Posts tagged neuroscience

This week over 150 neuroscientists were invited to meet in Arlington, Virginia to discuss the finer points of President Obama’s recently announced BRAIN Initative. Rather than discuss funding particulars, each participant was given the chance to broadly declare what they thought needed to be done in neuroscience. At least 75 of the participants initially responded to a request for a short white paper outlining the major obstacles currently impeding neuroscience research. A live webcast of some of the key talks was available, although many of the smaller workshops were held in private. Fortunately, updates regarding the content discussed at these workshops was posted live to twitter under the handle @openconnectome. This precipitated lively discussion, primarily under the hashtags #nsfBRAINmtg or #braini, and provided a way for a larger audience to be involved.

The working title of this inaugural NSF meeting was Physical and Mathematical Principles of Brain Structure and Function. In actuality, there was little discussion of all that, and for good reason—no such principles have been shown to exist. Even more concerning, only a few principles have ever even been proposed. Simplistic scaling laws dealing with connectivity, particularly within sensory systems or the cortex, have been suggested in the past. Generally they seek to account for only one or two structural parameters at a time, like for example, axon diameter and branching order. Typically, the chosen parameters are only considered in the context of optimizing a single physical variable, like for example, electrotonic function. While these efforts are a start, they usually do not garner much attention from the larger neuroscience community.

The early days of neuroscience were marked with the assertion of many principles and laws. They served well to focus ideas, but over time, they lost much of their original perceived generality. For example, concepts like one transmitter type per neuron, and no new neurons in adult brains later proved to have significant exceptions. The early breakthrough days in neuroscience have now given way to a grant system that stifles imagination, and by its competitiveness, encourages fraud. Many of the speakers at the BRAIN Initiative meeting have called for new tools and theories, but in most cases, they have offered only little has been offered. Instead of expanding the range acceptable pursuits, their vision appears to have imploded inward with calls for increased rigor, statistical power, diversity of animal models, experimental falsifiability, and most of all, data, on an increasingly limited range of ideas.

A lot of talk was given to the resolution at which connectivity, and activity maps should be detailed. Similar points were made for the need to develop electrode arrays of higher density and durability to more accurately record function. The ample discussion of an ideal animal model was punctuated by the notable advances made this year in whole brain recordings from Zebrafish, and also from large scale connectivity mapping now possible in small mammals with the new CLARITY transparent brain techniques. The general lack of agreement and clear path forward as to which organisms among many are ideal here was noted by representatives from several funding bodies who spoke at the meeting. Highlighting points made earlier in a talk by George Whitesides, they stressed the need to come to forward with a concrete plan that is comprehensible not only to the funding organizations, but the larger public as well.

Many discussions focused on brain mechanisms, like for example, how many neurons might contribute to a particular function. One participate, David Kleinfeld, called for a study of how many neurons are involved in communication at different scales. He also stressed the importance of looking at basic systems involving feedback, such as the brain stem and spinal cord, and their dynamic interaction with muscle. Michael Stryker observed that the goal should not be recording from the most neurons, and storing the most data, but rather finding the right neurons.

While it was not explicitly stated, a lot of the talk begged the conclusion that the answers to the questions we have will not be answered with animal studies. Knowing what a neuron does is itself an ill-posed question. In worms and flies, where the inputs and outputs of single neurons can be mapped to static sensory and motor functions in the real world, we might know what that neuron does. However in larger, human brains, we can ask an even better question—what does the neuron feel like? In most cases that answer will likely be, nothing.

If however, in a given human brain, a single neuron critically poised within that brain’s structural hierarchy can be stimulated to observable effect, some measure of its function has been gained. That effect might be a simple itch or twitch. Less plausibly perhaps it could be seeing a picture of a face undergo a change, sensing fear, or even imagining your grandmother. If that turns out not to be possible for most single neurons, we already know that we can find some minimal group of neurons where stimulation has uniquely perceivable effects.

While understanding the brain on different scales is important, the most rewarding endeavors likely exist where functionality can be correlated across those scales. Behavior at the scale of the organism within a given environment is readily observable. At the next scale down, the behavior of neurons witnessed by its spikes and structural alterations, is only observable now in part. Below the scale of the neuron, the mitochondria and other organelles move with a purpose and relation to activity of the neuron that has only been imagined, but is experimentally addressable.

