TL;DR

• Conducted in partnership with the University of California San Francisco (UCFC), researchers found that changes in micromovements of the brain — termed ‘headpulses’ — could detect the lasting impacts of a concussion. Using a custom-designed headset to evaluate headpulse biometrics among 101 amateur male and female Australian Rules Football players in South Australia, researchers identified brain abnormalities in 81% of players inflicted by concussion, signaling sustained injury beyond expected recovery times.
• Researchers have produced an engineered tissue representing a simplified cerebral cortex by 3D printing human stem cells. When implanted into mouse brain slices, the structures became integrated with the host tissue. The technique may ultimately be developed into tailored repairs to treat brain injuries.
• Scientists have created a new zebrafish xenograft platform to screen for novel treatments for an aggressive brain tumor called glioblastoma, according to a new study.
• A new study reveals the crucial role of vascular system cells — known as pericytes — in the formation of long-term memories of life events — memories that are lost in diseases such as Alzheimer’s disease.
• Researchers have illuminated one of the important ways that cells respond to stress. The findings could also be relevant to Alzheimer’s, ALS, and other diseases in which this mechanism may be abnormally active.
• Scientists have invested decades in piecing together how our vision is so good at recognizing what’s familiar. A new study overcomes an apparent discrepancy in data to reveal a new insight into how it works.
• A new study has provided the first clear picture of where language processes are located in the brain. The findings may be useful in clinical trials involving language recovery after brain injury.
• Scientists have used cutting-edge imaging techniques to shed light on the progression of Parkinson’s disease by studying how the main culprit, the protein alpha-synuclein, disrupts cellular metabolism.
• In lonely people, the boundary between real friends and favorite fictional characters gets blurred in the part of the brain that is active when thinking about others, a new study found.
• Short-term exposure to air pollution may be linked to an increased risk of stroke, according to a meta-analysis published in Neurology. Short-term exposure was defined as occurring within five days of the stroke.

Neuroscience market

The global neuroscience market size was valued at USD 28.4 billion in 2016 and it is expected to reach USD 38.9 billion by 2027.

The latest news and research

Headpulse Biometric Measures Following Concussion in Young Adult Athletes

by Cathra Halabi, Lynda Norton, Kevin Norton, Wade S. Smith in JAMA Network Open

Novel brain biometrics could help inform whether an athlete is ready to return to play following a concussion, according to new research from the University of South Australia.

Conducted in partnership with the University of California San Francisco (UCFC), researchers found that changes in micromovements of the brain — termed ‘headpulses’ — could detect the lasting impacts of a concussion.

Using a custom-designed headset* to evaluate headpulse biometrics among 101 amateur male and female Australian Rules Football players in South Australia, researchers identified brain abnormalities in 81% of players inflicted by concussion, signaling sustained injury beyond expected recovery times.

Study cohorts drawn from the Australian and University of California San Francisco Concussion Study in Athletes (AUSSIE), which included feasibility (A1) and validation (A2) phases. An individual was considered enrolled if they provided at least 1 headpulse recording. One concussed individual in the A2 cohort sustained 2 concussions separated by more than 1 month. Recordings with excess body motion or poor quality electrocardiogram recordings were excluded; this led to the exclusion of 1 control participant. Biometric onset and offset analysis required 2 or more recordings in the first week following injury; 12 individuals were excluded (5 because of poor quality recording and 7 withdrew after the first recording) resulting in 32 individuals for temporal analysis.

These headpulse alterations lasted 14 days beyond concussion symptoms and were exacerbated by return-to-play or unsupervised physical activity.

UniSA Professor of Exercise Science Kevin Norton says that headpulse measures could complement current return-to-play protocols.

“Traumatic brain injury inflicts more than 60 million people every year, with a third of these being sports-related,” Prof Norton says. “While we know that Australia’s sports sector takes concussions seriously — via considered return-to-play protocols — we also know that objective measures of concussion recovery are not fully established.

“In this research, we used headpulses — a normal measure of brain ‘wobble’ aligned with each heartbeat — to assess any changes in frequency resulting from a concussion. We discovered that almost all players who received a concussion had a ‘disconnect’ between their symptoms and the headpulse, such that even when the players said they felt good, the headpulse still showed evidence of brain injury.”

While most players felt that they’d recovered 10–14 days after their injury, the research showed that some players took up to four weeks to recover and return to normal headpulse patterns.

Biometric Z Scores and Neurobehavioral Symptom Inventory (NSI) Scores for 30 Days Following Concussion. A, individuals who did return to play (RTP) had marked increases in Z scores in the latter half of the month compared with those who did not. Most players who RTP had done so by day 14 (5 by day 7, 11 by day 14; indicated with black arrows). B, NSI scores plotted for individuals who RTP compared with those who did not showed that most individuals who RTP were symptom free for the second half of the month. NSI scores were lower in those who RTP.

