TAG: "Neuroscience"

Private partnerships for public benefit


Nobel laureate’s research into neurodegenerative diseases gets boost from Japanese firm.

Nobel laureate Stanley Prusiner (left), director of the UCSF Institute of Neurodegenerative Diseases, recently launched a partnership with pharmaceutical company Daiichi Sankyo that will accelerate his research into prion diseases. He credits the partnership largely to groundwork laid by IND’s associate director, David Ramsay (right).

Stanley Prusiner, M.D., is used to overcoming challenges in his career.

In 1982, as a UC San Francisco junior faculty member in the Department of Neurology, Prusiner published an article describing his discovery of an unprecedented class of pathogens that he named “prions.” These infectious proteins are now understood to be involved in numerous neurodegenerative diseases in humans and animals, including Alzheimer’s, Parkinson’s, frontotemporal dementia and Creutzfeldt-Jakob disease (CJD).

The article sparked a firestorm at the time.

Prusiner’s contention that a protein alone could be infectious flew in the face of the commonly held scientific belief that infections could only be transmitted by viruses, bacteria, fungi and parasites – all of which have genomes composed of either DNA or RNA. Proteins, however, are composed of amino acids.

Despite what he described as a “torrent of criticism” from the scientific community, the media and even funders of his research, Prusiner remained undeterred. He took comfort in the unwavering support of close colleagues, and mounting scientific evidence – much of it stemming his UCSF lab – that backed his claims.

The groundbreaking work led to Prusiner’s 1997 Nobel Prize in Physiology or Medicine.

“People often ask me why I persisted in doing research on a subject that was so controversial,” Prusiner said in his Nobel acceptance speech. “I frequently respond by telling them that only a few scientists are granted the great fortune to pursue topics that are so new and different that only a small number of people can grasp [their] meaning initially.”

In the decades since his discovery, Prusiner – now director of the Institute for Neurodegenerative Diseases (IND) at UCSF – has been committed to getting answers about prion diseases, and ultimately treatments and cures.

Even with a Nobel Prize under his belt, the road continues to pose challenges.

Federal funding from the National Institutes of Health (NIH) has been crucial to his research, but the recent recession – and resulting sequestration – highlighted the need to strengthen relationships with private industry. In 2013, the NIH awarded a total of $22.5 billion in funding to U.S. institutions, the lowest amount since 2003.

But this month, Prusiner’s work got a huge boost from an exciting new collaboration between the IND and the Japan-based global pharmaceutical company Daiichi Sankyo Co. Ltd. It will focus on developing therapeutics and molecular diagnostics for multiple neurodegenerative diseases.

“Alzheimer’s alone kills as many people every year as cancer does, but it only receives one-tenth of the funding that we dedicate to cancer research. This collaboration won’t fill that funding gap, but it will offer the tremendous value of Daiichi Sankyo’s scientific expertise to make progress on these diseases,” he said.

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Blood-pressure drug prevents epilepsy after brain injury


Drug may forestall further brain damage caused by seizures in those with epilepsy.

Daniela Kaufer, UC Berkeley

Between 10 and 20 percent of all cases of epilepsy result from severe head injury, but a new drug promises to prevent post-traumatic seizures and may forestall further brain damage caused by seizures in those who already have epilepsy.

A team of researchers from UC Berkeley, Ben-Gurion University in Israel and Charité-University Medicine in Germany reports in the current issue of the journal Annals of Neurology that a commonly used hypertension drug prevents a majority of cases of post-traumatic epilepsy in a rodent model of the disease. If independent experiments now under way in rats confirm this finding, human clinical trials could start within a few years.

“This is the first-ever approach in which epilepsy development is stopped, as opposed to common drugs that try to prevent seizures once epilepsy develops,” said co-author Daniela Kaufer, UC Berkeley associate professor of integrative biology and a member of the Helen Wills Neuroscience Institute. “Those drugs have a very limited success and many side effects, so we are excited about the new approach.”

The team, led by Kaufer; neurosurgeon Alon Friedman, associate professor of physiology and neurobiology at the Ben-Gurion University of the Negev; and Uwe Heinemann of the Charite, provides the first explanation for how brain injury caused by a blow to the head, stroke or infection leads to epilepsy. Based on 10 years of collaborative research, their findings point a finger at the blood-brain barrier – the tight wall of cells lining the veins and arteries in the brain that is breached after trauma.

