TAG: "Neuroscience"

Mapping the infant brain


Findings may be key in identifying, treating earliest signs of neurodevelopmental disorders.

A recent study conducted by researchers at the UC San Diego School of Medicine and the University of Hawaii demonstrates a new approach to measuring early brain development of infants, resulting in more accurate whole brain growth charts and providing the first estimates for growth trajectories of subcortical areas during the first three months after birth. Assessing the size, asymmetry and rate of growth of different brain regions could be key in detecting and treating the earliest signs of neurodevelopmental disorders, such as autism or perinatal brain injury.

The study will be published in JAMA Neurology today (Aug. 11).

For the first time, researchers used magnetic resonance imaging (MRI) of the newborn brain to calculate the volume of multiple brain regions and to map out regional growth trajectories during the infant’s first 90 days of life. The study followed the brain growth of full term and premature babies with no neurological or major health issues.

“A better understanding of when and how neurodevelopmental disorders arise in the postnatal period may help assist in therapeutic development, while being able to quantify related changes in structure size would likely facilitate monitoring response to therapeutic intervention. Early intervention during a period of high neuroplasticity could mitigate the severity of the disorders in later years,” said Dominic Holland, Ph.D., first author of the study and researcher in the Department of Neurosciences at UC San Diego School of Medicine.

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Target ID’d for rare inherited neurological disease in men


Finding provides insight for Kennedy’s disease, other neurodegenerative diseases.

Researchers at the UC San Diego School of Medicine have identified the mechanism by which a rare, inherited neurodegenerative disease causes often crippling muscle weakness in men, in addition to reduced fertility.

The study, published today (Aug. 10) in the journal Nature Neuroscience, shows that a gene mutation long recognized as a key to the development of Kennedy’s disease impairs the body’s ability to degrade, remove and recycle clumps of “trash” proteins that may otherwise build up on neurons, progressively impairing their ability to control muscle contraction. This mechanism, called autophagy, is akin to a garbage disposal system and is the only way for the body to purge itself of non-working, misshapen trash proteins.

“We’ve known since the mid-1990s that Alzheimer’s disease, Parkinson’s disease and Huntington’s disease are caused by the accumulation of misfolded proteins that should have been degraded, but cannot be turned over,” said senior author Albert La Spada, M.D., Ph.D. and professor of pediatrics, cellular and molecular medicine, and neurosciences. “The value of this study is that it identifies a target for halting the progression of protein build-up, not just in this rare disease, but in many other diseases that are associated with impaired autophagy pathway function.”

Of the 400 to 500 men in the U.S. with Kennedy’s disease, the slow but progressive loss of motor function results in about 15 to 20 percent of those with the disease becoming wheelchair bound during later stages of the disease.

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Gaining insights into the nervous system


Rita Allen Foundation Scholarship supports brain imaging studies.

Neuron picture: synaptic terminal of cortical layer2/3 neurons labeled with targeted genetically encoded sensors of neural activity.

Lin Tian’s fascination with neuroscience stems from a deep curiosity about the complexity and elegance of the human brain. As one of only five scientists in the U.S. and Canada — and the first at UC Davis — to be named a 2014 Rita Allen Foundation Scholar, Tian will be developing optical sensors and applications to acquire fundamental insights about how the nervous system functions in health and disease.

“The functioning brain receives thousands of chemical and electrical signals at the synapse, the area of connection between neurons,” Tian said. “Understanding how neurons integrate these multiple inputs to transmit information and to shape and refine the neural circuitry itself is an important area of research that can shed light on an array of neurological disorders, including depression, addiction, autism, schizophrenia and epilepsy.”

With a five-year, $500,000 grant from the Rita Allen Foundation, Tian will develop imaging tools to obtain a comprehensive view of both excitatory and inhibitory synapses in action at the cellular, tissue and whole-animal levels. She also will apply these tools to uncover the functional organization of cortical layer1 (L1) interneurons in shaping long-range interactions and their link to behavior, which can’t be done with current technology, Tian said.

