Category: Neurology

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Scientists Crack the Puzzle of How Retinoic Acid Works Against Neuroblastoma

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Photo by Anna Shvets

Neuroblastoma is a solid tumour that occurs in children. When high-risk, the disease has a poor prognosis. Decades ago, adding the drug retinoic acid to neuroblastoma treatment increased survival by 10–15%. However, this effect was only evident in post-chemotherapy consolidation after bulky primary tumours had largely been eliminated. Why retinoic acid is effective in this setting but not against primary tumours, has been speculated about for nearly 50 years. 

St. Jude Children’s Research Hospital scientists resolved the mystery in a new study, showing retinoic acid uses a novel mechanism to kill metastasised neuroblastoma. The drug “hijacks” a normal developmental pathway to trigger cancer cell death. The findings, which have implications for future combination therapy approaches, appears in Nature Communications. 

“We’ve come up with an explanation for a decades-long contradiction about why retinoic acid works in post-chemotherapy consolidation but has little impact on primary neuroblastoma tumours,” said senior co-corresponding author Paul Geeleher, PhD. “Retinoic acid’s activity heavily depends on the cellular microenvironment.” 

The cellular microenvironment is the soup of chemicals, proteins and other signals that surround a cell, and which is unique to that part of the body. For example, the bone marrow microenvironment contains signals to grow blood cells and restructure bone. Metastasised neuroblastoma cells often migrate to bone marrow, where the bone morphogenetic protein (BMP) pathway signalling is highly active. The researchers showed that BMP signaling makes neuroblastoma cells much more vulnerable to retinoic acid. 

“Unexpectedly, we found that cells expressing genes from the BMP signaling pathway were very sensitive to retinoic acid,” said co-first and co-corresponding author Min Pan, PhD, St. Jude Department of Computational Biology. “However, since the bone marrow microenvironment causes neuroblastoma cells there to have higher BMP activity, it neatly explained why retinoic acid is very effective at treating those cells during consolidation therapy, but not the primary tumours during up-front treatment.” 

Hijacking development to drive metastatic neuroblastoma cell death 

Using gene editing technology, the scientists uncovered the relationship between BMP signaling and retinoic acid. They assembled a group of neuroblastoma cell lines susceptible to retinoic acid, then cut out genes to find which were responsible for the drug’s activity. Genes in the BMP pathway had the largest effect while providing a plausible explanation for retinoic acid’s varying outcomes in patients.

“We found that, in neuroblastoma, BMP signaling works with retinoic acid signaling in the same way as during development,” said co-first author Yinwen Zhang, PhD, who characterised how transcription factors, the proteins that bind DNA to regulate gene expression, led to different results in highly retinoic acid-sensitive or insensitive neuroblastoma cells. “If there are a lot of BMP-signaling pathway transcription factors already on DNA, then retinoic acid signaling combines with it to promote downstream cell death–related gene expression. This occurs both in normal embryonic development and neuroblastoma cells in certain microenvironments.” 

“We are the first to uncover such an example of ‘hijacking’ a normal embryonic developmental process preserved in cancer that we can exploit therapeutically,” Geeleher said. “Now, we can look for similar processes in other diseases to design less toxic and more effective treatment strategies.” 

Source: St. Jude Children’s Research Hospital

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More Evidence Shows that 40Hz Gamma Stimulation is Beneficial for Brain Health

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A decade of studies from labs around the world provide a growing evidence base that increasing the power of the brain’s gamma rhythms could help fight Alzheimer’s, and perhaps other, neurological diseases.

Source: Pixabay

A decade after scientists in The Picower Institute for Learning and Memory at MIT first began testing whether sensory stimulation of the brain’s 40Hz “gamma” frequency rhythms could treat Alzheimer’s disease in mice, a growing evidence base supporting the idea that it can improve brain health – in humans as well as animals – has emerged from the work of labs all over the world. A new review article in PLOS Biology describes the state of research so far and presents some of the fundamental and clinical questions at the forefront of the non-invasive gamma stimulation now.

