an increased risk of adverse effects.

These adverse effects were found to be similar or greater than those for higher dose benzodiazepines or ‘benzos’ – which are also used to treat sleep disturbance, and are known to have several adverse effects.

The team say that patients already taking higher doses of Z-drugs should not stop taking their medication suddenly, however they should seek a review with their GP.

Prof Chris Fox, from UEA’s Norwich Medical School, said: “As many as 90 per cent of people with dementia suffer sleep disturbances and it has a big impact on their mental and physical health, as well as that of their carers.

“Z-drugs are commonly prescribed to help people sleep – however these medicines were never licensed for dementia and they have been associated with adverse events such as falls and fracture risks in older people.

“We wanted to find out how they affect people with dementia, who are frequently prescribed them to help with sleep disturbance.”

The team analysed data from 27,090 patients in England diagnosed with dementia between January 2000 and March 2016. The average age of the patients was 83 and 62 per cent were women.

They looked at the adverse events for 3,532 patients who had been prescribed Z-drugs and compared them to people suffering sleep disturbance who had not been prescribed sedatives, and patients who had been prescribed benzodiazepines.

They also looked to see whether Z-drug dosage played a part in adverse outcomes.

Prof Fox said: “We studied a range of adverse outcomes including fractures, falls, deep vein thrombosis, stroke and death – over two years. And we were particularly interested to see whether higher doses led to worse outcomes.”

Higher dose Z-drugs and benzodiazepines were defined as prescriptions equivalent to ≥7.5mg zopiclone or >5mg diazepam daily.

“For patients prescribed Z-drugs, 17 per cent were given higher doses. And we found that these patients on higher doses were more at risk of falls and fractures, particularly hip fractures, and stroke – compared with patients who were not taking any medication for sleep disturbance,” said Prof Fox.

Those on lower doses however (≤3.75mg zopiclone or equivalent) were not found to have an increased risk of adverse outcomes.

And there were no differences in adverse events for Z-drugs compared to benzodiazepines, except lower mortality rates with Z-drugs.

Prof Fox said: “This research shows us that higher dose Z-drugs should be avoided, if possible, in people living with dementia, and non-pharmacological alternatives preferentially considered.

“Patients already taking higher dose Z-drugs should not stop taking their medication, but we recommend that they should make an appointment to see their GP for a review,” he added.

Prof Clive Ballard, of the University of Exeter Medical School, who collaborated on the study, said: “Our findings serve an important caution regarding the harms of sleeping tablets in people with dementia.

“This research is a very timely and unfortunately necessary reminder that sedative medications are not a helpful way to manage social isolation during Covid-19.

“Our study also highlights the importance of research to develop non-drug approaches to help people with dementia to sleep – whether they are at home or in residential care.”

Dr Ian Maidment, Reader in Clinical Pharmacy at Aston University and lead pharmacist on the study, said: “Z-drugs are widely used to treat insomnia in people living with dementia, but are only recommended as a short-term treatment for the maximum of four weeks. Our work shows the importance of clinicians including GPs and pharmacists reviewing patients on long-term Z-drugs.”

The study was led by UEA, in collaboration with researchers from The Quadram Institute, Aston University, University College London, and the University of Exeter.

‘Adverse effects of Z-drugs for sleep disturbance in people living with dementia: a population-based cohort study’ is published in the journal BMC Medicine on November 24, 2020.

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