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Scientists identify neurons that control hibernation-like behaviour

The dream of suspended animation has long captivated the human imagination, reflected in countless works of mythology and fiction, from King Arthur and Sleeping Beauty to Han Solo.



By effectively pausing time itself for an individual, a state of stasis promises to enable the repair of lethal injuries, prolong life and allow for travel to distant stars.

While suspended animation may seem a fantasy, a strikingly diverse array of life has already achieved a version of it.

Through behaviours like hibernation, animals such as bears, frogs and hummingbirds can survive harsh winters, droughts, food shortages and other extreme conditions by essentially entering into biological stasis, where metabolism, heart rate and breathing slow to a crawl and body temperature drops.

Now, Harvard Medical School neuroscientists have discovered a population of neurons in the hypothalamus that controls hibernation-like behaviour, or torpor, in mice, revealing for the first time the neural circuits that regulate this state.

The team demonstrated that when these neurons are stimulated, mice enter torpor and can be kept in that state for days. When the activity of these neurons is blocked, natural torpor is disrupted.

Another study published simultaneously by the University of Tsukuba in Japan also identified a similar population of neurons in the hypothalamus.

By better understanding these processes in mice and other animal models, the authors envision the possibility of one day working toward inducing torpor in humans—an achievement that could have a vast array of applications, such as preventing brain injury during stroke, enabling new treatments for metabolic diseases or even helping NASA send humans to Mars.

“The imagination runs wild when we think about the potential of hibernation-like states in humans. Could we really extend lifespan? Is this the way to send people to Mars?” said study co-lead author Sinisa Hrvatin, instructor in neurobiology in the Blavatnik Institute at HMS.

“To answer these questions, we must first study the fundamental biology of torpor and hibernation in animals,” Hrvatin said. “We and others are doing this—it is not science fiction.”

To reduce energy expenditure in times of scarcity, many animals enter a state of torpor. Hibernation is an extended seasonal form of this. Unlike sleep, torpor is associated with systemic physiological changes, particularly significant drops in body temperature and suppression of metabolic activity.

While common in nature, the biological mechanisms that underlie torpor and hibernation are still poorly understood.

The role of the brain, in particular, has remained largely unknown, a question that drove the research efforts of Hrvatin and colleagues, including co-lead author Senmiao Sun, a graduate student in the Harvard Program in Neuroscience, and study senior author Michael Greenberg, the Nathan Marsh Pusey Professor and chair of the Department of Neurobiology in the Blavatnik Institute at HMS.

Neural TRAP

The researchers studied mice, which do not hibernate but experience bouts of torpor when food is scarce and temperatures are low.

When housed at 22 C (72 F), fasting mice exhibited a sharp drop in core body temperature and significant reduction in metabolic rate and movement. In comparison, well-fed mice retained normal body temperatures.

As mice began to enter torpor, the team focused on a gene called Fos—previously shown by the Greenberg lab to be expressed in active neurons. Labeling the protein product of the Fos gene allowed them to identify which neurons are activated during the transition to torpor throughout the entire brain.

This approach revealed widespread neuronal activity, including in brain regions that regulate hunger, feeding, body temperature and many other functions.

To see if brain activity was sufficient to trigger torpor, the team combined two techniques—FosTRAP and chemogenetics—to genetically tag neurons that are active during torpor. These neurons could then be re-stimulated later by adding a chemical compound.

The experiments confirmed that torpor could indeed be induced—even in well-fed mice—by re-stimulating neurons in this manner after the mice recovered from their initial bout of inactivity.

However, because the approach labelled neurons throughout the entire brain, the researchers worked to narrow in on the specific area that controls torpor. To do so, they designed a virus-based tool that they used to selectively activate neurons only at the site of injection.

Focusing on the hypothalamus, the region of the brain responsible for regulating body temperature, hunger, thirst, hormone secretion and other functions, the researchers carried out a series of painstaking experiments.

They systematically injected 54 animals with minute amounts of the virus covering 226 different regions of the hypothalamus, then activated neurons only in the injected regions and looked for signs of torpor.

Neurons in one specific region of the hypothalamus, known as the avMLPA, triggered torpor when activated. Stimulating neurons in other areas of the hypothalamus had no effect.

