Tag: neuroscience

Categories : Mental Health NeurologyTags :

Lithium Brain Variations Play Role in Depression

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New research into depression has uncovered a previously unknown role played by the trace element lithium appears to play a role, which has been shown to be different in healthy and depressive people. 

Image source: Pixabay

Lithium is widely known from rechargeable batteries but is also known in psychiatry as a first-line mood stabiliser for bipolar disorders. lithium is present in drinking water in trace amounts. Studies have shown that a higher natural lithium content in drinking water is associated with a lower suicide rate among the population. However, the exact role lithium that plays in the brain is still not known.

Forensic medical experts at Ludwig-Maximilians-Universitaet (LMU) in Munich teamed up with physicists and neuropathologists at the Technical University of Munich (TUM) and an expert team from the Research Neutron Source Heinz Maier-Leibnitz (FRM II) to develop a technique which can be used to precisely map the distribution of lithium in the brain.

Neutrons probe for lithium

The scientists investigated the brain of a patient who was a suicidal and compared it with two control persons. The investigation focused on the ratio of the lithium concentration in white brain matter to the concentration in the gray matter of the brain.

In order to determine where how much lithium is present in the brain, the researchers analysed 150 samples from various brain regions—for example those regions which are presumably responsible for processing feelings. At the FRM II Prompt Gamma-Ray Activation Analysis (PGAA) instrument the researchers irradiated thin brain sections with neutrons.

“One lithium isotope is especially good at capturing neutrons; it then decays into a helium atom and a tritium atom,” explains Dr. Roman Gernhäuser of the Central Technology Laboratory of the TUM Department of Physics. The two decay products are picked up by detectors which provide lithium’s location in the brain sections. 

Since the lithium concentration in the brain is usually very low, it is also very difficult to ascertain. “Until now it wasn’t possible to detect such small traces of lithium in the brain in a spatially resolved manner,” said Dr Jutta Schöpfer of the LMU Munich Institute for Forensic Medicine. “One special aspect of the investigation using neutrons is that our samples are not destroyed. That means we can repeatedly examine them several times over a longer period of time,” Gernhäuser points out.

Significant differences

“We saw that there was significantly more lithium present in the white matter of the healthy person than in the gray matter. By contrast, the suicidal patient had a balanced distribution, without a measurable systematic difference,” Dr Roman Gernhäuser summarised.

“Our results are fairly groundbreaking, because we were able for the first time to ascertain the distribution of lithium under physiological conditions,” Schöpfer said

“Since we were able to ascertain trace quantities of the element in the brain without first administering medication and because the distribution is so clearly different, we assume that lithium indeed has an important function in the body.”

Only the beginning

“Of course the fact that we were only able to investigate brain sections from three persons marks only a beginning,” Gernhäuser said. “However, in each case we were able to investigate many different brain regions which confirmed the systematic behaviour.”

“We would be able to find out much more with more patients, whose life stories would also be better known,” said Gernhäuser, adding that then the question of whether lithium distribution was a cause or a result of depression.

Source: Medical Xpress

Categories : NeurologyTags :

Use of Robotic ‘Third Thumb’ Reorganises Brain Area

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Image source: Pixabay

Scientists have found that adding an extra robotic “thumb” worn by healthy individuals results in reorganisation and shrinkage of the brain region devoted to controlling the other thumb.

The findings come from ongoing research at University College London (UCL) into a 3D-printed robotic thumb known as “Third Thumb.” Worn on the dominant hand and operated by moving the big toe, volunteers equipped with them rapidly learned how to use the extra thumb to do all sorts of tasks—lifting, carrying, sorting and stacking multiple objects with their single enhanced hand.

However, MRI scans showed that after just a few days, participants’ brains had reorganised the natural hand’s ‘representation’ in a region associated with movement, effectively shrinking it. The researchers are not sure whether this is good or bad.

But they said it should give the growing field of ‘motor augmentation’ something to consider going forward.

