Publisher Health

Our cells are surrounded by a fragile membrane that’s only 5 nanometers thick, 1/20 of a soap bubble. Cells are easily damaged by physiological activities, including muscle contraction and tissue injury. To cope with such damage, cells are equipped with mechanisms that can repair membrane damage to a certain degree.
Mechanical damage to the cell membrane was previously believed to trigger two simple cellular outcomes: recovery or death. In this study, however, the researchers uncovered a third outcome — cellular senescence.
“When I started this project, I simply aimed to understand the repair mechanisms of damaged cell membrane,” recalls Professor Keiko Kono, head of the Membranology unit and senior author of this study, which involved multiple members from the unit, including Kojiro Suda, Yohsuke Moriyama, Nurhanani Razali and colleagues. “Unexpectedly, we ended up discovering that cell membrane damage, in a sense, switches cell fate.”
The key to determining cell fate is the extent of damage and subsequent calcium ion influx. The thin cell membrane damage can be easily repaired, allowing the cells to continue cell division without any trouble. The highest level of cell membrane damage induces cell death. However, a middle level of cell membrane damage turns the cells into senescent cells several days later, even though membrane resealing seems successful.
Cancer cells divide unlimitedly. In contrast, non-cancerous normal cells have a limited capacity for cell division — around 50 times before division is irreversibly stopped, and the cells enter a state known as cellular senescence. Senescent cells are still metabolically active, but unlike young and healthy cells, they produce various secretory proteins that upregulate immune responses in both nearby tissues and distant organs. This mechanism can induce both beneficial and detrimental changes in our body, including acceleration of wound healing, cancer promotion, and aging. During the last decade, numerous studies have reported that senescent cells exist in animal bodies, including humans, and that the removal of senescent cells can rejuvenate body functions in experimental animals. However, the cause of cell senescence in the human body remains a controversial topic. “The gene expression profile and bioinformatics suggested that cell membrane damage explains the origin of senescent cells in our bodies, specifically the ones near damaged tissues,” explains Professor Kono.
The best-established inducer of cellular senescence is repeated cell division. Many other stresses also induce cellular senescence in a laboratory setting, such as DNA damage, oncogene activation, and epigenetic changes. The long-standing dogma in the research field was that various stresses induce cellular senescence ultimately via the activation of DNA damage response. However, the authors uncovered that cell membrane damage induces cellular senescence via a different mechanism that involves calcium ions and the tumor suppressor gene p53. These findings may contribute to develop a strategy to achieve healthy longevity in the future.

Today, a team of scientists from Trinity College Dublin and investigators from FutureNeuro announced a major discovery that has profound importance for our understanding of brain fog and cognitive decline seen in some patients with Long COVID.
In the months after the emergence of the novel coronavirus SARS-CoV2 in late 2019 a patient-reported syndrome termed Long-COVID began to come to the fore as an enduring manifestation of acute infection.
Long COVID has up to 200 reported symptoms to date, but in general patients report lingering symptoms such as fatigue, shortness of breath, problems with memory and thinking and joint/muscle pain. While the vast majority of people suffering from COVID-19 make a full recovery, any of these symptoms that linger for more than 12 weeks post infection can be considered Long COVID.
Long COVID has now become a major public health issue since the outbreak of the pandemic in 2020. While international incidence rates vary, it is estimated to affect up to 10% of patients infected with the SARS-CoV2 virus. Of these patients suffering from Long-COVID, just under 50% of them report some form of lingering neurological effect such as cognitive decline, fatigue and brain fog.
Now, the findings reported by the Trinity team in the top international journal Nature Neuroscience showed that there was disruption to the integrity of the blood vessels in the brains of patients suffering from Long COVID and brain fog. This blood vessel “leakiness” was able to objectively distinguish those patients with brain fog and cognitive decline compared to patients suffering from Long-COVID but not with brain fog.
The team led by scientists at the Smurfit Institute of Genetics in Trinity’s School of Genetics and Microbiology and neurologists in the School of Medicine have also uncovered a novel form of MRI scan that shows how Long-COVID can affect the human brain’s delicate network of blood vessels.?
“For the first time, we have been able to show that leaky blood vessels in the human brain, in tandem with a hyperactive immune system may be the key drivers of brain fog associated with Long COVID. This is critically important, as understanding the underlying cause of these conditions will allow us to develop targeted therapies for patients in the future,” said Prof. Matthew Campbell, Professor in Genetics and Head of Genetics at Trinity, and Principal Investigator at FutureNeuro.

