Brain Cells Responsible for Keeping Us Awake

Brain Cells Responsible for Keeping Us Awake

  11:46:00 PM    Science Lover

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Bright light arouses us. Bright light makes it easier to stay awake. Very bright light not only arouses us but is known to have antidepressant effects. Conversely, dark rooms can make us sleepy. It's the reason some people use masks to make sure light doesn't wake them while they sleep.

Researchers have identified the group of neurons
that mediates whether light arouses us and keeps
us awake, or not. (Credit: iStockphoto/Osman Safi)

Now researchers at UCLA have identified the group of neurons that mediates whether light arouses us -- or not. Jerome Siegel, a professor of psychiatry at the Semel Institute for Neuroscience and Human Behavior at UCLA, and colleagues report in the current online edition of the Journal of Neuroscience that the cells necessary for a light-induced arousal response are located in the hypothalamus, an area at the base of the brain responsible for, among other things, control of the autonomic nervous system, body temperature, hunger, thirst, fatigue -- and sleep.

These cells release a neurotransmitter called hypocretin, Siegel said. The researchers compared mice with and without hypocretin and found that those who didn't have it were unable to stay awake in the light, while those who had it showed intense activation of these cells in the light but not while they were awake in the dark.

This same UCLA research group earlier determined that the loss of hypocretin was responsible for narcolepsy and the sleepiness associated with Parkinson's disease. But the neurotransmitter's role in normal behavior was, until now, unclear.

"This current finding explains prior work in humans that found that narcoleptics lack the arousing response to light, unlike other equally sleepy individuals, and that both narcoleptics and Parkinson's patients have an increased tendency to be depressed compared to others with chronic illnesses," said Siegel, who is also a member of the UCLA Brain Research Institute and chief of neurobiology research at the Sepulveda Veterans Affairs Medical Center in Mission Hills, Calif.



Prior studies of the behavioral role of hypocretin in rodents had examined the neurotransmitter's function during only light phases (normal sleep time for mice) or dark phases (their normal wake time), but not both. And the studies only examined the rodents when they were performing a single task.

In the current study, researchers examined the behavioral capabilities of mice that had their hypocretin genetically "knocked-out" (KO mice) and compared them with the activities of normal, wild-type mice (WT) that still had their hypocretin neurons. The researchers tested the two groups while they performed a variety of tasks during both light and dark phases.

Surprisingly, they found that the KO mice were only deficient at working for positive rewards during the light phase. During the dark phase, however, these mice learned at the same rate as their WT littermates and were completely unimpaired in working for the same rewards.

Consistent with the data in the KO mice, the activity of hypocretin neurons in their WT littermates was maximized when working for positive rewards during the light phase, but the cells were not activated when performing the same tasks in the dark phase.

"The findings suggest that administering hypocretin and boosting the function of hypocretin cells will increase the light-induced arousal response," Siegel said. "Conversely, blocking their function by administering hypocretin receptor blockers will reduce this response and thereby induce sleep."

Further, Siegel noted, "The administration of hypocretin may also have antidepressant properties, and blocking it may increase tendencies toward depression. So we feel this work has implications for treating sleep disorders as well as depression."

Other authors on the study included Ronald McGregor (first author), Ming-Fung Wu, Grace Barber and Lalini Ramanathan, all of UCLA, the Veterans Affairs Greater Los Angeles Healthcare System and the UCLA Brain Research Institute.

The research was supported by the National Institutes of Health and the Medical Research Service of the Department of Veterans Affairs. The authors report no conflict of interest.

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Holograms Reveal Brain's Inner Workings: Microscopy Technique Used to Observe Activity of Neurons Like Never Before

Holograms Reveal Brain's Inner Workings: Microscopy Technique Used to Observe Activity of Neurons Like Never Before

  9:36:00 AM    Science Lover

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Like far away galaxies, powerful tools are required to bring the minute inner workings of neurons into focus. Borrowing a technique from materials science, a team of neurobiologists, psychiatrists, and advanced imaging specialists from Switzerland's EPLF and CHUV report in The Journal of Neuroscience how Digital Holographic Microscopy (DHM) can now be used to observe neuronal activity in real-time and in three dimensions -- with up to 50 times greater resolution than ever before. The application has immense potential for testing out new drugs to fight neurodegenerative diseases such as Alzheimer's and Parkinson's.

This is a 3-D image of living neuron taken by DHM 
technology. (Credit: Courtesy of Lyncée Tec)

Neurons come in various shapes and are transparent. To observe them in a Petri dish, scientists use florescent dyes that change the chemical composition and can skew results. Additionally, this technique is time consuming, often damages the cells, and only allows researchers to examine a few neurons at a time. But these newly published results show how DHM can bypass the limitations of existing techniques.

"DHM is a fundamentally novel application for studying neurons with a slew of advantages over traditional microscopes," explains Pierre Magistretti of EPFL's Brain Mind Institute and a lead author of the paper. "It is non-invasive, allowing for extended observation of neural processes without the need for electrodes or dyes that damage cells."

Senior team member Pierre Marquet adds, "DHM gives precious information not only about the shape of neurons, but also about their dynamics and activity, and the technique creates 3D navigable images and increases the precision from 500 nanometers in traditional microscopes to a scale of 10 nanometers."

