Category: Neuroscience

Patrik Verstreken (VIB/K.U.Leuven) has discovered the mechanism that ensures neurons can continue to send the right signals for long consecutive periods — a process that is disrupted in neurological diseases such as Parkinson's. Verstreken and his colleagues discovered that an enzyme called Skywalker controls the subtle balance in communication.

"I hope that unraveling the way Skywalker works will not only teach us more about the way neurons communicate with each other but will also lead to new diagnostics and therapies for neurological diseases such as Parkinson's," says Verstreken.

Communication between brain cells

Brain disorders take a major toll on society. More than 8% of the population in the West depends on analgesics. Twenty per cent suffers from a mental disturbance and the number of people suffering from the effects of neurological diseases is estimated at 1 billion. Many of these problems are caused by the disruption of communication between brain cells. Hence, finding a solution depends on understanding this communication in the smallest details.

Communication between brain cells occurs at the synapses, where an electrical signal is passed via a vesicle (a small membrane-enclosed sac with signaling substances). The vesicle releases the signaling substances, thus activating another brain cell.

An eye for the proper balance

The vesicles are reused several times. This results in the gradual degradation of the proteins they need for carrying out their function properly, which in turn affects the release of signaling substances. How the vesicles are kept operational during this recycling process was a mystery until now. Most types of cells have incorporated an extra step into this recycling process via special cell compartments called endosomes. In the endosomes, vesicle proteins are sorted to ensure optimal functioning of the recycled vesicles.

However, it was not clear whether this extra step was relevant for vesicle recycling in brain cells. Various studies seemed to demonstrate that it was in fact missing in brain cells.

Skywalker regulates communication between brain cells

Patrik Verstreken and his colleagues have now discovered an enzyme, christened Skywalker, which regulates this extra step. The VIB researchers tested fruit flies unable to produce Skywalker. In these so-called sky flies, they noticed that broken-down proteins from the vesicles were more easily replaced, and that many more signaling substances were released than in the synapses of normal fruit flies. In other words, a lack of Skywalker increases the signal between two brain cells, resulting in overstressed flies.

But the discovery that inhibition of Skywalker leads to a stronger signal between brain cells offers possibilities for the fight against neurological diseases such as Parkinson's. In the early stages of these diseases, the signals between brain cells are too weak. Verstreken wants to study this further, but realizes that it will be an enormous challenge to find ways to maintain the subtle balance that ensures optimal communication.

---

Journal Reference:

1. Valerie Uytterhoeven, Sabine Kuenen, Jaroslaw Kasprowicz, Katarzyna Miskiewicz, Patrik Verstreken. Loss of Skywalker reveals synaptic endosomes as sorting stations for synaptic vesicle proteins. Cell, Volume 145, Issue 1, 117-132, 1 April 2011 DOI: 10.1016/j.cell.2011.02.039

The moment we open our eyes, we perceive the world with apparent ease. But the question of how neurons in the retina encode what we "see" has been a tricky one. A key obstacle to understanding how our brain functions is that its components — neurons — respond in highly nonlinear ways to complex stimuli, making stimulus-response relationships extremely difficult to discern.

Now a team of physicists at the Salk Institute for Biological Studies has developed a general mathematical framework that makes optimal use of limited measurements, bringing them a step closer to deciphering the "language of the brain." The approach, described in the current issue of the Public Library of Science, Computational Biology, reveals for the first time that only information about pairs of temporal stimulus patterns is relayed to the brain.

"We were surprised to find that higher-order stimulus combinations were not encoded, because they are so prevalent in our natural environment," says the study's leader Tatyana Sharpee, Ph.D., an assistant professor in the Computational Neurobiology Laboratory and holder of the Helen McLorraine Developmental Chair in Neurobiology. "Humans are quite sensitive to changes in higher-order combinations of spatial patterns. We found it not to be the case for temporal patterns. This highlights a fundamental difference in the spatial and temporal aspects of visual encoding."

The human face is a perfect example of a higher-order combination of spatial patterns. All components — eyes, nose, mouth — have very specific spatial relationships with each other, and not even Picasso, in his Cubist period, could throw the rules completely overboard.

Our eyes take in the visual environment and transmit information about individual components, such as color, position, shape, motion and brightness to the brain. Individual neurons in the retina get excited by certain features and respond with an electrical signal, or spike, that is passed on to visual centers in the brain, where information sent by neurons with different preferences is assembled and processed.