This project was initiated by a rapid response grant funded by Science Foundation Ireland (SFI) at the height of the pandemic in 2020 and involved recruiting patients suffering from the effects of Long-COVID as well as patients who were hospitalised in St James’ Hospital.
“Undertaking this complicated clinical research study at a time of national crisis and when our hospital system was under severe pressure is a testament to the skill and resource of our medical trainees and staff. The findings will now likely change the landscape of how we understand and treat post-viral neurological conditions. It also confirms that the neurological symptoms of Long Covid are measurable with real and demonstrable metabolic and vascular changes in the brain,” said Prof. Colin Doherty, Professor of Neurology and Head of the School of Medicine at Trinity, and Principal Investigator at FutureNeuro.
Moving beyond COVID-19
In recent years, it has become apparent that many neurological conditions such as Multiple sclerosis (MS) likely have a viral infection as the initiating event that triggers the pathology. However, proving that direct link has always been challenging.
Prof. Campbell added: “Here, the team at Trinity was able to prove that every patient that developed Long-COVID had been diagnosed with SARS-CoV2 infection, because Ireland required every documented case to be diagnosed using the more accurate PCR-based methods. The concept that many other viral infections that lead to post-viral syndromes might drive blood vessel leakage in the brain is potentially game changing and is under active investigation by the team.”
Dr Chris Greene, Postdoctoral research fellow and first author of the study, added: “Our findings have now set the stage for further studies examining the molecular events that lead to post-viral fatigue and brain fog. Without doubt, similar mechanisms are at play across many disparate types of viral infection and we are now tantalisingly close to understanding how and why they cause neurological dysfunction in patients.”

Researchers from Melbourne-based medical research institute, WEHI, have unravelled how mutations in a gene can lead to an incurable neurodevelopmental disorder that causes abnormal brain development in newborns and infants.
The study is the first to prove that a protein called Trabid helps control neuronal development, and that mutations to this protein can lead to microcephaly — a condition where a baby’s brain is smaller than expected.
It’s hoped the milestone findings will provide a deeper understanding into the protein’s impact on healthy development and lead to treatments that can slow or stop the development of microcephaly and potentially other neurological disorders.
At a glance World-first study shows how mutations in the Trabid protein can cause microcephaly, an incurable brain disorder. The research is the first to uncover Trabid’s critical role in the development of healthy neurons, which are essential for the proper functioning of our nervous system and overall quality of life. Abnormalities in neuronal development can prevent the brain from developing properly. These findings could see Trabid used as a therapeutic target to treat neurodevelopmental disorders in the future.

Microcephaly is a neurodevelopmental condition leading to an underdeveloped brain that adversely affects learning and behaviour.
About 1 in 2,000 babies in Australia are reported to have microcephaly. There currently is no known cure or standard treatment for the disorder.
Neurons are the fundamental building blocks of the nervous system, responsible for transmitting electrical and chemical signals that enable communication between different parts of the body and the brain.
The new WEHI-led study is the first to show that Trabid plays a critical role in the development of healthy neurons by ensuring they are guided correctly in the developing brain — ultimately enabling normal brain function and behaviour.
Co-lead author, Associate Professor Grant Dewson, said the findings may aid diagnosis and treatment of neurodevelopmental disorders in the future, with 2.5 million Australians believed to be living with one of these conditions.
“Our understanding into how neurodevelopmental conditions, like microcephaly, develop continues to grow,” Assoc Prof Dewson, a Laboratory Head at WEHI, said.

“While previous research has indicated there could be a link between defects in Trabid and microcephaly, our study is the first to provide evidence for the gene’s function in neuronal guidance -filling a vital knowledge gap.”
The study, with first authors Dr Daniel Frank, Dr Maria Bergamasco and Dr Michael Mlodzianoski, is published in the journal, eLife.
Critical development
In 2015, UK researchers published a study that first suggested a possible connection between the gene encoding Trabid (ZRANB1) and microcephaly, after identifying two patients with the brain disorder who had mutations in this gene.
Dr Hoanh Tran, who has over 10 years of experience investigating Trabid, was able to build on this research by characterising these patient mutations in the lab using pre-clinical models.
“Abnormalities in neuron migration and guidance can lead to neurodevelopmental disorders like microcephaly” Dr Tran said.
“Cells in the developing brain must migrate to the right location. If the address is missed, developmental defects can occur.
“Healthy neurons extend long processes called axons in a directional, ordered manner. In our study, we found the neurons from models with defective Trabid project axons that migrate with a wayward trajectory.
“These significant findings provide an understanding of Trabid/ZRANB1 as a new human microcephaly gene.”
Therapeutic interventions
Currently, microcephaly can sometimes be diagnosed with an ultrasound test during the second or third trimester.
The team hopes that, in future, defects in Trabid, or the proteins that Trabid controls, could help identify babies who are at-risk of developing microcephaly — allowing for potential early interventions.
The research involved collaborations between WEHI’s Ubiquitin Signalling Division, Epigenetics and Development Division, Centre for Dynamic Imaging and Professor Elizabeth Vincan and her team from The Peter Doherty Institute for Infection and Immunity.
The work was supported by the National Health and Medical Research Council, the Bodhi Education Fund, Phenomics Australia, the Australian Government and the Victorian State Government.

