Neuroscience

ScienceDaily (Aug. 20, 2012) — The more that we understand the brain, the more complex it becomes. The same can be said about the genetics and neurobiology of psychiatric disorders. For “Mendelian” disorders, like Huntington disease, mutation of a single gene predictably produces a single clinical disorder, following relatively simple genetic principals. Compared to Mendelian disorders, understanding bipolar disorder has been extremely challenging. Its biology is not well understood and its genetics are complex.

In a new paper, Dr. Inti Pedroso and colleagues utilize an integrative approach to probe the biology of bipolar disorder. They combined the results of three genome-wide association studies, which examined the association of common gene variants with bipolar disorder throughout the genome, and a study of gene expression patterns in post-mortem brain tissue from people who had been diagnosed with bipolar disorder. The findings were analyzed within the context of how brain proteins relate to each other based on the Human Protein Reference Database protein-protein interaction network.

"None of our research approaches provides us with sufficient information, by itself, to understand the neurobiology of psychiatric disorders. This innovative paper wrestles with this challenge in a creative way that helps us to move forward in thinking about the neurobiology of bipolar disorder," commented Dr. John Krystal, Editor of Biological Psychiatry.

Dr. Pedroso explained, “We combined information about genetic variation from thousands of cases and controls with brain gene expression data and information from protein databases to identify networks of genes and proteins in the brain that are key in the development of bipolar disorder.”

The analysis resulted in the ability to define risk gene variants that were deemed functional, by virtue of the association with changes in gene expression levels, and to group these functional gene variants in biologically meaningful pathways.

The results implicated genes involved in several neural signaling pathways, including the Notch and Wnt signaling pathways. These pathways are key processes in neurotransmission and brain development and these findings indicate they are also likely to be involved in causing this severe disorder. The authors noted that three features stand out among these genes: i) they localized to the human postsynaptic density, which is crucial for neuronal function; ii) their mouse knockouts present altered behavioral phenotypes; and iii) some are known targets of the pharmacological treatments for bipolar disorder.

Dr. Gerome Breen, senior author on the study and Senior Lecturer at King’s College London Institute of Psychiatry, said, “Our study provides some of the first evidence to show the biochemical and developmental processes involved in causing risk for developing this life-long and costly illness. We have highlighted potential new avenues for new drug treatments and intervention.”

Source: Science Daily

ScienceDaily (Aug. 20, 2012) — Scientific advances in understanding the “addiction circuitry” of the brain may lead to effective treatment for obesity using deep brain stimulation (DBS), according to a review article in the August issue of Neurosurgery, official journal of the Congress of Neurological Surgeons.

Electrical brain stimulation targeting the “dysregulated reward circuitry” could make DBS — already an accepted treatment for Parkinson’s disease — a new option for the difficult-to-treat problem of obesity. Dr. Alexander Taghva of Ohio State University and University of Southern California was lead author of the new review.

New Insights into ‘Reward Circuitry’

Obesity is a major public health problem that is notoriously difficult to treat. Although various approaches can promote weight loss, patients typically gain weight soon after the end of treatment. Drug options have shown limited success, with several products removed from the market because of serious adverse effects. Bariatric surgery is effective in many cases of obesity but has a significant failure rate and is associated with side effects.

Drug treatments for obesity have targeted the homeostatic (self-regulating) mechanism regulating appetite and body weight. The homeostatic mechanism is thought to involve the “feeding center” in the hypothalamus, which produces hormones (such as leptin and insulin) that affect feeding behavior.

Initial experiments exploring DBS as a treatment for obesity have targeted the hypothalamus. However — as with drug options focusing on the homeostatic mechanisms — success has been limited.

Possible Role of DBS for Obesity

More recent studies have explored a different mechanism: specifically, the “reward circuitry,” of the brain. Research has suggested that obesity is associated with a “relative imbalance” of the reward circuitry. Studies show that obese subjects — like those with addictive behaviors — are more impulsive and less able to delay gratification. The reward circuitry is intimately interconnected with the homeostatic mechanisms.

Together, these studies raise the possibility of new DBS approaches to the treatment of obesity. In DBS, a small electrode is surgically placed in a precise location in the brain. A mild electrical current is delivered to stimulate that area of the brain, with the goal of interrupting abnormal activity. Deep brain stimulation has become a standard and effective treatment for movement disorders such as Parkinson’s disease.

Just as stimulation of the brain areas responsible for abnormal movement helps “turn off” tremors in patients with Parkinson’s disease, stimulation of the areas involved in dysregulated reward circuitry might be able to “turn off” abnormal feeding behaviors in obese patients. The authors outline evidence implicating several different brain areas involved in the brain’s reward circuitry — particularly the “frontostriatal circuitry” — which could be useful targets for DBS.