Motor augmentation refers to robotic devices that can act as extra fingers or even a whole arm, with the aim of expanding the normal human movement capacity.

It might sound like science fiction but there a whole range of real applications, according to researcher Dani Clode, the designer of the Third Thumb.

She cited the example of factory workers or engineers who routinely perform repetitive but physically demand tasks.

“An extra pair of hands or digits could assist them in difficult assembly situations, allowing them to do their job in a more safe and efficient way, and perhaps without assistance from others,” Clode said.

Workers already make use of robotic exoskeletons to reduce strain in physically demanding tasks, such as working underneath cars in assembly lines.

Tamar Makin, a professor of cognitive neuroscience at UCL, said robotic appendages could be used in everything from high-precision scenarios—like surgery—to mundane chores.

“There are so many things we could do if we had hand extension,” Makin said. “We could chop vegetables while stirring a broth, or sip our coffee while typing. The opportunities are endless, but because this is such a novel concept—and because our world has been designed to accommodate our five-fingered two hands—people might struggle to imagine what it could be used for.”

Though these robotic upgrades offer so many possibilities, there are many unknowns. And these latest findings, published May 19 in the journal Science Robotics, raise questions.

Makin, Clode and their colleagues had 36 able-bodied volunteers learn to use the Third Thumb, performing tasks in and out the lab.

The device is worn on the pinkie side of the hand, attached by straps that wrap around the wrist and palm. The wearer operates it by manipulating sensors strapped under each big toe.

Despite that complicated-sounding toe-robot coordination, the study participants became adept at using the thumb over just five days, the researchers said.

Some change in the brain is expected because the additional thumb forced people to alter the way they moved their hand, Makin said.

“What surprised us is how quickly this happened,” she said. “After five days of practice to use the thumb, their own hand representation—which they’ve been developing over the course of their entire life—has changed.”

The ability to use their natural fingers showed no signs of degradation, but that is something they will monitor going forward.

Neurologist Dr Eran Klein, an affiliate assistant professor at the University of Washington, who studies the intersection of neurology and philosophy, said he was unsure how much weight to give the new study’s findings. “The brain changes all the time in response to learning skills,” Klein noted.

Still, he believes the study raises interesting questions. Broadly, Klein said, there’s the matter of “what is lost” when humans outsource skills to devices, such as losing navigational ability with the use of GPS. With robotic appendages, Klein said, one issue is whether they’re inherently different from any other tool people use—like a screwdriver.

He noted that since the devices are worn on the body and resemble human digits or limbs, so it probably does. The question is what happens to the ‘schema’ of the body, but there are examples — such as people who use a cane, for instance, can start to feel it’s part of them, Klein pointed out.

“I think what’s interesting about this study,” he said, “is that it brings up the bigger question of, what are we going to allow as things that become ‘part of us’?”

Source: Medical Xpress

Categories : NeurologyTags :

Neural Connectivity can Predict Epilepsy Outcomes

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Researchers have found that neuron connectivity patterns within brain regions can better indicate disease progression and treatment outcomes for people with brain disorders such as epilepsy.

Many brain diseases lead to cell death and the removal of connections within the brain. A team led by Dr Marcus Kaiser from the School of Medicine at the University of Nottingham looked at epilepsy patients undergoing surgery. Their findings were published in Human Brain Mapping.

They found that changes in the local network within brain regions can predict disease progression, and also whether surgery will be successful or not.

The team found that looking at connectivity within regions of the brain, showed superior results compared to only observing fibre tract connectivity between brain regions, which is the current method. Dividing the surface of the brain into 50 000 network nodes of comparable size, each brain region could be studied as a local network with 100-500 nodes. There were distinct changes seen in these local networks in patients suffering from epileptic seizures.

Employing diffusion tensor imaging, a special measurement protocol for MRI scanners, the team of scientists showed that fibres within and between brain regions are removed for patients.

However, they found that connectivity within regions better predicted whether surgical removal of brain tissue was successful in preventing future seizures.

