̽��ֱ�� of Cambridge - NIHR Cambridge Biomedical Research Centre

Powerful new MRI scans enable life-changing surgery in first for adults with epilepsy

cjb250 — Fri, 21 Mar 2025 00:01:25 +0000

Scientists have developed a new technique that has enabled ultra-powerful MRI scanners to identify tiny differences in patients’ brains that cause treatment-resistant epilepsy. It has allowed doctors at Addenbrooke’s Hospital, Cambridge, to offer the patients surgery to cure their condition.

Prioritise vaccine boosters for vulnerable immunocompromised patients, say scientists

cjb250 — Wed, 12 Feb 2025 19:00:46 +0000

̽��ֱ��findings, published today in Science Advances, suggest that such individuals will need regular vaccine boosters to protect them and reduce the risk of infections that could be severe and also lead to new ‘variants of concern’ emerging.

Almost 16 million people worldwide are estimated to have died from Covid-19 during 2020 and 2021, though nearly 20 million deaths are thought to have been prevented as a result of the rapid rollout of vaccines against SARS-CoV-2, the virus that caused the pandemic.

During the pandemic, researchers discovered that immunocompromised individuals had difficulty clearing the virus, even when vaccinated. These are people whose immune systems are not functioning correctly, either as a direct result of disease or because they are on medication to dampen down their immune systems, for example to prevent organ transplant rejection. This meant that their infections lasted longer, giving the virus more opportunities to mutate.

Research from early in the pandemic showed that chronic infections can give rise to variants of concern that can then cause new waves of infection in the wider population.

When an individual is vaccinated, their immune systems produce antibodies that recognise and launch an attack on the virus. Such a process is known as seroconversion. Additional ‘booster’ vaccinations increase seroconversion and hence the likelihood of clearing infection.

However, although most immunocompromised individuals will have received three or more doses of the Covid-19 vaccine, they still account for more than a fifth of hospitalisations, admissions to intensive care units, and overall deaths associated with the disease.

To see why this is the case, scientists at the Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID) at the ̽��ֱ�� of Cambridge examined immunocompromised individuals who had been vaccinated against Covid-19. These patients, recruited from Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust, were living with vasculitis, a group of disorders that cause inflammation of blood vessels. Data from this group was compared against individuals who were not immunocompromised.

Treatments for vasculitis rely on immunosuppressant medicines. These include drugs such as rituximab, which depletes the number of B-cells in the body – but B-cells are the immune cells responsible for producing antibodies. As such, these individuals are a severely at-risk population.

When the researchers analysed bloods samples from the vasculitis patients, they found that even though vaccination induced seroconversion, this in itself was not always sufficient to neutralise the virus. Every immunocompromised individual required at least three doses of the vaccine to protect them across a range of variants up to and include Omicron (the variant that appeared towards the end of 2021 and caused a new wave of infections). In some cases, even four vaccinations were not sufficient to adequately protect them.

Kimia Kamelian, a Gates Cambridge Scholar at CITIID and St Edmund's College, Cambridge, said: “We know that immunocompromised individuals are particularly vulnerable to diseases such as Covid-19 because their immune systems struggle to clear infections. Vaccinations offer some protection, but our study shows that only repeated vaccinations – often four or more – offer the necessary protection.”

Professor Ravi Gupta, also from CITIID and a Fellow at Homerton College, Cambridge, added: “This of course has implications for the individual, who is more likely to have prolonged infection and a much greater risk of severe infection, but it also gives the virus multiple opportunities to mutate.

“We know from our previous work that at least some of the variants of concern probably emerged during chronic infections. That’s why these individuals must be given priority for updated vaccines against new variants.”

̽��ֱ��research was funded by Wellcome, Gates Cambridge, Addenbrooke’s Charitable Trust and Vasculitis UK, with additional support by the National Institute for Health and Care Research Cambridge Biomedical Research Centre.

Reference
Kamelian, K et al. Humoral responses to SARS-CoV-2 vaccine in vasculitis-related immune suppression. Sci Adv; 12 Feb 2025; DOI: 10.1126/sciadv.adq3342

Vaccinations alone may not be enough to protect people with compromised immune systems from infection, even if the vaccine has generated the production of antibodies, new research from the ̽��ֱ�� of Cambridge has shown.

We know that immunocompromised individuals are particularly vulnerable to diseases such as Covid-19 because their immune systems struggle to clear infections

Kimia Kamelian

NoSystem images

Vaccination of an senior male

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

Yes

Magnetic field applied to both sides of brain shows rapid improvement for depression

cjb250 — Mon, 28 Oct 2024 15:23:23 +0000

̽��ֱ��treatment – known as repetitive transcranial magnetic stimulation (TMS) – involves placing an electromagnetic coil against the scalp to relay a high-frequency magnetic field to the brain.