For simple sensory events — like turning on a light, for example — the brightness correlates well with the spike probability in a luminance-sensitive cell in the retina. "However, over the last decade or so, it has become apparent that neurons actually encode information about several features at the same time," says graduate student and first author Jeffrey D. Fitzgerald.

"Up to this point, most of the work has been focused on identifying the features the cell responds to," he says. "The question of what kind of information about these features the cell is encoding had been ignored. The direct measurements of stimulus-response relationships often yielded weird shapes, and people didn't have a mathematical framework for analyzing it."

To overcome those limitations, Fitzgerald and colleagues developed a so-called minimal model of the nonlinear relationships of information processing systems by maximizing a quantity that is referred to as noise entropy. The latter describes the uncertainty about a neuron's probability to spike in response to a stimulus.

When Fitzgerald applied this approach to recordings of visual neurons probed with flickering movies, which co-author Lawrence Sincich and Jonathan Horton at the University of California, San Francisco, had made, he discovered that on average, first-order correlations accounted for 78 percent of the encoded information, while second-order correlations accounted for more than 92 percent. Thus, the brain received very little information about correlations that were higher than second order.

"Biological systems across all scales, from molecules to ecosystems, can all be considered information processors that detect important events in their environment and transform them into actionable information," says Sharpee. "We therefore hope that this way of 'focusing' the data by identifying maximally informative, critical stimulus-response relationships will be useful in other areas of systems biology."

The work was funded in part by the National Institutes of Health, the Searle Scholar Program, The Alfred P. Sloan Fellowship, the W.M. Keck Research Excellence Award and the Ray Thomas Edwards Career Development Award in Biomedical Sciences

---

Journal Reference:

1. Jeffrey D. Fitzgerald, Lawrence C. Sincich, Tatyana O. Sharpee. Minimal Models of Multidimensional Computations. PLoS Computational Biology, 2011; 7 (3): e1001111 DOI: 10.1371/journal.pcbi.1001111

 Biologists at UC San Diego have identified the molecular mechanisms triggered by starvation in fruit flies that enhance the nervous system's response to smell, allowing these insects and presumably vertebrates — including humans — to become more efficient and voracious foragers when hungry.

Their discovery of the neural changes that control odor-driven food searches in flies, which they detail in a paper in the April 1 issue of the journal Cell, could provide a new way to potentially regulate human appetite.

By developing drugs to enhance or minimize the activity of nerve-signaling chemicals called neuropeptides released during starvation to enhance the sense of smell, scientists may be able to decrease the propensity among obese individuals to overeat when encountering delectable food odors, if similar molecular mechanisms exist in humans. They could also increase the appetites among the infirm, elderly and others who may have problems eating enough. The method could even be used to improve the growth of farmed animals or to reduce feed waste.

"Olfaction makes important contributions to the perception of food quality and profoundly influences our dietary choices," said Jing Wang, an associate professor of biology at UC San Diego who headed the research effort. His team identified a neuropeptide and a receptor neuron controlling the olfactory behavior in the fly that could be targeted by drugs to effect changes in appetite that are normally regulated by an organism's insulin levels, which changes radically when organisms are satiated or starved.

"Our studies in Drosophila address an important question — how starvation modulates olfactory processing," he added. "We were surprised to find that starvation modulation of smell happens at the periphery, because most of the literature on feeding regulations is about the function of the hypothalamus. There are hints to suggest that this kind of starvation modulation in the peripheral olfactory system is present in vertebrate systems as well."

While scientists had previously identified similar neuropeptides that control feeding behavior in vertebrates, not much was known until now about how these molecules control olfaction or an organism's behavior. Researchers had previously found that the injection into the hypothalamus of insulin, the hormone that regulates blood glucose levels, reduces food intake in rodents, for example, but how insulin affects olfactory circuits in a way that altered an organism's behavior was not well understood.

Wang and his team of UCSD biologists — Cory Root, Kang Ko and Amir Jafari — believed that by looking at the molecular mechanisms that enable fruit flies to improve their search for food when their insulin levels were low following a period of starvation the scientists would obtain a better understanding of this process. They used a computerized system to monitor over time the position of starved or well-fed flies as the flies circled around a droplet of apple cider vinegar, which served as a delectable food source.

"During the 10 min observation period," the researchers wrote in their paper, "starved flies spend most of the time walking near the food source, whereas fed flies wander in the entire arena with a preference for the perimeter."

The researchers found that surgical removal of the antennae used by the flies to sense odor destroyed the propensity of starved flies to hone in on the food source as did genetically suppressing the production of short neuropeptide F receptors, which the scientists found, increases in response to starvation or a drop in insulin levels. Using two-photon microscopy, a state-of-the-art imaging system, the researchers found starvation-dependent changes of olfactory response in specific neurons.

