Category: Disorders and Syndromes

 Imagine a prosthetic device capable of restoring decision-making in people who have reduced capacity due to brain disease or injury. While this may sound like science fiction, researchers at Wake Forest Baptist Medical Center have proven for the first time that it is possible in non-human primates, and believe that one day it will be possible in people.

In essence, the scientists used an electronic prosthetic system to tap into existing circuitry in the brain at the cellular level and record the firing patterns of multiple neurons in the prefrontal cortex, the part of the brain involved in decision-making. They then "played" that recording back to the same brain area to electrically stimulate decision-based neural activity. Not only did it restore function, in some cases, it also improved it.

"The prosthetic device is like 'flipping a switch' to turn on a decision in real time," said Sam Deadwyler, Ph.D., professor of physiology and pharmacology at Wake Forest Baptist, and senior author of the study, which is published in the Sept. 14 issue of the Journal of Neural Engineering.

In the study, the scientists trained five monkeys to match multiple images on a computer screen until they were correct 70 to 75 percent of the time. First, an image appeared on the screen, which the animals were trained to select using a hand-controlled cursor. The screen then went blank for up to two minutes, followed by the reappearance of two to eight images, including the initial one, on the same screen.

When the monkeys correctly chose the image they were shown first, the electronic prosthetic device recorded the pattern of neural pulses associated with their decision by employing a multi-input multi-output nonlinear (MIMO) mathematical model, developed by researchers at the University of Southern California.

In the next phase of the study, a drug known to disrupt cognitive activity, cocaine, was administered to the animals to simulate brain injury. When the animals repeated the image-selection task, their decision-making ability decreased 13 percent from normal. However, during these "drug sessions," the MIMO prosthesis detected when the animals were likely to choose the wrong image and played back the previously recorded "correct" neural patterns for the task.

According to the study findings, the MIMO device was exceedingly effective in restoring the cocaine-impaired decision-making ability to an improved level of 10 percent above normal, even when the drug was still present and active.

"The basis for why the MIMO prosthesis was effective in improving performance was because we specifically programmed the model to recognize neural patterns that occurred when the animals correctly performed the behavioral task in real time, which is a unique feature of this particular device," said Robert E. Hampson, Ph.D., associate professor of physiology and pharmacology at Wake Forest Baptist, and lead author of the study.

"Based on the findings of this study, we hope in the future to develop an implantable neuroprosthesis that could help people recover from cognitive deficiencies due to brain injuries," Hampson said.

Co-authors of the study are: Ioan Opris, Ph.D., and Lucas Santos, Ph.D., Wake Forest Baptist; Greg A. Gerhardt, Ph.D., University of Kentucky; and Dong Song, Ph.D., Vasilis Marmarelis, Ph.D., and Theodore W. Berger, Ph.D., University of Southern California.

The study was supported by the National Institutes of Health grants DA06634, DA023573 and DA026487; by National Science Foundation grant EEC-0310723; and by the Defense Advanced Research Projects Agency (DARPA), contract N66601-09-C-2080 to S.A.D.

Researchers have taken a key step towards recovering specific brain functions in sufferers of brain disease and injuries by successfully restoring the decision-making processes in monkeys.

By placing a neural device onto the front part of the monkeys' brains, the researchers, from Wake Forest Baptist Medical Centre, University of Kentucky and University of Southern California, were able to recover, and even improve, the monkeys' ability to make decisions when their normal cognitive functioning was disrupted.

The study, which has been published today (Sept. 14) in IOP Publishing's Journal of Neural Engineering, involved the use of a neural prosthesis, which consisted of an array of electrodes measuring the signals from neurons in the brain to calculate how the monkeys' ability to perform a memory task could be restored.

In the delayed match-to-sample task an image was flashed onto a screen and, after a delay, the monkeys were prompted to select the same image on the screen from a sampling which included 1-7 other images. Five monkeys (all rhesus, Macaca mulatta) were involved in the experiment and were trained for two years to perform to a 70-75 per cent proficiency in the task.