Several speakers also mentioned the idea of a neural code. Spikes are a convenient metric for assessing brain activity, and we should seek to correlate their occurrence with behaviors on various scales mentioned above. They are a universal and non-local currency, among others in the brain, that inflates rapidly with stimulation and arousal. Unfortunately, the most logical conclusion for us must be that there is no code for spikes. Anyone attempting to observe and record a code for one neuron would probably find that it has, in short order, become unrecognizable, particularly in the context of the next. There are however constraints on spikes, and on neurons, and while considerable mention of the word was made at the meeting none were detailed in depth.

To formulate constraints on a system, at a level we don’t understand, we might look at constraints on other systems that we have some knowledge about. Neurons are neither wholly like ants, nor tress, but share some aspects of both. Similarly brains are neither like ant colonies, or forests, but shares some features in common. The most obvious constraint that comes to mind, and applies to these systems at every level, is energy. A subtle refinement of that is the concept of entropy generation. One key idea is that entropy generation at different scales, while proceeding according to as yet determined laws, need not necessarily maximize entropy at each point in time, but rather along paths through time.

A voice heard throughout the conference was that of Bill Bialek who diffusely observed that attempts to apply the laws of statistical mechanics to aspects of brain functions are not very productive because the brain is not at an equilibrium state. That would have been a good sentence to begin the conference perhaps rather than end it. Hopefully, the next NSF meeting will be a little more transparent to the public than the first. A more thorough webcast, with uploading to a media channel would be desirable to many who like to participate, as would a path for two-way communication on the issues. Mention should also be made of the efforts of a few neuroscientists peripheral to the BRAIN Initiative that have been maintaining important blog discussions, and metablog publication lists to track the progress made over last few months. This morning, NIH announced a new website has just been set up to provide additional public feedback.

(Source: medicalxpress.com)

Johns Hopkins researchers believe they may have discovered an explanation for the sleepless nights associated with restless legs syndrome (RLS), a symptom that persists even when the disruptive, overwhelming nocturnal urge to move the legs is treated successfully with medication.

Neurologists have long believed RLS is related to a dysfunction in the way the brain uses the neurotransmitter dopamine, a chemical used by brain cells to communicate and produce smooth, purposeful muscle activity and movement. Disruption of these neurochemical signals, characteristic of Parkinson’s disease, frequently results in involuntary movements. Drugs that increase dopamine levels are mainstay treatments for RLS, but studies have shown they don’t significantly improve sleep. An estimated 5 percent of the U.S. population has RLS.

The small new study, headed by Richard P. Allen, Ph.D., an associate professor of neurology at the Johns Hopkins University School of Medicine, used MRI to image the brain and found glutamate — a neurotransmitter involved in arousal — in abnormally high levels in people with RLS. The more glutamate the researchers found in the brains of those with RLS, the worse their sleep.

The findings are published in the May issue of the journal Neurology.
 “We may have solved the mystery of why getting rid of patients’ urge to move their legs doesn’t improve their sleep,” Allen says. “We may have been looking at the wrong thing all along, or we may find that both dopamine and glutamate pathways play a role in RLS.”

For the study, Allen and his colleagues examined MRI images and recorded glutamate activity in the thalamus, the part of the brain involved with the regulation of consciousness, sleep and alertness. They looked at images of 28 people with RLS and 20 people without. The RLS patients included in the study had symptoms six to seven nights a week persisting for at least six months, with an average of 20 involuntary movements a night or more.

The researchers then conducted two-day sleep studies in the same individuals to measure how much rest each person was getting. In those with RLS, they found that the higher the glutamate level in the thalamus, the less sleep the subject got. They found no such association in the control group without RLS.

Previous studies have shown that even though RLS patients average less than 5.5 hours of sleep per night, they rarely report problems with excessive daytime sleepiness. Allen says the lack of daytime sleepiness is likely related to the role of glutamate, too much of which can put the brain in a state of hyperarousal — day or night.

If confirmed, the  study’s results may change the way RLS is treated,  Allen says, potentially erasing the sleepless nights that are the worst side effect of the condition. Dopamine-related drugs currently used in RLS do work, but many patients eventually lose the drug benefit and require ever higher doses. When the doses get too high, the medication actually can make the symptoms much worse than before treatment. Scientists don’t fully understand why drugs that increase the amount of dopamine in the brain would work to calm the uncontrollable leg movement of RLS.

