Category: Neurology

Categories : Neurology UrologyTags :

New Discovery Reveals the Spinal Cord’s Role in Bladder Control

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Urinary incontinence. Credit: Scientific Animations CC4.0

Urinary incontinence is a devastating condition, leading to significant adverse impacts on patients’ mental health and quality of life. Disorders of urination are also a key feature of all neurological disorders.

A USC research team has now made major progress in understanding how the human spinal cord triggers the bladder emptying process. The discovery could lead to exciting new therapies to help patients regain control of this essential function.

In the pioneering study, a team from USC Viterbi School of Engineering and Keck School of Medicine of USC has harnessed functional ultrasound imaging to observe real-time changes in blood flow dynamics in the human spinal cord during bladder filling and emptying.

The work was published in Nature Communications and was led by Charles Liu, the USC Neurorestoration Center director at Keck School of Medicine of USC and professor of biomedical engineering at USC Viterbi, and Vasileios Christopoulos, assistant professor at the Alfred E. Mann Department of Biomedical Engineering.

The spinal cord regulates many essential human functions, including autonomic processes like bladder, bowel, and sexual function. These processes can break down when the spinal cord is damaged or degenerated due to injury, disease, stroke, or aging. However, the spinal cord’s small size and intricate bony enclosure have made it notoriously challenging to study directly in humans.

Unlike in the brain, routine clinical care does not involve invasive electrodes and biopsies in the spinal cord due to the obvious risks of paralysis.

Furthermore, fMRI imaging, which comprises most of human functional neuroimaging, does not exist in practical reality for the spinal cord, especially in the thoracic and lumbar regions where much of the critical function localises.

“The spinal cord is a very undiscovered area,” Christopoulos said. “It’s very surprising to me because when I started doing neuroscience, everybody was talking about the brain. And Dr. Liu and I asked, “What about the spinal cord?”

“For many, it was just a cable that transfers information from the brain to the peripheral system. The truth was that we didn’t know how to go there—how to study the spinal cord in action, visualize its dynamics and truly grasp its role in physiological functions.”

Functional ultrasound imaging: A new window into the spinal cord

To overcome these barriers, the USC team employed functional ultrasound imaging (fUSI), an emerging neuroimaging technology that is minimally invasive. The fUSI process allowed the team to measure where changes in blood volume occur on the spinal cord during the cycle of urination.

However, fUSI requires a “window” through the bone to image the spinal cord. The researchers found a unique opportunity by working with a group of patients undergoing standard-of-care epidural spinal cord stimulation surgery for chronic low back pain.

“During the implantation of the spinal cord stimulator, the window we create in the bone through which we insert the leads gives us a perfect and safe opportunity to image the spinal cord using fUSI with no risk or discomfort to the study volunteers,” said co-first author Darrin Lee, associate director of the USC Neurorestoration Center, who performed the surgeries.

“While the surgical team was preparing the stimulator, we gently filled and emptied the bladder with saline to simulate a full urination cycle under anaesthesia while the research team gathered the fUSI data,” added Evgeniy Kreydin from the Rancho Los Amigos National Rehabilitation Center and the USC Institute of Urology, who was already working closely with Liu to study the brain of stroke patients during micturition using fMRI.

“This is the first study where we’ve shown that there are areas in the spinal cord where activity is correlated with the pressure inside the bladder,” Christopoulos said.

“Nobody had ever shown a network in the spinal cord correlated with bladder pressure. What this means is I can look at the activity of your spinal cord in these specific areas and tell you your stage of the bladder cycle – how full your bladder is and whether you’re about to urinate.”

Christopoulos said the experiments identified that some spinal cord regions showed positive correlation, meaning their activity increased as bladder pressure rose, while others showed negative (anti-correlation), with activity decreasing as pressure increased. This suggests the involvement of both excitatory and inhibitory spinal cord networks in bladder control.

“It was extremely exciting to take data straight from the fUSI scanner in the OR to the lab, where advanced data science techniques quickly revealed results that have never been seen before, even in animal models, let alone in humans,” said co-first author Kofi Agyeman, biomedical engineering postdoc.

New hope for patients

Liu has worked for two decades at the intersection of engineering and medicine to develop transformative strategies to restore function to the nervous system. Christopoulos has spent much of his research career developing neuromodulation techniques to help patients regain motor control.

Together, they noted that for patients, retaining control of the autonomic processes that many of us take for granted is more fundamental than even walking.

“If you ask these patients, the most important function they wanted to restore was not their motor or sensory function. It was things like sexual function and bowel and bladder control,” Christopoulos said, noting that urinary dysfunction often leads to poor mental health. “It’s a very dehumanising problem to deal with.”

Worse still, urinary incontinence leads to more frequent urinary tract infections (UTIs) because patients must often be fitted with a catheter. Due to limited sensory function, they may not be able to feel that they have an infection until it is more severe and has spread to the kidneys, resulting in hospitalisation.

This study offers a tangible path toward addressing this critical need for patients suffering from neurogenic lower urinary tract dysfunction. The ability to decode bladder pressure from spinal cord activity provides proof-of-concept for developing personalised spinal cord interfaces that could warn patients about their bladder state, helping them regain control.