The movement of the monkeys' arms were tracked with a camera and translated to movements of the cursor on the screen; they were awarded with a drop of juice when they correctly matched an image.

The prosthesis was placed into two cortical layers — L2/3 and L5 — of the brain and recorded brain activity within structures known as minicolumns in the prefrontal cortex area.

Once it was confirmed that minicolumn communication between layers L2/3 and L5 was involved in decision making, it was suppressed by administering the dopamine-modifying drug, cocaine, to the monkeys. The task was performed again but this time the researchers deployed a 'multi-input multi-output nonlinear' (MIMO) model to stimulate the neurons that were used in the task.

"The MIMO model is a specific type of calculation which looks for the complex mathematical relationship between an input (L2/3) and an output (L5). In the case of neural activity, the output is typically the pattern of firing of individual neurons during the task.

"Inputs to that pattern may be blood flow, temperature, the electrical activity of other neurons, and even the prior electrical activity of the same cell," said lead author of the study Professor Robert Hampson.

By recording the inputs from layer L2/3 neurons, the MIMO model could predict the output of layer L5 neurons and thus, through the electrodes, electrically stimulate the same necessary L5 neurons. The results showed that the MIMO model was exceedingly effective in recovering performance of the task and was even able to improve performance under normal conditions.

"The reason the MIMO model was effective in improving performance in the task was because we specifically 'tuned' the model to analyze the firing of neurons that occurred when the animals correctly performed the behavioral task; the brain doesn't always produce the full 'correct' pattern on every trial," said senior author Professor Sam Deadwyler.

On the utilization of this method in the treatment of human brain conditions, Professor Deadwyler continued: "In the case of brain injury or disease where larger areas are affected, the system would record the inputs to that area from other areas and, when they occur, program the delivery of the appropriate output patterns to brain regions that normally receive signals from the injured area, thereby restoring lost brain function."

All animal procedures were reviewed and approved by the Institutional Animal Care and Use Committee of Wake Forest University, in accordance with U.S. Department of Agriculture, International Association for the Assessment and Accreditation of Laboratory Animal Care, and National Institutes of Health guidelines.

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Journal Reference:

1. Robert E Hampson, Greg A Gerhardt, Vasilis Marmarelis, Dong Song, Ioan Opris, Lucas Santos, Theodore W Berger, Sam A Deadwyler. Facilitation and restoration of cognitive function in primate prefrontal cortex by a neuroprosthesis that utilizes minicolumn-specific neural firing. Journal of Neural Engineering, 2012; 9 (5): 056012 DOI: 10.1088/1741-2560/9/5/056012

Stress has long been pegged as the enemy of attention, disrupting focus and doing substantial damage to working memory — the short-term juggling of information that allows us to do all the little things that make us productive.

By watching individual neurons at work, a group of psychologists at the University of Wisconsin-Madison has revealed just how stress can addle the mind, as well as how neurons in the brain's prefrontal cortex help "remember" information in the first place.

Working memory is short-term and flexible, allowing the brain to hold a large amount of information close at hand to perform complex tasks. Without it, you would have forgotten the first half of this sentence while reading the second half. The prefrontal cortex is vital to working memory.

"In many respects, you'd look pretty normal without a prefrontal cortex," said Craig Berridge, UW-Madison psychology professor. "You don't need that part of the brain to hear or talk, to keep long-term memories, or to remember what you did as a child or what you read in the newspaper three days ago."

But without your prefrontal cortex you'd be unable to stay on task or modulate your emotions well.

"People without a prefrontal cortex are very distractible," Berridge said. "They're very impulsive. They can be very argumentative."

The neurons of the prefrontal cortex help store information for short periods. Like a chalkboard, these neurons can be written with information, erased when that information is no longer needed, and rewritten with something new.

It's how the neurons maintain access to that short-term information that leaves them vulnerable to stress. David Devilbiss, a scientist working with Berridge and lead author on a study published today in the journal PLoS Computational Biology, applied a new statistical modeling approach to show that rat prefrontal neurons were firing and re-firing to keep recently stored information fresh.