Previous reports in individual patients have suggested that DBS performed for other reasons — particularly severe obsessive-compulsive disorder — have unexpectedly had unpredicted beneficial effects on addictive behaviors like smoking and overeating. Dr. Taghva and colleagues hope their review will open the way to further exploration of DBS as part of new and effective strategies for the treatment of obesity, perhaps in combination with therapies targeting the homeostatic mechanism.

Source: Science Daily

The simple act of picking up a pencil requires the coordination of dozens of muscles: The eyes and head must turn toward the object as the hand reaches forward and the fingers grasp it. To make this job more manageable, the brain’s motor cortex has implemented a system of shortcuts. Instead of controlling each muscle independently, the cortex is believed to activate muscles in groups, known as “muscle synergies.” These synergies can be combined in different ways to achieve a wide range of movements.

This graphic shows the brain, with the motor cortex highlighted in yellow.
Graphic: Christine Daniloff

A new study from MIT, Harvard Medical School and the San Camillo Hospital in Venice finds that after a stroke, these muscle synergies are activated in altered ways. Furthermore, those disruptions follow specific patterns depending on the severity of the stroke and the amount of time that has passed since the stroke.

The findings, published this week in the Proceedings of the National Academy of Sciences, could lead to improved rehabilitation for stroke patients, as well as a better understanding of how the motor cortex coordinates movements, says Emilio Bizzi, an Institute Professor at MIT and senior author of the paper.

“The cortex is responsible for motor learning and for controlling movement, so we want to understand what’s going on there,” says Bizzi, who is a member of the McGovern Institute for Brain Research at MIT. “How does the cortex translate an idea to move into a series of commands to accomplish a task?”

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17 August 2012

A WA study of an isolated population of Eastern European Gypsies known as “Bowlmakers” has unlocked clues about a serious developmental disease - congenital cerebellar ataxia.

Professor Luba Kalaydjieva and Dr Dimitar Azmanov, from The University of Western Australia, say the discovery of an important genetic mutation is likely to inspire other scientific work around the world.

The result of their research for the UWA-affiliated Western Australian Institute for Medical Research (WAIMR) was published online today in the prestigious American Journal of Human Genetics.

It involved working collaboratively with other Australian and European researchers to discover mutations within a gene which has never before been linked to this form of heredity ataxia in humans.

Ataxias are a large group of neurodegenerative disorders that affect the ability to maintain balance, and learn and maintain motor skills.  While many genes have already been implicated in hereditary ataxias, understanding their molecular basis is far from complete.  New knowledge will help the understanding of normal brain development and function, and the mechanisms of degeneration. 

"Gypsies are a founder population," Professor Kalaydjieva said.  "They are derived from a small number of ancestors and have remained relatively isolated from surrounding populations.  The Bowlmakers - known for their wooden handicrafts such as bowls and spoons - were an ideal group to study because they are a younger sub-isolate, showing limited genetic diversity.

"We studied a novel form of ataxia in 3 families in this ethnic group.  Clinical and brain-imaging investigations were done in Bulgaria, in collaboration with radiologists from Sir Charles Gairdner Hospital and Princess Margaret Hospital, and were followed-up by genetic studies at WAIMR and the Walter and Eliza Hall Institute (WEHI), Melbourne.

"Signs of ataxia were detected in early infancy when motor skills like crawling and rolling over did not develop.  The affected individuals presented with global developmental delay, ataxia and intellectual deficit.  MRI scans showed signs of degeneration of the cerebellum, which is part of the brain controlling motor and learning skills.  Overall, the life expectancy is not decreased but the quality of life is severely affected.

"The parents of the affected individuals did not present with any clinical symptoms of the ataxia, suggesting recessive inheritance," Dr Azmanov said.  "Our genetic studies showed unique changes in the gene encoding metabotropic glutamate receptor 1 (GRM1), which is important for the normal development of the cerbellar cortex.  The mutations inherited by all affected individuals from their unaffected carrier parents dramatically altered the structure of the GRM1 receptor.”

Professor Kalaydjieva said the exact pathogenetic mechanisms leading to the clinical manifestations and cerebellar degeneration are yet to be explained and that this opens novel research avenues for the wider scientific community.  ”It also remains to be seen if other ataxia patients around the world carry mutations in GRM1,” she said.

Source: The University of Western Australia

The human genome that researchers sequenced at the turn of the century doesn’t really exist as we know it.

