Category: Neurology

Categories : NeurologyTags :

X-chromosomes: A New Lens on Autism’s Sex Bias

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Autism has a significant and enduring sex bias, with roughly four boys diagnosed for every girl. For many years, experts have believed this disparity arises primarily from diagnostic inequities because much of autism research – and the screening tools that grew out of it – has historically focused on boys, effectively setting a male standard for what autism “looks like.” As a result, girls and women are more likely to be overlooked, misdiagnosed, or diagnosed much later in life.

This disparity has also shaped the science around autism. When fewer females with the condition are identified, fewer are included in research studies, creating a feedback loop where scientific understanding of autism in females remains limited. Because of this underrepresentation of females, it has been difficult for scientists to disentangle how much of the sex bias in autism reflects social inequities versus underlying biological differences between the sexes. 

While the search for biological explanations has largely lagged behind, one leading theory, known as the “female protective effect,” proposes that females may be biologically buffered against developing autism in a way males aren’t. 

The idea can be traced back to studies showing that females diagnosed with autism tend to carry a higher number of genetic mutations or “hits” than males with the condition, meaning that they require a higher load of the same genetic mutations for autism to manifest. But, until now, there’s been little clarity on the exact biological mechanism behind this apparent resilience.

Now, a perspective from the lab of Whitehead Institute Member David Page, published March 30 in Nature Genetics, proposes a genetic explanation for the female protective effect and suggests that biological differences between males and females contribute to autism’s strong sex bias.

The work is one of many projects from the Page lab uncovering the biological underpinnings of sex bias in everything from heart health and autoimmune disease to certain cancers. 

“The fact that we see sex biases in disease all across the body gives credence to the notion that the sex bias in autism isn’t simply emerging from diagnostic inequities and gendered expectations of what the conditions looks like,” says Page, who is also a professor of biology at Massachusetts Institute of Technology and an investigator at the Howard Hughes Medical Institute (HHMI).

The researchers propose that this protective effect extends beyond autism, and could help explain why 17 other congenital and developmental disorders predominately affect males. By characterizing the biological factors that make one sex more or less likely to develop certain health conditions, scientists see an opportunity to improve how these conditions are diagnosed and how people receive care.

“The fact that we see sex biases in disease all across the body gives credence to the notion that the sex bias in autism isn’t simply emerging from diagnostic inequities and gendered expectations of what the conditions looks like,” says Page.

Page and Harvard-MIT MD-PhD student Maya Talukdar trace the female protective effect to the X chromosome. Talukdar is a graduate student in Page’s lab and the lead author of the perspective. 

Most females have two X chromosomes (XX) while most males have one X and one Y chromosome (XY). Sex chromosomes can dial up and down the expression of thousands of genes on the other 22 pairs of chromosomes in a cell, impacting cell function across the entire body. 

Historically, scientists believed that the second X chromosome in females is largely inactive. But, in recent years, research out of the Page lab has shown that the so-called “inactive X,” also called Xi, plays a crucial role in regulating gene expression on the active X chromosome, and the rest of the chromosomes.

In this perspective, the researchers point to a subset of genes that are expressed from both the active and inactive X chromosome — often known as genes that “escape” X chromosome inactivation. Many of these genes are dosage-sensitive regulators of key cellular processes. These processes influence thousands of other genes across the genome, including many linked to autism. 

Because females have an extra copy of these regulatory genes expressed from Xi, Page and Talukdar propose that they may be better able to buffer the effects of autism-associated mutations than males.

The female protective effect beyond autism

This mechanism, the researchers say, extends beyond autism to a range of congenital and developmental diseases with a male bias. 

“Many of the other congenital or developmental conditions we’re pointing to aren’t subject to diagnostic inequities in the way autism is,” says Talukdar. “This strengthens the idea that the female protective effect is emerging from genetic differences in males and females.”

One example is pyloric stenosis, which like autism, affects four boys for every girl. Infants with the condition experience severe vomiting due to thickening of the pyloric sphincter, the passage between the stomach and small intestine. As with autism, girls with pyloric stenosis appear to require more genetic “hits” in order to develop the condition.

The researchers’ new framework of looking at Xi to understand sex differences in disease could impact treatment and care not just for conditions that predominately affect males, but also for those that are more common in women, such as autoimmune diseases. 