Dr Kaiser, Professor of Neuroinformatics at the University of Nottingham, explained: “When someone has an epileptic seizure, it ‘spreads’ through the brain. We found that local network changes occurred for regions along the main spreading pathways for seizures. Importantly, regions far away from the starting point of the seizure, for example in the opposite brain hemisphere, were involved.

“This indicates that the increased brain activity during seizures leads to changes in a wide range of brain regions. Furthermore, the longer patients suffered, the more regions showed local changes and the more severe were these changes.”

The researchers from the involved universities, along with the company Biomax, evaluated the scans of 33 temporal lobe epilepsy patients and 36 control subjects.

Project partners used the NeuroXM™ knowledge management platform to develop a knowledge model for high-resolution connectivity with more than 50 000 cortical nodes and several millions of connections and corresponding automated processing pipelines accessible through Biomax’s neuroimaging product NICARA™.

Project manager Dr Markus Butz-Ostendorf from Biomax said: “Our software can be easily employed at hospitals and can also be combined with other kinds of data from genetics or from other imaging approaches such as PET, CT, or EEG.”

Professor Yanjiang Wang, who is one of the corresponding authors, and Ms Xue Chen, both from China University of Petroleum (East China), commented: “Local connectivity was not only better in overall predictions but particularly successful in identifying patients where surgery did not lead to any improvement, identifying 95% of such cases compared to 90% when used connectivity between regions”.

Source: University of Nottingham

Categories : Injury & Trauma NeurologyTags :

Why Nerves Fail to Regenerate

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Image source: Pixabay

Though there are many reasons why nerves fail to regenerate, researchers from Ruhr-Universität Bochum (RUB) have made a breakthrough in their discovery a new mechanism which could lead to effective treatments.

Damage to nerve fibers in the central nervous system – brain, spinal cord, or optic nerve– often results in lifelong and severe disabilities, such as paraplegia or blindness. Though there are various known reasons why nerves fail to regenerate, treating them has not thus far not resulted in success.

Now, the RUB researchers have discovered that nerves release a protein at the injury site that attracts growing nerve fibres — and keeps them entrapped there. This prevents them from growing in the right direction to bridge the injury. Their findings are published in the journal Proceedings of the National Academy of Science (PNAS).

There are three known main causes for the inability of injured nerves of the central nervous system (CNS) to regenerate: insufficient activation of a regeneration program in injured nerve cells that stimulates the growth of fibres, so-called axons; scar formation at the injury site that is difficult for nerve fibres to penetrate; and an inhibitory effect of molecules in the nerve on regrowing axons. “Although experimental approaches have been found in recent decades to address these individual aspects by therapeutic means, even combinatorial approaches have shown only little success,” said Fischer. “So there must be other yet unknown causes for why nerve fibres in the CNS don’t regenerate.”

Using the optic nerve as a model, the research time has now shown another — quite surprising — cause for the regenerative failure in the CNS. The underlying mechanism is not based on inhibition of axon growth, as in the previously identified causes, but instead on a positive effect of a protein at the injury site on the nerve. This molecule is a so-called chemokine known as CXCL12. “The protein actually promotes the growth of axons and attracts regenerating fibers. It is, therefore, chemoattractive,” explained lead investigator Professor Dietmar Fischer. However, this chemoattraction turned out to be more hindrance than help after nerve injury in living animals.

Nerve fibres are trapped

The scientists showed that this protein is released at the nerve’s lesion site and, as a result, keeps the axons at the injured area through the chemoattractive effect. As a result, even some fibres that had already regenerated across the injury site reversed direction, growing backwards to the injury site. The regrowing fibers thus remained trapped due to CXCL12’s attractive effect.

The researchers figured out this effect when they knocked out the receptor for CXCL12 in the retinal nerve cells, rendering them blind to this protein. “Surprisingly, this led to greatly increased fibre growth in the injured optic nerves, and axons showed significantly less regrowth back to the injury site,” Dietmar Fischer points out.