A good way to understand how DHM works is to imagine a large rock in an ocean of perfectly regular waves. As the waves deform around the rock and come out the other side, they carry information about the rock's shape. This information can be extracted by comparing it to waves that did not smash up against the rock, and an image of the rock can be reconstructed. DHM does this with a laser beam by pointing a single wavelength at an object, collecting the distorted wave on the other side, and comparing it to a reference beam. A computer then numerically reconstructs a 3D image of the object -- in this case neurons -- using an algorithm developed by the authors. In addition, the laser beam travels through the transparent cells and important information about their internal composition is obtained.



Normally applied to detect minute defects in materials, Magistretti, along with DHM pioneer and EPFL professor in the Advanced Photonics Laboratory, Christian Depeursinge, decided to use DHM for neurobiological applications. In the study, their group induced an electric charge in a culture of neurons using glutamate, the main neurotransmitter in the brain. This charge transfer carries water inside the neurons and changes their optical properties in a way that can be detected only by DHM. Thus, the technique accurately visualizes the electrical activities of hundreds of neurons simultaneously, in real-time, without damaging them with electrodes, which can only record activity from a few neurons at a time.

A major advance for pharmaceutical research

Without the need to introduce dyes or electrodes, DHM can be applied to High Content Screening -- the screening of thousands of new pharmacological molecules. This advance has important ramifications for the discovery of new drugs that combat or prevent neurodegenerative diseases such as Parkinson's and Alzheimer's, since new molecules can be tested more quickly and in greater numbers.

"Due to the technique's precision, speed, and lack of invasiveness, it is possible to track minute changes in neuron properties in relation to an applied test drug and allow for a better understanding of what is happening, especially in predicting neuronal death," Magistretti says. "What normally would take 12 hours in the lab can now be done in 15 to 30 minutes, greatly decreasing the time it takes for researchers to know if a drug is effective or not."

The promise of this technique for High Content Screening has already resulted in a start-up company at EPFL called LynceeTec (www.lynceetec.com).

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Scientists Have New Help Finding Their Way Around Brain's Nooks and Crannies

Scientists Have New Help Finding Their Way Around Brain's Nooks and Crannies

  12:53:00 AM    Science Lover

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Like explorers mapping a new planet, scientists probing the brain need every type of landmark they can get. Each mountain, river or forest helps scientists find their way through the intricacies of the human brain.

Scientists have found a way to use MRI scanning data 
to map myelin, a white sheath that covers some brain 
cell branches. Such maps, previously only available via 
dissection, help scientists determine precisely where they 
are at in the brain. Red and yellow indicate regions with 
high myelin levels; blue, purple and black areas have low 
myelin levels. (Credit: David Van Essen)

Researchers at Washington University School of Medicine in St. Louis have developed a new technique that provides rapid access to brain landmarks formerly only available at autopsy. Better brain maps will result, speeding efforts to understand how the healthy brain works and potentially aiding in future diagnosis and treatment of brain disorders, the researchers report in the Journal of Neuroscience Aug. 10.

The technique makes it possible for scientists to map myelination, or the degree to which branches of brain cells are covered by a white sheath known as myelin in order to speed up long-distance signaling. It was developed in part through the Human Connectome Project, a $30 million, five-year effort to map the brain's wiring. That project is headed by Washington University in St. Louis and the University of Minnesota.

"The brain is among the most complex structures known, with approximately 90 billion neurons transmitting information across 150 trillion connections," says David Van Essen, PhD, Edison Professor and head of the Department of Anatomy and Neurobiology at Washington University. "New perspectives are very helpful for understanding this complexity, and myelin maps will give us important insights into where certain parts of the brain end and others begin."

Easy access to detailed maps of myelination in humans and animals also will aid efforts to understand how the brain evolved and how it works, according to Van Essen.

Neuroscientists have known for more than a century that myelination levels differ throughout the cerebral cortex, the gray outer layer of the brain where most higher mental functions take place. Until now, though, the only way they could map these differences in detail was to remove the brain after death, slice it and stain it for myelin.

Washington University graduate student Matthew Glasser developed the new technique, which combines data from two types of magnetic resonance imaging (MRI) scans that have been available for years.



"These are standard ways of imaging brain anatomy that scientists and clinicians have used for a long time," Glasser says. "After developing the new technique, we applied it in a detailed analysis of archived brain scans from healthy adults."

As in prior studies, Glasser's results show highest myelination levels in areas involved with early processing of information from the eyes and other sensory organs and control of movement. Many brain cells are packed into these regions, but the connections among the cells are less complex. Scientists suspect that these brain regions rely heavily on what computer scientists call parallel processing: Instead of every cell in the region working together on a single complex problem, multiple separate teams of cells work simultaneously on different parts of the problem.

Areas with less myelin include brain regions linked to speech, reasoning and use of tools. These regions have brain cells that are packed less densely, because individual cells are larger and have more complex connections with neighboring cells.

"It's been widely hypothesized that each chunk of the cerebral cortex is made up of very uniform information-processing machinery," Van Essen says. "But we're now adding to a picture of striking regional differences that are important for understanding how the brain works."

According to Van Essen, the technique will make it possible for the Connectome project to rapidly map myelination in many different research participants. Data on many subjects, acquired through many different analytical techniques including myelination mapping, will help the resulting maps cover the range of anatomic variation present in humans.

"Our colleagues are clamoring to make use of this approach because it's so helpful for figuring out where you are in the cortex, and the data are either already there or can be obtained in less than 10 minutes of MRI scanning," Glasser says.

This research was funded by the National Institutes of Health (NIH).