The Human Genome project sequenced “the human genome” and is widely credited with setting in motion the most exciting era of fundamental new scientific discovery since Galileo. That’s remarkable, because in important ways “the human genome” that we have labeled as such doesn’t actually exist.

cosmin4000, istockphoto

Plato essentially asserted that things like chairs and dogs, which we observe in this physical world, and even concepts like virtues, are but imperfect representations or instances of some ideal that exists, but not in the material world. Such a Platonic ideal is “the human genome,” a sequence of about 3 billion nucleotides arrayed across a linear scale of position from the start of chromosome 1 to the end of the sex chromosomes. Whether it was obtained from one person or several has so far been shrouded in secrecy for bioethical reasons, but it makes no real difference. What we call the human genome sequence is really just a reference: it cannot account for all the variability that exists in the species, just like no single dog on earth, real or imagined, can fully incorporate all the variability in the characteristics of dogs.

Nor is the human genome we have a “’normal” genome. What would it mean to be “normal” for the nucleotide at position 1,234,547 on chromosome 11?  All we know is that the donor(s) had no identified disease when bled for the cause, but sooner or later some disease will arise. Essentially all available whole genome sequences show potentially disease-producing variants, even including nonfunctional genes, in donors who were unaffected at the time.

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August 16th, 2012

A parasite thought to be harmless and found in many people may actually be causing subtle changes in the brain, leading to suicide attempts.

New research appearing in the August issue of The Journal of Clinical Psychiatry adds to the growing work linking an infection caused by the Toxoplasma gondii parasite to suicide attempts. Michigan State University’s Lena Brundin was one of the lead researchers on the team.

About 10-20 percent of people in the United States have Toxoplasma gondii, or T. gondii, in their bodies, but in most it was thought to lie dormant, said Brundin, an associate professor of experimental psychiatry in MSU’s College of Human Medicine. In fact, it appears the parasite can cause inflammation over time, which produces harmful metabolites that can damage brain cells.

“Previous research has found signs of inflammation in the brains of suicide victims and people battling depression, and there also are previous reports linking Toxoplasma gondii to suicide attempts,” she said. “In our study we found that if you are positive for the parasite, you are seven times more likely to attempt suicide.”

The work by Brundin and colleagues is the first to measure scores on a suicide assessment scale from people infected with the parasite, some of whom had attempted suicide.

The Toxoplasma gondii parasite has been linked to inflammation in the brain, damaging cells. Image adapted from MSU press release image.

The results found those infected with T. gondii scored significantly higher on the scale, indicative of a more severe disease and greater risk for future suicide attempts. However, Brundin stresses the majority of those infected with the parasite will not attempt suicide: “Some individuals may for some reason be more susceptible to develop symptoms,” she said.

“Suicide is major health problem,” said Brundin, noting the 36,909 deaths in 2009 in America, or one every 14 minutes. “It is estimated 90 percent of people who attempt suicide have a diagnosed psychiatric disorder. If we could identify those people infected with this parasite, it could help us predict who is at a higher risk.”

T. gondii is a parasite found in cells that reproduces in its primary host, any member of the cat family. It is transmitted to humans primarily through ingesting water and food contaminated with the eggs of the parasite, or, since the parasite can be present in other mammals as well, through consuming undercooked raw meat or food.

Brundin has been looking at the link between depression and inflammation in the brain for a decade, beginning with work she did on Parkinson’s disease. Typically, a class of antidepressants called selective serotonin re-uptake inhibitors, or SSRIs, have been the preferred treatment for depression. SSRIs are believed to increase the level of a neurotransmitter called serotonin but are effective in only about half of depressed patients.

Brundin’s research indicates a reduction in the brain’s serotonin might be a symptom rather than the root cause of depression. Inflammation, possibly from an infection or a parasite, likely causes changes in the brain’s chemistry, leading to depression and, in some cases, thoughts of suicide, she said.

“I think it’s very positive that we are finding biological changes in suicidal patients,” she said. “It means we can develop new treatments to prevent suicides, and patients can feel hope that maybe we can help them.

“It’s a great opportunity to develop new treatments tailored at specific biological mechanisms.”

Source: Neuroscience News

ScienceDaily (Aug. 16, 2012) — Researchers have found what they believe is the key to understanding why the human brain is larger and more complex than that of other animals.

The human brain, with its unequaled cognitive capacity, evolved rapidly and dramatically.

"We wanted to know why," says James Sikela, PhD, who headed the international research team that included researchers from the University of Colorado School of Medicine, Baylor College of Medicine and the National Institutes of Mental Health. "The size and cognitive capacity of the human brain sets us apart. But how did that happen?"

