A brain-training task that increases the number of items an individual can remember over a short period of time may boost performance in other problem-solving tasks by enhancing communication between different brain areas. The new study being presented this week in San Francisco is one of a growing number of experiments on how working-memory training can measurably improve a range of skills – from multiplying in your head to reading a complex paragraph.

(Image: Nelson Marques)

“Working memory is believed to be a core cognitive function on which many types of high-level cognition rely, including language comprehension and production, problem solving, and decision making,” says Brad Postle of the University of Wisconsin-Madison, who is co-chairing a session on working-memory training at the Cognitive Neuroscience Society (CNS) annual meeting today in San Francisco. Work by various neuroscientists to document the brain’s “plasticity” – changes brought about by experience – along with technical advances in using electromagnetic techniques to stimulate the brain and measure changes, have enabled researchers to explore the potential for working-memory training like never before, he says.

The cornerstone brain-training exercise in this field has been the “n-back” task, a challenging working memory task that requires an individual to mentally juggle several items simultaneously. Participants must remember both the recent stimuli and an increasing number of stimuli before it (e.g., the stimulus “1-back,” “2-back,” etc). These tasks can be adapted to also include an audio component or to remember more than one trait about the stimuli over time – for example, both the color and location of a shape.

Through a number of experiments over the past decade, Susanne Jaeggi of the University of Maryland, College Park, and others have found that participants who train with n-back tasks over the course of approximately a month for about 20 minutes per day not only get better at the n-back task itself, but also experience “transfer” to other cognitive tasks on which they did not train. “The effects generalize to important domains such as attentional control, reasoning, reading, or mathematical skills,” Jaeggi says. “Many of these improvements remain over the course of several months, suggesting that the benefits of the training are long lasting.”

As yet unresolved and controversial, however, has been understanding which factors determine whether working-memory training will generalize to other domains, as well as how the brain changes in response to the training. Work by Postle’s group using a new technique of applying electromagnetic stimulation on the brains of people undergoing working-memory training addresses some of these questions.

Training increases connectivity

Bornali Kundu of the University of Wisconsin-Madison, who works in Postle’s laboratory, used transcranial magnetic stimulation (TMS) with electroencephalography (EEG) to measure activity in specific brain circuits before and after training with an n-back task. “Our main finding was that training on the n-back task increased the number of items an individual could remember over a short period of time,” explains Kundu, who is presenting these new results today. “This increase in short-term memory performance was associated with enhanced communication between distant brain areas, in particular between the parietal and frontal brain areas.”

In the n-back task, Kundu’s team presented stimuli one-at-a-time on a computer screen and asked participants to decide if the current stimulus matched both the color and location of the stimulus presented a certain number of presentations previously. The color varied among seven primary colors, and the location varied among eight possible positions arranged in a square formation. The control task was playing the video game Tetris, which involves moving colored shapes to different locations, but does not require participants to remember anything. Before and after the training, researchers administered a range of cognitive tasks on which subjects did not receive training, and simultaneously delivered TMS while recording EEG, to measure communication between brain areas during task performance.

After practicing the n-back task for 5 hours a day and 5 days per week over 5 weeks, subjects were able to remember more items over short periods of time. Importantly, for those whose working memory improved, communication between the dorsolateral prefrontal cortex (DLPFC) and parietal cortex also improved. “This is in comparison to the control group, who showed no such differences in neural communication after practicing Tetris for 5 weeks,” Kundu says.

Working-memory training also produced improvement on cognitive tasks for which participants were not trained that are also believed to rely on communication between the parietal cortex and DLPFC. For two of these tasks – the ability to detect a change in a briefly presented array of squares, and the ability to detect a red letter “C” embedded in a field of distracting stimuli of rotated red “C”s and blue “C”s – those who had trained in the n-back test also showed a decrease in task-related EEG. The training exercise had registered a similar decrease. “The overall picture seems to be that the extent of transfer of training to untrained tasks depends on the overlap of neural circuits recruited by the two,” Kundu says.