Australian Football concussion recovery protocols require 24 to 48 hours of strict physical and cognitive rest, followed by graded individual then team training, provided there is no symptom exacerbation; the earliest allowed return-to-play after protocol completion and medical clearance is 12 days after a concussion.

The Australian Senate Committee’s report Concussions and repeated head trauma in contact sports released this month, recommends that national sporting associations should explore further rule modifications for sports to prevent and reduce the impact of concussions and repeated head traumas.

This research contributes to the growing body of knowledge that informs concussion protocols.

Integration of 3D-printed cerebral cortical tissue into an ex vivo lesioned brain slice

by Yongcheng Jin, Ellina Mikhailova, Ming Lei, Sally A. Cowley, Tianyi Sun, Xingyun Yang, Yujia Zhang, Kaili Liu, Daniel Catarino da Silva, Luana Campos Soares, Sara Bandiera, Francis G. Szele, Zoltán Molnár, Linna Zhou, Hagan Bayley in Nature Communications

Researchers have produced an engineered tissue representing a simplified cerebral cortex by 3D printing human stem cells. When implanted into mouse brain slices, the structures became integrated with the host tissue.

The breakthrough technique developed by University of Oxford researchers could one day provide tailored repairs for those who suffer brain injuries. The researchers demonstrated for the first time that neural cells can be 3D printed to mimic the architecture of the cerebral cortex. The results have been published today in the journal Nature Communications.

Brain injuries, including those caused by trauma, stroke and surgery for brain tumours, typically result in significant damage to the cerebral cortex (the outer layer of the human brain), leading to difficulties in cognition, movement and communication. For example, each year, around 70 million people globally suffer from traumatic brain injury (TBI), with 5 million of these cases being severe or fatal. Currently, there are no effective treatments for severe brain injuries, leading to serious impacts on quality of life.

Tissue regenerative therapies, especially those in which patients are given implants derived from their own stem cells, could be a promising route to treat brain injuries in the future. Up to now, however, there has been no method to ensure that implanted stem cells mimic the architecture of the brain.

In this new study, the University of Oxford researchers fabricated a two-layered brain tissue by 3D printing human neural stem cells. When implanted into mouse brain slices, the cells showed convincing structural and functional integration with the host tissue.

Lead author Dr Yongcheng Jin (Department of Chemistry, University of Oxford) said: ‘This advance marks a significant step towards the fabrication of materials with the full structure and function of natural brain tissues. The work will provide a unique opportunity to explore the workings of the human cortex and, in the long term, it will offer hope to individuals who sustain brain injuries.’

Droplet-based 3D bioprinting. a Overview of the study. Patterned 3D printing of droplets containing the hiPSC-derived neural progenitors, deep-layer neural progenitors (DNPs) and upper-layer neural progenitors (UNPs), and extracellular matrix (ECM). The formation of adhesive DIBs secured the patterned network. The printed cerebral cortical tissues were cultured in vitro for functional studies and implanted into mouse brain explants. b Bright-field images of a single droplet in oil (left) and a pair of droplets connected through a DIB (right). The droplets contain solidified ECM. c, d Image of a droplet in oil containing RFP-labelled DNPs in ECM. e Side-view of an 8x8x8 printed droplet network containing DNPs. f Image of a printed droplet network containing RFP-labelled DNPs. g Image of a patterned droplet network containing GFP-labelled 3T3 cells (outer compartment) and RFP-labelled MDA breast cancer cells (centre compartment). h Side-view of two 8x8x8 printed droplet networks containing two layers (left and right). i Image of a printed two-layer droplet network containing RFP-labelled UNPs (left) and unlabelled DNPs (right). j Fluorescence image of a section of ‘i’ (indicated by the dashed box) at higher magnification. k Image of a printed 6-layered droplet network resembling the structure of a cortical column. l–n Images of centimetre-sized droplet networks. Scale bars: b–d, 100 µm; f, g, i and j, 200 µm; k–n, 1000 µm.

The cortical structure was made from human induced pluripotent stem cells (hiPSCs), which have the potential to produce the cell types found in most human tissues. A key advantage of using hiPSCs for tissue repair is that they can be easily derived from cells harvested from patients themselves, and therefore would not trigger an immune response.

The hiPSCs were differentiated into neural progenitor cells for two different layers of the cerebral cortex, by using specific combinations of growth factors and chemicals. The cells were then suspended in solution to generate two ‘bioinks’, which were then printed to produce a two-layered structure. In culture, the printed tissues maintained their layered cellular architecture for weeks, as indicated by the expression of layer-specific biomarkers.

When the printed tissues were implanted into mouse brain slices, they showed strong integration, as demonstrated by the projection of neural processes and the migration of neurons across the implant-host boundary. The implanted cells also showed signalling activity, which correlated with that of the host cells. This indicates that the human and mouse cells were communicating with each other, demonstrating functional as well as structural integration.

