A large, long-term study led by Cedars-Sinai Health Sciences University investigators suggests that some medications commonly prescribed to treat irritable bowel syndrome (IBS) – including antidepressants – may be associated with a small but measurable increase in the risk of death.
The findings, published in Communications Medicine, are based on nearly two decades of electronic health records from more than 650 000 US adults with IBS, making it the largest real-world study to examine the long-term safety of IBS treatments.
IBS is a chronic gastrointestinal condition which has no cure, but dietary modifications, behavioural therapy and medications can help manage symptoms.
“Many patients are diagnosed with IBS at a young age and may remain on medications for years,” said Ali Rezaie, MD, medical director of the GI Motility Program at Cedars-Sinai and senior author of the study. “However, most clinical trials of these medications last less than a year, so we know very little about their long-term safety. This study begins to address that gap.”
Researchers assessed patients taking Food and Drug Administration-approved IBS medications, as well as antidepressants, antispasmodics and opioid-based antidiarrhoeal drugs, such as loperamide and diphenoxylate – widely used and recommended in IBS care. They found that long-term antidepressant use was associated with a 35% higher risk of death, and that loperamide and diphenoxylate use were associated with roughly double the risk of death.
The study does not establish that these medications directly cause death; rather, the observed associations may reflect higher rates of adverse outcomes, such as cardiovascular events, falls and stroke, which were more frequent among exposed patients.
Although antidepressants are not FDA-approved for IBS, they are commonly prescribed for IBS patients to help reduce pain, calm symptoms and make the condition easier to manage. The study found that other recommended treatments, including FDA-approved medications and antispasmodics, were not associated with increased mortality risk.
Researchers emphasised that while the increase in risk is significant and may sound concerning, the overall risk to any individual patient is small.
“IBS patients should not panic, but they do need to understand and weigh the small but meaningful risks when considering long-term treatments,” said Rezaie, the director of Bioinformatics at the Medically Associated Science and Technology (MAST) Program at Cedars-Sinai. “Patients should speak with their healthcare provider about the safest and most effective options for managing their symptoms.”
Rezaie said more research is needed to confirm these findings and identify which patients may be at greatest risk. He also called for future treatment guidelines to better address the long-term safety of medications commonly used to manage IBS.
In the meantime, he emphasized a more personalised approach to IBS patient care.
“Treatment for IBS patients should focus on identifying the underlying causes and using the safest, evidence-based options available rather than relying on a single class of medications for long-term management,” Rezaie said.
Across the world, countless women enter perimenopause only to be told that “everything is normal” because their blood tests do not match their symptoms.
This is one of the most damaging failures in modern women’s health. Perimenopause is not a laboratory diagnosis. It is a clinical diagnosis, made by listening to the woman and recognising the pattern of hormonal transition. Yet many clinicians continue to rely on FSH, LH and oestrogen levels – tests that were never designed to diagnose perimenopause and are physiologically incapable of doing so.
1. Hormone levels in perimenopause are wildly erratic
Oestrogen does not decline smoothly. It surges, crashes, and oscillates unpredictably. FSH and LH follow the same chaotic pattern. A single blood test captures only a moment in this turbulence. It cannot represent the hormonal instability that defines the transition.
This is why women with severe vasomotor symptoms often have “normal” results, while women with mild symptoms may show “abnormal” ones.
Erratic physiology produces erratic numbers. The numbers do not reflect the suffering.
2. Lab ranges do not correlate with symptoms
Laboratory ranges were created for research and population studies – not for diagnosing perimenopause. They do not account for:
daily hormonal swings
stress
sleep deprivation
illness
cycle timing
individual sensitivity to hormonal change
A woman may be drenched in night sweats, unable to sleep, emotionally unstable, and struggling to function – yet her blood tests may look “normal”. This leads to the most common and harmful phrase in women’s health: “Your results are normal, so this is not hormonal.”
3. The harm of relying on lab results
When clinicians wait for “abnormal” results before offering help, women suffer. They are:
dismissed
misdiagnosed
told they are anxious or depressed
denied treatment
left to struggle through years of avoidable distress
Or are treated inappropriately for life with antidepressants, mood stabilisers, axyiolytics and sedatives. These do little to address the underlying problem but create another set of problems: addiction and a range of side effects. This is not medicine. This is neglect disguised as protocol.