Currently, almost all neuromodulation strategies for disorders of micturition are focused on the lower urinary tract, largely because the neural basis of this critical process remains unclear.

“One has to understand a process before one can rationally improve it,” Liu said.

This latest research marks a significant step forward, opening new avenues for precision medicine interventions that combine invasive and noninvasive neuromodulation with pharmacological therapeutics to make neurorestoration of the genitourinary system a clinical reality for millions worldwide.

Source: University of Southern Carolina

Categories : Mental Health NeurologyTags :

Astrocytes Identified as Hidden Culprit Behind PTSD

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Excessive astrocytic GABA impairs fear extinction in PTSD, new drug target offers hope for treatment

Figure 1. Astrocyte-Derived GABA and Therapeutic Effects of KDS2010 in PTSD. Brain imaging of PTSD patients revealed unusually high levels of GABA and reduced cerebral blood flow in the prefrontal cortex, showing that changes strongly correlated with symptom severity. In animal models, this excess GABA was traced to reactive astrocytes producing it abnormally due to increased MAOB and reduced levels of the GABA-degrading enzyme ABAT. This disrupted normal brain function and impaired the ability to extinguish fear. Treatment with KDS2010, a selective MAOB inhibitor, successfully lowered astrocytic GABA, restored brain activity, and rescued fear extinction, highlighting its potential as a therapeutic option. Credit: Institute for Basic Science

Why do patients with post traumatic stress disorder (PTSD) often struggle to forget traumatic memories, even long after the danger has passed? This failure to extinguish fear memories has long puzzled scientists and posed a major hurdle for treatment, especially since current medications targeting serotonin receptors offer limited relief for only a subset of patients.

In a new discovery, scientists at the Institute for Basic Science (IBS) and Ewha Womans University have uncovered a new brain mechanism driving PTSD – and a promising drug that may counteract its effects. The research is reported in Signal Transduction and Target Therapy.

Led by Dr C. Justin Lee at the IBS Center for Cognition and Sociality and Professor Lyoo In Kyoon at Ewha Womans University, the team has shown that excessive GABA (gamma-aminobutyric acid) produced by astrocytes, which are star-shaped support cells in the brain, impairs the brain’s ability to extinguish fear memories. This deficit is a core feature of PTSD and helps explain why traumatic memories can persist long after the threat has passed.

Crucially, the researchers found that a brain-permeable drug called KDS2010, which selectively blocks the monoamine oxidase B enzyme responsible for this abnormal GABA production, can reverse PTSD-like symptoms in mice. The drug has already passed Phase 1 safety trials in humans, making it a strong candidate for future PTSD treatments.

PTSD remains difficult to treat, with current medications targeting serotonin pathways providing limited relief for many patients. The new study focused on the medial prefrontal cortex (mPFC), a region of the brain critical for regulating fear, and found that PTSD patients had unusually high levels of GABA and reduced cerebral blood flow in this area. These findings emerged from brain imaging studies of more than 380 participants. Importantly, GABA levels decreased in patients who showed clinical improvement, pointing to the chemical’s central role in recovery.

To uncover the origin of this excess GABA, the researchers examined postmortem human brain tissue and used PTSD-like mouse models. They discovered that astrocytes, not neurons, were producing abnormal amounts of GABA via the enzyme monoamine oxidase B (MAOB). This astrocyte-derived GABA impaired neural activity, blocking the brain’s ability to forget traumatic memories.

When the researchers administered KDS2010, a highly selective, reversible MAOB inhibitor developed at IBS, the mice showed normalized brain activity and were able to extinguish fear responses. The drug reduced GABA levels, restored blood flow in the mPFC, and re-enabled memory extinction mechanisms. The study thus confirms astrocytic MAOB as a central driver of PTSD symptoms, and MAOB inhibition as a viable therapeutic path.

A major challenge of the study was linking clinical findings in humans with cellular mechanisms in the lab. The researchers addressed this by applying a “reverse translational” strategy: they began with clinical brain scans and moved backward to identify the cellular source of dysfunction, then confirmed the mechanism and tested drug effects in animal models. This approach led to a new understanding of how glial cells – long thought to be passive – actively shape psychiatric symptoms.

“This study is the first to identify astrocyte-derived GABA as a key pathological driver of fear extinction deficit in PTSD,” said Dr Won Woojin, a postdoctoral researcher and co-first author of the study. “Our findings not only uncover a novel astrocyte-based mechanism underlying PTSD, but also provide preclinical evidence for a new therapeutic approach using an MAOB inhibitor.”

Director C. Justin LEE, who led the study, emphasized that “This work represents a successful example of reverse translational research, where clinical findings in human guided the discovery of underlying mechanisms in animal models. By identifying astrocytic GABA as a pathological driver in PTSD and targeting it via MAOB inhibition, the study opens a completely new therapeutic paradigm not only for PTSD but also for other neuropsychiatric disorders such as panic disorder, depression, and schizophrenia.”

The researchers plan to further investigate astrocyte-targeted therapies for various neuropsychiatric disorders. With KDS2010 currently undergoing Phase 2 clinical trials, this discovery may soon lead to new options for patients whose symptoms have not responded to conventional treatments.