The researchers now intend to further refine the droplet printing technique to create complex multi-layered cerebral cortex tissues that more realistically mimic the human brain’s architecture. Besides their potential for repairing brain injuries, these engineered tissues might be used in drug evaluation, studies of brain development, and to improve our understanding of the basis of cognition.

The new advance builds on the team’s decade-long track record in inventing and patenting 3D printing technologies for synthetic tissues and cultured cells.

Senior author Dr Linna Zhou (Department of Chemistry, University of Oxford) said: ‘Our droplet printing technique provides a means to engineer living 3D tissues with desired architectures, which brings us closer to the creation of personalized implantation treatments for brain injury.’

Single‐cell profiling and zebrafish avatars reveal LGALS1 as immunomodulating target in glioblastoma

by Lise Finotto, Basiel Cole, Wolfgang Giese, Elisabeth Baumann, Annelies Claeys, Maxime Vanmechelen, Brecht Decraene, Marleen Derweduwe, Nikolina Dubroja Lakic, Gautam Shankar, Madhu Nagathihalli Kantharaju, Jan Philipp Albrecht, Ilse Geudens, Fabio Stanchi, Keith L Ligon, Bram Boeckx, Diether Lambrechts, Kyle Harrington, Ludo Van Den Bosch, Steven De Vleeschouwer, Frederik De Smet, Holger Gerhardt in EMBO Molecular Medicine

Glioblastoma is an aggressive and difficult-to-treat brain tumor in adults. On average, patients survive for only 1.5 years. The standard of care treatment for this disease, which includes surgery followed by radiation and chemotherapy, has not changed in 18 years. That’s partly because the cancer is highly variable with many differences across the patient population. Secondly, these cancer cells also deceive the body in insidious ways: they even recruit immune cells called macrophages to help them. And thirdly, they are out of reach for most anti-cancer drugs, which have only a limited capacity to penetrate brain tissues. Besides the standard of care treatment, oncologists try out drugs on glioblastoma patients without any guarantee they’ll work, often involving adverse side effects.

“These patients really are in need of new therapies,” says Professor Holger Gerhardt, the senior author of the study and vice-Scientific Director of the Max Delbrück Center in Berlin. “It is very important to identify the patients who do respond to a specific treatment, and the ones who do not.”

Lise Finotto, the lead author and a cancer researcher at the VIB-KU Leuven Center for Cancer Biology in Belgium and formerly at the Max Delbrück Center, and her senior collaborators Gerhardt and Professor Frederik De Smet at KU Leuven, have created a screening platform that could be refined to find novel targets for drugs against glioblastoma. It could also be used to check if a particular patient will respond to a therapy. The study was published in “EMBO Molecular Medicine.”

To understand how macrophages can interact with glioblastoma cells of different patients, the researchers created zebrafish “avatars.” Gerhardt’s lab works extensively with zebrafish. These three-centimeter-long fish are considered good model organisms as their embryos are translucent, making it possible to monitor what’s happening inside.

Finotto investigated glioblastoma stem cells from seven patients collected by scientists at the De Smet lab, which is establishing a living tissue bank of glioblastoma samples. She injected them into zebrafish embryos, creating xenograft models — an avatar for each specific patient. When she live-imaged the embryos, it appeared that the glioblastoma cells had adapted well to their new environment. She saw the zebrafish’s immune system sending macrophages as part of an immune response to control the tumor. But as is typical in glioblastoma, the macrophages were suppressed. The tumors have several mechanisms to reprogram the macrophages so they help them grow.

“We wanted to learn how to revert the macrophages to a tumor-attacking state,” Finotto says. And a clue surfaced when they noticed that the tumor of one patient did not suppress the normal macrophage response.

“Upon closer investigation of the medical details, we discovered that this patient was what we call a ‘long-term survivor’,” says De Smet at KU Leuven. “It’s a term used for glioblastoma patients with a survival of more than five years, which is exceptionally rare in this brain cancer.”

Their curiosity about the patient became the driving force behind the project, Finotto says. When they cultured the tumor cells and macrophages together and did single-cell RNA sequencing, they learned that one gene, LGALS1, was downregulated in the tumor of the long-term survivor compared to the others. Earlier studies have also shown that silencing of LGALS1 in glioblastoma cells can result in longer survival.

The scientists confirmed their results by knocking out the gene in another patient’s sample and observed in the zebrafish models that the tumor became less invasive.

This platform could be used to identify promising targets other than LGALS1 for the treatment of glioblastoma, Finotto says. And with some refinement, zebrafish avatars could be used to identify which treatments will work. Researchers could investigate whether the tumor cells from particular patients grafted into zebrafish respond when treated with various drugs to find the ones that lead to tumor regression, Gerhardt says.

“Armed with this information, we could inform oncologist and help them to make more supported treatment decisions for the patient,” De Smet says.

