TAG: "brain"

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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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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Building mini-brains to study disorders caused by HIV, meth use


UC San Diego scientist wins $2.5M award to create stem cell-derived models.

By Scott LaFee, UC San Diego

A UC San Diego School of Medicine project involving the creation of miniature models of the human brain – developed with stem cells – to study neurological disorders caused by HIV and methamphetamine use has been named one of five recipients of the 2015 Avant-Garde Award for HIV/AIDS Research from the National Institute on Drug Abuse (NIDA).

The project, headed by Tariq M. Rana, Ph.D., professor of pediatrics, will receive $500,000 per year for five years.

“The human cerebral cortex has evolved strikingly compared to those of other species, and no animal model accurately captures human-specific brain functions,” said Rana. “The creation of mini-brains, or organoids, will permit, for the first time, study of the toxic effects of addiction and HIV on the human brain in a dish. This offers us the exciting opportunity to design patient-specific model systems, which could potentially revolutionize drug discovery and precision medicine for central nervous system disorders.”

The Avant-Garde Awards are granted to scientists who propose high-impact research that could open new avenues for prevention and treatment of HIV/AIDS among drug abusers. The term “avant-garde” is used to describe highly innovative approaches that have the potential to be transformative.

“Despite the success of combined antiretroviral therapies, HIV remains a chronic disease with a host of debilitating side effects that are exacerbated in those suffering from substance use disorders,” said NIDA Director Nora D. Volkow, M.D.  “These scientists have proposed creative approaches that could transform the way we think about HIV/AIDS research, and could lead to the development of exciting new tools and strategies to prevent infections and improve the lives of substance abusers infected with HIV.”

The other 2015 recipients are:

  • Don C. Des Jarlais, Ph.D., Mount Sinai Beth Israel
  • Eli Gilboa, Ph.D., University of Miami School of Medicine
  • Nichole Klatt, Ph.D., University of Washington, Seattle
  • Alan D. Levine, Ph.D., Case Western Reserve University

For more information about the Avant-Garde Award Program and 2015 recipients, visit drugabuse.gov/about-nida.

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Meditation might slow age-related loss of gray matter in brain


UCLA study finds that meditation appears to help preserve the brain’s gray matter.

Areas of the brain affected by aging (in red) are fewer and less widespread in people who meditate, bottom row, than in people who don’t meditate. (Image courtesy of Eileen Luders, UCLA)

By Mark Wheeler, UCLA

Since 1970, life expectancy around the world has risen dramatically, with people living more than 10 years longer. That’s the good news.

The bad news is that starting when people are in their mid-to-late-20s, the brain begins to wither — its volume and weight begin to decrease. As this occurs, the brain can begin to lose some of its functional abilities.

So although people might be living longer, the years they gain often come with increased risks for mental illness and neurodegenerative disease. Fortunately, a new study shows meditation could be one way to minimize those risks.

Building on their earlier work that suggested people who meditate have less age-related atrophy in the brain’s white matter, a new study by UCLA researchers found that meditation appeared to help preserve the brain’s gray matter, the tissue that contains neurons.

The scientists looked specifically at the association between age and gray matter. They compared 50 people who had mediated for years and 50 who didn’t. People in both groups showed a loss of gray matter as they aged. But the researchers found among those who meditated, the volume of gray matter did not decline as much as it did among those who didn’t.

The article appears in the current online edition of the journal Frontiers in Psychology.

Dr. Florian Kurth, a co-author of the study and postdoctoral fellow at the UCLA Brain Mapping Center, said the researchers were surprised by the magnitude of the difference.

“We expected rather small and distinct effects located in some of the regions that had previously been associated with meditating,” he said. “Instead, what we actually observed was a widespread effect of meditation that encompassed regions throughout the entire brain.”

As baby boomers have aged and the elderly population has grown, the incidence of cognitive decline and dementia has increased substantially as the brain ages.

“In that light, it seems essential that longer life expectancies do not come at the cost of a reduced quality of life,” said Dr. Eileen Luders, first author and assistant professor of neurology at the David Geffen School of Medicine at UCLA. “While much research has focused on identifying factors that increase the risk of mental illness and neurodegenerative decline, relatively less attention has been turned to approaches aimed at enhancing cerebral health.”

Each group in the study was made up of 28 men and 22 women ranging in age from 24 to 77. Those who meditated had been doing so for four to 46 years, with an average of 20 years.

