Neuroscience

The tiny addition of a chemical mark atop a gene that is well known for its involvement in clinical depression and posttraumatic stress disorder can affect the way a person’s brain responds to threats, according to a new study by Duke University researchers.

The results, which appear online August 3 in Nature Neuroscience, go beyond genetics to help explain why some individuals may be more vulnerable than others to stress and stress-related psychiatric disorders.

The study focused on the serotonin transporter, a molecule that regulates the amount of serotonin signaling between brain cells and is a major target for treatment of depression and mood disorders. In the 1990s, scientists discovered that differences in the DNA sequence of the serotonin transporter gene seemed to give some individuals exaggerated responses to stress, including the development of depression.

(Image caption: An artist’s conception shows how molecules called methyl groups attach to a specific stretch of DNA, changing expression of the serotonin transporter gene in a way that ultimately shapes individual differences in the brain’s reactivity to threat. The methyl groups in this diagram are overlaid on the amygdala of the brain, where threat perception occurs. Credit: Annchen Knodt, Duke University)

Sitting on top of the serotonin transporter’s DNA (and studding the entire genome), are chemical marks called methyl groups that help regulate where and when a gene is active, or expressed. DNA methylation is one form of epigenetic modification being studied by scientists trying to understand how the same genetic code can produce so many different cells and tissues as well as differences between individuals as closely related as twins.

In looking for methylation differences, “we decided to start with the serotonin transporter because we know a lot about it biologically, pharmacologically, behaviorally, and it’s one of the best characterized genes in neuroscience,” said senior author Ahmad Hariri, a professor of psychology and neuroscience and member of the Duke Institute for Brain Sciences.

"If we’re going to make claims about the importance of epigenetics in the human brain, we wanted to start with a gene that we have a fairly good understanding of," Hariri said.

This work is part of the ongoing Duke Neurogenetics Study (DNS), a comprehensive study linking genes, brain activity and other biological markers to risk for mental illness in young adults.

The group performed non-invasive brain imaging in the first 80 college-aged participants of the DNS, showing them pictures of angry or fearful faces and watching the responses of a deep brain region called the amygdala, which helps shape our behavioral and biological responses to threat and stress.

The team also measured the amount of methylation on serotonin transporter DNA isolated from the participants’ saliva, in collaboration with Karestan Koenen at Columbia University’s Mailman School of Public Health in New York.

The greater the methylation of an individual’s serotonin transporter gene, the greater the reactivity of the amygdala, the study found. Increased amygdala reactivity may in turn contribute to an exaggerated stress response and vulnerability to stress-related disorders.

To the group’s surprise, even small methylation variations between individuals were sufficient to create differences between individuals’ amygdala reactivity, said lead author Yuliya Nikolova, a graduate student in Hariri’s group. The amount of methylation was a better predictor of amygdala activity than DNA sequence variation, which had previously been associated with risk for depression and anxiety.

The team was excited about the discovery but also cautious, Hariri said, because there have been many findings in genetics that were never replicated.

That’s why they jumped at the chance to look for the same pattern in a different set of participants, this time in the Teen Alcohol Outcomes Study (TAOS) at the University of Texas Health Science Center at San Antonio.

Working with TAOS director, Douglas Williamson, the group again measured amygdala reactivity to angry and fearful faces as well as methylation of the serotonin transporter gene isolated from blood in 96 adolescents between 11 and 15 years old. The analyses revealed an even stronger link between methylation and amygdala reactivity.

"Now over 10 percent of the differences in amygdala function mapped onto these small differences in methylation," Hariri said. The DNS study had found just under 7 percent.

Taking the study one step further, the group also analyzed patterns of methylation in the brains of dead people in collaboration with Etienne Sibille at the University of Pittsburgh, now at the Centre for Addiction and Mental Health in Toronto.

Once again, they saw that methylation of a single spot in the serotonin transporter gene was associated with lower levels of serotonin transporter expression in the amygdala.

"That’s when we thought, ‘Alright, this is pretty awesome,’" Hariri said.