“As we’ve made all our observations, many other people in the field have published results that are very consistent,” said Li-Huei Tsai, Picower Professor at MIT, director of MIT’s Aging Brain Initiative, and senior author of the new review with postdoc Jung Park. “People have used many different ways to induce gamma including sensory stimulation, transcranial alternating current stimulation or transcranial magnetic stimulation, but the key is delivering stimulation at 40 Hz. They all see beneficial effects.”

A decade of discovery at MIT

Starting with a paper in Nature in 2016, a collaboration led by Tsai has produced a series of studies showing that 40Hz stimulation via light, sound, a combination of the two, or tactile vibration reduces hallmarks of Alzheimer’s pathology such as amyloid and tau proteins, prevents neuron death, decreases synapse loss, and sustains memory and cognition in various Alzheimer’s mouse models. The collaboration’s investigations of the underlying mechanisms that produce these benefits has so far identified specific cellular and molecular responses in many brain cell types including neurons, microglia, astrocytes, oligodendrocytes and the brain’s blood vessels. Last year, for instance, the lab reported in Nature that 40Hz audio and visual stimulation induced interneurons in mice to increase release of the peptide VIP, prompting increased clearance of amyloid from brain tissue via the brain’s glymphatic “plumbing” system.

Meanwhile, at MIT and at the MIT spinoff company Cognito Therapeutics, phase II clinical studies have shown that people with Alzheimer’s exposed to 40Hz light and sound experienced a significant slowing of brain atrophy and improvements on some cognitive measures compared to untreated controls. Cognito, which has also measured significant preservation of white matter in volunteers, has been conducting a pivotal, nationwide phase III clinical trial of sensory gamma stimulation for more than a year.

“Neuroscientists often lament that it is a great time to have AD if you are a mouse,” Park and Tsai wrote in the review. “Our ultimate goal, therefore, is to translate GENUS discoveries into a safe, accessible, and non-invasive therapy for AD patients.” The MIT team often refers to 40Hz stimulation as “GENUS” for Gamma Entrainment Using Sensory Stimulation.

A growing field

As Tsai’s collaboration, which includes MIT colleagues Edward Boyden and Emery N. Brown, has published its results, many other labs have produced studies adding to the evidence that various methods of non-invasive gamma sensory stimulation can combat Alzheimer’s pathology. Among many examples cited in the new review, in 2024 a research team in China independently corroborated that 40Hz sensory stimulation increases glymphatic fluid flows in mice. In another example, a Harvard Medical School-based team in 2022 showed that 40Hz gamma stimulation using Transcranial Alternating Current Stimulation significantly reduced the burden of tau in three out of four human volunteers. And in another study involving more than 100 people, researchers in Scotland in 2023 used audio and visual gamma stimulation (at 37.5Hz) to improve memory recall.

Open questions

Amid the growing number of publications describing preclinical studies with mice and clinical trials with people, open questions remain, Tsai and Park acknowledge. The MIT team and others are still exploring the cellular and molecular mechanisms that underlie GENUS’s effects. Tsai said her lab is looking at other neuropeptide and neuromodulatory systems to better understand the cascade of events linking sensory stimulation to the observed cellular responses. Meanwhile the nature of how some cells, such as microglia, respond to gamma stimulation and how that affects pathology remains unclear, Tsai added.

Even with a national Phase III clinical trial underway, it is still important to investigate these fundamental mechanisms, Tsai said, because new insights into how non-invasive gamma stimulation affects the brain could improve and expand its therapeutic potential.

“The more we understand the mechanisms, the more we will have good ideas about how to further optimize the treatment,” Tsai said. “And the more we understand its action and the circuits it affects, the more we will know beyond Alzheimer’s disease what other neurological disorders will benefit from this.”

Indeed the review points to studies at MIT and other institutions providing at least some evidence that GENUS might be able to help with Parkinson’s disease, stroke, anxiety, epilepsy, and the cognitive side effects of chemotherapy and conditions that reduce myelin such as multiple sclerosis. Tsai’s lab has been studying whether it can help with Down syndrome as well.

The open questions may help define the next decade of GENUS research.