Developing future therapies

Moving forward, many cognitive neuroscientists are working to see how working-memory training may specifically help clinical populations, such as patients with ADHD. “If we can learn the ‘rules’ that govern how, why, and when cognitive training can produce improvements that generalize to untrained tasks, it may be that therapies can be developed for patients suffering from neurological or psychiatric disease,” Postle says.

Both Jaeggi’s team, as well as Torkel Klingberg of the Karolinska Institute in Sweden, who is also presenting at the symposium today in San Francisco, have had success with such training for children with ADHD, decreasing the symptoms of inattention. “Here, the reason working-memory training may transfer to tests of fluid intelligence, as well as to a reduction in ADHD-associated hyperactivity symptoms, may be because both of those complex behaviors use some of the same brain circuits also used in performing the working-memory training tasks,” Kundu says.

“Individual differences in working memory performance have been related to individual differences in numerous real world skills such as reading comprehension, performance on standardized tests, and much more,” she adds. “I would not expect the same sorts of transfer effects that have been seen with working-memory training to happen if an individual practiced a task that used a minimally overlapping network, such as, for example, shooting three-pointers – which presumably uses different brain areas like primary and secondary motor cortex and the cerebellum.”

Jaeggi says that it is important to understand that cognitive abilities are not as unchangeable as some might think. “Even though there is certainly a hereditary component to mental abilities, that does not mean that there are not also components that are malleable and respond to experience and practice,” she says. “Whereas we try to strengthen participants’ working memory skills in our research, there are other routes that are possible as well, such as for example physical or musical training, meditation, nutrition, or even sleep.”

Despite all the promising research, Jaeggi says, researchers still need to understand many aspects of this work, such as “individual differences that influence training and transfer effects, the question of how long the effects last, and whether and how the effects translate into more real-world settings and ultimately, academic achievement.”

(Source: cogneurosociety.org)

Even a mild injury to the brain can have long lasting consequences, including increased risk of cognitive impairment later in life. While it is not yet known how brain injury increases risk for dementia, there are indications that chronic, long-lasting, inflammation in the brain may be important. A new paper by researchers at the University of Kentucky Sanders-Brown Center on Aging (SBCoA), appearing in the Journal of Neuroscience, offers the latest information concerning a “switch” that turns “on” and “off” inflammation in the brain after trauma.

A team of researchers led by Linda Van Eldik, director of SBCoA, used a mouse model to study the role of p38a MAPK in trauma-induced injury responses in the microglia resident immune cell of the brain.

"The p38α MAPK protein is an important switch that drives abnormal inflammatory responses in peripheral tissue inflammatory disorders, including chronic debilitating diseases like rheumatoid arthritis," said Van Eldik.

"However, less is known about the potential importance of p38α MAPK in controlling inflammatory responses in the brain. Our work supports p38α MAPK as a promising clinical target for the treatment of CNS disorders associated with uncontrolled brain inflammation, including trauma, and potentially others like Alzheimer’s disease. We are excited by our findings, and are actively working to develop drugs targeting p38a MAPK designed specifically for diseases of the brain."

Lead author of the paper Adam D. Bachstetter said, “I was surprised when I looked under the microscope at the brain tissue of mice that had a diffuse brain injury. Microglia normally look like a small spider, but after suffering a brain injury the microglia become like angry spiders from a horror movie. In brain-injured mice that lack p38a MAPK there were no angry-looking microglia, only the normal small spider-like cells. When I started the study I never expected the results to be so clear and striking. I believe that the p38a MAPK is a promising clinical target for the treatment of CNS disorders with dysregulated inflammatory responses, but we are still a long way from development of CNS-active p38 inhibitor drugs. “

(Source: eurekalert.org)

Making decisions involves a gradual accumulation of facts that support one choice or another. A person choosing a college might weigh factors such as course selection, institutional reputation and the quality of future job prospects.