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Researchers can predict future actions from human brain activity

Researchers can predict future actions from human brain activity

  2:42:00 AM    Science Lover

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Bringing the real world into the brain scanner, researchers at The University of Western Ontario from The Centre for Brain and Mind can now determine the action a person was planning, mere moments before that action is actually executed.

A volunteer completes tasks while in the functional magnetic
imaging (fMRI) machine. This research project focuses
on understanding how the human brain plans actions.

The findings were published this week in the prestigious Journal of Neuroscience, in the paper, "Decoding Action Intentions from Preparatory Brain Activity in Human Parieto-Frontal Networks."



"This is a considerable step forward in our understanding of how the human brain plans actions," says Jason Gallivan, a Western Neuroscience PhD student, who was the first author on the paper.

University of Western Ontario researchers Jody Culham and Jason Gallivan describe how they can use a fMRI to determine the action a person was planning, mere moments before that action is actually executed. Credit: The University of Western Ontario

Over the course of the one-year study, human subjects had their brain activity scanned using functional magnetic resonance imaging (fMRI) while they performed one of three hand movements: grasping the top of an object, grasping the bottom of the object, or simply reaching out and touching the object. The team found that by using the signals from many brain regions, they could predict, better than chance, which of the actions the volunteer was merely intending to do, seconds later.

"Neuroimaging allows us to look at how action planning unfolds within human brain areas without having to insert electrodes directly into the human brain. This is obviously far less intrusive," explains Western Psychology professor Jody Culham, who was the paper's senior author.

Gallivan says the new findings could also have important clinical implications: "Being able to predict a human's desired movements using brain signals takes us one step closer to using those signals to control prosthetic limbs in movement-impaired patient populations, like those who suffer from spinal cord injuries or locked-in syndrome."

                    Brain timecourse video of subject's fMRI image during experiment

Provided by University of Western Ontario

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In Search of the Memory Molecule, Researchers Discover Key Protein Complex

In Search of the Memory Molecule, Researchers Discover Key Protein Complex

  9:40:00 AM    Science Lover

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Have a tough time remembering where you put your keys, learning a new language or recalling names at a cocktail party? New research from the Lisman Laboratory at Brandeis University points to a molecule that is central to the process by which memories are stored in the brain.

The CaMKII molecule has 12 lobes (6 are shown here), 
each of which has enzymatic activity. This molecule can 
bind to the NMDA receptor, forming a complex. The 
number of such complexes at the synapse may increase 
the amount of memory that can be stored. 
(Credit: Neal Waxham)

A paper published in the June 22 issue of the Journal of Neuroscience describes the new findings.

The brain is composed of neurons that communicate with each other through structures called synapses, the contact point between neurons. Synapses convey electrical signals from the "sender" neuron to the "receiver" neuron. Importantly, a synapse can vary in strength; a strong synapse has a large effect on its target cell, a weak synapse has little effect.

New research by John Lisman, professor of biology and the Zalman Abraham Kekst chair in neuroscience, helps explain how memories are stored at synapses. His work builds on previous studies showing that changes in the strength of these synapses are critical in the process of learning and memory.

"It is now quite clear that memory is encoded not by the change in the number of cells in the brain, but rather by changes in the strength of synapses," Lisman says. "You can actually now see that when learning occurs, some synapses become stronger and others become weaker."

But what is it that controls the strength of a synapse?

Lisman and others have previously shown that a particular molecule called Ca/calmodulin-dependent protein kinase II (CaMKII) is required for synapses to change their strength. Lisman's team is now showing that synaptic strength is controlled by the complex of CaMKII with another molecule called the NMDAR-type glutamate receptor (NMDAR). His lab has discovered that the amount of this molecular complex (called the CaMKII/NMDAR complex) actually determines how strong a synapse is, and, most likely, how well a memory is stored.

"We're claiming that if you looked at a weak synapse you'd find a small number of these complexes, maybe one," says Lisman. "But at a strong synapse you might find many of these complexes."

A key finding in their experiment used a procedure that reduced the amount of this complex. When the complex was reduced, the synapse became weaker. This weakening was persistent, indicating that the memory stored at that synapse was erased.



The experiments were done using small slices of rat hippocampus, the part of the brain crucial for memory storage.

"We can artificially induce learning-like changes in the strength of synapses because we know the firing pattern that occurs during actual learning in an animal," Lisman says.

To prove their hypothesis, he explained, his team first strengthened the synapse, eventually saturating it to the point where no more learning or memory could take place. They then added a chemical called CN-19 to the synapse, which they suspected would dissolve the CaMKII/NMDAR complex. As predicted, it did in fact make the synapse weaker, suggesting the loss of memory.

A final experiment, says Lisman, was the most exciting: They started out by making the synapse so strong that it was "saturated," as indicated by the fact that no further strengthening could be induced. They then "erased" the memory with the chemical CN-19. If the "memory" was really erased, the synapse should no longer be saturated. To test this hypothesis, Lisman's team again stimulated the synapse and found that it could once again "learn." Taken together, these results demonstrated the ability of CN19 to erase the memory of a synapse -- a critical criterion for establishing that the CaMKII/NMDAR complex is the long sought memory storage molecule in the brain.

Lisman's team used CN19 due to previous studies, which indicate that the chemical could affect the CaMKII/NMDAR complex. Lisman's team wanted to show that CN19 would decrease the complex in living cells. Several key control experiments proved this to be the case.

"Most people accept that the change in the synapses that you can see under the microscope is the mechanism that actually occurs during learning," says Lisman. "So this paper will have a lot of impact -- but in science you still have to prove things, so the next step would be to try this in an actual animal and see if we can make it forget something it has previously learned."

