TAG: "brain"

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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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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Retired NFL players who suffered concussions show pattern of protein deposits

New test may lead to better identification of brain disorders like CTE.

PET scan of a brain with suspected CTE. More red and yellow indicates more abnormal brain proteins.

By Rachel Champeau, UCLA

A new UCLA study takes another step toward the early understanding of a degenerative brain condition called chronic traumatic encephalopathy, or CTE, which affects athletes in contact sports who are exposed to repetitive brain injuries. Using a new imaging tool, researchers found a strikingly similar pattern of abnormal protein deposits in the brains of retired NFL players who suffered from concussions.

The innovative imaging technique uses a chemical marker combined with positron emission tomography, or PET scan, and was initially tested in five retired NFL players and described in an article published in 2013. Now, building on their previous work, the UCLA researchers found the same characteristic pattern in a larger number of retired players who had sustained concussions.

The latest study also shows that the brain imaging pattern of people who have suffered concussions is markedly different from the scans of healthy people and from those with Alzheimer’s disease. Researchers say the findings could help lead to better identification of brain disorders in athletes and would allow doctors and scientists to test treatments that might help delay the progression of the disease before significant brain damage and symptoms emerge.

The study appears in today’s (April 6) online edition of the Proceedings of the National Academy of Science.

CTE is thought to cause memory loss, confusion, progressive dementia, depression, suicidal behavior, personality changes and abnormal gaits and tremor.

Common factor in CTE and Alzheimer’s

Currently, CTE can only be diagnosed definitively following autopsy. To help identify the disease, doctors look for an accumulation of a protein called tau in the regions of the brain that control mood, cognition and motor function. Tau is also one of the abnormal protein deposits found in the brains of people with Alzheimer’s, although in a distribution pattern that is different from that found in CTE.

“The distribution pattern of the abnormal brain proteins, primarily tau, observed in these PET scans, presents a ‘fingerprint’ characteristic of CTE,” said Dr. Jorge Barrio, senior author of the study and a professor of molecular and medical pharmacology at the David Geffen School of Medicine at UCLA.

The team identified four stages of deposits that could signify early to advanced levels of CTE.

“These different stages reflected by the brain marker may give us more insight into how CTE develops and allow us to track the disease over time,” said Dr. Vladimir Kepe, an author of the study and a research pharmacologist in molecular and medical pharmacology at the Geffen School of Medicine.

The new, larger study included 14 retired NFL players (including the five subjects from the earlier study), all of whom had sustained at least one concussion. Their results were compared with those of 19 men and nine women with healthy brains and 12 men and 12 women with Alzheimer’s disease of similar ages.

Participants received a scan using the UCLA-developed technique, which previously was used for assessing neurological changes associated with Alzheimer’s disease. The test involves injecting a chemical marker called FDDNP, which binds to deposits of neurofibrillary tau “tangles” and amyloid beta “plaques” — the hallmarks of Alzheimer’s. Then, using PET scans, the researchers were able to pinpoint where in the brain these abnormal proteins accumulated.

Participants also underwent MRI scans, neuropsychological testing, and neurological and physical exams to determine whether they had symptoms consistent with CTE, Alzheimer’s dementia or normal aging.

“We found that the imaging pattern in people with suspected CTE differs significantly from healthy volunteers and those with Alzheimer’s dementia,” said Dr. Julian Bailes, an author of the study and director of the Brain Injury Research Institute and the Bennett Tarkington Chairman of the Department of Neurosurgery at NorthShore University HealthSystem in Evanston, Illinois. “These results suggest that this brain scan may also be helpful as a test to differentiate trauma-related cognitive issues from those caused by Alzheimer’s disease.”

Tau and CTE

The PET scans revealed that the imaging patterns of the retired football players showed tau deposit patterns consistent with those that have been observed in autopsy studies of people with CTE.

In addition, the areas in the brain where the patterns occurred were also consistent with the types of symptoms experienced by some of the study participants.

Compared with healthy people and those with Alzheimer’s, the former athletes had higher levels of FDDNP in the amygdala and subcortical regions of the brain, which are areas that control learning, memory, behavior, emotions, and other mental and physical functions.

People with Alzheimer’s, on the other hand, had higher levels of FDDNP in areas of the cerebral cortex that control memory, thinking, attention and other cognitive abilities. And the athletes who had experienced more concussions also had higher FDDNP levels.

