TAG: "Neuroscience"

Triathlete, actor share stories of recovery from traumatic brain injury


UCLA’s Brain Injury Research Center hosts symposium.

Greg Parks and Kathleen Pullen-Norris, a nurse at the Ronald Reagan UCLA Medical Center, were married for less than a year before Parks was in a bike accident and sustained a life-changing brain injury. (Photo courtesy of Greg Parks and Kathleen Pullen-Norris)

By Elaine Schmidt, UCLA

Triathlete Greg Parks never recalled the cause of the accident that left him lying unconscious in the road, still straddling the bicycle he’d been riding in Santa Clarita. But he will never forget what followed: four weeks of hospitalization and grueling rehabilitation. Then came another four months before he was able to resume his life as a newlywed husband and rocket-test engineer.

Actor Larry Miller was also able to pick up his life as the father of two after suffering a life-threatening head injury in 2012 and being on life support for a month. Well-known for the memorable characters he played in more than 100 films and TV shows, Miller also started back to work after his recovery.

Parks and Miller recently shared their experience of coming back from a life-changing brain injury at a public symposium hosted by the neurosurgery department’s Brain Injury Research Center at the Ronald Reagan UCLA Medical Center. Both men, as well as those who care for patients with traumatic brain injuries (TBI), talked about how to advocate for loved ones and how caregivers must also take time to tend to themselves.

“My accident was the best thing that could have happened to me,” said Miller, who has advocated for TBI patients before the California Senate. He opted to see the brighter side of his situation. “A brain injury wakes you up and makes you appreciate all that you have. Everything became funnier in my life.”

From her perspective as the wife of a patient, Kathleen Pullen-Norris, Parks’ wife, described the challenges she faced in obtaining proper treatment for her husband at the hospital where he was first taken and how she coped during his journey to recovery.

“Being the spouse of a TBI patient can be one of the world’s darkest places,” admitted Pullen-Norris, who happened to be a nurse at the Reagan UCLA Medical Center’s neuro-ICU unit, where her husband was eventually hospitalized. “You are not the injured, but you are the aching. Greg describes TBI as a fog. Being a TBI wife is like being a lighthouse — the best and brightest lighthouse I can muster.”

She emphasized the need for personal self-care. “Without the caregiver, the patient is lost,” she stressed. “That means taking time for yourself.”

Parks encouraged therapists to push their patients to recapture their mental and physical fitness. “My toughest therapist was my beautiful wife, Kathleen,” said Parks, who had married Pullen-Norris less than a year before his accident and raced in New Zealand’s Ironman competition together on their honeymoon.

“I am grateful to her for making fitness a priority and am living proof that a good support system is essential for surviving a brain injury,” Parks said.

Each year, an estimated 2.4 million Americans suffer a blow to the head that results in a traumatic brain injury, according to Dr. Paul Vespa, director of neurocritical care at the Reagan UCLA Medical Center and a professor of neurosurgery and neurology at the David Geffen School of Medicine.

“Swift treatment can prevent death and permanent brain damage, but not every hospital offers the trained specialists and sophisticated equipment required to treat TBIs effectively,” Vespa pointed out.  “As a result, tens of thousands of people die needlessly each year, and more than 5.3 million Americans live with a lifelong disability.”

Pullen-Norris echoed Vespa’s message. “Greg and I are deeply grateful to his UCLA physicians and nurses. Without their expertise and diligence, our work would be for nothing. They saved Greg and, in turn, saved me.”

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Altering brain chemistry makes us more sensitive to inequality


Prolonging dopamine’s effects in brain causes people to be more sensitive to inequality.

By Thomas Levy, UC Berkeley

What if there were a pill that made you more compassionate and more likely to give spare change to someone less fortunate? UC Berkeley scientists have taken a big step in that direction.

A new study by UC Berkeley and UC San Francisco researchers finds that giving a drug that changes the neurochemical balance in the prefrontal cortex of the brain causes a greater willingness to engage in prosocial behaviors, such as ensuring that resources are divided more equally.

The researchers also say that future research may lead to a better understanding of the interaction between altered dopamine-brain mechanisms and mental illnesses, such as schizophrenia or addiction, and potentially light the way to possible diagnostic tools or treatments for these disorders.

“Our study shows how studying basic scientific questions about human nature can, in fact, provide important insights into diagnosis and treatment of social dysfunctions,” said Ming Hsu, a co-principal investigator and assistant professor at UC Berkeley’s Haas School of Business.

“Our hope is that medications targeting social function may someday be used to treat these disabling conditions,” said Andrew Kayser, a co-principal investigator on the study, an assistant professor of neurology at UC San Francisco and a researcher in the Helen Wills Neuroscience Institute at UC Berkeley.

In the study, published online today (March 19) in the journal Current Biology, participants on two separate visits received a pill containing either a placebo or tolcapone, a drug that prolongs the effects of dopamine, a brain chemical associated with reward and motivation in the prefrontal cortex. Participants then played a simple economic game in which they divided money between themselves and an anonymous recipient. After receiving tolcapone, participants divided the money with the strangers in a fairer, more egalitarian way than after receiving the placebo.

“We typically think of fair-mindedness as a stable characteristic, part of one’s personality,” said Hsu. “Our study doesn’t reject this notion, but it does show how that trait can be systematically affected by targeting specific neurochemical pathways in the human brain.”

In this double-blind study of 35 participants, including 18 women, neither participants nor study staff members knew which pills contained the placebo or tolcapone, an FDA-approved drug used to treat people with Parkinson’s disease, a progressive neurological disorder affecting movement and muscle control.

Computational modeling showed Hsu and his colleagues that under tolcapone’s influence, game players were more sensitive to and less tolerant of social inequity, the perceived relative economic gap between a study participant and a stranger.