"Even though these neurons communicate on a scale of every thousandth of a second, they know what they did one second to one-and-a-half seconds ago," Devilbiss said. "But if the neuron doesn't stimulate itself again within a little more than a second, it's lost that information."

Apply some stress — in the researchers' case, a loud blast of white noise in the presence of rats working on a maze designed to test working memory — and many neurons are distracted from reminding themselves of … what was it we were doing again?

"We're simultaneously watching dozens of individual neurons firing in the rats' brains, and under stress those neurons get even more active," said Devilbiss, whose work was supported by the National Science Foundation and National Institutes for Health. "But what they're doing is not retaining information important to completing the maze. They're reacting to other things, less useful things."

Without the roar of white noise, which has been shown to impair rats in the same way it does monkeys and humans, the maze-runners were reaching their goal about 90 percent of the time. Under stress, the animals completed the test at a 65 percent clip, with many struggling enough to fall to blind chance.

Recordings of the electrical activity of prefrontal cortex neurons in the maze-running rats showed these neurons were unable to hold information key to finding the next chocolate chip reward. Instead, the neurons were frenetic, reacting to distractions such as noises and smells in the room.

The effects of stress-related distraction are well-known and dangerous.

"The literature tells us that stress plays a role in more than half of all workplace accidents, and a lot of people have to work under what we would consider a great deal of stress," Devilbiss said. "Air traffic controllers need to concentrate and focus with a lot riding on their actions. People in the military have to carry out these thought processes in conditions that would be very distracting, and now we know that this distraction is happening at the level of individual cells in the brain."

The researchers' work may suggest new directions for treatment of prefrontal cortex dysfunction.

"Based on drug studies, it had been believed stress simply suppressed prefrontal cortex activity," Berridge said. "These studies demonstrate that rather than suppressing activity, stress modifies the nature of that activity. Treatments that keep neurons on their self-stimulating task while shutting out distractions may help protect working memory."

 A transient ischemic attack, TIA or a "mini stroke," can lead to serious disability, but is frequently deemed by doctors too mild to treat, according to a study in the American Heart Association journal Stroke.

Patients with transient ischemic attack, TIA or "mini" stroke, are not typically given clot-busting drugs because the condition is considered too mild to treat. However, 15 percent of patients had some disability 90 days after a mini stroke. Some patients with minor stroke may benefit from clot-busting drug treatment.

"Our study shows that TIA and minor stroke patients are at significant risk of disability and need early assessment and treatment," said Shelagh Coutts, M.D., lead author of the study at Foothills Hospital in Calgary, Alberta, Canada. "We should be imaging patients earlier and be more aggressive in treating patients with thrombolysis if we can see a blockage no matter how minor the symptoms are."

Thrombolysis is a treatment used to dissolve dangerous clots and restore healthy blood flow to the brain. TIA and minor stroke patients don't typically receive this treatment because the condition is frequently not deemed serious enough to warrant it, researchers said.

Among the 499 patients studied, 15 percent had at least minor disability 90 days after their original "mini stroke." Minor disability was defined as being unable to carry out previous activities, but capable of and handling personal affairs without assistance.

Computed tomography (CT) scans showed some "mini stroke" patients had narrowed blood vessels in the brain, and others reported ongoing or worsening symptoms. Those patients were more than twice as likely to have disability at 90 days. Coutts suggests that thrombolysis treatment should be considered in these patients.

Patients with type 2 diabetes had a similarly high risk of disability. Also, women were nearly twice as likely as men to be disabled 90 days after TIA.

"For every second after a mini stroke, the patient's brain may be losing oxygen — possibly leading to a major event," Coutts said. "If a scan finds that you have a narrowing of a blood vessel in or outside of the brain, you are at a high risk of being disabled."

Recurrent strokes posed the greatest threat to patients. Of those who had recurrent strokes, 53 percent were disabled, compared to 12 percent of patients without a recurrent stroke.