"This research indicates that what drove the evolutionary expansion of the human brain may well be a specific unit within a protein — called a protein domain — that is far more numerous in humans than other species."

The protein domain at issue is DUF1220. Humans have more than 270 copies of DUF1220 encoded in the genome, far more than other species. The closer a species is to humans, the more copies of DUF1220 show up. Chimpanzees have the next highest number, 125. Gorillas have 99, marmosets 30 and mice just one. “The one over-riding theme that we saw repeatedly was that the more copies of DUF1220 in the genome, the bigger the brain. And this held true whether we looked at different species or within the human population.”

Sikela, a professor at the CU medical school, and his team also linked DUF1220 to brain disorders. They associated lower numbers of DUF1220 with microcephaly, when the brain is too small; larger numbers of the protein domain were associated with macrocephaly, when the brain is too large.

The findings were reported today in the online edition of The American Journal of Human Genetics. The researchers drew their conclusions by comparing genome sequences from humans and other animals as well as by looking at the DNA of individuals with microcephaly and macrocephaly and of people from a non-disease population.

"The take home message was that brain size may be to a large degree a matter of protein domain dosage," Sikela says. "This discovery opens many new doors. It provides new tools to diagnose diseases related to brain size. And more broadly, it points to a new way to study the human brain and its dramatic increase in size and ability over what, in evolutionary terms, is a short amount of time."

Source: Science Daily

ScienceDaily (Aug. 16, 2012) — In multiple sclerosis, the immune system attacks nerves in the brain and spinal cord, causing movement problems, muscle weakness and loss of vision. Immune cells called dendritic cells, which were previously thought to contribute to the onset and development of multiple sclerosis, actually protect against the disease in a mouse model, according to a study published by Cell Press in the August issue of the journal Immunity. These new insights change our fundamental understanding of the origins of multiple sclerosis and could lead to the development of more effective treatments for the disease.

"By transfusing dendritic cells into the blood, it may be possible to reduce autoimmunity," says senior study author Ari Waisman of University Medical Center of Johannes Gutenberg University Mainz. "Beyond multiple sclerosis, I can easily imagine that this approach could be applied to other autoimmune diseases, such as inflammatory bowel disease and psoriasis."

In an animal model of multiple sclerosis known as experimental autoimmune encephalomyelitis (EAE), immune cells called T cells trigger the disease after being activated by other immune cells called antigen-presenting cells (APCs). Dendritic cells are APCs capable of activating T cells, but it was not known whether dendritic cells are the APCs that induce EAE.

In the new study, Waisman and his team used genetic methods to deplete dendritic cells in mice. Unexpectedly, these mice were still susceptible to EAE and developed worse autoimmune responses and disease clinical scores, suggesting that dendritic cells are not required to induce EAE and other APCs stimulate T cells to trigger the disease. The researchers also found that dendritic cells reduce the responsiveness of T cells and lower susceptibility to EAE by increasing the expression of PD-1 receptors on T cells.

"Removing dendritic cells tips the balance toward T cell-mediated autoimmunity," says study author Nir Yogev of University Medical Center of Johannes Gutenberg University Mainz. "Our findings suggest that dendritic cells keep immunity under check, so transferring dendritic cells to patients with multiple sclerosis could cure defects in T cells and serve as an effective intervention for the disease."

Source: Science Daily

By: Richard C. Lewis | 2012.08.16

Everyone knows the adage: “If something sounds too good to be true, then it probably is.” So, why, then, do some people fall for scams and why are older folks especially prone to being duped?

An answer, it seems, is because a specific area of the brain has deteriorated or is damaged, according to researchers at the University of Iowa. By examining patients with various forms of brain damage, the researchers report they’ve pinpointed the precise location in the human brain, called the ventromedial prefrontal cortex, that controls belief and doubt, and which explains why some of us are more gullible than others.

Patients with damage to the ventromedial prefrontal cortex were roughly twice as likely to believe a given ad, even when given disclaimer information pointing out it was misleading. And, they were more likely to buy the item, regardless of whether misleading information had been corrected. Photo by Bill Adams.

“The current study provides the first direct evidence beyond anecdotal reports that damage to the vmPFC (ventromedial prefrontal cortex) increases credulity. Indeed, this specific deficit may explain why highly intelligent vmPFC patients can fall victim to seemingly obvious fraud schemes,” the researchers wrote in the paper published in a special issue of the journal Frontiers in Neuroscience.

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16 August 2012

Ten out of 11 patients with severe Tourette’s Syndrome have reported improvement after receiving deep brain stimulation surgery, according to University of New South Wales research published in the American Journal of Psychiatry. 