Around one in 20 adults is estimated to suffer from depression. Although treatments exist, such as anti-depressant medication and cognitive behavioural therapy (‘talking therapy’), they are ineffective for just under one in three patients.

One of the key characteristics of depression is under-activity of some regions (such as the dorsolateral prefrontal cortex) and over-activity of others (such as the orbitofrontal cortex (OFC)).

Repetitive transcranial magnetic stimulation applied to the left side of the dorsolateral prefrontal cortex (an area at the upper front area of the brain) is approved for treatment of depression in the UK by NICE and in the US by the FDA. It has previously been shown to lead to considerable improvements among patients after a course of 20 sessions, but because the sessions usually take place over 20-30 days, the treatment is not ideal for everyone, particularly in acute cases or where a person is suicidal.

In research published in Psychological Medicine, scientists from Cambridge, UK, and Guiyang, China, tested how effective an accelerated form of TMS is. In this approach, the treatment is given over 20 sessions, but with four sessions per day over a period of five consecutive days.

̽��ֱ��researchers also tested a ‘dual’ approach, whereby a magnetic field was additionally applied to the right-hand side of the OFC (which sits below the dorsolateral prefrontal cortex).

Seventy-five patients were recruited to the trial from the Second People’s Hospital of Guizhou Province in China. ̽��ֱ��severity of their depression was measured on a scale known as the Hamilton Rating Scale of Depression.

Participants were split randomly into three groups: a ‘dual’ group receiving TMS applied first to the right- and then to the left-hand sides of the brain; a ‘single’ group receiving sham TMS to the right-side followed by active TMS applied to the left-side; and a control group receiving a sham treatment to both sides. Each session lasted in total 22 minutes.

There was a significant improvement in scores assessed immediately after the final treatment in the dual treatment group compared to the other two groups. When the researchers looked for clinically-relevant responses – that is, where an individual’s score fell by at least 50% – they found that almost half (48%) of the patients in the dual treatment group saw such a reduction, compared to just under one in five (18%) in the single treatment group and fewer than one in 20 (4%) in the control group.

Four weeks later, around six in 10 participants in both the dual and single treatment groups (61% and 59% respectively) showed clinically relevant responses, compared to just over one in five (22%) in the control group.

Professor Valerie Voon from the Department of Psychiatry at the ̽��ֱ�� of Cambridge, who led the UK side of the study, said: “Our accelerated approach means we can do all of the sessions in just five days, rapidly reducing an individual’s symptoms of depression. This means it could be particularly useful in severe cases of depression, including when someone is experiencing suicidal thoughts. It may also help people be discharged from hospital more rapidly or even avoid admission in the first place.

“ ̽��ֱ��treatment works faster because, by targeting two areas of the brain implicated in depression, we’re effectively correcting imbalances in two import processes, getting brain regions ‘talking’ to each other correctly.”

̽��ֱ��treatment was most effective in those patients who at the start of the trial showed greater connectivity between the OFC and the thalamus (an area in the middle of the brain responsible for, among other things, regulation of consciousness, sleep, and alertness). ̽��ֱ��OFC is important for helping us make decisions, particularly in choosing rewards and avoiding punishment. Its over-activity in depression, particularly in relation to its role in anti-reward or punishment, might help explain why people with depression show a bias towards negative expectations and ruminations.

Dr Yanping Shu from the Guizhou Mental Health Centre, Guiyang, China, said: “This new treatment has demonstrated a more pronounced – and faster – improvement in response rates for patients with major depressive disorder. It represents a significant step forward in improving outcomes, enabling rapid discharge from hospitals for individuals with treatment-resistant depression, and we are hopeful it will lead to new possibilities in mental health care.”

Dr Hailun Cui from Fudan ̽��ֱ��, a PhD student in Professor Voon’s lab at the time of the study, added: “ ̽��ֱ��management of treatment-resistant depression remains one of the most challenging areas in mental health care. These patients often fail to respond to standard treatments, including medication and psychotherapy, leaving them in a prolonged state of severe distress, functional impairment, and increased risk of suicide.

“This new TMS approach offers a beacon of hope in this difficult landscape. Patients frequently reported experiencing ‘lighter and brighter’ feelings as early as the second day of treatment. ̽��ֱ��rapid improvements, coupled with a higher response rate that could benefit a broader depressed population, mark a significant breakthrough in the field.”

Just under a half (48%) of participants in the dual treatment group reported local pain where the dual treatment was applied, compared to just under one in 10 (9%) of participants in the single treatment group. However, despite this, there were no dropouts.