By connecting to previous studies showing that economic inequity is evaluated in the prefrontal cortex, a core area of the brain that dopamine affects, this study brings researchers closer to pinpointing how prosocial behaviors such as fairness are initiated in the brain.

“We have taken an important step toward learning how our aversion to inequity is influenced by our brain chemistry,” said the study’s first author, Ignacio Sáez, a postdoctoral researcher at the Haas School of Business. “Studies in the past decade have shed light on the neural circuits that govern how we behave in social situations. What we show here is one brain ‘switch’ we can affect.”

In addition to Hsu, Sáez, and Kayser, co-authors include Eric Set of UC Berkeley and Lusha Zhu of the Virginia Tech Carilion Research Institute. The study was funded by grants from the Department of Defense, Institute for Molecular Neuroscience, National Institutes of Health and Hellman Family Faculty Fund.

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Tales from both sides of the brain


Michael Gazzaniga chronicles his 50-year career in neuroscience, split-brain research.

When Michael Gazzaniga began working on the latest of his many books, he expected to write a scientific review of the last 50 years of the study of the split brain, work that added to the understanding of what many of us know as the left brain and the right brain.

What Gazzaniga, director of the SAGE Center for the Study of the Mind, soon realized was that one of the best stories he could tell was his own, in the form of a memoir: “Tales From Both Sides of the Brain: A Life in Neuroscience” (Ecco/HarperCollins, 2015).

“What became interesting to me was that a life in science is not this lonely, austere thing. Instead, you’re getting ideas from others. It’s a very social process,” said Gazzaniga, also a professor in the Department of Psychological and Brain Sciences.

“I think, in a way, people who are teetering on going into a life in science versus one in medicine or other ways of spending a life associated with science, they think it’s going to be isolated or it’s going to be lonely. It’s just not true,” he said. “I hope a lot of students who read this will understand you can keep all these other activities that make for a rich life outside the lab, and that’s part of what makes for a great life inside the lab.”

Gazzaniga’s tales include the intense and giddy early days of his academic career at the California Institute of Technology, where he earned his Ph.D. in psychobiology in 1964. While at Caltech, Gazzaniga conducted experiments under Roger Sperry, who later shared the 1981 Nobel Prize in Physiology or Medicine for his work in split-brain research, studying subjects with a severed corpus callosum. The corpus callosum connects the two hemispheres of the brain.

Gazzaniga’s work has earned him renown as one of the fathers of cognitive neuroscience, and his book predictably attracted the attention of the scholarly journal Nature.

The study of the brain is complicated stuff, of course, as are some of the issues Gazzaniga has been asked to address. As a member of The President’s Council on Bioethics under George W. Bush, he contributed to the discussion about ethical issues related to stem cells.

“What is the moral status of an embryo and should we really confer on it the status of an adult? There, bam, the first question,” Gazzaniga said. “What is a 14-day-old blastocyst? Is it a brain? No, the brain isn’t there yet. Are you really going to confer this status on a brainless group of cells? You realize neuroscience has to have a posture.”

The advances in the understanding of the brain over the more than 50 years Gazzaniga has studied it boggle the mind — both hemispheres. What lies ahead, he can only imagine.

“What’s happening is there’s an explosion coming of technological advances. You hear this all the time and it’s true: The computational capacity for analyzing complex data is exploding,” he said. “My guess is a scientific paper written 20 years from now will sound and read completely differently because of the changes going on in the field.”

However, Gazzaniga said, the goals ultimately remain what they long have been: “How does the brain make us who we are? That mental life that we all enjoy, how is it all built?”

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People with anorexia, body dysmorphic disorder have similar brain abnormalities


UCLA findings could lead to new strategies that improve how these disorders are treated.

People with anorexia (green areas) and BDD (blue areas) show less activity than healthy people in the brain regions that process “global” information when viewing houses (left) and faces (right). (Image courtesy of Wei Li, UCLA)

By Mark Wheeler, UCLA

People with anorexia nervosa and with body dysmorphic disorder have similar abnormalities in their brains that affect their ability to process visual information, a new UCLA study reveals.

People with anorexia have such an intense fear of gaining weight that they starve themselves even when they are dangerously thin. Body dysmorphic disorder is a psychiatric condition characterized by an obsessive preoccupation with a perceived flaw in physical appearance.

The researchers found that people with both disorders had abnormal activity in the visual cortex of the brain during the very first instants when the brain processes “global” information, or images as a whole, as opposed to a tiny detail. According to the authors, it could also mean that perceptual retraining may be an effective therapy for both disorders. Perceptual retraining is a behavioral exercise that attempts to help adjust or correct the participant’s balance of global and detailed processing. For both of these disorders, participants are encouraged to not focus on details and process objects more globally.

Previous research on body dysmorphic disorder has shown the same type of abnormal activity in the visual cortex, but the UCLA study was the first to link the locations of the abnormal brain activity with time periods beginning as early as one-tenth of a second after an image is viewed. Understanding that timing is significant, the authors write, because it may help scientists determine whether the problem is in lower-level perception that takes place in the visual cortex, or elsewhere in higher-level brain systems.

The study appears in the current online edition of the peer-reviewed journal Psychological Medicine.

The UCLA researchers used functional magnetic resonance imaging, or fMRI, to detect regional abnormalities in visual processing and electroencephalography, or EEG, to assess the timeline for how the brain processes those signals. They compared results for 15 people with anorexia nervosa, 15 people with body dysmorphic disorder and 15 healthy individuals.

“We now know that these abnormalities may be happening at the very early stages when the brain begins processing visual input, and that the similar distortions in perception shared by anorexia nervosa and body dysmorphic disorder may have similar neurobiological origins,” said Wei Li, a student in the UCLA Interdepartmental Ph.D. Program for Neuroscience and the study’s first author. “This understanding has the potential to lead to new strategies that can improve the way we treat these disorders.”