Source: Picower Institute at MIT

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VZV Reactivation Is Driving CNS Infections

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Varicella zoster vires (VZV). Credit: NIH/NIAID

The varicella zoster virus (VZV), an infectious virus from the herpes virus family, is primarily known to cause varicella in children and shingles in adults. But lately, this virus has also been reported to trigger severe complications like central nervous system (CNS) infections. Researchers from Fujita Health University, Japan, conducted a comprehensive study spanning 10 years (2013–2022), to identify the VZV-related infections affecting the CNS. Their study reveals a marked increase in adult VZV-related CNS infections, particularly since 2019. The findings were published in the journal Emerging Infectious Diseases.

The study was led by Professor Tetsushi Yoshikawa, along with Hiroki Miura and Ayami Yoshikane from the Department of Pediatrics, Fujita Health University School of Medicine. The researchers analysed cerebrospinal fluid samples of 615 adult patients with suspected CNS infections. VZV DNA was most frequently detected in these patients, with its presence in 10.2% of the cases, and aseptic meningitis being the most common infection.

The data from 2019 to 2022 revealed that there was a noticeable rise in VZV DNA-positive cases, forming a distinct temporal cluster during this period. Professor Yoshikawa highlighted the results of the patient demographic analysis, reporting that “the proportion of aseptic meningitis increased from 50% between 2013 and 2018 to 86.8% between 2019 and 2022.” He further adds, “Similar to the rise in herpes zoster cases through VZV reactivation in the elderly, we believe this increase is also linked to VZV reactivation.”

The universal varicella vaccination, introduced in Japan in 2014, has reduced the natural booster effects from re-exposure to the virus. This potentially accelerates the immunity decline, leading to VZV reactivation, especially in cases like shingles. The researchers highlight the connection between the vaccination and the current scenario, saying, “The increase in VZV-induced CNS infections coincides with changes in varicella vaccination programs and emphasises the need for better preventive strategies.”

Furthermore, the researchers examined trends in VZV-induced CNS infection throughout the observation period using Kulldorff’s circular spatial scan statistics. As a result, it was confirmed that there was an accumulation of VZV-related CNS infections from 2019 to 2022. Although no direct causation was established, six patients did develop CNS infections after receiving COVID-19 vaccines.

“Further studies are needed to understand these interactions,” Yoshikawa notes. None of the eligible patients in this study had received the zoster vaccine, which was introduced in Japan in 2016. Increasing the number of VZV-related CNS infections underscores the importance of zoster vaccination in adults.

The research team stresses the broader implications of their findings, stating that the reactivation of VZV in the CNS is linked to an increased risk of dementia, including Alzheimer’s disease. They hypothesize, “If the prevention of VZV-related aseptic meningitis through herpes zoster vaccination is possible, these vaccinations could play a pivotal role in mitigating these risks of dementia.”

To address the growing concern, the research team advocates expanding public health initiatives to promote zoster vaccination among at-risk populations. “Our research underscores the necessity of proactive measures to prevent not just shingles, but also severe neurological complications associated with VZV,” explains Yoshikawa.

With the rise of the aging population and CNS infections, the study calls for urgent action to evaluate and implement comprehensive vaccination strategies to prevent CNS infections in the future.

Source: Fujita Health University

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Scientists Discover that GLP-1 is Involved in Cocaine Addiction

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Photo by Colin Davis on Unsplash

Cocaine use disorder casts a long shadow, trapping individuals in a cycle of dependence and leaving limited options for effective treatment. A new study in Science Advances delves deep into the brain, offering crucial insights into the underlying mechanisms of this complex disorder. By understanding how this intricate circuitry functions, scientists can pave the way for the development of more effective therapies, offering new hope to those struggling with this debilitating disorder.

At the heart of this discovery lies the role of glucagon-like peptide-1 (GLP-1), a hormone known for its involvement in regulating food intake and blood sugar. The study reveals that chronic cocaine use is associated with reduced GLP-1 levels, effects that suggest that increasing central GLP-1 signalling could reduce cocaine seeking.

Further investigation pinpointed a specific brain circuit: GLP-1-producing neurons in the nucleus tractus solitarius (NTS) that project to the ventral tegmental area (VTA), a key brain region involved in reward and motivation. By manipulating this circuit, researchers were able to significantly reduce cocaine-seeking behavior in animal models.