Suffering is prolonged because clinicians rely on lab results rather than the woman’s symptoms. Treating the lab instead of the woman is a betrayal of clinical responsibility.
4. The only test worth doing
There is one test that adds value: TSH and T4 – to exclude thyroid disease, which can mimic some perimenopausal symptoms. Beyond this, further hormone testing wastes time, money, and emotional energy.
5. The clinical truth
Perimenopause is diagnosed by listening to the woman, not by chasing fluctuating hormones. If she has:
• hot flushes
• night sweats
• irritability
• emotional instability
• sleep disturbance
• cycle changes
— she is in perimenopause, regardless of what the blood tests say.
The woman’s story is the evidence.
The numbers are often unreliable and misleading tools.
Scientists use cutting-edge imaging to explore how Rooibos may support healthy brain cells. From left: Catherine Smit, Dr Sholto de Wet and Prof Ben Loos.
In a world of endless notifications, relentless multitasking and constant information overload, the ability to focus is slipping through our fingers. Research suggests the human attention span has shrunk dramatically over the past two decades, with a widely cited Microsoft study putting it at just eight seconds today, down from 12 seconds in 2000. That’s shorter than the attention span of a goldfish.
Meanwhile, chronic stress and cognitive overload are now recognised as major contributors to burnout, anxiety and reduced productivity.
The role of simple rituals in restoring focus
Against this backdrop, scientists are beginning to explore not only what we consume, but also how we consume it, including the role of simple rituals like tea preparation, in restoring mental clarity.
Emerging research into Rooibos, a naturally caffeine-free herbal tisane indigenous to South Africa, suggests that both its bioactive compounds and the act of drinking it may support the brain under pressure.
How stress impacts the brain
From a neuroscience perspective, chronic distraction has measurable consequences.
According to Prof Ben Loos from Stellenbosch University’s Department of Physiological Sciences, stress isn’t good for the brain and can affect how well it functions. “It can contribute to a pro-inflammatory state and neuro-inflammation.” He explains that prolonged cognitive overload increases the production of reactive oxygen species (ROS), creating a damaging cellular environment that impairs brain function.
Over time, this affects critical regions, such as the prefrontal cortex, responsible for attention and decision-making, and disrupts neuroplasticity – the brain’s ability to adapt and learn. “Individuals may feel depleted due to an overload of the prefrontal cortex,” Prof Loos notes, adding that unmanaged stress can impair memory and learning capacity.
While much of the modern response to fatigue involves stimulants like caffeine, researchers are increasingly interested in alternatives that support the nervous system without overstimulation. Naturally caffeine-free Rooibos presents one such option.
Antioxidants and cellular protection
At a molecular level, Rooibos contains potent antioxidants, notably aspalathin and quercetin, which have been studied for their neuro-protective potential.
Prof Loos explains that Rooibos works in different parts of the body to help protect cells from the kind of damage that can build up as we age. “In simple terms, the compounds in Rooibos help keep brain cells healthy, support the body’s natural energy levels and keep cells working as they should, which is important for maintaining a sharp, active mind.
“A big part of this comes down to structures in our cells called mitochondria. These are like tiny energy generators that turn the food we eat into fuel, giving both the body and brain the energy they need to function properly, grow and stay healthy,” he says. For the brain cells, this means, making new connections with other brain cells and simply aging healthier.
Research has highlighted that mitochondrial dysfunction is closely linked to cognitive decline and neurodegenerative diseases. By supporting mitochondrial health, Rooibos compounds may help create a more stable internal environment for cognitive function.
This microscopic image shows active mitochondria (in red) inside brain cells. Rooibos appears to help these energy-producing structures stay strong and adaptable, supporting overall cell health. (Image: Catherine Smit)
Supporting brain chemicals linked to learning and memory
Dr Taskeen Docrat from the Applied Microbial Health and Biotechnology Institute (AMHBI) at CPUT explains that the natural compounds in Rooibos not only help protect our cells, but might also support the brain chemicals that are important for memory and learning. These antioxidants help the body manage and reduce harmful stress that can damage cells.
Dr Taskeen Docrat, researcher from the Applied Microbial Health and Biotechnology Institute (AMHBI) at Cape Peninsula University of Technology (CPUT) explores how Rooibos antioxidants may support cognitive health.