“Our biology isn’t one-size-fits-all,” Talukdar says “Sex differences clearly play a huge role in health, and it’s so important that we understand them.”

By Shafaq Zia

Source: Whitehead Institute for Biomedical Research

Categories : Neurology Pain ManagementTags :

Pain Neurons Protect Nerve Health and Offer New Therapeutic Targets

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A healthy neuron. Credit: NIH

Researchers at Karolinska Institutet, have uncovered a previously unknown mechanism that helps pain sensing nerve cells stay healthy and respond to injury. The findings, published in Nature Communications, may improve understanding of chronic pain and nerve damage and maintenance of myelin integrity.

A new study shows that a molecule called RNase4, is produced by specialised pain-sensing neurons. It plays a key role in maintaining their normal function and influences both these neurons and the structure of nearby nerve fibres, positioning pain-sensing neurons not only as sensory transducers but also as sentinels of nerve integrity.

The researchers showed that RNase4 is expressed in unmyelinated sensory neurons, including neurons that innervate the auditory organ, and in the pain-sensing neurons that innervate the face, head, dura mater, and the rest of the body. By combining multiple experimental approaches on mice, they demonstrated that loss of RNase4 alters mechanical pain responses and disrupts the myelin structure surrounding neighbouring nerve fibres. They also found that RNase4 levels increase after nerve injury, both during the pain phase and the subsequent recovery period.

“Our results point to RNase4 as part of a regulatory pathway that supports nerve integrity. This molecule has not previously been linked to pain sensing neurons, so its presence and role came as a surprise,” says corresponding author Saida Hadjab, head of the Neurobiology of pain & Therapeutics laboratory at the Department of Neuroscience.

Chronic pain is often difficult to treat, partly because the underlying biology is still not fully understood. The findings suggest that pain sensing neurons may take on a more active role in maintaining the health of surrounding nerve tissue.

“This work has enabled us to identify a novel mechanism and position RNase4 as a regulator of afferent neuron integrity and local microenvironment. The localisation of RNase4 and its function in sensory neurons made it directly relevant to hearing dysfunction, headache, and chronic pain,” says Saida Hadjab.

RNase4 shows a comparable expression pattern in human pain-sensing neurons, supporting its potential relevance in humans. While further research is required to develop therapies targeting the RNase4 pathway, these findings provide a strong foundation for advancing the study of myelin integrity and long-lasting pain in humans.

Source: Karolinska Institutet

Categories : NeurologyTags :

The Most Common Recessive Neurodevelopmental Disorder Ever Discovered

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Photo by Anna Shvets

Researchers have identified and described a previously unknown recessive neurodevelopmental disorder (NDD) that appears to be the most prevalent ever discovered. The study, involving University of Bristol researchers and published in Nature Genetics, provides long-awaited answers for many families and may inform future drug development.

The condition is caused by changes in a small noncoding gene called RNU2-2. It is estimated to affect thousands of individuals and accounts for about ten percent of all recessive NDD cases with a known genetic cause.

The work was led by researchers from Icahn School of Medicine at Mount Sinai in New York in collaboration with colleagues from Stanford University and the University of Bristol. Clinical and scientific collaborators from other institutions in the UK, the Netherlands, Belgium, and Italy provided valuable contributions to this research.  

The team found that the disorder is caused by a near-complete absence of a molecule called U2-2 RNA, which is produced by the RNU2-2 gene. Children with the condition typically inherit one altered copy of the gene from each parent, although sometimes changes arise spontaneously by genetic mutation. While the parents are unaffected, the combined effect on both copies of the gene in their children leads to disrupted brain development in their child.

Symptoms of this disorder vary widely depending on the child’s specific genetic changes. Common features include low muscle tone, developmental delays, and limited speech. Some children have mild learning difficulties or autism traits, while others develop epilepsy, movement disorders, or trouble walking. Brain imaging may appear normal early on but can show changes over time. In the most severe cases, additional challenges may include feeding difficulties or respiratory problems. The wide range of symptoms reflects how the underlying U2-2 RNA deficiency affects each child differently.

“Our discovery gives families something they’ve often waited years for, a clear molecular explanation for their child’s condition,” said the study’s first author, Daniel Greene, Assistant Professor of Genetics and Genomic Sciences at the Icahn School of Medicine. “For many families, that clarity can be profoundly meaningful after a long and uncertain diagnostic journey. At the same time, it gives the research community a concrete biological target to guide future therapeutics.”

