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Neuroscience

Common Mechanism Found For Diverse Brain Disorders: Study (Neuroscience)

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Researchers at Vanderbilt University Medical Center (VUMC) have identified a common mechanism underlying a spectrum of epilepsy syndromes and neurodevelopmental disorders, including autism, that are caused by variations in a gene encoding a vital transporter protein in the brain.

Their findings, reported last month in the journal Brain, suggest that boosting transporter function via genetic or pharmacological means could be beneficial in treating brain disorders linked to these genetic variations.

“This points (to) a clear direction of treating a wide spectrum of neurodevelopmental disorders, from various epilepsy syndromes (and) autism to neurodevelopmental delay and intellectual disabilities, caused by the pathological variants in this gene,” said Jing-Qiong (Katty) Kang, MD, PhD, associate professor of Neurology and Pharmacology, and the paper/s corresponding author.

“The disorders associated with the gene mutations are rare and there is no effective treatment available,” Kang said. “If … the clinical syndromes we see are the tip of an iceberg, we now know what is going on underneath, and we start to know how to correct the problems.”

The gene, SLC6A1, encodes the GABA transporter 1 (GAT-1) at the axonal termini (ends) of neurons (nerve cells) and astrocytes (star-shaped glial cells that support and protect neurons). GAT-1 removes or “reuptakes” GABA, the major inhibitory neurotransmitter, from the synaptic cleft between two neurons.

GABA regulates nerve signals throughout the brain and plays a key role in normal brain development. Reuptake enables the brain to precisely regulate the supply of the neurotransmitter in concert with GABAA receptors, ion channels that bind it.

Kang and her colleagues have extensively studied GABAA receptors and are world leaders in determining how disrupted GABA signaling can affect brain function and development.

Jing-Qiong (Katty) Kang, M.D., Ph.D., associate professor of Neurology and Pharmacology, Vanderbilt University Medical Center. © Vanderbilt University Medical Center

SLC641 variants previously have been associated with a spectrum of epilepsy syndromes, autism and impaired cognition. But until now scientists did not know how these variants could cause such a broad range of brain disorders.

Using high-throughput assays such as flow cytometry and a radioactive labeling technique for measuring GABA reuptake by neurons and astrocytes, the VUMC researchers determined the impact of 22 different variants of SLC6A1 on GAT-1 function in several types of nerve cells derived from patients with neurodevelopmental disorders, epilepsy and autism.

The work was validated in patient-induced pluripotent stem cells that were “reprogrammed” to form neurons and astrocytes.

The researchers found that disease-causing variants were associated with misfoldings of the GAT-1 protein that led to its degradation and which reduced its expression on cell surfaces. Less GAT-1, in turn, lowered GABA reuptake by nerve cells and astrocytes and disrupted neurotransmitter function.

“This is the first large-scale study on SLC6A1 pathological variants,” Kang said. “Our work indicates that SLC6A1-mediated disorders are good candidates for pharmacological as well as gene therapy that restore the functional transporter at the cell surface.”

A compound identified at VUMC that corrects GAT-1 function in mouse models and cells from patients with urea cycle disorder is now being tested in a clinical trial. The inherited disease causes a buildup of ammonia in the bloodstream that can damage the brain and may be fatal.

Another potential approach is the use of antisense oligonucleotides, short, synthetic pieces of genetic material that may increase expression of the normal, “wild-type” GAT-1 protein.

Kang said the research could not have been done without the help of two “hero” mothers of children with rare genetic disorders: Amber Freed, founder and CEO of the Denver-based advocacy group SLC6A1 Connect; and Terry Jo Bichell, PhD, founder and director of Nashville-based COMBINEDBrain, which supports brain research.

“I have been very lucky and privileged to work with them,” Kang said. “They have taught me so much along the way and inspired me to do meaningful research.”

“She loves kids with SLC6A1 as her own and selflessly works to improve their lives with the urgency of a mother,” Freed responded. “Throughout this journey, Katty has been a loving person, inquisitive scientist and pillar of strength.”

“That empathy kept her discoveries progressing through the pandemic,” Bichell added. “She would ride her bicycle to the lab and care for the mouse and cell models at night, on weekends and even holidays … Dr. Kang is doing basic science that will translate to real treatments for real children she has met–and hugged.”

Felicia Mermer and Sarah Poliquin are the paper’s first authors. Other VUMC co-authors are Kathryn Rigsby, Anuj Rastogi, Wangzhen Shen, MD, Alejandra Romero-Morales, Gerald Nwosu and Vivian Gama, PhD.

The research was supported by SLC6A1 Connect, Taysha Gene Therapies, the Charles C. Gates Center Director’s Innovation Fund, the Stoddard family, and by National Institutes of Health grants NS082635, GM128915, CA227483 and MH116901.

Featured image: Terry Jo Bichell, Ph.D., founder and director of Nashville-based COMBINEDBrain. © Vanderbilt University Medical Center

Reference: Felicia Mermer, Sarah Poliquin, Kathryn Rigsby, Anuj Rastogi, Wangzhen Shen, Alejandra Romero-Morales, Gerald Nwosu, Patrick McGrath, Scott Demerast, Jason Aoto, Ganna Bilousova, Dennis Lal, Vivian Gama, Jing-Qiong Kang, Common molecular mechanisms of SLC6A1 variant-mediated neurodevelopmental disorders in astrocytes and neurons, Brain, 2021;, awab207, https://doi.org/10.1093/brain/awab207

Provided by Vanderbelt University Medical Center

Neuroscience

A New Theory For What’s Happening in the Brain When Something Looks Familiar (Neuroscience)

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This novel concept from the lab of neuroscientist Nicole Rust brings the field one step closer to understanding how memory functions. Long-term, it could have implications for treating memory-impairing diseases like Alzheimer’s.