Source: Institute for Basic Science

Categories : NeurologyTags :

How the Brain Controls Its Blood Volume

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Inhibitory neurons and astrocytes hold the key to sharper functional brain imaging –

Image of an astrocyte, a subtype of glial cells. Glial cells are the most common cell in the brain. Credit: Pasca Lab, Stanford University NIH support from: NINDS, NIMH, NIGMS, NCATS

Researchers at the Center for Neuroscience Imaging Research within the Institute for Basic Science (IBS) have uncovered a two-step mechanism by which the brain regulates blood volume – a breakthrough with significant implications for how scientists understand and interpret functional magnetic resonance imaging (fMRI).

At the core of this study are somatostatin-expressing interneurons (SST neurons), a specialised type of inhibitory neuron. Among all neurons in the brain, approximately 15% are inhibitory neurons, but the role of these neurons in regulating cerebral blood volume has not been clearly elucidated in previous studies, with most of earlier research mainly focusing on the excitatory neurons. The new study by the IBS team sheds light on how inhibitory neurons interact with astrocytes, a type of support cell, to precisely control blood vessel dilation in the brain.

To unravel this complex process, the research team developed mouse models (e.g., SST-ChR2, SST-hM4Di) that allowed selective activation or inhibition of SST neurons. The researchers also used advanced neuroscience techniques in these mice. Specifically, they applied optogenetics and chemogenetics to precisely control the activity of these neurons. To observe the cellular and vascular responses, the team employed calcium imaging to visualise astrocyte activity, electrophysiology to measure neural signals, and intrinsic optical imaging (OIS) alongside ultra-high-field functional MRI (fMRI) to track blood volume dynamics with high spatial and temporal resolution.

Through these experiments, the team uncovered a two-step mechanism of vasodilation. In the early phase, SST neurons, when activated, released nitric oxide (NO) – a powerful vasodilator that triggered rapid and widespread expansion of nearby blood vessels. This was followed by a late phase, in which astrocytes became activated and induced slower, more localised vasodilation, especially during periods of prolonged sensory stimulation.

Figure 1. Somatostatin neurons regulate astrocytes surrounding cerebral blood vessels, enabling more precise delivery of blood volume to specific brain regions, thereby enhancing the spatial accuracy of neurovascular responses. Credit: Institute for Basic Science

Notably, when SST neurons were silenced, the layer-specific precision of blood volume signals observed in fMRI was lost – a finding that links cellular activity directly to spatial specificity in imaging data.

“This two-step mechanism involving inhibitory neurons and astrocytes helps explain why high-resolution fMRI can distinguish activity between different layers of the brain cortex,” the researchers explained. “Our study fills a major gap in understanding how neural signals are translated into the blood volume changes we measure in brain imaging.”

The team also overcame several technical challenges – including distinguishing overlapping signals and timing differences – by integrating multiple imaging techniques and running extensive repeat experiments to validate the causal link between SST neuron activity and vascular responses.

Their findings not only advance basic knowledge of neurovascular coupling, but also open new avenues for investigating neurological and psychiatric conditions in which SST neuron function is impaired, such as Alzheimer’s disease, depression, and autism. The group plans to study disease-model mice to identify how disruptions in this neuron–astrocyte–vascular pathway affect blood volume, brain function, and fMRI signals.

Ultimately, this research lays the groundwork for improving the accuracy of brain imaging interpretation and may lead to better diagnostic and therapeutic strategies for brain disorders.

Source: Institute for Basic Science

Categories : NeurologyTags :

Why Do We Need Sleep? Oxford Researchers Find the Answer May Lie in Mitochondria

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New study uncovers how a metabolic “overload” in specialised brain cells triggers the need to sleep.

Photo by Cottonbro on Pexels

Sleep may not just be rest for the mind – it may be essential maintenance for the body’s power supply. A new study by University of Oxford researchers, published in Nature, reveals that the pressure to sleep arises from a build-up of electrical stress in the tiny energy generators inside brain cells.

The discovery offers a physical explanation for the biological drive to sleep and could reshape how scientists think about sleep, ageing, and neurological disease.

Led by Professor Gero Miesenböck from the Department of Physiology, Anatomy and Genetics (DPAG), and Dr Raffaele Sarnataro at Oxford’s Centre for Neural Circuits and Behaviour, the team found that sleep is triggered by the brain’s response to a subtle form of energy imbalance. The key lies in mitochondria – microscopic structures inside cells that use oxygen to convert food into energy.

When the mitochondria of certain sleep-regulating brain cells (studied in fruit flies) become overcharged, they start to leak electrons, producing potentially damaging byproducts known as reactive oxygen species. This leak appears to act as a warning signal that pushes the brain into sleep, restoring equilibrium before damage spreads more widely.

‘You don’t want your mitochondria to leak too many electrons,’ said Dr Sarnataro. ‘When they do, they generate reactive molecules that damage cells.’

The researchers found that specialised neurons act like circuit breakers – measuring this mitochondrial electron leak and triggering sleep when a threshold is crossed. By manipulating the energy handling in these cells – either increasing or decreasing electron flow – the scientists could directly control how much the flies slept.

