neuroinnovations

Researchers have just uncovered a whole new part of the brain

A new study has discovered a previously unknown structure, a few cells thick, that surrounds the brain. A newfound anatomical structure has been discovered in the brain, which appears to play an essential role in the brain’s waste disposal and immune systems, acting as a protective barrier and harboring immune cells that watch for toxic proteins. Playing a multi-faceted role in the brain’s immunity, the team posits that when this layer of tissue, dubbed the subarachnoid lymphatic-like membrane (SLYM), goes awry, it likely causes many brain disorders such as multiple sclerosis and Alzheimer’s disease. A vast system of interconnected cells and pathways, due to technological advances, the brain is still throwing up amazing discoveries from its fathomless depths – with this latest find taking us on a wondrous journey in and around its entirety. As the realm of the central nervous system (CNS) increases with each new study, a team led by the University of Copenhagen adds to this body of work by discovering a previously unknown protective barrier called the SLYM. The group says the distinct layer, found in both mouse and human brains using two-photon microscopy and dissections, acts as a platform for immune cells such as myeloid cells and macrophages – to monitor the brain for any harmful events that may cause inflammation. Their research, detailed in the journal Science, focuses on the membranes encasing the brain comprising individual layers called the dura, arachnoid, and pia matter. These shields, known collectively as the meninges, keep the brain bathed in the cerebral spinal fluid (CSF), protecting it from the rest of the body and the inflammatory white blood cells held within its bone marrow, blood, and lymph tissue: providing privileged immunity. As part of this exemption, the SLYM dissects the chamber below the arachnoid layer, the subarachnoid space, dividing it into two compartments where it appears to separate freshly made CSF from ‘tainted’ CSF containing waste products and antigens. Therefore, the group state that it is likely involved in the glymphatic system – a network responsible for waste removal in the brain. In their whitepaper, the team state: “SLYM is the host for a large population of myeloid cells, the number of which increases in response to inflammation and aging, so this layer represents an innate immune niche ideally positioned to surveil the cerebrospinal fluid.” Structural immunity The CNS’ privileged immunity also means it does not contain a lymphatic drainage system to flush away antigens and other foreign bodies, so it relies heavily on CSF to carry these unwanted substances to the lymphatic system in the peripheral nervous system. Transported through an extensive network of tubes and compartments all over the brain, CSF acts as a shock absorber for its percipient host while delivering nutrients and carrying away unwanted products. And this is where the SLYM plays a vital role. Sitting in its CSF-filled chamber housing blood vessels and connective tissue joining the arachnoid and pia mater layers, the team state that the new anatomical structure helps control the flow of CSF around the brain, providing us with a “greater appreciation of the sophisticated role that CSF plays not only in transporting and removing waste from the brain, but also in supporting its immune defenses,” said Maiken Nedergaard, co-director of the Center for Translational Neuromedicine in Live Science.  The SLYM itself is only a few cells thick and shares molecular markers with mesothelium, a type of membrane covering other organs in the body, such as the lungs and heart. Mesothelium also plays the role of lubricant between organs that slide against each other. For this reason, the researchers propose that the SLYM is the brain’s mesothelium, lining the connective tissue and blood vessels in the gap between the brain and skull. “Physiological pulsations induced by the cardiovascular system, respiration, and positional changes of the head are constantly shifting the brain within the cranial cavity,” the scientists explain in their whitepaper. “SLYM may, like other mesothelial membranes, reduce friction between the brain and skull during such movements.” Adding to the SLYM’s already extensive immune functionality, experiments in mice also suggest that these diminutive membranes block most proteins, including amyloid plaques that cause Alzheimer’s, from crossing from the ‘contaminated’ CSF compartment to the ‘clean’ CSF compartment–although it allows tiny molecules like electrolytes to pass through. But the large role it plays in neuroprotection has its downsides: The group theorizes that damage to the shield may disrupt its ability to direct these potentially harmful proteins out of the brain. Any damage may also result in immune cells from the skull’s bone marrow flooding the brain’s sterile surface, an interesting finding that could help explain why traumatic brain injuries can cause prolonged brain inflammation and disrupt the normal flow of cleansing CSF. However, they concede that understanding how this disruption impacts the healthy brain “will require more detailed studies.”  “We conclude that SLYM fulfills the characteristics of a mesothelium by acting as an immune barrier that prevents exchange of small solutes between the outer and inner subarachnoid space compartments and by covering blood vessels in the subarachnoid space,” the group write in their paper. Finally, these new findings could uncover vital information pertaining to a host of brain disorders affecting millions of people across the globe – which, the researchers hope, will lead to new targets and therapeutics to aid in their treatment.

