Hyperactivity in Brain May Explain Multiple Symptoms of Depression.

Brain hyperactivity. Maps showing the difference in the strength of brain connections between depressed subjects (left) and controls (right). Depressed subjects show much stronger connections, as evidenced by red colors in their maps. (Credit: Image courtesy of University of California - Los Angeles)

Source: Science Daily

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ScienceDaily (Feb. 27, 2012) — Most of us know what it means when it's said that someone is depressed. But commonly, true clinical depression brings with it a number of other symptoms. These can include anxiety, poor attention and concentration, memory issues, and sleep disturbances.

Traditionally, depression researchers have sought to identify the individual brain areas responsible for causing these symptoms. But the combination of so many symptoms suggested to UCLA researchers that the multiple symptoms of depression may be linked to a malfunction involving brain networks -- the connections that link different brain regions.
Now, for the first time, these UCLA researchers have shown that people with depression have increased connections among most brain areas. Indeed, their brains are widely hyperconnected. The report, published this week in the online journal PLoS One, sheds new light on the brain dysfunction that causes depression and its wide array of symptoms.
"The brain must be able to regulate its connections to function properly," said the study's first author, Dr. Andrew Leuchter, a professor of psychiatry at the Semel Institute for Neuroscience and Human Behavior at UCLA. "The brain must be able to first synchronize, and then later desynchronize, different areas in order to react, regulate mood, learn and solve problems."
The depressed brain, Leuchter said, maintains its ability to form functional connections but loses the ability to turn these connections off.
"This inability to control how brain areas work together may help explain some of the symptoms in depression," he said.
In the study, the largest of its kind, the researchers studied the functional connections of the brain in 121 adults diagnosed with major depressive disorder, or MDD. They measured the synchronization of electrical signals from the brain -- brain waves -- to study networks among the different brain regions.
While some previous studies have hinted at abnormal patterns of connections in MDD, the UCLA team used a new method called "weighted network analysis" to examine overall brain connections. They found that the depressed subjects showed increased synchronization across all frequencies of electrical activity, indicating dysfunction in many different brain networks.
Brain rhythms in some of these networks regulate the release of serotonin and other brain chemicals that help control mood, said Leuchter, who is also the director of UCLA's Laboratory of Brain, Behavior, and Pharmacology and chair of the UCLA Academic Senate.
"The area of the brain that showed the greatest degree of abnormal connections was the prefrontal cortex, which is heavily involved in regulating mood and solving problems," he said. "When brain systems lose their flexibility in controlling connections, they may not be able to adapt to change.
"So an important question is, to what extent do abnormal rhythms drive the abnormal brain chemistry that we see in depression? We have known for some time that antidepressant medications alter the electrical rhythms of the brain at the same time that levels of brain chemicals like serotonin are changing. It is possible that a primary effect of antidepressant treatment is to 'repair' the brain's electrical connections and that normalizing brain connectivity is a key step in recovery from depression. That will be the next step in our research."
Other authors of the study include Dr. Ian A. Cook, Aimee M. Hunter, Chaochao Cai and Steve Horvath, all of UCLA. Funding for the study was provided by the National Institutes of Health, Lilly Research Laboratories and Pfizer Pharmaceuticals.

In the Genes, but Which Ones? Studies That Linked Specific Genes to Intelligence Were Largely Wrong, Experts Say.

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ScienceDaily (Feb. 24, 2012) — For decades, scientists have understood that there is a genetic component to intelligence, but a new Harvard study has found both that most of the genes thought to be linked to the trait are probably not in fact related to it, and identifying intelligence's specific genetic roots may still be a long way off.