For some individuals, this treatment may be sufficient, but for others ‘maintenance therapy’ may be necessary, with an additional day session if their symptoms appear to be worsening over time. It may also be possible to re-administer standard therapy as patients can then become more able to engage in psychotherapy. Other options include using transcranial direct current stimulation, a non-invasive form of stimulation using weak electrical impulses that can be delivered at home.

̽��ֱ��researchers are now exploring exactly which part of the orbitofrontal cortex is most effective to target and for which types of depression.

̽��ֱ��research was supported by in the UK by the Medical Research Council and by the National Institute for Health and Care Research Cambridge Biomedical Research Centre.*

Reference
Cui, H, Ding, H & Hu, L et al. A novel dual-site OFC-dlPFC accelerated repetitive transcranial magnetic stimulation for depression: a pilot randomized controlled study. Psychological Medicine; 23 Oct 2024; DOI: 10.1017/S0033291724002289

*A full list of funders is available in the journal paper.

A type of therapy that involves applying a magnetic field to both sides of the brain has been shown to be effective at rapidly treating depression in patients for whom standard treatments have been ineffective.

Our accelerated approach means we can do all of the sessions in just five days, rapidly reducing an individual’s symptoms of depression

Valerie Voon

TheDigitalArtist

Digital image of a brain

Yes

Licence type:

Public Domain

Ultra-powered MRI scans show damage to brain’s ‘control centre’ is behind long-lasting Covid-19 symptoms

sc604 — Tue, 08 Oct 2024 01:28:45 +0000

Using ultra-high-resolution scanners that can see the living brain in fine detail, researchers from the Universities of Cambridge and Oxford were able to observe the damaging effects Covid-19 can have on the brain.

̽��ֱ��study team scanned the brains of 30 people who had been admitted to hospital with severe Covid-19 early in the pandemic, before vaccines were available. ̽��ֱ��researchers found that Covid-19 infection damages the region of the brainstem associated with breathlessness, fatigue and anxiety.

̽��ֱ��powerful MRI scanners used for the study, known as 7-Tesla or 7T scanners, can measure inflammation in the brain. Their results, published in the journal Brain, will help scientists and clinicians understand the long-term effects of Covid-19 on the brain and the rest of the body. Although the study was started before the long-term effects of Covid were recognised, it will help to better understand this condition.

̽��ֱ��brainstem, which connects the brain to the spinal cord, is the control centre for many basic life functions and reflexes. Clusters of nerve cells in the brainstem, known as nuclei, regulate and process essential bodily functions such as breathing, heart rate, pain and blood pressure.

“Things happening in and around the brainstem are vital for quality of life, but it had been impossible to scan the inflammation of the brainstem nuclei in living people, because of their tiny size and difficult position.” said first author Dr Catarina Rua, from the Department of Clinical Neurosciences. “Usually, scientists only get a good look at the brainstem during post-mortem examinations.”

“ ̽��ֱ��brainstem is the critical junction box between our conscious selves and what is happening in our bodies,” said Professor James Rowe, also from the Department of Clinical Neurosciences, who co-led the research. “ ̽��ֱ��ability to see and understand how the brainstem changes in response to Covid-19 will help explain and treat the long-term effects more effectively.”

In the early days of the Covid-19 pandemic, before effective vaccines were available, post-mortem studies of patients who had died from severe Covid-19 infections showed changes in their brainstems, including inflammation. Many of these changes were thought to result from a post-infection immune response, rather than direct virus invasion of the brain.

“People who were very sick early in the pandemic showed long-lasting brain changes, likely caused by an immune response to the virus. But measuring that immune response is difficult in living people,” said Rowe. “Normal hospital-type MRI scanners can’t see inside the brain with the kind of chemical and physical detail we need.”

“But with 7T scanners, we can now measure these details. ̽��ֱ��active immune cells interfere with the ultra-high magnetic field, so that we’re able to detect how they are behaving,” said Rua. “Cambridge was special because we were able to scan even the sickest and infectious patients, early in the pandemic.”

Many of the patients admitted to hospital early in the pandemic reported fatigue, breathlessness and chest pain as troubling long-lasting symptoms. ̽��ֱ��researchers hypothesised these symptoms were in part the result of damage to key brainstem nuclei, damage which persists long after Covid-19 infection has passed.

̽��ֱ��researchers saw that multiple regions of the brainstem, in particular the medulla oblongata, pons and midbrain, showed abnormalities consistent with a neuroinflammatory response. ̽��ֱ��abnormalities appeared several weeks after hospital admission, and in regions of the brain responsible for controlling breathing.