The next stage of the research will include multisite studies and will follow subjects over time to determine how effectively FDDNP can detect possible CTE and predict future symptoms. Researchers also will expand the studies to include other groups of people affected by brain injury, such as military personnel.

Previous brain autopsy studies have shown that amyloid plaques are present in less than 45 percent of retired football players, most typically in those with advanced CTE. Most of the retired players in the new study did not have advanced CTE, which suggests that their FDDNP signal represents mostly tau deposits in the brain.

The scans of people with the highest levels of FDDNP binding in areas where tau accumulates in CTE, also show binding in areas of the brain affected by amyloid plaques, which is consistent with autopsy findings indicating that this abnormal protein also plays a role in more serious cases of CTE.

The team also reported initial results of scans of two military veterans. Researchers note that more expanded studies will help them better understand how different causes of head injury may contribute to chronic brain disorders.

In the paper, the researchers note that the FDDNP PET scan is one of several methods — including blood-based biomarkers, diffusion tensor imaging MRI and resting state functional MRI — that are being studied by scientists across the country to help diagnose CTE early.

With more than 500 neuroscientists throughout campus, UCLA is a leader in research to understand the human brain, including efforts to treat, cure and prevent traumatic brain injury and brain disorders such as Alzheimer’s disease.

This study was supported by grants from the NIH (P01-AG025831 and M01-RR00865) and gifts to UCLA from the Toulmin Foundation and Robert and Marion Wilson. No company provided research funding for this study.

The FDDNP marker used with brain PET scans to identify abnormal proteins is intellectual property owned by UCLA and licensed to TauMark, LLC. UCLA authors Dr. Jorge Barrio, Dr. Gary Small and Dr. Sung-Cheng Huang are co-inventors of the PET marker. Barrio and Small have a financial interest in the company. Other disclosures are available in the manuscript.

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UC Davis: Study finds characteristic pattern of protein deposits in retired NFL players’ brains

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Shock treatment changes key areas of brain that play roles in memory, emotion

UCLA study may help physicians identify patients who will respond to treatment.

Katherine Narr, UCLA

By Kim Irwin, UCLA

Scientists know that depression affects the brain, but they still don’t know why some people respond to treatment and others do not.

Now UCLA researchers have shown for the first time in a large cohort of patients that electroconvulsive therapy, or ECT, changes certain areas of the brain that play a role in how people feel, learn and respond to positive and negative environmental factors. The team imaged the hippocampus and amygdala in patients before, during and after undergoing ECT — also known as shock treatment — and compared those images to scans of healthy brains.

The scientists also showed that in patients with major depression, as the hippocampus increases in size, mood improved and parts of the hippocampus and amygdala change more with treatment.

The findings provide vital clues that could help doctors identify patients who will respond well to treatment. They would also help spare patients who won’t respond to treatment from taking drugs that ultimately won’t work for them, said Katherine Narr, a senior author of the study and a UCLA associate professor of neurology.

Major depression affects 350 million people each year and it affects not only those who suffer but also their families, the health care system and the economy.

“Major depression affects all ages, races and ethnic groups, and it has serious consequences on people’s family lives and work,” Narr said. “People with depression also are at higher risk for suicide, which on average accounts for more deaths than car accidents, natural disasters and war each year. Unfortunately, standard types of medication used to treat major depression take a long time to work, and for at least a third of people, the medication will not work well enough to provide any real help.”

Finding better ways to select patients for treatments that will alleviate their symptoms would go a long way to reducing that suffering, Narr said.

The study was published online by the peer-reviewed journal Biological Psychiatry.

ECT, which has been used for more than 50 years, carries a certain stigma. However, within the past decade, advances in anesthesia and electrical stimulation equipment, and new evidence about electrode lead placement have improved the safety and reduced side effects of the procedure, said Shantanu Joshi, the study’s first author and a UCLA assistant professor of neurology.

In addition, advances in high-resolution MRI have allowed more accurate measurement of the changes to the brain induced by ECT.

“ECT has been shown to be very effective for treating patients with major depression who don’t respond well to other treatments,” Joshi said. “People with smaller hippocampal size prior to starting treatment are less likely to respond as well to treatment. While our research investigates structural neuroplasticity in depression in response to ECT, we believe our findings are of much broader interest to the field.”