But if the wrong choice is made, Princeton University researchers have found that it might be the information rather than the brain’s decision-making process that is to blame. The researchers report in the journal Science that erroneous decisions tend to arise from errors, or “noise,” in the information coming into the brain rather than errors in how the brain accumulates information.

These findings address a fundamental question among neuroscientists about whether bad decisions result from noise in the external information — or sensory input — or because the brain made mistakes when tallying that information. In the example of choosing a college, the question might be whether a person made a poor choice because of misleading or confusing course descriptions, or because the brain failed to remember which college had the best ratings.

Previous measurements of brain neurons have indicated that brain functions are inherently noisy. The Princeton research, however, separated sensory inputs from the internal mental process to show that the former can be noisy while the latter is remarkably reliable, said senior investigator Carlos Brody, a Princeton associate professor of molecular biology and the Princeton Neuroscience Institute (PNI), and a Howard Hughes Medical Institute Investigator.

"To our great surprise, the internal mental process was perfectly noiseless. All of the imperfections came from noise in the sensory processes," Brody said. Brody worked with first author Bingni Brunton, now a postdoctoral research associate in the departments of biology and applied mathematics at the University of Washington; and Matthew Botvinick, a Princeton associate professor of psychology and PNI.

The research subjects — four college-age volunteers and 19 laboratory rats — listened to streams of randomly timed clicks coming into both the left ear and the right ear. After listening to a stream, the subjects had to choose the side from which more clicks originated. The rats had been trained to turn their noses in the direction from which more clicks originated.

The test subjects mostly chose the correct side but occasionally made errors. By comparing various patterns of clicks with the volunteers’ responses, researchers found that all of the errors arose when two clicks overlapped, and not from any observable noise in the brain system that tallied the clicks. This was true in experiment after experiment utilizing different click patterns, in humans and rats.

The researchers used the timing of the clicks and the decision-making behavior of the test subjects to create computer models that can be used to indicate what happens in the brain during decision-making. The models provide a clear window into the brain during the “mulling over” period of decision-making, the time when a person is accumulating information but has yet to choose, Brody said.

"Before we conducted this study, we did not have a way of looking at this process without inserting electrodes into the brain," Brody said. "Now thanks to our model, we have an estimation of what is going on at each moment in time during the formation of the decision."

The study suggests that information represented and processed in the brain’s neurons must be robust to noise, Brody said. “In other words, the ‘neural code’ may have a mechanism for inherent error correction,” he said.

"The new work from the Brody lab is important for a few reasons," said Anne Churchland, an assistant professor of biological sciences at Cold Spring Harbor Laboratory who studies decision-making and was not involved in the study. "First, the work was very innovative because the researchers were able to study carefully controlled decision-making behavior in rodents. This is surprising in that one might have guessed rodents were incapable of producing stable, reliable decisions that are based on complex sensory stimuli.

"This work exposed some unexpected features of why animals, including humans, sometimes make incorrect decisions," Churchland said. "Specifically, the researchers found that errors are mostly driven by the inability to accurately encode sensory information. Alternative possibilities, which the authors ruled out, included noise associated with holding the stimulus in mind, or memory noise, and noise associated with a bias toward one alternative or the other."

(Source: princeton.edu)

Scientists at CWRU School of Medicine Discover New Technique that Holds Promise for the Treatment of Multiple Sclerosis and Cerebral Palsy

Researchers at Case Western Reserve School of Medicine have discovered a technique that directly converts skin cells to the type of brain cells destroyed in patients with multiple sclerosis, cerebral palsy and other so-called myelin disorders.

This discovery appears today in the journal Nature Biotechnology.

This breakthrough now enables “on demand” production of myelinating cells, which provide a vital sheath of insulation that protects neurons and enables the delivery of brain impulses to the rest of the body. In patients with multiple sclerosis (MS), cerebral palsy (CP), and rare genetic disorders called leukodystrophies, myelinating cells are destroyed and cannot be replaced.

The new technique involves directly converting fibroblasts - an abundant structural cell present in the skin and most organs - into oligodendrocytes, the type of cell responsible for myelinating the neurons of the brain.