“ ̽��ֱ��fact that we see abnormalities in the parts of the brain associated with breathing strongly suggests that long-lasting symptoms are an effect of inflammation in the brainstem following Covid-19 infection,” said Rua. “These effects are over and above the effects of age and gender, and are more pronounced in those who had had severe Covid-19.”

In addition to the physical effects of Covid-19, the 7T scanners provided evidence of some of the psychiatric effects of the disease. ̽��ֱ��brainstem monitors breathlessness, as well as fatigue and anxiety. “Mental health is intimately connected to brain health, and patients with the most marked immune response also showed higher levels of depression and anxiety,” said Rowe. “Changes in the brainstem caused by Covid-19 infection could also lead to poor mental health outcomes, because of the tight connection between physical and mental health.”

̽��ֱ��researchers say the results could aid in the understanding of other conditions associated with inflammation of the brainstem, like MS and dementia. ̽��ֱ��7T scanners could also be used to monitor the effectiveness of different treatments for brain diseases.

“This was an incredible collaboration, right at the peak of the pandemic, when testing was very difficult, and I was amazed how well the 7T scanners worked,” said Rua. “I was really impressed with how, in the heat of the moment, the collaboration between lots of different researchers came together so effectively.”

̽��ֱ��research was supported in part by the NIHR Cambridge Biomedical Research Centre, the NIHR Oxford Biomedical Research Centre, and the ̽��ֱ�� of Oxford COVID Medical Sciences Division Rapid Response Fund.

Reference:
Catarina Rua et al. ‘7-Tesla quantitative susceptibility mapping in COVID-19: brainstem effects and outcome associations.’ Brain (2024). DOI: 10.1093/brain/awae215

Damage to the brainstem – the brain’s ‘control centre’ – is behind long-lasting physical and psychiatric effects of severe Covid-19 infection, a study suggests.

̽��ֱ�� of Cambridge

3D projections of QSM maps on the rendered brainstem

Yes

Artificial intelligence outperforms clinical tests at predicting progress of Alzheimer’s disease

cjb250 — Fri, 12 Jul 2024 22:30:52 +0000

̽��ֱ��team say this new approach could reduce the need for invasive and costly diagnostic tests while improving treatment outcomes early when interventions such as lifestyle changes or new medicines may have a chance to work best.

Dementia poses a significant global healthcare challenge, affecting over 55 million people worldwide at an estimated annual cost of $820 billion. ̽��ֱ��number of cases is expected to almost treble over the next 50 years.

̽��ֱ��main cause of dementia is Alzheimer’s disease, which accounts for 60-80% of cases. Early detection is crucial as this is when treatments are likely to be most effective, yet early dementia diagnosis and prognosis may not be accurate without the use of invasive or expensive tests such as positron emission tomography (PET) scans or lumbar puncture, which are not available in all memory clinics. As a result, up to a third of patients may be misdiagnosed and others diagnosed too late for treatment to be effective.

A team led by scientists from the Department of Psychology at the ̽��ֱ�� of Cambridge has developed a machine learning model able to predict whether and how fast an individual with mild memory and thinking problems will progress to developing Alzheimer’s disease. In research published today in eClinical Medicine, they show that it is more accurate than current clinical diagnostic tools.

To build their model, the researchers used routinely-collected, non-invasive, and low-cost patient data – cognitive tests and structural MRI scans showing grey matter atrophy – from over 400 individuals who were part of a research cohort in the USA.

They then tested the model using real-world patient data from a further 600 participants from the US cohort and – importantly – longitudinal data from 900 people from memory clinics in the UK and Singapore.

̽��ֱ��algorithm was able to distinguish between people with stable mild cognitive impairment and those who progressed to Alzheimer’s disease within a three-year period. It was able to correctly identify individuals who went on to develop Alzheimer’s in 82% of cases and correctly identify those who didn’t in 81% of cases from cognitive tests and an MRI scan alone.

̽��ֱ��algorithm was around three times more accurate at predicting the progression to Alzheimer’s than the current standard of care; that is, standard clinical markers (such as grey matter atrophy or cognitive scores) or clinical diagnosis. This shows that the model could significantly reduce misdiagnosis.

̽��ֱ��model also allowed the researchers to stratify people with Alzheimer’s disease using data from each person’s first visit at the memory clinic into three groups: those whose symptoms would remain stable (around 50% of participants), those who would progress to Alzheimer’s slowly (around 35%) and those who would progress more rapidly (the remaining 15%). These predictions were validated when looking at follow-up data over 6 years. This is important as it could help identify those people at an early enough stage that they may benefit from new treatments, while also identifying those people who need close monitoring as their condition is likely to deteriorate rapidly.