Lisman says that if memory is understood at the biochemical level, the impact will be enormous.

"You have to understand how memory works before you can understand the diseases of memory."

Lisman assembled a large team to undertake this complex research. A key collaborator was Magdalena Sanhueza, who once worked with Dr. Lisman at Brandeis, and her student, German Fernandez-Villalobos, both now of the University of Chile, Department of Biology and Ulli Bayer of the University of Colorado Denver School of Medicine, Department of Pharmacology, who developed CN19, a particular form that could actually enter neurons.

Others involved include Nikolai Otmakhov and Peng Zhang from Brandeis and Gyulnara Kasumova, who worked in the Lisman laboratory for several years as an undergraduate. An additional group contributing to the work was that of Johannes Hell, Professor of Pharmacology at the UC Davis School of Medicine. He and his student, Ivar S. Stein, used immunoprecipitation methods to actually show that the CN19 had dissolved the CaMKII/NMDAR complex.

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Early Light Refines Brain's Circuitry for Vision: Studies Show Importance of Visual Stimulation in Wiring Up Species' Brains to See

Early Light Refines Brain's Circuitry for Vision: Studies Show Importance of Visual Stimulation in Wiring Up Species' Brains to See

  10:08:00 AM    Science Lover

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Any parent knows that newborns still have a lot of neurological work to do to attain fully acute vision. In a wide variety of nascent animals, genes provide them with only a rough wiring plan and then leave it to the developing nervous system to do its own finish work. Two studies by Brown University researchers provide new evidence of a role for exposure to light in the environment as mouse pups and tadpoles organize and refine the circuitry of their vision systems.

Light and sight: connected at the beginning Because 
the retinal layer of rods and cones is not connected 
early in mice, neuroscientists had no reason to suspect 
that light helps develop neural connections for vision. 
David Berson, right, with Jordan Renna, has shown 
that photosensitive cells he discovered a decade ago are 
connected and do help with neural development. 
(Credit: Mike Cohea/Brown University)

"Through a combination of light-independent and light-dependent processes, the visual system is getting tuned up over time," said David Berson, professor of neuroscience.

His new work, published in advance online June 5 in Nature Neuroscience, offers the surprising result that light exposure can enhance how well mice can organize the nerve endings from their left eye and their right eye in an area of the brain where they start out somewhat jumbled. Neuroscientists had thought that mammals were unable to see at this stage, but a new type of light-sensitive cell that Berson discovered a decade ago turns out to let in the light.

Meanwhile, Berson's colleague Carlos Aizenman, assistant professor of neuroscience, co-authored a paper online May 31 in the Journal of Neuroscience showing that newborn tadpoles depend on light to coordinate and improve the response speed, strength and reliability of a network of neurons in a vision-processing region of their brains.

"This is how activity is allowing visual circuits to refine and sort themselves out," said Aizenman. "Activity is fine-tuning all these connections. It's making the circuit function in a much more efficient, synchronous way."

Not completely blind mice
Berson, postdoctoral scholar Jordan Renna, and former postdoctoral researcher Shijun Weng conducted several experiments in newborn mice to see whether light influences the process by which the mice rewire to distinguish between their eyes.

"For certain functions, the brain wants to keep track of which eye is which," Berson said. Among those functions are the perception of depth and distance.

At a circuit level, the brain keeps signals from the two eyes distinct by segregating their nerve endings into separate regions in the dorsal lateral geniculate nucleus (dLGN), a key waystation on the path to the visual cortex and conscious visual perception. Scientists have long known this sorting-out process depends on waves of activity that spontaneously excite cells in the inner retina. They did not know until now that the waves are influenced by a light-sensitive type of cell called intrinsically photosensitive retinal ganglion cells (ipRGCs).

About a decade ago, a team Berson led at Brown discovered the ipRGCs, which are the first light-sensitive cells to develop in the eye. They reside in the inner retina, the home of retinal cells that send visual information directly to the brain. The outer retina is where the more familiar rods and cones sense light. Early in life, when the brain is segregating nerve endings into distinct regions in the dLGN, the two retinal layers are not connected, so until ipRGCs were discovered there was no reason to believe that light would affect the sorting process.

The new research doesn't say anything definitive about the consequences of light exposure at this stage for eyesight in adults, especially given that some mammals (such as monkeys) experience this developmental stage in utero.

"Whether different animals in nature are exposed to enough light to induce a change in segregation patterns is unclear," Renna said.

But the research shows that light exposure does improve how well the sorting goes, Berson said, and the work advances neuroscientists' understanding of the eye-distinction process, which is widely studied as a model of "activity-driven" neural development.

To assess the effect of light on retinal waves, Renna used electrodes to record the activity of cells in the inner retinas of newborn mice, first recording in the dark, then in the light, and then again in the dark. In every case retinas experienced waves, but when the retinas were exposed to light, the waves lasted about 50 percent longer.

Renna then tested whether the light-sensitive cells were really creating this wave-lengthening effect by repeating the study in "knock-out" mice in which the ability of the ipRGCs to sense light had been genetically abolished. With the cells disabled, exposure to light no longer made any difference in the duration of the waves.

Finally, to assess the effect of light on the left-right sorting process in the dLGN, Renna examined the tissues from normal mice and the mice whose ipRGCs couldn't sense light. In each case he fluorescently labeled the nerve endings from one eye red and the other green. A computer comparison of the tissues showed that the normal mice developed a higher degree of segregation between red and green than the knockout mice. In other words, the ability of ipRGCs to sense light improved sorting out one eye from another in the dLGN.

