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  • 11 June

    NT/ New tool activates deep brain neurons by combining ultrasound, genetics

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Fri, Jun 11, 2021 3:09 PM by Paradigm Fund

NT/ New tool activates deep brain neurons by combining ultrasound, genetics

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Neuroscience biweekly vol. 34, 28th May — 11th JuneTL;DRNeurological disorders such as Parkinson’s disease and epilepsy have had some treatment success with deep brain stimulation, but those require surgical device implantation. A multidisciplinary team at Washington University in St. Louis has developed a new brain stimulation technique using focused ultrasound that is able to turn specific types of neurons in the brain on and off and precisely control motor activity without surgical device implantation.Researchers have developed a new technique that allows microscopic fluorescence imaging at four times the depth limit imposed by light diffusion. Fluorescence microscopy is often used to image molecular and cellular details of the brain in animal models of various diseases but, until now, has been limited to small volumes and highly invasive procedures due to intense light scattering by the skin and skull.Psychotic disorders come with a progressive decline in IQ. If current drug treatments are successful in containing psychotic symptoms, nothing can be done to prevent the deterioration of intellectual skills that leads to loss of autonomy. Researchers have discovered that prescription of selective serotonin reuptake inhibitors (SSRIs) in late childhood can reduce the deterioration of intellectual abilities and have a neuroprotective effect on some of the brain regions affected by the psychotic illness.Researchers have developed a technique that could allow deep brain stimulation devices to sense activity in the brain and adjust stimulation accordingly.A strange thing sometimes happens when we listen to a spoken phrase again and again: It begins to sound like a song. This phenomenon, called the “speech-to-song illusion,” can offer a window into how the mind operates and give insight into conditions that affect people’s ability to communicate, like aphasia and aging people’s decreased ability to recall words. Now, researchers from the University of Kansas have published a study in PLOS ONE examining if the speech-to-song illusion happens in adults who are 55 or older as powerfully as it does with younger people.A team of multiple sclerosis (MS) experts led a pilot randomized controlled trial of robotic-exoskeleton assisted exercise rehabilitation (REAER) effects on mobility, cognition, and brain connectivity in people with substantial MS-related disability. Their results showed that REAER is likely an effective intervention, and is a promising therapy for improving the lives of those with MS.How old is your brain compared to your chronological age? A new measure of brain health developed by researchers at Rush University Medical Center may offer a novel approach to identifying individuals at risk of memory and thinking problems, according to research results published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.Through the Abecedarian Project, an early education, randomized controlled trial that has followed children since 1971, researchers have discovered an enhanced learning environment during the first five years of life shapes the brain in ways that are apparent four decades later.Stroke survivors’ recovery of speech predicted by computer simulation: Researchers have developed new methods to predict a person’s ability to improve language skills even before they start therapy.Scientists have recorded blood oxygen levels in the hippocampus and provided experimental proof for why the area is vulnerable to damage and degeneration, a precursor to Alzheimer’s disease.Nature neuroscience June issue is now live.Neuroscience marketThe 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.Latest news and researchesSonothermogenetics for noninvasive and cell-type specific deep brain neuromodulationby Yaoheng Yang, Christopher Pham Pacia, Dezhuang Ye, Lifei Zhu, Hongchae Baek, Yimei Yue, Jinyun Yuan, Mark J. Miller, Jianmin Cui, Joseph P. Culver, Michael R. Bruchas, Hong Chen in Brain StimulationNeurological disorders such as Parkinson’s disease and epilepsy have had some treatment success with deep brain stimulation, but those require surgical device implantation. A multidisciplinary team at Washington University in St. Louis has developed a new brain stimulation technique using focused ultrasound that is able to turn specific types of neurons in the brain on and off and precisely control motor activity without surgical device implantation.The team, led by Hong Chen, assistant professor of biomedical engineering in the McKelvey School of Engineering and of radiation oncology at the School of Medicine, is the first to provide direct evidence showing noninvasive, cell-type-specific activation of neurons in the brain of mammal by combining ultrasound-induced heating effect and genetics, which they have named sonothermogenetics. It is also the first work to show that the ultrasound- genetics combination can robustly control behavior by stimulating a specific target deep in the brain.The senior research team included experts from both the McKelvey School of Engineering and the School of Medicine, including Jianmin Cui, professor of biomedical engineering; Joseph P. Culver, professor of radiology, of physics and of biomedical engineering; Mark J. Miller, associate professor of medicine in the Division of Infectious Diseases in the Department of Medicine; and Michael Bruchas, formerly of Washington University, now professor of anesthesiology and pharmacology at the University of Washington.“Our work provided evidence that sonothermogenetics evokes behavioral responses in freely moving mice while targeting a deep brain site,” Chen said. “Sonothermogenetics has the potential to transform our approaches for neuroscience research and uncover new methods to understand and treat human brain disorders.”Using a mouse model, Chen and the team delivered a viral construct containing TRPV1 ion channels to genetically-selected neurons. Then, they delivered small burst of heat via low-intensity focused ultrasound to the select neurons in the brain via a wearable device. The heat, only a few degrees warmer than body temperature, activated the TRPV1 ion channel, which acted as a switch to turn the neurons on or off.