Neuronal activity drives IGF2 expression from pericytes to form long-term memory

by Kiran Pandey, Benjamin Bessières, Susan L. Sheng, Julian Taranda, Pavel Osten, Ionel Sandovici, Miguel Constancia, Cristina M. Alberini in Neuron

Research on long-term memories has largely focused on the role of neurons — the brain’s nerve cells. However, in recent years, scientists are discovering that other cell types are also vital in memory formation and storage.

A new study, published in the journal Neuron, reveals the crucial role of vascular system cells — known as pericytes — in the formation of long-term memories of life events — memories that are lost in diseases such as Alzheimer’s disease. The research, conducted by New York University neuroscientists, shows that pericytes, which wrap around the capillaries — the body’s small blood vessels — work in concert with neurons to help ensure that long-term memories are formed.

“We now have a firmer understanding of the cellular mechanisms that allow memories to be both formed and stored,” says Cristina Alberini, a professor in New York University’s Center for Neural Science and the paper’s senior author. “It’s important because understanding the cooperation among different cell types will help us advance therapeutics aimed at addressing memory-related afflictions.”

“This work connects important dots between the newly discovered function of pericytes in memory and previous studies showing that pericytes are either lost or malfunction in several neurodegenerative diseases, including Alzheimer’s disease and other dementia,” explains author Benjamin Bessières, a postdoctoral researcher in NYU’s Center for Neural Science.

Pericytes help maintain the structural integrity of the capillaries. Specifically, they control the amount of blood flowing in the brain and play a key role in maintaining the barrier that stops pathogens and toxic substances from leaking out of the capillaries and into brain tissue.

The discovery, reported in the new Neuron article, of the pericytes’ significance in long-term memory emerged because Alberini, Bessières, Kiran Pandey, and their colleagues examined the role of insulin-like growth factor 2 (IGF2) — a protein that was known to increase following learning in brain regions, such as the hippocampus, and to play a critical role in the formation and storage of memories.

They found that IGF2’s highest levels in the brain cells of the hippocampus do not come from neurons or glial cells, or other vascular cells, but, rather, from pericytes.

IGF2’s presence in pericytes, then, raises the following question: How is this linked to memory?

The scientists conducted a series of cognitive experiments using mice, comparing behaviors of those with pericytes that produced IGF2 and those that did not. By removing IGF2-producing capacity in some, the researchers could isolate the significance of both pericytes and IGF2 in neurological processes.

In these experiments, the mice were subjected to a series of memory tests — learning to associate a mild foot shock to a specific context or learning to identify objects placed in a new location.

Their results showed that production of IGF2 by pericytes in the hippocampus was enhanced by the learning event. More specifically, this increase in pericytic IGF2 took place in response to activity of neurons, revealing a concerted, neuron-pericytic action. In addition, IGF2 produced by pericytes were shown to circle back to influence biological responses of neurons that are critical for memory.

“IGF2 produced from pericytes and acting on neurons support the idea that a neurovascular unit regulates neuronal responses as well as functions of the blood barrier and may have repercussions on brain injury and inflammation,” notes Pandey, a postdoctoral researcher in NYU’s Center for Neural Science.

“Cooperation between neurons and pericytes is necessary to assure that long-term memories are formed,” observes Alberini. “Our study provides a new view of the biology of memory — though more research is needed to further understand the roles of pericytes and the vascular system in memory and its diseases.”

m6A governs length-dependent enrichment of mRNAs in stress granules

by Ryan J. Ries, Brian F. Pickering, Hui Xian Poh, Sim Namkoong, Samie R. Jaffrey in Nature Structural & Molecular Biology

Researchers at Weill Cornell Medicine have illuminated one of the important ways that cells respond to stress. The findings could also be relevant to Alzheimer’s, ALS and other diseases in which this mechanism may be abnormally active.

When stressed by heat, toxins, or other potentially damaging factors, cells gather many of their messenger RNAs (mRNAs), molecules that carry the instructions for making proteins, into droplet-like compartments called stress granules. These granules sequester affected mRNAs, preventing them from being translated into proteins. The resulting slowdown in protein production helps the cell conserve energy, declutter and focus on repairs.

In the study, which appeared in Nature Structural and Molecular Biology, the researchers confirmed that a tiny chemical modification on mRNAs, known as m6A, is key to the formation of stress granules.

“We were able to show that m6A has a primary role in driving mRNAs into these granules during cell stress,” said study senior author Dr. Samie Jaffrey, the Greenberg-Starr Professor of Pharmacology at Weill Cornell Medicine.

The study’s first author, Dr. Ryan Ries, was a Weill Cornell Graduate School of Medical Sciences doctoral student during the research.