New drug possibilities

The researchers then investigated where at the injury site the CXCL12 originated. They found out that about eight percent of the nerve cells in the retina produce this protein themselves, transport it along their fibers to the injury site in the optic nerve, and release it there from the severed axons. “It is still unknown why some of these nerve cells make CXCL12 and others make the receptor,” said Prof Fischer. “We don’t yet understand the physiological role of the protein, but we can see that it is a major inhibitor of neural repair.”

In further experiments, the researchers showed that knocking out CXCL12 in retinal nerve cells to prevent its release at the injury site equally improved axonal regeneration into the optic nerve. “These new findings open the opportunity to develop pharmacological approaches aimed at disrupting the interaction of CXCL12 and its receptor on the nerve fibres, to free them from their captivity at the site of injury,” concluded Prof Fischer.

His team is now investigating whether similar approaches can also promote the regeneration of axons in other areas of the injured brain or spinal cord.

Source: Ruhr-Universität Bochum

Journal information: Alexander M. Hilla, et al. CXCR4/CXCL12-mediated entrapment of axons at the injury site compromises optic nerve regeneration, in: PNAS, 2021, DOI: 10.1073/pnas.2016409118

Categories : Genetics NeurologyTags :

Researchers Close in on Genetic Cure for Congenital Deafness

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Researchers are a step closer in the quest to use gene therapy to enable people born deaf to hear, having uncovered a new role for a key protein.

The study, published in Molecular Biology of the Cell, focused on a large gene responsible for an inner-ear protein called otoferlin. Otoferlin mutations are linked to severe congenital hearing loss, a common type of deafness in which patients can hear almost nothing.

“For a long time otoferlin seemed to be a one-trick pony of a protein,” explained Colin Johnson, associate professor of biochemistry and biophysics in the Oregon State UniversityCollege of Science. “A lot of genes will find various things to do, but the otoferlin gene had appeared only to have one purpose and that was to encode sound in the sensory hair cells in the inner ear. Small mutations in otoferlin render people profoundly deaf.”

Because the otoferlin gene is too big as it normally is to package into a delivery vehicle for molecular therapy, Prof Johnson’s team explored the use of a shortened version.

Research led by graduate student Aayushi Manchanda showed the shortened version needed to have part of the gene known as the transmembrane domain, for a surprising reason: without it, the sensory cells matured slowly.

“That was surprising since otoferlin was known to help encode hearing information but had not been thought to be involved in sensory cell development,” Johnson said.

For years, scientists in Prof Johnson’s lab have been working with the otoferlin molecule and in 2017 they identified a shortened form of the gene that can function in the encoding of sound.

To find out if the transmembrane domain of otoferlin needed to be part of the shortened version of the gene, Manchanda shortened the transmembrane domain in zebrafish.

Zebrafish are a small freshwater species that is very popular as a research organism. They grow rapidly, from a cell to a swimming fish in about five days, and share a remarkable similarity to humans at the molecular, genetic and cellular levels due to the conservation of mammalian genes early in their evolution. Embryonic zebrafish are transparent and easily maintained, and are amenable to genetic manipulation.

“The transmembrane domain tethers otoferlin to the cell membrane and intracellular vesicles but it was not clear if this was essential and had to be included in a shortened form of otoferlin,” Manchanda said. “We found that the loss of the transmembrane domain results in the sensory hair cells producing less otoferlin as well as deficits in hair cell activity. The mutation also caused a delay in the maturation of the sensory cells, which was a surprise. Overall the results argue that the transmembrane domain must be included in any gene therapy construct.”

At the molecular level, Manchanda found that a lack of transmembrane domain led to otoferlin not properly linking the neurotransmitter-filled synaptic vesicles to the cell membrane, resulting in less neurotransmitter being released.

“Our study suggests otoferlin’s ability to tether the vesicles to the cell membrane is a key mechanistic step for neurotransmitter release during the encoding of sound,” Manchanda said.

