Neuroscience

To flexibly deal with our ever-changing world, we need to learn from both the negative and positive consequences of our behaviour. In other words, from punishment and reward. Hanneke den Ouden from the Donders Institute in Nijmegen demonstrated that serotonin and dopamine related genes influence how we base our choices on past punishments or rewards. This influence depends on which gene variant you inherited from your parents. These results were published in Neuron on 20 November.

The brain chemicals dopamine and serotonin partly determine our sensitivity to reward and punishment. At least, this was a common assumption. Hanneke den Ouden and Roshan Cools investigated this assumption together with colleagues from the Donders Institute and New York University. Den Ouden explains: ‘We used a simple computer game to test the genetic influence of the genes DAT1 and SERT, as these genes influence dopamine and serotonin. We discovered that the dopamine gene affects how we learn from the long-term consequences of our choices, while the serotonin gene affects our choices in the short term.’

Online game

‘In nearly 700 people we analysed which variant of the SERT and the DAT1 genes they had’, Den Ouden describes. ‘Using an online game, we investigated how well people are able to adjust their choice strategy after receiving a reward or a punishment.’ The players would repeatedly choose one of two symbols. Symbol A usually resulted in a reward whereas symbol B usually resulted in punishment. Halfway through the game, these rules were reversed. The game allowed the researchers to measure how flexible people are in adjusting their choices when the rules change. But it also showed whether people impulsively change their choice when the computer happened to give misleading feedback.

Different genes, different strategies

Den Ouden: ‘Different players use different strategies, which depend on their genetic material. People’s tendency to change their choice immediately after receiving a punishment depends on which serotonin gene variant they inherited from their parents. The dopamine gene variant, on the other hand, exerts influence on whether people can stop themselves making the choice that was previously rewarded, but no longer is.’

This study shows that dopamine and serotonin are important for different forms of flexibility associated with receiving reward and punishment. Many neuropsychiatric disorders caused by abnormal dopamine and/or serotonin levels are associated with forms of inflexibility, for example addiction, anxiety, or Parkinson’s disease. So this study not only tells us more about the heritability of our choice behaviour; a better understanding of the relationship between brain chemicals and behaviour in healthy people will ultimately help to provide us with better insight into these neuropsychiatric disorders.

Alexander disease is a devastating brain disease that almost nobody has heard of — unless someone in the family is afflicted with it. Alexander disease strikes young or old, and in children destroys white matter in the front of the brain. Many patients, especially those with early onset, have significant intellectual disabilities.

(Image: A mutant gene that causes the deadly Alexander disease creates an overgrowth of the protein GFAP in mouse brain cells called astrocytes (right) compared to normal brain cells (left))

Regardless of the age when it begins, Alexander disease is always fatal. It typically results from mutations in a gene known as GFAP (glial fibrillary acidic protein), leading to the formation of fibrous clumps of protein inside brain cells called astrocytes.

Classically, astrocytes and other glial cells were considered “helpers” that nourish and protect the neurons that do the actual communication. But in recent years, it’s become clear that glial cells are much more than passive bystanders, and may be active culprits in many neurological diseases.

Now, in a report in the Journal of Neuroscience, researchers at UW-Madison show that Alexander disease also affects neurons, and in a way that impacts several measures of learning and memory.

Mice were engineered to contain the same mutation in GFAP that is found in human patients. Their astrocytes spontaneously increased production of GFAP, the same response found after many types of injury or disease in the brain. In Alexander disease, the result is an increase in mutant GFAP that is “toxic to the cell, and unfortunately astrocytes respond by making more GFAP,” says first author Tracy Hagemann, an associate scientist with the university’s Waisman Center.

While GFAP is usually found in astrocytes, it also occurs in neural stem cells, a population of cells that persist in some areas of the brain to continually spawn new neurons throughout adulthood. In the mouse versions of Alexander disease, neural stem cells are present, but they fail to develop into neurons, Hagemann says. “Think of a garden where your green beans never sprouted. Was it too cold for them to sprout, or was there another problem? Something similar is happening with these neural stem cells. They are present, but inert, and we’re not sure why.”

The shortage of new neurons could explain why the mice with excess GFAP failed a test that required them to remember the location of a submerged platform in a tub of water.

The report is “the first to suggest that the problems in Alexander disease extend beyond just the white matter and astrocytes, and may provide a clue to the problems with learning and memory that are such prominent features in the human disease,” says lab leader Albee Messing, a professor of comparative biosciences in the UW School of Veterinary Medicine.

One immediate question that the team will try to answer is whether the same defect in stem cells can be found in autopsy samples stored over many years to allow just this kind of investigation.

Still to be clarified is whether the mutation affects the neural stem cells directly, or whether it acts through other astrocytes that are nearby. “We do know that the astrocytes become activated with this GFAP mutation,” Hagemann says. “That activation — a kind of inflammation — could be making the environment hostile to young neurons. Or the mutation could be changing the neural stem cells themselves in some other way.

"Medicine advances by teasing things apart," says Hagemann. "A single mutation can work in different ways — through different chains of cause and effect leading to different symptoms of a disease. In this case it’s like the old question of nature versus nurture. Was the stem cell born bad — was it genetically doomed? Or were the reactive astrocytes in the neighborhood a toxic influence? Or both? This is an important question for Alexander disease and other brain deteriorating disorders, especially with the current focus on stem cells as a source for new neurons and therapy."

Already, the Waisman group is screening drugs that might slow GFAP production. Eventually, Hagemann says, the work may illuminate the role of astrocyte dysfunction in other neural diseases featuring aggregates of misformed proteins, including ALS, Parkinson’s, and Alzheimer’s disease.

Studies have shown that resveratrol, a natural compound found in colored vegetables, fruits and especially grapes, may minimize the impact of Parkinson’s disease, stroke and Alzheimer’s disease in those who maintain healthy diets or who regularly take resveratrol supplements. Now, researchers at the University of Missouri have found that resveratrol may also block the effects of the highly addictive drug, methamphetamine.

(Image: Wikipedia)

Dennis Miller, associate professor in the Department of Psychological Sciences in the College of Arts & Science and an investigator with the Bond Life Sciences Center, and researchers in the Center for Translational Neuroscience at MU, study therapies for drug addiction and neurodegenerative disorders. Their research targets treatments for methamphetamine abuse and has focused on the role of the neurotransmitter dopamine in drug addiction. Dopamine levels in the brain surge after methamphetamine use; this increase is associated with the motivation to continue using the drug, despite its adverse consequences. However, with repeated methamphetamine use, dopamine neurons may degenerate causing neurological and behavioral impairments, similar to those observed in people with Parkinson’s disease.

