TAG: "Neuroscience"

Brain development suffers from lack of fish oil fatty acids


UC Irvine researchers point to dietary link for proper pre- and postnatal neural growth.

By Tom Vasich, UC Irvine

While recent reports question whether fish oil supplements support heart health, UC Irvine scientists have found that the fatty acids they contain are vitally important to the developing brain.

In a study appearing today (April 15) in The Journal of Neuroscience, UCI neurobiologists report that dietary deficiencies in the type of fatty acids found in fish and other foods can limit brain growth during fetal development and early in life. The findings suggest that women maintain a balanced diet rich in these fatty acids for themselves during pregnancy and for their babies after birth.

Susana Cohen-Cory, professor of neurobiology & behavior, and colleagues identified for the first time how deficits in what are known as n-3 polyunsaturated fatty acids cause molecular changes in the developing brain that result in constrained growth of neurons and the synapses that connect them.

These fatty acids are precursors of docosahexaenoic acid, or DHA, which plays a key role in the healthy creation of the central nervous system. In their study, which used female frogs and tadpoles, the UCI researchers were able to see how DHA-deficient brain tissue fostered poorly developed neurons and limited numbers of synapses, the vital conduits that allow neurons to communicate with each other.

“Additionally, when we changed the diets of DHA-deficient mothers to include a proper level of this dietary fatty acid, neuronal and synaptic growth flourished and returned to normal in the following generation of tadpoles,” Cohen-Cory said.

DHA is essential for the development of a fetus’s eyes and brain, especially during the last three months of pregnancy. It makes up 10 to 15 percent of the total lipid amount of the cerebral cortex. DHA is also concentrated in the light-sensitive cells at the back of the eyes, where it accounts for as much as 50 percent of the total lipid amount of each retina.

Dietary DHA is mainly found in animal products: fish, eggs and meat. Oily fish – mackerel, herring, salmon, trout and sardines – are the richest dietary source, containing 10 to 100 times more DHA than nonmarine foods such as nuts, seeds, whole grains and dark green, leafy vegetables.

DHA is also found naturally in breast milk. Possibly because of this, the fatty acid is used as a supplement for premature babies and as an ingredient in baby formula during the first four months of life to promote better mental development.

The UCI team utilized Xenopus laevis (the African clawed frog) as a model for this study because it allowed them to follow the progression and impact of the maternal dietary deficit in the offspring. Because frog embryos develop outside the mother and are translucent, the researchers could see dynamic changes in neurons and their synaptic connections in the intact, live embryos, where development can be easily studied from the time of fertilization to well after functional neural circuits form.

They focused on the visual system because it’s an accessible and well-established system known to depend on fatty acids for proper growth and utility.

Miki Igarashi and Rommel Santos of UC Irvine contributed to the study, which was supported by the National Eye Institute (grant EY-011912).

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Exploring the ADHD-autism link


UC Irvine research is revealing similarities between the two disorders.

“This is an emerging field with great promise,” says Jean Gehricke, an associate professor of pediatrics at UC Irvine and a licensed clinical psychologist with the Center for Autism & Neurodevelopmental Disorders. “We know a bit about the underlying causes of ADHD, and through this, we may be able to improve how we treat autism.” (Photo by Jocelyn Lee, UC Irvine)

By Tom Vasich, UC Irvine

For the better part of the last decade, a growing body of research has been revealing more and more similarities between attention-deficit/hyperactivity disorder and autism.

Jean Gehricke, an associate professor of pediatrics at UC Irvine and a licensed clinical psychologist with the Center for Autism & Neurodevelopmental Disorders, is focusing on this link to better understand why people with ADHD and autism may be more prone to substance abuse and, in the process, to develop more effective behavioral therapies.

“This is an emerging field with great promise,” Gehricke says. “We know a bit about the underlying causes of ADHD, and through this, we may be able to improve how we treat autism.”

The Center for Autism & Neurodevelopmental Disorders – which provides assessment, diagnosis, treatment, care coordination, family support and education for children, teens and young adults with autism and other developmental disorders – is one of only a few in the region to deliver a continuum of services until age 22 and to conduct research aimed at transforming the approach to autism.