Importantly, those 50% of people who have symptoms such as memory loss but remain stable, would be better directed to a different clinical pathway as their symptoms may be due to other causes rather than dementia, such as anxiety or depression.

Senior author Professor Zoe Kourtzi from the Department of Psychology at the ̽��ֱ�� of Cambridge said: “We’ve created a tool which, despite using only data from cognitive tests and MRI scans, is much more sensitive than current approaches at predicting whether someone will progress from mild symptoms to Alzheimer’s – and if so, whether this progress will be fast or slow.

“This has the potential to significantly improve patient wellbeing, showing us which people need closest care, while removing the anxiety for those patients we predict will remain stable. At a time of intense pressure on healthcare resources, this will also help remove the need for unnecessary invasive and costly diagnostic tests.”

While the researchers tested the algorithm on data from a research cohort, it was validated using independent data that included almost 900 individuals who attended memory clinics in the UK and Singapore. In the UK, patients were recruited through the Quantiative MRI in NHS Memory Clinics Study (QMIN-MC) led by study co-author Dr Timothy Rittman at Cambridge ̽��ֱ�� Hospitals NHS Trust and Cambridgeshire and Peterborough NHS Foundation Trusts (CPFT).

̽��ֱ��researchers say this shows it should be applicable in a real-world patient, clinical setting.

Dr Ben Underwood, Honorary Consultant Psychiatrist at CPFT and assistant professor at the Department of Psychiatry, ̽��ֱ�� of Cambridge, said: “Memory problems are common as we get older. In clinic I see how uncertainty about whether these might be the first signs of dementia can cause a lot of worry for people and their families, as well as being frustrating for doctors who would much prefer to give definitive answers. ̽��ֱ��fact that we might be able to reduce this uncertainty with information we already have is exciting and is likely to become even more important as new treatments emerge.”

Professor Kourtzi said: “AI models are only as good as the data they are trained on. To make sure ours has the potential to be adopted in a healthcare setting, we trained and tested it on routinely-collected data not just from research cohorts, but from patients in actual memory clinics. This shows it will be generalisable to a real-world setting.”

̽��ֱ��team now hope to extend their model to other forms of dementia, such as vascular dementia and frontotemporal dementia, and using different types of data, such as markers from blood tests.

Professor Kourtzi added: “If we’re going to tackle the growing health challenge presented by dementia, we will need better tools for identifying and intervening at the earliest possible stage. Our vision is to scale up our AI tool to help clinicians assign the right person at the right time to the right diagnostic and treatment pathway. Our tool can help match the right patients to clinical trials, accelerating new drug discovery for disease modifying treatments.”

This work was in collaboration with a cross-disciplinary team including Professor Peter Tino at the ̽��ֱ�� of Birmingham and Professor Christopher Chen at the National ̽��ֱ�� of Singapore. It was funded by Wellcome, the Royal Society, Alzheimer’s Research UK, the Alzheimer’s Drug Discovery Foundation Diagnostics Accelerator, the Alan Turing Institute, and the National Institute for Health and Care Research Cambridge Biomedical Research Centre.

Reference
Lee, LY & Vaghari, D et al. Robust and interpretable AI-guided marker for early dementia prediction in real-world clinical settings. eClinMed; 12 July 2024; DOI: 10.1016/j.eclinm.2024.102725

Cambridge scientists have developed an artificially-intelligent tool capable of predicting in four cases out of five whether people with early signs of dementia will remain stable or develop Alzheimer’s disease.

We’ve created a tool which is much more sensitive than current approaches at predicting whether someone will progress from mild symptoms to Alzheimer’s

Zoe Kourtzi

Yuichiro Chino (Getty Images)

Brain on molecular structure, circuitry, and programming code background

Yes

Genetic study points to oxytocin as possible treatment for obesity and postnatal depression

cjb250 — Tue, 02 Jul 2024 15:00:18 +0000

Obesity and postnatal depression are significant global health problems. Postnatal depression affects more than one in 10 women within a year of giving birth and is linked to an increased risk of suicide, which accounts for as many as one in five maternal deaths in high income countries. Meanwhile, obesity has more than doubled in adults since 1990 and quadrupled in adolescents, according to the World Health Organization.

While investigating two boys from different families with severe obesity, anxiety, autism, and behavioural problems triggered by sounds or smells, a team led by scientists at the ̽��ֱ�� of Cambridge, UK, and Baylor College of Medicine, Houston, USA, discovered that the boys were missing a single gene, known as TRPC5, which sits on the X chromosome.