“Dopamine is critical to the development of methamphetamine addiction—the transition from using a drug because one likes or enjoys it to using the drug because one craves or compulsively uses it,” Miller said. “Resveratrol has been shown to regulate these dopamine neurons and to be protective in Parkinson’s disease, a disorder where dopamine neurons degenerate; therefore, we sought to determine if resveratrol could affect methamphetamine-induced changes in the brain.”

Using procedures established by Parkinson’s and Alzheimer’s disease research, rats received resveratrol once a day for seven days in about the same concentration as a human would receive from a healthy diet. After a week of resveratrol, researchers measured how much dopamine was released by methamphetamine. Researchers found that resveratrol significantly diminished methamphetamine’s ability to increase dopamine levels in the brain. Furthermore, resveratrol diminished methamphetamine’s ability to increase activity in mice, a behavior that models the hyperactivity observed in people that use the stimulant.

“People are encouraged by physicians and dieticians to include resveratrol-containing products in their diet and protection against methamphetamine’s harmful effects may be an added bonus,” Miller said. “Additionally, there are no consistently effective treatments to help people who are dependent on methamphetamine. Our initial research suggests that resveratrol could be included in a treatment regimen for those addicted to methamphetamine and it has potential to decrease the craving and desire for the drug. Resveratrol is found in good, colorful foods, and has few side effects. We all ought to consume resveratrol for good brain health; our research suggests it may also prevent the changes in the brain that occur with the development of drug addiction.”

A vision is to implant nerve precursor cells in the diseased brains of patients with Parkinson’s and Huntington’s diseases, whereby these cells are to assume the function of the cells that have died off. However, the implanted nerve cells frequently do not migrate as hoped, rather they hardly move from the site. Scientists at the Institute for Reconstructive Neurobiology at Bonn University have now discovered an important cause of this: Attractants secreted by the precursor cells prevent the maturing nerve cells from migrating into the brain. The results are presented in the journal “Nature Neuroscience.”

One approach for treating patients with Parkinson’s or Huntington’s disease is to replace defective brain cells with fresh cells. To do this, immature precursor cells from neurons are implanted into the diseased brains; these cells are to then mature on-site and take over the function of the defective cells. “However, it has been shown again and again that the nerve cells generated by the transplant barely migrate into the brain but remain largely confined to the implant site,” says Prof. Dr. Oliver Brüstle, Director of the Institute for Reconstructive Neurobiology at Bonn University. Scientists have believed for a long time that this effect is associated with the fact that in the mature brain, there are unfavorable conditions for the uptake of additional nerve cells.

Immature and more mature nerve cells attract each other like magnets

The researchers from the Institute for Reconstructive Neurobiology of Bonn University have now discovered a fully unexpected mechanism to which the deficient migratory behavior of the graft-derived neurons can be attributed. The implanted cells mature at different rates and thus there is a mixture of the two stages. “Like magnets, the precursor cells which are still largely immature attract the nerve cells which have already matured further, which is why there is a sort of agglomeration,” says lead author Dr. Julia Ladewig, who was recently awarded a research prize of 1.25 million Euro by the North Rhine-Westphalian Stem Cell Network, which is supported by State Ministry of Science and Research.

The cause of the attractive force which has remained hidden to date involves chemical attractants which are secreted by the precursor cells. “In this way, the nerve precursor cells prevent the mature brain cells from penetrating further into the tissue,” says Dr. Philipp Koch, who performed the primary work for the study as an additional lead author, together with Dr. Ladewig.

The scientists had initially observed that, the more precursor cells contained in the transplant, the worse the migration of nerve cells is. In a second step, the researchers from the Institute for Reconstructive Neurobiology at Bonn University were able to decode and inactivate the attractants responsible for the agglomeration of mature and immature neurons. When the scientists deactivated the receptor tyrosine kinase ligands FGF2 and VEGF with inhibitors, mature nerve cells migrated better into the animal brains and dispersed over much larger areas.

Promising universal approach for transplants

“This is a promising new approach to solve an old problem in neurotransplantation,” Prof. Brüstle summarizes. Through the inhibition of attractants, the migration of implanted nerve precursor cells into the brain can be significantly improved. As the researchers have shown in various models with precursor cells from animals and humans, the mechanism is a fundamental principle which also functions across species. “However, more research is still needed to transfer the principle into clinical application,” says Prof. Brüstle.

A computer program called the Never Ending Image Learner (NEIL) is running 24 hours a day at Carnegie Mellon University, searching the Web for images, doing its best to understand them on its own and, as it builds a growing visual database, gathering common sense on a massive scale.

NEIL leverages recent advances in computer vision that enable computer programs to identify and label objects in images, to characterize scenes and to recognize attributes, such as colors, lighting and materials, all with a minimum of human supervision. In turn, the data it generates will further enhance the ability of computers to understand the visual world.

But NEIL also makes associations between these things to obtain common sense information that people just seem to know without ever saying — that cars often are found on roads, that buildings tend to be vertical and that ducks look sort of like geese. Based on text references, it might seem that the color associated with sheep is black, but people — and NEIL — nevertheless know that sheep typically are white.

"Images are the best way to learn visual properties," said Abhinav Gupta, assistant research professor in Carnegie Mellon’s Robotics Institute. "Images also include a lot of common sense information about the world. People learn this by themselves and, with NEIL, we hope that computers will do so as well."

A computer cluster has been running the NEIL program since late July and already has analyzed three million images, identifying 1,500 types of objects in half a million images and 1,200 types of scenes in hundreds of thousands of images. It has connected the dots to learn 2,500 associations from thousands of instances.

The public can now view NEIL’s findings at the project website, www.neil-kb.com.

The research team, including Xinlei Chen, a Ph.D. student in CMU’s Language Technologies Institute, and Abhinav Shrivastava, a Ph.D. student in robotics, will present its findings on Dec. 4 at the IEEE International Conference on Computer Vision in Sydney, Australia.

One motivation for the NEIL project is to create the world’s largest visual structured knowledge base, where objects, scenes, actions, attributes and contextual relationships are labeled and catalogued.

"What we have learned in the last 5-10 years of computer vision research is that the more data you have, the better computer vision becomes," Gupta said.

Some projects, such as ImageNet and Visipedia, have tried to compile this structured data with human assistance. But the scale of the Internet is so vast — Facebook alone holds more than 200 billion images — that the only hope to analyze it all is to teach computers to do it largely by themselves.

Shrivastava said NEIL can sometimes make erroneous assumptions that compound mistakes, so people need to be part of the process. A Google Image search, for instance, might convince NEIL that “pink” is just the name of a singer, rather than a color.

"People don’t always know how or what to teach computers," he observed. "But humans are good at telling computers when they are wrong."