In 2009, the American Heart Association/American Stroke Association recommended immediate action and thorough testing for TIA — much like the exams performed after a full-blown stroke. These exams can show blockage in a brain blood vessel, which can increase patients' risk of a subsequent, more serious event.

"The symptoms of a TIA — abrupt onset of inability to move one side of your body, numbness on one side, dizziness and trouble walking — may pass quickly," Coutts said. "But, if you experience them, you should immediately go to the hospital, where proper scans can be done. Based on these results we have started a trial in Canada giving clot busting drugs to patients with mild symptoms, but blocked blood vessels in the brain.

"If ignored, these symptoms can lead to death. This is not a benign disease."

A growing body of research shows that children who suffer severe neglect and social isolation have cognitive and social impairments as adults. A study from Boston Children's Hospital shows, for the first time, how these functional impairments arise: Social isolation during early life prevents the cells that make up the brain's white matter from maturing and producing the right amount of myelin, the fatty "insulation" on nerve fibers that helps them transmit long-distance messages within the brain.

The study also identifies a molecular pathway that is involved in these abnormalities, showing it is disrupted by social isolation and suggesting it could potentially be targeted with drugs. Finally, the research indicates that the timing of social deprivation is an important factor in causing impairment. The findings are reported in the Sept. 14 issue of the journal Science.

The researchers, led by Gabriel Corfas, PhD, and Manabu Makinodan, MD, PhD, both of the F.M. Kirby Neurobiology Center at Boston Children's Hospital, modeled social deprivation in mice by putting them in isolation for two weeks.

When isolation occurred during a "critical period," starting three weeks after birth, cells called oligodendrocytes failed to mature in the prefrontal cortex, a brain region important for cognitive function and social behavior. As a result, nerve fibers had thinner coatings of myelin, which is produced by oligodendrocytes, and the mice showed impairments in social interaction and working memory.

Studies of children raised in institutions where neglect was rampant, including another recent study from Boston Children's Hospital, have found changes in white matter in the prefrontal cortex, but the mechanism for the changes hasn't been clear. The new study adds to a growing body of evidence that so-called glial cells, including oligodendrocytes, do more than just support neurons, but rather participate actively in setting up the brain's circuitry as they receive input from the environment.

"In general, the thinking has been that experience shapes the brain by influencing neurons," explains Corfas, the study's team leader and senior investigator, who also holds an appointment in the Departments of Neurology and Otolaryngology at Boston Children's Hospital and Harvard Medical School. "We are showing that glial cells are also influenced by experience, and that this is an essential step in establishing normal, mature neuronal circuits. Our findings provide a cellular and molecular context to understand the consequences of social isolation."

Myelin is essential in boosting the speed and efficiency of communication between different areas of the brain, so the decreased myelination may explain the social and cognitive deficits in the mice. Corfas has previously shown that abnormal myelination alters dopaminergic signaling in the brain, which could provide an alternative explanation for the findings.

The new study also showed that effects of social isolation are timing-dependent. If mice were isolated during a specific period in their development, they failed to recover functioning even when they were put back in a social environment. Conversely, if mice were put in isolation after this so-called critical period, they remained normal.

Finally, Corfas and colleagues identified a molecular signaling pathway through which social isolation leads to abnormal myelination. The brains of socially isolated mice had less neuregulin-1 (NRG1), a protein essential to the development of the nervous system. Furthermore, when the team eliminated an NRG1 receptor known as ErbB3 from oligodendrocytes, the effect was the same as being in isolation — myelination and behavior were abnormal even when the mice were in a stimulating, social environment.

"These observations indicate that the mechanisms we found are necessary for the brain to 'benefit' from early social experience," says Corfas.

The Corfas lab is now investigating drugs that might stimulate myelin growth by targeting NRG1, ErbB3 or related pathways. "Having both too much and too little myelination is bad," Corfas cautions. "This is a pathway that requires very careful regulation."

A number of neuropsychiatric disorders such as schizophrenia and mood disorders have been linked to pathologic changes in white matter and myelination, and to disturbances in the NRG1-ErbB signaling pathway, Corfas notes. Thus, the findings of this study may offer a new approach to these disorders.