Even replacing electrons with energy from light (using proteins borrowed from microorganisms) had the same effect: more energy, more leak, more sleep.

Professor Miesenböck said: ‘We set out to understand what sleep is for, and why we feel the need to sleep at all. Despite decades of research, no one had identified a clear physical trigger. Our findings show that the answer may lie in the very process that fuels our bodies: aerobic metabolism. In certain sleep-regulating neurons, we discovered that mitochondria – the cell’s energy producers – leak electrons when there is an oversupply. When the leak becomes too large, these cells act like circuit breakers, tripping the system into sleep to prevent overload.’

The findings help explain well-known links between metabolism, sleep, and lifespan. Smaller animals, which consume more oxygen per gram of body weight, tend to sleep more and live shorter lives. Humans with mitochondrial diseases often experience debilitating fatigue even without exertion, now potentially explained by the same mechanism.

‘This research answers one of biology’s big mysteries,’ said Dr Sarnataro.

‘Why do we need sleep? The answer appears to be written into the very way our cells convert oxygen into energy.’

The paper, ‘Mitochondrial origins of the pressure to sleep‘, is published in Nature.

Source: University of Oxford

Categories : Implants and Prostheses NeurologyTags :

Building Better Cerebrospinal Fluid Shunts for the Brain

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Schematic of approach to simulating brain shunt fluid dynamics. Credit: Harvard SEAS

Millions of people worldwide suffer from hydrocephalus, a condition which recently received greater attention when Billy Joel announced his diagnosis. Treatment usually involves surgical placement of shunts to divert cerebrospinal fluid away, but this procedure often leads to complications, infections, and multiple re-treatments.  

Bioengineers in the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) have now developed a new computational model to aid the creation of shunts tailored to individual patients’ anatomy and needs. The model combines brain anatomy, fluid flow, and biomolecular transport dynamics to simulate shunt performance with pinpoint accuracy.

The work was supported by federal funding from the National Science Foundation and published in Proceedings of the National Academy of Sciences. It was led by SEAS postdoctoral fellow Haritosh Patel, who works in the labs of Joanna Aizenberg, Professor of Materials Science at SEAS and Professor of Chemistry and Chemical Biology; and Venkatesh Murthy, Professor of Molecular and Cellular Biology and Director of the Center for Brain Science.

Repeat surgeries due to infection or obstruction

Tens of thousands of shunt procedures are performed annually in the U.S. — many of which are repeat surgeries due to the inserted devices becoming blocked or obstructed, or the patient suffering an infection.

“Some elderly patients told me they had had over 10 surgeries — one every two to three years,” Patel said. “We really wanted to understand why this was happening, and we realised that many of these obstructions and infections were tied to shunt designs that didn’t fully consider fluid dynamics as a fundamental part of their geometry. We noticed that the tubing geometry used in shunts closely resembles the kind of piping we rely on in household plumbing. While that simplicity has its advantages, we saw an opportunity to explore more creative, biomimetic solutions that better suit the complexity of the brain’s environment.”

Pursuing the problem from both a material and design perspective, the team quickly realized there was no universally accepted fluid flow model for the brain ventricle space to guide them. “Okay, well, we can’t test our devices in a model, so why don’t we first make a better model?” Patel said.

Computational tool simulates fluid flow in brain

The result is their computational tool, called BrainFlow, which combines detailed anatomical and physiological features of the brain to simulate the flow of cerebrospinal fluid flow in the presence of shunt implants.

 The model incorporates patient-specific medical imaging data along with pulse-induced flow to mimic a patient’s cerebrospinal fluid dynamics, all to offer insight into optimal shunt design, placement, and even choice of materials.

“We believe that our model, combined with novel geometries and materials improvements such as anti-biofouling coatings developed in my lab, could lead to smoother integration of optimized, patient-specific medical devices into patients’ brains, with less likelihood of complications, and a better quality of life,” Aizenberg said.

The Harvard team is currently conducting studies that use the model to test different designs of shunts and calculate their efficacy.

Source: Harvard John A. Paulson School of Engineering and Applied Sciences

Categories : NeurologyTags :

New Discovery Reveals Dopamine Operates with Surgical Precision

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Neurotransmitters at a synapse. Credit: Scientific Animations CC4.0

A new study from the University of Colorado Anschutz Medical Campus has upended decades of neuroscience dogma by revealing that the neurotransmitter dopamine communicates in the brain with extraordinary precision – not broad diffusion as previously believed. This groundbreaking research offers fresh hope for millions of people living with dopamine-related disorders, marking a significant advance in the quest for precision-based neuroscience and medicine.

For years, scientists thought of dopamine as a kind of chemical “broadcast system,” flooding large areas of the brain to influence behaviour. But new research, published in Science, found that dopamine acts more like a finely-tuned postal service, delivering highly localised messages to specific nerve cell branches at exact moments in time.

“Our current research found that dopamine signaling and transmission in the brain is much more complex than we thought,” said Christopher Ford, PhD, professor at the University of Colorado School of Medicine and lead author. “We knew that dopamine plays a role in many different behaviours, and our work gives the beginning of a framework for understanding how all those different behaviours could all be regulated by dopamine.”