The researchers believe that the conclusions also would extend to more standard medications used to treat depression, including selective serotonin reuptake inhibitors, and could be used to predict patients’ responses.

The team took three sets of images of 43 patients who were undergoing ECT: before their treatments, after their second session and within one week after they completed treatment. The images were compared to two sets of brain scans from 32 healthy people.

Going forward, the UCLA team will examine the relationship between the neuroplasticity of the hippocampus structure and its neurochemistry in terms of the metabolite response, which could help them understand how metabolism in the brain is either suppressed or excited in response to ECT. Additionally, the researchers will use the shapes of the hippocampus and amygdala to classify and predict depression diagnosis and treatment response, and will investigate how structural changes are related to novel disease maintenance treatments for depression, as well as relapse and recurrence rates.

“Our findings newly show that hippocampal structure prior to ECT may be an important indicator of treatment outcome,” the study states. “That is, patients with smaller hippocampal volumes at baseline are shown to more likely exhibit increases in volume with ECT and to show concomitant improvements in clinical symptoms. Results further indicate that both clinical response to ECT and ECT-induced changes in volume occur rapidly.”

The study was funded by the National Institute of Mental Health (RO1MH092301 and K2MH102743).

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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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‘Gold standard’ method created for measuring key early sign of Alzheimer’s

UCLA helps validate first standardized protocol for measuring an early sign of Alzheimer’s.

Liana Apostolova, UCLA

By Mark Wheeler, UCLA

After six years of painstaking research, a UCLA-led team has validated the first standardized protocol for measuring one of the earliest signs of Alzheimer’s disease — the atrophy of the part of the brain known as the hippocampus.

The finding marks the final step in an international consortium’s successful effort to develop a unified and reliable approach to assessing signs of Alzheimer’s-related neurodegeneration through structural imaging tests, a staple in the diagnosis and monitoring of the disease. The study is published in the journal Alzheimer’s and Dementia.

Using brain tissue of deceased Alzheimer’s disease patients, a group headed by Dr. Liana Apostolova, director of the neuroimaging laboratory at the Mary S. Easton Center for Alzheimer’s Disease Research at UCLA, confirmed that the newly agreed-upon method for measuring hippocampal atrophy in structural MRI tests correlates with the pathologic changes that are known to be hallmarks of the disease — the progressive development of amyloid plaques and neurofibrillary tangles in the brain.

“This hippocampal protocol will now become the gold standard in the field, adopted by many if not all research groups across the globe in their study of Alzheimer’s disease,” said Apostolova, who was invited to play a key role in the consortium because of her reputation as one of the world’s leading experts in hippocampal structural anatomy and atrophy. “It will serve as a powerful tool in clinical trials for measuring the efficacy of new drugs in slowing or halting disease progression.”

The brain is the least accessible and most challenging organ to study in the human body; as a result, Alzheimer’s disease can be diagnosed definitively only by examining brain tissue after death. In living patients, physicians diagnose Alzheimer’s by evaluating other health factors, known as biomarkers, in combination with memory loss and other cognitive symptoms.

The hippocampus is a small region of the brain that is associated with memory formation, and memory loss is the earliest clinical feature of Alzheimer’s disease. Its shrinkage or atrophy, as determined by a structural MRI exam, is a well-established biomarker for the disease and is commonly used in both clinical and research settings to diagnose the disease and monitor its progression.

But until now, the effectiveness of structural MRI has been limited because of the widely different approaches being used to identify the hippocampus and measure its volume — which has called into question the validity of this approach. A typical hippocampus is about 3,000 to 4,000 cubic millimeters in volume. But, Apostolova notes, two scientists analyzing the same structure can come up with a difference of as much as 2,000 cubic millimeters.

In addition, no previous study had verified whether estimates for the volume of the hippocampus using MRI corresponded to actual tissue loss.

To address these deficiencies, the European Alzheimer’s Disease Consortium–Alzheimer’s Disease Neuroimaging Initiative was established to develop a Harmonized Protocol for Hippocampal Segmentation, or HarP — an effort to establish a definitive method for measuring hippocampal shrinkage through structural MRI in a way that best corresponds to the Alzheimer’s disease process.

Once the HarP was established, Apostolova and four other experts were invited to develop the gold standard for measuring the hippocampus to be used by anyone employing the HarP protocol. The UCLA-led team then validated the technique and ensured the changes in the hippocampus corresponded to the hallmark pathologic changes associated with Alzheimer’s disease.