Using whole-genome sequencing data from the UK’s National Genomics Research Library, the team examined rare genetic variants in more than 41 000 non-coding genes, genes that produce functional RNA molecules that do not encode proteins. They analysed genetic data from 14,805 individuals with an NDD and 52,861 ‘controls’ without an NDD. Their statistical approach was specifically designed to detect dominant and recessive conditions. RNA sequencing of blood from patients and controls further revealed the immediate biological consequence of the disease-causing variants: the severe reduction of U2-2 RNA.

This discovery builds on two earlier landmark developments from the research group:

The new study expands this story by demonstrating that recessive variants in RNU2-2 cause a distinct and surprisingly prevalent disorder, now referred to as recessive ReNU2 syndrome. Notably, the researchers estimate that this recessive condition may be 60% as common as ReNU syndrome, which is unusual — the most prevalent NDDs are dominant rather than recessive.

Andrew Mumford, Emeritus Professor of Genomic Medicine at the University of Bristol, said: “This research completes a set of three landmark genetic discoveries from our team that have identified faults in two hitherto unsuspected genes as a common cause of what can sometimes be a devastating developmental disorder. This work will rapidly improve genetic diagnosis for families and children and lead to significant advancements in clinical care.”

The investigators are now enrolling families into the INDEED study at Mount Sinai to help deliver diagnoses and better understand the condition. Future work will focus on deepening the understanding of the biology behind the disorder and identifying paths toward future treatments.

“Our discovery will enable tens of thousands of families affected by this previously hidden genetic condition to receive closure through a genetic diagnosis. Parents will have the opportunity to connect with each other through the recently established ReNU2 Syndrome Foundation. Given the recessive inheritance pattern, diagnoses will provide critical information for family planning,” added Dr Ernest Turro, the study’s senior author.

“While a specific treatment for recessive ReNU2 syndrome is not yet available, understanding that the disorder stems from a loss of U2-2 RNA points to potential gene replacement strategies in the future,” he explains. “We are now enrolling families into the INDEED study to diagnose affected individuals, improve our understanding of the natural course of the condition, develop clinical management guidelines, and uncover precisely how U2-2 RNA loss disrupts neurodevelopment. We hope these steps will lay a strong foundation for future clinical trials.”

Paper

’Biallelic variants in RNU2-2 cause the most prevalent known recessive neurodevelopmental disorder’ By D Greene et al. in Nature Genetics [open access]

Source: University of Bristol

Categories : Infection Control NeurologyTags :

Severe Infections May Raise Dementia Risk, Study Finds

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Finnish registry study finds that infections like cystitis and bacterial disease are linked to higher dementia risk independently of other coexisting conditions

Source: CC0

Severe infections increase the risk of dementia independently of other coexisting illnesses, according to a new study published March 24th in the open-access journal PLOS Medicine by Pyry Sipilä of the University of Helsinki, Finland, and colleagues.

Severe infections have been linked to an increased risk of dementia. However, it has been unclear whether this association is explained by other coexisting, non-infectious diseases that predispose people to both infections and dementia.

In the new study, researchers used nationwide Finnish health registry data covering more than 62 000 individuals aged 65 or older who were diagnosed with late-onset dementia between 2017 and 2020, along with more than 312 000 matched dementia-free controls. Taking a broad approach, they examined all hospital-treated diseases recorded during the previous twenty years, identifying 29 diseases that were robustly associated with increased dementia risk. Nearly half (47%) of dementia cases had at least one of the 29 identified diseases before their diagnosis.

Of those diseases, two were infections: cystitis (a urinary tract infection) and bacterial infection of an unspecified site. Among the non-infectious diseases, the strongest associations with dementia were seen for mental disorders due to brain damage or physical disease, Parkinson’s disease, and alcohol-related mental and behavioural disorders.

When the researchers then adjusted for all 27 non-infectious dementia-related diseases identified, the association between both infections and dementia remained largely intact. Less than one-seventh of the excess dementia risk among individuals with hospital-treated cystitis or bacterial infections was attributable to pre-existing conditions. The link between infections and dementia was even stronger for early-onset dementia (diagnosed before age 65), where five types of infection – including pneumonia and dental caries – were associated with elevated risk.