"The notion that starvation modulation at the peripheral olfactory system is linked to insulin signaling has potential implications for the therapeutic intervention of the seemingly unstoppable obesity epidemic trend in a large percentage of the population," said Wang.

He said his team's study has identified the insulin receptor, PI3K, and the short neuropeptide F receptor, which is also modulated by insulin levels, as potential molecular targets for controlling appetite in humans and other vertebrates. However, he added that more research is needed to know whether and to what extent insulin levels control olfactory sensitivity in human.

"Learning how olfactory neural circuits impact dietary choices is relevant towards better understanding factors that contribute to obesity and eating disorders," he added.

Based on their findings, the UCSD biologists have filed a patent application on their discovery, contending that blocking PI3K, a signaling molecule of the insulin receptor, could improve appetites in the infirm and elderly and that the intranasal delivery of insulin could decrease appetite in obese individuals. They also contend in their patent application that suppressing PI3K will increase feeding in farmed animals and reduce feed waste.

The researchers' work was funded by the National Institute on Deafness and Other Communication Disorders.

---

Journal Reference:

1. Cory M. Root, Kang I. Ko, Amir Jafari, Jing W. Wang. Presynaptic Facilitation by Neuropeptide Signaling Mediates Odor-Driven Food Search. Cell, Volume 145, Issue 1, 133-144, 1 April 2011 DOI: 10.1016/j.cell.2011.02.008

 Human beings understand words reflected in a mirror without thinking about it, just like those written normally, at least for a few instants. Researchers from the Basque Centre on Cognition, Brain and Languages (Spain) have shown this in a study that could also help to increase our understanding of the phenomenon of dyslexia.

Most people can read texts reflected in a mirror slowly and with some effort, but a team of scientists from the Basque Centre on Cognition, Brain and Language (BCBL) has shown for the first time that we can mentally turn these images around and understand them automatically and unconsciously, at least for a few instants.

"At a very early processing stage, between 150 and 250 milliseconds, the visual system completely rotates the words reflected in the mirror and recognises them," says Jon Andoni Duñabeitia, lead author of the study, "although the brain then immediately detects that this is not the correct order and 'remembers' that it should not process them in this way."

In order to carry out this study, which has been published in the journal NeuroImage, the researchers used electrodes to monitor the brain activity of 27 participants while carrying out two experiments in front of a computer screen.

In the first, the participants were shown words with some of the letters and other information rotated for 50 milliseconds (an imperceptible flash, which is processed by the brain); while in the second case the entire word in the mirror was rotated (for example HTUOM INSTEAD OF MOUTH).

The results of the encephalogram showed in both cases that, at between 150 and 250 milliseconds, the brain's response upon seeing the words as reflected in the mirror was the same as when they are read normally.

Better understanding of dyslexia

"These results open a new avenue for studying the effects of involuntary rotation of letters and words in individuals with reading difficulties (dyslexia) and writing problems (dysgrafia)," Duñabeitia explains.

The researcher gives reassurance to parents who worry when their children reverse their letters when they start to write: "This is the direct result of the mirror rotation property of the visual system." In fact, it is common for children to start to write this way until they learn the "established" forms at school.

"Now we know that rotating letters is not a problem that is exclusive to some dyslexics, since everybody often does this in a natural and unconscious way, but what we need to understand is why people who can read normally can inhibit this, while others with difficulties in reading and writing cannot, confusing 'b' for 'd', for example," explains Duñabeitia.

The scientific community has yet to discover how reading, a skill that is learnt relatively late in human development, can inhibit mental rotation in a mirror, a visual capacity that is common to many animals.

"A tiger is a tiger on the right side and the left side, but a word read in the mirror loses its meaning — although now we know that it is not as incomprehensible for our visual system as we thought, because it is capable of processing it as if it were correct," the researcher concludes.

---

Journal Reference:

1. Jon Andoni Duñabeitia, Nicola Molinaro, Manuel Carreiras. Through the looking-glass: Mirror reading. NeuroImage, 2011; 54 (4): 3004 DOI: 10.1016/j.neuroimage.2010.10.079

— If, as Shakespeare's Juliet declared, a rose by any other name smells as sweet — to you and to me and to anyone else who sniffs it — then one might assume that our odor-sensing nerve cells are all wired in the same way. Alas, they are not, according to a new study from scientists at The Scripps Research Institute.