‘We are really only at the tip of the iceberg in trying to understand how dysfunctions in dopamine contribute to diseases like Parkinson’s disease, schizophrenia or addiction.’

– Christopher Ford, PhD

Using advanced microscopy techniques, researchers found that dopamine is released in concentrated hotspots which enable targeted, rapid responses in nearby brain cells, while broader signals activate slower, widespread effects. This dual signaling system allows dopamine to simultaneously fine-tune individual neural connections and orchestrate complex behaviours like movement, decision-making, and learning.

The implications are far-reaching: dopamine system dysfunction plays a central role in a wide range of brain disorders, including Parkinson’s disease, addiction, schizophrenia, ADHD and depression. Current treatments largely focus on restoring overall dopamine levels – but this research suggests that the precision of dopamine signalling may be just as crucial.

“We are really only at the tip of the iceberg in trying to understand how dysfunctions in dopamine contribute to diseases like Parkinson’s disease, schizophrenia or addiction,” said Ford. “More work is needed to grasp how these specific changes in dopamine signalling are affected in these different neurological and psychiatric diseases. The goal, of course, would then be to build on those findings to come up with new and improved treatments for those disorders.”

Source: University of Colorado Anschutz Medical Campus

Categories : Neurology Regenerative MedicineTags :

Scientists Discover the Mechanism for Peripheral Nerve Regeneration

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Weizmann Institute scientists have discovered hundreds of molecules that promote nerve regeneration in mice – and may even encourage growth in brain neurons

Top: Overexpression of genes from the B2-SINE family in retinal ganglion neurons led to accelerated growth after injury. Bottom: Ganglion cells after injury without B2-SINE overexpression. Credit: Weizmann Institute of Science

Unlike the brain and spinal cord, peripheral nerve cells, whose long extensions reach the skin and internal organs, are capable of regenerating after injury. This is why injuries to the central nervous system are considered irreversible, while damage to peripheral nerves can, in some cases, heal, even if it takes months or years. Despite decades of research, the mechanisms behind peripheral nerve regeneration remain only partially understood.

In a new study published in Cell, researchers from Prof Michael (Mike) Fainzilber’s lab at the Weizmann Institute of Science discovered that a family of hundreds of RNA molecules with no known physiological function is essential to nerve regeneration. Remarkably, the study showed that these molecules can stimulate growth not only in the peripheral nervous system of mice but also in their central nervous system. These findings could pave the way for new treatments for a variety of nerve injuries and neurodegenerative diseases.

For a peripheral nerve to regenerate, it must maintain communication between the neuron’s cell body and its long extension – the axon – which in humans can reach more than a meter in length. In a series of studies over the past two decades, Fainzilber’s lab has revealed key components of this communication: proteins that act like postal couriers, delivering instructions for the production of growth-controlling factors and other proteins, from the cell body to the axon. These molecular couriers also help assess the distance between the cell body and the axon tip, allowing the neuron to modulate its growth accordingly. Yet one central issue remained: What triggers the regenerative growth after injury, and why does this not happen in central nervous system cells?

“While the growth acceleration observed in our study is not yet sufficient to address clinical paralysis, it is definitely significant”

In the new study, Dr Indrek Koppel of Fainzilber’s lab, in collaboration with Dr Riki Kawaguchi of the University of California, Los Angeles (UCLA), examined a specific kind of gene expression in the peripheral nerves of mice following injury. The researchers were surprised to find that one day after damage, the neurons increased the expression of an entire family of short genetic sequences called B2-SINEs, whose role was previously unknown. These sequences do not encode any proteins, and because they are known for “jumping” around the genome, meaning that they can appear at the wrong place or time, they have a bad reputation. But the researchers found that after injury, the neurons began expressing many B2-SINE RNA transcripts, in parallel with other processes preparing the cell for regeneration and repair.

However, B2-SINE is an enormous family, comprising some 150 000 sequences scattered throughout the mouse genome. The initial analysis could not determine which of these were responsible for promoting growth. Dr. Eitan Erez Zahavi, also of Fainzilber’s lab, who led the new study alongside Koppel, used bioinformatics tools to identify 453 B2-SINE sequences that are highly expressed after injury, promoting nerve growth. Collaborating with international research teams, the scientists showed that this overexpression after injury is unique to peripheral nerve cells and does not occur in the central nervous system.

The periphery leads, the center follows

The researchers then tested whether B2-SINEs from peripheral nerve cells could also stimulate neuronal growth in the central nervous system. They induced retinal neurons in mice to overexpress RNA molecules of the B2-SINE type and observed faster regeneration after injury. A similar experiment in the mouse motor cortex – the brain region that controls muscle movement via long axons projecting to the spinal cord – showed that neurons expressing high levels of B2-SINE also regenerated faster than control neurons.

“There are still no effective treatments to accelerate nerve cell growth and regeneration,” Fainzilber notes. “While the growth acceleration observed in our study is not yet sufficient to address clinical paralysis, it is definitely significant. Of course, the path from basic research to clinical application is long, and we must make sure that enhancing growth mechanisms does not, for example, increase the risk of cancer.”