“We can move the ultrasound device worn on the head of free-moving mice around to target different locations in the whole brain,” said Yaoheng Yang, first author of the paper and a graduate student in biomedical engineering. “Because it is noninvasive, this technique has the potential to be scaled up to large animals and potentially humans in the future.”The work builds on research conducted in Cui’s lab that was published in Scientific Reports in 2016. Cui and his team found for the first time that ultrasound alone can influence ion channel activity and could lead to new and noninvasive ways to control the activity of specific cells. In their work, they found that focused ultrasound modulated the currents flowing through the ion channels on average by up to 23%, depending on channel and stimulus intensity. Following this work, researchers found close to 10 ion channels with this capability, but all of them are mechanosensitive, not thermosensitive.The work also builds on the concept of optogenetics, the combination of the targeted expression of light-sensitive ion channels and the precise delivery of light to stimulate neurons deep in the brain. While optogenetics has increased discovery of new neural circuits, it is limited in penetration depth due to light scattering and requires surgical implantation of optical fibers.Sonothermogenetics has the promise to target any location in the mouse brain with millimeter-scale resolution without causing any damage to the brain, Chen said. She and the team continue to optimize the technique and further validate their findings.<a href="https://medium.com/media/30877c4d94b5c9db3d913e00bfbc6963/href">https://medium.com/media/30877c4d94b5c9db3d913e00bfbc6963/href</a>Diffuse optical localization imaging for noninvasive deep brain microangiography in the NIR-II windowby Quanyu Zhou, Zhenyue Chen, Justine Robin, Xosé-Luís Deán-Ben, Daniel Razansky in OpticaResearchers have developed a new technique that allows microscopic fluorescence imaging at four times the depth limit imposed by light diffusion. Fluorescence microscopy is often used to image molecular and cellular details of the brain in animal models of various diseases but, until now, has been limited to small volumes and highly invasive procedures due to intense light scattering by the skin and skull.“Visualization of biological dynamics in an unperturbed environment, deep in a living organism, is essential for understanding the complex biology of living organisms and progression of diseases,” said research team leader Daniel Razansky from the University of Zurich and ETH Zurich, both in Switzerland. “Our study represents the first time that 3D fluorescence microscopy has been performed fully noninvasively at capillary level resolution in an adult mouse brain, effectively covering a field of view of about 1 centimeter.”The researchers describe their new technique, which is called diffuse optical localization imaging (DOLI). It takes advantage of what is known as the second near-infrared (NIR-II) spectral window from 1000 to 1700 nanometers, which exhibits less scattering.“Enabling high-resolution optical observations in deep living tissues represents a long-standing goal in the biomedical imaging field,” said Razansky. “DOLI’s superb resolution for deep-tissue optical observations can provide functional insights into the brain, making it a promising platform for studying neural activity, microcirculation, neurovascular coupling and neurodegeneration.”Concept of diffuse optical localization imaging (DOLI) and characterization of microdroplets. (a) Layout of DOLI setup. A monochromatic laser beam illuminates fluorescent targets hidden behind the scattering media with backscattered fluorescence light detected by a SWIR camera. (b) WF image of microdroplets captured with a commercial bright-field microscope. © Histogram of microdroplet diameter distribution. (d) Localization and image formation workflow. (e) Experimental arrangement for measuring dependence of the PSF on the target depth in a scattering medium. (f) WF image of the microfluidic chip captured with the SWIR camera. (g) The recorded fluorescence spot size (FWHM of the line profiles) as a function of the target depth; both raw data and curve fitting are shown.For the new technique, the researchers intravenously inject a living mouse with fluorescent microdroplets at a concentration that creates a sparse distribution in the bloodstream. Tracking these flowing targets enables reconstruction of a high-resolution map of the deep cerebral microvasculature in the mouse brain.“The method eliminates background light scattering and is performed with the scalp and skull intact,” said Razansky. “Interestingly, we also observed strong dependence of the spot size recorded by the camera on microdroplet’s depth in the brain, which enabled depth-resolved imaging.”The new approach benefits from the recent introduction of highly efficient short-wave infrared cameras based on InGaAs sensors. Another key building block was the use of novel contrast agents exhibiting strong fluorescence responses in the NIR-II window, such as lead sulfide (PbS)-based quantum dots.The researchers first tested the new technique in synthetic models of tissue known as tissue phantoms that mimic average brain tissue properties, demonstrating that they could acquire microscopic resolution images at depths of up to 4 millimeters in optically opaque tissues. They then performed DOLI in living mice where cerebral microvasculature as well as blood flow velocity and direction could be visualized entirely noninvasively.The researchers are working to optimize precision in all three dimensions to improve DOLI’s resolution. They are also developing improved fluorescent agents that are smaller, have stronger fluorescence intensity and are more stable in vivo. This will significantly boost DOLI’s performance in terms of the achievable signal to noise and imaging depth.