Allen says there are already drugs on the market, such as the anticonvulsive gabapentin enacarbil, that can reduce glutamate levels in the brain, but they have not been given as a first-line treatment for RLS patients.

RLS wreaks havoc on sleep because lying down and trying to relax activates the symptoms. Most people with RLS have difficulty falling asleep and staying asleep. Only getting up and moving around typically relieves the discomfort. The sensations range in severity from uncomfortable to irritating to painful.

“It’s exciting to see something totally new in the field — something that really makes sense for the biology of arousal and sleep,” Allen says.

As more is understood about this neurobiology, the findings may not only apply to RLS, he says, but also to some forms of insomnia.

(Source: hopkinsmedicine.org)

When animals are on the hunt for food they likely use many senses, and scientists have wondered how the different senses work together.

New research from the laboratory of CSHL neuroscientist and Assistant Professor Adam Kepecs shows that when rats actively use the senses of smell (sniffing) and touch (through their whiskers) those two processes are locked in synchronicity. The team’s paper, published today in the Journal of Neuroscience, shows that sniffing and “whisking” movements are synchronized even when they are running at different frequencies.

Studies in the 1960s suggested these two sensory activities were coordinated: sniffing, a sharp, profound intake of air; and whisking, the back-and-forth movement of the whiskers to sample the near environment, akin to the sensation of touch as felt through the fingers in humans. Such coordination could be important for decisions that depend on multiple types of sensory information, for instance, locating food. “The question is how two very different streams of sensory information, touch and smell, are integrated into a single multisensory “snapshot” of the environment,” says Kepecs.

These snapshots can be taken at high frequency, up to 12 times a second. To determine whether these two sensorimotor rhythms are indeed phase-locked, Kepecs’ team, including postdocs Sachin Ranade and Balázs Hangya, simultaneously monitored sniffing and whisking in rats freely foraging for food pellets.

At different frequencies occurring between 4-12 times per second they found strong 1:1 phase locking — in other words, every time the rats extended their whiskers to feel their vicinity, they also smelled it. Surprisingly, they found even when the sniffing and whisking rhythms operating at different fundamental frequencies they were locked in phase. Key to this is that the phases of the sensory input – the start of inhalation and onset of whisking – are aligned, which facilitates multisensory integration.

This is similar to how a person’s breathing rhythm settles into place while running and is synchronized to the steps. In both cases, the coordination could be advantageous in terms of energy efficiency. A crucial difference, though, is that in humans, the breathing rate has to catch up to the running rhythm after changes in pace, while for sniffing and whisking in rats they lock into phase immediately.

Even though human behavior doesn’t seem to be overtly tied to rhythms, there are hints that it could be. “Underneath the smoothly executed movements of humans there are rhythm generators, which are sometimes revealed in some diseases, for example the tremors seen in Parkinson’s disease, or in the brain waves that result from the synchronized firing of neurons,” says Kepecs. Studying the rhythms of multisensory inputs in rodents could provide clues to a fundamental principle underlying sensory and brain rhythms that are essential to all animals, including humans.

(Source: cshl.edu)

Ever since its introduction in the 1990s, the “clot-busting” drug tPA has been considered a “double-edged sword” for people experiencing a stroke. It can help restore blood flow to the brain, but it also can increase the likelihood of deadly hemorrhage. In fact, many people experiencing a stroke do not receive tPA because the window for giving the drug is limited to the first few hours after a stroke’s onset.

But Emory neurologist Manuel Yepes may have found a way to open that window. Even when its clot-dissolving powers are removed, tPA can still protect brain cells in animals from the loss of oxygen and glucose induced by a stroke, Yepes’ team reported in the Journal of Neuroscience (July 2012).

"We may have been giving the right medication, for the wrong reason," Yepes says. "tPA is more than a clot-busting drug. It functions naturally as a neuroprotectant."

The finding suggests that a modified version of the drug could provide benefits to patients who have experienced a stroke, without increasing the risk of bleeding.

"This would be a major breakthrough in the care of patients with stroke, if it could be developed," says Michael Frankel, director of the Marcus Stroke and Neuroscience Center at Grady Memorial Hospital.

tPA is a protein produced by the body and has several functions. One is to activate the enzyme plasmin, which breaks down clots. But Yepes’ team has discovered that the protein has additional functions. For example, in cultured neurons, it appears to protect neurons in the brain, turning on a set of genes that help cells deal with a lack of oxygen and glucose. This result contradicts previous reports that the protein acts as a neurotoxin in the nervous system.