Source: EurekaAlert!

Categories : NeurologyTags :

Two-way Signalling Discovered in Certain Neurons

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It was long thought that information travelled in a one-way direction, but a new study has revealed that information also travels in the opposite direction at a key synapse in the hippocampus, the brain region responsible for learning and memory. 

Now, Peter Jonas and his group at the Institute of Science and Technology Austria (IST Austria) have demonstrated that information can also travel in the opposite direction at a key synapse in the hippocampus. At the ‘mossy fibre synapse’, the post-synaptic CA3 neuron influences the firing of the post-synaptic ‘mossy fibre neuron’. Their work was published in Nature Communications.

“We have shown, for the first time, that a retrograde information flow is physiologically relevant for pre-synaptic plasticity,” said Yuji Okamoto, a postdoc in the group of Peter Jonas at IST Austria and co-first author of the paper published in Nature Communications.

In the neuronal network, the mossy fibre synapse play a key role in information storage. Synaptic transmission is plastic, meaning that a variable amount of neurotransmitter is released into the synapse. To understand the mechanism of plasticity at work in this synapse, Okamoto precisely stimulated the pre-synaptic terminal of the mossy fibre synapse in rats and at the same time recorded electrical properties at the post-synaptic neuron. “We need to know the synapse’s exact properties—with the numerical values, eg, for its conductance—to create an exact model of this synapse. With his exact measurements, Yuji managed to obtain these numbers,” added Peter Jonas, co-corresponding author with postdoc David Vandael.

Smart teacher balances student’s workload

The researchers found that, unexpectedly, the post-synaptic neuron has an influence on plasticity in the pre-synaptic neuron. Previously the assumption was that the mossy fibre was a ‘teacher synapse’, inducing firing in the post-synaptic neuron. “Instead, we find that this synapse acts like a ‘smart teacher’, who adapts the lessons when students are overloaded with information. Similarly, the pre-synaptic mossy fibre detects when the post-synaptic neuron can’t take more information: When activity increases in the post-synaptic neuron, the pre-synaptic neuron reduces the extent of plasticity,” explained Jonas.

This finding raises the question of how the post-synaptic neuron sends information about its activity status to the pre-synaptic neuron. Pharmacological evidence suggests a role for glutamate, one of the key neurotransmitters used by neurons to send signals to other cells. Glutamate is also the transmitter released from pre-synaptic mossy fibre terminals. When calcium levels increase in the post-synaptic neuron—a sign that the neuron is active—the post-synaptic neuron may release vesicles with glutamate into the synapse. The glutamate travels back to the pre-synaptic neuron, against the usual flow of neuronal information.

“This retrograde modulation of plasticity likely helps to improve information storage in the downstream hippocampal network,” said Jonas, adding: “Once again, exact measurements have shown that reality is more complex than a simplified model would suggest.”

Source: Institute of Science and Technology Austria

Journal information: David Vandael et al. Transsynaptic modulation of presynaptic short-term plasticity in hippocampal mossy fiber synapses, Nature Communications (2021). DOI: 10.1038/s41467-021-23153-5

Categories : Medical Research & Technology NeurologyTags :

Brain-computer Interface Lets Paralysed People Write Letters

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Image by Gerd Altmann from Pixabay

Researchers have developed a new brain-computer interface (BCI) that can let paralysed people write by mentally writing letters by hand.

Working with a participant with paralysis who has sensors implanted in his brain, the team used an algorithm to identify letters in real time as he attempted to write them, putting the results on a screen.

This technology could be further developed to allow people with paralysis type rapidly without using their hands, said study coauthor Krishna Shenoy, a Howard Hughes Medical Institute Investigator at Stanford University who jointly supervised the work with Jaimie Henderson, a Stanford neurosurgeon.

By attempting handwriting, the study participant was able to ‘type’ 90 characters per minute — more than double the previous record for typing with such a brain-computer interface.