“The technique is meant to be used on scans of living human subjects, so it’s important that we are absolutely certain that this methodology measures what it is supposed to and captures disease presence accurately,” Apostolova said.

To do that, her group used a powerful 7 Tesla MRI scanner to take images of the brain specimens of 16 deceased individuals — nine who had Alzheimer’s disease and seven who were cognitively normal — each for 60 hours. This provided unprecedented visualization of the hippocampal tissue, Apostolova said.

After applying the protocol to measure the hippocampal structures, the researchers analyzed the tissues for two changes that signify the disease: a buildup of amyloid tau protein and loss of neurons. The team found a significant correlation between hippocampal volume and the Alzheimer’s disease indicators.

“As a result of the years of scientifically rigorous work of this consortium, hippocampal atrophy can finally be reliably and reproducibly established from structural MRI scans,” Apostolova said.

Although the technique can be used immediately in research settings such as clinical trials, the next step, Apostolova noted, will be to use the standardized protocol to validate automated techniques available for measuring the hippocampus so the approach could be used more widely — including for the diagnosis of the disease in doctor’s offices and other patient care settings.

Funding for the study was provided by the National Institute on Aging (P50 AG16570), the Jim Easton Consortium for Alzheimer’s Drug Discovery and Biomarker Development, the National Institutes of Health (R01 AG040770), and the Alzheimer’s Association (IIRG 10-174022). Please see the paper for a complete list of the study’s authors.

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Control switch for unfolded protein response may be key to multiple diseases

Discovery opens new drug development avenues for treating variety of diseases.

By Bonnie Ward, UC San Diego

Researchers at the UC San Diego School of Medicine have discovered a control switch for the unfolded protein response (UPR), a cellular stress relief mechanism drawing major scientific interest because of its role in cancer, diabetes, inflammatory disorders and several neural degenerative disorders, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS), otherwise known as Lou Gehrig’s disease.

The normal function of the UPR pathway is to protect cells from stress but it can also trigger their death if the stress is not resolved. The researchers’ discovery of a control switch that acts on the UPR pathway, published today (March 25) in the online edition of EMBO Reports, opens new drug development avenues for treating a wide variety of diseases by modulating the UPR pathway to prevent excessive cell death.

“Our paper reports that two highly conserved pathways – the UPR and the nonsense-mediated RNA decay pathway – intersect with each other at a pivotal point in cell stress,” said Miles Wilkinson, Ph.D., senior author and professor in the Department of Reproductive Medicine and a member of the UC San Diego Institute for Genomic Medicine. “In essence, we’ve shown that the nonsense-mediated RNA decay pathway, typically referred to as ‘NMD,’ keeps the UPR in check to avoid the potentially dangerous consequences if the UPR pathway were allowed to mount an inadvertent response to innocuous stress.”

In cells, like people, too much stress can cause bad things to happen. In the case of cells, one such bad consequence is the accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER), the cell’s protein-making factory. To carry out their many biological functions, proteins must be precisely folded in the correct shape. The body’s answer to excessive cell stress and accompanying misshapen proteins is the unfolded protein response. The UPR kicks in and restores normal ER-folding capacity by adjusting certain cellular processes. If this fails, the UPR instructs the cell to self-destruct, a process known as programmed cell death or apoptosis.

Wilkinson describes the UPR pathway as a double-edged sword. “In a large number of diseases, ranging from cancer to ALS, major stress occurs in the affected cells, leading the UPR pathway to be triggered,” he said. “And that’s meant to be helpful. But if the stress isn’t relieved in a timely fashion, it triggers cell death.  A limited amount of cell death is normal, but if too many cells die, especially critical cells, then it’s a problem. Chronic UPR activation and excessive cell death has been implicated in brain disorders like Alzheimer’s and Parkinson’s disease.”

In their study, Wilkinson, with first author Rachid Karam, Ph.D., and colleagues found that the NMD pathway plays a critical role in shaping the activities of UPR. Specifically, they discovered that NMD prevents inappropriate activation of the UPR and also promotes its timely termination to protect cells from prolonged ER stress.

“Because of the important role of UPR in regulating cell life/death decisions, it is critical that mechanisms are in place to prevent unnecessary UPR activation in response to innocuous or low-level stimuli,” said Wilkinson. “In this report we demonstrate that the NMD pathway serves in this capacity by raising the threshold for triggering UPR and also promoting its shut off at the appropriate time.”