“We expect that DOLI will emerge as a powerful approach for fluorescence imaging of living organisms at previously inaccessible depth and resolution regimes,” said Razansky. “This will greatly enhance the in vivo applicability of fluorescence microscopy and tomography techniques.”Long-term effects of early treatment with SSRIs on cognition and brain development in individuals with 22q11.2 deletion syndromeby Valentina Mancini, Johanna Maeder, Karin Bortolin, Maude Schneider, Marie Schaer, Stephan Eliez in Translational PsychiatryOne person in 2000 suffers from a microdeletion of chromosome 22 that can lead to the development of psychotic disorders, such as schizophrenia, in adolescence. In addition to symptoms such as hallucinations or delusions, psychotic disorders also come with a progressive decline in intelligence quotient (IQ). If current drug treatments are successful in containing psychotic symptoms, nothing can be done to prevent the deterioration of intellectual skills that leads to loss of autonomy. Researchers at the University of Geneva (UNIGE), Switzerland, have discovered that prescription of selective serotonin reuptake inhibitors (SSRIs) — a class of drugs used to treat anxiety and depression -in late childhood can reduce the deterioration of intellectual abilities, and have a neuroprotective effect on some of the brain regions affected by the psychotic illness. This study, to be read in the journal Translational Psychiatry, opens up a new field of research and new hope for people affected by the microdeletion of chromosome 22.The average IQ is around 100 points. However, for people who may develop a psychotic illness, such as those with a microdeletion of chromosome 22, the average drops to 70–80 points. “The problem is that when a psychotic disorder occurs, such as schizophrenia, the brain frontal lobe and the hippocampus are particularly affected, which leads to the gradual deterioration of already below-average intellectual capacities,” explains Valentina Mancini, a researcher in the Department of Psychiatry at UNIGE Faculty of Medicine and first author of the study. From then on, the average IQ drops to around 65–70 points, leading to a loss of autonomy that requires a protected environment. “At present, drug treatments manage to contain psychotic symptoms, such as hallucinations, anxiety or distortion of reality, but there is no treatment that can reduce the deterioration of affected people’s intellectual capacities,” notes the Geneva researcher.The team of Stéphan Eliez, professor in the Department of Psychiatry at UNIGE Faculty of Medicine, has been following 200 patients affected by the microdeletion of chromosome 22 for the past 20 years. “30 to 40% of them developed schizophrenia psychotic disorder,” he explains. “Thanks to this cohort, we found that people suffering from this syndrome lost 7 to 8 IQ points from childhood to adulthood. This figure rises to 15 IQ points for those who developed psychotic disorders.”Yet the physicians noted that two to three teenagers a year are exceptions, and even gained IQ points. Why? “We made a comprehensive analysis of these patients’ medical data to find out any common feature in the treatments prescribed to them by their GP,” explains Valentina Mancini. Two observations caught their attention.The first is the prescription of small, regular doses of SSRIs — a drug that increases the levels of serotonin, a neurotransmitter involved in the regulation of behaviour — in late childhood and throughout adolescence. “These drugs increase neurogenesis and act on synaptic plasticity. They are prescribed today to reduce anxiety and depressive symptoms,” explains the Geneva researcher. And the younger the patients received this treatment, at around 10–12 years of age, the more the frontal lobe and the hippocampus — and therefore the intellectual capacities — were preserved from deterioration caused by the psychotic illness. The second observation is that a neuroleptic drug — prescribed in small doses to control psychotic symptoms such as hallucinations or delusions — also seems to have a positive effect if added to SSRIs during adolescence. “These two medications, especially when combined, have thus preserved the anatomical structure of the brain affected by the degradation responsible for the decline in intellectual capacity,” remarks Stéphan Eliez.This study provides for the first time an indication of a neuroprotective preventive treatment for the development and preservation of IQ. “It should be stressed that too great a deterioration of intellectual skills progressively leads to a very problematic psychosocial dependence. Here, we could succeed in protecting this population,” notes Stéphan Eliez.Once the results of this study are confirmed, the effect of SSRIs could be tested on other types of patients and possibly prescribed preventively to people at risk of intellectual deterioration, such as individuals with other genetic syndromes like Fragile X or Down’s syndrome, or children of schizophrenic parents. “We also want to investigate whether the 3% to 4% of adolescents in the general population who develop psychotic symptoms would see this risk reduced by taking this drug,” continues Valentina Mancini.The Geneva team will now compare the results obtained from their research cohort with international databases in order to confirm the neuroprotective role induced by these treatments prescribed at the end of childhood, adolescence being the critical phase for the onset of psychotic diseases.Developmental trajectories of full-scale IQ (FSIQ), performance IQ (PIQ) and verbal IQ (VIQ) scores in deletion carriers with and without treatment with SSRIs (upper panel) and deletion carriers endorsing psychotic symptoms with and without treatment with SSRIs (lower panel)).Uncovering biomarkers during therapeutic neuromodulation with PARRM: Period-based Artifact Reconstruction and Removal Methodby Evan M. Dastin-van Rijn, Nicole R. Provenza, Jonathan S. Calvert, Ro’ee Gilron, Anusha B. Allawala, Radu Darie, Sohail Syed, Evan Matteson, Gregory S. Vogt, Michelle Avendano-Ortega, Ana C. Vasquez, Nithya Ramakrishnan, Denise N. Oswalt, Kelly R. Bijanki, Robert Wilt, Philip A. Starr, Sameer A. Sheth, Wayne K. Goodman, Matthew T. Harrison, David A. Borton in Cell Reports MethodsBy delivering small electrical pulses directly to the brain, deep brain stimulation (DBS) can ease tremors associated with Parkinson’s disease or help relieve chronic pain. The technique works well for many patients, but researchers would like to make DBS devices that are a little smarter by adding the capability to sense activity in the brain and adapt stimulation accordingly.Now, a new algorithm developed by Brown University bioengineers could be an important step toward such adaptive DBS. The algorithm removes a key hurdle that makes it difficult for DBS systems to sense brain signals while simultaneously delivering stimulation.