“Understanding how information is transferred across neural circuitry and systems is the key to innovation in the treatment of neurological disorders,” she said.

Tian is an assistant professor of biochemistry and molecular medicine at UC Davis. She holds a bachelor’s degree in neuroscience from the University of Science and Technology of China and a doctorate in biochemistry, molecular and cell biology from Northwestern University. She completed her postdoctoral training at Howard Hughes Medical Institute Janelia Farm.

Since 1976, more than one hundred young leaders in biomedical science have been selected as Rita Allen Foundation Scholars. The program embraces innovative research with above-average risk and promise. Scholars have gone on to win the Nobel Prize in Physiology or Medicine, the National Medal of Science, the Wolf Prize in Medicine, and the Breakthrough Prize in Life Sciences.

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Kids with autism, SPD show brain wiring differences


UCSF study builds on its research showing kids with SPD have measurable brain differences.

Pratik Mukherjee, UC San Francisco

Researchers at UC San Francisco have found that children with sensory processing disorders have decreased structural brain connections in specific sensory regions different than those in autism, further establishing SPD as a clinically important neurodevelopmental disorder.

The research, published in the journal PLOS ONE, is the first study to compare structural connectivity in the brains of children with an autism diagnosis versus those with an SPD diagnosis, and with a group of typically developing boys. This new research follows UCSF’s groundbreaking study published in 2013 that was the first to find that boys affected with SPD have quantifiable regional differences in brain structure when compared to typically developing boys. This work showed a biological basis for the disease but prompted the question of how these differences compared with other neurodevelopmental disorders.

“With more than 1 percent of children in the U.S. diagnosed with an autism spectrum disorder, and reports of 5 to 16 percent of children having sensory processing difficulties, it’s essential we define the neural underpinnings of these conditions, and identify the areas they overlap and where they are very distinct,” said senior author Pratik Mukherjee, M.D., Ph.D., a professor of radiology and biomedical imaging and bioengineering at UCSF.

SPD can be hard to pinpoint, as more than 90 percent of children with autism also are reported to have atypical sensory behaviors, and SPD has not been listed in the Diagnostic and Statistical Manual used by psychiatrists and psychologists.

Elysa Marco, UC San Francisco

“One of the most striking new findings is that the children with SPD show even greater brain disconnection than the kids with a full autism diagnosis in some sensory-based tracts,” said Elysa Marco, M.D., cognitive and behavioral child neurologist at UCSF Benioff Children’s Hospital San Francisco and the study’s corresponding author. “However, the children with autism, but not those with SPD, showed impairment in brain connections essential to the processing of facial emotion and memory.”

Children with SPD struggle with how to process stimulation, which can cause a wide range of symptoms including hypersensitivity to sound, sight and touch, poor fine motor skills and easy distractibility. Some SPD children cannot tolerate the sound of a vacuum, while others can’t hold a pencil or struggle with emotional regulation. Furthermore, a sound that is an irritant one day can be tolerated the next. The disease can be baffling for parents and has been a source of much controversy for clinicians who debate whether it constitutes its own disorder, according to the researchers.

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Aging brain influenced by experiences throughout life


Study from UC Davis and University of Victoria examines demographics and cognitive aging.

Early life experiences, such as childhood socioeconomic status and literacy, may have greater influence on the risk of cognitive impairment late in life than such demographic characteristics as race and ethnicity, a large study by researchers with the UC Davis Alzheimer’s Disease Center and the University of Victoria, Canada, has found.

“Declining cognitive function in older adults is a major personal and public health concern,” said Bruce Reed, professor of neurology and associate director of the UC Davis Alzheimer’s Disease Center.

“But not all people lose cognitive function, and understanding the remarkable variability in cognitive trajectories as people age is of critical importance for prevention, treatment and planning to promote successful cognitive aging and minimize problems associated with cognitive decline.”

The study, “Life Experiences and Demographic Influences on Cognitive Function in Older Adults,” is published online in Neuropsychology, a journal of the American Psychological Association. It is one of the first comprehensive examinations of the multiple influences of varied demographic factors early in life and their relationship to cognitive aging.