Further investigation revealed that both boys inherited the gene deletion from their mothers, who were missing the gene on one of their X chromosomes. ̽��ֱ��mothers also had obesity, but in addition had experienced postnatal depression.

To test if it was the TRPC5 gene that was causing the problems in the boys and their mothers, the researchers turned to animal models, genetically-engineering mice with a defective version of the gene (Trpc5 in mice).

Male mice with this defective gene displayed the same problems as the boys, including weight gain, anxiety, a dislike of social interactions, and aggressive behaviour. Female mice displayed the same behaviours, but when they became mothers, they also displayed depressive behaviour and impaired maternal care. Interestingly, male mice and female mice who were not mothers but carried the mutation did not show depression-like behaviour.

Dr Yong Xu, Associate Director for Basic Sciences at the USDA/ARS Children’s Nutrition Research Center at Baylor College of Medicine, said: “What we saw in those mice was quite remarkable. They displayed very similar behaviours to those seen in people missing the TRPC5 gene, which in mothers included signs of depression and a difficulty caring for their babies. This shows us that this gene is causing these behaviours.”

TRPC5 is one of a family of genes that are involved in detecting sensory signals, such as heat, taste and touch. This particular gene acts on a pathway in the hypothalamus region of the brain, where it is known to control appetite.

When the researchers looked in more detail at this brain region, they discovered that TRPC5 acts on oxytocin neurons – nerve cells that produce the hormone oxytocin, often nicknamed the ‘love hormone’ because of its release in response to displays of affection, emotion and bonding.

Deleting the gene from these oxytocin neurons led to otherwise healthy mice showing similar signs of anxiety, overeating and impaired sociability, and, in the case of mothers, postnatal depression. Restoring the gene in these neurons reduced body weight and symptoms of anxiety and postnatal depression.

In addition to acting on oxytocin neurons, the team showed that TRPC5 also acts on so-called POMC neurons, which have been known for some time to play an important role in regulating weight. Children in whom the POMC gene is not working properly often have an insatiable appetite and gain weight from an early age.

Professor Sadaf Farooqi from the Institute of Metabolic Science at the ̽��ֱ�� of Cambridge said: “There's a reason why people lacking TRPC5 develop all of these conditions. We’ve known for a long time that the hypothalamus plays a key role in regulating ‘instinctive behaviours’ – which enable humans and animals to survive – such as looking for food, social interaction, the flight or fight response, and caring for their infants. Our work shows that TRPC5 acts on oxytocin neurons in the hypothalamus to play a critical role in regulating our instincts.”

While deletions of the TRPC5 gene are rare, an analysis of DNA samples from around 500,000 individuals in UK Biobank revealed 369 people – around three-quarters of whom were women – that carried variants of the gene and had a higher-than-average body mass index.

̽��ֱ��researchers say their findings suggests that restoring oxytocin could help treat people with missing or defective TRPC5 genes, and potentially mothers experiencing postnatal depression.

Professor Farooqi said: “While some genetic conditions such as TRPC5 deficiency are very rare, they teach us important lessons about how the body works. In this instance, we have made a breakthrough in understanding postnatal depression, a serious health problem about which very little is known despite many decades of research. And importantly, it may point to oxytocin as a possible treatment for some mothers with this condition.”

There is already evidence in animals that the oxytocin system is involved in both depression and in maternal care and there have been small trials into the use of oxytocin as a treatment. ̽��ֱ��team say their work provides direct proof of oxytocin’s role, which will be crucial in supporting bigger, multi-centre trials.

Professor Farooqi added: “This research reminds us that many behaviours which we assume are entirely under our control have a strong basis in biology, whether that’s our eating behaviour, anxiety or postnatal depression. We need to be more understanding and sympathetic towards people who suffer with these conditions.”

This work was supported by Wellcome, the National Institute for Health and Care Research (NIHR), NIHR Cambridge Biomedical Research Centre, Botnar Fondation and Bernard Wolfe Health Neuroscience Endowment.

Reference
Li, Y, Cacciottolo, TM & Yin, N. Loss of Transient Receptor Potential Channel 5 Causes Obesity and Postpartum Depression. Cell; 2 July 2024; DOI: 10.1016/j.cell.2024.06.001

Scientists have identified a gene which, when missing or impaired, can cause obesity, behavioural problems and, in mothers, postnatal depression. ̽��ֱ��discovery, reported on 2 July in Cell, may have wider implications for the treatment of postnatal depression, with a study in mice suggesting that oxytocin may alleviate symptoms.