The participants’ brains were scanned using high-resolution magnetic resonance imaging. Although the researchers found a negative correlation between gray matter and age in both groups of people — suggesting a loss of brain tissue with increasing age — they also found that large parts of the gray matter in the brains of those who meditated seemed to be better preserved, Kurth said.

The researchers cautioned that they cannot draw a direct, causal connection between meditation and preserving gray matter in the brain. Too many other factors may come into play, including lifestyle choices, personality traits, and genetic brain differences.

“Still, our results are promising,” Luders said. “Hopefully they will stimulate other studies exploring the potential of meditation to better preserve our aging brains and minds. Accumulating scientific evidence that meditation has brain-altering capabilities might ultimately allow for an effective translation from research to practice, not only in the framework of healthy aging but also pathological aging.”

The research was supported by the Brain Mapping Medical Research Organization, the Robson Family and Northstar Fund, the Brain Mapping Support Foundation, the Pierson‐Lovelace Foundation, the Ahmanson Foundation, the Tamkin Foundation, the William M. and Linda R. Dietel Philanthropic Fund at the Northern Piedmont Community Foundation, the Jennifer Jones‐Simon Foundation, the Capital Group Companies Foundation and an Australian Research Council fellowship (120100227). Nicolas Cherbuin of the Australian National University was also an author of the study.

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Researchers to report progress on video game for vets with hearing loss


Pizza party for potential donors Feb. 9 as crowdfunding effort to support research continues.

Alison Smith, a disabled veteran and UCR graduate student, is part of a research team that is developing a brain-training game to help veterans suffering combat-related hearing loss.

By Bettye Miller, UC Riverside

A video game Wisp that guides players through a dark cave may lead combat veterans suffering blast wave damage to better hearing. The innovative brain-training game under development at UC Riverside will begin testing on university students this month, and may be ready for testing on veterans this summer.

UCR researchers will update potential donors on their progress at a pizza party on Monday, Feb. 9, from 6 to 8 p.m. at The Getaway, 3615 Canyon Crest Drive, Riverside. Free pizza and soda will be available to the first 100 people who register for the event. RSVP here. The event is sponsored by Experiment.com, a crowdfunding website the researchers are using to raise money to fund the project.

The team is seeking public support to raise the estimated $100,000 needed to fund the research and development of a computer game they believe will improve the brain’s ability to process and distinguish sounds. Funding generated so far through Experiment.com and the UCR Brain Game Center has supported the development of sounds the research team believes will revive auditory processing systems damaged by blast waves.

Tax-deductible donations may be given to the UCR Brain Game Center through UCR Online Giving; use the “special instructions” field to designate the gift for the “Can brain training help soldiers with brain injury regain hearing?” project.

Many combat veterans suffer hearing loss from blast waves that makes it difficult to understand speech in noisy environments – a condition called auditory dysfunction – which may lead to isolation and depression. There is no known treatment.

Building on promising brain-training research at UC Riverside related to improving vision, researchers at UCR and the National Center for Rehabilitative Auditory Research are developing a novel approach to treat auditory dysfunction by training the auditory cortex to better process complex sounds.

“This is exploratory research, which is extremely hard to fund,” said Aaron Seitz, UCR professor of neuropsychology. “Most grants fund basic science research. We are creating a brain-training game based on our best understanding of auditory dysfunction. There’s enough research out there to tell us that this is a solvable problem. These disabled veterans are a patient population that has no other resource.”

Seitz said the research team is committed to the project regardless of funding, but donations will accelerate development of the brain-training game by UCR graduate and undergraduate students in computer science and neuroscience; pilot studies on UCR students with normal hearing; testing the game with veterans; and refining the game to the point that it can be released for public use.

Auditory dysfunction is progressive, said Alison Smith, a graduate student in neuroscience studying hearing loss in combat vets who is a disabled veteran. Nearly 8 percent of combat veterans who served in Afghanistan and Iraq suffer from traumatic brain injury, she said. Of those, a significant number complain about difficulty understanding speech in noisy environments, even though they show no external hearing loss.

“Approximately 10 percent of the civilian population is at risk for noise-induced hearing loss, and there have been more than 20,000 significant cases of hearing loss per year since 2004,” added Smith, who served in the Army National Guard as a combat medic for five years.

This research also may help many other hearing-impaired populations, including musicians, mechanics and machinists; reduce the effects of age-related hearing loss; and aid individuals with hearing aids and cochlear implants.