People also tell NEIL what categories of objects, scenes, etc., to search and analyze. But sometimes, what NEIL finds can surprise even the researchers. It can be anticipated, for instance, that a search for “apple” might return images of fruit as well as laptop computers. But Gupta and his landlubbing team had no idea that a search for F-18 would identify not only images of a fighter jet, but also of F18-class catamarans.

As its search proceeds, NEIL develops subcategories of objects — tricycles can be for kids, for adults and can be motorized, or cars come in a variety of brands and models. And it begins to notice associations — that zebras tend to be found in savannahs, for instance, and that stock trading floors are typically crowded.

NEIL is computationally intensive, the research team noted. The program runs on two clusters of computers that include 200 processing cores.

This research is supported by the Office of Naval Research and Google Inc.

A genetic defect that profoundly affects speech in humans also disrupts the ability of songbirds to sing effective courtship tunes. This defect in a gene called FoxP2 renders the brain circuitry insensitive to feel-good chemicals that serve as a reward for speaking the correct syllable or hitting the right note, a recent study shows. 

The research, which was conducted in adult zebrafinches, gives insight into how this genetic mutation impairs a network of nerve cells to cause the stuttering and stammering typical of people with FoxP2 mutations. It appears Nov. 21 in an early online edition of the journal Neuron.

"Our results integrate a lot of different observations that have accrued on the FoxP2 mutation and cast a different perspective on what this mutation is doing," said Richard Mooney, Ph.D., the George Barth Geller professor of neurobiology at Duke University School of Medicine and a member of the Duke Institute for Brain Sciences. "FoxP2 mutations do not simply result in a cognitive or learning deficit, but also produce an ongoing motor deficit. Individuals with these mutations can still learn and can still improve; it is just harder for them to reliably hit the right mark." 

About 15 years ago, researchers discovered a British family with many members suffering from severe speech and language deficits. Geneticists eventually pinned down the culprit — a gene called forkhead box transcription factor or FoxP2 — that was mutated in all the affected individuals. The discovery led many to believe FoxP2 was a “language gene” that granted humans the ability to speak. But further studies showed that the gene wasn’t unique to humans, and in fact was conserved among all vertebrates, including songbirds. 

Though the gene is present in every cell, it is “active,” or turned on, mostly in brain cells, particularly ones residing in a region deep within the brain known as the basal ganglia. This region is dysfunctional in Tourette syndrome, known for its vocal tics and outbursts, and is also shrunk in individuals with FoxP2 mutations. 

To explore the complex circuitry involved in these deficits, Mooney and his former graduate student Malavika Murugan, Ph.D., decided to replicate the human mutation in this region of the brain in songbirds. Zebrafinches start learning how to sing 30 days after they hatch, listening to a male tutor and then practicing thousands of times a day until, 60 days later, they are able to make a very good copy of the tutor’s song. As good as that copy is at day 90, the male finch’s song gets even more precise when he “directs” it to a female as part of courtship. 

To investigate the role of FoxP2 in the generation of this directed song, Murugan introduced specifically targeted sequences of RNA to suppress FoxP2 activity in the basal ganglia of male zebrafinches. The birds were placed in a glass cage that revealed a female sitting on the other side. Murugan then recorded sonograms of their song to capture the subtle vocal variations indistinguishable to the human ear when they produced directed songs at the female. 

Murugan found that though the genetically manipulated males had already learned how to sing, their ability to hit the right note repeatedly in the presence of a female — a behavior critical to attracting a mate — was subpar. This indicates that in songbirds, FoxP2 has an ongoing role in vocal control separate from a role in learning, a distinction that has not been possible to make in humans with FOXP2 mutations. 

Having deduced the behavior associated with this genetic mutation, the researchers then identified underlying neural deficits by recording brain activity in birds with normal and altered FoxP2 genes. In one set of experiments, Murugan sent an electrical signal into the input side of the basal ganglia pathway and then used an electrode on the output side to measure how quickly the signal traveled from one side to the other. Surprisingly, the signal moved more quickly through the basal ganglia of FoxP2 mutant songbirds than it did in songbirds with the functional gene. 

Murugan also found that dopamine, an important brain chemical involved in brain signaling and the reinforcement of learned behaviors like singing or playing sports, could influence how fast basal ganglia signals propagated in birds with normal but not mutant forms of FoxP2.  

"This switch between undirected and directed song is actually dependent on the influx of this neurotransmitter called dopamine," said Murugan, first author of the study. "So what we think is happening is knocking down FoxP2 makes the male incapable of reducing song variability in the presence of a female. An adult male sees the female, there is an influx of dopamine, but because the system is insensitive, the dopamine has no effect and the adult male continues to sing a variable tune." In juveniles, the inability to constrain variability and to respond to dopamine could also account for poor learning.

Though the researchers are cautious not to draw too many parallels between their findings in birds and the deficits in humans, they think their study does highlight the value of songbirds in studying human behaviors and disease.

"Birds are one of the few non-human animals that learn to vocalize," said Mooney. "They produce songs for courtship that they culturally transmit from one generation to the next. Their brains might be a thousandth the size of ours, but in this one dimension, vocal learning, they are our equal."

UCL scientists have shown that there are widespread differences in how genes, the basic building blocks of the human body, are expressed in men and women’s brains.

Based on post-mortem adult human brain and spinal cord samples from over 100 individuals, scientists at the UCL Institute of Neurology were able to study the expression of every gene in 12 brain regions. The results are published today in Nature Communications.

They found that the way that the genes are expressed in the brains of men and women were different in all major brain regions and these differences involved 2.5% of all the genes expressed in the brain.

Among the many results, the researchers specifically looked at the gene NRXN3, which has been implicated in autism. The gene is transcribed into two major forms and the study results show that although one form is expressed similarly in both men and women, the other is produced at lower levels in women in the area of the brain called the thalamus. This observation could be important in understanding the higher incidence of autism in males.

Overall, the study suggests that there is a sex-bias in the way that genes are expressed and regulated, leading to different functionality and differences in susceptibility to brain diseases observed by neurologists and psychiatrists.

Dr. Mina Ryten, UCL Institute of Neurology and senior author of the paper, said: “There is strong evidence to show that men and women differ in terms of their susceptibility to neurological diseases, but up until now the basis of that difference has been unclear.

“Our study provides the most complete information so far on how the sexes differ in terms of how their genes are expressed in the brain. We have released our data so that others can assess how any gene they are interested in is expressed differently between men and women.”