Stress granules contain many different mRNAs from the cell, but not a random selection. Dr. Jaffrey and his team previously showed that mRNAs that are found in stress granules are often chemically tagged with a small cluster of atoms called a methyl group which attaches to adenosine, one of the mRNA building blocks. The resulting mRNA has regions that are enriched in N6-methyladenosine, or m6A. They also found that m6A-rich regions bind to YTHDF proteins — the more m6A an mRNA has, the more YTHDF proteins are present. The large amount of YTHDF proteins is needed to allow the m6A-mRNA-YTHDF complexes to accumulate into stress granules.

Dr. Jaffrey and others assumed that m6A wasn’t the only factor directing mRNA into stress granules because longer mRNAs are also overrepresented.

“We had thought that mRNA length was another factor, which is plausible since longer mRNAs have a tendency to stick to other mRNAs and form aggregates,” Dr. Jaffrey said.

However, in this study, when the researchers engineered cells that couldn’t form m6A and induced stress granule formation, they found that longer mRNAs weren’t overrepresented in the granules anymore. Dr. Jaffrey concluded that the m6A in the long mRNAs, and not mRNA length per se, was the key factor making longer mRNAs disproportionately abundant in stress granules.

During protein production, mRNAs are assembled in the nucleus of a cell from smaller regions of RNA called exons. The researchers observed that m6A is added to mRNAs as soon as the mRNAs are made in the nucleus. They also discovered that exons that were unusually long strongly triggered m6A formation in the corresponding mRNA. These long exons tend to be in long mRNAs, which explains why long mRNAs have high levels of m6A, and therefore are more likely to join stress granules, compared to mRNAs that are composed of only short exons.

Why does it benefit a cell to sequester longer mRNAs during episodes of cell stress? Dr. Jaffrey and colleagues speculate that in the distant evolutionary past, longer mRNAs were more likely to be dysfunctional or even from viruses. The development of cellular pathways to direct m6A-mRNAs into stress granules may have originated as a way to lock up these suspect mRNAs and prevent them from making unsafe proteins — though that process now appears to have evolved into a broader stress-response function.

While the new finding significantly advances the understanding of the basic biology underlying m6A and stress granule formation, it may also be relevant to neurodegenerative diseases.

“Maybe the abnormal stress granules that are formed in neurodegenerative diseases such as Alzheimer’s and ALS are driving those disease processes by chronically trapping beneficial m6A-containing mRNAs,” Dr. Jaffrey said. “We hope to find out whether blocking that mRNA-trapping process will help reverse pathology in these neurons.”

Electrophysiological signatures of visual recognition memory across all layers of mouse V1

by Dustin J. Hayden, Peter S.B. Finnie, Aurore Thomazeau, Alyssa Y. Li, Samuel F. Cooke, Mark F. Bear in The Journal of Neuroscience

Because figuring out what is new and what is familiar in what we see is such a critically important ability for prioritizing our attention, neuroscientists have spent decades trying to figure out how our brains are typically so good at it. Along the way they’ve made key observations that seem outright contradictory, but a new study shows that the mystifying measures are really two sides of the same coin, paving the way for a long-sought understanding of “visual recognition memory” (VRM).

VRM is the ability to quickly recognize the familiar things in scenes, which can then be de-prioritized so that we can focus on the new things that might be more important in a given moment. Imagine you walk into your home office one evening to respond to an urgent, late email. There you see all the usual furniture and equipment — and a burglar. VRM helps ensure that you’d focus on the burglar, not your book shelves or your desk lamp.

“Yet we do not yet have a clear picture of how this foundational form of learning is implemented within the mammalian brain,” wrote Picower Professor Mark Bear.

As far back as 1991 researchers found that when animals viewed something familiar, neurons in cortex, or outer layer of their brain, would be less activated than if they saw something new (two of that study’s authors later became Bear’s colleagues at MIT, Picower Professor Earl K. Miller and Doris and Don Berkey Professor Bob Desimone). But in 2003, Bear’s lab happened to observe the opposite: Mice would actually show a sharp jump in neural activity in the primary visual region of the cortex when a familiar stimulus was flashed in front of the animal. This spike of activity is called a “visually evoked potential” (VEP), and Bear’s lab has since shown that increases in the VEPs are solid indicators of VRM.

The findings in the new study, led by former Bear Lab postdocs Dustin Hayden and Peter Finnie, explain how VEPs increase even amid an overall decline in neural response to familiar stimuli (as seen by Miller and Desimone), Bear said. They also explain more about the mechanisms underlying VRM — the momentary increase of a VEP may be excitation that recruits inhibition, thereby suppressing activity overall.

Bear’s lab evokes VEPs by showing mice a black-and-white striped grating in which the stripes periodically switch their shade so that the pattern appears to reverse. Over several days as mice view this stimulus pattern, the VEPs increase, a reliable correlate of the mice becoming familiar with — and less interested in — the pattern. For 20 years Bear’s lab has been investigating how the synapses involved in VRM change by studying a phenomenon they’ve dubbed “stimulus-selective response plasticity” (SRP).