Led by David I. Laibson '88, the Robert I. Goldman Professor of Economics, and Christopher F. Chabris '88, Ph.D. '99, assistant professor of psychology at Union College in Schenectady, N.Y., a team of researchers examined a dozen genes using large data sets that included both intelligence testing and genetic data. As reported in a forthcoming article in the journal Psychological Science, they found that in nearly every case, the hypothesized genetic pathway failed to replicate. In other words, intelligence could not be linked to the specific genes that were tested.
"It is only in the past 10 or 15 years that we have had the technology for people to do studies that involved picking a particular genetic variant and investigating whether people who score higher on intelligence tests tend to have that genetic variant," said Chabris. "In all of our tests we only found one gene that appeared to be associated with intelligence, and it was a very small effect. This does not mean intelligence does not have a genetic component, it means it's a lot harder to find the particular genes, or the particular genetic variants, that influence the differences in intelligence."
To get at the question of how genes influence intelligence, researchers first needed data, and plenty of it.
Though it had long been understood, based on studies of twins, that intelligence was a heritable trait, it wasn't until relatively recently that the technology emerged to allow scientists to directly probe DNA in a search for genes that affected intelligence.
The problem, Chabris said, was that early technology for assaying genes was very expensive, meaning that such studies were typically limited to, at most, several hundred subjects, who would take IQ tests and provide DNA samples for testing.
As part of their study, Chabris and his colleagues relied on several pre-existing data sets -- a massive study of Wisconsin high school graduates that began in the 1950s, the Framingham Heart Study, and an ongoing survey of all twins born in Sweden -- to expand that subject pool from a few hundred to many thousands.
"What we want to emphasize is that we are not saying the people who did earlier research in this area were foolish or wrong," Chabris said. "They were using the best technology they had available. At the time it was believed that individual genes would have a much larger effect -- they were expecting to find genes that might each account for several IQ points."
To identify genes that might play a role in intelligence, previous researchers used the "candidate gene approach," which requires identifying a gene that is already linked with a known biological function -- such as Alzheimer's disease or the production of a specific neurotransmitter. If people who scored high on intelligence tests shared a particular variant of that gene, it was believed, that demonstrated the gene's role in intelligence.
"These were reasonable hypotheses," said study co-author Daniel J. Benjamin '99, Ph.D. '06, assistant professor of economics at Cornell University. "But in retrospect, either the findings were false positives or the effects of the genes are much, much smaller than anyone had anticipated."
Chabris, however, emphasized that the results don't point to the idea that the dozen genes examined in the study play no role in intelligence, but rather suggest that intelligence may be tied to many genes and the ways in which they interact.
"As is the case with other traits, like height, there are probably thousands of genes and their variants that are associated with intelligence," he said. "And there may be other genetic effects beyond the single gene effects -- there could be interactions between genes, there could be interactions between genes and the environment. What our results show is that the way researchers have been looking for genes that may be related to intelligence -- the candidate gene method -- is fairly likely to result in false positives, so other methods should be used."

Scientists Turn Memories Off and On With Flip of Switch

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ScienceDaily (June 17, 2011) — Scientists have developed a way to turn memories on and off -- literally with the flip of a switch. Using an electronic system that duplicates the neural signals associated with memory, they managed to replicate the brain function in rats associated with long-term learned behavior, even when the rats had been drugged to forget. "Flip the switch on, and the rats remember. Flip it off, and the rats forget," said Theodore Berger of the USC Viterbi School of Engineering's Department of Biomedical Engineering.
Berger is the lead author of an article that will be published in the Journal of Neural Engineering. His team worked with scientists from Wake Forest University in the study, building on recent advances in our understanding of the brain area known as the hippocampus and its role in learning.
In the experiment, the researchers had rats learn a task, pressing one lever rather than another to receive a reward. Using embedded electrical probes, the experimental research team, led by Sam A. Deadwyler of the Wake Forest Department of Physiology and Pharmacology, recorded changes in the rat's brain activity between the two major internal divisions of the hippocampus, known as subregions CA3 and CA1. During the learning process, the hippocampus converts short-term memory into long-term memory, the researchers prior work has shown.
"No hippocampus," says Berger, "no long-term memory, but still short-term memory." CA3 and CA1 interact to create long-term memory, prior research has shown.
In a dramatic demonstration, the experimenters blocked the normal neural interactions between the two areas using pharmacological agents. The previously trained rats then no longer displayed the long-term learned behavior.
"The rats still showed that they knew 'when you press left first, then press right next time, and vice-versa,'" Berger said. "And they still knew in general to press levers for water, but they could only remember whether they had pressed left or right for 5-10 seconds."
Using a model created by the prosthetics research team led by Berger, the teams then went further and developed an artificial hippocampal system that could duplicate the pattern of interaction between CA3-CA1 interactions.
Long-term memory capability returned to the pharmacologically blocked rats when the team activated the electronic device programmed to duplicate the memory-encoding function.
In addition, the researchers went on to show that if a prosthetic device and its associated electrodes were implanted in animals with a normal, functioning hippocampus, the device could actually strengthen the memory being generated internally in the brain and enhance the memory capability of normal rats.
"These integrated experimental modeling studies show for the first time that with sufficient information about the neural coding of memories, a neural prosthesis capable of real-time identification and manipulation of the encoding process can restore and even enhance cognitive mnemonic processes," says the paper.
Next steps, according to Berger and Deadwyler, will be attempts to duplicate the rat results in primates (monkeys), with the aim of eventually creating prostheses that might help the human victims of Alzheimer's disease, stroke or injury recover function.
The paper is entitled "A Cortical Neural Prosthesis for Restoring and Enhancing Memory." Besides Deadwyler and Berger, the other authors are, from USC, BME Professor Vasilis Z. Marmarelis and Research Assistant Professor Dong Song, and from Wake Forest, Associate Professor Robert E. Hampson and Post-Doctoral Fellow Anushka Goonawardena.
Berger, who holds the David Packard Chair in Engineering, is the Director of the USC Center for Neural Engineering, Associate Director of the National Science Foundation Biomimetic MicroElectronic Systems Engineering Research Center, and a Fellow of the IEEE, the AAAS, and the AIMBE
"A Cortical Neural Prosthesis for Restoring and Enhancing Memory." (Berger et al 2011 J. Neural Eng. 8 046017) Story Source:
The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by University of Southern California, via EurekAlert!, a service of AAAS.