When a person views a familiar image, even having seen it just once before for a few seconds, something unique happens in the human brain.

Until recently, neuroscientists believed that vigorous activity in a visual part of the brain called the inferotemporal (IT) cortex meant the person was looking at something novel, like the face of a stranger or a never-before-seen painting. Less IT cortex activity, on the other hand, indicated familiarity.

But something about that theory, called repetition suppression, didn’t hold up for University of Pennsylvania neuroscientist Nicole Rust. “Different images produce different amounts of activation even when they are all novel,” says Rust, an associate professor in the Department of Psychology. Beyond that, other factors—an image’s brightness, for instance, or its contrast—result in a similar effect.

In a paper published in the Proceedings of the National Academy of Sciences, she and postdoctoral fellow Vahid Mehrpour, along with Penn research associate Travis Meyer and Eero Simoncelli of New York University, propose a new theory, one in which the brain understands the level of activation expected from a sensory input and corrects for it, leaving behind the signal for familiarity. They call it sensory referenced suppression.

The visual system

Rust’s lab focuses on systems and computational neuroscience, which combines measurements of neural activity and mathematical modeling to figure out what’s happening in the brain. One aspect relates to the visual system. “The big central problem of vision is how to get the information from the world into our heads in an interpretable way. We know that our sensory systems have to break it down,” she says.

A close-up image of a person outside.
Nicole Rust is an associate professor in the Department of Psychology in the School of Arts & Sciences at the University of Pennsylvania. She is also director of the Visual Memory Lab, co-director of the Computational Neuroscience Initiative, and MindCORE’s executive director for research. (Image: Courtesy Nicole Rust)

It’s a complicated process, greatly simplified here for clarity: Information comes into the eye via the rods and cones. It travels neuron by neuron through a stack of brain areas that make up the visual system and finally to a visual brain area called the IT cortex. Its 16 million neurons activate in different patterns depending on what’s being viewed, and the brain must then interpret the patterns to understand what it’s seeing.

“You get one pattern for a specific face. You get a different pattern for ‘coffee cup.’ You get a different pattern for ‘pencil,’” Rust says. “That’s what the visual system does. It builds the world back up to help you decipher what you’re looking at.”

In addition to its role in vision, activation of the IT cortex is also thought to play a role in memory. Repetition suppression, the old theory, relies on the idea that there’s an activation threshold that gets crossed: More neural activity tells the brain the image is novel, less indicates one that’s previously seen.

Because several factors affect the total amount of neural activity, also called spikes, in the IT cortex, the brain can’t discern what’s specifically causing the reaction. It could be memory, image contrast, or something else altogether, Mehrpour says. “We propose a new idea that the brain corrects for the changes caused by these other factors, in our case contrast,” he says. After that calibration, what remains is the isolated brain activation for familiarity. In other words, the brain understands when it is viewing something that it has previously seen.

Long-term implications

To draw this conclusion, the researchers presented sequences of grayscale images to two adult male rhesus macaques. Every image appeared exactly twice, the first time as novel, the second time as familiar, in a range of high- and low-contrast combinations. Each viewing lasted precisely half a second. The animals were trained to use eye movements to indicate whether an image was new or familiar, disregarding the contrast levels.

As the macaques performed this memory task, the researchers recorded neural activity in the IT cortex, measuring the spikes for hundreds of individual neurons, a unique method that differs from those that measure proxies of neural activity averaged across 10,000 neurons firing. Because Rust and colleagues wanted to understand the neural code, they needed information for individual neurons.

By understanding how memory in a healthy brain works, you can lay the foundations to develop preventions and treatments for the memory-related disorders plaguing an aging population.Penn neuroscientist Nicole Rust

Using a mathematical approach, they deciphered the patterns of spikes that accounted for how the macaques could distinguish memory from contrast. This ultimately confirmed their hypothesis. “Familiarity and contrast both change the overall firing rate,” Rust says. “What we’re saying is the brain can tease apart and isolate one from the other.”

In the future, better understanding this process could have applications for artificial intelligence, Mehrpour says. “If we know how the brain represents and rebuilds information in memory in the presence of changes in sensory input like contrast, we can design AI systems that work in the same way,” he says. “We could potentially build machines that work in the same way that our brain does.”

Beyond that, Rust says that down the line the findings could have implications for treating memory-impairing diseases like Alzheimer’s. “By understanding how memory in a healthy brain works, you can lay the foundations to develop preventions and treatments for the memory-related disorders plaguing an aging population.”

But for any of this to come to pass, it will be crucial to keep digging, she says. “To get this right, we have to understand the memory signal that’s driving behavior.” This work brings neuroscientists one step closer.

Funding for this research came from the Simons Foundation (grants 543033 and 543047), National Eye Institute of the National Institutes of Health (Grant R01EY020851), National Science Foundation (CAREER Award 1265480), and Howard Hughes Medical Institute.

Vahid Mehrpour is a postdoctoral fellow in the Visual Memory Lab at the University of Pennsylvania.

Travis Meyer is a research associate in the Visual Memory Lab at the University of Pennsylvania.

Nicole Rust is an associate professor in the Department of Psychology in the School of Arts & Sciences at the University of Pennsylvania. She is also director of the Visual Memory Lab, co-director of the Computational Neuroscience Initiative, and MindCORE’s executive director for research.