Hariri said the work reveals a compelling mechanistic link: Higher methylation is generally associated with less reading of the gene, and that’s what they saw. He said methylation dampens expression of the gene, which then affects amygdala reactivity, presumably by altering serotonin signaling.

The researchers would now like to see how methylation of this specific bit of DNA affects the brain. In particular, this region of the gene might serve as a landing place for cellular machinery that binds to the DNA and reads it, Nikolova said.

The group also plans to look at methylation patterns of other genes in the serotonin system that may contribute to the brain’s response to threatening stimuli.

The fact that serotonin transporter methylation patterns were similar in saliva, blood and brain also suggests that these patterns may be passed down through generations rather than acquired by individuals based on their own experiences.

Hariri said he hopes that other researchers looking for biomarkers of mental illness will begin to consider methylation above and beyond DNA sequence-based variation and across different tissues.

New research at Washington University School of Medicine in St. Louis helps explain why brain tumors occur more often in males and frequently are more harmful than similar tumors in females. For example, glioblastomas, the most common malignant brain tumors, are diagnosed twice as often in males, who suffer greater cognitive impairments than females and do not survive as long.

The researchers found that retinoblastoma protein (RB), a protein known to reduce cancer risk, is significantly less active in male brain cells than in female brain cells.

The study appears Aug. 1 in The Journal of Clinical Investigation.

“This is the first time anyone ever has identified a sex-linked difference that affects tumor risk and is intrinsic to cells, and that’s very exciting,” said senior author Joshua Rubin, MD, PhD. “These results suggest we need to go back and look at multiple pathways linked to cancer, checking for sex differences. Sex-based distinctions at the level of the cell may not only influence cancer risk but also the effectiveness of treatments.”

Rubin noted that RB is the target of drugs now being evaluated in clinical trials. Trial organizers hope the drugs trigger the protein’s anti-tumor effects and help cancer patients survive longer.

“In clinical trials, we typically examine data from male and female patients together, and that could be masking positive or negative responses that are limited to one sex,” said Rubin, who is an associate professor of pediatrics, neurology and anatomy and neurobiology. “At the very least, we should think about analyzing data for males and females separately in clinical trials.”

Scientists have identified many sex-linked diseases that either occur at different rates in males and females or cause different symptoms based on sex. These distinctions often are linked to sex hormones, which create and maintain many but not all of the biological differences between the sexes.

However, Rubin and his colleagues knew that sex hormones could not account for the differences in brain tumor risk.

“Male brain tumor risk remains higher throughout life despite major age-linked shifts in sex hormone production in males and females,” he said. “If the sex hormones were causing this effect, we’d see major changes in the relative rates of brain tumors in males and females at puberty. But they don’t happen then or later in life when menopause changes female sex hormone production.”

Rubin used a cell model of glioblastoma to prove it is easier to make male brain cells become tumors. After a series of genetic alterations and exposure to a growth factor, male brain cells became cancerous faster and more often than female brain cells.

In experiments designed to identify the reasons for the differences in the male and female cells, the team evaluated three genes to see if they were naturally less active in male brain cells. The genes they studied — neurofibromin, p53 and RB — normally suppress cell division and cell survival. They are mutated and disabled in many cancers.

The scientists found RB was more likely to be inactivated in male brain cells than in female brain cells. When they disabled the RB protein in female brain cells, the cells were equally susceptible to becoming cancers.

“There are other types of tumors that occur at different rates based on sex, such as some liver cancers, which occur more often in males,” Rubin said. “Knowing more about why cancer rates differ between males and females will help us understand basic mechanisms in cancer, seek more effective therapies and perform more informative clinical trials.”

Parkinson’s disease affects neurons in the Substantia nigra brain region – their mitochondrial activity ceases and the cells die. Researchers at the Max Planck Institute of Molecular Cell Biology and Genetics show that supplying D-lactate or glycolate, two products of the gene DJ-1, can stop and even counteract this process: Adding the substances to cultured HeLa cells and to cells of the nematode C. elegans restored the activity of mitochondria and prevented the degeneration of neurons. They also showed that the two substances rescued the toxic effects of the weed killer Paraquat. Cells that had been treated with this herbicide, which is known to cause a Parkinson’s like harm of mitochondria, recovered after the addition of the two substances. Both glycolic and D-lactic acids occur naturally in unripe fruits and certain kinds of yoghurt.