Twinkling tadpoles

In his study, Aizenman collaborated with Arto Nurmikko, professor of engineering and physics, to investigate the function of in the optic tectum of tadpole brains. They flooded the tectal neurons in live tadpoles with a molecule that makes calcium ions fluoresce. As whole networks of neurons became active, they'd take in the ions and glow. The researchers recorded the tadpoles with a high-resolution, high-speed camera that could capture the millisecond-to-millisecond activity of the neurons.

Led in the lab by engineering graduate student Heng Xu, the lead author, and postdoctoral researcher Arseny Khakhalin, the team reared some young tadpoles under normal conditions of 12 hours of light and 12 hours of darkness during the crucial days of development when the tectum is developing. They reared others in the dark, and still others with a chemical that blocks the activity of NMDA receptors, a subtype of receptor to the neurotransmitter glutamate, that is known to promote neural rewiring.

Then they exposed all the tadpoles, however they were reared, to blue LED light flashes delivered via a fiber optic cable mounted next to the eye.

What they found over the course of several experiments was that the neural networks in the tectums of tadpoles reared under normal conditions developed a faster, more cohesive, and stronger response (in terms of the number of neurons) to light.

The tectal neural networks of tadpoles kept in the dark during development failed to progress at all. Those whose NMDA receptors were blocked occupied a middle ground, showing more progress than dark-reared tadpoles but less than normal tadpoles. Tadpoles, they found, train their brains with the light they see.

Aizenman said he hopes the calcium ion imaging technique will prove useful in a wide variety of other neuroscience experiments, including studying how tadpoles neurally encode behaviors such as fleeing when they see certain stimuli.

In the meantime, his team and Berson's have added to the understanding scientists have been building of how creatures turn the somewhat mushy approximations of their brains at birth into high-functioning animal minds.

"That's what everybody is after," Aizenman said. "How do you get this fine-tuned, finely wired brain in the first place?"

Berson and Renna's work was funded by the National Institutes of Health. Aizemnan and Nurmikko's research received support from the National Science Foundation, the NIH's National Eye Institute, and the Whitehall Foundation.

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Source of Key Brain Function Located: How to Comprehend a Scene in Less Than a Second

Source of Key Brain Function Located: How to Comprehend a Scene in Less Than a Second

  9:44:00 PM    Science Lover

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Scientists at the University of Southern California have pinned down the region of the brain responsible for a key survival trait: our ability to comprehend a scene -- even one never previously encountered -- in a fraction of a second.

The intraparietal sulcus (IPS), a groove in the brain 
closer to the top of the head, is engaged with 
implementing visual attention. Above: Lateral surface 
of left cerebral hemisphere, viewed from the side. 
Intraparietal sulcus visible at upper right, running 
horizontally. (Credit: Gray / Wikimedia Commons, 
public domain)

The key is to process the interacting objects that comprise a scene more quickly than unrelated objects, according to corresponding author Irving Biederman, professor of psychology and computer science in the USC Dornsife College and the Harold W. Dornsife Chair in Neuroscience.

The study appears in the June 1 issue of The Journal of Neuroscience.

The brain's ability to understand a whole scene on the fly "gives us an enormous edge on an organism that would have to look at objects one by one and slowly add them up," Biederman said. What's more, the interaction of objects in a scene actually allows the brain to identify those objects faster than if they were not interacting.

While previous research had already established the existence of this "scene-facilitation effect," the location of the part of the brain responsible for the effect remained a mystery. That's what Biederman and lead author Jiye G. Kim, a graduate doctoral student in Biederman's lab, set out to uncover with Chi-Hung Juan of the Institute of Cognitive Neuroscience at the National Central University in Taiwan.

"The 'where' in the brain gives us clues as to the 'how,'" Biederman said. This study is the latest in an ongoing effort by Biederman and Kim to unlock the complex way in which the brain processes visual experience. The goal, as Biederman puts it, is to understand "how we get mind from brain."

To find out the "where" of the scene-facilitation effect, the researchers flashed drawings of pairs of objects for just 1/20 of a second. Some of these objects were depicted as interacting, such as a hand grasping for a pen, and some were not, with the hand reaching away from the pen. The test subjects were asked to press a button if a label on the screen matched either one of the two objects, which it did on half of the presentations.

A recent study by Kim and Biederman suggested that the source of the scene-facilitation effect was the lateral occipital cortex, or LO, which is a portion of the brain's visual processing center located between the ear and the back of the skull. However, the possibility existed that the LO was receiving help from the intraparietal sulcus, or IPS, which is a groove in the brain closer to the top of the head.

The IPS is engaged with implementing visual attention, and the fact that interacting objects may attract more attention left open the possibility that perhaps it was providing the LO with assistance.

While participants took the test, electromagnetic currents were used to alternately zap subjects' LO or IPS, temporarily numbing each region in turn and preventing it from providing assistance with the task.

All of the participants were pre-screened to ensure they could safely receive the treatment, known as transcranial magnetic stimulation (TMS), which produces minimal discomfort.

By measuring how accurate participants were in detecting objects shown as interacting or not interacting when either the LO or IPS were zapped, researchers could see how much help that part of the brain was providing. The results were clear: zapping the LO eliminated the scene-facilitation effect. Zapping the IPS, however, did nothing.