“When the initial experiment worked, we knew we had something,” Greenberg said. “We gained control over torpor in these mice using FosTRAP, which allowed us to then identify the subset of cells that are involved in the process. It’s an elegant demonstration of how Fos can be used to study neuronal activity and behavioural states in the brain.”

Worthwhile goal

The team further analysed the neurons that occupy the region, using single-cell RNA sequencing to look at almost 50,000 individual cells representing 36 different cell types, ultimately pinpointing a subset of torpor-driving neurons, marked by the neurotransmitter transporter gene Vglut2 and the peptide Adcyap1.

Stimulating only these neurons was sufficient to induce rapid drops in body temperature and motor activity, key features of torpor. To confirm that these neurons are critical for torpor, the researchers used a separate virus-based tool to silence the activity of avMLPA-Vglut2 neurons. This prevented fasting mice from entering natural torpor, and in particular disrupted the associated decrease in core body temperature. In contrast, silencing these neurons in well-fed mice had no effect.

“In warm-blooded animals, body temperature is tightly regulated,” Sun said. “A drop of a couple of degrees in humans, for example, leads to hypothermia and can be fatal. However, torpor circumvents this regulation and allows body temperatures to fall dramatically. Studying torpor in mice helps us understand how this fascinating feature of warm-blooded animals might be manipulated through neural processes.”

The researchers caution that their experiments do not conclusively prove that one specific neuron type controls torpor, a complex behaviour that likely involves many different cell types. By identifying the specific brain region and subset of neurons involved in the process, however, scientists now have a point of entry for efforts to better understand and control the state in mice and other animal models, the authors said.

They are now studying the long-term effects of torpor on mice, the roles of other populations of neurons and the underlying mechanisms and pathways that allow avMLPA neurons to regulate torpor.

“Our findings open the door to a new understanding of what torpor and hibernation are, and how they affect cells, the brain and the body,” Hrvatin said. “We can now rigorously study how animals enter and exit these states, identify the underlying biology, and think about applications in humans. This study represents one of the key steps of this journey.”

The implications of one day being able to induce torpor or hibernation in humans, if ever realized, are profound.

“It’s far too soon to say whether we could induce this type of state in a human, but it is a goal that could be worthwhile,” Greenberg said. “It could potentially lead to an understanding of suspended animation, metabolic control and possibly extended lifespan. Suspended animation in particular is a common theme in science fiction, and perhaps our ability to traverse the stars will someday depend on it.”

Additional authors include Oren Wilcox, Hanqi Yao, Aurora Lavin-Peter, Marcelo Cicconet, Elena Assad, Michaela Palmer, Sage Aronson, Alexander Banks and Eric Griffith.

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‘Tidal wave’ of rehab needs post-pandemic, case managers predict



The UK faces a tidal wave” of brain injury rehab need post COVID-19, with a huge increase in reliance on private and charitable sectors due to stretched NHS resources, new research shows.

The extent of the expected impact on resources over the coming months is laid bare in newly-released research, which reveals 89 per cent of case managers across the UK expect a deluge in demand for rehabilitation resources.

With NHS capacity already being under strain, 91 per cent of the 152 case managers nationally who took part in the research, conducted by Calvert Reconnections, also predicted a significant increase in demand for private and charity resources.

Referrals to residential-based rehabilitation programmes have dropped significantly – only 10 per cent were currently referring patients – but the majority, 71 per cent, expected to recommence doing so within the next three months.

BABICM British Association of Brain Injury & Complex Case Management. Representing & advancing the brain injury complex case management profession in the UK & Beyond. Membership, Training & Events, Research & Policy.

Virtual means of communication will also remain important as the country emerges from the pandemic, according to case managers, which have proved such a vital tool in maintaining communication with patients during lockdown.

Many traditional practices have been forced to change as a result of the pandemic, with the use of video, telephone and other virtual means of communication coming to the fore – 84 per cent of case managers believed this was an essential” means of ensuring client rehab and mental health needs were met.

Additionally, outdoor activities are also predicted to grow in prevalence as a result of ongoing social distancing and restrictions on indoor meetings, with 86 per cent of case managers anticipating an increase in such activities as part of brain injury rehabilitation programmes.