The researchers developed a new virus-based technique for highlighting individual nerve pathways, then applied it to the olfactory systems of mice. They found that mouse olfactory neurons send signals to two key processing regions of the brain in ways that differ significantly from one mouse to another — a diversity that is likely to be found in humans, too.

"This shows that we still have a lot to learn about olfactory perception and how the brain is wired in general," said Kristin Baldwin, an assistant professor at Scripps Research and senior author of the study, published online on March 30, 2011, by the journal Nature.

The Expected Pattern

For the initial stages of odor perception, the wiring pattern in mammals is already well known. Each primary olfactory neuron has root-like input fibers, embedded in the nasal lining, which express odor-specific receptors. When these receptors detect the appropriate "odorant" chemical, their host neuron becomes activated and sends a signal via its output fiber to an initial processing center, the olfactory bulb. There, the signal terminates in a spherical bundle of fibers known as a glomerulus.

"These odor-specific glomeruli are ordered in a very consistent, stereotyped way in the olfactory bulb so that the spatial pattern of activity that an odor elicits is nearly identical among individuals," said Sulagna Ghosh, a graduate student in Baldwin's lab and the study's first author. "Just by observing which sets of glomeruli are activated in a given mouse, we can predict which smell the animal is perceiving."

But when these olfactory signals go from glomeruli to higher processing centers in the olfactory cortex, does this stereotyped pattern continue? That's the question Ghosh, Baldwin, and their colleagues set out to answer. "We see stereotyped maps in the cortex for other senses such as vision and touch," said Ghosh. "The same regularity is seen in the olfactory systems of flies, but in mammals, the wiring diagram of the olfactory brain has remained poorly understood."

A New Tracing Technique

Signals from activated glomeruli are relayed to higher processing regions of the olfactory cortex via so-called mitral and tufted (MT) neurons. Until now, researchers haven't had precise-enough tools to trace the connections in mammals from an individual glomerulus to its dedicated MT neurons and on to their terminals in the olfactory cortex.

However, Ghosh and her colleagues were able to develop a technique by which they could deliver a highly efficient fluorescent-tracer-expressing virus to individual glomeruli. "Using this, we could tag with different fluorescent colors the separate MT neurons serving a single glomerulus, and then trace their output fibers, called axons, into the cortex," said Ghosh.

Surprising Diversity

Ghosh's technique enabled her to trace the branching axons of any MT neuron to two cortical processing centers, the anterior olfactory nucleus pars externa (AON pE) and the piriform cortex. In both regions, the locations where the MT axons terminated no longer showed the clear pattern seen in the olfactory bulb.

"They turned out to be much more diverse and widely distributed than we expected," said Ghosh.

To help Ghosh and her colleagues compare these patterns from one mouse to another, a collaborating neuroinformatics expert, graduate student Stephen Larson of the University of California, San Diego, set up a software-based 3D anatomical "reference brain." The Scripps Research team then mapped their nerve tracings from individual mouse studies onto this reference.

"We found that MT projections from the same glomerulus in different mice were no more alike in where they landed than were projections from different glomeruli," said Ghosh. In other words, the wiring from the olfactory bulb to these two higher-processing regions is unique in each mouse — and because mice are at least a rough model for other mammals, it seems likely this same olfactory wiring is also unique for each human.

This is puzzling for two reasons: First, it leaves unclear how, during fetal development, axons from adjacent and seemingly identical MT neurons find their way to such different destinations in the olfactory cortex. Second, it begs the question of how mammals can experience the same odor in the same way, if each individual's olfactory cortex has such unique wiring.

Ghosh suggests that the regularity of olfactory experiences — which we infer from our similar descriptions of odors — may arise from a third set of MT neuron projections, into the amygdala, a brain region best known for its role in processing emotion. "The amygdala was the one region we were unable to look at because its distance is greater than our tracer could reach," she said. "It might be an area where there is a more ordered or stereotyped representation."

"What is clear is that our new virus-based nerve-tracing technique should help in resolving these issues, within the olfactory system and beyond," said Baldwin.

In addition to Baldwin, Ghosh, and Larson, co-authors of the study, "Sensory maps in the olfactory cortex defined by long-range viral tracing of single neurons," were Hooman Hefzi, Zachary Marnoy, and Kartheek Dokka of Scripps Research; and Tyler Cutforth of the University of California, Santa Cruz.

Research in the Baldwin lab is supported by the California Institute of Regenerative Medicine, the Whitehall Foundation, the O'Keefe Foundation, the Shapiro Family Foundation, and the Scripps Research Dorris Neuroscience Center.