He added that NMD doesn’t deter the UPR if an important stress comes along where more action is needed.

“Although NMD normally represses the UPR, our paper and previous work have shown that it gets out of the way if there’s a real problem,” Wilkinson noted.

Previous studies from the Wilkinson group and others have established that NMD has two broad roles. First, it is a quality control mechanism used by cells to eliminate faulty messenger RNA (mRNA) – molecules that are essential for transcribing genetic information into the construction of proteins critical for life. Second, NMD degrades a specific group of normal mRNAs.

The latest study shows that NMD suppresses inappropriate UPR activities by driving the rapid decay of several normal mRNAs encoding proteins critical for the UPR.

“We demonstrate that NMD directly targets the mRNAs encoding several UPR components, including the highly conserved UPR sensor, IRE1-alpha, whose NMD-dependent degradation partly underpins this process,” said Wilkinson.  “Our work not only sheds light on UPR regulation, but demonstrates the physiological relevance of NMD’s ability to regulate normal mRNAs.”

Co-authors include Chih-Hong Lou, Heike Kroeger, Jonathan H. Lin, all at UC San Diego; Lulu Huang, formerly of UC San Diego and now at ISIS Pharmaceuticals.

Funding for this research came, in part, from NIH grant (RO1 GM111838).

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ADHD program selected for new PEER patient portal by Genetic Alliance

‘This is citizen science at its best.’

Julie Schweitzer, UC Davis

By Phyllis Brown, UC Davis

The ADHD Program at the UC Davis MIND Institute has been selected to participate in an initiative that will link people with the condition in Sacramento and beyond with clinicians, researchers, advocates, support groups and each other, through an innovative privacy-assured online platform called Platform for Engaging Everyone Responsibly, or PEER.

The PEER program will create a customized portal for people with attention-deficit/hyperactivity disorder, funded by a $500,000 grant from the Robert Wood Johnson Foundation, which is underwriting the development of the ADHD site along with approximately 15 others.

PEER is a project of Genetic Alliance, which already has managed the development of portals for a wide array of diseases, many of which are rare genetic conditions, such as Gaucher disease or Joubert syndrome, and others that are more common, such as sickle cell disease and hepatitis.

The PEER platform creates a Web presence that allows people to share their health data, selecting privacy settings with which they are comfortable and that “strike a balance between the desire for solutions to their medical needs and their [concerns] about privacy.”

“The goal is to make the development of registries simple and easy,” said Sharon Terry, president and chief executive officer of Genetic Alliance and co-creator of PEER. “The members of community organizations will just sign up online, create their own instance of the software, and get to work. That is our plan for PEER.”

ADHD is one of several new PEER portals to be developed by PEER/Genetic Alliance. The condition is anything but rare. In fact, it is the most commonly diagnosed psychiatric disorder among children in the United States. Other new PEER collaborators will include the Asthma and Allergy Foundation of America, Celiac Support Association and the Center for Jewish Genetics.

“We’re grateful that the Genetic Alliance and PEER selected the ADHD Program and the MIND Institute as partners in this exciting endeavor,” said program Director Julie Schweitzer. “Through this partnership we can encourage families of people with ADHD to participate in research to help find treatments and possible preventive measures for the condition.”

The ADHD Program will partner with local and national ADHD support groups, including the Parent Education Network (PEN) and Children and Adults with Attention-Deficit Hyperactivity Disorder (CHADD).

“This is citizen science at its best,” Schweitzer said. “Families affected by ADHD will be able to learn information from one another by using a computer from their own homes. And, by sharing their health information, they will help researchers seeking improved treatments for people with ADHD.”

The ADHD Program offers clinical programs for people with ADHD across the lifespan, and conducts research into treatments for the condition.

Schweitzer will collaborate with Nick Anderson, UC Davis professor of informatics.

“We are very enthused to be partners in  this unique network – we greatly value advocacy groups’ participation, and the PEER platform provides the best privacy support currently available,” Anderson said.

More information about the institute is available on the Web at mindinstitute.ucdavis.edu.

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In anorexia nervosa, brain responds differently to hunger signals

Finding could lead to new treatment development efforts targeting specific brain pathways.