People with anorexia nervosa have a distorted sense of their body weight and shape. The disorder, which typically develops in adolescence, can lead to social withdrawal, cardiovascular or electrolyte disturbances severe enough to require hospitalization, and even death. There are few effective treatments, and many symptoms can be lifelong.

Individuals with body dysmorphic disorder see themselves as disfigured and ugly, even though they look normal to others. Those suffering from the disorder tend to fixate on minute details on their faces or bodies, and distress with their appearance can result in depression, anxiety, shame and severe functional impairment, which can lead to hospitalization and, in some cases, even suicide. The disorder affects approximately 2 percent of the population, making it more prevalent than schizophrenia or bipolar disorder — yet scientists know relatively little about the biology underlying the disease.

Although the two disorders share similar body image distortions, and are often diagnosed in the same person, no previous study directly compared the abnormalities in visual information processing that could significantly contribute to them, nor compared their neurobiology.

“Previously, we knew where these visual processing abnormalities existed in the brain in body dysmorphic disorder, but did not know when they were taking place,” said Dr. Jamie Feusner, the paper’s senior author, a UCLA associate professor of psychiatry and director of the Obsessive-Compulsive Disorder Program at the UCLA Semel Institute for Neuroscience and Human Behavior. “Now, knowing the timing, it is clearer that their perceptual distortions are more likely to be rooted early in their visual systems.

“Also, the fact that the results were recorded while people were viewing other people’s faces and images of houses suggests that this may be a more general abnormality in visual processing,” Feusner said.

The UCLA researchers found that people with anorexia and those with body dysmorphic disorder showed less activity in the regions of the brain that convey primarily global information, although the effect appeared in smaller regions in those with anorexia.

Further, the researchers found that individuals with body dysmorphic disorder exhibited greater activity in the areas of the brain that process detailed information. Interestingly, the more activity they had in these detail-processing regions, the less attractive they perceived the faces to be, suggesting a connection with distorted perceptions of appearance.

Both differences were linked to electrical activity occurring within the first 200 milliseconds after the person viewed an image.

“Among the questions to be answered in future research is whether this dysfunction improves as a result of treatment, and if not, what perceptual retraining techniques could help sufferers of these illnesses,” Li said.

The study’s other authors were Tsz Man Lai, Sandra Loo, Danyale McCurdy, Michael Strober and Susan Bookheimer, all of UCLA; and Cara Bohon of Stanford University. Funding for the study was provided by the National Institutes of Health (NIH MH093535-02S1).

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Anxious people more apt to make bad decisions amid uncertainty


They have tougher time reading environmental cues that could help avoid bad outcome.

By Yasmin Anwar, UC Berkeley

Highly anxious people have more trouble deciding how best to handle life’s uncertainties. They may even catastrophize, interpreting, say, a lovers’ tiff as a doomed relationship or a workplace change as a career threat.

In gauging people’s response to unpredictability, scientists at the University of California, Berkeley, and the University of Oxford found that people prone to high anxiety have a tougher time reading the environmental cues that could help them avoid a bad outcome.

Their findings, reported today (March 2) in the journal Nature Neuroscience, hint at a glitch in the brain’s higher-order decision-making circuitry that could eventually be targeted in the treatment of anxiety disorders, which affect some 40 million American adults.

“Our results show that anxiety may be linked to difficulty in using information about whether the situations we face daily, including relationship dynamics, are stable or not, and deciding how to react,” said study senior author Sonia Bishop, an assistant professor of psychology at UC Berkeley and principal investigator of the study.

“It’s a bit like being Alice in Wonderland, trying to work out if the same rules apply or if everything is different and if so, what choices you should make,” she added.

For example, a friend may suddenly lash out for no discernible reason. That friend’s behavior could reflect a typical variation in their day-to-day mood or interactions or, more dramatically, an underlying change in their relationship with you. The challenge for a person prone to anxiety is assessing the situation in context of what else has happened recently and responding appropriately.

Bishop and fellow researchers used decision-making tasks, behavioral and physiological measurements and computational models to gauge the probabilistic decision-making skills of 31 young and middle-aged adults whose baseline anxiety levels ranged from low to extreme. Probabilistic decision-making requires using logic and probability to handle uncertain situations, drawing conclusions from past events to determine the best choice.

“An important skill in everyday decision-making is the ability to judge whether an unexpected bad outcome is a chance event or something likely to reoccur if the action that led to the outcome is repeated,” Bishop said.

The researchers’ measures also included eye-tracking to detect pupil dilation, an indicator that the brain has released norepinephrine, which helps send signals to multiple brain regions to increase alertness and readiness to act.

Participants were asked to play a computerized “two-armed bandit-style” game in which they repeatedly chose between two shapes, one of which, if selected, would deliver a mild to moderate electrical shock.

To avoid getting shocked, participants needed to keep track of the shape that most frequently delivered electrical jolts. During one part of the game, the shock-delivering shape did not change for a long stretch of time. However, during another part of the game, it changed more frequently. Highly anxious people had more trouble than their less anxious counterparts adjusting to this and thus avoiding shocks.

“Their choices indicated they were worse at figuring out whether they were in a stable or erratic environment and using this to make the best choices possible,” Bishop said.

Also weaker in highly anxious participants was their pupil response to receiving a shock (or not) during the erratic phase of the game. Typically, our pupils dilate when we take in new information, and this dilation increases in volatile environments. Smaller pupils suggested a failure to process the rapidly changing information that was more prevalent during the erratic phase of the game.