One final mystery remained: How do B2-SINE RNA molecules actually promote regeneration? With help from Prof Alma L. Burlingame’s group at the University of California, San Francisco, the researchers discovered that these RNAs promote a physical link between the molecular “couriers” carrying instructions for producing growth-associated proteins and the ribosomes that read these instructions and carry them out. This means that production of the critical factors takes place closer to the cell body rather than to the tip of the axon. The researchers believe that this signals to the neuron that it is “too small,” triggering a growth response.

“There are over a million sequences called Alu elements in the human genome, the human equivalent of B2-SINEs in mice,” says Fainzilber. “These molecules had been previously shown to bind to ribosomes and mail couriers, but why this happens was unknown. We’re now trying to determine whether Alu or other noncoding RNA elements are involved in nerve regeneration in humans.”

“Recovery from peripheral nerve injuries, or from systemic diseases like diabetes that affect these nerves, can be very slow,” he adds. “That’s why we’re now testing a therapy that might speed up regeneration by mimicking B2-SINE activity. This therapy involves small molecules that connect the couriers to ribosomes while keeping them close to the nerve cell body, promoting faster growth. We are conducting this research in collaboration with Weizmann’s Bina unit for early-stage research with applicative potential.”

Beyond promoting peripheral nerve regeneration, the new study also hints at an even broader prospect: regeneration in the central nervous system. “We are currently working with UCLA on a study showing that the mechanism we discovered plays a role in recovery from stroke in mouse models,” Fainzilber says. “Additionally, we’re collaborating with Tel Aviv University, Hebrew University and Sheba Medical Center to study its possible role in ALS, a progressive neurodegenerative disease. Neurodegenerative conditions affect many millions of people worldwide. While the road ahead is long, I truly hope we’ll one day be able to harness our newly discovered regeneration mechanism to treat them.”

Science Numbers

After injury, the axon of a peripheral nerve cell regrows at a rate of around 1 millimetre a day.

Source: Weizmann Institute of Science

Categories : Lab Tests and Imaging NeurologyTags :

Researchers Discover a Significant Problem in Brain Imaging, Identify Fix

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Photo by Mart Production on Pexels

In a new study, investigators from McLean Hospital (a member of Mass General Brigham), Harvard Medical School, and the National Institute on Drug Abuse Intramural Research Program (NIDA-IRP) discovered that the tendency of people’s arousal to wane over the course of brain scans has been distorting the brain connection maps produced by functional magnetic resonance imaging (fMRI).

The study is out now in Nature Human Behaviour.

The team found that as people’s arousal levels dwindle during an fMRI, such as if they become more relaxed and sleepy, changes in breathing and heart rates alter blood oxygen levels in the brain—which are then falsely detected on the scan as neuronal activity.

“You’re laying down in a snug scanner for quite some time, often with only a low-engagement button press task to attend to or nothing to do at all, as the scanner monotonously hums and vibrates around you,” said first author Cole Korponay, PhD, MPA, a research fellow at the McLean Hospital Imaging Center. “These arousal-dampening conditions create the illusion that people’s brain connection strengths continuously inflate throughout the scan.”

fMRI scans are commonly used to non-invasively map brain connectivity, but the technique relies on changes in brain blood oxygen to indirectly measure neuronal activity. It is therefore vulnerable to “noise” from other processes that can affect blood oxygen – such as changes in breathing and heart rates.

And because breathing and heart rate patterns are closely tied to arousal levels, changes in arousal can introduce significant noise into fMRI data. Problematically, the conditions of an fMRI scan tend to progressively lull people into lower arousal states.

In the present study, the research team identified a specific blood flow signal that seemed to track both the decline in subject arousal levels and the illusory inflation of functional brain connection strengths.

This non-neuronal, physiological noise signal, termed the “systemic low frequency oscillation” (sLFO) signal, grew over time during scanning, in a spatial and temporal pattern that closely followed the pattern of the connection strength increases.

The researchers then demonstrated that a method called RIPTiDe, developed by co-senior author Blaise Frederick, PhD, an associate biophysicist at the McLean Imaging Center, to remove the sLFO signal from fMRI data, was able to eliminate the illusory connection strength increases.

“By adopting this sLFO denoising procedure, future studies can mitigate the distortive effects of arousal changes during brain scans and enhance the validity and reliability of fMRI findings,” said Korponay.

This research was supported by the National Institute on Drug Abuse, the National Institute of Mental Health, and the National Institute on Aging, all part of the National Institutes of Health.

Source: Mass General Brigham McLean Hospital

Categories : NeurologyTags :

People with ‘Young Brains’ Outlive ‘Old-brained’ Peers, Research Finds

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Image created with Gencraft AI

A blood-test analysis developed at Stanford Medicine can determine the “biological ages” of 11 separate organ systems in individuals’ bodies and predict the health consequences.

Beside our chronological age, research has shown that we also have what’s called a “biological age,” a cryptic but more accurate measure of our physiological condition and likelihood of developing aging-associated disorders from heart trouble to Alzheimer’s disease.