(Image caption: Inactivation of the DJ-1 gene results in mitochondrial dysfunction (left), which can be restored by glycolate or D-lactate (right). Active mitochondria are shown in red, DNA is shown in blue. Credit: © MPI-CBG)

Teymuras Kurzchalia and Tony Hyman both have labs at the Max Planck Institute of Molecular Cell Biology and Genetics with rather different research programs – but both happened to stumble upon the gene DJ-1 and joined forces. This gene, originally thought of as an oncogene, has been linked to Parkinson’s disease since 2003. Recent studies showed that DJ-1 belongs to a novel glyxolase family. The major function of these genes is assumed to detoxify aggressive aldehyde by-products from mitochondrial metabolism. The Dresden research team now showed that the products of DJ-1, D-lactate and glycolate, are actually required to maintain the high mitochondrial potential and thus can prevent the degeneration of neurons implicated in Parkinson’s disease.

Their experiments proved that both substances are lifesavers for neurons: Adding them to affected cells, in other words cells treated with the environmental poison Paraquat or with a down-regulated DJ-1, decreased the toxic effect of the herbicide, restored the activity of the mitochondria and thus ensured the survival of the neurons.

„We do not yet understand how exactly D-lactate and glycolate achieve this curative and preventive effect, but the next step will be to investigate the molecular mechanism underlying this process”, say Hyman and Kurzchalia. In addition to further molecular investigation, they also have more concrete plans for the future: As Kurzchalia says “we can develop a yoghurt enriched with D-lactate: It could serve as a protection against Parkinson’s and is actually very tasty at the same time!“ This is why the researchers have filed a patent for their finding.

Many diseases are associated with a decline in mitochondrial activity, not only Parkinson’s. Thus, the researchers believe that the DJ1-products could have a general role in protecting cells from decline.

Chronic pain is among the most abundant of all medical afflictions in the developed world. It differs from a short-term episode of pain not only in its duration, but also in triggering in its sufferers a psychic exhaustion best described by the question, “Why bother?”

A new study in mice, conducted by investigators at the Stanford University School of Medicine, has identified a set of changes in key parts of the brain that may explain chronic pain’s capacity to stifle motivation. The discovery could lead to entirely new classes of treatment for this damaging psychological consequence of chronic pain.

Many tens of millions of people in the United States suffer persistent pain due to diverse problems including migraines, arthritis, lower back pain, sports injuries, irritable bowel syndrome and shingles. For many of these conditions, there are no good treatments, and a crippling loss of mojo can result.

“With chronic pain, your whole life changes in a way that doesn’t happen with acute pain,” said Robert Malenka, MD, PhD, the Nancy Friend Pritzker Professor in Psychiatry and Behavioral Sciences and the study’s senior author. “Yet this absence of motivation caused by chronic pain, which can continue even when the pain is transiently relieved, has been largely ignored by medical science.”

A series of experiments in mice by Malenka and his colleagues, described in a study published Aug. 1 in Science, showed that persistent pain causes changes in a set of nerve cells in a deep-brain structure known to be important in reward-seeking behavior: the pursuit of goals likely to yield pleasurable results. Malenka’s lab has been studying this brain structure, the nucleus accumbens, for two decades.

“We showed that those brain changes don’t go away when you transiently relieve the mice’s pain,” Malenka said. The experiments also indicated that the mice’s diminished motivation to perform reward-generating tasks didn’t stem from their pain’s rendering them incapable of experiencing pleasure or from any accompanying physical impairment, he said.

How pain and reward interact

“This study is important — to my knowledge, the first to explain how pain and reward interact. It begins to get to an understanding of why it’s such a struggle for people undergoing chronic pain to get through the day,” said Howard Fields, MD, PhD, a professor of neurology at the University of California-San Francisco and founder of that school’s pain management center.