The research was conducted in a group of over 300 diverse men and women who spoke either English or Spanish. They were recruited from senior citizen social, recreational and residential centers, as well as churches and health-care settings. At the time of recruitment, all study participants were 60 or older, and had no major psychiatric illnesses or life threatening medical illnesses. Participants were Caucasian, African-American or Hispanic.

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Study links autistic behaviors to enzyme


Deleting the enzyme favorably impacts behaviors associated with fragile X syndrome.

Iryna Ethell, UC Riverside (Photo by L. Duka)

Fragile X syndrome (FXS) is a genetic disorder that causes obsessive-compulsive and repetitive behaviors, and other behaviors on the autistic spectrum, as well as cognitive deficits. It is the most common inherited cause of mental impairment and the most common cause of autism.

Now biomedical scientists at UC Riverside have published a study that sheds light on the cause of autistic behaviors in FXS. Appearing online today (July 23) in the Journal of Neuroscience, and highlighted also on the cover in this week’s print issue of the journal, the study describes how MMP-9, an enzyme, plays a critical role in the development of autistic behaviors and synapse irregularities, with potential implications for other autistic spectrum disorders.

MMP-9 is produced by brain cells. Inactive, it is secreted into the spaces between cells of the brain, where it awaits activation. Normal brains have quite a bit of inactive MMP-9, and the activation of small amounts has significant effects on the connections between neurons, called synapses. Too much MMP-9 activity causes synapses in the brain to become unstable, leading to functional deficits.

“Our study targets MMP-9 as a potential therapeutic target in fragile X and shows that genetic deletion of MMP-9 favorably impacts key aspects of FXS-associated anatomical alterations and behaviors in a mouse model of fragile X,” said Iryna Ethell, a professor of biomedical sciences in the UC Riverside School of Medicine, who co-led the study. “We found that too much MMP-9 activity causes synapses to become unstable, which leads to functional deficits that depend on where in the brain that occurs.”

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$1M grant funds study into neurochemistry behind addiction


Research could lead to improved therapies for those inclined toward addictive behaviors.

We’ve all heard the term “addictive personality,” and many of us know individuals who are consistently more likely to take the extra drink or pill that puts them over the edge. But the specific balance of neurochemicals in the brain that spurs him or her to overdo it is still something of a mystery.

“There’s not really a lot we know about specific molecules that are linked to vulnerability to addiction,” said Tod Kippin, a neuroscientist at UC Santa Barbara who studies cocaine addiction. In a general sense, it is understood that animals — humans included — take substances to derive that pleasurable rush of dopamine, the neurochemical linked with the reward center of the brain. But, according to Kippin, that dopamine rush underlies virtually any type of reward animals seek, including the kinds of urges we need to have in order to survive or propagate, such as food, sex or water. Therefore, therapies that deal with that reward system have not been particularly successful in treating addiction.

However, thanks to a collaboration between UCSB researchers Kippin; Tom Soh, professor of mechanical engineering and of materials; and Kevin Plaxco, professor of chemistry and biochemistry — and funding from a $1 million grant from the W. M. Keck Foundation — the neurochemistry of addiction could become a lot less mysterious and a lot more specific. Their study, “Continuous, Real-Time Measurement of Psychoactive Molecules in the Brain,” could, in time, lead to more effective therapies for those who are particularly inclined toward addictive behaviors.

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Researchers find epigenetic tie to neuropsychiatric disorders


Flawed dopamine signaling linked to mass alteration of gene activity in prefrontal cortex.

“Our work presents new leads to understanding neuropsychiatric disorders,” UC Irvine's Emiliana Borrelli said.

Dysfunction in dopamine signaling profoundly changes the activity level of about 2,000 genes in the brain’s prefrontal cortex and may be an underlying cause of certain complex neuropsychiatric disorders, such as schizophrenia, according to UC Irvine scientists.

This epigenetic alteration of gene activity in brain cells that receive this neurotransmitter showed for the first time that dopamine deficiencies can affect a variety of behavioral and physiological functions regulated in the prefrontal cortex.