This research reminds us that many behaviours which we assume are entirely under our control have a strong basis in biology. We need to be more understanding and sympathetic towards people who suffer with these conditions

Sadaf Farooqi

Olli Turho (Getty Images)

Illustration of a tired African American mother crying

Yes

Baby born deaf can hear after breakthrough gene therapy

Anonymous — Thu, 09 May 2024 07:32:03 +0000

Opal Sandy from Oxfordshire is the first patient treated in a global gene therapy trial, which shows 'mind-blowing' results. She is the first British patient in the world and the youngest child to receive this type of treatment.

Opal was born completely deaf because of a rare genetic condition, auditory neuropathy, caused by the disruption of nerve impulses travelling from the inner ear to the brain.

Within four weeks of having the gene therapy infusion to her right ear, Opal responded to sound, even with the cochlear implant in her left ear switched off.

Clinicians noticed continuous improvement in Opal’s hearing in the weeks afterwards. At 24 weeks, they confirmed Opal had close to normal hearing levels for soft sounds, such as whispering, in her treated ear.

Now 18 months old, Opal can respond to her parents’ voices and can communicate words such as “Dada” and “bye-bye.”

Opal’s mother, Jo Sandy, said: “When Opal could first hear us clapping unaided it was mind-blowing - we were so happy when the clinical team confirmed at 24 weeks that her hearing was also picking up softer sounds and speech. ̽��ֱ��phrase ‘near normal’ hearing was used and everyone was so excited such amazing results had been achieved.”

Auditory neuropathy can be due to a variation in a single gene, known as the OTOF gene. ̽��ֱ��gene produces a protein called otoferlin, needed to allow the inner hair cells in the ear to communicate with the hearing nerve. Approximately 20,000 people across the UK, Germany, France, Spain, Italy and UK and are deaf due to a mutation in the OTOF gene.

̽��ֱ��CHORD trial, which started in May 2023, aims to show whether gene therapy can provide hearing for children born with auditory neuropathy.

Professor Manohar Bance from the Department of Clinical Neurosciences at the ̽��ֱ�� of Cambridge and an ear surgeon at Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust is chief investigator of the trial. He said:

“These results are spectacular and better than I expected. Gene therapy has been the future of otology and audiology for many years and I’m so excited that it is now finally here. This is hopefully the start of a new era for gene therapies for the inner ear and many types of hearing loss.”

Children with a variation in the OTOF gene often pass the newborn screening, as the hair cells are working, but they are not talking to the nerve. It means this hearing loss is not commonly detected until children are 2 or 3 years of age – when a delay in speech is likely to be noticed.

Professor Bance added: “We have a short time frame to intervene because of the rapid pace of brain development at this age. Delays in the diagnosis can also cause confusion for families as the many reasons for delayed speech and late intervention can impact a children’s development.”

“More than sixty years after the cochlear implant was first invented – the standard of care treatment for patients with OTOF related hearing loss – this trial shows gene therapy could provide a future alternative. It marks a new era in the treatment for deafness. It also supports the development of other gene therapies that may prove to make a difference in other genetic related hearing conditions, many of which are more common than auditory neuropathy.”

Mutations in the OTOF gene can be identified by standard NHS genetic testing. Opal was identified as being at risk as her older sister has the condition; this was confirmed by genetic test result when she was 3 weeks old.

Opal was given an infusion containing a harmless virus (AAV1). It delivers a working copy of the OTOF gene and is delivered via an injection in the cochlea during surgery under general anaesthesia. During surgery, while Opal was given the gene therapy in right ear, a cochlear implant was fitted in her left ear.

James Sandy, Opal’s father said: “It was our ultimate goal for Opal to hear all the speech sounds. It’s already making a difference to our day-to-day lives, like at bath-time or swimming, when Opal can’t wear her cochlear implant. We feel so proud to have contributed to such pivotal findings, which will hopefully help other children like Opal and their families in the future.”

Opal’s 24-week results, alongside other scientific data from the CHORD trial are being presented at the American Society of Gene and Cell Therapy (ASGC) in Baltimore, USA this week.

Dr Richard Brown, Consultant Paediatrician at CUH, who is an Investigator on the CHORD trial, said: “ ̽��ֱ��development of genomic medicine and alternative treatments is vital for patients worldwide, and increasingly offers hope to children with previously incurable disorders. It is likely that in the long run such treatments require less follow up so may prove to be an attractive option, including within the developing world. Follow up appointments have shown effective results so far with no adverse reactions and it is exciting to see the results to date.

“Within the new planned Cambridge Children’s Hospital, we look forward to having a genomic centre of excellence which will support patients from across the region to access the testing they need, and the best treatment, at the right time.”

̽��ֱ��CHORD trial has been funded by Regeneron. Patients are being enrolled in the study in the US, UK and Spain.