When it comes to providing a competitive edge in identifying objects that are part of an interaction, the lateral occipital cortex appears to be working alone. Or, at least, without help from the intraparietal sulcus.

The research was funded through Biederman's National Science Foundation grants as well as a competitive grant awarded to Kim by the National Science Foundation designed to allow US students to collaborate with scientists in East Asia. Kim worked with Chi-Hung Juan, an expert in transcranial magnetic stimulation.

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Mechanism of Long-Term Memory Identified

Mechanism of Long-Term Memory Identified

  12:59:00 AM    Science Lover

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Using advanced imaging technology, scientists from the Florida campus of The Scripps Research Institute have identified a change in chemical influx into a specific set of neurons in the common fruit fly that is fundamental to long-term memory.

Researchers have identified a change in chemical influx 
into a specific set of neurons in the common fruit fly that 
is fundamental to long-term memory. 
(Credit: © Sebastian Kaulitzki / Fotolia)

The study was published in the April 13, 2011 issue of The Journal of Neuroscience.

"In studying fruit flies' learning and long-term memory storage, we observed an increase in calcium influx into a specific set of brain neurons in normal fruit flies that was absent in 26 different mutants known to impair long-term memory,," said Ron Davis, chair of the Scripps Research Department of Neuroscience, who led the study. "This logical conclusion is that this increase, which we call a memory trace, is a signature component of long-term memory."

The memory trace in question is an increased influx of calcium into a set of neurons after long-term memory forms in a part of the insect brain known as mushroom bodies, a pair of oversized lobes known to mediate learning and memory, particularly the memories of smell. They have been compared to the hippocampus, a site of memory formation in humans.

Increases in calcium influx also occur with learning in other animal models, Davis said, and it seems highly likely a similar correlation exists in humans.

Measuring Memory Traces


To measure the changes in the Drosophila neurons, Davis and his colleagues used functional optical imaging, an advanced technology that his laboratory helped pioneer for the study of learning and memory. Using protein sensors that become fluorescent when calcium levels are increased, the team was able to highlight changes in the levels of calcium influx into the mushroom body neurons in response to odor learning. These observed memory traces occur in parallel with behavioral changes.

Interestingly, these memory traces occur only with spaced conditioning -- where the insects receive multiple episodes of learning but with periods of rest between each episode. Spaced conditioning is required for long-term memories to form.

In an earlier study last December, also published in The Journal of Neuroscience, Davis found not only that fruit flies receiving spaced conditioning exhibited a long-term memory trace, but also that their memories lasted between four and seven days. In flies that were given a single episode of learning, memory formation lasted only a day and the long-term memory trace failed to form. These two studies are the newest in a series of six studies on the topic, including those published in the journal Neuron in 2004 and 2006, Cell in 2005, and Nature Neuroscience in 2008. Davis reviewed all of his studies of memory traces in the most recent issue of Neuron.

"The phenomenon of spaced conditioning is conserved across all species," Davis said. "No one really knows why it's important to long-term memory formation but there appears to be something magical about that rest period during learning."

The study was supported by the National Institutes of Health.

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Wireless Heart Implant Reduces HospitalizationsA pressure-sensing implant helps heart-failure patients stay healthy.

Wireless Heart Implant Reduces HospitalizationsA pressure-sensing implant helps heart-failure patients stay healthy.

  10:29:00 AM    Science Lover

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A wireless sensor developed by Atlanta-based CardioMEMS reduced the number of hospitalizations in patients with heart failure by 39 percent. The tiny implant monitors fluid pressure in the pulmonary artery and transmits the data wirelessly to physicians, who can adjust patients' medications accordingly.

Researchers say the sensor may significantly lower health-care costs and improve quality of life for people with congestive heart failure. The device is one of several prototypes being developed by CardioMEMS and other medical implant companies to provide continuous, personalized wireless monitors for such patients.

Pressure patrol: A new wireless sensor the size of a paper
clip measures fluid pressure in the pulmonary artery. The
metalloops on either end anchor the sensor to the artery
walls, while the self-contained transducer in the middle
takes pressure readings. The sensor is activated by radio
frequency, transmitting data wirelessly to physicians
via modem.Credit: OSU Medical Center/CardioMEMS

"I think the study shows this kind of device is incredibly useful in improving outcomes in patients and directing therapy," says Marc Jay Semigran, medical director of the Mass General Heart Failure and Cardiac Transplant Program, who was not involved in the study.

Hospitals admit 1.1 million adults each year for congestive heart failure, a condition in which pressure builds up in the circulatory system and the heart fails to pump blood adequately to the rest of the body. The American Heart Association estimates that the chronic condition costs the health-care system $29 billion per year. CardioMEMS aims to reduce that figure by providing an accurate way to continuously monitor patients after they've left the hospital.

The device is implanted in the pulmonary artery, an area that carries a low risk of clotting. It is smaller than other implants under development because it does not require a battery or a wire to take pressure readings. Two metal loops hold it to the sides of the artery, and a pressure transducer records the flow of fluids through the blood vessel. The sensor is powered externally by a receiver built into a pillow. When a patient lies on the pillow, the sensor is activated to take measurements and send them wirelessly to a computer, where physicians can review the data. In a large six-month clinical trial published this month in the Lancet, 550 patients from 64 centers across the United States were equipped with the device and instructed to take readings once a day. Patients were divided into two groups. The first took medication instructions from physicians who monitored the sensor data. The second took instructions from physicians who relied on traditional indicators like weight and blood pressure. Over the six months, patients in the first group experienced 39 percent fewer hospitalizations than those in the second.