Eero Simonelli is a professor of neural science, mathematics, data science, and psychology in the College of Arts & Science at New York University. He is also founding director of the Center for Computational Neuroscience at the Simons Foundation’s Flatiron Institute.

Featured image: How can the brain distinguish between something new and something familiar? Research from the Visual Memory Lab led by Nicole Rust has a new theory, replacing one long-held by the field. (Image: Julia Kuhl)

Reference: Vahid Mehrpour, Travis Meyer et al., “Pinpointing the neural signatures of single-exposure visual recognition memory”, PNAS May 4, 2021 118 (18) e2021660118; https://doi.org/10.1073/pnas.2021660118

Provided by Penn Today

Neuroscience

New Neuroelectronic System Can Read and Modify Brain Circuits (Neuroscience)

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Columbia team designs high-performance, implantable system that can manipulate brain signals and suppress pathological coupling; successfully tested in epileptic animal models, the new design could improve treatment of neuropsychiatric disorders

As researchers learn more about the brain, it has become clear that responsive neurostimulation is becoming increasingly effective at probing neural circuit function and treating neuropsychiatric disorders, such as epilepsy and Parkinson’s disease. But current approaches to designing a fully implantable and biocompatible device able to make such interventions have major limitations: their resolution isn’t high enough and most require large, bulky components that make implantation difficult with risk of complications.

A Columbia Engineering team led by Dion Khodagholy, assistant professor of electrical engineering, has come up with a new approach that shows great promise to improve such devices. Building on their earlier work to develop smaller, more efficient conformable bioelectronic transistors and materials, the researchers orchestrated their devices to create high performance implantable circuits that enable allow reading and manipulation of brain circuits. Their multiplex-then-amplify (MTA) system requires only one amplifier per multiplexer, in contrast to current approaches that need an equal number of amplifiers as number of channels.

“It is critical to be able to detect and intervene to treat brain-disorder-related symptoms, such as epileptic seizures, in real time,” said Khodagholy, a leader in bio- and neuroelectronics design. “Not only is our system much smaller and more flexible than current devices, but it also enables simultaneous stimulation of arbitrary waveforms on multiple independent channels, so it is much more versatile.

Khodagholy collaborated on the study, published today by Proceedings of the National Academy of Sciences (PNAS), with Jennifer N. Gelinas, Department of Neurology and the Institute for Genomic Medicine at Columbia University Irving Medical Center. Gelinas is a neuroscientist and specialist in pediatric epilepsy whose research focuses on understanding how neural networks become abnormal in epilepsy and designing methods to correct this dysfunction.

Micrograph of the micro-fabricated conformable conducting polymer-based electrode array © Zifang Zhao and Claudia Cea/Columbia Engineering

In order to record, detect, and localize epileptic discharges, scientists must log brain activity in multiple locations with high temporal resolution. This requires a high-sampling-rate multi-channel acquisition and stimulation device and circuit. Conventional circuits need an equal number of amplifying circuits as number of channels before they can combine these signals into a stream of data using multiplexing. This increases the size of the circuits linearly with the number of channels.

Khodagholy knew from working with neurologists like Gelinas that there was a great need for an all-in-one, fully implantable system that can record, process, and stimulate brain activity–such a system would enable researchers to design personalized therapies. To record brain activity, he needed multi-channel amplifiers but the available options were too big and unwieldy. As the team continued to make their electrodes more effective, lowering impedance by using a conducting polymer, they suddenly wondered what would happen if they took advantage of their electrode improvements in circuit design and placed the multiplexer in front of, rather than after, the amplifier.

With this new idea in mind, the team built the MTA device and then confirmed its functionality by developing a fully implantable, responsive embedded system that can acquire–in real time–individual neural action potentials using conformable conducting polymer-based electrodes. It can accomplish this with low-latency arbitrary waveform stimulation and local data storage–all within a miniaturized (approximately the size of a quarter) physical footprint.

“The key challenge was to create an electric-charge drainage path during the multiplexing operation to eliminate any unwanted charge accumulation,” said Zifang Zhao, postdoctoral fellow in the department of electrical engineering and the first author of the study.

The MTA device, which was fabricated at the Columbia Nano-Initiative, enabled the team to then develop a novel closed-loop protocol to suppress pathological coupling between the hippocampus and cortex in real-time within an epileptic network. This type of approach could help address memory problems that often accompany epilepsy.

“These devices will allow application of targeted high-spatiotemporal resolution responsive neurostimulation approaches to a variety of brain functions, greatly broadening our ability to chronically modify neural networks and treat neuropsychiatric disease,” Gelinas said.

The team is now integrating their system with various experimental platforms with the goal of improving neural network function and cognitive skills.

About the Study

The study is “Responsive manipulation of neural circuit pathology by fully implantable, front-end multiplexed embedded neuroelectronics.”

Featured image: Simplified schematic of the overall placement and location of the MTA in a rat. © Zifang Zhao and Claudia Cea/Columbia Engineering

Provided by Columbia University School of Engineering and Applied Science

Neuroscience

Study Suggests Role Of Sleep in Healing Traumatic Brain Injuries (Neuroscience)

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Technique developed at OHSU measures brain’s waste-clearance system through MRIs

Sound sleep plays a critical role in healing traumatic brain injury, a new study of military veterans suggests.