A large-scale clinical trial of treatment strategies for Crohn’s disease has shown that offering early advanced therapy to all patients straight after diagnosis can drastically improve outcomes, including by reducing the number of people requiring urgent abdominal surgery for treatment of their disease by ten-fold.
The PROFILE trial, led by researchers at the University of Cambridge, involved 386 patients with newly-diagnosed active Crohn’s disease. Recruiting from 40 hospitals across the UK, and supported by the National Institute for Health and Care Research (NIHR) Clinical Research Network, it sought to test whether a biomarker — a genetic signature — could predict which patients were at greatest risk of relapses of their condition, and to test two different approaches to treating the disease.
Crohn’s disease is a life-long condition characterised by inflammation of the digestive tract. It affects around one in 350 people in the UK. Even at its mildest, it can cause symptoms that have a major impact on quality of life including: stomach pain, diarrhoea, weight loss and fatigue. Typically patients experience ‘flares’ of inflammation, where their condition worsens for a time, producing more symptoms and progressive bowel damage. As many as one in 10 patients will require urgent abdominal surgery to treat their condition within their first year of diagnosis.
The findings of the PROFILE trial, sponsored by Cambridge University Hospitals (CUH) NHS Foundation Trust and the University of Cambridge, are published today in The Lancet Gastroenterology and Hepatology. While the biomarker did not prove useful in selecting treatments for individual patients, a ‘top-down’ treatment strategy involving use of the drug infliximab straight after diagnosis, showed dramatic results.
Infliximab works by blocking a protein found in the body’s immune system, TNF (tumour necrosis factor)-alpha, which plays an important role in inflammation. The drug is administered through regular intravenous infusions directly into the bloodstream or injections under the skin. However, due to historical concerns about cost and side-effects — including an increased risk of infection related to immunosuppression — it is currently only offered when patients experience regular flare-ups that do not respond to less potent treatments.
In the PROFILE trial, patients were assigned at random to one of two treatment groups. Each group was given a different treatment strategy and patients were followed up over the course of a year.
The first group was treated using an ‘accelerated step-up’ approach, which is the conventional treatment strategy used in the UK and across most countries around the world. In this group, patients only started on infliximab if their disease was progressing and not responding to other simpler treatments.

The second group, however, was treated using ‘top-down’ therapy — that is, they were provided with infliximab as soon as possible after their diagnosis, regardless of the severity of their symptoms.
The results were dramatic: 80% of people receiving the top-down therapy had both symptoms and inflammatory markers controlled throughout the course of the entire year compared to only 15% of people receiving the accelerated step-up therapy.
Two-thirds (67%) of patients in the ‘top-down’ group had no ulcers seen on their endoscopy camera test at the end of the trial — something known as endoscopic remission. Endoscopic remission is considered very important as this has been consistently associated with decreased risk of later complications in Crohn’s disease. Most previous clinical trials of therapies have been considered highly successful based on getting 20 to 30% of patients into endoscopic remission.
As well as these findings, patients in the top-down arm also had higher quality of life scores, less use of steroid medication and lower number of hospitalisations.
Strikingly, while around one in 20 patients (5%) in the conventional treatment arm of the trial required urgent abdominal surgery for their Crohn’s disease, only one in 193 (0.5%) receiving the ‘top-down’ therapy required such surgery.
Dr Nuru Noor from the Department of Medicine at the University of Cambridge, one of the study’s lead researchers and first author of the trial, said: “Historically, treatment with an advanced therapy like infliximab within two years of diagnosis has been considered ‘early’ and an ‘accelerated step-up’ approach therefore ‘good enough’. But our findings redefine what should be considered early treatment.