“Its ‘cellular alchemy,’” explained Paul Tesar, PhD, assistant professor of genetics and genome sciences at Case Western Reserve School of Medicine and senior author of the study. “We are taking a readily accessible and abundant cell and completely switching its identity to become a highly valuable cell for therapy.”

In a process termed “cellular reprogramming,” researchers manipulated the levels of three naturally occurring proteins to induce fibroblast cells to become precursors to oligodendrocytes (called oligodendrocyte progenitor cells, or OPCs).

Tesar’s team, led by Case Western Reserve researchers and co-first authors Fadi Najm and Angela Lager, rapidly generated billions of these induced OPCs (called iOPCs). Even more important, they showed that iOPCs could regenerate new myelin coatings around nerves after being transplanted to mice—a result that offers hope the technique might be used to treat human myelin disorders.

When oligodendrocytes are damaged or become dysfunctional in myelinating diseases, the insulating myelin coating that normally coats nerves is lost. A cure requires the myelin coating to be regenerated by replacement oligodendrocytes.

Until now, OPCs and oligodendrocytes could only be obtained from fetal tissue or pluripotent stem cells. These techniques have been valuable, but with limitations.
“The myelin repair field has been hampered by an inability to rapidly generate safe and effective sources of functional oligodendrocytes,” explained co-author and myelin expert Robert Miller, PhD, professor of neurosciences at the Case Western Reserve School of Medicine and the university’s vice president for research. “The new technique may overcome all of these issues by providing a rapid and streamlined way to directly generate functional myelin producing cells.”

This initial study used mouse cells. The critical next step is to demonstrate feasibility and safety using human cells in a lab setting. If successful, the technique could have widespread therapeutic application to human myelin disorders.
“The progression of stem cell biology is providing opportunities for clinical translation that a decade ago would not have been possible,” said Stanton Gerson, MD, professor of Medicine-Hematology/Oncology at the School of Medicine and director of the National Center for Regenerative Medicine and the UH Case Medical Center Seidman Cancer Center. “It is a real breakthrough.”

(Source: newswise.com)

The St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project has identified mutations responsible for more than half of a subtype of childhood brain tumor that takes a high toll on patients. Researchers also found evidence the tumors are susceptible to drugs already in development.

The study focused on a family of brain tumors known as low-grade gliomas (LGGs). These slow-growing cancers are found in about 700 children annually in the U.S., making them the most common childhood tumors of the brain and spinal cord. For patients whose tumors cannot be surgically removed, the long-term outlook remains bleak due to complications from the disease and its ongoing treatment. Nationwide, surgery alone cures only about one-third of patients.

Using whole genome sequencing, researchers identified genetic alterations in two genes that occurred almost exclusively in a subtype of LGG termed diffuse LGG. This subtype cannot be cured surgically because the tumor cells invade the healthy brain. Together, the mutations accounted for 53 percent of the diffuse LGG in this study. Researchers also demonstrated that one of the mutations, which had not previously been linked to brain tumors, caused tumors when introduced into the glial brain cells of mice.

The findings appear in the April 14 advance online edition of the scientific journal Nature Genetics.

“This subtype of low-grade glioma can be a nasty chronic disease, yet prior to this study we knew almost nothing about its genetic alterations,” said David Ellison, M.D., Ph.D., chair of the St. Jude Department of Pathology and the study’s corresponding author. The first author is Jinghui Zhang, Ph.D., an associate member of the St. Jude Department of Computational Biology.

The Pediatric Cancer Genome Project is using next-generation whole genome sequencing to determine the complete normal and cancer genomes of children and adolescents with some of the least understood and most difficult to treat cancers. Scientists believe that studying differences in the 3 billion chemical bases that make up the human genome will provide the scientific foundation for the next generation of cancer care.

“We were surprised to find that many of these tumors could be traced to a single genetic alteration,” said co-author Richard K. Wilson, Ph.D., director of The Genome Institute at Washington University School of Medicine in St. Louis. “This is a major pathway through which low-grade gliomas develop and it provides new clues to explore as we search for better treatments.”