By Bonnie Ward, UC San Diego

Researchers at the UC San Diego School of Medicine have pinpointed differences in brain function that may help to explain how people with anorexia nervosa can continue to starve themselves, even when already emaciated. The finding adds to growing evidence about the role of brain mechanisms in eating disorders and could lead to new treatment development efforts targeting specific brain pathways.

“When most people are hungry, they are motivated to eat,” said Christina E. Wierenga, Ph.D., the study’s first author and UC San Diego associate professor of psychiatry. “Yet individuals with anorexia can be hungry and still restrict their food intake. We wanted to identify brain mechanisms that may contribute to their ability to ignore rewards, like food.”

Wierenga said their study showed differences in brain response to reward in women recovered from anorexia. “They showed decreased response to reward, even when hungry. This is opposite of healthy women without an eating disorder, who showed greater sensitivity to rewards when hungry,” added Wierenga.

The study is published in the current issue of the journal Biological Psychiatry.

Walter H. Kaye, M.D., a professor of psychiatry and director of the Eating Disorders Treatment and Research Program at UC San Diego and senior author, said the study’s results further support the view that neurobiology contributes to this disorder. “Our study suggests that brain circuitry differences in anorexics make them less sensitive to reward and the motivational drive of hunger. Put another way, hunger does not motivate them to eat.”

Anorexia nervosa is an eating disorder characterized by abnormally low body weight, fear of gaining weight and a skewed perception of body image. Up to 24 million Americans are estimated to suffer from anorexia and other eating disorders, including bulimia and binge-eating disorder. Women are much more likely to develop eating disorders, which are associated with many medical problems and can be life-threatening.

In their study, the research team analyzed brain function in 23 women who had recovered from anorexia and a control group of 17 healthy women who had never had the disease. Individuals were studied who had previously had anorexia nervosa and were at normal weight, rather than those in an active disease phase, to avoid the potential of malnutrition confounding their research results. Researchers analyzed participants’ brain circuitry related to motivation and reward during two distinct metabolic periods: when they were hungry and again when satiated.

Along with differences in brain response to reward, Kaye said the researchers saw greater activity in regions of the brain important for self-control among the recovered anorexics, regardless of metabolic state. This suggests these individuals may possess a higher degree of self-control than people without eating disorders, he said.

“We are using these new insights about brain mechanisms that contribute to disordered eating to guide the development of new treatment approaches in our Eating Disorders program at UC San Diego,” he said. “We’re very motivated to help advance efforts to better understand and address this life-threatening disorder.”

Co-authors include Amanda Bischoff-Grethe, A. James Melrose, Zoe Irvine, Laura Torres, Ursula F. Bailer, Alan Simmons, and Alice Ely, at UCSD; Julie L. Fudge, at the University of Rochester; and Samuel M. McClure at Stanford.

Funding for this research came, in part, from the National Institutes of Health (grants R01-MH042984-17A1, R01-MH042984-18S1) and the Price Foundation.

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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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Heading off concussions

UC Irvine professor James Hicks leads novel probe of impact injuries in water polo.

By Tom Vasich, UC Irvine

As a result of ongoing probes into the short- and long-term effects of concussions in football, other sports are looking into whether additional steps can be taken to protect their athletes. Among them is water polo, and a novel research venture that includes UC Irvine scientists, coaches and athletes is helping.

The effort got rolling when James Hicks – a scientist, avid fan and father of three sons who played the sport – searched an NCAA database for concussion information related to water polo. But his inquiry came up empty.

“There was none,” says Hicks, professor of ecology & evolutionary biology at UC Irvine. “And given UCI’s historic place in the sport and the collaborative mission of the university, it became clear that we should take on this issue.”

Hicks’ research focuses on evolutionary physiology. While he’s best known in science circles for his work on alligator cardiovascular systems, he also directs UCI’s innovative Exercise Medicine & Sport Sciences Initiative, which unites an interdisciplinary cadre who share an interest in physical activity and its relationship to health. And he’s drawing on their expertise – with the assistance of USA Water Polo, the national governing body for the sport – to compile the first real data set on head impact injuries and concussions in water polo.

“Jim is the first in the world to look into these deeper issues in water polo, and it’s great,” says Dan Klatt, UCI women’s water polo head coach. “Our sport is a physical one, and we need to ask whether concussions are a real problem in the sport and if we’re using the proper equipment to protect our athletes. This study takes a giant step forward in order to answer that question.”