“As soon as a patient is diagnosed with Crohn’s disease, the clock is ticking — and has likely been ticking for some time — in terms of damage happening to the bowel, so there’s a need to start on an advanced therapy such as infliximab as soon as possible. We’ve shown that by treating earlier, we can achieve better outcomes for patients than have previously been reported.”
In fact, say the researchers, the improvements seen among the trial patients receiving ‘top-down’ therapy might be even more stark compared to usual clinical care. Few patients with Crohn’s disease in standard clinical care receive the rapid, ‘accelerated step-up’ approach provided by the trial protocol, and so the benefits of implementing a ‘top-down’ approach in standard clinical care might be even more pronounced.
Crucially, the team found no difference in risk of serious infection between treatment strategies, suggesting that infliximab straight after diagnosis was well tolerated, contrary to previous concerns about its safety. In addition, the cost of the drug, which is now an off-patent, generic and ‘biosimilar’ medicine, has fallen considerably from around £15,000 to around £3,000 per patient per year.
Chief Investigator of the PROFILE trial Professor Miles Parkes, Director of the NIHR Cambridge Biomedical Research Centre, said: “Up until now, the view has been ‘Why would you use a more expensive treatment strategy and potentially over-treat people if there’s a chance they might do fine anyway?’
“As we’ve shown, and as previous studies have demonstrated, there’s actually a pretty high risk that an individual with Crohn’s disease will experience disease flares and complications even in the first year after diagnosis.
“We now know we can prevent the majority of adverse outcomes, including need for urgent surgery, by providing a treatment strategy that is safe and becoming increasingly affordable. If you take a holistic view of safety, including the need for hospitalisations and urgent surgery, then the safest thing from a patient point of view is to offer ‘top-down’ therapy straight after diagnosis rather than having to wait and use ‘step-up’ treatment.”
The PROFILE team are now actively working on an analysis of the health economics to see whether the benefits of the therapy outweigh its cost.
Professor Parkes added: “It’s not just those five per cent of people requiring surgery that we need to think about. In the ‘step-up’ arm lots of people experienced disease flares without necessarily needing surgery. And every time somebody flares, they require several consultations with specialist doctors and nurses, clinical investigations such as scans and colonoscopies, time off work, time out of education and so on — all leading to major impacts on quality of life for individuals.”
While there are other anti-TNF drugs, such as adalimumab, that work in a similar manner to infliximab and are significantly cheaper, more research is required to understand if it would be as clinically effective.
Ruth Wakeman, Director of Services, Advocacy & Evidence at Crohn’s & Colitis UK said: “Crohn’s Disease affects over 200,000 people in the UK and we know that many of them have symptoms for a long time before they are diagnosed. But diagnosis is not the end of their journey, and the trial and error involved in finding the right treatment can be challenging and distressing.
“This study shows what a dramatic difference early treatment with advanced therapy can make to newly-diagnosed patients. People with Crohn’s don’t want to be stuck in hospital or having surgery, they want to be out in the world, living their lives. Anything that speeds up the path to remission can only be a good thing.”
The research was funded by Wellcome and PredictImmune Ltd and supported by the NIHR Cambridge Biomedical Research Centre.