“Our findings help explain why anxious individuals may find decision-making under uncertainty hard as they struggle to pick up on clues as to whether they are in a stable or changing situation,” Bishop said.

In addition to Bishop, co-authors and researchers on the study were Timothy Behrens, Michael Browning, Gerard Jocham and Jill O’Reilly at the University of Oxford in England. The study was funded by grants from the European Research Council and the National Institutes of Health.

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UCSF researchers redefine role of brain’s ‘hunger circuit’


Unexpected findings have implications for anti-obesity therapies.

By Pete Farley, UC San Francisco

Using techniques developed only over the past few years, UC San Francisco researchers have completed experiments that overturn the scientific consensus on how the brain’s “hunger circuit” governs eating.

Because of this circuit’s potential role in obesity, it has been extensively studied by neuroscientists and has attracted intense interest among pharmaceutical companies. According to the UCSF scientists, their unexpected new findings could reshape basic research on feeding behavior as well as strategies for the development of new anti-obesity drugs.

Scientists have generally believed that the hunger circuit, made up of two groups of cells known as AgRP and POMC neurons, senses long-term changes in the body’s hormone and nutrient levels, and that the activation of AgRP neurons directly drives eating. But the new work shows that the AgRP-POMC circuit responds within seconds to the mere presence of food, and that AgRP neurons motivate animals to seek and obtain food, rather than directly prompting them to consume it.

“No one would have predicted this. It’s one of the most surprising results in the field in a long time,” said Zachary Knight, Ph.D., assistant professor of physiology at UCSF. “These findings really change our view of what this region of the brain is doing.”

It has been known for 75 years that a region at the base of the brain called the hypothalamus exerts profound control over eating behavior. As neuroscientists refined this observation over the ensuing decades, they zeroed in first on a small area of the hypothalamus known as the arcuate nucleus, and more recently on AgRP and POMC neurons, two small populations of cells within that nucleus.

These two groups of cells, which collectively occupy an area smaller than a millimeter in the mouse brain, are functionally organized in a seesaw-like fashion: when AgRP neurons are active, POMC neurons are not, and vice versa.

Hundreds of experiments in which scientists added hormones or nutrients to brain slices while recording the activity of AgRP and POMC neurons have laid the foundation of the dominant model of how the hunger circuit works. As we grow hungry, this view holds, gradual changes in hormone levels send signals that begin to trigger AgRP neurons, the activity of which eventually drives us to eat. As we become sated, circulating nutrients such as glucose activate POMC neurons, which suppresses the desire to eat more food.

Yiming Chen, a graduate student in Knight’s lab, was expecting to build on the prevailing model of the hunger circuit when he began experiments using newly developed fiber optic devices that allowed him to record AgRP-POMC activity in real time as mice were given food after a period of fasting. “No one had actually recorded the activity of these neurons in a behaving mouse, because the cells in this region are incredibly heterogeneous and located deep within the brain,” said Chen. “The technology to do this experiment has only existed for a few years.”

But as reported in the Feb. 19 online issue of Cell, just seconds after food was given to the mice, and before they had begun to eat, Chen saw AgRP activity begin to plummet, and POMC activity correspondingly begin to rise.

“Our prediction was that if we gave a hungry mouse some food, then slowly, over many minutes, it would become satiated and we would see these neurons slowly change their activity,” Knight said. “What we found instead was very surprising. If you simply give food to the mouse, almost immediately the neurons reversed their activation state. This happens when the mouse first sees and smells the food, before they even take a bite.”

The researchers found that the AgRP-POMC circuit could be quickly “reset,” with POMC cell activity dampened and AgRP neurons again beginning to fire, if the food were taken away. The magnitude of the transition from AgRP to POMC activity was also directly correlated with the palatability of the food offered: peanut butter and chocolate, both of which are much preferred by mice over standard lab chow, caused a stronger and more rapid reversal of AgRP-POMC activity. The AgRP-POMC responses also depended on the accessibility of the food. A slower and weaker transition was seen if the mice were able to detect the presence of peanut butter through smell, but couldn’t see the food.

These results show that, while slow, hunger-induced changes in hormones and nutrients activate AgRP neurons over the long term, these neurons are rapidly inactivated by the sight and smell of food alone. A major implication of this discovery, Knight and Chen said, is that the function of AgRP neurons is to motivate hungry animals to seek and find food, not to directly control eating behavior itself.

The fact that more accessible and more palatable, energy-rich foods engage POMC neurons and shut down AgRP activity more strongly suggests that the circuit also has “anticipatory” aspects, by which these neurons predict the nutritional value of a forthcoming meal and adjust their activity accordingly.

Both of these roles of the AgRP-POMC circuit make sense, said the researchers: if an animal has successfully obtained food, the most adaptive brain mechanism would suppress the motivation to continue searching; likewise, since energy-dense foods alleviate hunger for longer periods, discovery of these foods should more strongly tamp down the hunger circuit and the desire to seek additional nutrition.

“Evolution has made these neurons a key control point in the hunger circuit, but it’s primarily to control the discovery of food,” said Knight. “It’s controlling the motivation to go out and find food, not the intake of food itself.”

So far, clinical trials of drugs that target AgRP-related pathways have been disappointing, Knight said, and he believes the new research may provide a new perspective on these efforts. “What probably drives obesity is the rewarding aspect of food. When you want dessert after you’ve finished dinner, it’s because it tastes good, and that doesn’t require hunger at all,” Knight said. “Finding that this circuitry primarily controls food discovery rather than eating changes our view of what we might be manipulating with drugs targeting AgRP pathways. We might be manipulating the decision to go to the grocery store, not necessarily the decision to take the next bite of food.”