Manabu Makinodan, MD, PhD, a postdoctoral fellow in Corfas' lab, was first author on the paper. The study was funded by the NIH, the National Institute of Neurologic Disorders and Stroke of the NIH.

Moderate exercise may help people cope with anxiety and stress for an extended period of time post-workout, according to a study by kinesiology researchers in the University of Maryland School of Public Health published in the journal Medicine and Science in Sports and Exercise.

"While it is well-known that exercise improves mood, among other benefits, not as much is known about the potency of exercise's impact on emotional state and whether these positive effects endure when we're faced with everyday stressors once we leave the gym," explains J. Carson Smith, assistant professor in the Department of Kinesiology. "We found that exercise helps to buffer the effects of emotional exposure. If you exercise, you'll not only reduce your anxiety, but you'll be better able to maintain that reduced anxiety when confronted with emotional events."

Smith, whose research explores how exercise and physical activity affect brain function, aging and mental health, compared how moderate intensity cycling versus a period of quiet rest (both for 30 minutes) affected anxiety levels in a group of healthy college students. He assessed their anxiety state before the period of activity (or rest), shortly afterward (15 minutes after) and finally after exposing them to a variety of highly arousing pleasant and unpleasant photographs, as well as neutral images. At each point, study participants answered 20 questions from the State-Trait Anxiety inventory, which is designed to assess different symptoms of anxiety. All participants were put through both the exercise and the rest states (on different days) and tested for anxiety levels pre-exercise, post-exercise, and post-picture viewing.

Smith found that exercise and quiet rest were equally effective at reducing anxiety levels initially. However, once they were emotionally stimulated (by being shown 90 photographs from the International Affective Picture System, a database of photographs used in emotion research) for ~20 minutes, the anxiety levels of those who had simply rested went back up to their initial levels, whereas those who had exercised maintained their reduced anxiety levels.

"The set of photographic stimuli we used from the IAPS database was designed to simulate the range of emotional events you might experience in daily life," Smith explains. "They represent pleasant emotional events, neutral events and unpleasant events or stimuli. These vary from pictures of babies, families, puppies and appetizing food items, to very neutral things like plates, cups, furniture and city landscapes, to very unpleasant images of violence, mutilations and other gruesome things."

The study findings suggest that exercise may play an important role in helping people to better endure life's daily anxieties and stressors.

Smith plans to explore if exercise could have the same persistent beneficial effect in patients who regularly experience anxiety and depression symptoms. In collaboration with the new Maryland Neuroimaging Center, he is also exploring the addition of functional magnetic resonance imaging, or fMRI, to measure brain activity during the period of exposure to emotionally stimulating images to see how exercise may alter the brain's emotion-related neural networks.

Smith also investigates the role of exercise in preventing cognitive decline in older adults. His research has shown that physical activity promotes changes in the brain that may protect those at high risk for Alzheimer's disease.

His article, "Effects of Emotional Exposure on State Anxiety after Acute Exercise," was published online ahead of print on Aug. 14, 2012 in the journal Medicine and Science in Sports and Exercise.

Parents may feel it's clear that missing a nap means their young children will be grumpy and out-of-sorts, but scientists who study sleep say almost nothing is known about how daytime sleep affects children's coping skills and learning.

Now neuroscientist Rebecca Spencer at the University of Massachusetts Amherst has received a five-year, $2 million grant from NIH's Heart, Lung and Blood Institute to significantly advance knowledge about how napping and sleep affect memory, behavior and emotions in preschoolers.

Spencer says with pressure mounting in some school districts to eliminate naps, "we feel it's important to study this and know their value more precisely. There's a sense among some educators that kids have to 'get over' napping in preparation for kindergarten, but it could be misguided. There's some evidence in young adults and in older children that naps are beneficial. So I suspect there is a benefit for younger children too. We need to know whether keeping naps in the school day is important."