Early studies had suggested that SRP occurs among excitatory neurons in layer 4 of the visual cortex and specifically might require the molecular activation of their NMDA receptors. The lab had seen that knocking out the receptors across the visual cortex prevented the increase in VEPs and therefore SRP, but a follow-up in 2019 found that knocking them out just in layer 4 had no effect. So, in the new study they decided to study VEPs, SRP and VRM across the whole visual cortex, layer by layer, in search of how it all works.

What they found was that many of the hallmarks of VRM, including VEPs, occur in all layers of the cortex but that it seemed to depend on NMDA receptors on a population of excitatory neurons in layer 6, not layer 4. This is an intriguing finding, the authors said, because those neurons are well connected to the thalamus (a deeper brain region that relays sensory information) and to inhibitory neurons in layer 4, where they had first measured VEPs. They also measured changes in brain waves in each layer that confirmed a previous finding that when the stimulus pattern is new, the prevailing brain wave oscillations are in a higher “gamma” frequency that depends on one kind of inhibitory neuron, but as it becomes more familiar, the oscillations shift toward a lower “beta” frequency that depends on a different inhibitory population.

The team’s rigorous and precise electrophysiology recordings of neural electrical activity in the different layers also revealed a potential resolution to the contradiction between VEPs and the measures of labs like that of Miller and Desimone.

“What this paper reveals is that everybody is right,” Bear quipped.

How so? The new data show that VEPs are very pronounced but transient spikes of neural electrical activity that occur amid a broader, overall lull of activity. Previous studies have reflected only the overall decrease because they have not had the temporal resolution to detect the brief spike. Bear’s team, meanwhile, has seen the VEPs for years but didn’t necessarily focus on the surrounding lull.

The new evidence suggests that what’s happening is that the VEP is a sign of the activity of the brain quickly recognizing a familiar stimulus and then triggering an inhibition of activity related to it.

“What I think is exciting about this is that it suddenly sheds light on the mechanism, because it’s not that the encoding of familiarity is explained by the depression of excitatory synapses,” Bear said. “Rather, it seems to be accounted for by the potentiation of excitatory synapses on to neurons that then recruit inhibition in the cortex.”

Cortical, subcortical, and cerebellar contributions to language processing: A meta-analytic review of 403 neuroimaging experiments

by Sabrina Turker, Philipp Kuhnke, Simon B. Eickhoff, Svenja Caspers, Gesa Hartwigsen in Psychological Bulletin

Language is the most important tool for human communication and essential for life in our society. “Despite a great deal of neuroscientific research on the representation of language, little is known about the organisation of language in the human brain. Much of what we do know comes from single studies with small numbers of subjects and has not been confirmed in follow-up studies,” says Dr Sabrina Turker from the Max Planck Institute for Human Cognitive and Brain Sciences in Leipzig. This meta-analysis aims to help change that.

Based on more than 400 neuroscientific experiments using functional imaging and involving more than 7000 subjects, the analysis provides in-depth insights into how the brain organizes language. A quantitative, coordinate-based meta-analysis was used to integrate the many findings from different studies in the most complete and objective way possible. This makes it possible to see where the brain is activated when particular language processes occur. This approach provides insights into fundamental principles of how the brain organizes language processing. The researchers not only studied language as a process in general, but also explicitly addressed subordinate processes: the meaning of language at the level of words and sentences (semantics); the phonetic structure of language (phonology); grammar and the arrangement of linguistic elements (syntax); and the phonetic structure of language at sentence level, including melody, intonation and rhythm (prosody).

In addition to the classical language regions in the left hemisphere of the brain, the authors of the study found that structures in the brain regions below the cerebral cortex and the cerebellum play a key role in language processes.

“These regions have been rather neglected in previous neuroscientific research on language,” says Gesa Hartwigsen, Professor of Cognitive and Biological Psychology at Leipzig University. “In particular, the left and right cerebellum are involved in processes related to the meaning of language and the processing of sounds. Similarly, phonetic patterns that transcend individual words and also convey emotional meaning are associated with activation in the right amygdala, a paired core area of the brain.” She points out that this part influences emotion and memory.

Professor Gesa Hartwigsen adds: “Our findings may serve future studies involving language recovery after brain injury, for example caused by stroke. And they could help to refine models of language processing.”

Stable isotope labeling and ultra-high-resolution NanoSIMS imaging reveal alpha-synuclein-induced changes in neuronal metabolism in vivo

by Sofia Spataro, Bohumil Maco, Stéphane Escrig, Louise Jensen, Lubos Polerecky, Graham Knott, Anders Meibom, Bernard L. Schneider in Acta Neuropathologica Communications

Parkinson’s disease is a complex neurodegenerative disorder that leads to the deterioration of specific types of neurons in the brain, resulting in a number of motor and non-motor symptoms. It is currently estimated that more than 10 million people in the world are living with Parkinson’s disease, the second most common neurodegenerative disorder after Alzheimer’s. That number is expected to swell up to 14 million by 2040 in what is being referred to as the Parkinson’s pandemic.