The study, led by Emiliana Borrelli, a UCI professor of microbiology & molecular genetics, appears online in the journal Molecular Psychiatry.

“Our work presents new leads to understanding neuropsychiatric disorders,” Borrelli said. “Genes previously linked to schizophrenia seem to be dependent on the controlled release of dopamine at specific locations in the brain. Interestingly, this study shows that altered dopamine levels can modify gene activity through epigenetic mechanisms despite the absence of genetic mutations of the DNA.”

Dopamine is a neurotransmitter that acts within certain brain circuitries to help manage functions ranging from movement to emotion. Changes in the dopaminergic system are correlated with cognitive, motor, hormonal and emotional impairment. Excesses in dopamine signaling, for example, have been identified as a trigger for neuropsychiatric disorder symptoms.

Borrelli and her team wanted to understand what would happen if dopamine signaling was hindered. To do this, they used mice that lacked dopamine receptors in midbrain neurons, which radically affected regulated dopamine synthesis and release.

The researchers discovered that this receptor mutation profoundly altered gene expression in neurons receiving dopamine at distal sites in the brain, specifically in the prefrontal cortex. Borrelli said they observed a remarkable decrease in expression levels of some 2,000 genes in this area, coupled with a widespread increase in modifications of basic DNA proteins called histones – particularly those associated with reduced gene activity.

Borrelli further noted that the dopamine receptor-induced reprogramming led to psychotic-like behaviors in the mutant mice and that prolonged treatment with a dopamine activator restored regular signaling, pointing to one possible therapeutic approach.

The researchers are continuing their work to gain more insights into the genes altered by this dysfunctional dopamine signaling.

Borrelli is affiliated with UCI’s Center for Epigenetics & Metabolism and manages the INSERM/UCI U904 laboratory there. Karen Brami-Cherrier, Andrea Anzalone, Maria Ramos and Fabio Macciardi of UCI, as well as Ignasi Forne and Axel Imhof of Ludwig Maximilian University of Munich, contributed to the study, which received support from the National Institutes of Health (grant DA024689) and INSERM (grant 44790).

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New direction suggested for treating mental health disorders


Experts urge new discipline combining benefits of neuroscience, psychology treatments.

Michelle Craske, UCLA

When a patient talks with a psychological therapist, what changes occur in the patient’s brain that relieve mental disorders? UCLA psychology professor Michelle Craske says the honest answer is that we don’t know. But, according to Craske and two colleagues, we need to find out.

Mental health disorders — such as depression, schizophrenia, post-traumatic stress disorder, obsessive–compulsive disorder and eating disorders — affect 1 in 4 people worldwide. Psychological treatments “hold the strongest evidence base for addressing many such conditions,” but they need improvement, according to a study by Craske, Cambridge University professor Emily Holmes and MIT professor Ann Graybiel.

Their article was published online July 16 in the journal Nature.

For some conditions, such as bipolar disorder, psychological treatments are not effective or are in their infancy, the life scientists report, and a “culture gap” between neuroscientists and clinical scientists has hindered the progress of mental health treatments. The authors call on scientists from both disciplines to work together to advance the understanding and treatment of psychological disorders.

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Personalized approach enhances communications skills in children with autism


Computer tablets play key role in the blended therapy, UCLA-led study finds.

Connie Kasari, UCLA

A UCLA-led study has found that the communication skills of minimally verbal children with autism can be greatly improved through personalized interventions that are combined with the use of computer tablets.

The three-year study examined different approaches to improving communication abilities among children with autism spectrum disorder and minimal verbal skills. Approximately 30 percent of children with ASD overall remain minimally verbal even after years of intervention.

UCLA professor Connie Kasari, the paper’s senior author, worked with researchers at Vanderbilt University and the Kennedy Krieger Institute. They found that children’s language skills greatly improved when spoken- and social-communication therapy was tailored based on their individual progress and delivered using computer tablets.