“We know that there are electrical signals in the brain associated with disease states, and we’d like to be able to record those signals and use them to adjust neuromodulation therapy automatically,” said David Borton, an assistant professor of biomedical engineering at Brown and corresponding author of a study describing the algorithm. “The problem is that stimulation creates electrical artifacts that corrupt the signals we’re trying to record. So we’ve developed a means of identifying and removing those artifacts, so all that’s left is the signal of interest from the brain.”The work was co-led by Nicole Provenza, a Ph.D. candidate working in Borton’s lab at Brown, and Evan Dastin-van Rijn, a Ph.D. student at the University of Minnesota who worked on the project while he was an undergraduate at Brown advised by Borton and Matthew Harrison, an associate professor of applied mathematics. Borton’s lab is affiliated the Brown’s Carney Institute for Brain Science.DBS systems typically consist of an electrode implanted in the brain that’s connected to a pacemaker-like device implanted in the chest. Electrical pulses are delivered at a consistent frequency, which is set by a doctor. The stimulation frequency can be adjusted as disease states change, but this has to be done manually by a physician. If devices could sense biomarkers of disease and respond automatically, it could lead to more effective DBS therapy with potentially fewer side effects.There are several factors that make it difficult to sense and stimulate at the same time, the researchers say. For one thing, the frequency signature of the stimulation artifact can sometimes overlap with that of the brain signal researchers want to detect. So merely cutting out swaths of frequency to eliminate artifacts might also remove important signals. To eliminate the artifact and leave other data intact, the exact waveform of the artifact needs to be identified, which presents another problem. Implanted brain sensors are generally designed to run on minimal power, so the rate at which sensors sample electrical signals makes for fairly low-resolution data. Accurately identifying the artifact waveform with such low-resolution data is a challenge.To get around that problem, the researchers came up with a way to turn low-resolution data into a high-resolution picture of the waveform. Even though sensors don’t collect high-resolution data, they do collect a lot of data over time. Using some clever mathematics, the Brown team found a way to cobble bits of data together into a high-resolution picture of the artifact waveform.“We basically take an average of samples recorded at similar points along the artifact waveform,” Dastin-van Rijn said. “That allows us to predict the contribution of the artifact in those kinds of samples, and then remove it.”In a series of laboratory experiments and computer simulations, the team showed that their algorithm outperforms other techniques in its ability to separate signal from artifact. The team also used the algorithm on previously collected data from humans and animal models to show that they could accurately identify artifacts and remove them.“I think one big advantage to our method is that even when the signal of interest closely resembles the simulation artifact, our method can still tell the difference between the two,” Provenza said. “So that way we’re able to get rid of the artifact while leaving the signal intact.”Another advantage, the researchers say, is that the algorithm isn’t computationally expensive. It could potentially run in real time on current DBS devices. That opens the door to real-time artifact-filtering, which would enable simultaneous recording and stimulation.“That’s the key to an adaptive system,” Borton said. “Being able to get rid of the stimulation artifact while still recording important biomarkers is what will ultimately enable a closed-loop therapeutic system.”Does age affect perception of the Speech-to-Song Illusion?by Hollie A. C. Mullin, Evan A. Norkey, Anisha Kodwani, Michael S. Vitevitch, Nichol Castro in PLOS ONEA strange thing sometimes happens when we listen to a spoken phrase again and again: It begins to sound like a song. This phenomenon, called the “speech-to-song illusion,” can offer a window into how the mind operates and give insight into conditions that affect people’s ability to communicate, like aphasia and aging people’s decreased ability to recall words. Now, researchers from the University of Kansas have published a study in PLOS ONE examining if the speech-to-song illusion happens in adults who are 55 or older as powerfully as it does with younger people.The KU team recruited 199 participants electronically on Amazon’s Mechanical Turk (MTurk), a website used to conduct research in the field of psychology. The subjects listened to a sound file that exemplified the speech-to-song illusion, then completed surveys relating to three different studies.“In the first study, we just played them the canonical stimulus made by the researcher that discovered this illusion — if that can’t create the illusion, then nothing can,” said co-author Michael Vitevitch, professor of psychology at KU. “Then we simply asked people, ‘Did you experience the illusion or not?’ There was no difference in the age of the number of people that said yes or no.”While the researchers hypothesized fewer older people would perceive the illusion than younger people, the study showed no difference due to age.While older and younger people perceived the speech-to-song illusion at the same rates, in the second study investigators sought to discover if older people experienced it less powerfully.“We thought maybe ‘yes or no’ was too coarse of a measurement, so let’s try to use a five-point rating scale,” Vitevitch said. “Maybe older adults would rate it as being a little bit more speech-like and younger adults will rate it as being more song-like and you’ll see it on this five-point scale, maybe. But there was no difference in the numbers with the younger and older adults.”In the third study, Vitevitch wanted to see if older adults perhaps experience the illusion more slowly than younger people.“We thought maybe it’s not the strength of the illusion that’s different but maybe it’s when the illusion occurred,” he said. “So, we did a final study and asked people to click a button on the screen when their perception shifted from speech to song — we thought maybe older adults would need a few more repetitions for it to switch over. But we got the same number for both younger adults and older.”Nodes representing phonemes, syllables, and semantic information associated with the word frisbee as it might be represented in Node Structure Theory. Additional higher-level and lower-level nodes have been omitted to simplify the image.Vitevitch’s co-authors were KU undergraduate researchers Hollie Mullin, Evan Norkey and Anisha Kodwani, as well as Nichol Castro of the University of Buffalo.According to Vitevitch, the findings might translate to good news for older adults.“We have this common misconception that everything goes downhill cognitively as we age,” said the KU researcher. “That’s not the case. There are some things that do get worse with age, but there are some things that actually get better with age, and some things that stay consistent with age — in the case of this illusion, you’re going to get equally suckered whether you’re an older adult or a younger adult.”In another aspect of the research, the investigators found people with musical training experienced the speech-to-song illusion at similar rates as people with no background in music.