Carrying a particular version of the gene for apolipoprotein E (APOE) is the major known genetic risk factor for the sporadic, late-onset form of Alzheimer’s disease, but exactly how that variant confers increased risk has been controversial among researchers. Now an animal study led by Massachusetts General Hospital (MGH) investigators shows that even low levels of the Alzheimer’s-associated APOE4 protein can increase the number and density of amyloid beta (A-beta) brain plaques, characteristic neuronal damage, and the amount of toxic soluble A-beta within the brain in mouse models of the disease. Introducing APOE2, a rare variant that has been associated with protection from developing Alzheimer’s disease, into the brains of animals with established plaques actually reduced A-beta deposition, retention and neurotoxicity, suggesting the potential for gene-therapy-based treatment.

"Using a technique developed by our collaborators at the University of Iowa, we were able to get long-term expression of these human gene variants in the fluid that bathes the entire brain," says Bradley Hyman, MD, PhD, of the MassGeneral Institute for Neurodegenerative Disease (MGH-MIND), senior author of the report in the Nov. 20 Science Translational Medicine. “Our results suggest that strategies aimed at decreasing levels of APOE4, the harmful form of the protein, and increasing concentrations of protective variant APOE2 could be helpful to patients.”

The association between the APOE4 variant and increased Alzheimer’s risk was first made more than 20 years ago. Subsequent research has established that carrying two copies of the harmful variant increases risk 12 times compared with having two copies of the more common form, APOE3. Inheriting the APOE2 variant, however, appears to cut the risk in half. The extremely rare gene variants that directly cause the familial forms of the disease all participate in the production and deposition of A-beta, but exactly how APOE variants contribute to the process has been poorly understood. 

Secreted by certain brain cells, APOE is known to regulate cholesterol metabolism within the brain and can bind to A-beta peptides, suggesting that the different forms of the protein may affect whether and how toxic A-beta plaques form. While previous investigations into the protein’s effects have used either mice in which gene expression was knocked out or transgenic animals that expressed human gene variants throughout their lifetimes, the MGH-MIND-led study used a different approach to investigate the effects of introducing the variant forms of the protein into brains in which plaque formation had already begun. They directly injected into the cerebrospinal fluid of a mouse model of Alzheimer’s – adult animals in which plaques were well established – viral vectors carrying genes for one of the three APOE variants or a control protein.

Two month after the vectors had been injected, about 10 percent of the APOE in the brains of animals that received one of the variants was found to be the introduced human version. At five months after injection, examination of brain tissue revealed that the A-beta plaques in mice that received APOE4 injections were more numerous and significantly denser than those of mice receiving APOE2. The growth of plaques in animals receiving APOE3 was intermediate between that of the other two groups and similar to what was seen in control animals. Levels of A-beta in the blood of mice that received APOE2 were higher than in the other groups, suggesting that the protective variant had increased clearance of A-beta from the brain. 

In a group of animals in which tiny implanted windows allowed direct imaging of brain tissue, the progression of A-beta plaque deposition was fastest in animals receiving APOE4 and slowest, sometimes even appearing to regress, in mice injected with APOE2. Signs of neuronal damage around plaques also varied depending on the APOE variant the animals received, and experiments in a different Alzheimer’s model in which plaques appear more slowly showed that injection of APOE4 increased levels of free, soluble A-beta in the fluid that bathes the brain. 

"This study has allowed us to sort out, in mice, which effects of the different types of APOE were most important to variation in amyloid plaque deposition," says Eloise Hudry, PhD, of MGH-MIND, lead author of the Science Translational Medicine report. “Our results imply that APOE-based therapeutic approaches may help to alleviate the progression of Alzheimer’s disease. More study is needed to pursue that possibility and to investigate the potential use of this gene transfer technology to introduce other protective proteins into the brain.”

After a mild concussion, special brain scans show evidence of brain abnormalities four months later, when symptoms from the concussion have mostly dissipated, according to research published in the November 20, 2013, online issue of Neurology®, the medical journal of the American Academy of Neurology.

“These results suggest that there are potentially two different modes of recovery for concussion, with the memory, thinking and behavioral symptoms improving more quickly than the physiological injuries in the brain,” said study author Andrew R. Mayer, PhD, of the Mind Research Network and University of New Mexico School of Medicine in Albuquerque.

Mayer further suggests that healing from concussions may be similar to other body ailments such as recovering from a burn. “During recovery, reported symptoms like pain are greatly reduced before the body is finished healing, when the tissue scabs. These finding may have important implications about when it is truly safe to resume physical activities that could produce a second concussion, potentially further injuring an already vulnerable brain.”

Mayer noted that standard brain scans such as CT or MRI would not pick up on these subtle changes in the brain. “Unfortunately, this can lead to the common misperception that any persistent symptoms are psychological.”

The study compared 50 people who had suffered a mild concussion to 50 healthy people of similar age and education. All the participants had tests of their memory and thinking skills and other symptoms such as anxiety and depression two weeks after the concussion, as well as brain scans. Four months after the concussion, 26 of the patients and 26 controls repeated the tests and scans.

The study found that two weeks after the injury the people who had concussions had more self-reported problems with memory and thinking skills, physical problems such as headaches and dizziness, and emotional problems such as depression and anxiety than people who had not had concussions. By four months after the injury, the symptoms were significantly reduced by up to 27 percent.

The people who had concussions also had evidence of abnormalities in the gray matter in the frontal cortex area of both sides of the brain, based on the diffusion tensor imaging scans. The increase equated to about 10 percent compared to the healthy people in the study. These abnormalities were still apparent four months after the concussion. In contrast, there was no evidence of cellular loss on scans.

Mayer said possible explanations for the brain abnormalities could be cytotoxic edema, which results from changes in where fluids are located in and around brain cells, or reactive gliosis, which is the change in glial cells’ shape in response to damage to the central nervous system.

A new blood biomarker correctly predicted which concussion victims went on to have white matter tract structural damage and persistent cognitive dysfunction following a mild traumatic brain injury (mTBI). Researchers in the Perelman School of Medicine at the University of Pennsylvania, in conjunction with colleagues at Baylor College of Medicine, found that the blood levels of a protein called calpain-cleaved αII-spectrin N-terminal fragment (SNTF) were twice as high in a subset of patients following a traumatic injury. If validated in larger studies, this blood test could identify concussion patients at increased risk for persistent cognitive dysfunction or further brain damage and disability if returning to sports or military activities.

More than 1.5 million children and adults suffer concussions each year in the United States, and hundreds of thousands of military personal endure these mild traumatic brain injuries worldwide. Current tests are not capable of determining the extent of the injury or whether the injured person will be among the 15-30 percent who experience significant, persistent cognitive deficits, such as processing speed, working memory and the ability to switch or balance multiple thoughts.