“This study for the first time offers a new mechanism and an existing, FDA-approved drug to potentially prevent epilepsy in patients after brain injuries or after they develop an abnormal blood-brain barrier,” Friedman said.

The drug, losartan (Cozaar), prevented seizures in 60 percent of the rats tested, when normally 100 percent of the rats develop seizures after injury. In the 40 percent of rats that did develop seizures, they averaged about one quarter the number of seizures typical for untreated rats. Another experiment showed that administration of losartan for three weeks at the time of injury was enough to prevent most cases of epilepsy in normal lab rats in the following months.

“This is a very exciting result, telling us that the drug worked to prevent the development of epilepsy and not by suppressing the symptoms,” Kaufer said.

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Progressive neurodegenerative disorder linked to R-loop formation


UC Davis findings suggest R-loops may be potential targets for drug development.

Paul Hagerman, UC Davis

Researchers at UC Davis have identified a new feature of the genetic mutation responsible for the progressive neurodegenerative disorder fragile X-associated tremor/ataxia syndrome (FXTAS) — the formation of “R-loops,” which they believe may be associated with the disorder’s neurological symptoms, such as tremors, lack of balance, features of Parkinsonism and cognitive decline.

The finding suggests that the R-loops may be potential targets for drug development, said Paul Hagerman, senior study author, professor in the Department of Biochemistry and Molecular Medicine and director of the UC Davis NeuroTherapeutics Research Institute. The study, “Transcription-associated R-loop Formation across the Human FMR1 CGG-repeat Region,” is published today in the online journal PLoS Genetics.

An R-loop is formed when the messenger RNA being made at the gene reinserts itself into the DNA helix, displacing one strand of DNA, which creates the “loop.” Such loops are known to be prone to damage, which can in turn lead to loss of cell function, particularly in neurons.

Hagerman and his collaborators discovered the R-loops while investigating mutations in the gene that causes FXTAS and other conditions associated with the fragile X mental retardation gene 1 (FMR1). R-loops are not unique to FXTAS and can occur in the promoter regions of many genes.

“But in FXTAS, the R-loops are more numerous and much longer than they are in FMR1 genes that are not mutated,” said Hagerman, a researcher who also is affiliated with the UC Davis MIND Institute.

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UCSF launches online registry to drive brain disease research


Brain Health Registry brings promise of speeding advances.

A new online project led by researchers at UC San Francisco promises to dramatically cut the time and cost of conducting clinical trials for brain diseases, while also helping scientists analyze and track the brain functions of thousands of volunteers over time.

With easy online registration, the Brain Health Registry is designed to create a ready pool of research subjects for studies on neurological diseases, such as Alzheimer’s and Parkinson’s, as well as depression, post-traumatic stress disorder and many other brain ailments. About one third of the cost of running a clinical trial comes from having to recruit patients, and many trials fail or are delayed because of it.

Michael Weiner, UC San Francisco

The Brain Health Registry is the first neuroscience project to use the Internet on such a scale to advance clinical research, according to Michael Weiner, M.D., founder and principal investigator of the initiative and a professor of radiology, biomedical engineering, medicine, psychiatry and neurology at UCSF. One of his roles is serving as principal investigator of the Alzheimer’s Disease Neuroimaging Initiative, the largest observational study of Alzheimer’s.

“This registry is an innovative 21st century approach to science with tremendous potential,” Weiner said. “The greatest obstacles to finding a cure for Alzheimer’s and other brain disorders are the cost and time involved in clinical trials. This project aims to cut both and greatly accelerate the search for cures.”

Leading funders for the project include the Rosenberg Alzheimer’s Project, the Ray and Dagmar Dolby Family Fund and Kevin and Connie Shanahan. The initial focus will be on the San Francisco Bay Area, and the goal is to recruit 100,000 people by the end of 2017. Nearly 2,000 people already signed up during the online registry’s beta phase.