She mentions that Aspalathin, one of the compounds in Rooibos, helps protect the brain by lowering this kind of stress. Quercetin, another compound, may boost the levels of a protein called BDNF, which plays an important role in helping the brain learn, adapt and store new information.
The science of ritual and the nervous system
But beyond biochemistry, there is growing recognition of the psychological benefits of ritual. Structured, repetitive behaviours, such as preparing and drinking tea, can activate the parasympathetic nervous system, which promotes relaxation and recovery.
Dr Docrat explains that ritualised behaviours activate the part of our nervous system that calms us down. This can lower stress hormones in our body, specifically, cortisol. When cortisol levels drop, we tend to feel less stressed, which can lead to better emotional regulation and clearer thinking.”
This aligns with broader psychological research showing that small, intentional rituals can reduce anxiety and improve focus by creating a sense of control and predictability in otherwise chaotic environments.
Importantly, Rooibos offers these benefits without the potential downsides of caffeine. While moderate caffeine intake can enhance alertness, excessive consumption – particularly in high-stress contexts – may increase heart rate, anxiety and sleep disruption.
“Opting for a caffeine-free drink like Rooibos could provide safer support for the nervous system without the crash,” Dr Docrat notes.
A holistic approach to focus and mental clarity
Although direct evidence linking Rooibos consumption to improved focus is still emerging, the underlying mechanisms are compelling. Prof Loos cautions that it’s not easy to correlate what they see on the molecular level to high-level functions, such as mental focus, but adds that improved cellular health in the brain likely supports better neuronal function overall.
In a world where distraction is the norm, the solution may not lie in pushing the brain harder, but in creating conditions that allow it to function optimally. Incorporating simple, non-caffeinated rituals like drinking Rooibos may offer a dual benefit – biochemical support for brain health and a psychological pause that resets attention.
As Prof Loos concludes, we need moments of calm, silence and focus to manage stress, sharpen the mind and support resilience and creative thinking.
New research reveals how oestrogen levels in the brain influence vulnerability to stress-related memory problems, helping explain sex differences in PTSD risk.
For some people, a single traumatic event like a shooting, a natural disaster or a violent assault, can leave an imprint that lingers long after the immediate danger has passed. Memories of that event may return with unusual intensity, shaping mood, behaviour, and mental health in ways that are difficult to predict. Others exposed to similar trauma recover without developing lasting memory problems or trauma-related symptoms.
Why those outcomes diverge is a central question in stress and trauma research. Clinicians have long observed that severe acute stress can permanently alter memory for some people but not others, and that women face roughly twice the lifetime risk of posttraumatic stress disorder (PTSD). Recent research from the University of Pennsylvania in collaboration with the University of California-Irvine suggests that part of the answer may lie in the brain’s biological state at the precise moment trauma occurs.
Elizabeth Heller, PhD, an associate professor of Pharmacology in the Perelman School of Medicine at the University of Pennsylvania, and her team in the Heller Lab, have now shed light on how the brain’s biological state at the time of stress, particularly its oestrogen levels, can shape vulnerability long after the acute stress has lifted. Heller helped uncover that oestrogen levels in the brain may play a surprising role in this vulnerability, and for both sexes. The study, published in Neuron, also provides new insight into why women are more likely than men to develop post-traumatic stress disorder (PTSD) and to face higher dementia risk later in life.
Unpacking oestrogen’s role in memory vulnerability
Oestrogen is widely known to support learning and memory. This study found that high levels of oestrogen in the hippocampus, a brain region critical for memory, help the brain’s cells change and adjust more easily. However, in the context of severe acute stress, this flexibility can increase vulnerability to stress-related memory problems.
Heller and the Penn team mapped how high levels of oestrogen interact with chromatin structure (the storage packaging up DNA inside cells) in the hippocampus to make some brains more susceptible to PTSD‑like memory changes.
The findings help explain why traumatic events such as natural disasters, mass violence, and assaults can cause long-term memory problems, and why women are roughly twice as likely as men to develop PTSD.
“A lot of what determines vulnerability is the state your brain is already in,” Heller explained. “If a traumatic event hits during a period when oestrogen is already unusually high, the resulting plasticity can amplify the impact in lasting ways, promoting vulnerability to stress. Even with these findings in hand, the word oestrogen can mislead readers into assuming the biology applies only to women. That assumption shaped public understanding for decades, but it doesn’t hold up against what this research, and years of foundational neuroscience, actually shows.