Gehricke, who teaches 25 students in his lab, has expertise in the assessment and treatment of autism, ADHD and co-occurring problems such as depression, anxiety and drug abuse.

He joined the center in 2013. Before that, he worked at the UCLA Neuropsychiatric Institute & Hospital, the UCI Transdisciplinary Tobacco Use Research Center and the UCI Child Development Center, where he also provided comprehensive clinical assessments and cognitive behavioral therapy.

Gehricke is well-known for his scientific work on the underlying mechanisms of ADHD and drug abuse, having published a number of breakthrough articles showing why individuals with ADHD are more prone to smoke cigarettes or get hooked on other nicotine and tobacco products.

He’s taking this knowledge and applying it to autism. While people with ADHD and high-functioning autism share certain characteristics, such as difficulty interacting with others and problems with emotional control, Gehricke is especially interested in whether these issues have similar neurobiological underpinnings.

In a December 2014 study, he and his colleagues identified a genetic trait shared by those with ADHD and those with autism that sheds light on some of the more troubling behaviors associated with the disorders.

Gehricke explains that aggression and health-risk actions are driven by distorted dopamine signaling in the brain and that the DRD4 gene is critical in regulating this function. The researchers found that one form of the gene – called the 7R allele and linked to altered dopamine regulation – is overrepresented in both individuals with ADHD and those with autism. It’s the genetic fingerprint of these types of conduct, Gehricke says.

“This study provides a conceptual model for risky behaviors, which we often see in our patients, and explores the possibility of tailoring information to reduce them,” he says. “More specifically, it points to the need to use strong visual images to induce behavioral changes.”

Gehricke is especially focused on nicotine addiction – which, he points out, is another shared ADHD-autism inclination. He believes that early behavioral intervention with autistic children could be a particularly effective deterrent to smoking – the No. 1 preventable health threat in the world – and “vaping.”

Gehricke says that the intervention should include warning labels (such as those used with nicotine and tobacco) depicting the negative consequences of health-risk behaviors and presenting distinctive imagery visually stimulating enough to alter the activities of teenagers and young adults with ADHD and autism. Testing the effectiveness of this deterrent is the next step Gehricke plans to take with his 7R allele group.

“Research – such as the projects conducted by Jean – is one of the core pillars of our mission at the Center for Autism & Neurodevelopmental Disorders,” says Catherine Brock, executive director. “Through his efforts and the families that participate, we are better able to understand the underlying mechanisms of autism spectrum disorders and ADHD.”

The Santa Ana-based center is a collaboration of the UC Irvine School of Medicine, CHOC Children’s Hospital, Chapman University’s College of Educational Studies, the Children & Families Commission of Orange County, and the William & Nancy Thompson Family Foundation.

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How deep-brain simulation reshapes neural circuits in Parkinson’s


UCSF study reveals mode of action of highly effective but poorly understood therapy.

In the new research, during surgery to implant a permanent DBS device (green with yellow tip) deep in the brains of Parkinson's disease patients, six recording electrodes (red) were temporarily placed on the surface of the brain. (Photo by Coralie de Hemptinne, UC San Francisco)

By Pete Farley, UC San Francisco

UC San Francisco scientists have discovered a possible mechanism for how deep-brain stimulation (DBS), a widely used treatment for movement disorders, exerts its therapeutic effects.

Few medical treatments show results as rapid and dramatic as those seen with DBS, in which surgically implanted devices deliver electrical pulses to inner brain structures involved in movement. In most Parkinson’s disease (PD) patients who receive the treatment, symptoms of slow movement, tremor and rigidity sharply diminish soon after the stimulation device is activated, and quickly return if the device is turned off.

But surprisingly, there has been very little understanding of precisely why and how DBS works so well — a lack of knowledge that has held back efforts to further improve the therapy. Despite the great success of DBS, some significant problems remain. Customizing the stimulation delivered by DBS devices for each patient to maximally reduce symptoms is challenging and time-consuming. And a minority of patients never obtains the full benefit their physicians expect. With a better understanding of how DBS acts on brain circuits, researchers hope to address these shortcomings and make DBS an even more effective treatment.