Tourette’s Syndrome is a neurological disorder characterised by repetitive involuntary movements and vocalisations called tics and can also include behavioural difficulties. 

Deep brain stimulation is a therapeutic technique that involves placing electrodes at specific sites in the brain to deliver continuous stimulation from an implanted generator.

Study leader, UNSW Scientia Professor Perminder Sachdev, says deep brain stimulation may have an important role in treating Tourette’s Syndrome in its most severe form. He says tics are generally treated with medications that work well in about 50 to 70 per cent of cases. Drugs, however, can have side effects in some patients. 

Eleven patients, eight of them in their late thirties with severe Tourette’s Syndrome, underwent deep brain stimulation at St Andrew’s Hospital in Brisbane - under the care of neurologist Professor Peter Silburn and neurosurgeon Associate Professor Terry Coyne - as part of the study. They were followed up initially one month after surgery and then around a year after the procedure.

Ten out of the 11 patients involved in the joint UNSW Medicine and Asia-Pacific Centre for Neuromodulation study reported immediate improvement in tic severity soon after the treatment, with an overall 48 per cent reduction in monitor tics and a 57 per cent reduction in phonic tics at final follow-up. Associated psychiatric symptoms also improved.

“Because deep brain stimulation involves brain surgery, it has some risks, even though these are low. It is therefore only likely to be used in individuals who are significantly affected by their tics,” Scientia Professor Sachdev says.

“Our study demonstrates that when suitably selected, patients can benefit greatly from deep brain stimulation.”

Source: University of New South Wales

TAU research says genetics can reveal your geographic ancestral origin

While your DNA is unique, it also tells the tale of your family line. It carries the genetic history of your ancestors down through the generations. Now, says a Tel Aviv University researcher, it’s also possible to use it as a map to your family’s past.

Prof. Eran Halperin of TAU’s Blavatnik School of Computer Science and Department of Molecular Microbiology and Biotechnology, along with a group of researchers from University of California, Los Angeles, are giving new meaning to the term “genetic mapping.” Using a probabilistic model of genetic traits for every coordinate on the globe, the researchers have developed a method for determining more precisely the geographical location of a person’s ancestral origins.

The new method is able to pinpoint more specific locations for an individual’s ancestors, for example placing an individual’s father in Paris and mother in Barcelona. Previous methods would “split the difference” and place this origin inaccurately at a site between those two cities, such as Lyon.

Published in the journal Nature Genetics, this method has the potential to reveal the ancestry, origins, and migration patterns of many different human and animal populations. It could also be a new model for learning about the genome.

Points of origin

There are points in the human genome called SNPs that are manifested differently in each individual, explains Prof. Halperin. These points mutated sometime in the past and the mutation was then passed to a large part of the population in a particular geographic region. The probability of a person possessing these mutations today varies depending on the geographical location of those early ancestors.

"We wanted to ask, for example, about the probability of having the genetic mutation ‘A’ in a particular position on the genome based on geographical coordinates," he says. When you look at many of these positions together in a bigger picture, it’s possible to group populations with the same mutation by point of origin.

To test their method, Prof. Halperin and his fellow researchers studied DNA samples from 1,157 people from across Europe. Using a probabilistic mathematical algorithm based on mutations in the genome, they were able to accurately determine their ancestral point or points of origin using only DNA data and the new mathematical model, unravelling genetic information to ascertain two separate points on the map for the mother and father. The researchers hope to extend this model to identify the origins of grandparents, great-grandparents, and so on.

The new method could provide information that has applications in population genetic studies — to study a disease that impacts a particular group, for example. Researchers can track changes in different genomic traits across a map, such as the tendency for southern Europeans to have a mutation in a gene that causes lactose intolerance, a mutation missing from that gene in northern Europeans.

A closer look at migration

The researchers believe that their model could have also relevance for the animal kingdom, tracking the movement of animal populations. “In principle, you could figure out where the animals have migrated from, and as a result learn about habitat changes due to historical climate change or other factors,” says Prof. Halperin.

Source: Tel Aviv University

The vast majority of people with addiction have suffered significant previous trauma, and many people who struggle with addiction suffer from post-traumatic stress disorder (PTSD) simultaneously. But the treatment of these patients has posed a conundrum: experts have believed that PTSD treatment should not begin until the addicted person achieves lasting abstinence, because of the risk that PTSD treatment may trigger relapse, yet addicted people with untreated PTSD are rarely able to abstain for long.