Attending preschool offers life-long benefits in physical health, emotional stability and quality of life, Spencer points out, and in the United States, 70 percent of four- and five-year-olds attend. There is a trend now toward incorporating new curricula in preschool such as anti-bullying messages and lessons on how to brush your teeth. If sleep protects and enhances physical and emotional learning in young children as it does in older kids, taking away naptime could undercut such efforts, she adds.

"Right now, there's nothing to support teachers who feel that naps can really help young children, there's no concrete science behind that," the neuroscientist says. "But if sleep is going to enhance all these benefits of attending preschool, we need to know it."

Over the next five years, Spencer and her graduate students hope to study about 480 preschoolers between 3 and 5 years old, boys and girls in diverse communities across western Massachusetts. The research will include fact-based and emotional memory studies with and without napping, measures of physical activity levels and parent reports of their children's' nighttime sleep, to find out how classroom experience interacts with sleep and physical activity and whether daytime sleep enhances learning. The research will also explore the relationship between sleep and behavior disorders.

"I think we'll have a rich data set for examining sleep, physical activity and the child's behavior," says Spencer. "We think that the nap benefit is going to be especially useful for kids who don't get optimal overnight sleep. Culture plays a role in how late you stay up, and some kids live in noisy inner city neighborhoods. If we can help them with a nap, we want to know that."

Researchers at The Scripps Research Institute have found new links between a protein that controls our urge to eat and brain cells involved in the development of alcoholism. The discovery points to new possibilities for designing drugs to treat alcoholism and other addictions.

The new study, published online ahead of print by the journal Neuropsychopharmacology, focuses on the peptide ghrelin, which is known to stimulate eating.

"This is the first study to characterize the effects of ghrelin on neurons in a brain region called the central nucleus of the amygdala," said team leader Scripps Research Institute Associate Professor Marisa Roberto, who was knighted last year by the Italian Republic for her work in the alcoholism field. "There is increasing evidence that the peptide systems regulating food consumption are also critical players in excessive alcohol consumption. These peptide systems have the potential to serve as targets for new therapies aimed at treating alcoholism."

Excessive alcohol use and alcoholism cause approximately 4 percent of deaths globally each year. In the United States, that translates to 79,000 deaths annually and $224 billion in healthcare and other economic costs, according to a 2011 report by the Centers for Disease Control and Prevention.

Key Brain Region

The brain region known as the central nucleus of the amygdala is thought to be a key region in the transition to alcohol dependence, that is, a biological change from experiencing a pleasant sensation upon the consumption of alcohol to the need to consume alcohol to relieve unpleasant, negative feelings due to the lack of its consumption. In animals addicted to alcohol, the central nucleus of the amygdala controls increased consumption.

"Given the importance of the central nucleus of the amygdala in alcohol dependence, we wanted to test ghrelin's effects in this region," said Maureen Cruz, the first author of the study and former research associate in the Roberto laboratory, now an associate at Booz Allen Hamilton in Rockville, MD.

The peptide ghrelin is best known for stimulating eating through its action on a receptor known as GHSR1A in the hypothalamus region of the brain. But scientists had recently shown that gene defects in both ghrelin and the GHSR1A receptor were associated with severe cases of alcoholism in animal models. In addition, alcoholic patients have higher levels of the ghrelin peptide circulating in their blood compared to non-alcoholic patients. And, the higher the ghrelin levels, the higher the patients' reported cravings for alcohol.

New Evidence

In the new study, Roberto, Cruz, and colleagues at Scripps Research and the Oregon Health and Sciences University first demonstrated that GHSR1A is present on neurons in the central nucleus of the amygdala in the rat brain.

Using intracellular recording techniques, the team then measured how the strength of the GABAergic synapses (the area between neurons transmitting the inhibitory neurotransmitter GABA) changed when ghrelin was applied. They found that ghrelin caused increased GABAergic transmission in the central amygdala neurons. With further testing, the scientists determined that most likely this was due to increased release of the GABA neurotransmitter.

Next, the researchers blocked the GHSR1A receptor with a chemical inhibitor and measured a decrease in GABA transmission. This revealed tonic, or continuous, ghrelin activity in these neurons.