Although head injuries and concussions do happen in water polo, information about their prevalence is, so far, primarily anecdotal. Hicks and his collaborators aim to provide a factual basis for considering whether such injuries are sufficiently common that they need to be addressed and, if so, how best to do this.

“It’s a hard sport,” Hicks says. “Head butts, elbows, shoulders – and at the highest levels, players throw the ball as fast as 50 miles an hour at short distances. Goalies appear to be most at risk, but we want to obtain scientific data to assess that risk, as well as seeing what other positions in the pool may be prone to concussion injury.”

The study has three components. In one, Dr. Steven Small, professor and chair of neurology at UCI, and Robert Blumenfeld, assistant adjunct professor of neurology at UCI, will oversee an email survey of water polo players, who will be asked a number of questions about how long they’ve been in the sport, what positions they’ve played, and the number of serious head blows they’ve received. USA Water Polo will assist in the survey by inviting its 40,000 members to participate.

In the second project – now almost done – UCI engineering students shot water polo balls at a National Highway Traffic Safety Administration-certified crash-test dummy head to gauge the impact of blows at various speeds and levels of inflation. In addition, they measured the effectiveness of protective headgear. The results are currently being analyzed.

In the third component, Hicks will outfit UCI men’s and women’s water polo players with small G-force monitors incorporated into standard water polo caps to record the intensity of head impacts. “It’s challenging to understand what’s going on in the game, and the monitors will help,” he says.

The long-term goal is to broaden the study and outfit more college, high school and age-group teams with these devices. Several local water polo programs have expressed interest in the headgear monitoring, and Hicks is scheduled to give a presentation on it at Harvard-Westlake School in Los Angeles.

He notes that this is a particularly opportune time for the study, given water polo’s recent growth in popularity. According to Christopher Ramsey, CEO of USA Water Polo, participation is increasing dramatically, especially among women. Water polo is the fastest-growing sport in California high schools, and the NCAA administers an expanding number of men’s and women’s varsity teams across the nation. It’s a sport on the rise.

According to Klatt, the mecca of water polo is here in Orange County, where highly competitive high schools and club teams produce a steady stream of the world’s top talent. USA Water Polo is based in Huntington Beach, and the men’s and women’s national teams practice at Santa Ana’s Segerstrom High School and at the organization’s training center in Los Alamitos, respectively.

UCI holds a unique position in this epicenter. Its former men’s coach, the legendary Ted Newland, profoundly influenced the sport; his UCI teams won three NCAA championships and finished second seven times. And the Exercise Medicine & Sport Sciences Initiative allows UCI’s world-class researchers, coaches and athletes to collaborate in fresh and inventive ways.

“This is a great opportunity for a national governing body to assist a world-class university in groundbreaking research,” says USA Water Polo’s Ramsey. “Universities in the U.S. have a distinctive role with sport, and because there’s a close relationship between USA Water Polo and UCI, we start with a stronger bond to work on an issue like this. We both bring valuable perspectives to this enterprise.”

The crash-test dummy exercise is already providing some interesting – if preliminary – results. While Hicks stresses that more analysis is needed, he says the data indicates that ball inflation does matter, with less-inflated, softer balls absorbing more energy upon impact.

In addition, newly developed silicon-based protective headgear – the kind not approved for NCAA play – appears to reduce impact forces by as much as 25 percent. However, Hicks points out, the precise relationship between head impacts and concussion rates requires more study, both in the lab and in the pool.

“I love science, and I’m a fan of the game, and I want to see what we can do for water polo,” Hicks says. “This is exciting stuff.”

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UCLA opens center for brain and behavioral health

Gift from Staglin family will fund research on returning unhealthy brains to health.

Michael Fanselow’s research addresses fear, memory and anxiety disorders, including how traumatic memories lead to post-traumatic stress disorder, anxiety disorders and depression. (Photo by Reed Hutchinson, UCLA)

By Stuart Wolpert, UCLA

More than 30 percent of Americans will experience an anxiety disorder at some time in their lives. A new research center at UCLA will be dedicated to increasing our understanding of the brain and learning how to help the brain recover when those, and other malfunctions, occur.

The formation of the Staglin Family Music Festival Center for Brain and Behavioral Health, which is scheduled to open July 1, was announced today (March 17) by UCLA Life Sciences Dean Victoria Sork. Michael Fanselow, distinguished professor of psychology in the UCLA College, was appointed its director.