Thought-powered communication

Even if injury or disease the ability to move, the brain’s neural activity for being able to do so remains. By making use of this activity, researchers can help people with paralysis or amputations regain lost abilities.

In recent years, Shenoy’s team has decoded the neural activity associated with speech in the hopes of reproducing it. Patients with implanted sensors mentally pointed at and clicked on letters on a screen to type at about 40 characters per minute, the previous speed record for typing with a BCI.
Wanting to try something new and different, Frank Willett, a neuroscientist in Shenoy’s group, wondered if it might be possible to harness the brain signals evoked by writing by hand “We want to find new ways of letting people communicate faster,” he said. 

The team worked with a participant enrolled in a clinical trial involving BCIs. Henderson implanted two tiny sensors into the part of the brain that controls the hand and arm, making it possible for the person to, for example, move a robotic arm or a cursor on a screen by attempting to move their own paralysed arm.
The participant, who was 65 years old at the time of the research, had a spinal cord injury that left him paralysed from the neck down. A machine learning algorithm recognised the patterns his brain produced when he attempted to write each letter.

With this system, the man could copy sentences and answer questions at a rate similar to that of someone his age typing on a smartphone. The reason why this so-called “Brain-to-Text” BCI is so fast is because each letter elicits a highly distinctive activity pattern, making it relatively easy for the algorithm to distinguish one from another, Willett explained.

A new system

Shenoy’s team envisions using attempted handwriting for text entry as part of a more comprehensive system that also includes point-and-click navigation, much like that used on current smartphones, and even attempted speech decoding. “Having those two or three modes and switching between them is something we naturally do,” he said.
The team intends to next work with a participant who cannot speak, such as a person with amyotrophic lateral sclerosis, a degenerative neurological disorder leading to loss of movement and speech.

The new system could potentially help those suffering from paralysis caused by a number of conditions, Henderson added. Those include brain stem stroke, which afflicted Jean-Dominique Bauby, the author of the book The Diving Bell and the Butterfly. “He was able to write this moving and beautiful book by selecting characters painstakingly, one at a time, using eye movement,” Henderson said. “Imagine what he could have done with Frank’s handwriting interface!”

Source: Howard Hughes Medical Institute

Categories : Mental Health NeurologyTags :

Scientists Find How Enriched Environments Boost Brains

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Image by Colin Behrens from Pixabay

A recent study in Frontiers in Molecular Neuroscience has shown how environmental enrichment ‘opens up’ chromosomes through the action of ‘master switches’.

Environmental enrichment, that is, making stimulating and interesting surroundings, is often used in zoos, laboratories, and farms to stimulate animals and increase their wellbeing.

Stimulating environments are better for mental health and cognition because they boost the growth and function of neurons and their connections, the glia cells that support and feed neurons, and blood vessels within the brain. But what are the deeper molecular mechanisms that first set in motion these large changes in neurophysiology? 

The study investigators utilised a large molecular toolbox to map how environmental enrichment leads to changes in the 3D organisation of chromosomes in neurons and glia cells of the mouse brain, which change the activation of some genes within the genome. 

They show that genes which in humans are important for cognitive mental health are particularly affected, possibly leading to new treatments.

Chromosome ‘opens up’ with enrichment

“Here we show for the first time, with large-scale data from many state-of-the-art methods, that young adolescent mice that grew up in an extra stimulating environment have highly specific ‘epigenetic’ changes—that is, molecular changes other than in DNA sequence—to the chromosomes within the cells of the brain cortex,” said corresponding author Dr Sergio Espeso-Gil from the Centre for Genomic Regulation in Barcelona, Spain.

He continued, “These increase the local ‘openness’ and ‘loopiness’ of the chromosomes, especially around DNA stretches called enhancers and insulators, which then fine-tune more ‘downstream’ genes. This happens not only in neurons but also in the supportive glia cells, too often ignored in studies about learning.”