Today, physicians often assess pulmonary pressure when initially evaluating a patient, but they do so far less frequently in follow-up evaluation. That's because the measurement requires doctors to snake a catheter into a patient's heart and inflate a balloon. However, fluid pressure changes by the day, and monitoring those fluctuations continuously is essential to treating heart failure effectively.

"Over the years, we found that pressures go up long before patients develop symptoms and call a doctor to say they're sick," says Philip Adamson, director of the Heart Failure Institute at Oklahoma Heart Hospital, the principal investigator in the CardioMEMS clinical trial. "By utilizing the pressure sensor information, we're given the ability to make changes in medications long before patients bring themselves to the doctor, and that's how we reduced hospitalizations."

Over the past few years, several companies have jockeyed to be first on the market with a continuous pressure-sensing cardiac implant. In 2007, Medtronic failed to get FDA approval for its sensor, a stopwatch-size, battery-powered implant wired to the heart. The device reduced hospitalizations by 22 percent, but FDA regulators did not consider that worth the risks associated with implanting it. Researchers also found that the wire connecting the sensor to the heart degraded over time.

CardioMEMS is currently seeking approval for its sensor from the U.S. Food and Drug Administration and has submitted results from the clinical study for FDA review. In the next two or three years, the company plans to integrate the sensor's receiver into a patient's cell phone, which will be able to instantly read pressure data and upload it for both physicians and patients to review.

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Robot Arm Improves Performance of Brain-Controlled Device

Robot Arm Improves Performance of Brain-Controlled Device

  10:34:00 AM    Science Lover

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The performance of a brain-machine interface designed to help paralyzed subjects move objects with their thoughts is improved with the addition of a robotic arm providing sensory feedback, a new study from the University of Chicago finds.

During the experiment, monkeys used their brain signals to move a computer cursor (red circle) to randomly placed targets (squares). When visual and proprioceptive feedback were included, the monkey's hand was moved by a robotic exoskeleton. The additional sensory information resulted in the cursor hitting the target faster and more directly. (Credit: Courtesy, with permission: Hatsopoulos, et al. The Journal of Neuroscience 2010.)

Devices that translate brain activity into the movement of a computer cursor or an external robotic arm have already proven successful in humans. But in these early systems, vision was the only tool a subject could use to help control the motion.

Adding a robot arm that provided kinesthetic information about movement and position in space improved the performance of monkeys using a brain-machine interface in a study published December 14 in The Journal of Neuroscience. Incorporating this sense may improve the design of "wearable robots" to help patients with spinal cord injuries, researchers said.

"A lot of patients that are motor-disabled might have partial sensory feedback," said Nicholas Hatsopoulos, PhD, Associate Professor and Chair of Computational Neuroscience at the University of Chicago. "That got us thinking that maybe we could use this natural form of feedback with wearable robots to provide that kind of feedback."

In the experiments, monkeys controlled a cursor without actively moving their arm via a device that translated activity in the primary motor cortex of their brain into cursor motion. While wearing a sleeve-like robotic exoskeleton that moved their arm in tandem with the cursor, the monkey's control of the cursor improved, hitting targets faster and via straighter paths than without the exoskeleton.

"We saw a 40 percent improvement in cursor control when the robotic exoskeleton passively moved the monkeys' arm," Hatsopoulos said. "This could be quite significant for daily activities being performed by a paralyzed patient that was equipped with such a system."

When a person moves their arm or hand, they use sensory feedback called proprioception to control that motion. For example, if one reaches out to grab a coffee mug, sensory neurons in the arm and hand send information back to the brain about where one's limbs are positioned and moving. Proprioception tells a person where their arm is positioned, even if their eyes are closed.

But in patients with conditions where sensory neurons die out, executing basic motor tasks such as buttoning a shirt or even walking becomes exceptionally difficult. Paraplegic subjects in the early clinical trials of brain-machine interfaces faced similar difficulty in attempting to move a computer cursor or robot arm using only visual cues. Those troubles helped researchers realize the importance of proprioception feedback, Hatsopoulos said.

"In the early days when we were doing this, we didn't even consider sensory feedback as an important component of the system," Hatsopoulos said. "We really thought it was just one-way: signals were coming from the brain, and then out to control the limb. It's only more recently that the community has really realized that there is this loop with feedback coming back."

Reflecting this loop, the researchers on the new study also observed changes in the brain activity recorded from the monkeys when sensory feedback was added to the set-up. With proprioception feedback, the information in the cell firing patterns of the primary motor cortex contained more information than in trials with only visual feedback, Hatsopoulos said, reflecting an improved signal-to-noise ratio.

The improvement seen from adding proprioception feedback may inform the next generation of brain-machine interface devices, Hatsopoulos said. Already, scientists are developing different types of "wearable robots" to augment a person's natural abilities. Combining a decoder of cortical activity with a robotic exoskeleton for the arm or hand can serve a dual purpose: allowing a paralyzed subject to move the limb, while also providing sensory feedback.

To benefit from this solution, a paralyzed patient must have retained some residual sensory information from the limbs despite the loss of motor function -- a common occurrence, Hatsopoulos said, particularly in patients with ALS, locked-in syndrome, or incomplete spinal cord injury. For patients without both motor and sensory function, direct stimulation of sensory cortex may be able to simulate the sensation of limb movement. Further research in that direction is currently underway, Hatsopoulos said.