The study also sheds light on the specific cells involved. GLP-1 receptors were found to be primarily located on GABA neurons within the VTA. GABA, an inhibitory neurotransmitter, plays a crucial role in regulating brain activity. Importantly, activating these GLP-1 receptors increases the activity of GABA neurons, which in turn reduces the activity of dopamine neurons, a key neurotransmitter involved in reward and addiction.

“This research provides exciting new insights into the brain mechanisms underlying cocaine seeking,” said Schmidt, the Killebrew-Censits Chair of Undergraduate Education and a Professor of Neuroscience and Pharmacology in the Department of Biobehavioral Health Sciences. “By understanding how GLP-1 signaling influences brain activity in this context, we can potentially develop new GLP-1-based treatments to treat cocaine use disorder.”

This research opens a new chapter in the fight against cocaine use disorder. The findings offer a promising avenue for developing innovative therapies that target this critical brain circuit, potentially offering a lifeline to individuals struggling to break free from the grip of this devastating disorder.

Source: University of Pennsylvania School of Nursing

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These Newly Discovered Brain Cells Enable us to Remember Objects

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Discovery of ‘ovoid cells’ reshapes our understanding of how memory works, and could open the door to new treatments for Alzheimer’s disease, epilepsy and more.

Ovoid cells. Photo credit: Dr. Mark Cembrowski

Take a look around your home and you’ll find yourself surrounded by familiar comforts – photos of family and friends on the wall, well-worn tekkies by the door, a shelf adorned with travel mementos.

Objects like these are etched into our memory, shaping who we are and helping us navigate environments and daily life with ease. But how do these memories form? And what if we could stop them from slipping away under a devastating condition like Alzheimer’s disease?

Scientists at the University of British Columbia have just uncovered a crucial piece of the puzzle. In a study published in Nature Communications, the researchers have discovered a new type of brain cell that plays a central role in our ability to remember and recognise objects. 

Called ‘ovoid cells,’ these highly-specialised neurons activate each time we encounter something new, triggering a process that stores those objects in memory and allowing us to recognise them months, even years, later.

“Object recognition memory is central to our identity and how we interact with the world,” said Dr Mark Cembrowski, the study’s senior author, and an associate professor of cellular and physiological sciences at UBC and investigator at the Djavad Mowafaghian Centre for Brain Health. “Knowing if an object is familiar or new can determine everything from survival to day-to-day functioning, and has huge implications for memory-related diseases and disorders.”

Hiding in plain sight

Named for the distinct egg-like shape of their cell body, ovoid cells are present in relatively small numbers within the hippocampus of humans, mice and other animals.

Adrienne Kinman, a PhD student in Dr Cembrowski’s lab and the study’s lead author, discovered the cells’ unique properties while analysing a mouse brain sample, when she noticed a small cluster of neurons with highly distinctive gene expression.

“They were hiding right there in plain sight,” said Kinman. “And with further analysis, we saw that they are quite distinct from other neurons at a cellular and functional level, and in terms of their neural circuitry.”

To understand the role ovoid cells play, Kinman manipulated the cells in mice so they would glow when active inside the brain. The team then used a miniature single-photon microscope to observe the cells as the mice interacted with their environment.

The ovoid cells lit up when the mice encountered an unfamiliar object, but as they grew used to it, the cells stopped responding. In other words, the cells had done their jobs: the mice now remembered the objects.

“What’s remarkable is how vividly these cells react when exposed to something new. It’s rare to witness such a clear link between cell activity and behaviour,” said Kinman. “And in mice, the cells can remember a single encounter with an object for months, which is an extraordinary level of sustained memory for these animals.”

New insights for Alzheimer’s disease, epilepsy

The researchers are now investigating the role that ovoid cells play in a range of brain disorders. The team’s hypothesis is that when the cells become dysregulated, either too active or not active enough, they could be driving the symptoms of conditions like Alzheimer’s disease and epilepsy.

“Recognition memory is one of the hallmarks of Alzheimer’s disease – you forget what keys are, or that photo of a person you love. What if we could manipulate these cells to prevent or reverse that?” said Kinman. “And with epilepsy, we’re seeing that ovoid cells are hyperexcitable and could be playing a role in seizure initiation and propagation, making them a promising target for novel treatments.”

For Dr Cembrowski, discovering the highly specialised neuron upends decades of conventional thinking that the hippocampus contained only a single type of cell that controlled multiple aspects of memory.