---

Journal Reference:

1. Sulagna Ghosh, Stephen D. Larson, Hooman Hefzi, Zachary Marnoy, Tyler Cutforth, Kartheek Dokka, Kristin K. Baldwin. Sensory maps in the olfactory cortex defined by long-range viral tracing of single neurons. Nature, 2011; DOI: 10.1038/nature09945

Gliomas are brain invaders. A kind of malignant tumor cell, gliomas branch out like tendrils from a central tumor source, spreading cancer throughout the brain. Traditional therapies, such as cutting out the tumor surgically, can be ineffective if the cells have already spread. Researchers at the University of Alabama at Birmingham may have come upon a way to stop a glioma invasion in its tracks, using a drug already approved for use in Europe.

Much like early explorers of the Old West followed rivers and streams, depending on them to provide drinking water and food, gliomas spread through the brain by following the path of blood vessels, tapping into those vessels for the nutrients they need to survive. Cut that glioma off from the blood supply, and it starves.

"An explorer lost in the wilderness without food and water soon succumbs and dies," said Harald Sontheimer, Ph.D., director of the UAB Center for Glial Biology in Medicine and senior author on the paper. "A glioma that can't find and tap into a blood vessel will also die."

In a paper published March 30, 2011 in the Journal of Neuroscience, Sontheimer and co-author Vedrana Montana, Ph.D., discovered that bradykinin, a peptide that increases the size of blood vessels, is the mechanism glioma cells use to find blood vessels. Glioma cells carry a receptor for bradykinin, called the B2R receptor. Using that receptor to attract bradykinin gives the cell a navigator to lead it to blood vessels. Block the receptor from interacting with bradykinin and the cell will end up lost in the wilderness.

The researchers introduced a B2R inhibitor known as HOE 140, a laboratory version of a drug approved for use in Europe for hereditary angioedema called Icatibant. HOE 140 bound to the B2R receptor on glioma cells, interfering with the receptor's opportunity to bind to bradykinin. The results were impressive.

"We found that 77 percent of glioma cells with bradykinin were able to locate a blood vessel and tap into its nutrients," said Montana. "However, when we blocked the B2R receptors from interacting with bradykinin, only 19 percent of glioma cells were able to find a blood vessel."

The researchers used human glioma cells transplanted into a mouse model and, using time-lapse techniques on a laser-scanning microscope, tracked the ability of the cells to navigate to blood vessels by means of fluorescent markers attached to the cells.

"Targeting the B2R receptors is an elegant and so far unexplored approach to treat gliomas, one of the most devastating types of brain tumor," said Sontheimer. "Icatibant, which is already in use in Europe, and its ability to block B2R receptors may prove to be very promising target for further investigation."

The American Brain Tumor Association provided funding for this research through a post-doctoral fellowship awared to Montana.

About 18,000 Americans develop gliomas each year and about half will die within 12 months of diagnosis, according to the Society for Neuroscience.

— Patients suffering from dystonia, an uncommon yet potentially crippling movement disorder, get better results if they begin deep brain stimulation therapy sooner rather than later, according to an international study published in the March issue of the Journal of Neurology.

"Our data suggest that patients who begin treatment earlier in the disease process may expect a better general outcome than those with longer disease duration. Also, age at surgery appears to influence the time necessary to achieve the best clinical response, meaning that older patients need more time before reaching their potential benefit," said Michele Tagliati, M.D., director of the Movement Disorders Program at Cedars-Sinai Medical Center and the article's senior author.

Dystonia causes muscles to contract, with the affected body part twisting involuntarily and symptoms ranging from mild to severe. The Food and Drug Administration approved deep brain stimulation as a therapy for certain treatment-resistant dystonias in 2003 after approving it for essential tremor in 1997 and Parkinson's disease in 2002. The procedure recently was approved on a limited basis for obsessive-compulsive disorder.

"We knew from earlier work that younger patients with shorter disease duration had better clinical outcomes in the short term. Now we know they fare best in the long term, as well. Our study uniquely showed that age and disease duration play complementary roles in predicting long-term clinical outcomes. The good news for older patients is that while they may not see the rapid gains of younger patients, their symptoms may gradually improve over several years," said Tagliati, who is considered one of the world's top experts on the therapy.