As Heller notes, oestrogen is a critical brain hormone in both sexes. It is produced locally in regions like the hippocampus where it helps regulate learning, mood, and responses to stress. Recognising that universality is essential to understanding what this study truly reveals.
“The striking thing is that oestrogen levels are actually high in both males and in females in some parts of the hormonal cycle. Thus, the effects of high oestrogen levels happen in both males and females,” Heller said. “We tend to treat oestrogen as a women’s health hormone, but the brain makes its own oestrogen, and it plays powerful roles in stress, memory, mood, and emotion across sexes.”
Memory cells in the nose slow the influenza virus as soon as it enters the body. They reduce viral levels and may help protect against more severe illness. A new study from the University of Gothenburg may help guide the development of better influenza vaccines.
Today’s influenza vaccines are given as injections in the arm and mainly stimulate immune responses in the blood. At the same time, researchers are working to develop influenza vaccines that can be administered through the nose – an effort this study helps inform. The goal is to strengthen the body’s defences where the virus first encounters the immune system.
Memory cells remain in the nose
The researchers identified a group of memory cells, known as CD4 memory T cells, that remain in nasal tissue after an influenza infection. When the body encounters the virus again, these cells can rapidly reactivate and help other parts of the immune system fight the infection. The study shows that these cells can reduce viral replication in the nose and thereby contribute to better protection against illness.
“We show that CD4 memory T cells can remain in nasal tissue after an influenza infection and rapidly reactivate when the virus returns. This means the immune system can respond directly at the site where the virus first enters the body,” says Nimitha R. Mathew, a researcher at the Sahlgrenska Academy, University of Gothenburg, and one of the study’s lead authors.
In studies in mice, the researchers showed that these immune cells help limit viral levels and reduce tissue damage in the nose during a subsequent infection.
Similar cells found in humans
The researchers also analysed cells from the nasal mucosa of healthy adults. There, they found the same type of influenza-specific memory cells, suggesting that a similar local immune defence may also exist in humans. The study is published in the Journal of Experimental Medicine.
“Many people likely already have these kinds of memory cells in their noses after previous infections, but they are not always enough to stop the virus completely. The important thing about our findings is that we now know which immune cells can limit the virus where infection begins. That knowledge can be used when developing future nasal vaccines,” says Davide Angeletti, professor at the Sahlgrenska Academy, University of Gothenburg, and also one of the study’s lead authors.
Article: Nasal CD4⁺ tissue resident memory T cells provide cross protective immunity to influenza; 10.1084/jem.20251793
Two new vaccines to prevent tuberculosis (TB) are safe for use in adults and children, but they do not offer protection against all forms of TB, finds a large trial from India published by The BMJ.
TB remains a major global public health concern. In 2023, an estimated 10.8 million people worldwide were reported to have TB and the rate of new cases increased by 4.6% between 2020 and 2020, highlighting the growing scale of the problem. BCG is currently the only licensed vaccine against TB. Yet although it is effective against severe forms of TB in young children, it does not offer protection for adolescents and adults.
To address this gap, researchers in India conducted a large trial to evaluate whether two new TB vaccines (VPM1002 and Immuvac) can protect against all forms of tuberculosis (pulmonary and extrapulmonary), prevent latent (dormant) infection, and generate an immune response against the TB bacterium.
The study enrolled 12 717 household contacts (aged 6 years and older) of recently diagnosed TB patients across 18 sites in six Indian states between July 2019 and December 2020.
Participants were randomly allocated to receive a first dose of either VPM1002, Immuvac, or a placebo (4 239 in each group) and were followed up for 38 months. A second dose was administered to 11,829 participants one month later. A total of 12 295 participants (96.7% of those enrolled) completed 38 months of follow-up.
While neither vaccine offered general protection against TB or prevented latent TB infection, both demonstrated an ability to prevent the progression to active TB in those who developed latent TB.