Fields, who did not participate in the Malenka group’s study but wrote an accompanying perspective piece published simultaneously in Science, described the psychological effect of chronic pain as “the clouding of the future. There’s no escape from it. You want it to end, but it doesn’t.” As a result, people become pessimistic and irritable, he said. “People come to expect the next day is going to wind up being painful. It just takes the edge off of life’s little pleasures — and big pleasures, for that matter.”

The experiments were spearheaded by the study’s first author, Neil Schwartz, PhD, a postdoctoral scholar in Malenka’s lab. “You can’t just ask a hungry mouse how motivated it is to pursue its heart’s desire,” Malenka said. “But there are ways of asking that mouse, ‘How hard are you willing to work for food?’”

Schwartz, Malenka and their associates looked at lab mice enduring chronic paw pain due either to persistent inflammation or to nerve damage. The mice also happened to be hungry. The scientists trained the mice to poke their noses into a hole to get a food pellet. At first, a single nose poke earned a pellet. But over time, the number of nose pokes required for a reward was increased. In essence, the researchers were asking these mice: How hard are you willing to work for food? Will you poke your nose into that hole once to satisfy your hunger? Ten times? Even 150 times?

Fading motivation

Within a week after the onset of chronic pain, the animals grew increasingly less likely to work hard for food than pain-free control animals were. The researchers next explored three possible explanations: Were the mice unable to work because their pain was too severe? Did something about being in pain cause them to not value the food reward as much? Or was their failure to seek food due simply to a lack of motivation? Additional tests showed that the mice had no movement problems. “Like other research groups, we found that they can scamper around just fine,” said Malenka. Also, when the mice were given free access to food, they ate just as much as the animals who weren’t in pain — so they still valued the food. But they were less willing to put in an effort to obtain food than mice who’d suffered no pain.

Moreover, the difference didn’t disappear even when the scientists relieved the mice’s pain with analgesics. “They were in demonstrably less pain, but they were still less willing to work,” Malenka said.

The Stanford scientists then focused on the nucleus accumbens, a brain structure known to be involved in computing the behavioral strategies that prompt us to seek or avoid things that can affect our survival. They found that chronic pain permanently changed certain connections to the nucleus accumbens, causing an enduring downshift in the excitation transmitted by them. Importantly, Malenka’s group showed that a particular brain chemical called galanin plays a critical role in this enduring suppression of nucleus accumbens excitability.

Galanin is a short signaling-protein snippet secreted by certain cells in various places in the brain. While its presence in the brain has been known for a good 60 years or so, galanin’s role is not well-defined and probably differs widely in different brain structures. There have been hints, though, that galanin activity might play a role in pain. For example, it’s been previously shown in animal models that galanin levels in the brain increase with the persistence of pain.

Possible therapies?

Schwartz, Malenka and their peers identified receptors for galanin on a set of nerve cells in the nucleus accumbens and demonstrated that disabling galanin’s signaling via this receptor prevented the long-term suppression of motivation seen in mice — and people — with chronic pain. This suggests that therapeutic compounds with similar effects could someday be developed, although they would have to be carefully targeted so as to not disrupt galanin signaling in other important brain circuits.

“There’s no reason to think this finding won’t generalize to people,” said Fields of UCSF. “Our brains have galanin, and a nucleus accumbens, just as mouse brains do. However, before jumping from mice to humans it would be wise to test other animal species. If the same things happen in a non-rodent species that happen in mice, then it’s probable they happen in humans, too.”

New research by clinical psychologists from Arizona State University and the United Kingdom has revealed seizures that could be mistaken for epilepsy are linked to feelings of anxiety.

The team of researchers devised a new set of tests to determine whether there was a link between how people interpret and respond to anxiety, and incidences of psychogenic nonepileptic seizures (PNES).

Nicole Roberts, an associate professor in ASU’s New College of Interdisciplinary Arts and Sciences, collaborated with colleagues from the University of Lincoln, University of Nottingham and University of Sheffield in the United Kingdom. The team’s findings were published in the journal Epilepsy and Behavior.

The researchers used a series of questionnaires and computer tests to determine if a patient regularly avoids situations which might bring on anxiety.

These tests correctly predicted whether a patient had epilepsy or PNES – seizures that can be brought on by threatening situations, sensations, emotions, thoughts or memories – in 83 percent of study participants. Such seizures appear on the surface to be similar to epileptic fits, which are caused by abnormal brain activity.