Noninvasive Brain Implant Could Someday Translate Thoughts Into Movement.

Source: ScienceDaily

ScienceDaily (June 17, 2011) — A brain implant developed at the University of Michigan uses the body's skin like a conductor to wirelessly transmit the brain's neural signals to control a computer, and may eventually be used to reactivate paralyzed limbs. The implant is called the BioBolt, and unlike other neural interface technologies that establish a connection from the brain to an external device such as a computer, it's minimally invasive and low power, said principal investigator Euisik Yoon, a professor in the U-M College of Engineering, Department of Electrical Engineering and Computer Science.
Currently, the skull must remain open while neural implants are in the head, which makes using them in a patient's daily life unrealistic, said Kensall Wise, the William Gould Dow Distinguished University professor emeritus in engineering.
BioBolt does not penetrate the cortex and is completely covered by the skin to greatly reduce risk of infection. Researchers believe it's a critical step toward the Holy Grail of brain-computer interfacing: allowing a paralyzed person to "think" a movement.
"The ultimate goal is to be able to reactivate paralyzed limbs," by picking the neural signals from the brain cortex and transmitting those signals directly to muscles, said Wise, who is also founding director of the NSF Engineering Research Center for Wireless Integrated MicroSystems (WIMS ERC). That technology is years away, the researchers say.
Another promising application for the BioBolt is controlling epilepsy, and diagnosing certain diseases like Parkinson's.
The concept of BioBolt is filed for patent and was presented on June 16 at the 2011 Symposium on VLSI Circuits in Kyoto, Japan. Sun-Il Chang, a PhD student in Yoon's research group, is lead author on the presentation.
The BioBolt looks like a bolt and is about the circumference of a dime, with a thumbnail-sized film of microcircuits attached to the bottom. The BioBolt is implanted in the skull beneath the skin and the film of microcircuits sits on the brain. The microcircuits act as microphones to 'listen' to the overall pattern of firing neurons and associate them with a specific command from the brain. Those signals are amplified and filtered, then converted to digital signals and transmitted through the skin to a computer, Yoon said.
Another hurdle to brain interfaces is the high power requirement for transmitting data wirelessly from the brain to an outside source. BioBolt keeps the power consumption low by using the skin as a conductor or a signal pathway, which is analogous to downloading a video into your computer simply by touching the video.
Eventually, the hope is that the signals can be transmitted through the skin to something on the body, such as a watch or a pair of earrings, to collect the signals, said Yoon, eliminating the need for an off-site computer to process the signals.
Story Source:
The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by University of Michigan, via EurekAlert!, a service of AAAS.

Dual Role for Immune Cells in the Brain.

Endothelial cells and macrophages work together to transmit and modulate the strength of inflammatory immune signals to the brain. (Credit: Image: Courtesy of Jamie Simon, Salk Institute for Biological Studies.)

Source: ScienceDaily

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ScienceDaily (Jan. 16, 2010) — We all have at one time or another experienced the typical signs of an infection: the fever, the listlessness, the lack of appetite. They are orchestrated by the brain in response to circulating cytokines, the signaling molecules of the immune system. But just how cytokines' reach extends beyond the almost impenetrable blood-brain barrier has been the topic of much dispute.