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Study shows that as your brain gets slower with age – you get happier

The study could offer incites into delaying the onset of dementia. New research from UC San Diego, which incorporates key areas in healthy brain aging, pits younger adults against their elderly counterparts to compare intelligence and well-being. Results consolidating brain-imaging and psychological evaluation indicated that even though older participants scored considerably lower in cognitive tests than their younger counterparts–they are far healthier mentally. The work centers around what is known as ‘senior moments,’ where an older friend or family member forgets a word or misplaces their keys. And even though studies have firmly established that these mild declines in cognition are perfectly normal as the brain changes with age: dementia is not. In fact, in up to forty percent of these cases, people can prevent or delay mild cognitive decline making it essential to understand which areas of the brain are affected in the normal aging process – by doing this, researchers hope to see how they differ in abnormal decline while training and improving them. The study, recently published in Psychology and Aging, saw sixty-two participants in their twenties and fifty-four healthy older adults over 60 undergo a gauntlet of cognitive tests. At the same time, scientists measured their brain activity using electroencephalography (EEG) to discern whether the two groups were using different areas of the brain for each task due to their age. Results showed that each group was indeed using different connections to perform the task, with the elderly contingent scoring significantly worse than their younger peers. However, when researchers interviewed both cohorts to evaluate their mental state: younger participants exhibited markedly worse mental well-being than their far happier elderly competitors. Lead author Jyoti Mishra, associate professor of psychiatry at UC San Diego, explains, “We wanted to better understand the interplay between cognition and mental health across aging, and whether they rely on activation of similar or different brain areas.” Mapping cognitive decline According to past studies, on average, our mental agility appears to peak around thirty years of age. And even though these subtle declines in cognition are normal, they can lead to a condition known as mild cognitive impairment (MCI) – where difficulties with recall and speech become more noticeable. In turn, MCI may increase the risk of dementia-including Alzheimer’s disease-involving the deterioration of memory, language, reasoning, and judgment severe enough to interfere with daily life. Despite this, some people with MCI might never develop dementia or even get better due to certain lifestyle changes. Subsequently, if scientists could identify the processes involved in normal brain aging, they could find ways to improve them – making inroads in the fight against MCI and dementia. The team set out to discern which brain areas decline or become more active with age by comparing young and old participants’ cognitive abilities and mental health. They began by hooking the volunteers up to an EEG while they all underwent cognitive tests. In this way, the team could glean which brain areas were active or no longer used in specific tasks depending on the person’s age. For instance, in the younger volunteers, EEG data showed that higher cognitive scores were achieved by those who exhibited more activity in the dorsolateral prefrontal cortex: part of the brain’s executive control system known to degrade as we age. However, during the same tasks, the elderly contingent showed increased activity in anterior portions of the brain’s Default Mode Network (DMN): a brain region usually active when an individual is in deep contemplation or daydreaming and inhibited during tasks denoting honed concentration. In this case, overactivity in this area may explain why they scored so much lower than their younger competitors. “The default mode network is useful in other contexts, helping us process the past and imagine the future, but it’s distracting when you’re trying to focus on the present to tackle a demanding task with speed and accuracy,” said Mishra.  But all was not lost for this cohort – activity in an area that helps guide attention and avoid distractions, known as the inferior frontal cortex, was increased, kicking in to improve scores in the older sample. Excitingly, taken together, these results validate the group’s premise that different brain areas are being activated and suppressed during brain aging as opposed to the regions used by young people. After all the volunteers had completed these tests, the team used a verified survey to gain insight into their mental states. They found significantly more symptoms of anxiety, depression, and loneliness in young people and, in contrast, greater mental well-being in older adults.  For this reason, Jyoti feels their study could also inspire new ways of addressing the mental health of younger adults. “We tend to think of people in their twenties as being at their peak cognitive performance, but it is also a very stressful time in their lives, so when it comes to mental well-being, there may be lessons to be learned from older adults and their brains,” she adds. The team is now looking into therapeutic interventions to strengthen these frontal networks, such as brain stimulation methods while suppressing the DMN through mindfulness meditation or other practices that orient individuals to the present.  “These findings may provide new neurological markers to help monitor and mitigate cognitive decline in aging, while simultaneously preserving well-being,” concludes Mishra. 