The study involved whole genome sequencing of 39 paired tumor and normal tissue samples from 38 children and adolescents with different subtypes of LGG and related tumors called low-grade glioneuronal tumors (LGGNTs). Although many cancers develop following multiple genetic abnormalities, 62 percent of the 39 tumors in this study stemmed from a single genetic alteration.

Previous studies have linked LGGs to abnormal activation of the MAPK/ERK pathway. The pathway is involved in regulating cell division and other processes that are often disrupted in cancer. Until now, however, the genetic alterations involved in driving this pathway were unknown for some types of LGG and LGGNT.

This study linked activation in the pathway to duplication of a key segment of the FGFR1 gene, which investigators discovered in brain tumors for the first time. The segment is called a tyrosine kinase domain. It functions like an on-off switch for several cell signaling pathways, including the MAPK/ERK pathway. Investigators also demonstrated that experimental drugs designed to block activity along two altered pathways worked in cells with theFGFR1 tyrosine kinase domain duplication. “The finding suggests a potential opportunity for using targeted therapies in patients whose tumors cannot be surgically removed,” Ellison said.

Researchers also showed that the FGFR1 abnormality triggered an aggressive brain tumor in glial cells from mice that lacked the tumor suppressor gene Trp53.

Whole-genome sequencing found previously undiscovered rearrangements in the MYB and MYBL1 genes in diffuse LGGs. These newly identified abnormalities were also implicated in switching on the MAPK/ERK pathway.

Researchers checked an additional 100 LGGs and LGGNTs for the same FGFR1, MYB and MYBL1 mutations. Overall, MYB was altered in 25 percent of the diffuse LGGs, and 24 percent had alterations in FGFR1. Researchers also turned up numerous other mutations that occurred in just a few tumors. The affected genes included BRAF, RAF1, H3F3A, ATRX, EP300, WHSC1 and CHD2.

“The Pediatric Cancer Genome Project has provided a remarkable opportunity to look at the genomic landscape of this disease and really put the alterations responsible on the map. We can now account for the genetic errors responsible for more than 90 percent of low-grade gliomas,” Ellison said. “The discovery that FGFR1 and MYB play a central role in childhood diffuse LGG also serves to distinguish the pediatric and adult forms of the disease.”

(Source: stjude.org)

Some breast tumor circulating cells in the bloodstream are marked by a constellation of biomarkers that identify them as those destined to seed the brain with a deadly spread of cancer, said researchers led by those at Baylor College of Medicine in a report that appears online in the journal Science Translational Medicine.

"What prompted us to initiate this study was our desire to understand the characteristics of these cells," said Dr. Dario Marchetti, professor of pathology at BCM, director of the CTC (circulating tumor cell) Core Facility at BCM and a member of the NCI-designated Dan L. Duncan Cancer Center at BCM. Often, he said, circulating tumor cells (CTCs) from breast cancer patients which spread or metastasize to the brain are not identified by the current method for identifying such cells approved by the U.S. Food and Drug Administration (CellSearch® platform).

While this system is based on the detection of antibodies that target the epithelial cell adhesion molecule (EpCAM), the biomarkers identified by Marchetti and his colleagues include human epidermal growth factor receptor 2 (HER2+), epidermal growth factor receptor (EGFR), heparanase (HPSE) and Notch1 - and not EpCAM. Together, said Marchetti, these four proteins, previously known to be associated with cancer metastasis, spell out the signature of circulating tumors cells that travel to the brain.

Marchetti, using sophisticated techniques to test samples provided by Dr. Morris D. Groves of The University of Texas MD Anderson Cancer Center, also found this same pattern of proteins in the tissue taken from brain metastases of animals injected with breast cancer circulating tumor cells (CTCs).

They tested these special circulating tumor cells in laboratory models and found that they are highly invasive and capable of spread in live animals. They also found cells with this signature in the metastatic tumors of animals with breast cancer.