The study, published in the Journal of Neurotrauma, used a new technique involving magnetic resonance imaging developed at Oregon Health & Science University. Researchers used MRI to evaluate the enlargement of perivascular spaces that surround blood vessels in the brain. Enlargement of these spaces occurs in aging and is associated with the development of dementia.

Among veterans in the study, those who slept poorly had more evidence of these enlarged spaces and more post-concussive symptoms.

Juan Piantino, M.D., MCR

“This has huge implications for the armed forces as well as civilians,” said lead author Juan Piantino, M.D., MCR, assistant professor of pediatrics (neurology) in the OHSU School of Medicine and Doernbecher Children’s Hospital. “This study suggests sleep may play an important role in clearing waste from the brain after traumatic brain injury – and if you don’t sleep very well, you might not clean your brain as efficiently.”

Piantino, a physician-scientist with OHSU’s Papé Family Pediatric Research Institute, studies the effects of poor sleep on recovery after traumatic brain injuries.

The new study benefited from a method of analyzing MRIs developed by study co-author Daniel Schwartz and Erin Boespflug, Ph.D., under the direction of Lisa Silbert, M.D., M.C.R., professor of neurology in the OHSU School of Medicine. The technique measures changes in the brain’s perivascular spaces, which are part of the brain’s waste clearance system known as the glymphatic system.

“We were able to very precisely measure this structure and count the number, location and diameter of channels,” Piantino said.

Co-author Jeffrey Iliff, Ph.D., professor of psychiatry and behavioral sciences and of neurology at the University of Washington and a researcher at the VA Puget Sound Health Care System, has led scientific research into the glymphatic system and its role in neurodegenerative conditions such as Alzheimer’s disease. During sleep, this brain-wide network clears away metabolic proteins that would otherwise build up in the brain.

The study used data collected from a group of 56 veterans enrolled by co-authors Elaine Peskind, M.D., and Murray Raskind, M.D., at the Mental Illness Research, Education and Clinical Center at the VA Puget Sound between 2011 and 2019.

“Imagine your brain is generating all this waste and everything is working fine,” Piantino said. “Now you get a concussion. The brain generates much more waste that it has to remove, but the system becomes plugged.”

Piantino said the new study suggests the technique developed by Silbert could be useful for older adults.

“Longer term, we can start thinking about using this method to predict who is going to be at higher risk for cognitive problems including dementia,” he said.

The study is the latest in a growing body of research highlighting the importance of sleep in brain health.

Improving sleep is a modifiable habit that can be improved through a variety of methods, Piantino said, including better sleep hygiene habits such as reducing screen time before bed. Improving sleep is a focus of research of other OHSU scientists, including Piantino’s mentor, Miranda Lim, M.D., Ph.D., associate professor of neurology, medicine and behavioral neuroscience in the OHSU School of Medicine.

“This study puts sleep at the epicenter of recovery in traumatic brain injury,” Piantino said.

The study was supported by the National heart, Lung and Blood Institute of the National Institutes of Health, award K23HL150217-01; the U.S. Department of Veterans Affairs Rehabilitation Research and Development Service Merit Review grant B77421; and NIH award P30AG008017-18.

Featured image: A new study of military veterans suggests that sound sleep may help in healing traumatic brain injuries. The research was conducted by scientists at OHSU, the University of Washington and the VA Puget Sound Medical Center. (Getty Images)

Reference: Dr. Juan Piantino, Mr. Daniel L Schwartz, Mrs. Madison Luther, Dr. Craig D Newgard, Dr. Lisa Silbert, Murray Raskind, Dr. Kathleen Pagulayan, Dr. Natalia Kleinhans, Dr. Jeffrey Iliff, and Dr. Elaine Peskind, “Link between mild traumatic brain injury, poor sleep, and MRI-visible perivascular spaces in Veterans“, Journal of Neurotrauma, 2021. https://doi.org/10.1089/neu.2020.7447

Provided by OHSU

Neuroscience

Are There Differences in the Brains of Autistic Men and Women? (Neuroscience)

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Large-scale brain imaging study suggest that atypical connectivity between brain hemispheres in autism reflects a combination of biological sex-dependent (i.e., specific to male or females) and independent (i.e., common across sexes) effects

Around three times as many males are diagnosed with autism than females. This suggests that biological sex factors may play a role in the development and presentation of autism.

Studies on the neurobiology (brain biology) of males and females with autism have begun to examine brain networks but results have been mixed. This is largely due to the limited availability of data from autistic females.

In response, researchers from Child Mind Institute and colleagues involved in the AIMS2TRIALS, have combined thousands of MRI data openly available for scientific discovery in the Autism Brain Imaging Exchange (ABIDE) repository to explore brain network differences between autistic and neurotypical control males and females. They used the ABIDE sample for discovery of new information and two additional large samples to see if those findings could be repeated (i.e., replicated). These included one sample derived from the Gender Explorations of Neurogenetics and Development to Advance Autism Research made available through the National Database for Autism Research and another one shared by the collaborators of the AIMS2TRIALS.

Across these three samples, the researchers found that both neurotypical males and autistic people showed reduced resting-state brain function in the so-called ‘default network’, a network that is active when we engage in social cognition or thoughts about ourselves. Additionally, in the discovery sample and in one of the largest of the two replication samples, it was shown that connections between hemispheres (the two halves of the brain) in the visual cortex are reduced in autistic females, while autistic males are not different from males who are not autistic. The results suggest that many autistic people may have different interactions between the two hemispheres of their brain when compared to non-autistic people. This reflects a combination of effects, including some that appear to be unrelated to sex, and some in which there is an interaction between sex and autism diagnosis. Each of these effects appears specific to a different system in the brain.