Volunteers will provide a brief personal history and take online neuropsychological tests in an online game format. The games give the Brain Health Registry scientific team a snapshot of the participant’s brain function. The data collected will help scientists study brains as they age, identify markers for diseases, develop better diagnostic tools to stop disease before it develops and increase the ready pool of pre-qualified clinical trial participants.

A select number of volunteers will be asked by researchers to do more, such as providing saliva or blood samples, or participating in clinical trials to test potential cures. Volunteers can participate as little or as much as they like. All information will be gathered in accordance with federal privacy laws under the Health Insurance Portability and Accountability Act (HIPAA), as well as the highest standards of medical ethics.

“For those of us who know people suffering from Parkinson’s, Alzheimer’s, PTSD and other brain disorders, this is a way we can be involved in the search for a cure,” said Douglas Rosenberg, of the Rosenberg Alzheimer’s Project, which is helping to fund the project. “We’ve worked to make the process very easy and very fulfilling for our volunteers.”

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Daiichi Sankyo, UCSF announce collaboration in drug discovery research


They will focus on developing drugs and diagnostics for neurodegenerative diseases.

Daiichi Sankyo Co. Ltd. and UC San Franciscohave established a drug-discovery collaboration focused on developing novel therapeutics and molecular diagnostics for multiple neurodegenerative diseases.

Under the terms of the agreement, Daiichi Sankyo will provide its compound library to the UCSF Institute for Neurodegenerative Diseases (IND), and both parties will perform high-throughput compound screening and optimization together. The project will bring together the drug development capabilities of Daiichi Sankyo with the expertise of world-renowned neuroscientists at UCSF, in a collaborative effort to create multiple drug-discovery programs in debilitating disease areas such as Alzheimer’s, Parkinson’s, Creutzfeldt-Jakob disease and fronto-temporal dementias — all conditions for which there currently are no effective therapeutics available.

Daiichi Sankyo will provide research funding and milestone payments and royalties for successful clinical progression and commercialization of new products. Daiichi Sankyo will receive the option to enter into an exclusive license agreement to develop and commercialize promising compounds.

“This is a golden opportunity. These diseases require a big-picture approach, and that’s what Daiichi Sankyo is taking,” said Stanley Prusiner, M.D., who received the 1997 Nobel Prize in Physiology or Medicine for his discovery of prions, a new biological principle of infection. Prions are alternatively folded proteins that undergo replication — some prions perform critical cellular functions but others cause neurodegenerative diseases. Initially, Prusiner studied prions causing “mad cow” disease and Creutzfeldt-Jakob disease (CJD), but recently, he and many others have focused their work on other replicating, misfolded proteins— which Prusiner and others argue are prions—that are thought to cause the more common neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases.

“Alzheimer’s alone kills as many people every year as cancer does, but it only receives one-tenth of the funding that we dedicate to cancer research. This collaboration won’t fill that funding gap, but it will offer the tremendous value of Daiichi Sankyo’s scientific expertise to make progress on these diseases,” said Prusiner, UCSF professor of neurology and director of the IND.

“Daiichi Sankyo is committed to identifying potential new therapies to help fuel our passion to find medicines for the patients who need them. Using the compound screening technology at UCSF, along with their expertise in prion research, will give us an opportunity to explore the potential.  I am excited about this collaboration and look forward to seeing results of this partnership.” said Glenn Gormley, M.D., Ph.D., senior executive officer and global head of research and development, Daiichi Sankyo Co. Ltd.

Founded in 1999, the UCSF IND is one of the top academic laboratories focused on discovering causes and developing cures for neurodegenerative diseases. As the leader of the IND, which is based at UCSF and includes neuroscience research at several other UC campuses, Prusiner is committed to creating therapeutics and diagnostics that will halt neuronal diseases with his experience in prion research.

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New test makes Parkinson’s-like disorder detectable in young adults


Brain abnormalities may begin to develop two decades before symptoms might occur.

UC Davis MIND Institute

The very earliest signs of a debilitating neurodegenerative disorder, in which physical symptoms are not apparent until the fifth decade of life, are detectable in individuals as young as 30 years old using a new, sophisticated type of neuroimaging, researchers at UC Davis, the University of Illinois and UCLA have found.