Patients in the first phase of the study receive a low dose to one ear. ̽��ֱ��second phase are expected to use a higher dose of gene therapy in one ear only, following proven safety of the starting dose. ̽��ֱ��third phase will look at gene therapy in both ears with the dose selected after ensuring the safety and effectiveness in parts 1 and 2. Follow up appointments will continue for five years for enrolled patients, which will show how patients adapt to understand speech in the longer term.

In Cambridge, the trial is supported by NIHR Cambridge Clinical Research Facility and NIHR Cambridge Biomedical Research Centre.

Adapted from a press release from CUH

A baby girl born deaf can hear unaided for the first time, after receiving gene therapy when she was 11 months old at Addenbrooke’s Hospital in Cambridge.

Gene therapy has been the future of otology and audiology for many years and I’m so excited that it is now finally here

Manohar Bance

Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust

Baby Opal and mother Jo

Yes

Study unpicks why childhood maltreatment continues to impact on mental and physical health into adulthood

cjb250 — Thu, 11 Apr 2024 14:31:51 +0000

Individuals who experienced maltreatment in childhood – such as emotional, physical and sexual abuse, or emotional and physical neglect – are more likely to develop mental illness throughout their entire life, but it is not yet well understood why this risk persists many decades after maltreatment first took place.

In a study published in Proceedings of the National Academy of Sciences, scientists from the ̽��ֱ�� of Cambridge and Leiden ̽��ֱ�� found that adult brains continue to be affected by childhood maltreatment in adulthood because these experiences make individuals more likely to experience obesity, inflammation and traumatic events, all of which are risk factors for poor health and wellbeing, which in turn also affect brain structure and therefore brain health.

̽��ֱ��researchers examined MRI brain scans from approximately 21,000 adult participants aged 40 to 70 years in UK Biobank, as well as information on body mass index (an indicator of metabolic health), CRP (a blood marker of inflammation) and experiences of childhood maltreatment and adult trauma.

Sofia Orellana, a PhD student at the Department of Psychiatry and Darwin College, ̽��ֱ�� of Cambridge, said: “We’ve known for some time that people who experience abuse or neglect as a child can continue to experience mental health problems long into adulthood and that their experiences can also cause long term problems for the brain, the immune system and the metabolic system, which ultimately controls the health of your heart or your propensity to diabetes for instance. What hasn’t been clear is how all these effects interact or reinforce each other.”

Using a type of statistical modelling that allowed them to determine how these interactions work, the researchers confirmed that experiencing childhood maltreatment made individuals more likely to have an increased body mass index (or obesity) and experience greater rates of trauma in adulthood. Individuals with a history of maltreatment tended to show signs of dysfunction in their immune systems, and the researchers showed that this dysfunction is the product of obesity and repeated exposure to traumatic events.

Next, the researchers expanded their models to include MRI measures of the adult’s brains and were able to show that widespread increases and decreases in brain thickness and volume associated with greater body mass index, inflammation and trauma were attributable to childhood maltreatment having made these factors more likely in the first place. These changes in brain structure likely mean that some form of physical damage is occurring to brain cells, affecting how they work and function.

Although there is more to do to understand how these effects operate at a cellular level in the brain, the researchers believe that their findings advance our understanding of how adverse events in childhood can contribute to life-long increased risk of brain and mind health disorders.

Professor Ed Bullmore from the Department of Psychiatry, Cambridge, said: “Now that we have a better understanding of why childhood maltreatment has long term effects, we can potentially look for biomarkers – biological red flags – that indicate whether an individual is at increased risk of continuing problems. This could help us target early on those who most need help, and hopefully aid them in breaking this chain of ill health.”

Professor Bullmore is a Fellow at Lucy Cavendish College and and an Honorary Fellow at Downing College.

̽��ֱ��research was supported by MQ: Transforming Mental Health, the Royal Society, Medical Research Council, National Institute for Health and Care Research (NIHR) Cambridge Biomedical Research Centre, the NIHR Applied Research Collaboration East of England, Girton College and Darwin College.

Reference
Orellana, SC et al. Childhood maltreatment influences adult brain structure through its effects on immune, metabolic and psychosocial factors. PNAS; 9 Apr 2024 ; DOI: 10.1073/pnas.230470412

Childhood maltreatment can continue to have an impact long into adulthood because of how it effects an individual’s risk of poor physical health and traumatic experiences many years later, a new study has found.

We’ve known for some time that people who experience abuse or neglect as a child can continue to experience mental health problems long into adulthood

Sofia Orellana

mali desha (Unsplash)

Black and white image of boy curled up on the floor

Yes

Licence type:

Public Domain