Other members of the Knight laboratory participating in the research were Yen-Chu Lin, research specialist, and graduate student Tzu-Wei Kuo. The research was supported by the New York Stem Cell Foundation, the Rita Allen Foundation, the McKnight Foundation, the Alfred P. Sloan Foundation, a NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation, the Esther A. and Joseph Klingenstein Foundation, the Program for Breakthrough Biomedical Research, the UCSF Diabetes Center Obesity Pilot Program, and the National Institutes of Health.

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UCSF receives $100M gift to advance health sciences mission


Landmark gift cements Chuck Feeney’s role as UC system’s top philanthropist.

Chuck Feeney

By Jennifer O’Brien, UC San Francisco

UC San Francisco has received a $100 million gift from visionary philanthropist Charles F. “Chuck” Feeney to support its new Mission Bay hospitals, world-class faculty and students, and research programs focused on the neurosciences and aging.

This donation brings the longtime supporter’s total UCSF giving to more than $394 million, making Feeney the single largest contributor to the University of California system.

“I get my gratification from knowing that my investments in medical research, education, and the delivery of health care at UCSF will provide lifelong benefits to millions of people not only in the Bay Area but also around the world,” said Feeney, who, despite his global presence as a successful entrepreneur and discerning philanthropist, prefers remaining out of the limelight. “I can’t imagine a more effective way to distribute my undeserved wealth.”

Reflecting on Feeney’s contributions, UCSF Chancellor Sam Hawgood, M.B.B.S., said, “As we celebrate UCSF’s 150th anniversary this year, it is only fitting that we acknowledge the unique role Chuck has played in our history. While his impact has been felt most profoundly during this past decade, his generosity will carry on forever at our university, in the San Francisco community, throughout the Bay Area and globally, as our faculty and students advance knowledge and provide the finest clinical care. We are honored that he has decided to invest again in UCSF.”

Feeney’s gifts to UCSF are most visible at the university’s Mission Bay campus, where he has provided indispensable support to create advanced facilities and foster the environment for the biomedical research and patient care that goes on within them.

Before the latest funding, Feeney’s most recent gift to the campus was to UCSF Global Health Sciences, enabling the October 2014 opening of Mission Hall, which houses global health researchers, scientists and students under the same roof for the first time. Feeney, who coined the term “giving while living,” also generously supported the building of the Smith Cardiovascular Research Building and the Helen Diller Family Cancer Research Building.

“Chuck Feeney has been our partner at Mission Bay for more than 10 years,” added Hawgood. “He immediately embraced the Mission Bay concept, and he has enthusiastically helped us shape a larger vision for the campus and finance its development because he knew that our research and clinical programs could not flourish without state-of-the-art buildings.”

Gift to support four primary areas

The Campaign for the UCSF Medical Center at Mission Bay
Funds will support the $600 million philanthropy goal of the $1.5 billion hospitals project. The latest donation builds upon the transformative $125 million matching gift Feeney made to support the hospitals complex and its programs in 2009, the largest gift received toward the campaign.

The opening of the 289-bed hospital complex – which includes UCSF Benioff Children’s Hospital San Francisco, UCSF Betty Irene Moore Women’s Hospital, UCSF Bakar Cancer Hospital, and the UCSF Ron Conway Family Gateway Medical Building – was the culmination of more than 10 years of planning and construction. Strategically located adjacent to UCSF’s renowned Mission Bay biomedical research campus, the new medical center places UCSF physicians in close proximity to UCSF researchers and nearby bioscience companies who are working to understand and treat a range of diseases, from cancer to neurological disorders.

“It’s been thrilling to see the reactions of our patients and their families as they encounter the amazing care offered at our new UCSF Mission Bay hospitals,” said Mark Laret, CEO of UCSF Medical Center and UCSF Benioff Children’s Hospitals. “This world-class experience would never have been possible without the support of Chuck Feeney who, as the largest contributor to the project, helped us create the hospitals of our dreams. Every patient cured, every breakthrough discovered at Mission Bay, will be thanks in part to Chuck. His legacy is unparalleled.”

Neuroscience and aging
The gift also supports UCSF’s pre-eminent neuroscience enterprise, including its Sandler Neurosciences Center and neurology programs at Mission Bay.

The center, a five-story, 237,000-square-foot building that opened in 2012, brings under one roof several of the world’s leading clinical and basic research programs in a collaborative environment. UCSF’s neurology and aging efforts are focused on finding new diagnostics, treatments, and cures for a number of intractable disorders, including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, stroke, migraine, epilepsy and autism. The programs also seek to integrate neuroscience and clinical disciplines with public health initiatives in order to disseminate and implement novel findings from research centers of excellence, as well as conduct community outreach to raise awareness about the diseases of aging.

“Chuck Feeney has taken a keen interest in the challenges of aging,” said Hawgood. “In turn, he has recognized UCSF’s extraordinary talent in the neurosciences, among both basic researchers and those who translate research into clinical care and public policy. This gift will build on UCSF’s strengths while encouraging strong partnerships at other research institutions around the world where Chuck also has made important investments.”

Student scholarships and housing
Even with its extraordinary academic firepower, UCSF has extremely limited funds to support scholarships for professional students in its schools of dentistry, medicine, nursing and pharmacy. Part of the gift will provide scholarship support, bolstering UCSF’s ability to recruit the best and brightest students, regardless of their financial circumstances.

Recent decreases in state funding led to tuition increases and higher demand for scholarships. This, in turn, increased student debt. Combined with Bay Area housing prices that are among the highest in the nation – from 2011 to 2013, the median rent increased by 24 percent – the prospect of overwhelming debt can deter economically vulnerable students as well as those from middle-class backgrounds from attending UCSF. By minimizing debt upon graduation, the scholarships will help ensure that a UCSF education remains in reach for students from underserved populations, as well as for those students who choose to become health care leaders in underserved communities.