“This research underscores the fact that PNES is a ‘real’ and disabling disorder with a potentially identifiable pathophysiology,” said Roberts, who directs New College’s Emotion, Culture, and Psychophysiology Laboratory, located on ASU’s West campus. “We need to continue to search for answers, not just in epilepsy clinics, but also in the realm of affective science and complex brain-behavior relationships.”

“PNES can be a very disabling condition, and it is important that we understand the triggers so that we provide the correct care and treatment,” said Lian Dimaro, a clinical psychologist based at Nottinghamshire Healthcare NHS Trust, who served as lead researcher for the study.

“This study was one of the first to bring modern psychological tools of investigation to this problem,” Dimaro said. “The findings support the idea that increasing a person’s tolerance of unpleasant emotions and reducing avoidant behavior may help with treatment, suggesting that patients could benefit from a range of therapies, including acceptance and commitment therapy to help reduce the frequency of seizures, although more research is needed in this area.”

Participants completed questionnaires to determine the level to which they suffered from anxiety, their awareness of their experiences and if they would avoid situations which would make them feel anxious.

They then completed a computer task which required rapid responses to true or false statements. This test was designed to gather data on immediate, or implicit, beliefs about anxiety. Participants also answered questions about common physical complaints that may have no medical explanation, also called somatic symptoms. These can include things like gastrointestinal problems, tiredness and back pain.

Results showed that those with PNES reported significantly more somatic symptoms than others in the study, as well as avoidance of situations which might make them anxious. The group with PNES also scored significantly higher on a measure of how aware they were of their anxiety compared with the control group.

The test subjects were 30 adults with PNES, 25 with epilepsy and 31 with no reported history of seizures who served as a nonclinical control group.

The researchers suggest that including tests to determine levels of anxiety and avoidance behavior may enable health professionals to make earlier diagnosis, and develop more effective intervention plans.

“Epileptic seizures are caused by abnormal electrical activity in the brain, while most PNES are thought to be a consequence of complex psychological processes that manifest in physical attacks,” said David Dawson, a research clinical psychologist from the University of Lincoln.

“It is believed that people suffering with PNES may have difficulty actively engaging with anxiety – a coping style known as experiential avoidance,” Dawson said. “We wanted to examine whether it was possible to make a clear link between seizure frequency and how people experience and manage anxiety. Our study is another step in understanding PNES, which could ultimately lead to better treatment and, therefore, patient outcomes in the future.”

Roberts, who received her doctorate in clinical psychology from the University of California, Berkeley, focuses her research on the study of emotion and on the cultural and biological forces that shape emotional responses. Examples include investigating how ethnicity and culture influence emotional displays and experiences; how the daily hassles of life, such as job stress and sleep deprivation, impact emotion regulation among individuals and couples; and how the emotion system breaks down in patients with psychopathology (such as PNES and post-traumatic stress disorder) or neurological dysfunction (such as epilepsy).

The hallmark of an excellent researcher is an open mind. That flexibility and openness is what led Nina Schor, M.D., Ph.D., the William H. Eilinger Chair of Pediatrics at the University of Rochester, to follow a hunch about a brain receptor – resulting in a new mouse model that may give researchers a new avenue for testing drugs for autism. Nature Publishing Groups’ Translational Psychiatry published the study online today.

Schor had been studying p75 neurotrophin receptors in her long-standing neuroblastoma research, but she also knew that p75NTR is involved in the reaction to oxidative stress in the brain, which some research posits plays a role in the development of autism. The receptor is also prevalent in the developing brain and drops off as a child reaches 2 to 3 years old, which is when autism symptoms often begin to appear. P75NTR stays present in the typically developing cerebellum, hippocampus and basal forebrain, parts of the brain that are anatomically abnormal in autism.

“Science doesn’t always travel in a straight line,” Schor said. “Sometimes the importance of a scientific study in one field is what it unexpectedly tells us about another field.”