People with the condition — fragile X-associated tremor/ataxia syndrome (FXTAS) — experience tremors, poor balance, cognitive impairments and Parkinsonism. The genetic condition results from a mutation in the fragile X mental retardation gene (FMR1). FXTAS develops in about 40 percent of male and 15 percent of female carriers of the mutated FMR1 gene.

“Our findings suggest that the brain abnormalities of FXTAS may begin to develop about two decades before symptoms might occur,” said Tony J. Simon, study senior author and professor, Department of Psychiatry and Behavioral Sciences.

“Altered Structural Brain Connectome in Young Adult Fragile X Premutation Carriers,” is published in Human Brain Mapping.

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New dean is biological sciences booster


Frank LaFerla, renowned for his Alzheimer’s work, hopes to raise UC Irvine school’s profile.

Frank LaFerla, UC Irvine

For a scientist widely considered an international leader in Alzheimer’s disease research, Frank LaFerla joined the UC Irvine faculty in 1995, interestingly enough, without ever having taken a single neuroscience class.

LaFerla had received a doctorate in virology and was studying AIDS-related dementia when he sat in on his first neurobiology course, one taught by James McGaugh and Norman Weinberger, two of the nation’s top learning and memory researchers. The lessons obviously made a great impression on the young scientist.

Since that time, LaFerla has made key research breakthroughs that show promise for treating Alzheimer’s and other neurodegenerative diseases. He has served in numerous leadership roles, including as chair of the Department of Neurobiology & Memory and director of the campus’s Institute for Memory Impairments and Neurological Disorders (UCI MIND), a research center internationally acclaimed for its work on disorders of the brain, particularly those that are age-related.

Last December, LaFerla became the Hana & Francisco J. Ayala Dean of the newly renamed Francisco J. Ayala School of Biological Sciences, heading the third-largest school on campus, with nearly 4,000 students majoring in one of its four undergraduate degree programs.

“Frank brings enormous enthusiasm and optimism to everything he does,” says McGaugh, a research professor of neurobiology & behavior and former biological sciences dean. “He wants to take actions that emphasize the character and the contributions of the school to the campus and to the public. It’s hard to imagine a more qualified person for the position.”

And with UC Irvine approaching its golden anniversary, LaFerla says, he aims to “take the school to the next level.”

He assumes the helm at a time when the biological sciences are critical to addressing such global concerns as sustainable food production, ecosystem restoration, optimized biofuel manufacturing and improved human health. And he wants to ensure that UC Irvine plays a part.

“Our brand is ‘Understanding Life: Transforming Our World,’” LaFerla says. “We will be excellent ambassadors of science who are trying to solve very important issues.”

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Brain differences found in college-aged occasional drug users


UC San Diego findings point to potential biomarkers for early detection of at-risk youth.

Martin Paulus, UC San Diego

Researchers at the UC  San Diego School of Medicine have discovered impaired neuronal activity in the parts of the brain associated with anticipatory functioning among occasional 18- to 24-year-old users of stimulant drugs, such as cocaine, amphetamines and prescription drugs such as Adderall.

The brain differences, detected using functional magnetic resonance imaging (fMRI), are believed to represent an internal hard wiring that may make some people more prone to drug addiction later in life.

Among the study’s main implications is the possibility of being able to use brain activity patterns as a means of identifying at-risk youth long before they have any obvious outward signs of addictive behaviors.

The study is published in the March 26 issue of the Journal of Neuroscience.

“If you show me 100 college students and tell me which ones have taken stimulants a dozen times, I can tell you those students’ brains are different,” said Martin Paulus, M.D., professor of psychiatry and a co-senior author with Angela Yu, Ph.D., professor of cognitive science at UC San Diego. “Our study is telling us, it’s not ‘this is your brain on drugs,’ it’s ‘this is the brain that does drugs.’”

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Brain insights


UCSF’s Neuroscape Lab vividly displays brain activity as tool to develop targeted therapies.

In Adam Gazzaley’s new lab, the brain is a kaleidoscope of colors, bursting and pulsing in real time to the rhythm of electronic music.

The mesmerizing visual on the screen is a digital masterpiece – but the UC San Francisco neuroscientist has a much bigger aspiration than just creating art. He wants this to lead to treatments for a variety of brain diseases, including Alzheimer’s, autism and multiple sclerosis.