“From a fundamental neuroscience perspective, it really transforms our understanding of how memory works,” he said. “It opens the door to the idea that there may be other undiscovered neuron types within the brain, each with specialised roles in learning, memory and cognition. That creates a world of possibilities that would completely reshape how we approach and treat brain health and disease.”

Source: University of British Columbia

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‘Healthy’ Vitamin B12 Levels not Enough to Ward off Neuro Decline

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Meeting the minimum requirement for vitamin B12, needed to make DNA, red blood cells and nerve tissue, may not actually be enough – particularly if for older adults. It may even put them at risk for cognitive impairment, according to a study published in Annals of Neurology.

The research found that older, healthy volunteers, with lower concentrations of B12, but still in the normal range, showed signs of neurological and cognitive deficiency. These levels were associated with more damage to the brain’s white matter – the nerve fibres that enable communication between areas of the brain – and test scores associated with slower cognitive and visual processing speeds, compared to those with higher B12.

The UC San Francisco researchers, led by senior author Ari J. Green, MD, of the Departments of Neurology and Ophthalmology and the Weill Institute for Neurosciences, said that the results raise questions about current B12 requirements and suggest the recommendations need updating.

“Previous studies that defined healthy amounts of B12 may have missed subtle functional manifestations of high or low levels that can affect people without causing overt symptoms,” said Green, noting that clear deficiencies of the vitamin are commonly associated with a type of anaemia. “Revisiting the definition of B12 deficiency to incorporate functional biomarkers could lead to earlier intervention and prevention of cognitive decline.”

Lower B12 correlates with slower processing speeds, brain lesions

In the study, researchers enrolled 231 healthy participants without dementia or mild cognitive impairment, whose average age was 71. They were recruited through the Brain Aging Network for Cognitive Health (BrANCH) study at UCSF.

Their blood B12 amounts averaged 414.8pmol/L, well above the U.S. minimum of 148pmol/L. Adjusted for factors like age, sex, education and cardiovascular risks, researchers looked at the biologically active component of B12, which provides a more accurate measure of the amount of the vitamin that the body can utilize. In cognitive testing, participants with lower active B12 were found to have slower processing speed, relating to subtle cognitive decline. Its impact was amplified by older age. They also showed significant delays responding to visual stimuli, indicating slower visual processing speeds and general slower brain conductivity.

MRIs revealed a higher volume of lesions in the participants’ white matter, which may be associated with cognitive decline, dementia or stroke.

While the study volunteers were older adults, who may have a specific vulnerability to lower levels of B12, co-first author Alexandra Beaudry-Richard, MSc, said that these lower levels could “impact cognition to a greater extent than what we previously thought, and may affect a much larger proportion of the population than we realize.” Beaudry-Richard is currently completing her doctorate in research and medicine at the UCSF Department of Neurology and the Department of Microbiology and Immunology at the University of Ottawa.

“In addition to redefining B12 deficiency, clinicians should consider supplementation in older patients with neurological symptoms even if their levels are within normal limits,” she said. “Ultimately, we need to invest in more research about the underlying biology of B12 insufficiency, since it may be a preventable cause of cognitive decline.”

Source: University of California – San Francisco

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Scientists Discover Brain Mechanism that Helps Override Fear

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Coronal brain slice showing projections from different visual areas in the cerebral cortex to the ventrolateral geniculate nucleus (vLGN). These pathways are part of the circuit identified as mediating the suppression of instinctive fear responses.

Researchers at the Sainsbury Wellcome Centre (SWC) at UCL have unveiled the precise brain mechanisms that enable animals to overcome instinctive fears. Published today in Science, the study in mice could have implications for developing therapeutics for fear-related disorders such as phobias, anxiety and post-traumatic stress disorder (PTSD).

The research team, led by Dr Sara Mederos and Professor Sonja Hofer, mapped out how the brain learns to suppress responses to perceived threats that prove harmless over time. 

“Humans are born with instinctive fear reactions, such as responses to loud noises or fast-approaching objects,” explains Dr Mederos, Research Fellow in the Hofer Lab at SWC. “However, we can override these instinctive responses through experience – like children learning to enjoy fireworks rather than fear their loud bangs. We wanted to understand the brain mechanisms that underlie such forms of learning”.