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Injectable tissue provides relief from chronic back pain in humans–could cut out the need for opioids

The new treatment cures the source of back pain, not just the symptoms. An injection comprising pulverized vertebral discs has successfully been used to treat degenerative disc disease, one of the world’s most common medical conditions. The therapy was shown to regrow the discs while reducing inflammation and pain, significantly improving the patient’s mobility and quality of life without surgical intervention. If rolled out to the general population, the team says their treatment could finally alleviate the suffering of millions of chronic lower back pain patients, possibly curbing the rampant opioid epidemic that kills thousands of Americans every year. The nonsurgical intervention from Summit Medical Center, Oklahoma, tackles chronic low back pain: the most common cause of disability worldwide and the sole cause of more than half of all opioids prescribed in the United States, helping to cripple the global economy. As there is no gold standard for diagnosing or treating degenerative disc disease, therapies derived from natural materials found in the body called biologics are being explored to regrow these degenerated discs. However, as the disc loses vital liquids as it deteriorates and cracks, to end the pain, the treatment would need to rehydrate these structures as it repopulates native cells to gain the desired height restoration- no easy feat. In the current study, researchers used a biological platform known as viable disc allograft supplementation, a human tissue graft (allograft) containing micronized or pulverized vertebral discs injected directly into a patient’s damaged disc. The investigation, involving 50 participants, is part of the larger Viable Allograft Supplemented Disc Regeneration in the Treatment of Patients With Low Back Pain (VAST) Trial, following 220 patients with chronic lower back pain over three years. Researchers injected forty-six volunteers with the allograft in this extension, and four received a saline placebo. Using radiography and Magnetic Resonance Imaging (MRI), the scientists saw that the therapy encourages the cells in the damaged discs to regenerate, leaving healthy tissue. These results were also validated using various pain and disability indices which record patient-reported symptoms, functional outcomes, and quality of life. In this way, the group obtained a complete picture of the pain relief gained by the patients, which imaging alone cannot always depict. The group states the allograft, acquired from cadavers, requires no incisions and can be administered by a clinician using a mild sedative – meaning patients can go home the same day. “The significant improvement in pain and function is promising for patients living with chronic low back pain – a condition that can greatly impact a person’s quality of life,” said lead author Douglas Beall, chief of radiology at Clinical Radiology of Oklahoma. “Back pain is the leading cause of limited activity and workplace absenteeism. This treatment may help patients return to a normal activity level for a longer period time.” Images at 12 months demonstrated improvement in morphology, disc height, and patient indices of pain and functional improvement followed. Credit: Beall et al. Int J Spine Surg. 2020 Why does the back degenerate? The spine has 26 vertebrae bones cushioned by small gel-filled sacs known as vertebral discs, which act like shock absorbers to allow the flexible movement of the spine. The discs comprise a firm, tough outer layer called the annulus fibrosis, surrounding a soft, jellylike layer, the nucleus pulposus. Degenerative disc disease occurs when these layers show wear and tear due to aging, injury, or disease. As these structures lose their integrity and dry out, the vertebrae drop to come closer together, reducing the disc’s ability to act like a buttress and provide support. A lack of blood supply means damaged discs do not repair themselves – as a consequence, they can bulge, tear or slip out of place, causing chronic pain and problems with mobility. The problem with treating this condition is that existing therapies treat the symptoms of the disease rather than the causes. In the present study, the researchers developed a biologic consisting of a nucleus pulposus allograft, saline components, and a cryopreserved vial of cells (VIA Disc Matrix). According to their past whitepapers, once they thaw the vial, all the ingredients are mixed together and injected using a 22-gauge spinal needle into 1 or 2 degenerated intervertebral discs in the lower spine. To ensure the participants incur no injuries, the scientists use continuous fluoroscopic imaging or computed tomography to guide the procedure, which takes 10-11 minutes for one disc and roughly 15 minutes for two. Sturdy results in humans Appearing sound in theory, the researchers have trialed their allograft multiple times. They first ran a one-year pilot study involving 24 patients; next came the larger VAST trial, which followed 220 participants over 12 months; and finally, the newest 50-patient VAST extension study running over three years, whose results the team reported at the Society of Interventional Radiology Annual Scientific Meeting in Phoenix. In the pilot and large-scale VAST trial, scientists compared the results from participants receiving the allograft to those from the saline placebo and nonsurgical management (NSM) cohorts.  In the pilot study, subjects receiving the allograft exhibited a more considerable reduction of pain and a significant increase in functional improvement than the placebo group over the 12 months. In the 224 patients aged 19 to 73 years, pain improved by fifty-four percent at the one-year mark in patients receiving the allograft – accompanied by a fifty-three percent improvement in the self-reported Oswestry Disability Index (ODI): indicating that disc tissue allograft may be a beneficial nonsurgical treatment for patients who have chronically painful lumbar degenerative discs. The extension further validates these results by showing that after three years, sixty percent of patients who received the allograft injection for chronic low back pain reported a fifty percent reduction in pain, with seventy percent of this group reporting more than a 20-point improvement in their ODI scores.  Limitations and future plans Despite the positive results of the studies, the group remains realistic, voicing concerns about the small number of reported adverse events as they lost many participants in the follow-up. And