Of those surveyed, 92 per cent felt they currently had clients who could benefit from such an alternative approach which included outdoor activities as part of their rehab.

Calvert Reconnections carried out its research among case managers during August, at a time when restrictions began to be lifted in some parts of the country, before being re-imposed.

Speaking to NR Times, Sarah Green, centre manager at Calvert Reconnections, part of the Lake District Calvert Trust, said the research shows that traditional rehabilitation models are changing, with the support of case managers in achieving that. 

During the pandemic, it is a great time to highlight the importance of maintaining strong service delivery that is safe and effective in the lived outcomes for the individuals,” she said. 

The pandemic does not have to stop outstanding rehabilitation in its tracks. Through strategic planning, organisational oversight and up-to-date knowledge, the delivery of a needs-led pathway can still be maintained. 

We are in unprecedented times and services are having to improvise, adapt and overcome. But let’s not forget about the importance of rehabilitation. Life has stopped and changed for us all, but most of all for the vulnerable individuals in our society that still need continuity, support and progression.”

Outdoor rehabilitation, such as that being offered at the Calvert Reconnections centre in Keswick – which has won praise for its groundbreaking focus on a range of outdoor activities for patients with acquired brain injuries – is now being given renewed focus as a result of the pandemic, added Sarah.

The unique nature of outdoor education as an integral part of our pathway plays to our advantage during COVID-19,” she said.

The great outdoors still offers a safe place for rehabilitation to continue. We have on-site facilities such as the stables and equine therapy, which offer not only vocational support to individuals, but also the emotional connection that is of upmost importance for wellbeing.

We feel that our assets and connections to the great outdoors as the fundamental principle to our model means that lived outcomes will be able to be maintained at a time when life has literally been locked down.” 


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Traumatic brain injury vs psychological injury



By Alice Hall, serious injury solicitor at Irwin Mitchell.

Neurocognitive deficits caused by traumatic brain injury (TBI) can be one of the more challenging injuries to prove and as a Claimant solicitor; it is my client who bears the burden of proving every aspect of their injuries and resultant losses.

I have seen that it is often the case that mild TBIs are just one of many injuries, whilst other injuries may present as far more life-threatening, particularly during the emergency stage of treatment.

Sometimes, therefore, mild TBIs are either not fully diagnosed at the outset, or they are noted but are not treated as a priority in comparison with other more seriously recognised injuries at the time, which may be more obvious and more pressing.

Claimants are often then discharged from hospital with their physical injuries having been treated and follow up arranged for Occupational Therapy input and Physiotherapy, but with no neurological or neuropsychological investigation or follow-up.

This is then often further complicated by the subtle ways a mild TBI can manifest itself. For example, they may cause issues such as dizziness, fatigue, tinnitus, loss of smell or taste, difficulty concentrating, multi-tasking or changes in mood or personality.

Sometimes, these issues are picked up only by family members or friends; with the symptoms being so subtle that they go unnoticed by the injured party themselves, particularly when they are focused on recovery from their more obvious physical injuries.

I have had Claimants approach me following a serious injury and it is only at that point through my discussions with them that the possibility of a TBI is first explored, and that can be something which can be quite shocking and upsetting for an injured person to first consider.

In proving such an injury, expert evidence, particularly neurological and neuropsychological, will obviously be key.

The difficulty is often that, in the absence of objective evidence of a TBI shown for example by way of day-of-injury imaging, expert evidence must be unequivocal in determining the presence of any TBI or otherwise, which of course is not always possible for a variety of reasons.

However, in recent years, there have been reports regarding seemingly exciting new technologies that have been developed with the aim of gathering objective evidence regarding the presence of TBI.

For example, there has been research into the use of ‘Diffusion Tensor Magnetic Resonance Imaging (DR-MRI)’ – which evaluates water movement within the brain to locate brain cells that are not functioning properly – which has been shown to provide objective evidence of TBI.

There have been other developments for example, specific blood tests which may measure plasma-based metabolomic biomarkers, which have been shown to indicate elevations in metabolites in individuals who have suffered TBI when compared to non-injured control participants.