The study was limited by the lack of baseline cognitive assessments and clinical examination data before dementia diagnoses, as well as a lack of data on infection treatments.

“Overall, our findings support the possibility that severe infections increase dementia risk; however, intervention studies are required to establish whether preventing or effectively treating infections yields benefits for dementia prevention,” the authors say.

The authors add, “We found 27 diverse severe, hospital-treated diseases that were robustly associated with an increased risk of dementia. Two of these diseases were infections, namely urinary tract infections and unspecified bacterial infections.” 

“In our study, dementia-related infections occurred on average 5 to 6 years before dementia diagnosis. Given that the development of dementia often takes years or even decades, these findings suggest that severe infections might accelerate underlying cognitive decline. However, as these findings were observational, we cannot exclude the possibility that some unmeasured confounding factors might also have affected our findings. Thus, we cannot prove cause and effect.”

“Ideally, intervention trials should examine whether better infection prevention helps reduce dementia occurrence or delay the onset of this disease.”

Provided by PLOS

Categories : Neurology PaediatricsTags :

Intensive Therapy Approaches Benefit Infants and Toddlers with Cerebral Palsy

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Trial provides new evidence to guide early treatment decisions for families and clinicians

An infant participating in the Baby CHAMP study raises both hands while seated in a stroller. The NIH-funded trial led by the Fralin Biomedical Research Institute at VTC examines early therapies designed to improve arm and hand function in young children with cerebral palsy affecting one side of the body. Credit: Jennifer Murray

Infants and toddlers with unilateral cerebral palsy, which affects the brain’s control of muscles on one side of the body, show lasting improvements in hand and arm function when they receive early, high-dose therapy, according to a new multisite clinical trial led by Virginia Tech researchers at the Fralin Biomedical Research Institute at VTC.

The Baby CHAMP (Children with Hemiparesis Arm-and-Hand Movement Project) study directly compared three therapist-delivered interventions: two forms of constraint-induced movement therapy, which limit the stronger arm to encourage use of the weaker one when combined with therapy, and bimanual therapy, which promotes coordinated use of both hands.

The researchers found that children ages 6 to 24 months showed similar gains whether therapy involved full-time casting, a splint worn during sessions, or bimanual training without constraining the stronger arm.

Published in Pediatrics Open Science, the study addresses a long-standing gap in clinical evidence. 

“The brain in the first two years of life is remarkably plastic,” said Stephanie DeLuca, associate professor at the Fralin Biomedical Research Institute at VTC and co-principal investigator of the trial. “By delivering high-dose, play-based therapy early, we’re capitalizing on a window of opportunity when the nervous system is especially responsive to experience.” 

While both constraint-induced movement therapy and bimanual therapy are widely recommended for children older than 2 years with unilateral cerebral palsy, limited data have been available to guide treatment decisions for infants and toddlers. 

“This gives families and clinicians evidence-based options,” said Sharon Landesman Ramey, a Virginia Tech Distinguished Scholar, professor at the Fralin Biomedical Research Institute at VTC, and co-principal investigator of the Baby CHAMP trial. “The encouraging message is that early, intensive therapy works — and multiple approaches can help children build critical motor skills. Caregivers and families now have actionable evidence that can shape care during one of the most important periods of brain development.”

Unilateral cerebral palsy affects movement on one side of the body and can result in lifelong impairment of upper extremity function. Early intervention is considered critical because the brain is especially adaptable during the first two years of life.

DeLuca is director of the Fralin Biomedical Research Institute at VTC Neuromotor Research Clinic, which investigates novel treatments for children with a range of biomedical conditions and provides worldwide training for therapists to become certified in new evidence-based therapies. 

All children received three hours of therapy per day, five days a week, for four consecutive weeks, totaling 60 hours of structured intervention. Parents also supported additional guided home practice.

Fifty-eight children were enrolled in the randomized controlled trial, funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health. Fifty-three completed treatment and end-of-therapy assessments, and 41 returned for evaluation six months later.

Across all three groups, children demonstrated significant improvements in the ability to use both hands, individually and together. Improvements were measured using standardized developmental assessments administered by evaluators who were unaware of each child’s treatment assignment.

Children also showed gains in fine motor skills in their less-affected arm. Improvements were most pronounced at the six-month follow-up, suggesting that benefits continued to build after formal therapy ended.