This month the team will begin testing on UCR students to determine if the sounds developed for the brain-training game are relevant to speech perception, said Dominique Simmons, a cognitive psychology graduate student studying audiovisual speech perception. Testing will continue through late March.

If these sounds test well, they will be incorporated into a video game in which players move through a cave guided by a Wisp whose route is determined by the volume and direction of these sounds.

In addition to Seitz, Smith and Simmons, team members include Frederick J. Gallun, a researcher at the National Center for Rehabilitative Auditory Research and associate professor in otolaryngology and the Neuroscience Graduate Program at Oregon Health and Science University; and Victor Zordan, UCR associate professor of computer science who specializes in video game design and intelligent systems.

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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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Brain region vulnerable to aging is larger in those with longevity gene variant


1 in 5 carry KLOTHO allele associated with better cognition.

The dorsolateral prefrontal cortex, depicted in blue and red, is larger and linked with better function in those who carry one copy of the KLOTHO gene variant. (Illustration by Michael Griffin Kelly)

By Laura Kurtzman, UC San Francisco

People who carry a variant of a gene that is associated with longevity also have larger volumes in a front part of the brain involved in planning and decision-making, according to researchers at UC San Francisco.

The finding bolsters their previous discovery that middle-aged and older people who carry a single copy of the KLOTHO allele, called KL-VS, performed better on a wide range of cognitive tests. When they modeled KL-VS in mice, they found this strengthened the connections between neurons and enhanced learning and memory.

KLOTHO codes for a protein, called klotho, which is produced in the kidney and brain and regulates many different processes in the body. About 1 in 5 people carry a single copy of KL-VS, which increases klotho levels and is associated with a longer lifespan and better heart and kidney function. A small minority, about 3 percent, carries two copies, which is associated with a shorter lifespan.

Examining part of prefrontal cortex

In the current study, published today (Jan. 27), in Annals of Clinical and Translational Neurology, researchers scanned the brains of 422 cognitively normal men and women aged 53 and older to see if the size of any brain area correlated with carrying one, two or no copies of the allele.

They found that the KLOTHO gene variant predicted the size of a region called the right dorsolateral prefrontal cortex (rDLPFC), which is especially vulnerable to atrophy as people age. Deterioration in this area may be one reason why older people have difficulty suppressing distracting information and doing more than one thing at a time.

Researchers found that the rDLPFC shrank with age in all three groups, but those with one copy of KL-VS – about a quarter of the study group – had larger volumes than either non-carriers or those with two copies. Researchers also found that the size of the rDLPFC predicted how well the three groups performed on cognitive tests, such as working memory – the ability to keep a small amount of newly acquired information in mind – and processing speed. Both tests are considered to be good measures of the planning and decision-making functions that the rDLPFC controls.

“We’ve known for a long time that people lose cognitive abilities as they age, but now we’re beginning to understand that factors like klotho can give people a boost and confer resilience in aging,” said senior author Dena Dubal, M.D., Ph.D., assistant professor of neurology at UCSF and the David A. Coulter Endowed Chair in Aging and Neurodegenerative Disease. “Genetic variation in KLOTHO could help us predict brain health and find ways to protect people from the devastating diseases that happen to us as we grow old, like Alzheimer’s and other dementias.”

Bigger size means better function

In statistical tests, the researchers concluded that the larger rDLPFC volumes seen in single copy KL-VS carriers accounted for just 12 percent of the overall effect that the variant had on the abilities tested.

However, the allele may have other effects on the brain, such as increasing levels or changing the actions of the klotho protein to enhance synaptic plasticity, or the connections between neurons. In a previous experiment, they found that raising klotho in mice increased the action of a cell receptor critical to forming memories.

“The brain region enhanced by genetic variation in KLOTHO is vulnerable in aging and several psychiatric and neurologic diseases including schizophrenia, depression, substance abuse and frontotemporal dementia,” said Jennifer Yokoyama, Ph.D., first author and assistant professor of neurology at UCSF. “In this case, bigger size means better function. It will be important to determine whether the structural boost associated with carrying one copy of KL-VS can offset the cognitive deficits caused by disease.”

Other authors of the study include Virginia Sturm, Luke Bonham, Joel Kramer and Bruce Miller of UCSF; Eric Klein and Giovanni Coppola of UCLA; Lei Yu and David Bennett of Rush University Medical Center; and Konstantinos Arfanakis of Rush and the Illinois Institute of Technology.