"We were able to grow these cells in vitro (in the laboratory in culture) for the first time ever," said Marchetti.

Circulating tumor cells are a promising method of identifying and monitoring solid tumors and could replace tumor biopsies in some cases. However, the promise is still being studied by experts such as Marchetti. In this case, he has identified a new signature for such cells - one that directs their activities toward spreading cancer to brain - an outcome with frequently fatal consequences.

The study not only identifies a novel signature of circulating tumor cells, it shows the limitations of currently approved platforms used to identify cancer in this way. Understanding such cells can help scientist understand how the disease spreads - an initial step in developing new methods of treating metastatic disease.

"We don’t claim that these biomarkers are the only important ones," said Marchetti. "We hope to find novel markers in brain metastasis that will make diagnosis and monitoring even more targeted."

They are also trying to find ways to link these circulating tumor cells back to the signature of the original or primary tumor.

(Source: bcm.edu)

Tapeworm infection in the brain that can trigger seizures is a growing health concern, doctors say.

But the infection, which leads to swelling in the brain, is usually treatable with medication, according to a leading association of neurologists.

Estimated cases of neurocysticercosis, as the tapeworm infection is called, range from 40,000 to 160,000 each year in the United States, said Dr. Peter Hotez, dean of the National School of Tropical Medicine at Baylor College of Medicine in Houston. “It’s been around a long time, affecting people living in severe poverty, but the disease is not well-studied or understood,” Hotez said.

Texas is one area of the country with many cases. “The disease has now become a leading cause of epilepsy in Houston,” Hotez said. “Every [week], we have patients come into our tropical medicine clinic with it.”

Concerns about an apparent increase of neurocysticercosis within the United States led the American Academy of Neurology to issue treatment guidelines for doctors and patients in the April 9 issue of the journal Neurology.

The recommendations are based on a review of 10 studies published between 1980 and 2010 that evaluated so-called cysticidal drugs for treatment of tapeworm infections. The infection involves infestation of the brain with the larvae of the Taenia solium tapeworm. In severe cases, it can cause death.

Tapeworm infection is common in Third World countries because of inadequate sanitation and hygiene, and an estimated 2 million people worldwide have epilepsy as a result. The good news is that good hygiene and food preparation can prevent it.

People develop the tapeworm infection when they consume improperly cooked meat, such as pork, or any food or drink that contains the tapeworm eggs or larvae (also known as cysts). Touching the fecal matter of an infected person is another means of transmission. The larvae then transform into full-sized tapeworms, which can grow to several feet, Hotez said.

In pigs, tapeworm larvae travel to the brain and await transmission to another animal (a human, for instance) when the pigs are eaten, he said. The parasites do the same thing in humans, but there’s nowhere to go from the human brain. Ultimately, the larvae die, and that’s when the trouble begins.

As the larvae die, they lose the ability to hide from the body’s immune system. The immune system responds by causing inflammation, which leads to epileptic seizures and brain swelling, Hotez said.

The guidelines for children and adults recommend using the medication albendazole to kill the cysts if they’re alive and treating brain swelling with corticosteroid drugs that dampen the immune system. The study found that albendazole (Albenza), used with or without the corticosteroids, reduced seizure frequency and the number of brain lesions seen in imaging scans. Not enough data was available to evaluate another drug, praziquantel, the researchers said.

Only limited evidence exists to support specific treatment approaches, however, and the treatments may produce side effects, such as abdominal complaints, according to the guidelines. It’s also unclear whether anti-epileptic medications may help prevent the seizures caused by the inflammation.

For now, the key is physician awareness, said Dr. Karen Roos, a professor of neurology at the Indiana University School of Medicine and lead author of the guidelines. “Physicians from areas of the world where this infection is endemic are very knowledgeable about this infection,” she said. “They know more than U.S. physicians.”

Infection with the tapeworm is preventable through proper sanitation, good hygiene and thorough cooking of meat.

(Source: nlm.nih.gov)