Researchers had hypothesized that bimanual therapy might lead to greater improvements in two-handed skills and that full-time casting might yield stronger gains in the affected arm. The data did not support those predictions. Instead, outcomes were broadly comparable across approaches.

The study also addressed concerns that constraining the stronger arm could impair its development. No evidence of harm was observed. In fact, children in the full-time cast group showed slightly greater gains in fine motor skills in their non-affected arm at six months compared with the bimanual group. 

“This is important to the field because many people have worried that the use of a constraint might slow the developmental process of the less-affected arm,” DeLuca said. “Our findings confirm that this did not occur and this therapy may even help promote improvements in skills on the less-affected arm and hand.”

Some parents reported their child showed short-term frustration wearing a cast or splint, and minor skin irritation occurred in a small number of children using casts, but no were caused by the therapy itself.

The trial was conducted in collaboration with researchers at Virginia Tech, The Ohio State University, and Nationwide Children’s Hospital. Therapists were centrally trained to deliver structured, play-based interventions grounded in motor learning principles, including repetition, reinforcement, and progressively challenging activities.

Longer-term studies will be needed to better understand how early therapy influences development across many dimensions of a child’s life.

Original study: 10.1542/pedsos.2025-000676

Source: Virginia Tech

Categories : NeurologyTags :

Mechanoreceptors Set off Cascade of Damage Milliseconds After Spinal Trauma

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View of the spinal cord. Credit: Scientific Animations CC4.0

Mechanoreceptors are present in the spinal cord from birth, are sensitive to mechanical stimuli, and play an important role in triggering the pathological events that follow trauma. What happens if they are blocked? The extent of the damage decreases. This is the finding of a new study published in The Journal of Physiology and conducted by a team at Scuola Internazionale Superiore di Studi Avanzati (SISSA), led by Professor Giuliano Taccola, with Atiyeh Mohammadshirazi as first author.

Everything happens within the very first milliseconds after the trauma, the scientists explained. It is during this brief time window that these spinal mechanoreceptors become active, triggering an impairment of the electrical signals that underlies normal neural communication. This initial event sets off a cascade of neurotoxic factors known as secondary damage, which amplifies and spreads the original traumatic lesion over the following hours and days.

Understanding the role of these receptors, according to the authors, is important not only for clarifying what happens during spinal shock. As demonstrated in the experiments, when their activity is blocked, the functional damage is also reduced. For this reason, spinal mechanoreceptors may represent a potential target for strategies aimed at reducing the disabling consequences of spinal cord injury.

Physical trauma disrupts electrical signaling

“It is well known that physical trauma to the spinal cord disrupts the flow of electrical signals that underlie the functioning of our nerve fibers. This phenomenon is known as DIP (Depolarizing Injury Potential). It begins almost immediately after trauma and continues propagating the primary damage over the following weeks, progressively worsening the lesion,” explain Atiyeh Mohammadshirazi and Giuliano Taccola. “However, the origins of this phenomenon are not yet fully understood.”

Yet, thanks to experiments carried out using highly sophisticated instrumentation invented by Professor Taccola and John Fischetti, the two scientists say, “we were able to discover something truly new.”

Mechanoreceptors and their role in the spread of damage

Receptors are cellular structures that respond to specific signals. Among them are mechanoreceptors, specialized proteins located on the cell membrane of sensitive cells that act as sensors for mechanical forces such as compression. Mechanoreceptors are found throughout the body, including around the spinal cord and within its central canal. In this environment, according to the SISSA research, they appear to play an important role in the propagation of injury.

The two authors explain, “In the progression of damage, depolarization precedes other well-known events such as the release of neurotoxic agents, and the inflammatory response that ultimately leads to cell death, the transient spinal hypoxia, and the rapid cell neuronal loss in the area of the primary lesion.” In this context, mechanoreceptors seem to contribute to initiating the depolarization process.

Mohammadshirazi and Taccola confirm: “When we blocked their activity in our experiments, we observed that the functional damage was significantly contained and limited.”

A possible avenue for reducing trauma-induced damage

“Our work,” conclude Giuliano Taccola and Carmen Falcone, who contributed to the histological analysis of the study, “explored what happens at the cellular level immediately after spinal trauma. As we explained, these injuries do not only involve the initial mechanical damage; they also trigger a cascade of complex neurotoxic events that amplify and worsen cellular damage and disrupt communication between neurons.”