In the final set of experiments, the researchers examined neurons from alcohol-addicted and control rats when both ghrelin and ethanol were added. First, the scientists added ghrelin followed by ethanol. This resulted in an even stronger increase in GABAergic responses in these neurons. However, when the scientists reversed the order, adding ethanol first and ghrelin second, ghrelin did not further increase GABAergic transmission. This suggests that ghrelin could be potentiating the effects of alcohol in the central nucleus of the amygdala, in effect, priming the system.

New Possibilities

"Our results point to both shared and different mechanisms involved in the effects of ghrelin and ethanol in the central nucleus of the amygdala," said Roberto. "Importantly, there is a tonic ghrelin signal that appears to interact with pathways activated by both acute and chronic ethanol exposure. Perhaps if we could find a way to block ghrelin's activity in this region, we could dampen or even turn off the cravings felt by alcoholics."

Roberto cautions, though, that current therapies for alcoholism only work in a subset of patients.

"Because alcohol affects a lot of systems in the brain, there won't be a single pill that will cure the multiple and complex aspects of this disease," she said. "That is why we are studying alcoholism from a variety of angles, to understand the different brain targets involved."

In addition to Roberto and Cruz, authors of the paper, "Ghrelin Increases GABAergic Transmission and Interacts with Ethanol Actions in the Rat Central Nucleus of the Amygdala," were Melissa Herman of Scripps Research and Dawn Cote and Andrey Ryabinin of Oregon Health and Science University. For more information, see http://www.nature.com/npp/journal/vaop/ncurrent/full/npp2012190a.html

This research was supported by the Pearson Center for Alcoholism and Addiction Research and the U.S. National Institute on Alcohol Abuse and Alcoholism (grants AA015566, AA06420, AA016985, AA017447, AA016647, AA013498 and AA010760).

Emotions tag our experiences and act as signposts to steer our behavior. Avoiding danger and pursuing rewards is essential for successful navigation through a complex environment, and thus for survival. The search for the neural correlate of emotions has fascinated not only scientists — after all, emotions are a central part of our mental self.

A team of researchers, led by Wulf Haubensak at the IMP, has set out to understand how emotions are generated in the brain. Just like seeing or hearing, our feelings are based on the activity of nerve cells or neurons. Emotions are characterized by the activity of multiple areas of the brain: the neocortex, brain stem and an almond-shaped region in the limbic system called amygdala. Together, these components form a complex network of neuronal circuits whose detailed structure and function are not yet understood.

Cartography of the Brain

The generous ERC funds will support an IMP-project to map the emotional circuitry within this network and to study how activity in these circuits gives rise to emotions. In their experimental setups, the researchers will use mice as experimental model system. Mice are able to show basic emotional behaviors and have a brain-anatomy sufficiently similar to ours, which allows us to draw conclusions that might be relevant for humans as well.

To address the origin of emotions, the neuroscientists use a combination of advanced methods that have been developed in recent years. To visualize neuronal circuit elements, they take advantage of the characteristics of certain viruses, such as the rabies pathogen. These viruses infect specific nerve cells and migrate along them to the brain. A fluorescent protein, engineered into the virus in advance, leaves a visible trace of light. This "viral circuit mapping" is able to highlight networks of interacting neurons with cartographic precision.

For a functional analysis of the tagged circuits, the scientists then employ sophisticated optogenetic technology. These methods make it possible to selectively switch groups of neurons on or off, using visible light like a remote control.

Circuit Therapies for the Future

The IMP-project will also address the question of how genes and pharmaceutical substances affect the activity of neuronal circuits and influence emotions. The researchers hope to gain valuable insights into emotional dysfunctions such as post-traumatic stress or anxiety disorders. Ultimately, this could lead to the development of specific "circuit therapies" to treat psychiatric disorders more selectively and with less side effects.

Wulf Haubensak is delighted by the ERC's decision to support his project: "The generous funding will allow us to broaden our studies and to develop new experimental approaches. It also reflects the appreciation of the scientific community for our ideas and will certainly help to attract young, enthusiastic scientists to our project."