“There’s a debate about whether musicians or musically trained people experienced the illusion more or less or sooner or more strongly,” Vitevitch said. “We looked at it and there was really no difference there either. Musicians and non-musically trained people experience this at about the same rates and have the same sort of experience. The amount of musical training didn’t matter. It was just amazingly consistent however we looked at it.”Not everybody experiences the speech-to-song illusion. The study found about 73% of participants heard spoken words become song-like after several repetitions. But the ability to perceive it didn’t correlate to age or musical training.A pilot randomized controlled trial of robotic exoskeleton-assisted exercise rehabilitation in multiple sclerosisby Ghaith J. Androwis, Brian M. Sandroff, Peter Niewrzol, Farris Fakhoury, Glenn R. Wylie, Guang Yue, John DeLuca in Multiple Sclerosis and Related DisordersA team of multiple sclerosis (MS) experts at Kessler Foundation led the first pilot randomized controlled trial of robotic-exoskeleton assisted exercise rehabilitation (REAER) effects on mobility, cognition, and brain connectivity in people with substantial MS-related disability. Their results showed that REAER is likely an effective intervention, and is a promising therapy for improving the lives of those with MS.It is common for people with MS to experience impairments in both mobility and cognition, and few therapies exist to manage the range of debilitating symptoms. This lack of treatment options is a major problem for people with MS, especially those with substantial MS-related neurological disability.Previous research shows that exercise rehabilitation, such as walking, is an effective approach to symptom management, with some research suggesting that even a single exercise rehabilitation intervention can improve both mobility and cognition.Yet there is a lack of efficacy of exercise rehabilitation on mobility and cognitive outcomes in people with MS who have substantial disability. Adaptive exercise rehabilitation approaches such as body-weight supported treadmill training and robot-assisted gait training have not demonstrated convincing results. Moreover, adaptive interventions lack key interactions between patients and therapists that may improve efficacy.In this pilot study of 10 participants with significant MS-related neurological disability, researchers explored the use of robotic exoskeletons to manage symptoms. Rehabilitation exercise using robotic exoskeletons is a relatively new approach that enables participants to walk over-ground in a progressive regimen that involves close engagement with a therapist. The Foundation has dedicated a Ekso NR to MS studies to facilitate further research in this area.As compared to conventional gait training, REAER allows participants to walk at volumes needed to realize functional adaptations — via vigorous neurophysiological demands — that lead to improved cognition and mobility. Effects on brain activity patterns were studied using the functional MRI capabilities of the Rocco Ortenzio Neuroimaging Center at Kessler Foundation.Investigators compared participants’ improvement after four weeks of REAER vs four weeks of conventional gait training, looking at functional mobility, walking endurance, cognitive processing speed, and brain connectivity.The results were positive: Relative to conventional gait training, four weeks of REAER was associated with large improvements in functional mobility (?p2=.38), cognitive processing speed (?p2=.53), and brain connectivity outcomes, most significantly between the thalamus and ventromedial prefrontal cortex (?p2=.72). “Four weeks is relatively short for an exercise training study,” noted Dr. Sandroff, senior research scientist at Kessler Foundation and director of the Exercise Neurorehabilitation Research Laboratory. “Seeing improvements within this timeframe shows the potential for exercise to change how we treat MS. Exercise is really powerful behavior that involves many brain regions and networks that can improve over time and result in improved function.”“This is particularly exciting because therapy using robotic exoskeletons shows such promise for improving the lives of people with co-occurring mobility and cognitive disability, a cohort that likely has the greatest potential to benefit from this new technology,” said Dr. Androwis, lead author and research scientist in the Center for Mobility and Rehabilitation Engineering Research at Kessler Foundation. “We’re eager to design a larger trial to further study these effects. Based on our initial results, we’re optimistic that this approach may be superior to the current standard of care.”(A) Participant with MS engaging in REAER (Ekso-GT, Ekso Bionics, Inc.); (B) Participant with MS engaging in CGT.The “cognitive clock”: A novel indicator of brain healthby Patricia A. Boyle, Tianhao Wang, Lei Yu, Robert S. Wilson, Robert Dawe, Konstantinos Arfanakis, Julie A. Schneider, Todd Beck, Kumar B. Rajan, Denis Evans, David A. Bennett in Alzheimer’s & DementiaHow old is your brain compared to your chronological age? A new measure of brain health developed by researchers at Rush University Medical Center may offer a novel approach to identifying individuals at risk of memory and thinking problems, according to research results published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.Dubbed the “cognitive clock” by the researchers, the tool is a measure of brain health based on cognitive performance. It may be used in the future to predict the likelihood of memory and thinking problems that develop as a person ages.“Alzheimer’s disease, which is of the most common cause of dementia, and other diseases of the brain accumulate slowly over time as people get older. Age is widely recognized as the main risk factor for Alzheimer’s disease, but it’s a very imperfect predictor, since not everyone develops dementia as they age,” said Patricia Boyle, PhD, professor in Rush Medical College’s Division of Behavioral Sciences neuropsychologist in the Rush Alzheimer’s Disease Center (RADC), and lead author of the study.