“Scholarships give our students the gift of freedom: to make career choices based on purpose and passion, rather than the price of education; to use time to study, explore science, and volunteer to help others, rather than working to make ends meet; and to succeed because someone who never met them saw enough potential to invest in their dreams,” said Catherine Lucey, M.D., vice dean for education at UCSF’s School of Medicine. “These scholarships catalyze our schools’ ability to find, recruit, educate and nurture the workforce our country needs: talented professionals whose life experiences enable them to provide compassionate care to today’s diverse communities and advance science to improve the health of future communities.”

Faculty recruitment
The donation also will help UCSF recruit the next generation of promising faculty in an increasingly competitive marketplace.

New funding will attract junior faculty – who frequently find it more challenging to secure research funding – and provide initial startup funds as they launch their research careers and clinical practices. With decreasing federal support for young investigators, this gift will underwrite a new generation of brilliant upcoming faculty.

“While Chuck’s unprecedented generosity has been focused primarily on Mission Bay, he understands the power of the entire UCSF enterprise, from our cutting-edge stem cell research at Parnassus to our innovative cancer programs at Mount Zion,” Hawgood said. “We’re thrilled that Chuck has inspired other philanthropists to join him in creating one of the most vibrant life science communities in the world, where progress will ripple far beyond Mission Bay and the campus for generations to come.”

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Brain’s iconic seat of speech goes silent when we actually talk


UC Berkeley discovery has implications for diagnoses, treatments of stroke, epilepsy.

New findings will better help map out the brain’s speech regions (Photo courtesy of Adeen Flinker)

By Yasmin Anwar, UC Berkeley

For 150 years, the iconic Broca’s area of the brain has been recognized as the command center for human speech, including vocalization. Now, scientists at UC Berkeley and Johns Hopkins University in Maryland are challenging this long-held assumption with new evidence that Broca’s area actually switches off when we talk out loud.

The findings, reported today (Feb. 16) in the Proceedings of the National Academy of Sciences journal, provide a more complex picture than previously thought of the frontal brain regions involved in speech production. The discovery has major implications for the diagnoses and treatments of stroke, epilepsy and brain injuries that result in language impairments.

“Every year millions of people suffer from stroke, some of which can lead to severe impairments in perceiving and producing language when critical brain areas are damaged,” said study lead author Adeen Flinker, a postdoctoral researcher at New York University who conducted the study as a UC Berkeley Ph.D. student. “Our results could help us advance language mapping during neurosurgery as well as the assessment of language impairments.”

Flinker said that neuroscientists traditionally organized the brain’s language center into two main regions: one for perceiving speech and one for producing speech.

“That belief drives how we map out language during neurosurgery and classify language impairments,” he said. “This new finding helps us move towards a less dichotomous view where Broca’s area is not a center for speech production, but rather a critical area for integrating and coordinating information across other brain regions.”

In the 1860s, French physician Pierre Paul Broca pinpointed this prefrontal brain region as the seat of speech. Broca’s area has since ranked among the brain’s most closely examined language regions in cognitive psychology. People with Broca’s aphasia are characterized as having suffered damage to the brain’s frontal lobe and tend to speak in short, stilted phrases that often omit short connecting words such as “the” and “and.”

Specifically, Flinker and fellow researchers have found that Broca’s area — which is located in the frontal cortex above and behind the left eye — engages with the brain’s temporal cortex, which organizes sensory input, and later the motor cortex, as we process language and plan which sounds and movements of the mouth to use, and in what order. However, the study found, it disengages when we actually start to utter word sequences.

“Broca’s area shuts down during the actual delivery of speech, but it may remain active during conversation as part of planning future words and full sentences,” Flinker said.

The study tracked electrical signals emitted from the brains of seven hospitalized epilepsy patients as they repeated spoken and written words aloud. Researchers followed that brain activity – using event-related causality technology – from the auditory cortex, where the patients processed the words they heard, to Broca’s area, where they prepared to articulate the words to repeat, to the motor cortex, where they finally spoke the words out loud.

In addition to Flinker, other co-authors and researchers on the study are Robert Knight and Avgusta Shestyuk at the Helen Wills Neuroscience Institute at UC Berkeley, Nina Dronkers at the Center for Aphasia and Related Disorders at the Veterans Affairs Northern California Health Care System, and Anna Korzeniewska, Piotr Franaszczuk and Nathan Crone at Johns Hopkins School of Medicine.

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UC experts urge Congress to fund brain research


UCSF’s Bruce Miller, UC Davis’ Cameron Carter, UCLA’s Christopher Giza speak at briefing.

(From left) UC Davis' Cameron Carter, UCLA's Christopher Giza and UCSF's Bruce Miller spoke at a Jan. 29 Capitol Hill briefing discussing the current state of brain research. (Photo by Bara Vaida)

By Bara Vaida

The funding support provided by the National Institutes of Health remains crucial to finding treatments for neurodegenerative diseases, UC San Francisco’s Bruce Miller, M.D., told U.S. congressional staff last week on Capitol Hill.

The NIH’s research grants to the Department of Neurology at the UCSF School of Medicine have resulted in tremendous strides in understanding how neurodegenerative diseases, like Alzheimer’s, Parkinson’s and frontotemporal dementias develop, according to Miller, director of the UCSF Memory and Aging Center. With that understanding is the potential for treating and preventing those diseases, he added.

“The work you do here is unbelievably important to our mission,” Miller said during the Jan. 29 congressional briefing, attended by about three dozen people who work for members of Congress. The staff were invited by the University of California to learn about the latest on brain research.