Gazzaley, M.D., Ph.D., opened the Neuroscape lab this month at UCSF’s Mission Bay campus, where he’s developed a way to display a person’s brain activity while it’s thinking, sensing and processing information, allowing researchers to see what areas of the person’s brain are being triggered – or, in the case of certain diseases, not triggered.

Until recently, it was impossible to study brain activity without immobilizing the person inside a big, noisy machine or tethering him or her to computers. At the Neuroscape lab, subjects can move freely to simulate real-world conditions.

One of its first projects was the creation of new imaging technology called GlassBrain, in collaboration with the Swartz Center at UC San Diego and Nvidia, which makes high-end computational computer chips. Brain waves are recorded through electroencephalography (EEG), which measures electrical potentials on the scalp, and projected onto the structures and connecting fibers of a brain image created with magnetic resonance imaging and diffusion tensor imaging.

To demonstrate the technology at the lab’s opening, Grateful Dead drummer Mickey Hart donned an Oculus Rift virtual reality headset and played a drumming video game designed to enhance brain function, while colorful images of his brain in action showed on the screen. Video games like NeuroDrummer are an entertaining and accessible way that Gazzaley is developing to train the brain.

“I want us to have a platform that enables us to be more creative and aggressive in thinking how software and hardware can be a new medicine to improve brain health,” said Gazzaley, an associate professor of neurology, physiology and psychiatry and director of the UCSF neuroimaging center. “Often, high-tech innovations take a decade to move beyond the entertainment industry and reach science and medicine. That needs to change.”

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Walk this way


UCSF study reveals that movement kicks visual system into higher gear.

Michael Stryker, UC San Francisco

Whether you’re a Major League outfielder chasing down a hard-hit ball or a lesser mortal navigating a busy city sidewalk, it pays to keep a close watch on your surroundings when walking or running. Now, new research by UC San Francisco neuroscientists suggests that the body may get help in these fast-changing situations from a specialized brain circuit that causes visual system neurons to fire more strongly during locomotion.

There has been a great deal of research on changes among different brain states during sleep, but the new findings, reported in today’s (March 13) issue of Cell, provide a compelling example of a change in state in the awake brain.

It has long been known that nerve cells in the visual system fire more strongly when we pay close attention to objects than when we view scenes more passively. But the new research, led by Yu Fu, Ph.D., a postdoctoral fellow in the UCSF lab of senior author Michael P. Stryker, Ph.D., the W.F. Ganong Professor of Physiology, breaks new ground, mapping out a visual system amplifier that is directly activated by walking or running.

Though this circuit has not yet been shown to exist in humans, Stryker is designing experiments to find out if it does. He said he would be surprised if his group did not identify a similar mechanism in people, since such systems have been found in fruit flies, and the mouse visual system has so far proved to be a good model of many aspects of human vision.

“The sense of touch only tells you about objects that are close, and the auditory system is generally not as sensitive as the visual system to the exact position of objects,” he said. “It seems that it would be generally useful to have vision — the sensory modality that tells you the most about things that are far away — work better as you’re moving through the world.”

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UC Davis MIND Institute joins ranks of elite neurodevelopmental centers


Joins UCLA among 15 Intellectual and Developmental Disabilities Research Centers in nation.

The UC Davis MIND Institute has been named an Intellectual and Developmental Disabilities Research Center (IDDRC), through a prestigious grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health — a distinction held by only a handful of neurodevelopmental centers nationwide committed to the diagnosis, prevention, treatment and amelioration of developmental disorders such as autism, fragile X syndrome and Down syndrome.

Intellectual and Developmental Disabilities Research Centers conduct comprehensive interdisciplinary research that promotes the discovery and translation of basic science investigations into clinical applications. The designation will provide the MIND Institute with new tools to further strengthen its neurodevelopmental research across the schools, programs and departments of the entire university, cementing its stature as “the house that collaboration built,” and knitting together the work of basic science researchers and clinicians to advance the development of new therapies for people with neurodevelopmental disorders.