“Our new cognitive clock provides a measure of brain health that tells us more about how well a person’s brain is functioning than chorological age. In this way, the clock can help us detect who is at highest risk of developing cognitive impairment in the coming years. “For some people, cognition remains fairly stable as they age,” Boyle added. “But, for others, cognition declines slowly over time, and still others show steep declines.”The researchers believed that cognitive performance data, even using a simple cognitive screening test, could be used to distinguish people exhibiting normal cognitive aging from those who are on their way to developing memory and thinking problems that are often coupled with aging.This thesis led the Rush researchers to look at data they acquired from several long-term studies conducted by the RADC, including the Rush Memory and Aging Project (MAP) which included people living in the community in greater Chicago; the Religious Orders Study (ROS), which included older Catholic clergy from across the United States; and the Chicago Health and Aging Project (CHAP), a biracial population-based study.“We used long-term cognitive testing data from our participants to develop a profile of cognitive aging, what we call the cognitive clock” Boyle said. “The cognitive clock reflects the general pattern of age-related cognitive decline and allows us to see who is doing better than average and who is doing worse at a given point in time. This helps us identify who might be at high risk of developing memory and thinking problems.”The cognitive clock was first developed working with data from 1057 participants from the MAP and the ROS, who began without cognitive impairment and underwent yearly cognitive assessments for up to 24 years. The cognitive assessment included the Mini-Mental State Exam, a widely used test of cognitive function among the elderly that measures orientation, attention, memory, language and visual-spatial skills. In addition to the MMSE, detailed evaluations also included a structured medical history, neurologic examinations, and a set of neurocognitive tests.The researchers examined how cognitive performance changes over time with advancing age using a novel statistical approach to identify the typical profile of cognitive aging. Using this cognitive clock, researchers can estimate an individual’s cognitive age — their position on the clock — at any given point in time.Cognitive age is an indicator of brain health. “We found that, on average, cognition remains stable until a cognitive age of around 80 years of age, then declines moderately until 90, then declines more rapidly until death,” Boyle said.“Further, we found that cognitive age is a much better predictor than chronological age of dementia, mild cognitive impairment and mortality. It also is more strongly associated with other aspects of brain health.”The researchers then applied the clock to an independent sample of 2,592 participants from CHAP to confirm its accuracy for predicting outcomes such as Alzheimer’s dementia, mild cognitive impairment, and mortality. Again, they found that cognitive age was a better predictor of these outcomes than chronological age.“Essentially, what we did is use cognitive data collected over many years to create a single, easy-to-understand metric that may be used to predict health outcomes with good accuracy,” Boyle said.This tool may serve as an aid in aging research moving forward and may offer a new tool to identify at risk individuals.“It is very difficult to develop a test or biomarker that accurately predicts health outcomes on an individual level. This has been a longstanding challenge in aging research. However, we are hoping that with additional research and validation, we may be able extend the approach applied here to clinical settings,” Boyle said. “Ideally, we could have a patient come into a clinic or hospital and complete a brief cognitive screen that gives us information to plug into a formula to estimate their cognitive age. That will provide important information about their brain health, and from there, we can estimate likelihood of developing Alzheimer’s disease or dementia in the coming years. That would be an exciting advance.”Randomized Manipulation of Early Cognitive Experience Impacts Adult Brain Structureby Martha J. Farah, Saul Sternberg, Thomas A. Nichols, Jeffrey T. Duda, Terry Lohrenz, Yi Luo, Libbie Sonnier, Sharon L. Ramey, Read Montague, Craig T. Ramey in Journal of Cognitive NeuroscienceAn enhanced learning environment during the first five years of life shapes the brain in ways that are apparent four decades later, say Virginia Tech and University of Pennsylvania scientists writing in the June edition of the Journal of Cognitive Neuroscience.The researchers used structural brain imaging to detect the developmental effects of linguistic and cognitive stimulation starting at six weeks of age in infants. The influence of an enriched environment on brain structure had formerly been demonstrated in animal studies, but this is the first experimental study to find a similar result in humans.“Our research shows a relationship between brain structure and five years of high-quality, educational and social experiences,” said Craig Ramey, professor and distinguished research scholar with Fralin Biomedical Research Institute at VTC and principal investigator of the study. “We have demonstrated that in vulnerable children who received stimulating and emotionally supportive learning experiences, statistically significant changes in brain structure appear in middle age.”The results support the idea that early environment influences the brain structure of individuals growing up with multi-risk socioeconomic challenges, said Martha Farah, director of the Center for Neuroscience and Society at Penn and first author of the study.“This has exciting implications for the basic science of brain development, as well as for theories of social stratification and social policy,” Farah said.The study follows children who have continuously participated in the Abecedarian Project, an early intervention program initiated by Ramey in Chapel Hill, North Carolina, in 1971 to study the effects of educational, social, health, and family support services on high-risk infants.Both the comparison and treatment groups received extra health care, nutrition, and family support services; however, beginning at six weeks of age, the treatment group also received five years of high quality educational support, five days a week, 50 weeks a year.When scanned, the Abecedarian study participants were in their late 30s to early 40s, offering the researchers a unique look at how childhood factors affect the adult brain.