The ERC Starting Grants aim to support up-and-coming research leaders who are about to establish a proper research team and to start carrying out independent research in Europe. The scheme targets promising young scientists who have the proven potential of conducting excellent research. In the current call, nine researchers from institutions based in Austria were selected to receive a Starting Grant, out of 91 applications.

Osteoporosis, or reduced bone mineral density (BMD), is defined by an absolute decrease in total bone mass, caused mostly by an imbalance between osteoclastic bone resorption and osteoblastic bone formation. Reduced BMD often co-occurs with alcoholism. A study of the passage of bone formation and resorption in abstinent alcoholics has found that eight weeks of abstinence may be enough to initiate a healthier balance between the two.

Results will be published in the December 2012 issue of Alcoholism: Clinical & Experimental Research and are currently available at Early View.

"There are many reasons why alcoholics may develop reduced BMD: lack of physical activity, liver disease, and a suspected direct toxic effect of alcohol on bone-building cells," explained Peter Malik, a senior scientist and physician at the Medical University Innsbruck, Austria as well as corresponding author for the study. "A reduced BMD carries an increased risk of fractures with all the consequences; osteoporotic fractures also put an enormous financial burden on health care systems due to high rehabilitation costs."

"This study contributes to our understanding of various deteriorating effects of long-term consumption of high amounts of alcohol on the human body," commented Sergei Mechtcheriakov, associate professor of psychiatry at the Medical University Innsbruck, Austria. "We can see that even bone tissue which is often — and wrongly — perceived as inert, can be affected by alcoholism. It would seem that a combination of direct toxic effects of alcohol and its metabolites on bone tissue turnover as well as life style factors, such as low physical activity, may play a significant role."

Malik and his collegues examined BMD in 53 male abstinent patients, 21 to 50 years of age, at an alcohol rehabilitation clinic. Blood work was drawn for various measures at baseline and after eight weeks of treatment. Study authors also used x-rays to determine BMD in the lumbar spine and the proximal right femur, as well as a questionnaire to determine levels of physical activity prior to inpatient treatment.

"We found that BMD is reduced in alcoholic men without liver disease," said Malik. "However, the initial imbalance between bone formation and resorption seems to straighten out during abstinence. This means that an increased fracture risk could be reduced during abstinence if no manifest osteoporosis is already present. In addition, regular physical exercise seems to be 'bone-protective' in alcoholic patients, likely due to the fact that a dynamic strain on bone through physical activity increases the rate of bone formation and resorption, which is good for bone density."

"This study supports the view that recovery treatment programs should contain long-term moderate physical activity regimes," said Mechtcheriakov, "which treatment programs generally do. But the study also suggests that deficits in the musculoskeletal system, such as BMD reduction or muscular atrophy, should be taken into account during the rehabilitation. The study shows that during the first weeks of abstinence the bone metabolism is slowly improving but not fully recovered. Recovery after long-term alcoholism takes months and probably years. We need better understanding of these processes in order to be able to conceive better rehabilitation programs."

Based on these findings, Malik recommended that patients with a longer history of alcohol abuse or dependence undergo dual-energy X-ray absorptiometry, a measurement of BMD, especially when other risk factors such as co-medication or smoking are present.

Mechtcheriakov added that even though a full recovery may take months or even years, it is important to remember that it is possible with abstinence.

"This is probably true for many other alcohol-associated diseases," Mechtcheriakov said. "It pays to stop drinking or at least reduce alcohol consumption to the low-risk levels recommended by the National Institute on Alcohol Abuse and Alcoholism. We need a better scientific understanding of the multiple consequences of alcoholism and its associated long-term recovery processes. The latter aspect has been underestimated in alcohol research for decades. This applies also to alcohol-associated neuronal sensibility disorder, motor coordination deficits, muscular atrophy, and bone metabolism. The application of scientifically based methods to support and stimulate long-term recovery processes in post-withdrawal alcoholics can dramatically improve quality of life and rehabilitation success for this large group of patients."