How old someone’s internal organs are is a challenge to determine compared to looking at wrinkles and greying hair. Internal organs are ageing at different speeds, too, according to a new study by Stanford Medicine investigators.

“We’ve developed a blood-based indicator of the age of your organs,” said Tony Wyss-Coray, PhD, professor of neurology and neurological sciences and director of the Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute. “With this indicator, we can assess the age of an organ today and predict the odds of your getting a disease associated with that organ 10 years later.”

They can even predict who is most likely to die from medical conditions associated with one or more of the 11 separate organ systems the researchers looked at: brain, muscle, heart, lung, arteries, liver, kidneys, pancreas, immune system, intestine and fat.

The brain is the gatekeeper of longevity. If you’ve got an old brain, you have an increased likelihood of mortality. If you’ve got a young brain, you’re probably going to live longer.”

The biological age of one organ, the brain, plays an outsized role in determining how long you have left to live, Wyss-Coray said.

“The brain is the gatekeeper of longevity,” he said. “If you’ve got an old brain, you have an increased likelihood of mortality. If you’ve got a young brain, you’re probably going to live longer.”

Wyss-Coray is the senior author of the study, published online July 9 in Nature Medicine. The lead author is Hamilton Oh, PhD, a former graduate student in Wyss-Coray’s group.

Eleven organ systems, 3000 proteins, 45 000 people

The scientists used 44 498 randomly selected participants, ages 40 to 70, who were drawn from the UK Biobank. This ongoing effort has collected multiple blood samples and updated medical reports from some 600 000 individuals over several years. These participants were monitored for up to 17 years for changes in their health status.

Wyss-Coray’s team made use of an advanced commercially available laboratory technology that counted the amounts of nearly 3000 proteins in each participant’s blood. Some 15% of these proteins can be traced to single-organ origins, and many of the others to multiple-organ generation.

The researchers fed everybody’s blood-borne protein levels into a computer and determined the average levels of each of those organ-specific proteins in the blood of those people’s bodies, adjusted for age. From this, the scientists generated an algorithm that found how much the composite protein “signature” for each organ being assessed differed from the overall average for people of that age.

Based on the differences between individuals’ and age-adjusted average organ-assigned protein levels, the algorithm assigned a biological age to each of the 11 distinct organs or organ systems assessed for each subject. And it measured how far each organ’s multiprotein signature in any given individual deviated in either direction from the average for people of the same chronological age. These protein signatures served as proxies for individual organs’ relative biological condition. A greater than 1.5 standard deviation from the average put a person’s organ in the “extremely aged” or “extremely youthful” category.

One-third of the individuals in the study had at least one organ with a 1.5-or-greater standard deviation from the average, with the investigators designating any such organ as “extremely aged” or “extremely youthful.” One in four participants had multiple extremely aged or youthful organs.

For the brain, “extremely aged” translated to being among the 6% to 7% of study participants’ brains whose protein signatures fell at one end of the biological-age distribution. “Extremely youthful” brains fell into the 6% to 7% at the opposite end.

Health outcomes foretold

The algorithm also predicted people’s future health, organ by organ, based on their current organs’ biological age. Wyss-Coray and his colleagues checked for associations between extremely aged organs and any of 15 different disorders including Alzheimer’s and Parkinson’s diseases, chronic liver or kidney disease, Type 2 diabetes, two different heart conditions and two different lung diseases, rheumatoid arthritis and osteoarthritis, and more.

Risks for several of those diseases were affected by numerous different organs’ biological age. But the strongest associations were between an individual’s biologically aged organ and the chance that this individual would develop a disease associated with that organ. For example, having an extremely aged heart predicted higher risk of atrial fibrillation or heart failure, having aged lungs predicted heightened chronic obstructive pulmonary disease (COPD) risk, and having an old brain predicted higher risk for Alzheimer’s disease.

The association between having an extremely aged brain and developing Alzheimer’s disease was particularly powerful: 3.1 times that of a person with a normally aging brain. Meanwhile, having an extremely youthful brain was especially protective against Alzheimer’s – barely one-fourth that of a person with a normally aged brain.

In addition, Wyss-Coray said, brain age was the best single predictor of overall mortality. Having an extremely aged brain increased subjects’ risk of dying by 182% over a roughly 15-year period, while individuals with extremely youthful brains had an overall 40% reduction in their risk of dying over the same duration.

Predicting the disease, then preventing it

“This approach could lead to human experiments testing new longevity interventions for their effects on the biological ages of individual organs in individual people,” Wyss-Coray said.

Medical researchers may, for example, be able to use extreme brain age as a proxy for impending Alzheimer’s disease and intervene before the onset of outward symptoms, when there’s still time to arrest it, he said.

Careful collection of lifestyle, diet and prescribed- or supplemental-substance intake in clinical trials, combined with organ-age assessments, could throw light on the medical value of those factors’ contributions to the aging of various organs, as well as on whether existing, approved drugs can restore organ youth before people develop a disease for which an organ’s advanced biological age puts them at high risk, Wyss-Coray added.