The study involved 44 patients with generalized dystonia ranging in age from 10 to 59 years, with a midpoint of 31 years. Disease duration ranged from two to 42 years, with a midpoint of 15 years. There were three key clusters of patients whose medical records were analyzed:

• Those younger than 27 and who had suffered from dystonia fewer than 17 years (17 patients)
• Those older than 27 but who had suffered fewer than 17 years (eight patients)
• Those older than 27 and who had suffered more than 17 years (19 patients)

Patients were evaluated on a standard dystonia rating scale at three intervals: after treatment began (baseline) and at one- and three-years. Specific results included:

• Every patient experienced overall improvement in motor function — their ability to control muscles and movements — after surgery and device activation. All ratings of individual body regions or functions such as speech (sub-scores) improved significantly at one year. Further gains were seen at three years.
• Three patients' overall outcomes declined, with mild worsening of some symptoms between years one and three.
• Five more patients had some worse sub-scores at year three but continued to show overall improvement and did not return to their pre-treatment impairment levels.
• Patients older than 27 at the time of surgery showed an additional 10 percent average improvement between years one and three of therapy.
• Thirty-two patients were taking prescription drugs before surgery but this number declined by 52 percent at year one and 80 percent at year three.

The stimulation device consists of electrical leads implanted in the brain and an electrical pulse generator located near the collarbone. The stimulator is programmed with a remote, hand-held controller to modulate abnormal nerve signals that cause dystonia's uncontrolled muscle contractions.

Dystonia is less common than Parkinson's disease — and has been more of a medical mystery, even among many movement disorders specialists. Proper surgical placement of the stimulation device and precise, individualized programming are critical to successful treatment, said Tagliati, who leads an educational course on deep brain stimulation programming every year at the American Academy of Neurology meetings. He said many cases of seemingly "failed" therapy can be corrected through expert fine-tuning of the device, along with optimal medication management.

The study was funded in part by a grant from the Bachmann-Strauss Dystonia & Parkinson Foundation and the Mariani Foundation for Paediatric Neurology. Although Tagliati and other authors receive speaking honoraria and consulting fees from Medtronic Inc., none are related to this study.

Citation: Journal of Neurology, "Factors predicting protracted improvement after pallidal DBS for primary dystonia: the role of age and disease duration." Published online ahead of print March 2, 2011.

Researchers seeking to unravel the most ancient yet least understood of the five senses — smell — have discovered a previously unknown step in how odors are detected and processed by the brain.

The four year study, focusing on how mice respond to odors, showed that smells are picked up by the olfactory bulb — the first stop on the way to the brain — then sent to the olfactory cortex for further analysis.

But scientists discovered something else — a dialogue between the bulb and the cortex conducted by rapidly firing nerve cells.

"It was originally thought that the olfactory bulb filtered and the olfactory cortex made decisions on whether something is, for example, edible," said lead researcher Diego Restrepo, professor of Cell and Developmental Biology and co-director of the University of Colorado School of Medicine Center for NeuroScience. "Our study says it's not quite like that. You process information on reward in the olfactory bulb, send it to the cortex and there is a dialogue between the two. Then the brain will act."

The study was published March 24 in the science journal Neuron.

Restrepo, an expert on the science of taste and smell, said the discovery expands our understanding of how the olfactory system filters and categorizes the thousands of odors that bombard the brain daily.

"We know very little about olfaction and we tend to think that it is not very important in humans compared to the other creatures," he said. "But much of what goes on is subtle and we are only beginning to understand it."

For example, scientists recently found that when men sniffed the odorless tears of women, their levels of testosterone dropped. And for years it's been known that humans, like animals, secrete pheromones that may subconsciously help them choose a mate.

But unlike hearing, taste, sight and touch — smell is the only sense not processed exclusively through the thalamus in the brain, Restrepo said. So the exact path odors take to the brain and how they can trigger often vivid reactions is still not fully understood. The new research suggests that perhaps part of the answer lies within the dialogue between olfactory bulb and cortex.

In describing their work, the researchers noted that "olfaction is a primitive sensory system connected to the brain in a fundamentally different way from other systems."

"Decision-making in olfaction is challenging with a large number of input dimensions and hundreds of olfactory receptors," they wrote. "We show that information about what odors predict is integrated into the earliest stages of neural encoding compared to other senses."

Along with Restrepo, researchers contributing to the study include Wilder Doucette, MD, David Gire, PhD, and neuroscience graduate students Jennifer Whitesell and Vanessa Carmean of the University of Colorado School of Medicine. Mary T. Lucero, professor of Physiology at the University of Utah in Salt Lake City, also took part.