Genetic risk factors, combined with environmental experiences, can cause the brain to malfunction. The center’s researchers will seek to discover what those changes are and develop novel methods to address them.

“The center will focus on brain health and will develop novel methods to get the unhealthy brain back to the healthy state,” said Fanselow, who also holds a UCLA faculty appointment in psychiatry.

Fanselow said anxiety disorders are generally chronic and do not go away on their own. Some of these disorders, like post-traumatic stress, are devastating.

Understanding fear

Fanselow’s research addresses fear, memory and anxiety disorders, including how traumatic memories lead to post-traumatic stress disorder, anxiety disorders and depression. He has studied how fear works in the brain using rats and mice, whose fear systems work in remarkably similar ways to that of humans.

Fear serves an important function: to protect us from danger.

“When we’re in danger, it’s really adaptive to be afraid. When we’re not in danger, it’s adaptive not to be afraid,” Fanselow said. “But we can make mistakes. One mistake is when there’s true danger and I don’t defend myself. The other mistake, which is much less costly, is when there’s no danger and I do become afraid. That’s an anxiety disorder.”

Fanselow’s laboratory is identifying and learning about the brain circuits that give rise to inappropriate fear, with the goals of reducing — or even eliminating — unnecessary fear, while preserving healthy fear.

Fanselow also was appointed to the Staglin Family Chair in Psychology.

“We are delighted to have such a prominent scientist assume our Staglin Family Chair and the leadership of the Staglin Center,” said Shari Staglin.

Garen Staglin said, “UCLA is among the leading institutions studying brain health, and we applaud its approach to campus-wide collaborations to accelerate the science of the brain and resultant treatments.”

Getting the brain back to where it should be

Psychology and psychiatry professor Michelle Craske, an expert on fear and anxiety disorders, will be associate director of the center, which is being funded by the family of Shari and Garen Staglin through the Staglin Family Music Festival for Brain Health and their philanthropic organization, the International Mental Health Research Organization.

Fanselow and Craske are currently studying whether cognitive behavior therapy, combined with a pharmaceutical called scopolamine, will help suppress fear in people with anxiety. In cognitive behavior therapy, people with anxiety disorders are repeatedly exposed to the object or situation they fear, in a non-threatening environment, and eventually they learn not to be afraid.

“We want to get the brain back to where it should be, either by combining drugs with psychotherapy or by finding different drug approaches,” said Fanselow, whose research is funded by the National Institute of Mental Health, a branch of the National Institutes of Health.

Fanselow and colleagues reported in 2013 that at the right dose, scopolamine — which has been used to treat including nausea, motion sickness, depression and other conditions — might also be useful in treating anxiety disorders.

“UCLA and the UCLA College are extremely grateful to Shari and Garen Staglin and their family, for their extremely deep and long-standing commitment to fighting mental illness, and their generosity over many years to UCLA and the College,” Sork said.

The center will also provide seed money to interdisciplinary teams of scholars to advance our understanding of many areas in brain health, ranging from depression to memory loss to schizophrenia.

Dedicated philanthropists

“The Staglins are providing UCLA with wonderful opportunity to accelerate research, enhance treatment and lead to new approaches in combatting mental illness,” Fanselow said.

Garen Staglin, a UCLA alumnus and private equity investor, is co-chair of the $4.2 billion Centennial Campaign for UCLA. His wife, Shari, a UCLA alumna, has been a director of the UCLA Foundation and a member of UCLA’s Women and Philanthropy. The Staglins own the acclaimed Staglin Family Vineyard in Napa Valley. Shari Staglin is the vineyard’s CEO and the Staglins’ daughter, Shannon, also a UCLA alumna, is president.

The Staglins became active in supporting mental health research and treatment after their son, Brandon, was diagnosed with schizophrenia. Brandon has since graduated with honors from Dartmouth and is currently marketing communications director for both the Staglin Family Vineyard and IMHRO. He also is a member of the joint board of directors of IMHRO and One Mind.

The Staglins raise funds for brain health charities and research through a variety of major events including The Music Festival for Brain Health. All of the music festival’s expenses are underwritten by its sponsors, and all proceeds go to scientific research. They also serve as founders and board members of One Mind, where Garen is co-chairman.

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