They conclude: “With our laboratory model experiments, we demonstrated that blocking mechanosensitive receptors can effectively reduce the immediate pathological effects of spinal trauma. Our research is basic research, of course, and practical applications are still far away. Nevertheless, it may open a promising path to explore in the future to reduce spinal shock and the damage that follows trauma.”

Categories : Ageing NeurologyTags :

Popular Anti-ageing Compound Causes Callosal Brain Damage

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Part of the brain disappears in mice treated with dasatinib and quercetin

The image shows a section of the brain of a mouse treated with dasatinib and quercetin. The bluish area is the corpus collosum. The dotted outline shows the part of the corpus collosum that is affected by the medication. (Image courtesy of Crocker Lab/UConn School of Medicine)

A two-drug combination frequently used in anti-ageing research causes brain damage in mice, University of Connecticut researchers report in the March 16 issue of PNAS. The findings should make doctors cautious about prescribing the drug combo prophylactically, but also suggest new ways to understand multiple sclerosis.

“When you administer this cocktail to an animal, young or old, the myelin is damaged, which makes it disappear. Even worse in the young animals” than in the aged ones, says UConn School of Medicine immunologist Stephen Crocker.

Myelin is the insulation around the nerves. When it disappears, nerves don’t work as well, and people can develop numbness, pain, and lose the ability to walk. They can also have problems thinking and remembering. Missing myelin is the primary cause of multiple sclerosis. And Crocker and his colleagues saw it happen to mice when treated with dasatinib+quercetin (D+Q) at doses often used to treat ageing-related inflammation and metabolic disorders.

D+Q is a popular combination of medicines in anti-ageing research. Many studies have shown it works to eliminate aged cells that contribute to inflammation and other age-related symptoms. It is being tested for a range of diseases, from type II diabetes to Alzheimer’s. People in the anti-ageing scene sometimes even use it off-label, though the medical community discourages this. Very few studies have looked at its effect on the brain.

Evan Lombardo ’23 (CLAS), currently a Dartmouth neuroscience graduate student, and Robert Pijewski ’21 PhD, now at Anna Maria College, were working in Crocker’s lab when they wondered if it was possible to rejuvenate the brains of people with multiple sclerosis, and potentially heal their symptoms, using D+Q. They tried it on mice, both young (6 to 9 months) and old (22 months), as well as on brain cells cultured in a dish in the lab. The brain cells were oligodendrocytes, the cells that are supposed to grow and maintain myelin.

The results were dramatic. Healthy mice have myelin surrounding the axons (nerve cells) in the brain. It looks like dark rings around the lighter axon (see figure 1, the left panel.) But the mice treated with D+Q had much less myelin around their axons after the treatment, and the damage was worse in the younger mice. The corpus callosum, a region that connects the cerebral cortex to other parts of the brain and is associated with a range of important functions, also disappeared in mice treated with D+Q. This is known to happen sometimes to people who received chemotherapy, and causes the symptoms sometimes referred to as “chemo brain.”

When the researchers looked closely at the damaged brain tissue, they found clues as to why the myelin had disappeared. The myelinating cells – oligodendrocytes – hadn’t died. They’d regressed into a juvenile form of themselves. And the metabolism of the cells was abnormal, too.

“We suspect the drugs are choking off energy the cells need, and the cells respond by reducing complexity, reverting to a younger state, but less functional,” Crocker says.

Interestingly, these cells that have reverted look very much like a distinct population of cells found in people with multiple sclerosis. It suggests that in multiple sclerosis, myelinating cells might come under stress and revert to a younger stage. It also means those cells might be able to recover. And that is what the researchers are working on now.

“If we can mimic this, we have an amazing opportunity to see if the cells can recover and repair the brain,” Crocker says.

Source: University of Connecticut

Categories : Neurology Obstetrics & GynaecologyTags :

More Evidence Tying Epilepsy Drugs in Pregnancy to Developmental Risks

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Study adds weight to previously reported risks and calls for monitoring of new antiseizure drugs

Photo by SHVETS production

Findings published by The BMJ reinforce previous research linking use of the antiseizure drug valproate during pregnancy to neurodevelopmental disorders such as ADHD and autism in children, and indicate no substantial risk for several other antiseizure drugs including levetiracetam and lamotrigine.