---

Journal Reference:

1. Wilder Doucette, David H. Gire, Jennifer Whitesell, Vanessa Carmean, Mary T. Lucero, Diego Restrepo. Associative Cortex Features in the First Olfactory Brain Relay Station. Neuron, 2011; 69 (6): 1176 DOI: 10.1016/j.neuron.2011.02.024

— Demonstrating an important milestone for the longevity and utility of implanted brain-computer interfaces, a woman with tetraplegia using the investigational BrainGate system continued to control a computer cursor accurately through neural activity alone more than 1,000 days after receiving the BrainGate implant, according to a team of physicians, scientists, and engineers developing and testing the technology at Brown University, the Providence VA Medical Center, and Massachusetts General Hospital (MGH).

Results from five consecutive days of device use surrounding her 1,000th day in the device trial appeared online March 24 in the Journal of Neural Engineering.

"This proof of concept — that after 1,000 days a woman who has no functional use of her limbs and is unable to speak can reliably control a cursor on a computer screen using only the intended movement of her hand — is an important step for the field," said Dr. Leigh Hochberg, a Brown engineering associate professor, VA rehabilitation researcher, visiting associate professor of neurology at Harvard Medical School, and director of the BrainGate pilot clinical trial at MGH.

The woman, identified in the paper as S3, performed two "point-and-click" tasks each day by thinking about moving the cursor with her hand. In both tasks she averaged greater than 90 percent accuracy. Some on-screen targets were as small as the effective area of a Microsoft Word menu icon.

In each of S3's two tasks, performed in 2008, she controlled the cursor movement and click selections continuously for 10 minutes. The first task was to move the cursor to targets arranged in a circle and in the center of the screen, clicking to select each one in turn. The second required her to follow and click on a target as it sequentially popped up with varying size at random points on the screen.

From fundamental neuroscience to clinical utility

Under development since 2002, the investigational BrainGate system is a combination of hardware and software that directly senses electrical signals produced by neurons in the brain that control movement. By decoding those signals and translating them into digital instructions, the system is being evaluated for its ability to give people with paralysis control of external devices such as computers, robotic assistive devices, or wheelchairs. The BrainGate team is also engaged in research toward control of advanced prosthetic limbs and toward direct intracortical control of functional electrical stimulation devices for people with spinal cord injury, in collaboration with researchers at the Cleveland FES Center.

The system is currently in pilot clinical trials, directed by Hochberg at MGH.

BrainGate uses a tiny (4×4 mm, about the size of a baby aspirin) silicon electrode array to read neural signals directly within brain tissue. Although external sensors placed on the brain or skull surface can also read neural activity, they are believed to be far less precise. In addition, many prototype brain implants have eventually failed because of moisture or other perils of the internal environment.

"Neuroengineers have often wondered whether useful signals could be recorded from inside the brain for an extended period of time," Hochberg said. "This is the first demonstration that this microelectrode array technology can provide useful neuroprosthetic signals allowing a person with tetraplegia to control an external device for an extended period of time."

Moving forward

Device performance was not the same at 2.7 years as it was earlier on, Hochberg added. At 33 months fewer electrodes were recording useful neural signals than after only six months. But John Donoghue — VA senior research career scientist, Henry Merritt Wriston Professor of Neuroscience, director of the Brown Institute for Brain Science, and original developer of the BrainGate system — said no evidence has emerged of any fundamental incompatibility between the sensor and the brain. Instead, it appears that decreased signal quality over time can largely be attributed to engineering, mechanical or procedural issues. Since S3's sensor was built and implanted in 2005, the sensor's manufacturer has reported continual quality improvements. The data from this study will be used to further understand and modify the procedures or device to further increase durability.

"None of us will be fully satisfied with an intracortical recording device until it provides decades of useful signals," Hochberg said. "Nevertheless, I'm hopeful that the progress made in neural interface systems will someday be able to provide improved communication, mobility, and independence for people with locked-in syndrome or other forms of paralysis and eventually better control over prosthetic, robotic, or functional electrical stimulation systems [stimulating electrodes that have already returned limb function to people with cervical spinal cord injury], even while engineers continue to develop ever-better implantable sensors."

In addition to demonstrating the very encouraging longevity of the BrainGate sensor, the paper also presents an advance in how the performance of a brain-computer interface can be measured, Simeral said. "As the field continues to evolve, we'll eventually be able to compare and contrast technologies effectively."

As for S3, who had a brainstem stroke in the mid-1990s and is now in her late 50s, she continues to participate in trials with the BrainGate system, which continues to record useful signals, Hochberg said. However, data beyond the 1000th day in 2008 has thus far only been presented at scientific meetings, and Hochberg can only comment on data that has already completed the scientific peer review process and appeared in publication.

In addition to Simeral, Hochberg, and Donoghue, other authors are Brown computer scientist Michael Black and former Brown computer scientist Sung-Phil Kim.