Using an innovative experimental approach, the team studied mice presented with an overhead expanding shadow that mimicked an approaching aerial predator. Initially, the mice sought shelter when encountering this visual threat. However, with repeated exposure and no actual danger, the mice learned to remain calm instead of escaping, providing researchers with a model to study the suppression of fear responses. 

Based on the lab’s previous work, the team knew that the ventrolateral geniculate nucleus (vLGN) could suppress fear reactions when active and was able to track knowledge of previous experience of threat. The vLGN also receives strong input from visual areas in the cerebral cortex, and so the researchers explored whether this neural pathway had a role in learning not to fear a visual threat. 

The study revealed two key components in this learning process: (1) specific regions of the visual cortex proved essential for the learning process, and (2) a brain structure called the ventrolateral geniculate nucleus (vLGN) stores these learning-induced memories.

“We found that animals failed to learn to suppress their fear responses when specific cortical visual areas were inactivated. However, once the animals had already learned to stop escaping, the cerebral cortex was no longer necessary,” explained Dr Mederos.

“Our results challenge traditional views about learning and memory,” notes Professor Hofer, senior author of the study. “While the cerebral cortex has long been considered the brain’s primary centre for learning, memory and behavioural flexibility, we found the subcortical vLGN and not the visual cortex actually stores these crucial memories. This neural pathway can provide a link between cognitive neocortical processes and ‘hard-wired’ brainstem-mediated behaviours, enabling animals to adapt instinctive behaviours.”

The researchers also uncovered the cellular and molecular mechanisms behind this process. Learning occurs through increased neural activity in specific vLGN neurons, triggered by the release of endocannabinoids – known to regulate mood and memory. This release decreases inhibitory input to vLGN neurons, resulting in heightened activity in this brain area when the visual threat stimulus is encountered, which suppresses fear responses. 

The implications of this discovery extend beyond the laboratory. “Our findings could also help advance our understanding of what is going wrong in the brain when fear response regulation is impaired in conditions such as phobias, anxiety and PTSD. While instinctive fear reactions to predators may be less relevant for modern humans, the brain pathway we discovered exists in humans too,” explains Professor Hofer. “This could open new avenues for treating fear disorders by targeting vLGN circuits or localised endocannabinoid systems.”

The research team is now planning to collaborate with clinical researchers to study these brain circuits in humans, with the hope of someday developing new, targeted treatments for maladaptive fear responses and anxiety disorders.

Source: Sainsbury Wellcome Centre

Categories : Neurology Pain ManagementTags :

Epidural Steroid Injections for Chronic Back Pain

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The American Academy of Neurology (AAN) has developed a new systematic review to summarise for neurologists and other clinicians the evidence for epidural steroid injections and whether they reduce pain and disability for people with certain kinds of chronic back pain. The systematic review is published online in Neurology®.

It updates a 2007 assessment by the AAN. With an epidural steroid injection, a steroid or corticosteroid medication is injected into the epidural space with the aim of helping reduce certain kinds of back pain.

“Chronic back pain is common and can negatively impact a person’s quality of life, making it difficult to move, sleep and participate in daily activities,” said author Carmel Armon, MD, of Loma Linda University School of Medicine in California and a Fellow of the American Academy of Neurology. “In our review, studies show epidural steroid injections may have limited efficacy. They may modestly reduce pain in some situations for up to three months and reduce disability for some people for up to six months or more.”

For the review, researchers analysed all available studies over a 16-year period. A total of 90 studies were examined. The review focused on the use of epidural steroid injections to reduce pain for people with radiculopathy and spinal stenosis. Radiculopathy is a condition caused by a pinched nerve in your spine. Spinal stenosis is a condition where spinal cord or nerves have become compressed because the space around the spinal cord has become too small. For people with radiculopathy, the review says studies show epidural steroid injections may be effective at modestly reducing pain and disability for up to three months after the procedure.

When compared to people not receiving the treatment, 24% more people receiving the treatment reported reduced pain, and 16% more reported reduced disability for up to 3 months. The treatment may also reduce disability for up to six months or more, with 11% more of those treated reporting reduced disability. Most of the reviewed studies looked at people with radiculopathy in their lower backs, so it is unclear how effective the treatment is for those with radiculopathy in their necks. For people with spinal stenosis, studies show epidural steroid injections might modestly reduce disability for up to six months or more after the procedure.