The trial involved 61 children with ASD, ages 5 to 8. For six months, each child received communication therapy focusing on social communication gestures, such as pointing, as well as play skills and spoken language.

Half of the children were randomly selected to also use speech-generating applications on computer tablets for at least half of the time during their sessions. The tablets were programmed with audio clips of words the children were learning about during their therapy sessions and images of the corresponding objects. Working with a therapist, the child could tap a picture of a block, for example, and the tablet would play audio of the word “block.”

The researchers found that children who had access to the tablets during therapy were more likely to use language spontaneously and socially than the children who received the communication intervention alone — and that incorporating the tablets at the beginning of the treatment was more effective than introducing it later in the therapy.

“It was remarkable how well the tablet worked in providing access to communication for these children,” said Kasari, professor of human development and psychology in the UCLA Graduate School of Education and professor of psychiatry at UCLA’s Semel Institute for Neuroscience and Human Behavior. “Children who received the behavioral intervention along with the tablet to support their communication attempts made much faster progress in learning to communicate, and especially in using spoken language.”

Researchers also conducted follow-up visits with the children three months after the initial study period and found that their improvement had been maintained during that time.

The study was the first ASD research to use a sequential multiple assignment randomized trial, or SMART, design. The approach, which enables researchers to tailor interventions according to how each child in the study responds, was designed by Daniel Almirall and Susan Murphy, biostatisticians at the University of Michigan who were members of the research team. It also was the first randomized, controlled trial on this underserved population of children to use a computer tablet combined with an effective behavioral intervention.

Other study authors were Rebecca Landa of Kennedy Krieger and Johns Hopkins University, and Ann Kaiser of Vanderbilt. The study was funded by a High Risk High Impact grant from the Autism Speaks Foundation.

The findings were published in the June issue of the Journal of the American Academy of Child and Adolescent Psychiatry.

Based on this study, Kasari, who also is a member of UCLA’s Center for Autism Research and Treatment, received a $13 million grant from the National Institutes of Health’s Autism Centers of Excellence to fund continued research involving minimally verbal children.

The ACE Network–funded research, which is now under way, compares two types of intensive, daily instruction for children who attend schools in underserved communities and have an autism spectrum disorder and minimal communication abilities. The study also uses a SMART design and computer tablets. Researchers on the five-year network study are enrolling nearly 200 children at UCLA, Weill Cornell Medical Center in New York City, the University of Rochester and Vanderbilt University in Nashville.

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Novel biomarker predicts febrile seizure-related epilepsy


Noninvasive diagnostic technique could greatly enhance use of preventive therapies.

Tallie Baram, UC Irvine

A newly discovered biomarker – visible in brain scans for hours after febrile seizures – predicts which individuals will subsequently develop epilepsy, according to UC Irvine researchers. This diagnostic ability could lead to improved use of preventive therapies for the disorder.

A team led by Dr. Tallie Z. Baram found that rats exhibiting this novel signal in magnetic resonance imaging scans of their brains manifested symptoms of epilepsy months after experiencing very long febrile seizures. Those that did not possess this biomarker remained free of the disorder. The study appears in today’s (June 25) issue of The Journal of Neuroscience.

Up to 40 percent of children who have fever-related seizures lasting more than 30 minutes (known as febrile status epilepticus) will eventually develop epilepsy. However, it has not been possible to predict early on who will get the disorder, which can arise 10 or more years later.

ManKin Choy, a postdoctoral scholar in Baram’s group, induced long febrile seizures in young rats. The rodents had brain scans after two, four and 18 hours, then were allowed to grow and evaluated for the emergence of epilepsy. Choy identified a new type of signal in certain parts of the brain in some post-seizure rats, and these same ones developed epilepsy after several months.

“We were stunned to find that specific regions of the brain in rats ‘destined’ to become epileptic were ‘lighting up’ so early,’’ said Baram, the Danette Shepard Chair in Neurological Studies. “The signal indicating which rats would go on to have spontaneous epileptic seizures months later was in brain regions known to be involved in temporal lobe epilepsy, which is the type of the disease associated with long febrile seizures in children.”