However, the researchers say continued monitoring of the few signals – possible associations between a medicine and an unintended side effect – that emerged (eg, for zonisamide) will be important.

Antiseizure drugs are commonly and increasingly used by women of childbearing age for conditions like epilepsy, bipolar disorders, and migraine prevention. Women with epilepsy are advised to continue taking these during pregnancy, as uncontrolled seizures pose risks to both mother and child.

Yet, while valproate use during pregnancy has been linked to impaired neurodevelopment in children, information on other antiseizure drugs is limited.

To address this gap, researchers analysed claims data for pregnancies with diagnosed epilepsy from two large US public and commercial insurance databases, spanning the period from 2000 to 2021.

They compared 14,993 children exposed to at least one antiseizure medication during the second half of pregnancy with 8,887 unexposed children. Of these, 5,505 were followed for at least 5 years and 2,516 for at least 8 years after birth.

Potentially influential factors including mother’s age, ethnicity, mental health, substance use, other medication use and underlying conditions were also taken into account.

Valproate and zonisamide showed associations with several neurodevelopmental disorders, whereas levetiracetam and phenytoin were not associated with an increased risk of any of the studied outcomes.

Although no meaningful associations were found for topiramate and lamotrigine across most outcomes, there was a potential signal for intellectual disability (both drugs) and learning difficulty (topiramate only). However, the authors note that  these findings are based on small numbers and require confirmation in follow-up studies.

Several other drugs were also associated with a risk increase for intellectual disability. However, the authors note that these estimates are based on small numbers and therefore should be interpreted with caution.

Carbamazepine and oxcarbazepine also showed a modest risk increase for ADHD and behavioral disorders.

This is an observational study, so no definitive conclusions can be drawn about cause and effect, and the authors point to several limitations including relying on insurance claims data and the potential influence of other unmeasured factors such as underlying epilepsy type and severity.

However, the use of two large nationwide databases of insured pregnant women linked to their children enhanced the generalisability of their findings and enabled them to assess the risk of specific neurodevelopmental disorders associated with individual antiseizure medications. Results were also consistent after additional analyses, suggesting that they are robust.

As such, they conclude: “Our study reinforces the substantial risks of neurodevelopmental disorders associated with prenatal valproate exposure and suggests the need to further evaluate the safety of zonisamide during pregnancy.”

“Continued monitoring of newer antiseizure drugs and the few potential signals that emerged (ie, the moderate increased risk of ADHD and behavioural disorder after carbamazepine and oxcarbazepine exposure, and the association of several antiseizure drugs with intellectual disability) will be important,” they add.

Source: BMJ Group

Categories : Cardiovascular Disease NeurologyTags :

Algorithm for Paramedics Predicts Brain Damage Risk After Cardiac Arrest

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Photo by Ian Taylor in Unsplash

Researchers at King’s College London have shown that a widely used cardiac arrest risk score can be applied before patients reach hospital, enabling paramedics to assess the risk of brain injury at an earlier stage of care.

Results from the RAPID-MIRACLE trial have found, for the first time, that the widely used MIRACLE2 risk score can be applied outside a hospital setting to accurately predict brain injury following a cardiac arrest. This could inform the type of immediate care patients receive, helping to ensure they have the best treatment available while saving crucial resources.

An out of hospital cardiac arrest (OHCA) carries a high risk of death, with fewer than 10% of patients surviving. Even when a patient’s heart is successfully restarted through CPR and circulation is restored, known as return of spontaneous circulation (ROSC), clinicians often face uncertainty about the extent of brain injury.

Despite current UK and European guidelines recommending that patients who experience an out of hospital cardiac arrest are sent to a specialist cardiac centre, the majority of patients are still conveyed to local emergency departments. The MIRACLE2 score, when applied in the pre-hospital setting, may now open up the possibility of identifying patients earlier and enabling direct transfer to specialist centres, allowing faster access to expert care and advanced treatments for patients who might otherwise have been conveyed to a local hospital.

Created by Dr Nilesh Pareek, Adjunct Senior Lecturer and Consultant Interventional Cardiologist, the MIRACLE2 score accurately predicts the extent of brain damage after 30 days following an OHCA. Until now, it has only been applied once a patient reaches hospital.

Dr Pareek and his team worked with the London Ambulance Service and Heart Research UK to evaluate whether the score could be calculated immediately after ROSC in the community.