In their latest study, researchers at the Salk Institute for Biological Studies describe how, depending on the nature of the stimulus, resident macrophages lined up along the blood-brain barrier play opposing roles in the transmission of immune signals into the brain.
"These macrophages act as accelerators to enlist the brain's participation in dealing with immune insults, but when necessary slam on the brakes to prevent the central inflammatory response from going overboard," explains postdoctoral researcher Jordi Serrats, Ph.D., who co-led the study with Jennifer C. Schiltz, Ph.D., formerly a postdoctoral researcher in the Salk's Neuronal Structure and Function Laboratory and now an assistant professor at the Uniformed Services University in Bethesda, Maryland.
The Salk researchers' findings, which are published in the Jan. 14, 2010 edition of the journal Neuron, may pave the way for novel therapies for sufferers of chronic neurodegenerative diseases, such as Amyotrophic Lateral Sclerosis (ALS), Parkinson's, Alzheimer's and prion diseases, in which central inflammatory mechanisms play an important role.
"The fact that we have identified a potent anti-inflammatory mechanism in the brain presents a new target to intervene in the wide range of central nervous system diseases that possess an inflammatory component," says the study's senior author, Paul E. Sawchenko, Ph.D., a professor in the Neuronal Structure and Function Laboratory.
In response to an infection, inflammatory cytokines such as interleukin-1 are generated at the site of infection. These cytokines circulate in the blood and communicate with neurons in the brain to engage the hypothalamo-pituitary-adrenal (HPA) axis, an integral part of the brain's stress response machinery. The HPA axis involves the interaction of the hypothalamus, the pituitary gland, which sits just below the hypothalamus and the adrenal glands at the top of the kidneys.
Like a central command center, the hypothalamus sends out corticotropin-releasing factor, which stimulates the pituitary gland to secrete adrenocorticotropic hormone. The latter signals the adrenal glands to ramp up the production of glucocorticoids, which mobilize energy reserves to cope with inflammatory insults. But they also act as very powerful immunosuppressants preventing excessive cytokine production and immune cell proliferation.
"Cytokines are big molecules that don't cross the blood-brain barrier freely," says Sawchenko. "The question of how these molecules access the brain to trigger this whole array of adaptive responses such as fever, inactivity, sleepiness, and activation of the brain's stress response machinery has been a nagging problem in the side of neuroimmunology for many years."
Earlier research by Sawchenko and others suggested a vascular route whereby cytokines interact with vessel walls to generate secondary messengers, which then engage the relevant circuitry in the brain. Tightly packed endothelial cells, which line almost 400 miles of narrow capillaries throughout the brain, are perfectly positioned to record circulating immune signals but they require a very strong signal to become activated. Perivascular macrophages, on the other hand, are more sensitive but don't have direct access to the bloodstream.
To disentangle the exact role of these two cell types, Serrats took advantage of the macrophages' ability to engulf and ingest solid particles. He injected liposomes containing clodronate, a drug that can cause cell death, into the lateral cerebral ventricle. The liposomes were taken up by the macrophages, which were selectively killed off.
Without perivascular macrophages, the animals were unable to respond to blood-borne interleukin-1 and initiate the brain's so-called acute phase responses, which help the body deal with the challenge at hand but also cause the familiar feeling of "being sick." But to their surprise, the Salk researchers found that the same cells put a damper on the pro-inflammatory activities of endothelial cells, which form the lining of blood vessels and are only stirred to action-but very powerfully once they are-when they encounter lipopolysaccharide, a key component of the cell wall of certain bacteria.
"Many neurodegenerative diseases are worsened by systemic inflammation or infections," says Sawchenko. "Once we identify the molecules that mediate the two-way communication between perivascular macrophages and endothelial cells we can develop strategies for managing the adverse health consequences of central inflammatory responses."
Researchers who also contributed to the study include postdoctoral researchers Borja García-Bueno, Ph.D., and Teresa M. Reyes, Ph.D., at the Salk Institute as well as Nico van Rooijen, Ph.D., a professor at the Vrije Universiteit Medical Center in Amsterdam, The Netherlands.
The work was funded in part by the Clayton Medical Research Foundation, the National Institutes of Health, the Spanish Ministry of Education and Science and CIBERsam.

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Adapted from materials provided by Salk Institute, via EurekAlert!, a service of AAAS.

How Music 'Moves' Us: Listeners' Brains Second-Guess the Composer.

New research predicts that expectations about what is going to happen next in a piece of music should be different for people with different musical experience and sheds light on the brain mechanisms involved. (Credit: iStockphoto/Anna Bryukhanova)

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ScienceDaily (Jan. 16, 2010) — Have you ever accidentally pulled your headphone socket out while listening to music? What happens when the music stops? Psychologists believe that our brains continuously predict what is going to happen next in a piece of music. So, when the music stops, your brain may still have expectations about what should happen next.