This study highlights the importance of data sharing and collaboration for implementing discovery science and addressing critical challenges related to reproducibility of findings – which affect all of fields of science. The researchers suggest that there remains an urgent need for more research with similarly large groups of participants, as only then do studies have enough statistical power to reliably account for sources of variability and therefore generate robust conclusions. Until now, limited replication of imaging findings has hampered brain imaging research in autism. The open sharing policies of the Autism Brain Imaging Data Exchange and the NIMH Data Archive, through which the Gender Explorations of Neurogenetics Development to Advance Autism Research was made available, are particularly promising for accelerating the pace of advancement.

Reference: Floris, D.L., Filho, J.O.A., Lai, MC. et al. Towards robust and replicable sex differences in the intrinsic brain function of autism. Molecular Autism 12, 19 (2021). https://doi.org/10.1186/s13229-021-00415-z

Provided by Child Mind Institute

Neuroscience

Diverse Neural Signals Are Key to Rich Visual Information! (Neuroscience)

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Low signal heterogeneity results in severe loss of neural information; optimal stimulation method increasing the heterogeneity of neural signals may improve prosthetic vision with richer artificial visual information

Visual sensation begins at the retina, which is the neural tissue located at the back of eyeballs. It has been known that the retina detects light using photoreceptors which are light-sensitive nerve cells.In case of retinal degenerative diseases such as retinitis pigmentosa and age-related macular degeneration, those light sensing neurons are gradually damaged, leading to a profound vision loss. At this moment, no cure is available for the abovementioned ailments. But, microelectronic retinal prostheses can create artificial vision by electrically stimulating remaining retinal neurons although the prosthetic vision is still far removed from normal vision.

To further improve the quality of prosthetic artificial vision, Dr. Maesoon Im’s group of the Brain Science Institute at the Korea Institute of Science and Technology (KIST) applied computational neuroscience and information theory to neural signals of the retina. The retina, which has remarkably complex neural circuits, is known to compress visual neural signals. For example, the retina converts light into neural signals using over 100 million photoreceptor cells. Then, the vision is formed at the brain using visual information that is conveyed from over 1 million retinal ganglion cells. The KIST research team revealed that high signal heterogeneity from different retinal ganglion cells is a key element for efficient transmission of visual information. However, random signal patterns that maximize the heterogeneity are not used; it is thought to be due to some level of redundancy for correcting any potential error during the information transmission from the retina to the brain. These findings have been recently published in the IEEE Transactions on Neural Systems and Rehabilitation Engineering. This study is expected to be of high practical value in the field of prosthetic vision.

The KIST research team applied computational neuroscience and information theory to neural signals recorded from rabbit retinal neurons in order to quantify the transmission of visual information. At the same time, they observed that heterogeneity is slightly reduced, and some redundancy is allowed in order to prevent errors in the process of information transmission.

Dr. Maesoon Im, Brain Science Institute (BSI), KIST © Korea Institute of Science and Technology(KIST)

The KIST team compared neural signals arising in retinal ganglion cells of the rabbit retinas in response to light and electric stimulations, each representing neural responses of the healthy retina and the diseased retina activated by reitnal prostheses, respectively. Among the properties of neural signals, the researchers focused specifically on their heterogeneity, and found that cell-to-cell neural signal heterogeneity is altered by electric stimulation in some type of retinal ganglion cells, which are output neurons of the retina. This suggest that neural information of artificial vision is different across retinal ganglion cell types which are channels of retinal broadcasting to the brain. Particularly, in some cell types, neural signals arising in diverse neurons were highly similar in response to electric stimulation, which were much different from their heterogeneous responses to normal visual stimulation. This reduction in neural signal diversity leads to a severe decrease in the amount of transmitted information for artificial vision which may cause difficulties interpreting the artificially-delivered visual information by the prosthetic users.

KIST’s Dr. Joon Ho Kang explained, “This means that it is difficult to successfully replace highly complex visual information simply by stimulating neurons. Probably, microelectronic retinal implants need to produce unique neural signals in different retinal neurons for high heterogeneity of whole retinal neural signals.” Last year, in experiments using mice that have progressive retinal degeneration, Dr. Im’s group demonstrated that the consistency of the neural signals transmitted by individual retinal ganglion cells is gradually reduced as the disease advances. The neural signal consistency is belived to be important for stable visual percepts. Dr. Im stated, “Combined with our last year’s findings regarding reduced consistency in the degenerate retinas, it seems that near-normal artificial vision may be achieved if different retinal ganglion cells consistently transmit diverse neural signals.” Further clarifying the significance of the study, he continued, “This study demonstrates that, in order to control brain function in prosthetic vision and other various applications, it is insufficient to simply create any neural signals. Rather, given the remarkable complexity of neural networks, we need to develop more efficient stimulation strategies that would reproduce more sophisticated features of neural signals such as neuron-to-neuron signal heterogeneity.”

This study was conducted as a part of KIST Institutional Research program and the Young Researcher Program of the National Research Foundation of Korea, funded by the Ministry of Science and ICT (MSIT).