Now, a new study suggests that there may be no need to wait. Researchers found that using exposure therapy — the gold-standard treatment for PTSD, which involves exposure to memories and reminders of patients’ past trauma — can successfully reduce symptoms of PTSD, even when people with addiction continue to use drugs. And, although exposure therapy requires patients to face some of their worst fears, it does not increase their drug use or prompt them to drop out of treatment more than ordinary addiction therapy, the study found.

“The exciting thing in my view is that [the study] supports people with drug and alcohol problems having access to other forms of psychological interventions, rather than being fobbed off and told to sort out their alcohol or drug problem first,” says Michael Farrell, director of the National Drug and Alcohol Research Center at the University of New South Wales in Sydney, Australia, where the research was conducted.

The finding could potentially help the majority of those who suffer from addiction or PTSD: one-half to two-thirds of people with addictions suffer from PTSD concurrently, or have in the past, and about the same proportion of people with PTSD also have substance use disorders.

The new study involved 103 people with both conditions. Most were addicted to multiple drugs, primarily heroin, marijuana and alcohol. More than two-thirds of the participants had been traumatized during childhood, with almost half reporting a history of sexual abuse.

Researchers randomly assigned half of the participants to simply continue the addiction treatment of their choice, whether it was detoxification leading to abstinence, residential treatment or maintenance on medications like methadone and buprenorphine (Suboxone, Subutex).

The other half received their usual treatment, plus exposure therapy for PTSD, which consisted of 13 one-on-one sessions with a clinical psychologist, meeting about once a week for 90 minutes at a time. The therapy began with education about PTSD and addiction, including instruction on cognitive techniques to address distressing thoughts that could lead to relapse. Then, when patients were ready, they were exposed to reminders of their traumatic experience, which they usually avoided out of fear of triggering flashbacks and intense anxiety. Exposure therapy works to reduce or eliminate these PTSD symptoms by breaking patients’ cycle of fear and avoidance.

Indeed, participants in the exposure treatment “demonstrated significantly greater reductions in PTSD symptom severity compared with participants randomized to receive usual treatment alone,” the authors wrote. However, drug use in the exposure therapy group didn’t decline any more than it did in the usual treatment group. Both groups saw a reduction in the severity of addiction but in each case, the majority of participants continued to use drugs. Notably, however, drug use did not increase due to exposure therapy.

“These findings challenge the widely held view that patients need to be abstinent before any trauma work, let alone prolonged exposure therapy, is commenced,” the authors wrote. “[F]indings from the present study demonstrate that abstinence is not required.”

Importantly, however, while the findings showed that carefully delivered exposure therapy can help, they did not support the practice of forcing addicts to confront trauma in settings where they do not feel safe or in control. Exposure therapy is calibrated so that patients do not become overwhelmed or feel helpless; in contrast, coercion by the therapist can re-traumatize patients and worsen both PTSD and addiction symptoms, previous studies have shown.

In other words, it’s not clear that treating people with addiction by compelling them to recall or re-enact traumatic experiences — a commonly used tactic in group settings — actually helps. What the current study shows is that when trained clinical psychologists carefully deliver exposure therapy in a tightly monitored trial, they can help ease PTSD symptoms in people with addiction.

By Maia Szalavitz | August 15, 2012

Source: TIME

In 2000, a team of neuroscientists put an unusual idea to the test. Stress and depression, they knew, made neurons wither and die – particularly in the hippocampus, a brain area crucial for memory. So the researchers put some stressed-out rats on an antidepressant regimen, hoping the mood boost might protect some of those hippocampal neurons. When they checked in a few weeks later, though, the team found that rats’ hippocampuses hadn’t just survived intact; they’d grown whole new neurons – bundles of them. But that’s only the beginning of our tale.

Neural stem cells (green) in the hippocampus huddle around a neuron (purple), listening for stray signals.

By the time 2009 rolled around, another team of researchers was suggesting that human brains might get a similar hippocampal boost from antidepressants. The press announced the discovery with headlines like, “Antidepressants Grow New Brain Cells” – although not everyone agreed with that conclusion. Still, whether the principle applied to humans or not, a far more basic question was begging to be answered: How, exactly, does a brain tell new cells to form?

“Well, through synapses, of course,” you might answer – and that’d be a very reasonable guess. After all, synapses are how most neurons talk to each other: electrochemical information is “squirted” from a tiny tendril of one neuron into the tip of a tendril on another; and cells throughout most of the brain share essentially this same mechanism for passing signals along: The signals coming out of Neuron A’s synapses keep bugging Neuron B by stimulating its synapses, until finally Neuron B caves under peer pressure and bugs Neuron C with the signal… and so on.

There are, however, two significant exceptions to this system.