"New tests that are fast, simple, and reliable are badly needed to predict who may experience long-term effects from concussions, and as new treatments are developed in the future, to identify who should be eligible for clinical trials or early interventions," said lead author Robert Siman, PhD, research professor of Neurosurgery at Penn. "Measuring the blood levels of SNTF on the day of a brain injury may help to identify the subset of concussed patients who are at risk of persistent disability." 

In a study published yesterday in Frontiers in Neurology, Penn and Baylor researchers evaluated blood samples and diffusion tensor images from a subgroup of 38 participants in a larger study of mTBI with ages ranging from 15 to 25 years old. 17 had sustained a head injury caused by blunt trauma, acceleration or deceleration forces, 13 had an orthopaedic injury, and 8 were healthy, uninjured, demographically matched controls.

In taking neuropsychological and cognitive tests over the course of three months, results within the mTBI group varied considerably, with some patients performing as well as the healthy controls throughout, while others showed impairment initially that resolved by three months, and a third group with cognitive dysfunction persisting through three months. The nine patients who had abnormally high levels of SNTF (7 mTBI and 2 orthopaedic patients) also had significant white matter damage apparent in radiological imaging.

"The blood test identified SNTF in some of the orthopaedic injury patients as well, suggesting that these injuries could also lead to abnormalities in the brain, such as a concussion, that may have been overlooked with existing tests," said Douglas Smith, MD, director of the Penn Center for Brain Injury and Repair and professor of Neurosurgery. "SNTF as a marker is consistent with our earlier research showing that calcium is dumped into neurons following a traumatic brain injury, as SNTF is a marker for neurodegeneration driven by calcium overload."

The blood test given on the day of the mild traumatic brain injury showed 100 percent sensitivity to predict concussions leading to persisting cognitive problems, and 75 percent specificity to correctly rule out those without functionally harmful concussions. If validated in larger studies, a blood test measuring levels of SNTF could be helpful in diagnosing and predicting risk of long term consequences of concussion. The Penn and Baylor researchers hope to determine the robustness of these findings with a second larger study, and determine the best time after concussion to measure SNTF in the blood in order to predict persistent brain dysfunction. The team also wants to evaluate their blood test for identifying when repetitive concussions begin to cause brain damage and persistent disability.

Are monkeys, like humans, able to ascertain where objects are located without much more than a sideways glance? Quite likely, says Lau Andersen of the Aarhus University in Denmark, lead author of a study conducted at the Yerkes National Primate Research Center of Emory University, published in Springer’s journal Animal Cognition. The study finds that monkeys are able to localize stimuli they do not perceive.

Humans are able to locate, and even side-step, objects in their peripheral vision, sometimes before they perceive the object even being present. Andersen and colleagues therefore wanted to find out if visually guided action and visual perception also occurred independently in other primates.

The researchers trained five adult male rhesus monkeys (Macaca mulatta) to perform a short-latency, highly stereotyped localization task. Using a touchscreen computer, the animals learned to touch one of four locations where an object was briefly presented. The monkeys also learned to perform a detection task using identical stimuli, in which they had to report the presence or absence of an object by pressing one of two buttons. These techniques are similar to those used to test normal humans, and therefore make an especially direct comparison between humans and monkeys possible. A method called “visual masking” was used to systematically reduce how easily a visual target was processed.

Andersen and his colleagues found that the monkeys were still able to locate targets that they could not detect. The animals performed the tasks very accurately when the stimuli were unmasked, and their performance dropped when visual masking was employed. But monkeys could still locate targets at masking levels for which they reported that no target had been presented. While these results cannot establish the existence of phenomenal vision in monkeys, the discrepancy between visually guided action and detection parallels the dissociation of conscious and unconscious vision seen in humans.

“Knowing whether similar independent brain systems are present in humans and nonverbal species is critical to our understanding of comparative psychology and the evolution of brains,” explains Andersen.

Patients with the most common form of focal epilepsy have widespread, abnormal connections in their brains that could provide clues toward diagnosis and treatment, according to a new study published online in the journal Radiology.

(Image: MP-RAGE volumes are segmented into 83 ROIs, which are further parcellated into 1000 cortical and 15 subcortical ROIs. Whole-brain white matter tractography is performed after voxelwise tensor calculation, and the density of fibers that connect each pair of cortical ROIs is used to calculate structural connectivity. T1w = T1-weighted. Credit: Courtesy of Radiology and RSNA)

Temporal lobe epilepsy is characterized by seizures emanating from the temporal lobes, which sit on each side of the brain just above the ear. Previously, experts believed that the condition was related to isolated injuries of structures within the temporal lobe, like the hippocampus. But recent research has implicated the default mode network (DMN), the set of brain regions activated during task-free introspection and deactivated during goal-directed behavior. The DMN consists of several hubs that are more active during the resting state.

To learn more, researchers performed diffusion tensor imaging, a type of MRI that tracks the movement, or diffusion, of water in the brain’s white matter, the nerve fibers that transmit signals throughout the brain. The study group consisted of 24 patients with left temporal lobe epilepsy who were slated for surgery to remove the site from where their seizures emanated. The researchers compared them with 24 healthy controls using an MRI protocol dedicated to finding white matter tracts with diffusion imaging at high resolution. The data was analyzed with a new technique that identifies and quantifies structural connections in the brain.

Patients with left temporal lobe epilepsy exhibited a decrease in long-range connectivity of 22 percent to 45 percent among areas of the DMN when compared with the healthy controls.

"Using diffusion MRI, we found alterations in the structural connectivity beyond the medial temporal lobe, especially in the default mode network," said Steven M. Stufflebeam, M.D., from the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital in Boston.

In addition to reduced long-range connectivity, the epileptic patients had an 85 percent to 270 percent increase in local connectivity within and beyond the DMN. The researchers believe this may be an adaptation to the loss of the long-range connections.

"The increase in local connections could represent a maladaptive mechanism by which overall neural connectivity is maintained despite the loss of connections through important hub areas," Dr. Stufflebeam said.

The results are supported by prior functional MRI studies that have shown decreased functional connectivity in DMN areas in temporal lobe epilepsy. Researchers are not certain if the structural changes cause the functional changes, or vice versa.

"It’s probably a breakdown of myelin, which is the insulation of neurons, causing a slowdown in the propagation of information, but we don’t know for sure," Dr. Stufflebeam said.

Dr. Stufflebeam and colleagues plan to continue their research, using structural and functional MRI with electroencephalography and magnetoencephalography to track diffusion changes and look at real-time brain activity.

"Our long-term goal is to see if we can we predict from diffusion studies who will respond to surgery and who will not," he said.

People with autism are more likely to also have synaesthesia, suggests new research in the journal Molecular Autism.