The new research, published online today (April 13) in Nature Neuroscience, reveals that DBS keeps PD symptoms in check by reducing excessive synchronization of brain activity in the motor cortex, a region on the outer surface of the brain that governs movements of the body.

“This therapy is becoming widespread for many brain disorders aside from movement disorders, including psychiatric conditions such as depression, but no one knows how it works,” said UCSF’s Philip Starr, M.D., Ph.D., the Dolores Cakebread Chair in Neurological Surgery and senior author of the new study. “This is a significant step in answering this question on the level of brain networks, not just addressing where you’re actually applying the stimulation in the brain.”

Previous research led by Coralie de Hemptinne, Ph.D., a postdoctoral fellow in Starr’s laboratory, laid the groundwork for the new study. In 2013, de Hemptinne, Starr, and colleagues reported in the Proceedings of the National Academy of Sciences that a measure of synchronized rhythmic activity in the brain, which normally varies with movement or other behaviors, is excessively high in in the cortex in PD.

In that paper, the team hypothesized that this lockstep synchronization of brain circuits in PD thwarts the flexibility the brain requires to plan and execute movements, and that DBS might work by decoupling activity patterns in the motor cortex.

In the new work, “since we had found this excessive synchrony in PD patients, we decided to see if there’s a relationship between that synchrony and symptoms, and whether synchrony is lessened when symptoms are improved by DBS,” said de Hemptinne, first author of the Nature Neuroscience paper. “We measured synchrony in the motor area of the brain before, during, and after DBS, and while the patient was resting or engaged in a movement task in which they had to reach and touch a computer screen.”

During surgery on 23 patients with Parkinson’s disease in whom permanent DBS electrodes were being surgically implanted, the UCSF team slid a temporary strip of six recording electrodes under the skull and placed it over the motor cortex. As in the prior research, recordings of neural activity showed excessive synchronization of activity rhythms in the patients.

As the name of the therapy implies, the end of the stimulating lead of DBS devices is placed in a structure deep in the brain known as the subthalamic nucleus (STN), which is part of a “loop” of neural circuitry that includes the motor cortex on the brain’s surface. When the DBS device was activated and began stimulating the STN, the effect of the stimulation reached the motor cortex, where over-synchronization rapidly diminished. If the device was turned off, excessive synchrony re-emerged, more gradually in some patients than others.

DBS surgery generally takes about six hours, and during the middle of the  procedure patients are awakened for testing of the device and to ensure that the stimulating lead is properly placed in the STN. During this period the researchers asked 12 of the patients to perform a reaching task in which they had to touch a blue dot appearing on a computer screen. Importantly, said Starr, recordings revealed that DBS eliminated excessive synchrony of motor cortex activity and facilitated movement without altering normal changes in brain activity that accompany movements.

“Our 2013 paper showed how Parkinson’s disease affects the motor cortex, and this paper shows how DBS affects the motor cortex,” said Starr. “With these two pieces of information in hand, we can begin to think of news ways for stimulators to be automatically controlled by brain activity, which is the next innovation in the treatment of movement disorders.”

Because in these experiments the recording strip had to be removed before the end of surgery, recording data was collected over a relatively short time. To broaden opportunities for research, Starr and his team have collaborated with medical device company Medtronic on a new generation of permanently implantable DBS devices that can record activity in the motor cortex while delivering stimulation to the STN.

Five UCSF patients have been implanted with these new devices, and all data they collect can be uploaded for research during follow-up visits, de Hemptinne said, which will bring an even deeper understanding of how DBS reshapes brain activity.

“Now we can try to find even better correlations between DBS and symptoms, and we can even look at the effects of medications,” said de Hemptinne. “This new ability to collect data over a longer time course will be very powerful in driving new research.”

Other UCSF researchers taking part in the work were postdoctoral fellow Nicole Swann, Ph.D.; Jill L. Ostrem, M.D., professor of neurology; Elena Ryapolova-Webb, now a graduate student at UC Berkeley; Marta San Luciano, M.D., professor of neurology; and Nicholas Galifianakas, M.D., M.P.H., assistant professor of neurology.