The study followed patients from paramedic care through to hospital treatment across multiple London sites, providing real-world evidence of how the score performs outside a hospital environment.

The researchers tested two new versions of the score – one which included a blood test and one which didn’t. While the version with the blood test was highly accurate, paramedics frequently found it impractical due to technical failures and time pressure. The version without the blood test, known as Pre-MIRACLE2, was almost identical in terms of accuracy.

While MIRACLE² has supported early in-hospital risk stratification following out-of-hospital cardiac arrest, RAPID-MIRACLE extends this work into the pre-hospital setting, enabling paramedics to assess risk earlier in a patient’s care pathway. By validating the model in the field, we have taken an important step towards integrating earlier risk assessment into routine emergency care.”Dr Nilesh Pareek, senior author of the study and Adjunct Senior Lecturer, King’s College London and Consultant Interventional Cardiologist, King’s College Hospital

Alongside the study, the MIRACLE² app, led by Dr Pareek, has been updated to incorporate the newly validated pre-hospital model. The app, developed by Ensono Digital, uses the MIRACLE2 algorithm and is designed as a practical tool to help clinicians calculate the score quickly and accurately, without needing to recall each variable from memory.

By entering patient information such as age, initial heart rhythm and other markers, paramedics and hospital clinicians can generate an immediate estimate of a patient’s risk of poor neurological outcome following out-of-hospital cardiac arrest.

The research team is now in discussion with emergency medical services regarding a potential service evaluation to explore how the updated tool could be implemented in routine practice.

Heart Research UK were delighted to fund the RAPID-MIRACLE trial with the aim of improving outcomes for this poorly served patient group. The promising results from the trial suggest that better outcomes can be delivered, and we hope the risk score can be adopted nationally for all patients.”Dr Kate Langton, Director of Research at Heart Research UK

The research findings were presented in Washington at the CRT 2026 conference and the full study was published in European Heart Journal – Acute Cardiovascular Care.

Source: King’s College London

Categories : NeurologyTags :

Psychological Study Shows that Multitasking has Limits

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Even with highly extensive training, the human brain is not really capable of performing two tasks simultaneously. Moreover, even the smallest deviations from trained routines can have a significant impact on how quickly and successfully people complete tasks simultaneously. This is shown by a new study conducted by Martin Luther University Halle-Wittenberg (MLU), the FernUniversität in Hagen and the Medical School Hamburg. It was recently published in the Quarterly Journal of Experimental Psychology.

In three experiments, the researchers investigated how people perform two tasks simultaneously that involve different senses: participants were asked to indicate the size of a circle that was briefly displayed with their right hand and simultaneously to say whether a sound played at the same time was high, medium or low. The speed at which the participants completed the tasks and the number of mistakes they made were measured. The tasks were repeated over a period of up to twelve days. The results showed that the more often the test subjects completed the test, the faster they solved both tasks without errors.

Earlier studies with similar findings had therefore suggested that so-called dual-task costs, ie, performance losses when working on two tasks simultaneously, could almost completely disappear after extensive practice. “This phenomenon, known as virtually perfect time sharing, has long been considered evidence of true parallel processing in the brain and proof that our brain is capable of unlimited multitasking. The results of our study clearly contradict this assumption,” says psychologist Professor Torsten Schubert from MLU.

The new study shows that the underlying cognitive processes still do not run completely in parallel. What’s more, even the smallest changes to the tasks caused the error rate to rise and the participants to take longer to complete the tasks. “Our brain is very adept at sequencing processes so that they no longer interfere with each other. However, this optimisation has its limits. In particularly challenging situations, our cognitive apparatus therefore tires very quickly and becomes error prone,” Schubert continues.

The study also provides new impetus for safety research. “Our results show why multitasking can often be risky in everyday life, despite routine, for example when driving and talking on the phone at the same time. This is also relevant for professions with complex activities where several tasks have to be performed in parallel, such as air traffic controllers or simultaneous translators,” says Professor Tilo Strobach from the Medical School Hamburg. Professor Roman Liepelt from the FernUniversität in Hagen adds: “Our study sheds new light on the limits of human information processing. Understanding such cognitive bottlenecks is crucial for improving work processes, learning environments and safety measures in everyday life.”

The results were published in the Quarterly Journal of Experimental Psychology.

Tom Leonhardt

Source: Martin Luther University Halle-Wittenberg