Tweaking tPA so that it is unable to activate plasmin—while keeping intact the rest of its functions—allowed the researchers to preserve its protective effect on neurons in culture. This modified tPA also reduced the size of the damaged area of the brain after simulated stroke in mice, with an effect comparable in strength to regular tPA. The next step is to test the modified version of tPA in a pilot clinical trial.

The possibility that tPA may be working as a neuroprotectant may explain why, in large clinical studies, tPA’s benefits sometimes go unobserved until several weeks after treatment, Yepes says. “If it was just a matter of the clot, getting rid of the clot should make the patient better quickly,” he says. “It’s been difficult to explain why you should have to wait three months to see a benefit.”

(Source: emoryhealthmagazine.emory.edu)

Scientists at the Virginia Tech Carilion Research Institute have discovered how the predominant class of Alzheimer’s pharmaceuticals might sharpen the brain’s performance.

One factor even more important than the size of a television screen is the quality of the signal it displays. Having a life-sized projection of Harry Potter dodging a Bludger in a Quidditch match is of little use if the details are lost to pixilation.

The importance of transmitting clear signals, however, is not relegated to the airwaves. The same creed applies to the electrical impulses navigating a human brain. Now, new research has shown that one of the few drugs approved for the treatment of Alzheimer’s disease helps patients by clearing up the signals coming in from the outside world.

The discovery was made by a team of researchers led by Rosalyn Moran, an assistant professor at the Virginia Tech Carilion Research Institute. Her study indicates that cholinesterase inhibitors — a class of drugs that stop the breakdown of the neurotransmitter acetylcholine — allow signals to enter the brain with more precision and less background noise.

“Increasing the levels of acetylcholine appears to turn your fuzzy, old analog TV signal into a shiny, new, high-definition one,” said Moran, who holds an appointment as an assistant professor in the Virginia Tech College of Engineering. “And the drug does this in the sensory cortices. These are the workhorses of the brain, the gatekeepers, not the more sophisticated processing regions — such as the prefrontal cortex — where one may have expected the drugs to have their most prominent effect.”

Alzheimer’s disease affects more than 35 million people worldwide — a number expected to double every 20 years, leading to more than 115 million cases by 2050. Of the five pharmaceuticals approved to treat the disease by the U.S. Food and Drug Administration, four are cholinesterase inhibitors. Although it is clear that the drugs increase the amount of acetylcholine in the brain, why this improves Alzheimer’s symptoms has been unknown. If scientists understood the mechanisms and pathways responsible for improvement, they might be able to tailor better drugs to combat the disease, which costs more than $200 billion annually in the United States alone.

In the new study, Moran recruited 13 healthy young adults and gave them doses of galantamine, one of the cholinesterase inhibitors commonly prescribed to Alzheimer’s patients. Two electroencephalographs were taken — one with the drugs and one without — as the participants listened to a series of modulating tones while focusing on a simple concentration task.

The researchers were looking for differences in neural activity between the two drug states in response to surprising changes in the sound patterns that the participants were hearing.

The scientists compared the results with computer models built on a Bayesian brain theory, known as the Free Energy Principle, which is a leading theory that describes the basic rules of neuronal communication and explains the creation of complex networks.

The theory hypothesizes that neurons seek to reduce uncertainty, which can be modeled and calculated using free energy molecular dynamics. Connecting tens of thousands of neurons behaving in this manner produces the probability machine that we call a brain.

Moran and her colleagues compiled 10 computer simulations based on the different effects that the drugs could have on the brain. The model that best fit the results revealed that the low-level wheels of the brain early on in the neural networking process were the ones benefitting from the drugs and creating clearer, more precise signals.

“When people take these drugs you can imagine the brain bathed in them,” Moran said. “But what we found is that the drugs don’t have broad-stroke impacts on brain activity. Instead, they are working very specifically at the cortex’s entry points, gating the signals coming into the network in the first place.”

The study appears in Wednesday’s (May 8) issue of The Journal of Neuroscience in the article, “Free Energy, Precision and Learning: The Role of Cholinergic Neuromodulation.”

(Source: newswise.com)