“People generally know about the potentially large benefits of early education for children from very low resource circumstances,” said co-author Sharon Landesman Ramey, professor and distinguished research scholar at Fralin Biomedical Research Institute. “The new results reveal that biological effects accompany the many behavioral, social, health, and economic benefits reported in the Abecedarian Project. This affirms the idea that positive early life experiences contribute to later positive adjustment through a combination of behavioral, social, and brain pathways.”During follow-up examinations, structural MRI scans of the brains of 47 study participants were conducted at the Fralin Biomedical Research Institute Human Neuroimaging Lab. Of those, 29 individuals had been in the group that received the educational enrichment focused on promoting language, cognition, and interactive learning.The other 18 individuals received the same robust health, nutritional, and social services supports provided to the educational treatment group, and whatever community childcare or other learning their parents provided. The two groups were well matched on a variety of factors such as maternal education, head circumference at birth and age at scanning.Analyzing the scans, the researchers looked at brain size as a whole, including the cortex, the brain’s outermost layer, as well as five regions selected for their expected connection to the intervention’s stimulation of children’s language and cognitive development.Those included the left inferior frontal gyrus and left superior temporal gyrus, which may be relevant to language, and the right inferior frontal gyrus and bilateral anterior cingulate cortex, relevant to cognitive control. A fifth, the bilateral hippocampus, was added because its volume is frequently associated with early life adversity and socioeconomic status.The researchers determined that those in the early education treatment group had increased size of the whole brain, including the cortex.Several specific cortical regions also appeared larger, according to study co-authors Read Montague, professor and director of the Human Neuroimaging Lab and Computational Psychiatry Unit at the Fralin Biomedical Research Institute, and Terry Lohrenz, research assistant professor and member of the institute’s Human Neuroimaging Laboratory.The scientists noted the group intervention treatment results for the brain were substantially greater for males than for females. The reasons for this are not known, and were surprising, since both the boys and girls showed generally comparable positive behavioral and educational effects from their early enriched education. The current study cannot adequately explain the sex differences.Percent differences in volume of individual ROIs resulting from treatment in male (top) and female (bottom) participants, with 95% confidence intervals.“When we launched this project in the 1970s, the field knew more about how to assess behavior than it knew about how to assess brain structure,” Craig Ramey said. “Because of advances in neuroimaging technology and through strong interdisciplinary collaborations, we were able to measure structural features of the brain. The prefrontal cortex and areas associated with language were definitely affected; and to our knowledge, this is the first experimental evidence on a link between known early educational experiences and long-term changes in humans.”“We believe that these findings warrant careful consideration and lend further support to the value of ensuring positive learning and social-emotional support for all children — particularly to improve outcomes for children who are vulnerable to inadequate stimulation and care in the early years of life,” Craig Ramey said.Predicting language treatment response in bilingual aphasia using neural network-based patient modelsby Grasemann U, Peñaloza C, Dekhtyar M, Miikkulainen R, Kiran S. in Sci RepAt Boston University, a team of researchers is working to better understand how language and speech is processed in the brain, and how to best rehabilitate people who have lost their ability to communicate due to brain damage caused by a stroke, trauma, or another type of brain injury. This type of language loss is called aphasia, a long-term neurological disorder caused by damage to the part of the brain responsible for language production and processing that impacts over a million people in the US.“It’s a huge problem,” says Swathi Kiran, director of BU’s Aphasia Research Lab, and College of Health & Rehabilitation Sciences: Sargent College associate dean for research and James and Cecilia Tse Ying Professor in Neurorehabilitation. “It’s something our lab is working to tackle at multiple levels.”For the last decade, Kiran and her team have studied the brain to see how it changes as people’s language skills improve with speech therapy. More recently, they’ve developed new methods to predict a person’s ability to improve even before they start therapy. In a new paper published in Scientific Reports, Kiran and collaborators at BU and the University of Texas at Austin report they can predict language recovery in Hispanic patients who speak both English and Spanish fluently — a group of aphasia patients particularly at risk of long-term language loss — using sophisticated computer models of the brain. They say the breakthrough could be a game changer for the field of speech therapy and for stroke survivors impacted by aphasia.“This [paper] uses computational modeling to predict rehabilitation outcomes in a population of neurological disorders that are really underserved,” Kiran says. In the US, Hispanic stroke survivors are nearly two times less likely to be insured than all other racial or ethnic groups, Kiran says, and therefore they experience greater difficulties in accessing language rehabilitation. On top of that, oftentimes speech therapy is only available in one language, even though patients may speak multiple languages at home, making it difficult for clinicians to prioritize which language a patient should receive therapy in.“This work started with the question, ‘If someone had a stroke in this country and [the patient] speaks two languages, which language should they receive therapy in?’” says Kiran. “Are they more likely to improve if they receive therapy in English? Or in Spanish?”This first-of-its-kind technology addresses that need by using sophisticated neural network models that simulate the brain of a bilingual person that is language impaired, and their brain’s response to therapy in English and Spanish. The model can then identify the optimal language to target during treatment, and predict the outcome after therapy to forecast how well a person will recover their language skills. They found that the models predicted treatment effects accurately in the treated language, meaning these computational tools could guide healthcare providers to prescribe the best possible rehabilitation plan.