The team raised mice for the first month after birth in social groups inside housing with Lego blocks, ladders, balls, and tunnels that were frequently changed and moved around. As a control, other mice were raised in smaller groups inside standard housing. The researchers then used a variety of tools to pick up molecular changes in neurons and glia cells within the brain cortex. These included alterations in the 3D structure of chromosomes, particularly the local “chromatin accessibility” (openness) and “chromatin interactions” (where distant genes are brought together through loops, to coordinate activity). Chromatins are the proteins which make up chromosomes, carrying DNA and the proteins to package them.

Epigenetic ‘master’ switches

They show that two ‘master’ switches operational after environmental enrichment increase chromatin interactions and another increases chromatin availability, important for the pyramidal neurons involved in cognition. A third works on a key chromosomal protein histone H3, activating nearby genes as a result.

These switches mainly occur around genomic regions that contain enhancers, regulatory DNA that (when bound to proteins called transcription factors) can activate neighboring genes. Also affected were genomic regions with insulators, regulatory DNA that can override the gene-activating effect of neighboring enhancers.

The team concluded that growing up in an enriched environment causes highly local and specific epigenetic changes in neurons and glia cells. These then mostly increase the activity of a few genes within the genome.

Mental health in humans

“Our results show that many of the genes involved are known to play a role in the growth and differentiation of neurons, the development of blood vessels, the formation and patterning of new synaptic connections on neurons, and molecular pathways implicated in memory and learning in mice,” said Dr Espeso-Gil.

“And when we look for parallel regions in the human genome, we find many regions that are statistically associated with differences in complex traits such as insomnia, schizophrenia, and Alzheimer’s in humans, which means that our study could inform future research on these disorders. This points to the potential of environmental enrichment in therapies for mental health. Our research could also help to guide future research on chromatin interactions and the poorly known importance of glial cells for cognitive mental health.”

Source: Medical Xpress

Journal information: Sergio Espeso-Gil et al, Environmental Enrichment Induces Epigenomic and Genome Organization Changes Relevant for Cognition, Frontiers in Molecular Neuroscience (2021). DOI: 10.3389/fnmol.2021.664912

Categories : Neurology PaediatricsTags :

Early Interventions May Improve Infant Brain Health

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Image by Raman Oza from Pixabay

At the Cognitive Neuroscience Society’s (CNS) annual meeting, researchers from the University of Minnesota presented their work on early interventions to ameliorate negative effects on infant brain health.

Their two interventions consist of using engineered gut microbes for antibiotic-exposed infants and the other is a choline supplement to treat infants exposed to alcohol in the womb.

Dr Gale’s new research shows that infants with different compositions of gut bacteria process auditory and visual stimuli differently during memory tasks. “These results raise the possibility that gut bacteria are involved in the development of brain function,” she said.

The study compared the brain activity of infants who received antibiotics within their first month of life to those who did not. Using EEG, the researchers recorded a type of electrical activity called event related potentials (ERPs) in the infants’ brains in response to either their mother’s voice or a stranger’s voice – a “recognition memory” that can be assessed in preverbal infants before any behavioral changes are apparent. This has been shown to be an effective assessment of many aspects of cognitive development.

“Recognition memory is one of the earliest types of explicit memory to develop and is known to be dependent on medial temporal lobe structures, including the hippocampus, the brain region affected by microbiome perturbation in animal models,” explained Dr Cheryl Gale, of the University of Minnesota.

The ERP measurements of infants exposed to antibiotics showed an abnormal response to their mother’s voices compared to those unexposed.
While antibiotics were associated with impact on brain function, a causal relationship could not be established. “We don’t yet know if there is a definitive cause and effect relationship between microbes and brain function in human infants, but future research will hopefully be able to shed light on this,” Gale says.

The work raises the prospect of creating engineered microbes as an early life intervention. “Infancy is a critical time window for brain development, when therapeutic interventions can have effects for the life-course,” Gale said.

The other study was on foetal alcohol exposure, which is still a widespread problem, involved in some 8 in 1000 births worldwide, resulting in serious cognitive consequences. Dr Jeff Wozniak became aware of a lack of neural imaging studies in this very high-need population.