When compared to people not receiving the treatment, 26% more people receiving the treatment reported reduced disability up to three months, and 12% more for up to six months or more. The treatment was not found to reduce pain for up to three months. All studies looked at people with stenosis in their lower backs, so researchers do not know how effective the treatment is for people with stenosis in their necks.

“Our review affirms the limited effectiveness of epidural steroid injections in the short term for some forms of chronic back pain,” said author Pushpa Narayanaswami, MD, of Beth Israel Deaconess Medical Center in Boston and a Fellow of the American Academy of Neurology. “We found no studies looking at whether repeated treatments are effective or examining the effect of treatment on daily living and returning to work. Future studies should address these gaps.”

Source: American Academy of Neurology

Categories : NeurologyTags :

The Surprising Link between Muscle Signalling and Brain Memory

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New research shows that how a network of subcellular structures is responsible for transmitting signals in neurons. This movie shows 3D renderings of these structures in high-resolution 3D electron microscopy images of fruit fly neurons. The endoplasmic reticulum (green), plasma membrane (blue), mitochondria (pink), microtubules (tan), and ER-plasma membrane contacts (magenta) are segmented from FIB-SEM datasets of a Drosophila melanogaster MBON1 neuron. Credit: Benedetti et al.

New research led by the Lippincott-Schwartz Lab shows that a network of subcellular structures similar to those responsible for propagating molecular signals that make muscles contract are also responsible for transmitting signals in the brain that may facilitate learning and memory.

“Einstein said that when he uses his brain, it is like he is using a muscle, and in that respect, there is some parallel here,” says Janelia Senior Group Leader Jennifer Lippincott-Schwartz. “The same machinery is operating in both cases but with different readouts.” The research appears in the journal Cell.

The first clue about the possible connection between brain and muscle cells came when Janelia scientists noticed something strange about the endoplasmic reticulum, or ER – the membranous sheets and folds inside cells that are crucial for many cellular functions.

Research scientist Lorena Benedetti was tracking molecules at high resolution along the surface of the ER in mammalian neurons when she saw that the molecules were tracing a repeating, ladder-like pattern along the entire length of the dendrites.

Around the same time, Senior Group Leader Stephan Saalfeld alerted Lippincott-Schwartz to high-resolution 3D electron microscopy images of neurons in the fly brain where the ER was also forming regularly spaced, transversal structures.

This movie shows time-lapse high-resolution imaging in neurons, revealing the dynamic behavior of ER tubules contrasted with the persistence of ER-PM junctional sites over time. Time-lapse acquired using 2D lattice-SIM in burst mode of HaloTag-Sec61β (labeled with JF585 HaloTag-ligand) expressing neurons. Scale bars: 0.5 μm. Credit: Benedetti et al.

The ER normally appears like a huge, dynamic net, so as soon as Lippincott-Schwartz saw the structures, she knew her lab needed to figure out what they were for.

“In science, structure is function,” says Lippincott-Schwartz, who also heads Janelia’s 4D Cellular Physiology research area. “This is an unusual, beautiful structure that we are seeing throughout the whole dendrite, so we just had this feeling that it must have some important function.”

The researchers, led by Benedetti, started by looking at the only other area of the body known to have similar, ladder-like ER structures: muscle tissue. In muscle cells, the ER and the plasma membrane – the outer membrane of the cell – meet at periodic contact sites, an arrangement controlled by a molecule called junctophilin.

Using high-resolution imaging, the researchers discovered that dendrites also contain a form of junctophilin that controls contact sites between their ER and plasma membrane. Further, the team found that the same molecular machinery controlling calcium release at muscle cells’ contact sites – where calcium drives muscle contraction – was also present at dendrite contact sites – where calcium regulates neuronal signalling.

Because of these clues, the researchers had a hunch that the molecular machinery at the dendritic contact sites must also be important for transmitting calcium signals, which cells use to communicate. They suspected that the contact sites along the dendrites might act like a repeater on a telegraph machine: receiving, amplifying, and propagating signals over long distances. In neurons, this could explain how signals received at specific sites on dendrites are relayed to the cell body hundreds of micrometres away.  