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Human brain organoids successfully integrate into the mouse cortex and respond to visual stimuli

Could these mini-brain ‘grafts’ be used to repair brain injuries in the future? In a world’s first, researchers have shown that human brain organoids transplanted into live animals’ brains successfully formed human-mouse synaptic connections and reacted to visual stimuli. The results, made possible by an unprecedented multi-faceted technology, show the cross-species transplant merged with the animal’s visual cortex and tapped into the local blood supply. The study from UC San Diego revolves around brain organoids or mini-brains – structures designed to resemble a specific brain region or to simulate isolated changes caused by a neurological disorder. To date, scientists have successfully implanted human brain organoids into animal tissue, hoping these structures can repair or replace damaged tissue in the brain to act as a neural prosthesis. And although these studies hold promise for neuroscientific research, scientists have still been unable to prove that human brain organoids implanted in the animal brain could merge with their native structures and react to stimuli along with them–Until now. In the new study, the UC San Diego researchers developed a new type of ultra-sensitive electrode to record neuronal activity and combined it with a technology called two-photon imaging, which captures live cell activity in biological tissue. Using the electrodes, they recorded neural activity from the implanted organoid, showing that it had formed functional connections with the mouse cortex and reacted to external stimuli. Through the two-photon imaging, they were able to observe that mouse blood vessels grew into the organoid, providing it with nutrients and oxygen– a big deal as organoids do not contain vascular cells. “No other study has been able to record optically and electrically at the same time,” states Madison Wilson, the paper’s first author and Ph.D. candidate in Professor Duygum Kuzum’s group at UC San Diego. “Our experiments reveal that visual stimuli evoke electrophysiological responses in the organoids, matching the responses from the surrounding cortex.” Unprecedented imaging The organoids used in this study were human cortical organoids designed to typify some, but not all, of the features of the cerebral cortex. The team grew the mini-brains from differentiated human induced pluripotent stem cells: special cells created from adult cells (in this case, skin cells) exposed to a chemical cocktail to revert them back to their embryonic state. To measure the activity of the organoid once transplanted into the mouse cortex, the team used platinum nanoparticles to lower a special property of graphene electrodes known as impedance – which blocks or ‘resists’ the flow of electricity. Once they had achieved this, 100 times more of the electrical potential created by neurons could flow through the electrodes, enabling this activity to be recorded and analyzed. Amazingly, the scientists achieved this while keeping the electrodes transparent to lower the electrical resistance and increase conductivity while viewing the activity of neurons directly beneath the arrays. Duygu Kuzum, a professor of electrical and computer engineering at UC San Diego, says, “By lowering impedance, we can shrink electrode dimensions down to single cell size and record neural activity with single cell resolution.” In tests on mice, these highly sensitive graphene electrodes could record and image neuronal activity at both the macroscale and single-cell levels. Accordingly, the data indicated that the neurons within the organoids became synchronized with the surrounding tissue. At the same time, the two-photon imaging clearly showed the organoid’s integration with the mouse’s cortex and blood supply to back these results. Live brain implants Taken together, the team states their multi-modal imaging platform indicates that human and mouse cortical tissues established functional connections enabling the organoid to react to external sensory stimuli. They later verified their findings during dissection, where the organoid was stained with two different types of antibodies – one that ‘traces’ human cells and the other that marks synaptic connections. Via this investigation, the team confirmed that the human cells had traveled as far as 4mm away from the boundary of the graft site migrating along the mouse’s corpus callosum, a thick nerve tract just below the cerebral cortex – providing further proof of integration. In their white paper, the team writes this combination of stem cell and neurorecording technologies could herald the next generation of disease models, drug screening and personalized medicine platforms, and transplantable neural prosthetics to restore specific lost, degenerated, or damaged brain regions. “We envision that, further along the road, this combination of stem cells and neurorecording technologies will be used for modeling disease under physiological conditions; examining candidate treatments on patient-specific organoids; and evaluating organoids’ potential to restore specific lost, degenerated or damaged brain regions,” Kuzum concludes.

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