If commercialised, the test could be available in the next two to three years, Wyss-Coray said. “The cost will come down as we focus on fewer key organs, such as the brain, heart and immune system, to get more resolution and stronger links to specific diseases.”

Source: Stanford University

Categories : Neurology Pain ManagementTags :

From Injury to Agony: The Brain Pathway that Turns Pain into Suffering

On By ModernMedia

Salk scientists uncover a key neural circuit in mice that gives pain its emotional punch, opening new doors for treating fibromyalgia, migraine, and PTSD


CGRP-expressing neurons (green) in the parvocellular subparafascicular nucleus (SPFp) of the thalamus.
Credit: Salk Institute

More than just a physical sensation, pain also carries emotional weight. That distress, anguish, and anxiety can turn a fleeting injury into long-term suffering.

Salk Institute researchers have now identified a brain circuit that gives physical pain its emotional tone, revealing a new potential target for treating chronic and affective pain conditions such as fibromyalgia, migraine, and post-traumatic stress disorder (PTSD).

Published in PNAS, the study identifies a group of neurons in a central brain area called the thalamus that appears to mediate the emotional or affective side of pain in mice. This new pathway challenges the textbook understanding of how pain is processed in the brain and body.

“For decades, the prevailing view was that the brain processes sensory and emotional aspects of pain through separate pathways,” says senior author Sung Han, associate professor and holder of the Pioneer Fund Developmental Chair at Salk. “But there’s been debate about whether the sensory pain pathway might also contribute to the emotional side of pain. Our study provides strong evidence that a branch of the sensory pain pathway directly mediates the affective experience of pain.”

The physical sensation of pain allows immediate detection, assessment of its intensity, and identification of its source. The affective part of pain is what makes it so unpleasant – the emotional discomfort motivates avoidance.

This is a critical distinction. Most people start to perceive pain at the same stimulus intensities, meaning the sensory side of pain is processed similarly. But the ability to tolerate pain varies greatly. The degree of suffering or feeling threatened by pain is determined by affective processing, and if that becomes too sensitive or lasts too long, it can result in a pain disorder. This makes it important to understand which parts of the brain control these different dimensions of pain.

Sensory pain was thought to be mediated by the spinothalamic tract, a pathway that sends pain signals from the spinal cord to the thalamus, which then relays them to sensory processing areas across the brain.

Affective pain was generally thought to be mediated by a second pathway called the spinoparabrachial tract, which sends pain information from the spinal cord into the brainstem.

However, previous studies using older research methods have suggested the circuitry of pain may be more complex. This long-standing debate inspired Han and his team to revisit the question with modern research tools.

Using advanced techniques to manipulate the activity of specific brain cells, the researchers discovered a new spinothalamic pathway in mice. In this circuit, pain signals are sent from the spinal cord into a different part of the thalamus, which has connections to the amygdala, the brain’s emotional processing center. This particular group of neurons in the thalamus can be identified by their expression of CGRP (calcitonin gene-related peptide), a neuropeptide originally discovered in Professor Ronald Evans’ lab at Salk.

When the researchers “turned off” (genetically silenced) these CGRP neurons, the mice still reacted to mild pain stimuli, such as heat or pressure, indicating their sensory processing was intact. However, they didn’t seem to associate lasting negative feelings with these situations, failing to show any learned fear or avoidance behaviors in future trials. On the other hand, when these same neurons were “turned on” (optogenetically activated), the mice showed clear signs of distress and learned to avoid that area, even when no pain stimuli had been used.

“Pain processing is not just about nerves detecting pain; it’s about the brain deciding how much that pain matters,” says first author Sukjae Kang, a senior research associate in Han’s lab. “Understanding the biology behind these two distinct processes will help us find treatments for the kinds of pain that don’t respond to traditional drugs.”

Many chronic pain conditions—such as fibromyalgia and migraine—involve long, intense, unpleasant experiences of pain, often without a clear physical source or injury. Some patients also report extreme sensitivity to ordinary stimuli like light, sound, or touch, which others would not perceive as painful.

Han says overactivation of the CGRP spinothalamic pathway may contribute to these conditions by making the brain misinterpret or overreact to sensory inputs. In fact, transcriptomic analysis of the CGRP neurons showed that they express many of the genes associated with migraine and other pain disorders.

Notably, several CGRP blockers are already being used to treat migraines. This study may help explain why these medications work and could inspire new nonaddictive treatments for affective pain disorders.

Han also sees potential relevance for psychiatric conditions that involve heightened threat perception, such as PTSD. Growing evidence from his lab suggests that the CGRP affective pain pathway acts as part of the brain’s broader alarm system, detecting and responding to not only pain but a wide range of unpleasant sensations. Quieting this pathway with CGRP blockers could offer a new approach to easing fear, avoidance, and hypervigilance in trauma-related disorders.

Importantly, the relationship between the CGRP pathway and the psychological pain associated with social experiences like grief, loneliness, and heartbreak remains unclear and requires further study.

“Our discovery of the CGRP affective pain pathway gives us a molecular and circuit-level explanation for the difference between detecting physical pain and suffering from it,” says Han. “We’re excited to continue exploring this pathway and enabling future therapies that can reduce this suffering.”

Source: Salk Institute