The first exception was discovered a few years ago, as scientists got more and more curious about the role of neuroglia (also known as just “glia”), synapse-less cells that many had assumed were just there to serve as structural support for neurons. A 2008 study showed that glia help control cerebral blood flow, and research in 2010 demonstrated that some glia – cells known as astrocytes – actively listen for and respond to certain neurotransmitter messages. These so-called “quiet cells” are actually pretty loud talkers once you learn to tune in to their chatter.

The second exception to the synapse rule is even more mysterious – in large part because it’s a brand-new discovery: As the journal Nature reports, a team led by Hongjun Song at the Johns Hopkins University School of Medicine have found that neural stem cells “listen in” on the stray chemical signals that leak from synapses.

You can imagine neural stem cells as being sort of “neural embryos” – depending on the surrounding conditions, they can develop into neurons or into glia. And here’s what’s strange about the way these cells communicate: They respond not to any single synaptic signal, but to the overall chemical “vibe” of their environment – to chronic feelings of stress, for instance. By way of response, they may morph into neurons or glia – or even tell the brain to crank out some all-new cells.

Neural stem cells seem to be particularly interested in the chemical GABA (gamma-aminobutyric acid) – a neurotransmitter that’s known to be involved in inhibiting signals from other neurons. When scientists artificially block these stem cells’ GABA receptors from receiving messages, the cells “wake up” and start replicating – but when those GABA signals are allowed to reach the receptors, the stem cells stay dormant.

“In this case,” Song explains, “GABA communication keeps the brain stem cells in reserve, so if we don’t need them, we don’t use them up.”

In short, leaky synapses aren’t wasteful – as a matter of fact, they’re essential to the brain’s self-sculpting abilities. And this implies something pretty interesting: It isn’t just individual signals that convey neural information, but whole experiences. In that respect, a brain – whether it belongs to a rat or a human – is unlike any computer on earth.

By Ben Thomas | August 15, 2012

Source: Scientific American

When something goes wrong in your brain, you’d think it would be a good idea to get rid of the problem. Turns out, sometimes it’s best to keep hold of it. By preventing faulty proteins from being destroyed, researchers have delayed the symptoms of a degenerative brain disorder.

SNAP25 is one of three proteins that together make up a complex called SNARE, which plays a vital role in allowing neurons to communicate with each other. In order to work properly, all the proteins must be folded in a specific way. CSP alpha is one of the key proteins that ensures SNAP25 is correctly folded.

Cells have a backup system to deal with any misfolded proteins – they are destroyed by a bell-shaped enzyme called a proteasome, which pulls the proteins inside itself and breaks them down.

People with a genetic mutation that affects the CSP alpha protein – and its ability to correctly fold SNAP25 – can develop a rare brain disorder called neuronal ceroid lipofuscinosis (NCL). The disorder causes significant damage to neurons – people affected gradually lose their cognitive abilities and struggle to move normally.

To find out what role proteasomes might play in NCL, Manu Sharma and his colleagues at Stanford University in California blocked the enzyme in mice that were bred to lack CSP alpha. “We weren’t sure what would happen,” says Sharma. Either the misfolded SNAP25 would accumulate and harm the cells, or some of the misfolded proteins may work well enough to retain some of their function.

It appears it was the latter. Mice bred to lack CSP alpha suffer the same physical and cognitive problems as humans, and tend to survive for about 65 to 80 days, rather than the normal 670 days. But mice injected with a drug that blocked protease lived, on average, an extra 15 days. “Fifteen days might not sound like much, but as a percentage it’s quite significant,” says Sharma. What’s more, treated mice were able to stave off measurable movement and cognitive symptoms for an extra 10 days.

The finding goes against the idea that neurodegenerative disorders should be treated by clearing away misfolded proteins, rather than trying to rescue their function. “People normally think that protease isn’t working hard enough,” says Nico Dantuma at the Karolinska Institute in Stockholm, Sweden, who was not involved in the study.

But whether or not the drugs are likely to work in other neurodegenerative disorders involving aggregations of misfolded proteins, such as Alzheimer’s and Parkinson’s disease, is up for debate. “I don’t think their results prove that clearing misfolded proteins is not a useful therapeutic,” says Ana Maria Cuervo at Albert Einstein College of Medicine in New York. Other studies that increase the degrading of misfolded proteins have been shown to improve symptoms in other neurodegenerative diseases, she says.

"There are two sides of the coin," says Dantuma. "You might rescue functioning proteins from being degraded… but it’s too early to extrapolate these results to Alzheimer’s and Parkinson’s disease."

In the meantime, drugs that block proteasome are already used to treat cancer, so Sharma hopes they can soon be trialled in people with NCL.