Featured image: Electric stimulation triggers spiking activities of retinal ganglion cells (RGCs), which will activate the occipital lobe for eliciting artificial visual percepts. Optic fibers in gray or color represent the optic nerve and the optic radiation which delivers those neural signals (lateral geniculate nucleus is omitted for brevity). Heterogeneous population codes (i.e. diverse spiking patterns of RGCs) (B) are likely to encode and transfer richer neural information than homogeneous counterparts (A). © Korea Institute of Science and Technology(KIST)

Reference: J. H. Kang, Y. J. Jang, T. Kim, B. C. Lee, S. H. Lee and M. Im, “Electric Stimulation Elicits Heterogeneous Responses in ON but Not OFF Retinal Ganglion Cells to Transmit Rich Neural Information,” in IEEE Transactions on Neural Systems and Rehabilitation Engineering, vol. 29, pp. 300-309, 2021.
doi: 10.1109/TNSRE.2020.3048973

Provided by National Research of Science and Technology

Psychiatry, Psychology

For Breakthroughs in Slowing Aging, Scientists Must Look Beyond Biology (Psychiatry / Psychology)

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Incorporating social and behavioral factors alongside biological mechanisms is critical for improving aging research, according to a trio of studies by leading social scientists

A trio of recent studies highlight the need to incorporate behavioral and social science alongside the study of biological mechanisms in order to slow aging.

The three papers, published in concert in Ageing Research Reviews, emphasized how behavioral and social factors are intrinsic to aging. This means they are causal drivers of biological aging. In fact, the influence of behavioral and social factors on how fast people age are large and meaningful. However, geroscience–the study of how to slow biological aging to extend healthspan and longevity–has traditionally not incorporated behavioral or social science research. These papers are by three pioneers in aging research and members of the National Academy of Medicine who study different aspects of the intersection of biology and social factors in shaping healthy aging through the lifespan.

Improving translation of aging research from mice to humans

Exciting biological discoveries about rate of aging in non-human species are sometimes not applicable or lost when we apply them to humans. Including behavioral and social research can support translation of geroscience findings from animal models to benefit humans, said Terrie Moffitt, the Nannerl O. Keohane University Professor of Psychology and Neuroscience at Duke University.

“The move from slowing fundamental processes of aging in laboratory animals to slowing aging in humans will not be as simple as prescribing a pill and watching it work,” Moffitt said. “Compared to aging in laboratory animals, human aging has many behavioral/social in addition to cellular origins and influences. These influences include potential intervention targets that are uniquely human, and therefore are not easily investigated in animal research.”

Several of these human factors have big impacts on health and mortality: stress and early life adversity, psychiatric history, personality traits, intelligence, loneliness and social connection, and purpose in life are connected to a variety of late-life health outcomes, she explained. These important factors need to be taken into account to get a meaningful prediction of human biological aging.

Elissa Epel, professor and vice chair in the Department of Psychiatry at UC San Francisco © R Searcy

“Geroscience can be augmented through collaboration with behavioral and social science to accomplish translation from animal models to humans, and improve the design of clinical trials of anti-aging therapies,” Moffitt said. “It’s vital that geroscience advances be delivered to everyone, not just the well-to-do, because individuals who experience low education, low incomes, adverse early-life experiences, and prejudice are the people who age fastest and die youngest.”

Social factors associated with poor aging outcomes

“Social hallmarks of aging” can be strongly predictive of age-related health outcomes – in many cases, even more so than biological factors, said USC University Professor and AARP Chair in Gerontology Eileen Crimmins. While the aging field commonly discusses the biological hallmarks of aging, we don’t tend to include the social and behavioral factors that lead to premature aging. Crimmins has called the main five factors below “the Social Hallmarks of aging” and poses that these should not be ignored in any sample of humans and the concepts should be incorporated where possible into non-human studies.

Crimmins examined data that was collected in 2016 from the Health and Retirement Study, a large, nationally representative study of Americans over the age of 56 that incorporates both surveys regarding social factors and biological measurements, including a blood sample for genetic analysis. For the study, she focused the five social hallmarks for poor health outcomes:

  1. low lifetime socioeconomic status, including lower levels of education
  2. adversity in childhood and adulthood, including trauma and other hardships
  3. being a member of a minority group
  4. adverse health behaviors, including smoking, obesity and problem drinking
  5. adverse psychological states, such as depression, negative psychological outlook and chronic stress

The presence of these five factors were strongly associated with older adults having difficulty with activities of daily living, experiencing problems with cognition, and multimorbidity (having five or more diseases). Even when controlling for biological measurements – including blood pressure, genetic risk factors, mitochondrial DNA copy number and more – the social differences, as well as demographic factors such as age and gender, explained most of the differences in aging outcomes between study subjects, she said. However, biological and social factors aren’t completely independent from one another, Crimmins added, which is why she advocates for further incorporation of social and behavioral factors in aging biology research.

Terrie Moffitt, the Nannerl O. Keohane University Professor of Psychology and Neuroscience at Duke University. Courtesy Terrie Moffitt

“Variability in human aging is strongly related to the social determinants of aging; and it remains so when extensive biology is introduced as mediating factors. This means that the social variability in the aging process is only partly explained by the biological measures researchers currently use,” she said. “Our hypothesis is that if we could fully capture the basic biological mechanisms of aging, they would even more strongly explain the social variability in the process of aging, as social factors need to ‘get under the skin’ through biology.”

Understanding stress and stress resilience

Elissa Epel, professor and vice chair in the Department of Psychiatry and Behavioral Sciences at UC San Francisco, detailed how research on stress and resilience needs to incorporate psychosocial factors in order to understand how different kinds of stress affect aging. Not all types of stress are equal and in fact some are salutary.