The study was funded by the Larry L. Hillblom Foundation, the National Institute on Aging, the American Federation for Aging Research, the Coulter-Weeks Foundation and the Bakar Foundation.

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Caring for the child’s brain


Pediatric Brain Center provides holistic care for patients’ full range of brain-related needs.

Audrey Price

By Kathleen Masterson, UC San Francisco

Fifteen-year-old Audrey Price slowly reaches for an orange plastic cup sitting on the counter. In a concerted effort, her fingers close around it, and she lifts it to chest height, shaking ever so slightly.

For Audrey, this simple act marks a tremendous journey from diagnosis to brain surgery to therapy and slow healing.

Just 11 months ago, she was living a typical middle-schooler’s life in a Bay Area suburb, hanging out with friends, playing tennis and obsessing over the British boy band, One Direction.

Then Audrey began developing weakness in her right side. After a series of doctor’s appointments, she ended up visiting a neurologist, who ordered scans of her brain that showed an aneurysm the size of a golf ball pressing on her brain stem.

That’s when her neurologist called UC San Francisco.

Audrey was brought into the newly formed Pediatric Brain Center at the UCSF Benioff Children’s Hospital San Francisco, which integrates neurology, neurosurgery, physical and occupational therapy, speech, social work and neuro-psychology to provide seamless holistic care for patients’ full range of brain-related needs. It’s one of just a few specialized pediatric brain centers in the U.S.

The center’s unique structure and specializations ended up being an ideal match for Audrey’s rare and complex condition.

Heather Fullerton and Nalin Gupta lead UC San Francisco's Pediatric Brain Center, which opens a new, centralized location at the new UCSF Benioff Children's Hospital at Mission Bay on Feb. 1. (Photo by Cindy Chew)

Bringing the doctors to the patient

The Pediatric Brain Center was founded about two years ago, spearheaded by Heather Fullerton, M.D., and Nalin Gupta, M.D. The center brings together a diverse range of UCSF experts from across multiple departments to treat patients together, as a team.

Rather than the typical experience in which a patient may see one doctor and then be referred to another specialist, and then another, chasing multiple appointments over weeks, at the Pediatric Brain Center the physicians, nurses and other key staff coordinate the care around the patient. One coordinator books all the patient’s appointments, from check-ups to arranging tests to surgery, and each patient is treated by a team assembled specifically to meet his or her unique medical needs.

“The goal was to make not only the patient experience, but also the problem solving and treatment, more rational. We wanted to be able to design our care around the patient’s medical issue, as opposed to simply following the organizational structure of the institution,” said Gupta.

Initially the center existed mainly as an organization change, with all the experts still located in separate offices at Parnassus. With the Feb. 1 opening of the UCSF Medical Center at Mission Bay, the Pediatric Brain Center will soon have it’s own central location to further streamline the patient experience.

“It’s so much easier for the family to have one place to go for all their child’s care, all the way from the initial treatment to rehabilitation,” said Fullerton.

Unique expertise in research and care

Having a centralized space will help make the patient experience smoother, but the crux of the Pediatric Brain Center is its network of highly specialized researchers, clinicians and surgeons.

“Having clinicians and researchers together helps inform what we study,” said Fullerton, a practicing neurologist who also researches pediatric strokes. “So many of our clinicians are also researchers, so when a question comes up in clinic, we can use our own local expertise to start the search for an answer. For example if I keep seeing this strange-looking blood vessel, I can turn around and start a study to investigate what’s happening.”

That’s a distinct advantage of an academic medical center. Private practices couldn’t afford the freedom to develop deep expertise in narrow areas, said Gupta. Furthermore, a child’s brain isn’t like the adult brain; treating a growing brain requires specialized neurology expertise.

“With the Pediatric Brain Center, we’re explicitly trying to leverage the strengths of the institution,” said Gupta. “We have people that have lot of expertise in narrow areas, and by definition those are often rare things.”

Building a specialized team

The Pediatric Brain Center brings all these diverse experts together, forming a unique treatment team made up of specialists relevant to each patient’s needs.

That’s vital for patients like Audrey, said Gupta.

“What Audrey had was very rare and complex. She’s an example of type of patient that there isn’t a list of 500 patients like that,” he said. “It’s not like other conditions where we could simply look to see what did we do for last 500.”

So Audrey’s doctors assembled a team of neurologists and neurosurgeons to develop a plan to remove the brain aneurysm.