Matters can be further complicated in litigation if, once expert evidence is obtained, the waters become muddied with suggestions of there being overlying psychological components to what is suspected as being a TBI, or potentially experts being of the opinion that the symptoms complained of are entirely psychologically based.

Of course, when Claimants have been through trauma, it is not uncommon that they will present with some sort of psychological injury in addition to their other injuries.

The difference – whether the presenting symptoms are caused by TBI or some psychological component – is essential in many respects. First and foremost, the treatment that the Claimant will be recommended to address any neurocognitive deficits that they present with, must be recommended in line with its underlying cause.

Failing this, a Claimant risks undergoing potentially lengthy, costly and challenging rehabilitation which may turn out to be wholly inappropriate to their condition.

Secondly, the quantification of damages is also influenced heavily by the nature of the injury, both in terms of the PSLA (pain, suffering and loss of amenity) element of the claim, which refers to the sum of compensation that a Claimant is awarded to compensate them for having suffered the injury itself.

This element of any award is guided by a set of guidelines which include brackets of awards for every injury and, within that, a range of severity.

Whether such neurocognitive deficits are presenting as a result of TBI, or psychological injury, or a combination of both, will determine which section of those guidelines, and which bracket, a Claimant will be assessed under, hence influencing the ultimate award that they receive.

Further, thought must also be given in any personal injury claim regarding what other losses a Claimant has, or will, suffer as a result of their injuries e.g. loss of earnings, care, case management, rehabilitation, aids, equipment.

Again, the nature of the injury will permeate all other aspects of the quantification of the claim, particularly if, depending on the nature of the injury, the experts consider that the prognosis is significantly different in either scenario.

The danger in this situation would be that a Claimant would be at risk of either being significantly under or over compensated, which would of course be entirely inappropriate.

Whether such deficits are caused by TBI or psychological elements will potentially have a significant impact on a Claimant’s long-term prognosis, and therefore the compensation to ensure that they are adequately compensated to reflect whatever their future needs look like.

For example, it is widely accepted that there is an increased risk of various serious long-term medical conditions, including epilepsy and dementia, in people who have suffered TBI.

One recent study concluded that there was more than a two-fold increase in the risk of dementia in those with TBI, even in those who did not suffer any documented loss of consciousness at the point of injury.

Of course, the costs involved if either of these conditions materialise are potentially huge. This is often addressed in litigation by way of provisional damages. Provisional damages allow greater security for Claimants if there is a chance in the future that may develop some disease or serious deterioration in their condition.

This provides the Claimant with an option to return to the Court to seek a further sum of compensation if they do indeed deteriorate significantly after the original claim has been settled.

This is in contrast to the normal course whereby a personal injury claim is settled in “full and final” terms, meaning that there would be no scope to re-open a case and pursue additional compensation should the injured person’s injuries or condition significantly deteriorate beyond what had originally been envisaged.




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When your life gets saved, you know you’re on this earth to help



SameYou is only one year old, but the charity is making real changes to bran injury recovery. Jenny and Emilia Clarke share their ambitions for the charity, and the motivations behind them.

Last year, Game of Thrones actor Emilia Clarke wrote in a New Yorker essay that, while filming Game of Thrones, she had two subarachnoid haemorrhages, a life-threatening type of stroke caused by bleeding into the space surrounding the brain.

She was 24 when the first one struck almost 10 years ago. Around the time the essay was published, Emilia’s mum Jenny Clarke had a subarachnoid haemorrhage too.

Emilia’s essay was published in conjunction with the launch of SameYou in May 2019, a charity Emilia has set up with Jenny in response to seeing a lack of brain injury recovery, with the aim to help improve patients’ and carers’ experience, and remove stigma and misunderstanding surrounding brain injuries.

When Emilia told her own story last year, she said, “I told you mine, now you tell me yours”. The charity received thousands of replies. Now, Jenny has hired someone to work full time, dedicated to responding to people getting in touch about their experiences.

“When you’ve had a brain injury, it’s a very difficult thing to do to talk about it,” Jenny, chief executive of Same You, tells NR Times. “It’s about hearing stories and giving people the sense they’re not alone.

“One of the problems with brain injury is that you can feel very isolated, and it feels very difficult to believe you can be the same as you were before, when inside, you’re the same.”