The researchers found that although both vaccines did not show effectiveness against all TB and pulmonary TB (PTB), one of the vaccines, VPM1002 showed effectiveness (50.4%) against extrapulmonary TB (EPTB) across all age groups, including those aged 36-60 years (79.5%). These findings suggest a potentially significant public health benefit, because extrapulmonary TB, which affects organs beyond the lungs, is often associated with a higher risk of mortality than pulmonary TB.
A promising key finding was the protection seen against TB in children, whereby VPM1002 provided protection against all TB, PTB and EPTB in the 6 to under 14 year age group, while Immuvac provided protection against EPTB only in the 6 to under 10 year age group.
However, neither vaccine protected children and adults who were underweight. This suggests that nutritional support may be needed along with vaccination, especially for younger children, report the authors.
Both vaccines were found to be safe and induced an immune response.
The researchers acknowledge that the covid-19 pandemic affected the study, leading to the exclusion of some participants who missed the second dose and sometimes delayed follow-ups. Furthermore, the findings may not apply in other countries or ethnicities.
Nevertheless, this was a large, well-designed study that reflects a real world scenario because it included both children and adults, regardless of pre-existing conditions like diabetes and risk factors, as reported by authors. Further research on commonly targeted high-risk groups for TB could be undertaken, they conclude.
Asthma can lead to childhood hospitalisations, missed school days, missed workdays for caregivers, and a lower quality of life for both children and their caregivers. The global prevalence of asthma has increased over the past fifty years. A study published April 9th in the open-access journal PLOS Medicine by Annelise Blomberg at Lund University, Lund, Sweden and colleagues suggests that high prenatal PFAS exposure is associated with a higher incidence of asthma in childhood.
PFAS (Perfluoroalkyl substances) are widespread synthetic chemicals that impact the immune system and may play a role in the development of asthma. Previous epidemiological studies of PFAS and asthma only investigated low exposure levels and had inconclusive results. Due to decades-long contamination of a municipal waterworks in Ronneby, Sweden, researchers were able to study the impacts of high PFAS exposure. They accessed a register-based open cohort of all children born in Blekinge County between 2006 and 2013, including Ronneby. The researchers then linked maternal addresses during the exposure period to water distribution records to estimate prenatal exposure, and used asthma diagnosis data from the National Patient Register to assess individual asthma outcomes and prenatal exposure levels.
The researchers found that very high prenatal PFAS exposure was associated with a higher incidence of asthma in childhood. Future studies are needed to better understand exposure-response relationships and to address potential confounding variables, such as exposure beyond the prenatal period into early-childhood, exposure to other environmental contaminants or smoking among household members.
According to the authors, “PFAS contamination is a major source of high environmental exposure globally, and evidence from Ronneby offers important insights into the potential health effects of such contamination in affected communities. These results point to a substantial and previously unrecognized public health consequence of PFAS contamination.”
Blomberg adds, “We found that children whose mothers were exposed to very high levels of PFAS during pregnancy had a substantially higher incidence of clinically diagnosed asthma. The association was not observed at lower exposure levels, which may help explain why previous studies in general populations have reported mixed results.”
“Most previous research has examined populations exposed only to background levels of PFAS. In Ronneby, drinking water contamination resulted in exposure levels hundreds of times higher than the general population. This allowed us to evaluate potential health effects across a much broader exposure range.”
“Communities around the world have been affected by PFAS contamination from aqueous film-forming foams and other industrial sources. Our findings suggest that very high prenatal exposure may have lasting consequences for children’s respiratory health. At the same time, replication in other highly exposed populations will be important to confirm these results.”
Recently published research from the University of Oklahoma and the University of Tulsa proposes a new model to explain why nightmares can persist over time in children and how therapy can be designed to break that cycle.
The study, published in Frontiers in Sleep, introduces the DARC-NESS model, a mnemonic for the factors that can keep a child stuck in chronic nightmares. At the centre of the model is “nightmare efficacy,” or the idea that children can learn skills to rid themselves of nightmares and restore good sleep.
“The DARC-NESS model looks at the mechanisms of what is maintaining nightmares, as well as the mechanisms that can break the cycle of nightmares,” said Lisa Cromer, PhD., a professor of psychology at the University of Tulsa and a volunteer child psychiatry faculty member at the OU School of Community Medicine in Tulsa. “It’s a child’s response to a nightmare that causes the chronic nightmares to happen, which means if we can learn to respond to nightmares differently, then we can interrupt that cycle. It’s empowering to understand that we can take steps to master our dreams.”