"I think all the components are there; there's nothing here that's holding us back conceptually," Hatsopoulos said. "I think using these wearable robots and controlling them with the brain is, in my opinion, probably the most promising approach to take in helping paralyzed individuals regain the ability to move."

Funding for the research was provided by the National Institute of Neurological Disorders and Stroke and the Paralyzed Veterans of America Research Foundation.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect to us.

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Nerves, Muscle Regenerated With Sodium Ions

Nerves, Muscle Regenerated With Sodium Ions

  12:35:00 AM    Science Lover

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Sodium gets a bad rap for contributing to hypertension and cardiovascular disease. Now biologists at Tufts University's School of Arts and Sciences have discovered that sodium also plays a key role in initiating a regenerative response after severe injury. The Tufts scientists have found a way to regenerate injured spinal cord and muscle by using small molecule drugs to trigger an influx of sodium ions into injured cells.

Tufts biologists have regenerated spinal cord and 
muscle by using a "pharmaceutical cocktail" to 
trigger an influx of sodium ions into injured cells. The 
treatment method is most directly applicable to spinal
cord repair and limb loss, which are significant problems
worldwide, but the proof-of-principle may apply to many 
complex organs and tissues. The Tufts team found that a 
localized increase in sodium ions was necessary for young 
tadpoles to regenerate their tails -- complex appendages
containing spinal cord, muscle and other tissue. Like 
human beings, who regenerate fingertips only as children, 
tadpoles lose the ability to regenerate their tail with 
age. The Tufts biologists showed that such "refractory" 
tadpoles whose tails had been removed could be induced 
to make a perfect new tail by only an hour of treatment. 
The tadpole on the left, which received the "cocktail" to 
trigger an influx of sodium ions, grew a perfectly formed tail. 
The control tadpole on the right did not regenerate. This 
approach breaks new ground in biomedicine because it 
requires no gene therapy; can be effectively administered
for some time after an injury has occurred; and is bioelectric, 
rather than chemically based. (Credit: Ai-Sun Tseng and 
Michael Levin-Tufts University)

The approach breaks new ground in the field of biomedicine because it requires no gene therapy; can be administered after an injury has occurred and even after the wound has healed over; and is bioelectric, rather than chemically based.

In a paper appearing as the cover story of the September 29, 2010, issue of the Journal of Neuroscience, the Tufts team reported that a localized increase in sodium ions was necessary for young Xenopus laevis tadpoles to regenerate their tails - complex appendages containing spinal cord, muscle and other tissue.

Like human beings, who regenerate fingertips only as children, these tadpoles lose the ability to regenerate their tail with age. Most remarkably, it was shown that such "refractory" tadpoles whose tails had been removed could be induced to make a perfect new tail by only an hour of treatment with a specific drug cocktail.

The findings have tremendous implications for treating wounds sustained in war as well as accidental injuries. The treatment method used is most directly applicable to spinal cord repair and limb loss, which are highly significant medical problems world-wide. It also demonstrates a proof-of-principle that may be applicable to many complex organs and tissues.

"We have significantly extended the effective treatment window, demonstrating that even after scar-like wound covering begins to form, control of physiological signals can still induce regeneration. Artificially causing an influx of sodium for just one hour can overcome a variety of problems, such as the decline in regenerative ability that comes with age and the effect of regeneration-blocking drugs," said Tufts Professor of Biology Michael Levin, Ph.D., corresponding author on the paper and director of the Center for Regenerative and Developmental Biology at Tufts. Co-authors were Research Associate Ai-Sun Tseng, Postdoctoral Associate Wendy S. Beane, Research Associate Joan M. Lemire, and Alessio Masi, a former post-doctoral associate in Levin's laboratory.

The transport of ions in and out of cells is regulated by electronic security doors, or gates, that let in specific ions under certain circumstances. A role for sodium current in tissue regeneration had been proposed in the past, but this is the first time the molecular-genetic basis of the ion flow has been identified, and a specific drug-based treatment demonstrated. Until now, advances in this model system had involved administering therapies before the injury was sustained.

"This is a novel, biomedically-relevant approach to inducing regeneration of a complex appendage," noted Levin.

The Tufts research established a novel role in regeneration for the sodium channel Nav1.2, a crucial component of nerve and cardiac function. It showed that local, early increase in intracellular sodium is required for initiating regeneration following Xenopus tail amputation, while molecular and pharmacological inhibition of sodium transport causes regenerative failure. The new treatment induced regeneration only of correctly-sized and patterned tail structures and did not generate ectopic or other abnormal growth.

"The ability to restore regeneration using a temporally-controllable pharmacological approach not requiring gene therapy is extremely exciting," said the researchers.

Of critical importance, they said, was the discovery that the tail could be induced to regenerate as late as 18 hours after amputation, revealing that tissues normally fated for regenerative failure still maintain their intrinsic characteristics and can be programmed to reactivate regeneration.

Amphibians such as frogs can restore organs lost during development, including the lens and tail. The frog tail is a good model for human regeneration because it repairs injury in the same way that people do: each tissue makes more of itself. (In contrast, regeneration in some other animals occurs through transdifferentiation (one cell type turns into another cell type) or adult stem cell differentiation. Furthermore, though small, the Xenopus larval tail is complex, with muscle, spinal cord, peripheral nerves and vasculature cells.

The National Institutes of Health, National Highway Traffic Safety Administration, Department of Defense and Defense Advanced Research Projects Agency funded the work.

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