Jenny, who was previously vice-president of marketing for a global management consultancy, helped care for her daughter when she recovered, so has had experience as both a patient and a carer. Both of their lived experiences, Jenny says, puts them at an advantage.

“Every clinician I’ve spoken to believes this is right approach,” Jenny says.

Jenny argues there also needs to be more funding put into recovery.

“When we talk about health, everyone understands the value of research and how that feeds into treatment. Recovery is the third element,” Jenny says.

“But provision for recovery is inadequate. It’s a postcode lottery whether you get the care because brain injury is so complex and there are limited options on the NHS.

“There’s strong evidence, and it’s our belief, that with increased, high intensity treatment you can make huge progress, which isn’t always the message doctors tell patients after they’ve had a brain injury.”

Same You is also looking at finding ways to fund innovations that help to improve the treatment of patients in brain recovery. While the charity is young, it is already making real-world changes.

“At the moment we’re showing we’re taking action and that we’re a credible, long-term, viable resource for people. We have a few programmes underway where we’re making a difference with action,” Jenny says.

“We’ve got an opportunity to do things a bit differently. We’re a nimble, agile organisation, we’re able to create a fundraiser in a few days.”

For example, when coronavirus hit, Jenny and Emilia put a call out to help fund a virtual rehab clinic for people with brain injury, in collaboration with Queen’s Square National Hospital in London. Halfway through the programme, 131 so far have benefitted from the programme.

The charity is also working with the Spaulding Rehab Hospital in Boston, US, funding a two-year programme of pilot treatments. Researchers there are looking at what happens in young adults and how resilience can play a part in their recovery.

Another project the charity has just launched is the Nightingale Challenge Global Solutions initiative, involving almost 30,000 nurses and midwives, which aims to aims to empower and equip them in brain injury care, starting on the 22 July until the 23 September.

The programme, Emilia said in a recent Nursing Now webinar about the programme, will challenge nurses to look at the whole area of rehab.

“You get a huge amount of attention when you’re in hospital, rightly so. But not enough is being done for patients and their families after a brain injury between leaving hospital and getting back to society,” Emilia said on the webinar.

After her first brain haemorrhage, Emilia says she couldn’t wait to leave hospital and go home.

“But in the car leaving hospital I panicked because I’d been in such a safe space in hospital,” she says.

“Leaving hospital feels very unsafe, it’s an alien environment.”

“When you’ve broken a limb, you have something to show the world what’s wrong with you. When you look perfectly normal you feel doubly anxious, you need to be doubly cautious about the situations you put yourself in. It suddenly felt like home was the most dangerous place in the world.

“I was incredibly lucky. I has a specialist nurse who I could call when I had another headache, or didn’t know when I could wash my hair, or felt dizzy or sick. She was on the other end of the phone and could talk me through it.”

Nurses also ‘translated’ the jargon doctors told her, a lot of which she says she didn’t understand.

“It’s only when we feel safe we have confidence to feel better,” she said.

The Nightingale initiative will encourage nurses to look closely at brain injury patients and identify any gaps, and come up with solutions together.

One example of a solution, Emilia says, could be finding places on a ward where nurses can take a patient and their family to explain what has happened and what they can expect to happen next.

“Our personal experience is that patients have had such a shock they don’t always take it in the first or second time. It takes repetition before what has happened to them sinks in,” she said.

“Ask patients how they’re feeling and listen to what they have to say, because when you’re on a ward as a patient and someone asks you if you’re okay you say you’re fine. You’re on display on a ward. Take the patient to a quieter place and ask them honestly how they’re feeling. This can have a huge impact.”

Jenny and Emilia are encouraging nurses to speak to patients who’ve been discharged and ask them about their experience of rehab, and what they think is missing, as well as medical professionals across disciplines.

“It’s important for nurses to amplify hope. A great number of people can improve a patients’ quality of life by the dedication they put into it, help empower patients to take control back and take over their recovery when they get out of hospital,” Jenny said.

While Jenny wrote in the New Yorker essay that she has made a full recovery, she says she’s dedicated to improving care and treatment for others in the position she was.

“I knew I wanted to try and give back in some way,” she said. “When your life gets saved twice, you know you’re on this earth to help.”

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