About the BrainGate collaboration

This advance is the result of the ongoing collaborative BrainGate research at Brown University, Massachusetts General Hospital, and Providence VA Medical Center. The BrainGate research team is focused on developing and testing neuroscientifically inspired technologies to improve the communication, mobility, and independence of people with neurologic disorders, injury, or limb loss.

For more information, visit www.braingate2.org.

The implanted microelectrode array and associated neural recording hardware used in the BrainGate research are manufactured by BlackRock Microsystems, LLC (Salt Lake City, UT).

This research was funded in part by the Rehabilitation Research and Development Service, Department of Veterans Affairs; The National Institutes of Health (NIH), including NICHD-NCMRR, NINDS/NICHD, NIDCD/ARRA, NIBIB, NINDS-Javits; the Doris Duke Charitable Foundation; MGH-Deane Institute for Integrated Research on Atrial Fibrillation and Stroke; and the Katie Samson Foundation.

The BrainGate pilot clinical trial was previously directed by Cyberkinetics Neurotechnology Systems, Inc., Foxborough, MA (CKI). CKI ceased operations in 2009. The clinical trials of the BrainGate2 Neural Interface System are now administered by Massachusetts General Hospital, Boston, Mass. Donoghue is a former chief scientific officer and a former director of CKI; he held stocks and received compensation. Hochberg received research support from Massachusetts General and Spaulding Rehabilitation Hospitals, which in turn received clinical trial support from Cyberkinetics. Simeral received compensation as a consultant to CKI.

---

Journal Reference:

1. j D Simeral, S-P Kim, M J Black, J P Donoghue, L R Hochberg. Neural control of cursor trajectory and click by a human with tetraplegia 1000 days after implant of an intracortical microelectrode array. Journal of Neural Engineering, 2011; 8: 025027 DOI: 10.1088/1741-2560/8/2/02502

A new study is providing fascinating insight into how projections conveying sensory information in the brain are guided to their appropriate targets in different species. The research, published in the March 24 issue of the journal Neuron, reveals a surprising new evolutionary scenario that may help to explain how subtle changes in the migration of "guidepost" neurons underlie major differences in brain connectivity between mammals and nonmammalian vertebrates.

The neocortex (the "new" cortex) is a brain area that is unique to mammals and plays a central role in cognition, motor behavior, and sensory perception. A deeper brain region, called the thalamus, sends sensory information to the neocortex via a major highway called the internal capsule. As might be expected given the differences in brain anatomy, thalamic projections vary tremendously among vertebrates, with paths in reptiles and birds taking a completely different route than that seen in mammals.

"What controls the differential path-finding of thalamic axons in mammals versus nonmammalian vertebrates and how these essential projections have evolved remains unknown," explains senior study author, Dr. Sonia Garel from Ecole Normale Supérieure in Paris. "We examined how thalamic axons, which constitute the main input to the neocortex, are directed internally to their evolutionarily novel target in mammals, while they follow an external path to other targets in reptiles and birds."

Using a series of comparative and functional studies, Dr. Garel and colleagues observed species-specific differences in the migration and positioning of well-characterized "corridor guidepost" neurons. The researchers went on to show that a protein called Slit2, previously implicated in cell migration and axon guidance, was critical for local positioning of mammalian guidepost cells and functioned as a kind of switch to reroute thalamic axons from the default external route to an internal path to the neocortex.

"Taken together, our results show that minor differences in the positioning of conserved guidepost neurons, which is controlled by Slit2, plays an essential role in the species-specific pathfinding of thalamic axons, thereby providing a novel framework to understand the shaping and evolution of a novel and major brain projection," concludes Dr. Garel. "Furthermore, our study opens the possibility that changes in cell migration may more generally control the evolution of brain connectivity, particularly the formation of other mammalian-specific tracts. Since an increase in cell migration has participated in the morphogenesis of the neocortex itself, these novel findings reveal that cell migration can be considered as a general player in the evolutionary changes that led to the emergence of the mammalian brain."

---

Journal Reference:

1. Franck Bielle, Paula Marcos-Mondejar, Maryama Keita, Caroline Mailhes, Catherine Verney, Kiml Nguyen Ba-Charvet, Marc Tessier-Lavigne, Guillermina Lopez-Bendito, Sonia Garel. Slit2 Activity in the Migration of Guidepost Neurons Shapes Thalamic Projections during Development and Evolution. Neuron, Volume 69, Issue 6, 1085-1098, 24 March 2011 DOI: 10.1016/j.neuron.2011.02.026