“How that information travels over long distances and how the calcium signal gets specifically amplified was not known,” says Benedetti. “We thought that ER could play that role, and that these regularly distributed contact sites are spatially and temporally localised amplifiers: they can receive this calcium signal, locally amplify this calcium signal, and relay this calcium signal over a distance.”

The researchers found that this process is triggered when a neuronal signal causes calcium to enter the dendrite through voltage-gated ion channel proteins, which are positioned at the contact sites. Although this initial calcium signal dissipates quickly, it triggers the release of additional calcium from the ER at the contact site.

Source: Howard Hughes Medical Institute

Categories : Cardiovascular Disease NeurologyTags :

Thrombolytic Drug Still Effective up to 24 Hours after Ischaemic Stroke Onset

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Credit: American Heart Association

The thrombolytic medication, alteplase, improved stroke patients’ recovery by more than 50% when given up to 24 hours after the beginning of an ischaemic stroke, according to preliminary late-breaking science presented at the American Stroke Association’s International Stroke Conference 2025.

These results give hope to stroke patients worldwide who may not be able to access thrombolytic medications within the approved time window, which in China is within 4.5 hours, said the trial’s principal investigator Min Lou, MD, PhD, a professor at the Second Affiliated Hospital of Zhejiang University’s School of Medicine in China.

In the US, alteplase is approved to treat stroke within three hours of symptom onset and is recommended for use up to 4.5 hours for select patients. Other research has indicated it may also work well in some patients 4.5 to 9 hours after stroke onset.

The American Heart Association/American Stroke Association 2019 Guidelines for the Early Management of Patients with Acute Ischemic Stroke note that IV alteplase within 4.5 hours of stroke onset is the standard of care for most ischaemic stroke patients in the United States.

Researchers enrolled 372 stroke patients whose symptoms began 4.5 hours to 24 hours earlier. They used widely available CT perfusion imaging (advanced brain scanning) to confirm that these patients still had brain tissue that could recover with treatment. Participants were randomised to receive alteplase, while the other received standard stroke care of antiplatelet therapy at the discretion of the investigator, based on the Chinese Guidelines for Diagnosis and Treatment of Acute Ischemic Stroke 2018. Functional recovery was assessed at 90 days.

“We believe these findings mean more people may return to normal or near-normal lives after a stroke, even if they receive treatment later than originally thought beneficial,” Lou said. “This method of treatment could become the new standard, especially in hospitals that use CT perfusion imaging. This technology helps health care professionals see how blood flows in different parts of the brain after an ischemic stroke. This could extend treatment eligibility to millions more patients across the globe.”

The study found:

  • 40% of participants treated with alteplase had little to no disability after 90 days, compared to 26% of those who received standard care – a 54% higher chance of functional recovery.
  • Less than 3% of participants in either group received rescue mechanical clot removal as an additional treatment.
  • Rates of death were the same (10.8%) for both groups.
  • The risk of brain bleeding was higher among those who received alteplase than among participants who did not (3.8% vs. 0.5%), but researchers believe this is a manageable risk.

“We also need to look more closely at how safe and effective other clot-dissolving medications, like tenecteplase, are when given after a stroke, especially beyond the usual time frames. It’s also important to learn if our findings apply to other groups of people, especially in areas with different stroke risks and health care resources,” Lou explained.

Study limitations include the that both participants and researcher knew which treatment was being given, which could have introduced bias, and results may not be generalizable to patients outside of China.

Study design, background and details:

  • The study enrolled 372 stroke patients in a multicenter, prospective, randomized trial at 26 stroke centers in China.
  • The patient’s average age was 72 years, and 43% were women.
  • The trial used widely available CT perfusion imaging software to gauge salvageable brain tissue, making the findings more applicable to real-world clinical settings.
  • Enrolled patients were assigned to the alteplase group or a standard medical treatment group.
  • The primary outcome was a score of 0 or 1 on the modified Rankin scale, which scores disability from 0 (no symptoms) to 6 (death) at 90 days.

Study co-authors, funding and disclosures are available in the abstract.

Source: American Heart Association