Anxiety-related disorders can have a profound impact on the mental health and quality of life of affected individuals. Understanding the neural circuits and molecular mechanisms that trigger anxiety can aid in the development of effective targeted pharmacological treatments. Delta opioid receptors (DOP), which localize in the regions of the brain associated with emotional regulation, play a key role in the development of anxiety. Several studies have demonstrated the therapeutic effects of DOP agonists (synthetic compounds which selectively bind to DOPs and mimic the effect of the natural binding compound) in a wide range of behavioral disorders. One such selective DOP agonist — KNT-127 — has been shown to exert ‘anxiolytic’ or anxiety-reducing effects in animal models, with minimal side effects. However, its mechanism of action is not clearly understood, thereby limiting its widespread clinical application.
To bridge this gap, Professor Akiyoshi Saitoh, along with Ms. Ayako Kawaminami and team from the Tokyo University of Science, Japan, conducted a series of experiments and behavioral studies in mice. Explaining the rationale behind their work, Prof. Saitoh says, “There are currently no therapeutic drugs mediated by delta opioid receptors (DOPs). DOPs likely exert anti-depressant and anti-anxiety effects through a mechanism of action different from that of existing psychotropic drugs. DOP agonists may, therefore, be useful for treatment-resistant and intractable mental illnesses which do not respond to existing treatments.” Their study was published on 29 December 2023, in Neuropsychopharmacology Reports.
The neuronal network projecting from the ‘prelimbic cortex’ (PL) of the brain to the ‘basolateral nucleus of the amygdala’ (BLA) region, has been implicated in the development of depression and anxiety-like symptoms. The research team has previously shown that KNT-127 inhibits the release of glutamate (a key neurotransmitter) in the PL region. Based on this, they hypothesized that DOP activation by KNT-127 suppresses glutamatergic transmission and attenuates PL-BLA-mediated anxiety-like behavior. To test this hypothesis, they developed an ‘optogenetic’ mouse model wherein they implanted a light-responsive chip in the PL-BLA region of mice and activated the neural circuit using light stimulation. Further, they went on to assess the role of PL-BLA activation on innate and conditioned anxiety-like behavior.
They used the elevated-plus maze (EPM) test, which consists of two open arms and two closed arms on opposite sides of a central open field, to assess behavioral anxiety in the mice. Notably, mice with PL-BLA activation spent lesser time in the central region and open arms of the maze, compared to controls, which was consistent with innate anxiety-like behavior. Next, the researchers assessed conditioned fear response of the animals by exposing them to foot shocks and placing them in the same shock chamber the following day without re-exposing them to current. They recorded the freezing response of the animals which reflects fear. Notably, animals with PL-BLA activation and controls exhibited similar behavior, suggesting that distinct neural pathways control innate anxiety-like behavior and conditioned fear response.
Finally, they examined the effects or KNT-127 treatment on anxiety-like behavior of mice using the EPM test. Remarkably, animals treated with KNT-127 exhibited an increase in the percentage time spent in the open arms and central field of the maze, compared to controls. These findings suggest that KNT-27 reduces anxiety-like behavior induced by the specific activation of the PL-BLA pathway.
Overall, the study reveals the role of the PL-BLA neuronal axis in the regulation of innate anxiety, and its potential function in DOP-mediated anxiolytic effects. Further studies are needed to understand the precise underlying molecular and neuronal mechanisms, for the development of novel therapies targeting DOP in the PL-BLA pathway.
Highlighting the long-term clinical applications of their work, Prof. Saitoh remarks, “The brain neural circuits focused on in this study are conserved in humans, and research on human brain imaging has revealed that the PL-BLA region is overactive in patients with depression and anxiety disorders. We are optimistic that suppressing overactivity in this brain region using DOP-targeted therapies can exert significant anxiolytic effects in humans.”

A large-scale review published in The Lancet Regional Health Europe provides an update on the recent advances in understanding and managing risk factors for atrial fibrillation (AF).
AF is a heart condition that causes an irregular and often abnormally fast heart rate and is the most common heart rhythm disturbance, affecting around 1.4 million people in the UK.
From researchers at the University of Liverpool and Seoul National University College of Medicine, Korea, this meta-analysis of European and global data includes a discussion of lifestyle, somatic, psychological and socioeconomic risk factors.
Corresponding author the University of Liverpool’s Dr Eduard Shantsila said: “Modern anticoagulation therapy has dramatically reduced the risk of stroke and systemic thromboembolism in people with AF. However, AF still impairs quality of life, increases the risk of stroke and heart failure, and is linked to cognitive impairment. We wanted to help address the need for a more comprehensive understanding of risk factors predisposing to the development of this arrhythmia, its’ complications and interventions to mitigate these risks.”
The researchers found that: A sedentary lifestyle is a risk factor for the development of AF, and high-intensity interval training improves functional capacity and quality of life in AF. Obesity increases the risk of AF, whilst weight loss reduces AF recurrence and symptoms. There is a linear dose-response relationship between alcohol use and AF risk. Hypertension is associated with a 1.7-2.5-fold increased risk of AF, which can be reduced by antihypertensive therapy. Diabetes mellitus is associated with a 1.28-fold increased relative risk of incident AF. A history of myocardial infarction increases the risk of AF by 60-77%. Chronic obstructive pulmonary disease doubles AF risk. Men are usually reported to have a 30-70% higher prevalence of AF than women, but the lifelong risk of AF is similar. White people more often develop AF than people of South Asian and Black origin.Dr Shantsila, who conducted this research alongside University of Liverpool colleagues Professor Deirdre Lane and Professor Gregory Lip said: “The findings call for a practice shift towards a more individualised approach considering an increasingly broader range of health and patient factors contributing to AF-related health burden. The review highlights the needs of people living with co-morbidities (especially with multimorbidity), polypharmacy and the role of the changing population demographics affecting the European region and globally.”