The research was funded by the Michael J. Fox Foundation for Parkinson’s Research and by the National Institutes of Health.

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UC Davis neuroscientist recognized for color vision, aging contributions


John Werner to receive Verriest Medal from International Colour Vision Society.

John Werner, UC Davis

By Carole Gan, UC Davis

John S. Werner, a UC Davis neuroscientist and international authority on visual perception, has been selected to receive the 2015 Verriest Medal from the International Colour Vision Society for his contributions to understanding the structural and functional basis of color vision, how and why vision changes across the life span, and factors that contribute to loss of vision associated with disease. He will receive the award at the society’s biennial symposium in Sendai, Japan, in July.

Understanding, monitoring visual mechanisms

A distinguished professor at the UC Davis Eye Center and director of the Vision Science and Advanced Retinal Imaging Laboratory, Werner uses several different approaches to investigate both normal aging and age-
related diseases leading to blindness. These include psychophysical methods to show how perception of color adapts to changes in the degree of illumination throughout the day; electrophysiological methods to detect and quantify the response of cells at the back of the eye when stimulated by light; and custom instruments unique to his laboratory for ultra-high resolution. Imaging of the human retina at the cellular level, revolutionizing the field of vision science and the noninvasive diagnosis and monitoring of eye diseases.

One class of instrument uses adaptive optics to correct temporally varying, higher-order aberrations of the eye. Another class of instrument uses interferometry to detect faint reflections from cells that would otherwise make them invisible in the living eye.

Phase-variance optical coherence tomography, for example, is a noninvasive imaging technique that generates 3-D volumetric images of the retina, its microvasculature and other retinal layers without the need for fluorescent dyes. This discovery, recently published in the Proceedings of the National Academy of Sciences, has the potential to evaluate therapies and understand the underlying mechanisms of diseases of the retina and optic nerve, such as age-related macular degeneration progression, the latter of which is a leading cause of vision loss among people age 50 and older in the U.S. for which there is no cure. This movie shows the region of the retina, called the optic nerve, where fibers leave the eye and send their signals to different regions of the brain.

Innovating to advance vision science

Werner has made important contributions to understanding the development and aging of color mechanisms, as well as the processes of aging in perception, particularly as they relate to plasticity and potential clinical applications. He has demonstrated the function of the different classes of color receptor and their connections to the first visual area of the brain in infants as young as four weeks of age. Reductions in the response of these receptor types changes slowly from early adulthood and continues throughout life. His work showed that when the lens of the eye is removed in cataract surgery, the light reaching the back of the eye changes dramatically, leading to color vision changes that are slowly compensated in the brain to restore normal perception.

Throughout his career, Werner has maintained an active interest in opponent color mechanisms, color in art and color illusions. Some examples have appeared in popular venues such as Scientific American and a series of lectures held at the Crocker Art Museum in Sacramento, the Duke Institute for Brain Sciences and Duke University’s Nasher Museum of Art.

Career history

Werner received his doctoral degree in psychology from Brown University and conducted postdoctoral research at the Institute for Perception TNO in Soesterberg, The Netherlands. He was a member of the psychology faculty at the University of Colorado, Boulder, before joining UC Davis in 2000, where he holds appointments in the Center for Neuroscience, College of Biological Sciences and School of Medicine. He has co-edited several books that bring together discoveries from anatomy, physiology and psychophysics to illuminate fundamental mechanisms underlying human perception. These include “Visual Perception: The Neurophysiological Foundations,” “Color Vision: Perspectives from Different Disciplines,” “The Visual Neurosciences”  and “The New Visual Neurosciences.”

For his many contributions to the field of visual perception Werner has received many honors and awards. He is a fellow of the American Association for the Advancement of Science, American Psychological Association, American Psychological Society, Association for Research in Vision and Ophthalmology, the Gerontological Society of America and the Optical Society of America. He received the Pisart Vision Award from Lighthouse International and he presented the University of Colorado, Boulder, distinguished research lecture and the Optical Society of America Robert M. Boynton lecture. He has received a research prize from the Alexander von Humboldt Foundation in Bonn and was an elected scholar at Caius College, University of Cambridge.

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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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