Rather than focusing only on the content of a nightmare, the model encourages clinicians to consider a broader set of factors, including how a child interprets the dream, worries about going to sleep, experiences anxiety at bedtime and copes after waking.
That information can help guide a personalized treatment plan instead of a one-size-fits-all approach. For some children, treatment may focus on reducing bedtime anxiety. Others may benefit from improving sleep habits or participating in exposure-based therapy, such as describing, writing about or drawing the nightmare and then working with a clinician to “rewrite” it.
“We believe we have created a way to conceptualize why nightmares persist and how we can better treat them in kids,” said OU Health child and adolescent psychiatrist Tara Buck, MD, an associate professor at the OU School of Community Medicine in Tulsa. “What’s unique about the model is that it’s customisable to what the patient needs, and it focuses on what the patient can control. We look for the potential intervention points and target those in a collaborative way with patients and their families.”
Unlike insomnia, in which people fear they won’t sleep, children with chronic nightmares are afraid they will sleep. According to Buck, helping children build confidence in their ability to address nightmares can have benefits far beyond sleep.
“Self-efficacy is at the heart of the model,” she said. “When children feel empowered to do something about the nightmares, they begin to see how things are interconnected – because they’re sleeping better, they have more energy, they go to school more consistently and their parents report improved behaviour.”
The model is designed for use by a range of clinicians, including therapists and pediatricians. For many years, health care providers either assumed that nightmares couldn’t be treated or that they would go away if an underlying trauma or mental health condition were addressed. However, that’s not always the case.
“We’ve worked with children who have been in mental health treatment for a long time and their nightmares are still persistent,” Buck said. “There is a need for a nightmare treatment model to help children when their nightmares are recurrent and distressing.”
“A nightmare is a bad dream that you wake up from,” Cromer said. “If you don’t wake up, then the brain is doing its job of resolving the fear of the dream. But if a child does wake up, they’re trying to escape the nightmare. And when a child wakes up, they’re not able to resolve the nightmare, which actually exacerbates the problem. That’s why nightmares are so important to treat.”
A new analysis from UC San Francisco argues that diagnostics are being overlooked both in the United States and around the world. This is slowing progress against major diseases, despite rapid advances in targeted therapies and precision health.
The authors note that nearly half of the world’s population lacks adequate access to diagnostics. These tests receive less investment for research and development, as well as lower insurance reimbursement than drugs, and this is creating barriers to innovation.
“Most people can easily understand how a new drug or surgery might help a patient,” said Kathryn Phillips, Ph.D., a professor of Health Economics in the School of Pharmacy at UC San Francisco and the lead author of the study, which appears in Science. “But the tests that guide medical decisions are just as critical.”
When treatments advance faster than tests
Advances in therapies are outpacing the development of the tests that are needed to guide their use. For example, many people do not respond to GLP-1 drugs for obesity and diabetes, but few tests exist yet to predict which patients will benefit.
Alzheimer’s is another example. New drugs exist to slow disease progression, but the blood tests that could match patients to the most beneficial drugs cost around $1000 and, unlike the drugs, which cost $30 000 a year, they rarely qualify for insurance coverage. This can leave doctors to make medical decisions without the necessary information. Some patients may not get the right treatments, and others may not get any treatments.
Regulatory misalignment and policy fixes
Even though they are essential to care, these diagnostic tests are often handled apart from the treatments they support. The FDA reviews tests differently than drugs, and insurers pay for them differently. Drugs are also much more likely to receive expedited FDA review than tests.
“Regulatory and payment policy should evolve in tandem with scientific and technological advances,” said Robert M. Califf, MD, former commissioner of the FDA and co-author of the paper.
“The current misalignment between how we evaluate diagnostics for consideration of allowing marketing and the system for reimbursement decisions about diagnostics versus drugs leaves powerful tools on the shelf and provides inadequate data to make good decisions about which diagnostic tools should be eschewed for lack of benefit in the real world.”
The authors say there are clear steps policymakers can take to fix these gaps, including reviewing tests and treatments together, streamlining approvals for tests, and improving how diagnostics are evaluated and paid for.