“There is more recognition with the pandemic that people from different populations — whether [those be differences of] race, ethnicity, different disability, socioeconomic status — don’t receive the same level of [healthcare],” says Kiran. “The problem we’re trying to solve here is, for our patients, health disparities at their worst; they are from a population that, the data shows, does not have great access to care, and they have communication problems [due to aphasia].”As part of this work, the team is examining how recovery in one language impacts recovery of the other — will learning the word “dog” in English lead to a patient recalling the word “perro,” the word for dog in Spanish?“If you’re bilingual you may go back and forth between languages, and what we’re trying to do [in our lab] is use that as a therapy piece,” says Kiran.Clinical trials using this technology are already underway, which will soon provide an even clearer picture of how the models can potentially be implemented in hospital and clinical settings.“We are trying to develop effective therapy programs, but we also try to deal with the patient as a whole,” Kiran says. “This is why we care deeply about these health disparities and the patient’s overall well-being.”(a) The BiLex model consists of three interconnected SOMs, one for word meanings shared across languages, and two for their phonetic representations in L1 and L2. Bidirectional associative connections transfer activation between maps. (b) The semantic map organizes the model’s vocabulary according to word meanings, such that similar words are close together on the map. Plot c shows a detail of this map. Phonetic maps are organized in the same way, but reflect phonetic similarity.Neurovascular coupling and oxygenation are decreased in hippocampus compared to neocortex because of microvascular differencesby Shaw K, Bell L, Boyd K, et al. in Nature CommunicationsIn a world first, scientists from the University of Sussex have recorded blood oxygen levels in the hippocampus and provided experimental proof for why the area, commonly referred to as ‘the brain’s memory centre’, is vulnerable to damage and degeneration, a precursor to Alzheimer’s disease. To understand why this region is so sensitive, the University of Sussex researchers, headed up by Dr Catherine Hall from the School of Psychology and Sussex Neuroscience, studied brain activity and blood flow in the hippocampus of mice. The researchers then used simulations to predict that the amount of oxygen supplied to hippocampal neurons furthest from blood vessels is only just enough for the cells to keep working normally.Dr Catherine Hall, Senior Lecturer in Psychology at the University of Sussex says:“These findings are an important step in the search for preventative measures and treatments for Alzheimer’s, because they suggest that increasing blood flow in the hippocampus might be really effective at preventing damage from happening. If it’s right that increasing blood flow in the hippocampus is important in protecting the brain from diseases like Alzheimer’s, then it will throw further weight behind the importance of regular exercise and a low-cholesterol diet to long-term brain health. We think that the hippocampus exists at a watershed. It’s just about OK normally, but when anything else happens to decrease brain blood flow, oxygen levels in the hippocampus reduce to levels that stop neurons working. We think that’s probably why Alzheimer’s disease first causes memory problems — because the early decrease in blood flow stops the hippocampus from working properly. The same factors that put you at risk of having a heart attack make you more likely to develop dementia. That’s because our brains need enough blood flow to provide energy — in the form of oxygen and glucose — so brain cells can work properly, and because blood flow can clear away waste products such as the beta amyloid proteins that build up in Alzheimer’s disease. Now we want to discover whether the lower blood flow and oxygen levels in the hippocampus are what causes beta amyloid to start to build up in Alzheimer’s disease. Understanding what causes early damage will be really important to help us learn how to treat or prevent disease.”Dr Kira Shaw, a psychology researcher at the University of Sussex who undertook the main experiments, said:“We found that blood flow and oxygen levels in the hippocampus were lower than those in the visual cortex. Also, when neurons are active, there is a large increase in blood flow and oxygen levels in the visual cortex. This provides energy to hungry neurons. But in the hippocampus, these responses were much smaller.”The scientists also found that blood vessels in the hippocampus contained fewer mRNA transcripts (codes for making proteins) for proteins that shape blood vessel dilation. Additionally, the cells that dilate small blood vessels, called pericytes, were a different shape in the hippocampus than in the visual cortex.Dr Shaw concluded: “We think blood vessels in the hippocampus are less able to dilate than in the visual cortex”.Representative schematic showing the GCaMP6f-positive pyramidal neurons (green) and blood vessels (red) accessible for two-photon imaging after a visual cortical or b hippocampal surgery, with example maximum-projected images across each layer. Scale bars represent 100 µm, and similar z-stack images across layers were taken for nine animals in HC and 11 animals in V1. c Schematic of the imaging set-up. Either the two-photon objective or oxy-CBF probe was used to collect data while the mouse was head-fixed but awake and able to run on the cylinder. d Representative locomotion recorded by the rotary encoder during one imaging session (centimetres per second). Distinct periods of running are indicated by the black bars. A virtual reality maze e or drifting gratings f were presented on the screens in c. Locomotion advanced the mice through the virtual reality maze. The arrows beneath the drifting gratings display show the direction the gratings travelled. g Example, haemodynamic recordings from visual cortex using the oxy-CBF probe during visual stimulation (grey bar represents stimulation, N = 4 animals, 10 sessions, 202 trials). h The cerebral metabolic rate of oxygen consumption (CMRO2) is calculated from the haemodynamic parameters collected using the oxy-CBF probe for the data in g. All data traces are unsmoothed averages, and error bands represent mean ± SEM.MISC — @NatureNeuro — @CellCellPress — @NaturePortfolioSubscribe to Paradigm!Medium. Twitter. Telegram. Telegram Chat. Reddit. LinkedIn.Main sourcesResearch articlesNature NeuroscienceScience DailyTechnology NetworksNeuroscience NewsFrontiersCellNT/ New tool activates deep brain neurons by combining ultrasound, genetics was originally published in Paradigm on Medium, where people are continuing the conversation by highlighting and responding to this story.

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