One of the key events in Parkinson’s disease is the accumulation of a protein called alpha-synuclein inside neurons. That accumulation disrupts the normal functioning of the cells, giving rise to the symptoms of Parkinson’s and other disorders, and progresses into aggregates called Lewy bodies.

In a new study, researchers from two labs at EPFL have combined their expertise to explore how alpha-synuclein disrupts metabolic processes within neurons. The study is a truly interdisciplinary collaboration between the Bertarelli Platform for Gene Therapy of Bernard Schneider and the group of Anders Meibom at EPFL, with support from EPFL’s Bioelectron Microscopy Core Facility.

The researchers used cutting-edge imaging techniques, including an analytical instrument called NanoSIMS (Nanoscale Secondary Ion Mass Spectrometry). NanoSIMS is an “ion microprobe” that combines high spatial resolution (50–150 nm), high-resolution mass spectrometry, and high analytical sensitivity, which allow it to produce sub-cellular maps of metabolic turnover with extreme sensitivity. Meibom’s lab at EPFL has famously used NanoSIMS for a number of ecological and geological studies.

SILK-SIMS measurement of 13C labeling in a model of induced α-syn overexpression. a Pathogenic conditions were induced in the rat ventral midbrain by unilateral AAV-mediated α-syn overexpression for one month. Subsequently, the animal was subjected to a 48 h pulse with 13C-labeled glucose administered in the drinking water. The effects of α-syn overexpression on the kinetics of 13C incorporation were determined by comparing the brain hemisphere injected with AAV6-α-syn with the control hemisphere injected with a non-coding AAV6 vector. b Representative example showing how the SEM ultrastructure image was aligned with the isotopic image measured by NanoSIMS. Note that the NanoSIMS image was rotated relative to the SEM image and acquired with a lower lateral resolution (about 15-fold). Additionally, the NanoSIMS image was slightly distorted (stretched or squeezed) relative to the SEM image because of the movement of the sample stage caused by temperature variations during the relatively long NanoSIMS measurement. The alignment of the two images was done by matching the locations of multiple reference points manually defined by the user. In the ‘alignment’ image, points indicated by ‘ + ’ and ‘✕’ were defined in the SEM and NanoSIMS image, respectively. Superimposed reference points are indicated with ❊.

In this study, the researchers combined NanoSIMS with stable isotope labeling, to visualize isotopic variations within tissues at high resolution, providing insights into the metabolic activity of individual cellular compartments and organelles. They combined this with Electron Microscopy to “see” more information from biological samples.

To model Parkinson’s disease, the team used genetically modified rats that overexpressed human alpha-synuclein in one hemisphere of the brain, leaving the other healthy as a control. By comparing the neurons overexpressing alpha-synuclein to those in the control hemisphere, the scientists uncovered significant changes in the way carbon molecules are incorporated and processed within neurons.

One of the most remarkable findings was the effect of alpha-synuclein on the turnover of carbon within neurons. Neurons overexpressing alpha-synuclein showed a heightened overall turnover of macromolecules, suggesting that the accumulation of alpha-synuclein may lead to increased metabolic demands on these cells.

The study also found changes in the distribution of carbon between different cellular compartments, such as the nucleus and cytoplasm, which may be influenced by alpha-synuclein’s interaction with DNA and histones.

The metabolic disruptions caused by alpha-synuclein also seem to affect specific organelles: Mitochondria, for example, showed abnormal carbon incorporation and turnover patterns, which agrees with previous studies showing that alpha-synuclein impairs mitochondrial function. Similarly, the Golgi apparatus — responsible for cellular trafficking and communication — exhibited metabolic defects that were likely caused by alpha-synuclein disrupting inter-organelle communication.

“This study shows the potential of the NanoSIMS technology to reveal metabolic changes in the brain, with unprecedented resolution, at the subcellular level,” says Bernard Schneider. “It hands us a tool to study early pathological changes occurring in vulnerable neurons as a consequence of alpha-synuclein accumulation, a mechanism directly linked to Parkinson’s disease.”

The boundary between real and fictional others in the medial prefrontal cortex is blurred in lonelier individuals

by Timothy W Broom, Dylan D Wagner in Cerebral Cortex

In lonely people, the boundary between real friends and favorite fictional characters gets blurred in the part of the brain that is active when thinking about others, a new study found.

Researchers scanned the brains of people who were fans of “Game of Thrones” while they thought about various characters in the show and about their real friends. All participants had taken a test measuring loneliness.

The difference between those who scored highest on loneliness and those who scored lowest was stark, said Dylan Wagner, co-author of the study and associate professor of psychology at The Ohio State University.

“There were clear boundaries between where real and fictional characters were represented in the brains of the least lonely participant in our study,” Wagner said. “But the boundaries between real and some fictional people were nearly nonexistent for the loneliest participant.”