There are only 15 IDDRCs nationwide. Others are situated at UCLA, the Children’s Hospital of Philadelphia, Children’s Hospital of Boston and Children’s National Medical Center in Washington, D.C. The MIND Institute IDDRC is funded through a five-year, $6.5 million grant.

“To be selected for the IDDRC program, an institution must meet rigorous scientific criteria,” said Melissa Parisi, chief of the National Institute of Child Health and Human Development’s Intellectual and Developmental Disabilities Branch. “We eagerly await the MIND Institute’s contributions to the centers program and to intellectual and developmental disabilities research.”

MIND Institute Director Leonard Abbeduto, Tsakopoulos-Vismara Endowed Chair in the Department of Psychiatry and Behavioral Sciences, directs the new center.

“Across its schools and colleges, divisions and programs, UC Davis has made a firm and lasting commitment to build better, healthier lives for children with neurodevelopmental disorders,” Abbeduto said.

“Designation as an IDDRC gives the MIND Institute critical new resources that will allow it to advance its mission to speed transformation of basic scientific discoveries into clinical applications, in order to aide children and adults affected by neurodevelopmental disorders and their families worldwide and impact their lives today,” he said.

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New high-tech lab records the brain, body in action


UCSF’s Neuroscape Lab seeks to understand, treat brain disease.

How does an autistic child take in information when he sits in a classroom abuzz with social activity? How long does it take someone with multiple sclerosis, which slows activity in the brain, to process the light bouncing off the windshield while she drives?

Until recently, the answers to basic questions of how diseases affect the brain – much less the ways to treat them – were lost to the limitations on how scientists could study brain function under real-world conditions. Most technology immobilized subjects inside big, noisy machines or tethered them to computers that made it impossible to simulate what it’s really like to live and interact in a complex world.

But now UC San Francisco neuroscientist Adam Gazzaley, M.D., Ph.D., is hoping to paint a fuller picture of what is happening in the minds and bodies of those suffering from brain disease with his new lab, Neuroscape, which bridges the worlds of neuroscience and high-tech.

In the Neuroscape lab, wireless and mobile technologies set research participants free to move around and interact inside 3-D environments, while scientists make functional recordings with an array of technologies. Gazzaley hopes this will bring his field closer to understanding how complex neurological and psychiatric diseases really work and help doctors like him repurpose technologies built for fitness or fun into targeted therapies for their patients.

“I want us to have a platform that enables us to be more creative and aggressive in thinking how software and hardware can be a new medicine to improve brain health,” said Gazzaley, an associate professor of neurology, physiology and psychiatry and director of the UCSF Neuroscience Imaging Center. “Often, high-tech innovations take a decade to move beyond the entertainment industry and reach science and medicine. That needs to change.”

As a demonstration of what Neuroscape can do, Gazzaley’s team created new imaging technology that he calls GlassBrain, in collaboration with the Swartz Center at UC San Diego and Nvidia, which makes high-end computational computer chips. GlassBrain creates vivid, color visualizations of the structures of the brain and the white matter that connects them, as they pulse with electrical activity in real time.

These brain waves are recorded through electroencephalography (EEG), which measures electrical potentials on the scalp. Ordinary EEG recordings look like wavy horizontal lines, but GlassBrain turns the data into bursts of rhythmic activity that speed along golden spaghetti-like connections threading through a glowing, multi-colored glass-like image of a brain. Gazzaley is now looking at how to feed this information back to his subjects, for example by using the data from real-time EEG to make video games that adapt as people play them to selectively challenge weak brain processes.

Gazzaley has already used the technology to image the brain of former Grateful Dead drummer Mickey Hart as he plays a hypnotic, electronic beat on a Roland digital percussion device with NeuroDrummer, a game the Gazzaley Lab is designing to enhance brain function through rhythmic training. Hart, whose brain is healthy, is collaborating with Gazzaley to develop the game and performed on NeuroDrummer while immersed in virtual reality on an Oculus Rift at the Neuroscape lab opening today (March 5).

The Neuroscape lab will be available to all UCSF researchers who study the brain. And Gazzaley ultimately hopes it will aid in the development of therapies to treat diseases as various as Alzheimer’s, post-traumatic stress disorder, attention deficit and hyperactivity disorder, schizophrenia, autism, depression and multiple sclerosis.

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