Synaesthesia involves people experiencing a ‘mixing of the senses’, for example, seeing colours when they hear sounds, or reporting that musical notes evoke different tastes. Autism is diagnosed when a person struggles with social relationships and communication, and shows unusually narrow interests and resistance to change. The team of scientists from Cambridge University found that whereas synaesthesia only occurred in 7.2% of typical individuals, it occurred in 18.9% of people with autism.

On the face of it, this is an unlikely result, as autism and synaesthesia seem as if they should not share anything. But at the level of the brain, synaesthesia involves atypical connections between brain areas that are not usually wired together (so that a sensation in one channel automatically triggers a perception in another). Autism has also been postulated to involve over-connectivity of neurons (so that the person over-focuses on small details but struggles to keep track of the big picture).

The scientists tested – and confirmed – the prediction that if both autism and synaesthesia involve neural over-connectivity, then synaesthesia might be disproportionately common in autism.

The team, led by Professor Simon Baron-Cohen at the Autism Research Centre at Cambridge University, tested 164 adults with an autism spectrum condition and 97 adults without autism. All volunteers were screened for synaesthesia. Among the 31 people with autism who also had synaesthesia, the most common forms of the latter were ‘grapheme-colour’ (18 of them reported black and white letters being seen as coloured) and ‘sound-colour’ (21 of them reported a sound triggering a visual experience of colour). Another 18 of them reported either tastes, pains, or smells triggering a visual experience of colour.

Professor Baron-Cohen said: “I have studied both autism and synaesthesia for over 25 years and I had assumed that one had nothing to do with the other. These findings will re-focus research to examine common factors that drive brain development in these traditionally very separate conditions. An example is the mechanism ‘apoptosis,’ the natural pruning that occurs in early development, where we are programmed to lose many of our infant neural connections. In both autism and synaesthesia apoptosis may not occur at the same rate, so that these connections are retained beyond infancy.”

Professor Simon Fisher, a member of the team, and Director of the Language and Genetics Department at Nijmegen’s Max Planck Institute, added: “Genes play a substantial role in autism and scientists have begun to pinpoint some of the individual genes involved. Synaesthesia is also thought to be strongly genetic, but the specific genes underlying this are still unknown. This new research gives us an exciting new lead, encouraging us to search for genes which are shared between these two conditions, and which might play a role in how the brain forms or loses neural connections.”

Donielle Johnson, who carried out the study as part of her Master’s degree in Cambridge, said: “People with autism report high levels of sensory hyper-sensitivity. This new study goes one step further in identifying synaesthesia as a sensory issue that has been overlooked in this population. This has major implications for educators and clinicians designing autism-friendly learning environments.”

Researchers from the University of Missouri School of Medicine have found that a new protocol that uses preventive blood-thinning medication in the treatment of patients with traumatic brain injuries reduces the risk of patients developing life-threatening blood clots without increasing the risk of bleeding inside the brain.

According to the Centers for Disease Control and Prevention, at least 1.7 million traumatic brain injuries occur each year. One of the most common complications associated with traumatic brain injuries is the risk of dangerous blood clots that can form in the circulatory system elsewhere in the body. For patients with traumatic injuries, the body forms blood clots which can break loose and travel to the lungs or other areas, causing dangerous complications.

"Our study found that treating traumatic brain-injured patients with an anticoagulant, or blood-thinning medication, is safe and decreases the risk of these dangerous clots," said N. Scott Litofsky, MD, chief of the MU School of Medicine’s Division of Neurological Surgery and director of neuro-oncology and radiosurgery at MU Health Care. "We found that patients treated with preventive blood thinners had a decreased risk of deep-vein blood clots and no increased risk of intracranial hemorrhaging."

In May 2009, Litofsky, along with study co-author Stephen Barnes, MD, acute care surgeon and chief of the MU Division of Acute Care Surgery, created a new protocol for treating head trauma patients in University Hospital’s Frank L. Mitchell Jr., M.D., Trauma Center using blood-thinning medications.

"One of the main challenges in treating patients with traumatic brain injuries is balancing the risk of intracranial bleeding with the risk of blood clots formed elsewhere in the body," Litofsky said.

In the study, the researchers compared the outcomes of 107 patients with traumatic brain injuries who were treated before the new protocol was put into place with the outcomes of 129 patients who were treated with the blood-thinning medication. Among the patients who did not receive blood thinners, six experienced deep-venous clotting, compared with zero instances of the condition in patients who received the medication. Among the patients who did not receive blood thinners, three patients experienced increased bleeding in the brain, compared with one patient who received the medication.

"Based on our results, we will continue to follow the new protocol in our trauma center, and we believe that other trauma centers would benefit from adopting a similar protocol in their practice," Litofsky said. "If we look at this issue across the country, we should hopefully see this complication occurring less often in brain-injured patients."

The study, “Safety and Efficacy of Early Thromboembolism Chemoprophylaxis After Intracranial Hemorrhage from Traumatic Brain Injury,” was published online Sept. 20 by the Journal of Neurosurgery, the journal for the American Association of Neurological Surgeons.

Researchers from TAU demonstrate hyperbaric oxygen therapy significantly revives brain functions and life quality

Every year, nearly two million people in the United States suffer traumatic brain injury (TBI), the leading cause of brain damage and permanent disabilities that include motor dysfunction, psychological disorders, and memory loss. Current rehabilitation programs help patients but often achieve limited success.

Now Dr. Shai Efrati and Prof. Eshel Ben-Jacob of Tel Aviv University’s Sagol School of Neuroscience have proven that it is possible to repair brains and improve the quality of life for TBI victims, even years after the occurrence of the injury.

In an article published in PLoS ONE, Dr. Efrati, Prof. Ben Jacob, and their collaborators present evidence that hyperbaric oxygen therapy (HBOT) should repair chronically impaired brain functions and significantly improve the quality of life of mild TBI patients. The new findings challenge the often-dismissive stand of the US Food and Drug Administration, Centers for Disease Control and Prevention, and the medical community at large, and offer new hope where there was none.

The research trial

The trial included 56 participants who had suffered mild traumatic brain injury one to five years earlier and were still bothered by headaches, difficulty concentrating, irritability, and other cognitive impairments. The patients’ symptoms were no longer improving prior to the trial.

The participants were randomly divided into two groups. One received two months of HBOT treatment while the other, the control group, was not treated at all. The latter group then received two months of treatment following the first control period. The treatments, administered at the Institute of Hyperbaric Medicine at Assaf Harofeh Medical Center, headed by Dr. Efrati, consisted of 40 one-hour sessions, administered five times a week over two months, in a high pressure chamber, breathing 100% oxygen and experiencing a pressure of 1.5 atmospheres, the pressure experienced when diving under water to a depth of 5 meters. The patients’ brain functions and quality of life were then assessed by computerized evaluations and compared with single photon emission computed tomography (SPECT) scans.