The results suggest that lonelier people may be thinking of their favorite fictional characters in the same way they would real friends, Wagner said.

Wagner conducted the study with Timothy Broom, a PhD graduate of Ohio State who is now a postdoctoral researcher at Columbia University. It was published recently in the journal Cerebral Cortex.

Data for the study was collected in 2017 during the seventh season of the HBO series “Game of Thrones.” The study involved scanning the brains of 19 self-described fans of the series while they thought about themselves, nine of their friends and nine characters from the series. (The characters were Bronn, Catelyn Stark, Cersei Lannister, Davos Seaworth, Jaime Lannister, Jon Snow, Petyr Baelish, Sandor Clegane and Ygritte.)

Participants reported which “Game of Thrones” character they felt closest to and liked the most.

“Game of Thrones” was a fantasy drama series lasting eight seasons and concerning political and military conflicts between ruling families on two fictional continents. It was ideal for this study, Wagner said, because the large cast presented a variety of characters that people could become attached to.

For the study, the participants’ brains were scanned in an fMRI machine while they evaluated themselves, friends and “Game of Thrones” characters. An fMRI indirectly measures activity in various parts of the brain through small changes in blood flow.

The researchers were particularly interested in what was happening in a part of the brain called the medial prefrontal cortex (MPFC), which shows increased activity when people think about themselves and other people.

While in the fMRI machine, participants were shown a series of names — sometimes themselves, sometimes one of their nine friends, and other times one of the nine characters from “Game of Thrones.”

Each name appeared above a trait, like sad, trustworthy or smart.

Participants simply responded “yes” or “no” to whether the trait accurately described the person while the researchers simultaneously measured activity in the MPFC portion of their brains.

The researchers compared results from when participants were thinking about their friends to when they were thinking about the fictional characters.

“When we analyzed brain patterns in the MPFC, real people were represented very distinctly from fictional people in the non-lonely participants,” Wagner said. “But among the lonelier people, the boundary starts breaking down. You don’t see the stark lines between the two groups.”

The findings suggest that lonely people may turn to fictional characters for a sense of belonging that is lacking in their real life, and that the results can be seen in brain, Wagner said.

“The neural representation of fictional characters comes to resemble those of real-world friends,” he said.

But even the least lonely participants were affected by the characters they cared about most in “Game of Thrones,” the study found.

Results showed that the participants’ favorite characters in “Game of Thrones” looked more like their real friends in their brains than did other characters in the show.

That was true for all people in the study, no matter how lonely and no matter who their favorite character was, Wagner said. “Your favorite characters are more real to you, regardless of loneliness,” he said.

Short-term Exposure to Air Pollution and Ischemic Stroke: A Systematic Review and Meta-analysis

by Ahmad Toubasi, Thuraya N Al-Sayegh in Neurology

Short-term exposure to air pollution may be linked to an increased risk of stroke, according to a meta-analysis published in Neurology. Short-term exposure was defined as occurring within five days of the stroke.

“Previous research has established a connection between long-term exposure to air pollution and an increased risk of stroke,” said study author Ahmad Toubasi, MD, of the University of Jordan in Amman.

“However, the correlation between short-term exposure to air pollution and stroke had been less clear. For our study, instead of looking at weeks or months of exposure, we looked at just five days and found a link between short-term exposure to air pollution and an increased risk of stroke.”

The meta-analysis involved a review of 110 studies that included more than 18 million cases of stroke.

Researchers looked at pollutants such as nitrogen dioxide, ozone, carbon monoxide and sulfur dioxide.

They also looked at different sizes of particulate matter, including PM1, which is air pollution that is less than 1 micron (µm) in diameter, as well as PM2.5 and PM10. PM2.5 or smaller includes inhalable particles from motor vehicle exhaust, the burning of fuels by power plants and other industries as well as forest and grass fires. PM10 includes dust from roads and construction sites.

People who had exposure to a higher concentration of various types of air pollution had an increased risk of stroke. Higher concentrations of nitrogen dioxide were linked to a 28% increased risk of stroke; higher ozone levels were linked to a 5% increase; carbon monoxide had a 26% increase; and sulfur dioxide had a 15% increase. A higher concentration of PM1 was linked to a 9% increased risk of stroke, with PM2.5 at 15% and PM10 at 14%.

Higher levels of air pollution were also linked to higher risk of death from stroke. Higher concentrations of nitrogen dioxide were linked to a 33% increased risk of death from stroke, sulfur dioxide, a 60% increase, PM2.5, a 9% increase and PM10, a 2% increase.

“There is a strong and significant association between air pollution and the occurrence of stroke as well as death from stroke within five days of exposure,” Toubasi said. “This highlights the importance of global efforts to create policies that reduce air pollution. Doing so may reduce the number of strokes and their consequences.”

A limitation of the meta-analysis was most of the studies were conducted in high-income countries, while limited data was available from low- and middle-income countries.

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