A large language model (LLM) artificial intelligence (AI) system can match, or in some cases outperform, human ophthalmologists in the diagnosis and treatment of patients with glaucoma and retina disease, according to research from New York Eye and Ear Infirmary of Mount Sinai (NYEE).
The provocative study, published February 22, in JAMA Ophthalmology, suggests that advanced AI tools, which are trained on vast amounts of data, text, and images, could play an important role in providing decision-making support to ophthalmologists in the diagnosis and management of cases involving glaucoma and retina disorders, which afflict millions of patients.
The study matched the knowledge of ophthalmic specialists against the capabilities of the latest generation AI system, GPT-4 (Generative Pre-Training-Model 4) from OpenAI, designed to replicate human-level performance. Within medicine, sophisticated AI tools are seen as potentially revolutionizing diagnosis and treatment tools through the accuracy and comprehensiveness of their LLM-generated responses. Ophthalmology, with its high volume of often complex patients, could be a particularly fertile field for AI, giving specialists more time to practice evidence-based medicine.
“The performance of GPT-4 in our study was quite eye-opening,” says Andy Huang, MD, an ophthalmology resident at NYEE, and lead author of the study. “We recognized the enormous potential of this AI system from the moment we started testing it and were fascinated to observe that GPT-4 could not only assist but in some cases match or exceed, the expertise of seasoned ophthalmic specialists.”
For the human side of its study, the Mount Sinai team recruited 12 attending specialists and three senior trainees from the Department of Ophthalmology at the Icahn School of Medicine at Mount Sinai. A basic set of 20 questions (10 each for glaucoma and retina) from the American Academy of Ophthalmology’s list of commonly asked questions by patients was randomly selected, along with 20 deidentified patient cases culled from Mount Sinai-affiliated eye clinics. Responses from both the GPT-4/AI system and human specialists were then statistically analyzed and rated for accuracy and thoroughness using a Likert scale, which is commonly used in clinical research to score responses.
The results showed that AI matched or outperformed human specialists in both accuracy and completeness of its medical advice and assessments. More specifically, AI demonstrated superior performance in response to glaucoma questions and case-management advice, while reflecting a more balanced outcome in retina questions, where AI matched humans in accuracy but exceeded them in completeness.
“AI was particularly surprising in its proficiency in handling both glaucoma and retina patient cases, matching the accuracy and completeness of diagnoses and treatment suggestions made by human doctors in a clinical note format,” says Louis R. Pasquale, MD, FARVO, Deputy Chair for Ophthalmology Research for the Department of Ophthalmology, and senior author of the study. “Just as the AI application Grammarly can teach us how to be better writers, GPT-4 can give us valuable guidance on how to be better clinicians, especially in terms of how we document findings of patient exams.”
While emphasizing that additional testing is needed, Dr. Huang believes this work points to a promising future for AI in ophthalmology. “It could serve as a reliable assistant to eye specialists by providing diagnostic support and potentially easing their workload, especially in complex cases or areas of high patient volume,” he explains. “For patients, the integration of AI into mainstream ophthalmic practice could result in quicker access to expert advice, coupled with more informed decision-making to guide their treatment.”