“So I became interested in using some of the tools that we had available here at the University of Minnesota to do high-quality imaging of brain structure and function in this understudied population to learn something about how the brain is altered by prenatal alcohol exposure at the earliest stages of development,” he said.

Together with colleagues, they identified a number of pathways by which alcohol impacts the foetus, such as interfering with the myelination of nerves. The researchers came up with a treatment: choline, an essential nutrient. This has been used in a number of double-blind, placebo-controlled clinical trials in 2-5 year olds with foetal alcohol exposure.
Children receiving choline early in life showed higher non-verbal intelligence, higher visual-spatial skill, higher working memory ability, better verbal memory, and fewer behavioral symptoms of attention deficit hyperactivity disorder (ADHD) than those in the placebo group.

“The further back you go and do your intervention, the more leverage you have to alter the developmental trajectory of that particular child,” Dr Wozniak said. “So that was the exciting thing about bringing those children back and looking at their development and seeing much larger choline versus placebo effects in cognitive functions like working memory and even behavioural differences in terms of ADHD.”

Source: News-Medical.Net

Categories : Mental Health NeurologyTags :

Repurposed Drug Exploits Ion Channel in The Brain To Treat Depression

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Researchers from the Icahn School of Medicine at Mount Sinai Hospital have repurposed a drug to treat depression by using an ion channel that is a completely different mechanism than regular antidepressants.

A study demonstrated that a drug called ezogabine, which opens KCNQ2/3 type of potassium channels in the brain, is linked to significant improvements in depressive symptoms and anhedonia (a lack of ability to feel pleasure) in patients with depression. Anhedonia is a complex, core symptom of depression and is associated with poor outcomes such as increased risk of suicide and reduced responsiveness to antidepressants.
Ezogabine is an anticonvulsant for epilepsy treatment; this novel application in treating depression opens up the investigation of the KCNQ2/3 channel as a potential drug target.

“Our study is the first randomized, placebo-controlled trial to show that a drug affecting this type of ion channel in the brain can improve depression and anhedonia in patients. Targeting this channel represents a completely different mechanism of action than any currently available antidepressant treatment,” said Professor James Murrough, MD, PhD, at the Icahn School of Medicine at Mount Sinai, and senior author of the paper.

The KCNQ2/3 channel belongs to the KCNQ (or Kv7) family of ion channels which are important controllers of brain cell excitability and function in the central nervous system, affecting brain cell function by controlling electrical charge flow across the cell membrane in the form of potassium (K+) ions. Previous research in mice also showed involvement of KCNQ2/3 in depression. Mice that were more resilient to stress had increased KCNQ2/3 channels in their brains.

“We viewed enhanced functioning of the KCNQ channel as a potential molecular mechanism of resilience to stress and depression,” said Ming-Hu-Han, PhD, who also discovered that by increasing the activity of this channel, such as by administering ezogabine, to depressed mice, the drug acted as an antidepressant.

A trial with adult human patients showed that, compared to placebo, those treated with ezogabine showed a large reduction in a number of key measures of depression severity, anhedonia, and overall illness severity.
“The fundamental insight by Dr Han’s group that a drug that essentially mimicked a mechanism of stress resilience in the brain could represent a whole new approach to the treatment of depression was very exciting to us,” said Dr Murrough.

In collaboration with Dr Han, Dr Murrough carried out a series of human studies, with an initial open-label (no placebo) study in patients with depression providing initial evidence that ezogabine could improve symptoms of depression and anhedonia.

“I think it’s fair to say that most of us on the study team were quite surprised at the large size of the beneficial effect of ezogabine on clinical symptoms across multiple measures related to depression. We are greatly encouraged by these findings and the hope they offer for the prospect of developing novel, effective treatments for depression and related disorders. New treatments are urgently needed given that more than one-third of people suffering from depression are inadequately treated with currently approved therapeutics.”

Source: Eureka Alert