A new paper published in NeuroImage predicts that these expectations should be different for people with different musical experience and sheds light on the brain mechanisms involved.
Research by Marcus Pearce Geraint Wiggins, Joydeep Bhattacharya and their colleagues at Goldsmiths, University of London has shown that expectations are likely to be based on learning through experience with music. Music has a grammar, which, like language, consists of rules that specify which notes can follow which other notes in a piece of music. According to Pearce: "the question is whether the rules are hard-wired into the auditory system or learned through experience of listening to music and recording, unconsciously, which notes tend to follow others."
The researchers asked 40 people to listen to hymn melodies (without lyrics) and state how expected or unexpected they found particular notes. They simulated a human mind listening to music with two computational models. The first model uses hard-wired rules to predict the next note in a melody. The second model learns through experience of real music which notes tend to follow others, statistically speaking, and uses this knowledge to predict the next note.
The results showed that the statistical model predicts the listeners' expectations better than the rule-based model. It also turned out that expectations were higher for musicians than for non-musicians and for familiar melodies -- which also suggests that experience has a strong effect on musical predictions.
In a second experiment, the researchers examined the brain waves of a further 20 people while they listened to the same hymn melodies. Although in this experiment the participants were not explicitly informed about the locations of the expected and unexpected notes, their brain waves in responses to these notes differed markedly. Typically, the timing and location of the brain wave patterns in response to unexpected notes suggested that they stimulate responses that synchronise different brain areas associated with processing emotion and movement. On these results, Bhattacharya commented, "… as if music indeed 'moves' us!"
These findings may help scientists to understand why we listen to music. "It is thought that composers deliberately confirm and violate listeners' expectations in order to communicate emotion and aesthetic meaning," said Pearce. Understanding how the brain generates expectations could illuminate our experience of emotion and meaning when we listen to music.

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Adapted from materials provided by University of Goldsmiths London.
Journal Reference:
Pearce MT, Ruiz MH, Kapasi S, Wiggins G, Bhattacharya J. Unsupervised statistical learning underpins computational, behavioural, and neural manifestations of musical expectation. NeuroImage, 2009; DOI: 10.1016/j.neuroimage.2009.12.019

Neural Thermostat Keeps Brain Running Efficiently.

A 'neuronal thermostat' keeps our energy-hungry brains operating reliably and efficiently while processing a flood of sensory information, new research has found. (Credit: iStockphoto)

Source: ScienceDaily

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ScienceDaily (Jan. 15, 2010) — Our energy-hungry brains operate reliably and efficiently while processing a flood of sensory information, thanks to a sort of neuronal thermostat that regulates activity in the visual cortex, Yale researchers have found.

The actions of inhibitory neurons allow the brain to save energy by suppressing non-essential visual stimuli and processing only key information, according to research published in the January 13 issue of the journal Neuron.
"It's called the iceberg phenomenon, where only the tip is sharply defined yet we are aware that there is a much larger portion underwater that we can not see," said David McCormick, the Dorys McConnell Duberg Professor of Neurobiology at Yale School of Medicine, researcher of the Kavli Institute of Neuroscience and co-senior author of the study. "These inhibitory neurons set the water level and control how much of the iceberg we see. We don't need to see the entire iceberg to know that it is there."
The brain uses the highest percentage of the body's energy, so scientists have long wondered how it can operate both efficiently and reliably when processing a deluge of sensory information. Most studies of vision have concentrated on activity of excitatory neurons that fire when presented with simple stimuli, such as bright or dark bars. The Yale team wanted to measure what happens outside of the classical field of vision when the brain has to deal with more complex scenes in real life.
By studying brains of animals watching movies of natural scenes, the Yale team found that inhibitory cells in the visual cortex control how the excitatory cells interact with each other.
"We found that these inhibitory cells take a lead role in making the visual cortex operate in a sparse and reliable manner," McCormick said.
James Mazer was co-senior author of the paper with McCormick. Bilal Haider, a Yale graduate student, was lead author. Other Yale authors of the paper were Matthew R. Krause, Alvaro Duque, Yuguo Yu and Jonathan Touryan.
The work was funded by the National Eye Institute and the Kavli Foundation.

Story Source:
Adapted from materials provided by Yale University.
Journal Reference:
Bilal Haider, Matthew R. Krause, Alvaro Duque, Yuguo Yu, Jonathan Touryan, James A. Mazer, David A. McCormick. Synaptic and Network Mechanisms of Sparse and Reliable Visual Cortical Activity during Nonclassical Receptive Field Stimulation. Neuron, 2010; 65 (Issue 1): 107-121 DOI: 10.1016/j.neuron.2009.12.005