A new study led by investigators from Mass General Brigham demonstrated the use of deep brain stimulation (DBS) to map a ‘human dysfunctome’ — a collection of dysfunctional brain circuits associated with different disorders. The team identified optimal networks to target in the frontal cortex that could be used for treating Parkinson’s disease, dystonia, obsessive compulsive disorder (OCD) and Tourette’s syndrome. Their results are published in Nature Neuroscience.
“We were able to use brain stimulation to precisely identify and target circuits for the optimal treatment of four different disorders,” said co-corresponding author Andreas Horn, MD, PhD, of the Center for Brain Circuit Therapeutics in the Department of Neurology at Brigham and Women’s Hospital and the Center for Neurotechnology and Neurorecovery at Massachusetts General Hospital. “In simplified terms, when brain circuits become dysfunctional, they may act as brakes for the specific brain functions that the circuit usually carries out. Applying DBS may release the brake and may in part restore functionality.”
Connections between the frontal cortex in the forebrain and basal ganglia, structures located deeper in the brain, are known to control cognitive and motor functions. If brain disorders occur, these circuits may become affected, and their communication may become overactive or malfunction. Previous studies have shown that electrically stimulating the subthalamic nucleus, a small region in the basal ganglia that receives inputs from the entire frontal cortex, can help alleviate symptoms of these disorders.
To understand this relationship better, the authors analyzed data from 534 DBS electrodes in 261 patients from across the globe. Of this cohort, 70 patients were diagnosed with dystonia, 127 with Parkinson’s disease, 50 with OCD and 14 with Tourette’s syndrome. Using software developed by Horn’s team, the researchers mapped the precise location of each electrode and registered results to a common reference atlas to compare locations across patients. The researchers used computer simulations to map tracts that were activated in patients with optimal or suboptimal outcomes.
Using these results, they were able to identify specific brain circuits that had become dysfunctional in each of the four disorders, such as those mapping to sensorimotor cortices in dystonia, the primary motor cortex in Tourette’s, the supplementary motor cortex in Parkinson’s disease and parts of the cingulate cortex in OCD. Notably, the identified circuits partially overlapped, implying that interconnected pathways are disrupted in these disorders.
Further, the investigators were able to apply these findings to fine tune DBS treatments and demonstrate preliminary improved results in three cases, including one at Massachusetts General Hospital, a founding member of Mass General Brigham. This patient, a female in her early 20s, was diagnosed with severe, treatment-resistant OCD involving obsessions about food and water intake, along with compulsive skin picking. Following electrode implantation and targeted stimulation, the researchers were able to show a significant improvement in her symptoms one month after treatment.
Except for the three patients that were tested prospectively, the study was a retrospective analysis of data aggregated from multiple centers. Further studies are needed to validate findings in prospective fashion.
“We can take this technique further and finely segregate dysfunctional circuits in order to have greater impact with treatment,” said lead author Barbara Hollunder, MSc, of the Movement Disorders and Neuromodulation Unit in the Department of Neurology, Charité — University Medicine Berlin. “For example, with OCD, we can look at isolating circuits for obsessions versus compulsions and so on.”

Children born in October are most likely to be vaccinated for the flu in October — and are least likely to be diagnosed with influenza, according to results of the first large-scale study of optimal timing for the flu shot.
The study, by researchers from the Department of Health Care Policy in the Blavatnik Institute at Harvard Medical School, amplifies public health guidance that encourages getting flu vaccinations in October for those in the northern hemisphere.
Findings are published Feb. 21 in the BMJ.
“There are a lot of variables when it comes to the timing and severity of flu season or a person’s risk of getting sick, and many of those are out of our control,” said Anupam Jena, the Joseph P. Newhouse Professor of Health Care Policy at HMS, physician at Massachusetts General Hospital, and senior author of the study. Christopher Worsham, HMS assistant professor of medicine and critical care physician at Mass General, led the study.
“One thing we have some control over is the timing of the shot,” Jena said, “and it looks like October is indeed the best month for kids to get vaccinated against the flu.”
In January the U.S. Centers for Disease Control and Prevention reported at least 150,000 hospitalizations and 9,400 deaths due to flu as of the time of the report and noted that high demand for hospital care for influenza has contributed to strained hospital capacity in some parts of the country. Over the past decade in the U.S., between one and 199 children have died of influenza each flu season. Across the years, most children who die are not fully vaccinated against the flu.
Part of the reason the timing of the shot is tricky is the way the immune system responds to a vaccine. If a person gets the shot too early, their immunity may fade by the time flu season peaks. If they wait too long, their body may not have time to build immunity strong enough to protect against the peak level of infections.

How soon is too soon, and how late is too late?
Public health recommendations in the U.S. have long promoted September and October flu shots, but Jena said there has never been a randomized clinical trial to test the best timing, nor a large-scale effort to see how likely people who get vaccinated in other months are to get sick.
When Jena was at a late summer meeting in 2022, he mentioned that his arm was sore from getting his flu shot. A colleague asked whether he was concerned about his immunity waning before flu season.
“It hadn’t occurred to me to check if one month or the other might make a big difference,” Jena said. “When we looked at the science, we were surprised that no one had ever looked at the question in a big population.”
Organizing a clinical trial would require a lot of time and resources to coordinate the random distribution of flu jabs across hundreds or thousands of people.
But Jena, Worsham, and study co-author Charles Bray, HMS research assistant in health care policy, had a good idea where they could find an already randomized study population.