Source: NewScientist

Depression takes a substantial toll on brain health. Brain imaging and post-mortem studies provide evidence that the wealth of connections in the brain are reduced in individuals with depression, with the result of impaired functional connections between key brain centers involved in mood regulation. Glial cells are one of the cell types that appear to be particularly reduced when analyzing post-mortem brain tissue from people who had depression. Glial cells support the growth and function of nerve cells and their connections.

Over the past several years, it has become increasingly recognized that antidepressants produce positive effects on brain structure that complement their effects on symptoms of depression. These structural effects of antidepressants appear to depend, in large part, on their ability to raise the levels of growth factors in the brain.

In a new study, Elsayed and colleagues from the Yale University School of Medicine report their findings on a relatively novel growth factor named fibroblast growth factor-2 or FGF2. They found that FGF2 can increase the number of glial cells and block the decrease caused by chronic stress exposure by promoting the generation of new glial cells.

Senior author Dr. Ronald Duman said, “Our study uncovers a new pathway that can be targeted for treating depression. Our research shows that we can increase the production and maintenance of glial cells that are important for supporting neurons, providing an enriched environment for proper neuronal function.”

To study whether FGF2 can treat depression, the researchers used rodent models where animals are subjected to various natural stressors, which can trigger behaviors that are similar to those expressed by depressed humans, such as despair and loss of pleasure. FGF2 infusions restored the deficit in glial cell number caused by chronic stress. An underlying molecular mechanism was also identified when the data showed that antidepressants increase glial generation and function via increasing FGF2 signaling.

"Although more research is warranted to explore the contribution of glial cells to the antidepressant effects of FGF2, the results of this study present a fundamental new mechanism that merits attention in the quest to find more efficacious and faster-acting antidepressant drugs," concluded Duman.

"The deeper that science digs into the biology underlying antidepressant action, the more complex it becomes. Yet understanding this complexity increases the power of the science, suggesting reasons for the limitations of antidepressant treatment and pointing to novel approaches to the treatment of depression," commented Dr. John Krystal, Editor of Biological Psychiatry and Chairman of the Department of Psychiatry at the Yale University School of Medicine.

Source: Bio-Medicine

ScienceDaily (Aug. 15, 2012) — Long-term methadone treatment can cause changes in the brain, according to recent studies from the Norwegian Institute of Public Health. The results show that treatment may affect the nerve cells in the brain. The studies follow on from previous studies where methadone was seen to affect cognitive functioning, such as learning and memory.

Since it is difficult to perform controlled studies of methadone patients and unethical to attempt in healthy volunteers, rats were used in the studies. Previous research has shown that methadone can affect cognitive functioning in both humans and experimental animals.

Sharp decrease in key signaling molecule

Rats were given a daily dose of methadone for three weeks. Once treatment was completed, brain areas which are central for learning and memory were removed and examined for possible neurobiological changes or damage.

In one study, on the day after the last exposure to methadone, there was a significant reduction (around 70 per cent) in the level of a signal molecule which is important in learning and memory, in both the hippocampus and in the frontal area of the brain. This reduction supports findings from a previous study (Andersen et al., 2011) where impaired attention in rats was found at the same time. At this time, methadone is no longer present in the brain. This indicates that methadone can lead to cellular changes that affect cognitive functioning after the drug has left the body, which may be cause for concern.

No effect on cell generation

The second study, a joint project with Southwestern University in Texas, investigated whether methadone affects the formation of nerve cells in the hippocampus. Previous research has shown that new nerve cells are generated in the hippocampus in both adult humans and rats, and that this formation is probably important for learning and memory. Furthermore, it has been shown that other opiates such as morphine and heroin can inhibit this formation. It was therefore reasonable to assume that methadone, which is also an opiate, would have the same effect.

However, the researchers did not find any change in the generation of new nerve cells after long-term methadone treatment. If the same is true in humans, this is probably more positive for methadone patients than continuing with heroin. However, the researchers do not know what effect methadone has on nerve cells that have previously been exposed to heroin.

Large gaps in knowledge

Since the mid-1960s, methadone has been used to treat heroin addiction. This is considered to be a successful treatment but, despite extensive and prolonged use, little is known about possible side effects. There are large knowledge gaps in this field.

Our studies show that prolonged methadone treatment can affect the nerve cells, and thus behaviour, but the results are not always as expected. Many more pre-clinical and clinical studies are needed to understand methadone’s effect on the brain, how this can result in altered cognitive function, and, if so, how long these changes last. Knowledge of this is important — both for the individual methadone patient and the outcome of treatment.

Source: Science Daily