Persuasive confirmation

In both groups, the hyperbaric oxygen therapy sessions led to significant improvements in tests of cognitive function and quality of life. No significant improvements occurred by the end of the period of non-treatment in the control group. Analysis of brain imaging showed significantly increased neuronal activity after a two-month period of HBOT treatment compared to the control periods of non-treatment.

"What makes the results even more persuasive is the remarkable agreement between the cognitive function restoration and the changes in brain functionality as detected by the SPECT scans," explained Prof. Ben-Jacob. "The results demonstrate that neuroplasticity can be activated for months and years after acute brain injury."

"But most important, patients experienced improvements such as memory restoration and renewed use of language," Dr. Efrati said. "These changes can make a world of difference in daily life, helping patients regain their independence, go to work, and integrate back into society."

The regeneration process following brain injury involves complex processes, such as building new blood vessels and rebuilding connections between neurons, and requires much energy.

"This is where HBOT treatment can help," said Dr. Efrati. "The elevated oxygen levels during treatment supply the necessary energy for facilitating the healing process."

The findings offer new hope for millions of traumatic brain injury patients, including thousands of veterans wounded in action in Iraq and Afghanistan. The researchers call for additional larger scale, multi-center clinical studies to further confirm the findings and determine the most effective and personalized treatment protocols. But since the hyperbaric oxygen therapy is the only treatment proven to heal TBI patients, the researchers say that the medical community and the US Armed Forces should permit the victims of TBI benefit from the new hope right now, rather than waiting until additional studies are completed.

A study out today in the journal Nature Medicine suggests a potential new treatment for the seizures that often plague children with genetic metabolic disorders and individuals undergoing liver failure. The discovery hinges on a new understanding of the complex molecular chain reaction that occurs when the brain is exposed to too much ammonia. 

The study shows that elevated levels of ammonia in the blood overwhelm the brain’s defenses, ultimately causing nerve cells to become overexcited. The researchers have also discovered that bumetanide – a diuretic drug used to treat high blood pressure – can restore normal electrical activity in the brains of mice with the condition and prevent seizures. 

 “Ammonia is a ubiquitous waste product of regular protein metabolism, but it can accumulate in toxic levels in individuals with metabolic disorders,” said Maiken Nedergaard, M.D., D.M.Sc., co-director of the University of Rochester Medical Center (URMC) Center for Translational Neuromedicine and lead author of the article. “It appears that the key to preventing the debilitating neurological effects of ammonia toxicity is to correct a molecular malfunction which causes nerve cells in the brain to become chemically unbalanced.”

In healthy people, ammonia is processed in the liver, converted to urea, and expelled from the body in urine. Because it is a gas, ammonia can slip through the blood-brain-barrier and make its way into brain tissue. Under normal circumstances, the brain’s housekeeping cells – called astrocytes – sweep up this unwanted ammonia and convert it into a compound called glutamine which can be more easily expelled from the brain. 

However, individuals with certain genetic metabolic disorders and people with impaired liver function because of chronic hepatitis, alcoholism, acetaminophen overdose, and other toxic liver conditions cannot remove ammonia from their bodies quickly enough. The result is a larger than normal concentration of ammonia in the blood, a condition called hyperammonemia. 

When too much ammonia makes its way into the central nervous system, it can lead to tremors, seizures and, in extreme cases, can cause comas and even lead to death. In children with metabolic disorders the frequent seizures can lead to long-term neurological impairment. 

While ammonia has long been assumed to be the culprit behind the neurological problems associated with inherited metabolic disorders and liver failure, the precise mechanisms by which it triggers seizures and comas have not been fully understood. The new study reveals that ammonia causes a chain of events that alters the chemistry and electrical activity of the brain’s nerve cells, causing them to fire in uncontrolled bursts.

One of the keys to unraveling the effects of ammonia on the brain has been new imagining technologies such as two-photon microscopy which allow researchers to watch this phenomenon in real time in the living brains of mice. As suspected, they observed that when high levels of ammonia enter the brain, astrocytes become quickly overwhelmed and cannot remove it fast enough. 

The abundant ammonia in the brain mimics the function of potassium, an important player in neurotransmission, and tricks neurons into becoming depolarized. This makes it more likely that electrical activity in the brain will exceed the threshold necessary to trigger seizures.

Furthermore, the researchers observed that one of the neuron’s key molecular gatekeepers – a transporter known as NKCC1 – was also fooled into thinking that the ammonia was potassium. As a result, it went into overdrive, loading neurons with too much chloride. This in turn prevents the cells from stabilizing itself after spikes in activity, keeping the cells in a heightened level of electrical “excitability.” 

The team found that the drug bumetanide, a known NKCC1 inhibitor, blocked this process and prevented the cells from overloading with chloride. By knocking down this “secondary” cellular effect of ammonia, the researchers were able to control the seizures in the mice and prolong their survival.

“The neurologic impact of hyperammonemia is a tremendous clinical problem without an effective medical solution,” said Nedergaard.   “The fact that bumetanide is already approved for use gives us a tremendous head start in terms of developing a potential treatment for this condition. This study provides a framework to further explore the therapeutic potential of this and other NKCC1 inhibitors.”

Pregnant women may pass on the effects of stress to their fetus by way of bacterial changes in their vagina, suggests a study in mice. It may affect how well their baby’s brain is equipped to deal with stress in adulthood.

The bacteria in our body outnumber our own cells by about 10 to 1, with most of them found in our gut. Over the last few years, it has become clear that the bacterial ecosystem in our body – our microbiome – is essential for developing and maintaining a healthy immune system.

Our gut bugs also help to prevent germs from invading our bodies, and help to absorb nutrients from food.

A baby gets its first major dose of bacteria in life as it passes through its mother’s birth canal. En route, the baby ingests the mother’s vaginal microbes, which begin to colonise the newborn’s gut.

Chris Howerton, then at the University of Pennsylvania in Philadelphia, and his colleagues wanted to know if this initial population of bacteria is important in shaping a baby’s neurological development, and whether that population is influenced by stress during pregnancy.

Stressful pregnancy

The first step was to figure out what features of the mother’s vaginal microbiome might be altered by stress, and then see if any of those changes were transmitted to the offspring’s gut.

To do this, the team exposed 10 pregnant mice to a different psychologically stressful experience, such as exposing them to fox odour, keeping their cages lit at night, or temporarily restraining them every day for what would be the equivalent of the first trimester of their pregnancy. Another 10 pregnant mice were housed normally during the same time.

The team took samples of their vaginal bacteria throughout the pregnancy and again just after the mice had given birth. These samples were genetically sequenced to see what types of bacteria were present.