The surprising link between birth dates and childhood flu vaccination
In prior research reported in the New England Journal of Medicine in 2020, Jena and Worsham documented the way birth month determines how likely it is that children get the flu shot at all.
Young children in the U.S. tend to get their yearly checkup around their birthday. That’s also when they get most of their vaccines. Children with spring and summer birthdays often don’t get the flu shot because it’s not available when they go for their annual visit, and many parents don’t make an extra trip for it.
The NEJM research was meant to highlight the importance of promoting the flu vaccine in the fall for children with birthday months that make it less likely that they will get the vaccine. Jena and Worsham realized they could also leverage this quirk of health care to study a ready-made distribution of children who get checkups — and flu shots — across all the months when the vaccine is commonly available.
Randomized by birthday
Studying children who got a flu shot in their birth month minimized certain factors related to the risk of infection that would have made it harder to measure the true impact of the timing of the shot.
For instance, families who proactively sought out shots in a non-birthday month might have done so because the child had a higher risk of catching the flu or because family members were more cautious and more likely to take actions that would protect them from the flu, such as handwashing and disinfecting.
For the BMJ study, Jena, Worsham, and Bray analyzed the anonymized commercial health insurance records of more than 800,000 children in the U.S. from 2 to 5 years old who received influenza vaccines from 2011 to 2018.
The analysis showed that children born in October had the lowest rate of influenza diagnosis. For example, 2.7 percent of children born and vaccinated in October were diagnosed with the flu that season, compared to 3 percent of those born and vaccinated in August or January, 2.9 percent of those born and vaccinated in September or December, and 2.8 percent of those born and vaccinated in November.
The findings suggest that U.S. public health interventions focused on vaccination of young children in October may yield the best protection in typical flu seasons, the authors said.
“This study can help people pinpoint the best time to get flu vaccines for their children — especially the ones who weren’t born in October,” Worsham said.
“We’ve had several rough winters in a row for respiratory viruses, between COVID-19, RSV, and the flu,” Worsham said. “We need all the help we can get to keep people safe from these diseases.”

Published36 minutes agoShareclose panelShare pageCopy linkAbout sharingImage source, PA MediaBy Yasmin Rufo & Ian YoungsBBC NewsITV is to follow its hit drama about the Post Office scandal with a new series about what it calls the “biggest health scandal” in British history.Writer Peter Moffat will tell the story behind the contaminated blood scandal.It is thought that about 30,000 people were infected with HIV and hepatitis C through contaminated blood products in the 1970s and 1980s.Bafta winner Moffat said victims had been “let down” by the state and his show would let “their voices be heard”.The announcement comes after Mr Bates Vs the Post Office drew in more than 10 million viewers and dominated the headlines last month.Following an outcry, the government has announced plans for new legislation to quash the convictions of hundreds of people who were wrongly convicted of false accounting, theft and fraud.Image source, ITVHow Post Office drama shone light on scandalToby Jones proud of effect of Post Office dramaMoffat was working on the contaminated blood scandal series before Mr Bates Vs the Post Office was broadcast, but it has now been “fast-tracked” following that show’s “monumental success”, Deadline reported.More than 3,000 people are thought to have died in what has been described by MPs as the worst treatment disaster in NHS history.The untitled series will focus on the “courage and dignity of victims and their families who have campaigned for truth, justice and accountability against impossible odds”, according to ITV.Moffat, who is behind dramas including Silk, Criminal Justice, North Square and Your Honour, said: “It’s been a great privilege to meet those infected and affected and to learn about what they have been through.”I’m ashamed to say that when I started researching this story I knew next to nothing about it. I’m even more ashamed that this ignorance is shared by nearly everyone I mention it to.”The victims of this scandal have been let down again and again by the state – I hope in some small way this drama can help their voices be heard.” ITV’s head of drama Polly Hill said: “Peter’s scripts are brilliant and do justice to this important story, while bringing it to screen with real clarity and compassion.”Infected blood inquiry: Five things we have learnedDes Collins, senior partner of Collins Solicitors, which represents 1,500 victims and their families, welcomed the news.The series will “expose much of what our clients have endured, not only emotionally and health-wise, but also in terms of shoddy treatment by government, in their decades-long battle for justice during which too many lives have unnecessarily been lost”, he said.A five-year public inquiry into the contaminated blood scandal ended last year. The final recommendations included a full compensation scheme for those directly affected and their relatives.The government has said it accepts the “moral case” for compensation, and interim payouts of £100,000 each have already been made to about 4,000 victims and some bereaved partners.However, in December it said it was still not in a position to make a final decision on compensation until it has seen the inquiry’s findings in full. The publication of the final report has been delayed until May.More on this storyToby Jones proud of effect of Post Office dramaPublished3 days agoHow Post Office drama shone light on scandalPublished10 JanuaryInfected blood inquiry report delayed until MayPublished17 JanuaryPM faces ‘wrong side of history’ on blood scandalPublished5 December 2023Ministers lose infected blood vote in Tory revoltPublished5 December 2023Infected blood inquiry: Five things we have learnedPublished3 February 2023