“Our hope is that this work helps people – patients, policymakers, insurers, and researchers – recognise diagnostics as essential to good health care – and not just an afterthought,” said Phillips, who directs the UCSF Center for Translational and Policy Research on Precision Medicine (TRANSPERS) and is a member of the Philip R. Lee Institute for Health Policy at UCSF.
Photoreceptor cells in the retina. Credit: Scientific Animations
A new Yale School of Medicine (YSM) study has uncovered surprising new details about how our eyes process what we see.
When we look at something, our visual system breaks down different aspects of the scene – such as colour, contrast, and motion – and processes those components separately. It’s called parallel visual processing and it’s what allows our brains to work out what we’re seeing so quickly.
This separation of information starts in the retina, and scientists have thought that separation is maintained as the information travels through the visual system. But in a study published in Neuron, researchers have found that information channels are more integrated than previously thought. This may help cells process weak visual signals, such as low-light conditions, the researchers say.
“We found that while different channels can deliver their own features, they’re also interconnected by underlying electrical circuitry,” says Yao Xue, PhD, a postdoctoral fellow in the department of ophthalmology and visual science at YSM and the study’s first author.
Untangling bipolar cell signals in the retina
The rods and cones in our retinas detect light and transmit signals to a type of neuron called bipolar cells. In these cells, visual components such as night, day, colour, shape, and contrast begin to separate into more than a dozen parallel channels.
But when researchers zoomed in on bipolar cell synapses, they found these information channels intermingle.
Neurons have two types of synapses: chemical and electrical. At chemical synapses, neurons release chemical messengers known as neurotransmitters that bind to the recipient cell. Electrical synapses, also known as gap junctions, facilitate communication with electric currents. Bipolar cells primarily communicate through chemical synapses.
The researchers found, however, that in the mouse and human retinas they studied, electric synapses were integrating most of those seemingly separate bipolar cell information channels. When the scientists electrically stimulated one bipolar cell, instead of seeing a localised release of neurotransmitters just within that cell’s channel, they observed cloud-like patterns of signalling – suggesting crosstalk among the different types of cells.
“When we stimulated one bipolar cell, many bipolar cells released neurotransmitters,” says Z. Jimmy Zhou, PhD, Professor of Ophthalmology and Visual Science and principal investigator.
“If the signal is already very weak and is divided into several channels, there isn’t much left for each channel to process. The integration is particularly useful for detecting low contrast signals or signals from very small objects.”
To their surprise, they also identified one type of bipolar cell, called BC6, that drove this signalling. These cells generated strong signals that travelled through the parallel channels in a hierarchical manner. “People had assumed that the different types of bipolar cells were more or less autonomous,” Zhou says. “But we found a driver among all these cell types that creates this network with a hierarchy.”
Having distinct parallel channels can help bipolar cells divide and conquer as they process different parts of a visual signal. The linkage of these channels through electrical synapses, on the other hand, could help the cells process weak visual signals, the researchers say.
“If the signal is already very weak and is divided into several channels, there isn’t much left for each channel to process,” says Seunghoon Lee, PhD, a research scientist in the department of ophthalmology and visual Science at YSM and co-corresponding author of the study. “The integration is particularly useful for detecting low contrast signals or signals from very small objects.”
“And the cells aren’t cooperating in a random way,” adds Xue. “There’s a commander within them – BC6 – that leads them in relaying signals to the downstream target.”
Recording from hard-to-reach cells
For the study, the researchers used several methods to study the synaptic circuitry of bipolar cells, including imaging to observe the cells’ activity and how they released and responded to neurotransmitters, as well as stimulating activity in bipolar cells and recording responses in recipient cells.
One challenge of studying signal transmission in bipolar cells is that they live in the middle of the retina. Previous studies have cut the retina into slices in order to access the cells, but that can disrupt the synaptic circuitry. In the new study, however, the researchers were able to apply the dual patch-clamp technique in fully intact mouse retinas. This method uses electrodes to stimulate activity in different types of bipolar cells and records the responses of recipient cells.
“No other lab in the world has been able to pull off these kinds of recordings systematically,” says Zhou. “It is a tour de force of Yao Xue’s PhD thesis work, pairing an innovative approach with exceptional electrophysiological skill.”
The team then repeated the experiment in human retinas, which they obtained from the department of pathology’s Legacy Tissue Donation Program. These are the first experiments of their kind in an intact human retina, the YSM researchers say.