The microbiomes of the stressed mice were remarkably different to those of the unstressed mice after they had each given birth. There were more types of bacteria present, and the proportion of one common gut bacteria, Lactobacillus, was significantly reduced.

Like mother, like pup

To see whether these changes had been passed on to the pups, a few days after birth the pups’ nascent gut bacteria was removed from their colon and sequenced. Sure enough, the same bacterial patterns were seen in the pups of stressed mothers.

By analysing tissue from the pups’ hypothalamus – a brain area involved in hormone control, behaviour and sleep, among other things – the team was able to infer which genes were affected by the stress-induced changes in each mother’s microbiome.

They found that the expression of 20 genes was affected by the decrease in Lactobacillus, including genes related to the production of new neurons and the growth of synaptic connections in the brain.

These genetic outcomes in the brain are probably a result of a different suite of nutrients and metabolites circulating in the “stressed” pup’s blood, thanks to the altered gut flora they inherited. Indeed, when the team analysed the blood of the pups of the stressed mothers, they found that there were fewer molecules present necessary for the formation of essential neurotransmitters – chemicals that transmit signals to the brain. Furthermore, there were lower levels of a molecule thought to protect the brain from harmful oxidative stress.

"These changes are significant and are likely to be important for determining how the brain initially develops and how it will respond in the future to things like stress or changes in the environment," says Tracy Bale, Howerton’s supervisor during the research and director of the University of Pennsylvania lab.

As well as changing the nutrients available, the microbiome could also affect the brain via the immune system or by innervating the nerves in the gut that connect to it. “These three mechanisms aren’t mutually exclusive. It’s likely that they all play a role,” says Howerton.

Human angle

If the same effects are seen in humans, there may be a straightforward solution. “We can easily manipulate the bacteria we have inside of us,” says Howerton. For example, if a certain cocktail of bacteria is found to be beneficial to the newborns of stressed mothers, we could give it to them right after birth, he suggests. This approach could also benefit babies born via C-section, who do not pass through their mother’s birth canal, or those born to mothers whose gut bacteria has been disrupted as a result of antibiotic use during pregnancy.

Bale is now investigating the link between bacteria and brain development in pregnant women who have been through several traumatic experiences to analyse the effects on their babies’ gut bacteria. She also intends to follow their children’s behaviour as they grow up.

Resource rationale

"This is a remarkable trans-disciplinary study in how it bridged multiple organ systems to illuminate a complex question," says Catherine Hagan from the University of Missouri in Columbia. She says that more work needs to be done to show a causal link. "Mice are not tiny people – people are not big mice – more data is needed to understand how stress in mothers affects brain development in children," she says. "That said, mice and people have enough in common that this study provides a rationale for allocating resources to address such a concern."

"At the end of the day, most of what makes you ‘you’, and what drives your quality of life, comes down to the brain," says Bale. "It’s this very important, vulnerable tissue that is susceptible to many perturbations. If the microbiome is proven to be one of these driving forces, then it’s essential we know just how factors in our environment can change it and can reprogram the brain."

A drug that mimics some effects of alcohol but lacks its harmful properties would have real benefit for public health, a leading scientist has argued.

Professor David Nutt, the Edmond J. Safra Professor of Neuropsychopharmacology at Imperial College London, has identified candidate molecules that reproduce the pleasurable effects of alcohol but are much less toxic. He is looking for investors to help develop the product and bring it to the market.

Alcohol mimics a chemical called GABA which is produced in the brain, but it also acts on receptors for other brain chemicals. The alcohol substitute would be designed to target GABA receptors very selectively, avoiding undesirable side effects such as hangovers and loss of coordination. An antidote could also be made to block the receptor, allowing drinkers to sober up quickly.

Professor Nutt told the Today programme on BBC Radio 4 that he first tested such a compound many years ago, but even better substitutes could be developed.

“There’s no question that you can produce a whole range of effects like alcohol by manipulating this system in the brain,” he said. “In some experiments, the effect is indistinguishable from alcohol.

“What we want to do is get rid of any the unwanted effects of inebriation, like aggression and memory impairment, and we just want to keep the pleasure and the sense of relaxation.

“We think by clever molecular modelling we can get rid of the risk of addiction as well.”

Professor Nutt hopes to make a range of cocktails containing his synthetic alcohol substitute. He has spoken to investors about taking the product to market, but many are wary that the drug might be controlled by legislation.

“I would like the government to make a recommendation that we try to improve on the health of our people by allowing these kind of substitute alcohols to be legal.”

Alcohol is responsible for 2.5 million deaths worldwide each year. Making safer alternatives available could reduce the harms significantly, Professor Nutt argued.

“I think this would be a serious revolution in health benefits, just as the e-cigarette is going to revolutionise the smoking of tobacco. I find it weird that we haven’t been talking about this before because it’s such an obvious target for health improvement.”

Nicotine withdrawal might take over your body, but it doesn’t take over your brain. The symptoms of nicotine withdrawal are driven by a very specific group of neurons within a very specific brain region, according to a report in Current Biology, a Cell Press publication, on November 14. Although caution is warranted, the researchers say, the findings in mice suggest that therapies directed at this group of neurons might one day help people quit smoking.

(Image: Fotolia)

"We were surprised to find that one population of neurons within a single brain region could actually control physical nicotine withdrawal behaviors," says Andrew Tapper of the Brudnick Neuropsychiatric Research Institute at the University of Massachusetts Medical School.

Tapper and his colleagues first obtained mice addicted to nicotine by delivering the drug to mice in their water for a period of 6 weeks. Then they took the nicotine away. The mice started scratching and shaking in the way a dog does when it is wet. Close examination of the animals’ brains revealed abnormally increased activity in neurons within a single region known as the interpeduncular nucleus.

When the researchers artificially activated those neurons with light, animals showed behaviors that looked like nicotine withdrawal, whether they had been exposed to the drug or not. The reverse was also true: treatments that lowered activity in those neurons alleviated nicotine withdrawal symptoms.

That the interpeduncular nucleus might play such a role in withdrawal from nicotine makes sense because the region receives connections from other areas of the brain involved in nicotine use and response, as well as feelings of anxiety. The interpeduncular nucleus is also densely packed with nicotinic acetylcholine receptors that are the molecular targets of nicotine.

It is much less clear whether the findings related to nicotine will be relevant to other forms of addiction, but there are some hints that they may.

"Smoking is highly prevalent in people with other substance-use disorders, suggesting a potential interaction between nicotine and other drugs of abuse," Tapper says. "In addition, naturally occurring mutations in genes encoding the nicotinic receptor subunits that are found in the interpeduncular nucleus have been associated with drug and alcohol dependence."