“Audrey’s surgical team in consultation was so calm, they really explained things really well in terms we understood,” said her mother, Barbara Price. “We left there feeling very relieved this was treatable, that we were not in emergency situation and we had one of best surgical teams in the world that would treat her.”

Audrey’s surgery went well, and the team was able to remove the brain aneurism safely.

However, when she came out of surgery, she could hardly move the right side of her body. Her doctors quickly called in another team member, Jonathan Bixby, M.D., who specializes in physical rehabilitation.

“Unlike some other aspects of medicine, rehabilitation is dependent on how much effort the patient puts in,” said Bixby.

“Audrey was great. With any patient dealing with significant changes to the body, there can be issues adjusting. Audrey adjusted quickly, and was very willing to work with a therapist.”

Ongoing team care

Audrey is continuing to get stronger every day. She does her physical therapy daily at home, has learned to do nearly everything with her left hand and was able to start high school last fall.

She got there after spending six weeks living at the hospital after her surgery; she practiced physical therapy six hours a day, six days a week. It’s exhausting work, but her therapists strived to incorporate Audrey’s interests into her exercises to make it more fun, including using therapy dogs and playing One Direction’s music during sessions.

“The hardest part is not knowing when my body is going to be back to the way it was,” she said. “The doctors said, ‘all brains are different,’ and that was the most frustrating part.”

Throughout her hospital stay, her bed was covered in a fleece blanket with the One Direction’s faces on it, including her favorite singer, Niall.

Barbara Price recalled that one day Audrey came back to her room to find a note atop her One Direction blanket that read something like: “‘Dear Audrey, I’m really proud of all the hard work you’re doing’ then the note quoted lyrics from one of the songs. It was signed,  ‘Love, Niall,” she said with a laugh. One of the doctors had scripted this joking note of encouragement.

“The team was so funny and thoughtful, so we had a lot of laughs that got us through some tough times.”

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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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Related link:
UC Davis Medicine magazine

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Risk of brain disorder rare in healthy newborns with jaundice


UCSF-Kaiser study shows high bilirubin alone rarely causes type of cerebral palsy.

By Suzanne Leigh, UC San Francisco

A study tracking more than 100,000 infants has shown that newborns with jaundice that are otherwise healthy are highly unlikely to develop a severe and potentially deadly form of cerebral palsy.

Researchers at UCSF Benioff Children’s Hospital San Francisco and the Kaiser Permanente Northern California Division of Research sought to examine the correlation between elevated levels of the liver-produced pigment bilirubin, which causes the yellowing of the skin and eyes associated with jaundice, and cerebral palsy — a range of disorders that impairs control of movement. The team was especially interested in kernicterus, a rare and life-threatening type of cerebral palsy triggered by escalating bilirubin that injures the brain.

Jaundice occurs in most newborns because the immature liver is unable to break down the pigment fast enough. Treatment is not usually required, but in some cases babies undergo phototherapy, in which they are exposed to special lights that change bilirubin into a compound that can be excreted.

In cases when very high bilirubin fails to drop, an infant may have an exchange transfusion, which is the replacement of blood with donor blood.

The study, which evaluated the health records of two groups of babies selected from 525,409 births, was led by Yvonne W. Wu, M.D., M.P.H., professor of clinical neurology and pediatrics at UCSF Benioff Children’s Hospital San Francisco. The babies had been born at 15 hospitals within the Kaiser Permanente Northern California region from 1995 through 2011. One group comprised 1,833 newborns with levels of bilirubin above those at which the American Academy of Pediatrics (AAP) recommends exchange transfusions. The second group was made up of 104,716 randomly sampled newborns, born at least 35 weeks’ gestation with lower levels of the pigment. The two groups were followed for an average of seven and six years respectively.

The researchers, whose work was published on Jan. 5 in the journal JAMA Pediatrics, confirmed three cases of kernicterus based on the brain MRIs of children with cerebral palsy. All three cases had occurred in newborns with the highest levels of bilirubin. But further study revealed that each child had two or more risk factors for brain damage.

“We found that cerebral palsy consistent with kernicterus did not occur in a single infant with high bilirubin without the presence of additional risk factors for neurotoxicity, such as prematurity, sepsis and the hereditary blood disorder G6PD deficiency. This was the case even in infants with very high bilirubin,” said second author Michael W. Kuzniewicz, M.D., M.P.H., assistant professor of neonatology in the department of pediatrics at UCSF Benioff Children’s Hospital San Francisco, and head of the perinatal research unit of the division of research at Kaiser Permanente Northern California.