The social hallmarks of aging can shape the rate of aging in part through toxic stress responses, she said. While acute responses to minor or moderate stressors, including infection or injury, is critical to survival, chronic exposure to high amounts of stress–including long-term psychological stressors such as abuse–can prove toxic and result in poor health outcomes.

“Brief, intermittent, low-dose stressors can lead to positive biological responses, improving resistance to damage, which is called hormesis,” Epel explained. For example, physiological hormetic stressors include short term exposure to cold, heat, exercise, or hypoxia. Hormetic stress turns on mechanisms of cell repair and rejuvenation. “In contrast, a high dose of a chronic exposure can override these mechanisms, resulting in damage or death,” she added. Thus, toxic stress can accelerate biological aging processes, whereas hormetic stress can slow aging.

However, the types, timing, and frequency of hormetic stress need to be better delineated in order to be useful to human aging research and interventions, Epel said.

“Stress resilience, an umbrella term including hormetic stress, can be measured across cellular, physiological, and psychosocial functioning,” she said. “Developing a deeper understanding of stress resilience will lead to more targeted innovative interventions.” Stress resilience can also include social interventions that protect from the malleable social hallmarks of aging, including safe neighborhoods to reduce trauma and violence, and social support programs to combat loneliness and depression.

Geroscience is now more important than ever, both to our aging global demography but also to the health challenges we face going forward, and stress resilience is an especially important topic at the moment, Epel added. “In our new era, we have dramatically increasing temperature extremes, wildfires and small particle pollution, and new zoonotic viruses to contend with intermittently,” she said. “Reducing social disparities, improving stress resilience and bolstering immune function have become critical public health goals.”

In sum, the three papers together point to a promising decade ahead for aging research.

Humans, as complex social mammals, age together in response to social conditions and behavioral factors that are partly malleable. Epel explains “As we discover and test biological processes of aging that we can manipulate, we can do this in tandem with capitalizing on the natural levers of healthy aging that are powerful, interactive, and cannot be ignored. In this way, the fountain of youth becomes more attainable.”

“Behavioral and Social Research to Accelerate the Geroscience Translation Agenda” by Terrie E. Moffitt was supported by the National Institute on Aging (AG032282, R01 AG049789) and the U.K. Medical Research Council (P005918). “Social hallmarks of aging: Suggestions for geroscience research” by Eileen Crimmins was funded by grants from the National Institute on Aging (U01 AG009740, P30 AG017265, and R01 AG AG060110). “The geroscience agenda: Toxic stress, hormetic stress, and the rate of aging” by Elissa Epel was funded by National Institute on Aging grant R24 AG048024.

Featured image: USC University Professor and AARP Chair in Gerontology Eileen Crimmins © John Skalicky/USC

Reference: Eileen M. Crimmins, Social hallmarks of aging: Suggestions for geroscience research, Ageing Research Reviews, Volume 63, 2020, 101136, ISSN 1568-1637, https://doi.org/10.1016/j.arr.2020.101136. (https://www.sciencedirect.com/science/article/pii/S1568163720302713)

Provided by University of South California

Neuroscience

Precise Mapping Shows How Brain Injuries Inflict Long-term Damage (Neuroscience)

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Researchers have shown how forces acting on the brain during traumatic injury are linked to damage seen years after the initial trauma.

The findings, from a cross-disciplinary team at Imperial College London, could be used to predict the severity of brain injuries and help design more effective helmets for a range of sports and activities. 

Understanding the link between (initial injury and ongoing effects) is crucial for predicting who is at risk for long-term damage, and how protection may be better designed to prevent this damage.

— Dr Mazdak Ghajari, Dyson School of Design Engineering

Traumatic brain injury (TBI) results from a sudden impact or jolt to the head, such as during a road traffic accident or bomb blast, or during sports like rugby and American football. Immediate impacts of TBI can include bleeding and unconsciousness, but it can also result in changes to regions of the brain that lead to symptoms like memory loss, mood and personality changes, and lack of concentration, sometimes many years after the initial injury. 

However, the link between the mechanical forces that act on the brain during TBI and the resulting long-term changes is poorly understood. 

Now, researchers from the Faculties of Engineering and Medicine at Imperial, including the teams of Dr Mazdak Ghajari, Professor David Sharp and Dr Magdalena Sastre, have shown a clear link  between the forces acting on the brain during TBI and its associated long-term changes. The research, which is published in Brain, combined a computational model of brain injury with experimental studies on rat brains. 

Dr Mazdak Ghajari, from the Dyson School of Design Engineering at Imperial, said: “The initial damage during a traumatic brain injury takes only milliseconds to occur, but it triggers many changes that result in ongoing effects which can be felt years later. Understanding the link between the two is crucial for predicting who is at risk for long-term damage, and how protection may be better designed to prevent this damage.”

The shear stresses on the brain correlated with markers of brain inflammation.

— Dr Magdalena Sastre, Department of Brain Sciences

Previously, the team had built a human computer model to predict the location of long-term brain damage following TBI, focusing on the ‘white matter’ of the brain. The white matter contains nerve fibres called axons: extensions of neurons which help connect them. Axons play a large role in the brain networks that are altered in long-term brain damage.  

Now, they have tested this modelling approach to see if it can accurately predict the pattern of white matter damage in rats given mild or moderate TBI. They simulated the rats’ brains during injury, revealing the location and duration of mechanical forces linked to damage. Using a precise experimental model, this damage was induced in the rat brain and followed up after several weeks, which correlates to years of changes in a human brain. 

They found that the effect of shear stresses on the white matter helped to predict the location of long-term damage. Shear stresses push two parts of the same object, in this case the brain, in different directions. 