NIH funding had helped foster understanding and treatment of schizophrenia, said Cameron Carter, M.D., director of UC Davis’s Center for Neuroscience and the Imaging Research Center. Christopher Giza, M.D., director of UCLA’s Steve Tisch BrainSPORT program, also spoke at the briefing. He underscored how federal research money was used to better understand and treat brain injuries.

All three physicians emphasized the need for more public money to be invested in brain disease research.

“While other diseases are declining, like heart disease, cancer and stroke, Alzheimer’s is not. We think its going to double in prevalence,” Miller told congressional staff. “The NIH is spending about $500 million a year on Alzheimer’s research. Our mantra is, this year, spend $1 billion.”

A growing risk of brain disease

Alzheimer’s is one of the most costly diseases in the U.S. – $109 billion to $240 billion a year in medical and caregiver costs, according to Rand Corp. It is also the sixth leading cause of death. About 5 million people currently live with Alzheimer’s and 500,000 of them live in California.

Miller went on to describe how NIH funding had helped scientists understand which proteins caused different types of dementias, and how those proteins aggregate and destroy brain cells. With NIH money, scientists developed molecular imaging technology that now enable researchers to see proteins accumulating in the brain before symptoms develop, offering an opportunity to potentially prevent dementia from developing.

“I am proud to say, that with NIH funding, we are starting to treat pre-symptomatic” dementia, Miller said. “Those imaging costs are huge – $3,000 to $5,000 per patient– so there are very few places in the U.S. that can do that.”

Earlier in the day, all three physicians held private discussions with staff members working for California lawmakers, including Democratic House Minority Leader Nancy Pelosi and Reps. Doris Matsui and Ted Lieu.

“I was really struck by how helpful our legislators are,” Miller said. “We reach out to them, and they reach back out to us.”

Miller provided the briefing to staff as Congress begins considering the budget for 2016, which begins on Oct. 1, 2015. The NIH’s annual budget was about $30 billion in 2015. President Barack Obama proposed increasing the NIH budget to $31.3 billion in 2016.

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Tackling brain injuries head on


UC Davis scientists developing system to better assess on-field concussions.

For much of this fall, as in falls past, a Friday night crowd comes out for the weekly football game and likely witnesses the star running back getting rattled by a hard tackle.

The coach faces a decision: keep the player in the game and risk serious head injury or pull him and face the wrath of the player, the team and the crowd. What the coach needs is a way to accurately assess the player’s status – right now.

This scenario is being played out at sports fields around the world. How do we make objective decisions about a player’s health in the heat of competition?

The problem intrigues UC Davis physician Khizer Khaderi. A neuro-ophthalmologist, Khaderi is applying his expertise in the eye-brain connection to investigate traumatic brain injury (TBI). Whether the result of a car accident, explosion, skiing or a tackle, TBI can affect vision, memory and even mental health.

Imperfect solutions

Khaderi and colleagues are developing a system that will take the guesswork out of assessing an on-field concussion, an early form of TBI.

It would replace a system of neurocognitive tests that many teams use now. In these tests, a player is asked a number of questions, of which answers are compared to baseline results recorded earlier. However, with players’ strong incentive to stay in the game, some have learned to circumvent the system.

“One of the problems with the neurocognitive approach is that it’s very subjective,” says Khaderi, an assistant professor of clinical ophthalmology and head of the Sports Vision Lab. “Players will intentionally do poorly on the baseline test, so if they do get injured, it won’t look as severe.”

Khaderi’s solution focuses on the eyes. A third of the brain is devoted to the visual system, making the eyes an ideal window on brain health. Several biometric tests exist but Khaderi’s team has found that relying on three established biometric tests greatly increases the chances of accurately assessing TBI risk on the field in real time.

UC Davis neuro-ophthalmologist Khizer Khaderi tests a system he and his team developed to facilitate a quick assessment of an on-field concussion, an early form of traumatic brain injury. Helping with the test is medical resident Rachel Simpson.

Eyes, pupils and brain waves

Using eye movements to assess TBI has advantages. For example, researchers have measured how long the eye takes to move from a central to peripheral focus. This would be the motion a driver would make when shifting attention from the road to a child crossing it. This motion takes less than seven-tenths of a second for a healthy person, but much longer for those who’ve experienced a brain injury.

The opposite motion is also informative. In the same scenario, the driver could make the decision to look away from the child stepping into the road.

“The natural reaction is to look at the child,” says Khaderi, “but instead you look away. This involves cognition, so it’s a good measure of executive function.”

Pupil function can also measure an injury’s severity. A coach could use a flashlight to assess dilation, but background light can skew results. To combat this, Khaderi has adopted a psychological method called the International Affective Picture System, which uses pictures to make the pupil respond.

The third metric measures brain waves. When they’re awake, people generally have a higher ratio of fast alpha waves to slow theta waves. However, that ratio is reversed after a brain injury. High theta waves indicate a dreamy state of mind.

Moving forward

Khaderi plans to bring these tools to playing fields everywhere. Fortunately, much of this technology is being used for other purposes and can be repurposed for TBI detection.

“Our goal is to create a platform that integrates commercially available eye tracking hardware and EEG (brain wave) systems,” says Khaderi.

The group has found a development partner and is working with the UC Davis athletic department to set up clinical trials. The ultimate goal is to create a system that could be accessed through a tablet computer or other device.

“These injuries don’t just strike kids who are playing sports, but anyone who leads an active life,” says Khaderi. “Our brains are precious and we need to do all we can to protect them.”

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Why protein mutations lead to familial form of Parkinson’s


UC San Diego study focuses on alpha-synuclein.

By Jan Zverina, UC San Diego

Researchers at the San Diego Supercomputer Center (SDSC) at the University of California, San Diego, have shown for the first time why protein mutations lead to the familial form of Parkinson’s disease.