In 2004, the AAP published a guideline for treating infants whose bilirubin remained high despite phototherapy. It recommended exchange transfusions based on the level of bilirubin, the age of the infant and other risk factors for brain damage.

“Our study was the first to evaluate how well the exchange transfusion guidelines predicted risk of cerebral palsy and kernicterus in babies with jaundice,” said principal investigator Thomas B. Newman, M.D., M.P.H., of the departments of epidemiology and pediatrics at UCSF Benioff Children’s Hospital San Francisco. “It was reassuring that brain injury due to high bilirubin was rare and that only those infants whose levels were well above exchange transfusion guidelines developed kernicterus.”

An exchange transfusion is an invasive procedure that entails risks to the baby, such as blood clot formation, blood pressure instability, bleeding and changes in blood chemistry, said Wu. “Based on our study, the current guidelines for when to perform exchange transfusions have been quite successful in preventing kernicterus. However, our study also raises the question whether the threshold for exchange transfusion could be higher for infants with high bilirubin levels who are otherwise healthy and who have no other risk factors for brain injury,” she said.

Co-authors of the study are Andrea C. Wickremasinghe, M.D., and Charles E. McCulloch, Ph.D., of the Department of Epidemiology and Biostatistics at UCSF; and Eileen M. Walsh, R.N., M.P.H., and Soora Wi, M.P.H., of the Kaiser Permanente Northern California Division of Research.

Funding was provided by a grant from the Agency for Healthcare Research and Quality.

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8 top trends in health and science in 2015


From hacking the brain to diagnosing diseases through DNA.

With advances in technology and better understanding of people, the health sciences are constantly pushing toward more effective treatments and cures. The question is, where will we see the next breakthroughs?

Experts across UC San Francisco were asked to identify what’s ahead in key areas from basic science to digital health, from aging research to cancer treatments, from approaches in the lab to access at the hospital.

Here are some of the hottest areas in health and science to look out for in 2015:

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Related link:
2014: The year in review at UCSF

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First real-time MRI-guided brain surgery for Parkinson’s in SoCal


Deep brain stimulator also can be used to treat other movement disorders.

By Jackie Carr, UC San Diego

Neurosurgeons at UC San Diego Health System are the first in Southern California to implant a deep brain stimulator (DBS) in a patient with Parkinson’s disease using real-time 3-D magnetic resonance image (MRI) guidance.

Parkinson’s disease is a progressive disorder of the nervous system that affects movement. Symptoms include shaking, slowness of movement and difficulty walking. These unpredictable movements are caused by abnormal nerve cell activity in the brain. DBS therapy, like a heart pacemaker, transmits electrical signals to help restore normal activity.

Traditionally, DBS surgery is conducted while the patient is awake, and under pain management. This approach allows surgeons to continuously monitor the patient’s brain function and to ensure accurate placement of the device.

“Now, for some patients, this surgery can be performed in the MRI suite under general anesthesia so that a patient can sleep during the placement of the DBS electrodes,” David Barba, M.D., director of functional neurosurgery, UC San Diego Health System. “Within a few days of DBS therapy, many patients can resume life’s everyday activities.”

“Placing a DBS device while a patient is awake can be exhausting for the patient due to the length of the procedure and the need to perform neurologic testing in the operating room,” added Clark Chen, M.D., Ph.D., director of stereotactic and radiosurgery, UC San Diego Health System. “Fortunately, with continuous real-time MRI monitoring, we can now place the electrode in a safe location that provides maximal neurological benefit while the patient is under the comfort of general anesthesia.”

Bob S. Carter, M.D., Ph.D., professor and chief of neurosurgery and co-director of the UC San Diego Neurological Institute, said the collaborative endeavor introduces a new technology strategy to improve the care of patients with Parkinson’s and other diseases.

“Our capacity to perform these procedures will be further enhanced in the new A. Vassiliadis Family Hospital for Advanced Surgery at Jacobs Medical Center, which opens in 2016,” said Carter.

DBS also can be used to treat other movement disorders, including dystonia, essential tremor and obsessive compulsive disorder. It is in clinical trial testing as treatment for depression.

UC San Diego Health System is an internationally recognized leader in functional neurosurgery. Barba is a pioneer in the neurosurgical treatment of patients affected with movement disorders. Chen is an expert in MRI guided neurosurgery.

To learn more about MRI-guided DBS placement, please visit: health.ucsd.edu.

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