Dr Magdalena Sastre, from the Department of Brain Sciences at Imperial, said: “The shear stresses on the brain correlated with markers of brain inflammation, which is associated with memory loss and other future functional cognitive alterations.”

Development of injury after moderate impact © Imperial College London

We are also looking at how the type of impacts experienced by American football players affects whether they lose consciousness, and whether new helmet designs might protect soldiers from the effects of blast waves following explosions.

— Professor David Sharp, Department of Brain Sciences

The brain is jelly-like in consistency, so when it received a jolt, it shakes in a similar way, causing shear between adjacent parts. The intensity of the shear at different locations caused by different impacts, for example what angle they come from, predicts where the most severe white matter damage will occur. This could potentially help doctors predict the likely long-term effects in patients who have suffered a TBI. 

Dr Ghajari said: “Different types of injuries will cause different kinds of shear. With this new model we can now more accurately predict which injuries will cause severe, long-term damage, and potentially avert it. For example, motorbike accidents involve a lot of rotational movement, which causes lots of shear. We are studying dozens of bike helmets to see which best protect against excess rotation.” 

Now the team’s computational model has been validated in real rat brains, they can use it to ask a range of research questions by modelling different kinds of TBI. 

Professor David Sharp, also from the Department of Brain Sciences, added: “We are also looking at how the type of impacts experienced by American football players affects whether they lose consciousness, and whether new helmet designs might protect soldiers from the effects of blast waves following explosions. These types of studies can also help explain whether repeated small impacts, such as heading the ball in football, could lead to similar long-term brain injury.”

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The research comes out of a long-term collaboration between engineers, medics and biologists at Imperial, a partnership Dr Ghajari describes as “requiring lots of patience and energy, but producing extremely rewarding results.” 

Researchers come from the Department of Brain Sciences, the Biological Imaging Centre, the Dyson School of Design Engineering, the Centre for Blast Injury Studies, and the UK Dementia Research Institute at Imperial, as well as colleagues at King’s College London. 

The work was funded by the Wellcome Trust and the Royal British Legion at the Centre for Blast Injury Studies. 

‘From biomechanics to pathology: predicting axonal injury from patterns of strain after traumatic brain injury,’ by Cornelius K. Donat, Maria Yanez Lopez et al. is published in Brain. 

Featured image: Imaging and computational models depicting the development of brain injury after a mild impact on rat brains © Imperial College London

Provided by Imperial College London

Neuroscience

Deep Brain Stimulation Prevents Epileptic Seizures in Mouse Model (Neuroscience)

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Experimental approach reveals new avenues for treating people with drug-resistant epilepsy

Epileptic activity originating from one or more diseased brain regions in the temporal lobe is difficult to contain. Many patients with so-called temporal lobe epilepsy often do not respond to treatment with anti-epileptic drugs, and the affected brain areas must therefore be surgically removed. Unfortunately, this procedure only gives seizure freedom to about one third of patients, so the development of alternative therapeutic approaches is of great importance. Scientists led by neurobiologist Prof. Dr. Carola Haas, head of the research group at the Department of Neurosurgery at Medical Center – University of Freiburg and the BrainLinks-BrainTools research center, have investigated a new therapeutic approach to prevent epileptic seizures in temporal lobe epilepsy. They showed in mice that low-frequency stimulation of specific brain areas could completely stop epileptic activity. Instead of using electric current, the researchers stimulated the cells with light. To do this, they had previously introduced a light-sensitive molecule into the cells that allows particularly precise stimulation. They published the results in December 2020 in the scientific journal elife.

“As soon as we stimulated the brain region with a frequency of one hertz, the epileptic seizures disappeared. This effect was stable over several weeks,” Haas says. Habituation, which can occur with drug therapy, did not take place. The brain region was stimulated for one hour daily.

Circuits and cells identified

In temporal lobe epilepsy, the hippocampus is often pathologically altered and usually represents the so-called focus of epileptic activity. Previous studies have used precise genetic labeling techniques to map the fiber system and its synaptic contacts between the temporal lobe and hippocampus, which are typically preserved in temporal lobe epilepsy. The researchers used this fiber system to manipulate hippocampal activity in a specific and temporally precise manner using light-dependent proteins. Measuring brain waves showed that rhythmic activation of the diseased hippocampus at a low frequency of one hertz suppressed epileptic activity and prevented it from spreading.

Haas and her colleagues demonstrated that the anti-epileptic effect is largely due to the repeated activation of surviving granule cells in the seizure focus. Single cell studies confirmed the assumption that the granule cells are less excitable due to the stimulation, making the epileptic seizure less likely to spread. “It’s also possible that we have a widespread network effect because the stimulation can spread through the hippocampal circuitry,” Haas said.

In the future, the team, along with the medical physics department at the Medical Center – University of Freiburg, would like to use magnetic resonance imaging to observe the entire brain during stimulation. This technique could be used to identify additional brain regions that are affected by the stimulation. Corresponding findings on these could provide information on how they are connected and what further consequences stimulation has.

Featured image: When the hippocampus was stimulated slowly, epileptic seizures failed to occur in the mouse model. Image source: Medical Center – University of Freiburg / AG Haas

Reference: Enya Paschen, Claudio Elgueta et al., “Hippocampal low-frequency stimulation prevents seizure generation in a mouse model of mesial temporal lobe epilepsy”, ELife, 2021. https://elifesciences.org/articles/54518

Provided by University of Freiburg