“This remarkable discovery led us to ask two key questions,” she added. “First, can we figure out what is going on in the brain that causes this new signal? And second, can we detect a similar predictive signal in children?”

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Cal-BRAIN kickstarts California efforts to map the brain


UC-led statewide initiative signed into law.

UC San Diego's Ralph Greenspan (center) is helping lead the Cal-BRAIN initiative.

The California budget signed by Gov. Jerry Brown today (June 20) creates a statewide research grants program called Cal-BRAIN, an initiative led by UC San Diego. With an initial allocation of $2 million, Cal-BRAIN – short for California Blueprint for Research to Advance Innovations in Neuroscience – is a state complement to the federal BRAIN Initiative announced by President Barack Obama in April 2013. It aims to “accelerate the development of brain mapping techniques, including the development of new technologies.”

UC San Diego played a significant role in the national initiative and will now lead the state effort to revolutionize our understanding of the brain and the diagnosis and treatment of brain disorders of all kinds. By improving our ability to see what goes on in the brain in much greater detail and at a much faster timescale, we aim to make discoveries around autism, Alzheimer’s, PTSD and other behavioral health issues and injuries that affect everyone from our children to our homeless veterans.

In this leadership role, UC San Diego will guide the collaboration among the UC campuses and is currently discussing a significant financial investment of non-state, university resources in Cal-BRAIN.

Ralph Greenspan, director of UC San Diego’s Center for Brain Activity Mapping, established at the university in May 2013, is co-author with Paul Alivisatos, director of the Lawrence Berkeley National Laboratory, of a proposal to the University of California Office of the President and to the state Legislature that served as a blueprint for the bill just signed into law.

The proposal calls for organizational hubs in Southern and Northern California, at UC San Diego and Berkeley Lab, to coordinate research activities, facilitate communication and seek additional funds from private and industry partners.

Both Cal-BRAIN and the national initiative are expected to spur not only a new academic discipline but also a new industry cluster of “neurotechnology.” And the tools and inventions needed for mapping the brain will also likely have broad applications to a range of disease monitoring beyond the brain and even to fields beyond health.

“UC San Diego’s leadership role in Cal-BRAIN is of vital importance — not only to the university and the San Diego region but for the state as a whole,” said UC San Diego Chancellor Pradeep K. Khosla. “We will be developing the next technology cluster in ‘neurotech’ just as we did in high-tech, clean-tech and more, creating high paying jobs and world renowned results. I am confident that, with our strengths in neuroscience and biotechnology in San Diego, we will be producing ground-breaking research with significant social impacts.”

Since helping state Senate Majority Leader Ellen Corbett to convene the first hearing on California’s possible role in the BRAIN Initiative at UC San Diego in October 2013, Greenspan and other representatives from the university have traveled numerous times to Sacramento, presenting the case for Cal-BRAIN before members of the state Senate and state Assembly.

Senate President Pro Tem Darrell Steinberg (D-Sacramento) and state Sen. Marty Block (D-San Diego) were early champions. Assembly Speaker Toni Atkins (D-San Diego) also supported the bill.

“UC San Diego is a world leader in the biosciences, and it is a perfect fit to have UC San Diego serve as the Southern California hub of Cal-BRAIN,” Atkins said. “Cal-BRAIN will help develop brain mapping technologies and has the potential to make significant advances in treating conditions such as Alzheimer’s and Parkinson’s. I am proud San Diego will be at the forefront of this important effort.”

Greenspan – who is also associate director of the Kavli Institute for Brain and Mind at UC San Diego and professor in residence of neurobiology and cognitive science – is one of the original writers, as was Alivisatos of LBNL, of the white paper that sparked the national BRAIN Initiative.

“Our vision was for Cal-BRAIN to serve as a driver for trying out different possible technologies and converging on a unified approach for doing effective brain mapping, in which UC San Diego will play a key role,” Greenspan said. “Cal-BRAIN is a great start to realizing the ultimate goal: mapping the brain’s trillions of connections in real time.”

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