The study, available online in prepublication in ACS Chemical Neuroscience and partially funded by the National Institutes of Health, focuses specifically on alpha-synuclein (αsyn), a protein whose function in healthy tissue is unknown but which represents the major structural component of Lewy bodies – protein clumps found in the brains of individuals with Parkinson’s disease and other neurological disorders.

Parkinson’s disease is characterized by impairment or deterioration of neurons in an area of the brain known as the substantia nigra. In the familial form of the disorder, a set of mutations in αsyn had been identified but what was unknown was the molecular mechanism by which these mutations caused disease.

“As an unstructured protein, αsyn is sometimes called ‘chameleon’ because it has no stable configuration and constantly changes its shape,” said lead author Igor F. Tsigelny, a research scientist with SDSC as well as the UC San Diego Moores Cancer Center and the Department of Neurosciences. “Nevertheless when these changes seem to be random on first glance, they have specific intrinsic rules that control the evolution of the αsyn shape.”

Using SDSC’s data-intensive Gordon supercomputer to find hidden rules of the conformational changes of αsyn, researchers conducted extensive calculations of the possible evolution of the protein structure.

Through computer modeling, researchers showed that αsyn mostly can bind the membrane with four main sites, or zones. While binding was shown to be superficial by three of the sites, one site – Zone 2 – had a particular affinity for the membrane. Researchers found that αsyn contacting the neuron membrane in that site immediately and deeply penetrated it, which led to the creation of ring oligomers in the membrane, and eventually opened pores that allowed an uncontrolled influx of ions that ultimately killed the cell. Most of the mutations changed the shape of the protein in a way that increased binding of αsyn to the membrane by this zone.

These theoretical predications were confirmed by a set of experimental methods conducted in the laboratory of Eliezer Masliah, a professor in UC San Diego’s Department of Neurosciences. “Previous to this study, researchers could not say why these mutations caused Parkinson’s disease,” said Tsigelny. “The discovery of Zone 2 as the distinguishing feature of the membrane-penetrating configurations of αsyn paves the road to possible prevention of such a binding. Now we can affect this region with rational drug design, for example by creating compounds that would change its electrostatic profile.”

In addition to Tsigelny and Masliah, researchers involved in the study include Yuriy Sharikov, Valentina L. Kouznetsova, and Jerry P. Greenberg from SDSC; Wolf Wrasidlo from the Moores Cancer Center; and Cassia Overk, Tania Gonzalez, Margarita Trejo, Brian Spencer, and Kori Kosberg, from the Department of Neurosciences at UC San Diego.

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Multiple, short learning sessions strengthen memory formation in fragile X


UC Irvine study suggests the method could aid children with the autism-related condition.

Christine Gall and Gary Lynch found that fragile X model mice trained in three short, repetitious episodes spaced one hour apart performed as well on memory tests as normal mice. (Photo by Chris Nugent, UC Irvine)

By Tom Vasich, UC Irvine

A learning technique that maximizes the brain’s ability to make and store memories may help overcome cognitive issues seen in fragile X syndrome, a leading form of intellectual disability, according to UC Irvine neurobiologists.

Christine Gall, Gary Lynch and colleagues found that fragile X model mice trained in three short, repetitious episodes spaced one hour apart performed as well on memory tests as normal mice. These same fragile X rodents performed poorly on memory tests when trained in a single, prolonged session – which is a standard K-12 educational practice in the U.S.

“These results are dramatic and never seen before. Fragile X model mice trained using this method had memory scores equal to those of control animals,” said Gall, professor of anatomy & neurobiology and neurobiology & behavior. “Our findings suggest an easily implemented, noninvasive strategy for treating an important component of the cognitive problems found in patients with fragile X syndrome.”

Fragile X syndrome is an inherited genetic condition that causes intellectual and developmental disabilities and is commonly associated with autism. Symptoms include difficulty learning new skills or information.

It’s been known since classic 19th century educational psychology studies that people learn better when using multiple, short training episodes rather than one extended session.

Two years ago, the Lynch and Gall labs found out why. They discovered a biological mechanism that contributes to the enhancing effect of spaced training: Brain synapses – which are the connection points among neurons that transfer signals – encode memories in the hippocampus much better when activated briefly at one-hour intervals.

The researchers found that synapses have either low or high thresholds for learning-related modifications and that the high-threshold group requires hourlong delays between activation in order to store new information.

“This explains why prolonged ‘cramming’ is inefficient – only one set of synapses is being engaged,” said Lynch, professor of psychiatry & human behavior and anatomy & neurobiology. “Repeated short training sessions, spaced in time, engage multiple sets of synapses. It’s as if your brain is working at full power.”

The finding was significant, Gall added, because it demonstrated that a ubiquitous and fundamental feature of psychology can, at least in part, be explained by neurobiology.

It also gave the researchers time-sequencing rules for optimizing forms of learning dependent upon the hippocampus – utilized in the current study. Results appear in the Nov. 25 issue of Proceedings of the National Academy of Sciences.

The UCI scientists stress that the new brain-based training protocols, if applied during childhood, have the potential to offset many aspects of fragile X-related autism. “We believe that synaptic memory mechanisms are used during postnatal development to build functional brain circuits for dealing with confusing environments and social interactions,” Lynch said. “Implementing the brain-based rules during childhood training could result in lifelong benefits for patients.”

He and Gall look forward to collaborating with UCI’s Center for Autism Research & Translation to further evaluate the effect of multiple, short training episodes on learning in fragile X children.

Ronald Seese led the study as part of his work toward a Ph.D. and was assisted by Kathleen Wang and Yue Qin Yao. The research was funded by the National Science Foundation (grant 1146708), the National Institutes of Health (grants MH082042 and NS04260), and the William & Nancy Thompson Family Foundation, via UCI’s Center for Autism Research & Translation.

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