While other researchers are focused on the proteins found to be abnormal in patients with autism, Schor approached her investigation from the opposite direction. She thought about what characteristics a protein would have to have to be involved in processes thought to play a role in autism. “That list of characteristics looked suspiciously like those we had found to be associated with p75NTR.”

Then, Schor and her colleagues prevented mouse brains from making p75NTR in one autism-associated type of cell in the cerebellum. What they found was that not only does the mouse’s cerebellum resemble that of children with autism, but the mouse also behaves much like children with autism. They don’t engage in typical social behaviors of mice and instead, ignore stranger mice and lack curiosity about their surroundings. They also jump twice as much as typical mice, which is like a “stimming,” or self-stimulatory, behavior typical in children with autism.

“Whether or not p75NTR turns out to be abnormal in children with autism,” Schor explained, “these studies still hold the promise of helping us explain the mechanisms behind the component behaviors of children with autism.

Schor plans to continue the research, focusing on more behavioral testing, finding evidence of whether children with autism have a p75NTR deficit in their cerebellum and starting pharmaceutical testing to see whether there is a drug that can replace the role p75NTR plays in that part of the brain.

“It’s a long way from a mouse model to a successful treatment in humans, but this is a good clue,” Schor said.

Research to be presented at the Annual Meeting of the Society for the Study of Ingestive Behavior (SSIB), the foremost society for research into all aspects of eating and drinking behavior, describes a way that brain chemistry may make some people notice food more easily, which can tempt overeating even in people who are not overweight. Dopamine activity in the striatum, an area of the brain sensitive to food reward, was linked to how quickly men noticed a food picture hidden among neutral pictures. In turn, the men who quickly noticed food pictures also ate more.

From rodent research it is clear that dopamine action in the striatum motivates eating, and this goes awry in obesity. “We do know that in human obesity the striatal dopamine system is affected, but interesting enough we know little about the striatal dopamine system of young, healthy individuals and how it relates to the motivation to eat” says Susanne la Fleur from the Academic Medical Center in Amsterdam, who directed the study linking dopamine, attention to food, and eating.

Ordinarily the burst of dopamine during a rewarding activity is eventually stopped when it is re-absorbed into the cells it came from. That re-uptake process requires a brain chemical called “dopamine transporter” (DAT). Lower DAT means dopamine is reabsorbed more slowly, causing it to keep acting on the brain. The researchers scanned brains of healthy, non-obese young men to determine available DAT. The men completed a computerized visual attention task to see how quickly they could detect food pictures among neutral pictures. Subjects were also asked to report food intake during 7 days.

The researchers found that the men with lower DAT, which means higher dopamine activity, showed a stronger visual attention bias towards food, detecting food pictures more quickly. “We could speculate that in healthy humans dopamine does motivate eating, however although we did observe a correlation between striatal dopamine transporter binding and the visual attention bias for food; and between visual attention bias for food and actual food intake, we did not observe a correlation between striatal dopamine transporter binding and actual food intake. Thus, a factor in addition to dopamine must be involved in going from being motivated to actual eating”, la Fleur concluded.

People who have the most common genetic mutation linked to obesity respond differently to pictures of appetizing foods than overweight or obese people who do not have the genetic mutation, according to a new study published in the Endocrine Society’s Journal of Clinical Endocrinology & Metabolism (JCEM).

More than one-third of adults are obese. Obesity typically results from a combination of eating too much, getting too little physical activity and genetics. In particular, consumption of appetizing foods that are high in calories can lead to weight gain. Highly palatable foods such as chocolate trigger signals in the brain that give a feeling of pleasure and reward. These cravings can contribute to overeating. Reward signals are processed in specific areas of the brain, where sets of neurons release chemicals such as dopamine. However, very little is known about whether the reward centers of the brain work differently in some people who are overweight or obese.

The most common genetic cause of obesity involves mutations in the melanocortin 4 receptor (MC4R), which occur in about 1 percent of obese people and contribute to weight gain from an early age. The researchers compared three groups of people: eight people who were obese due to a problem in the MC4R gene, 10 people who were overweight or obese without the gene mutation and eight people who were normal weight. They performed functional Magnetic Resonance Imaging (fMRI) scans to look at how the reward centers in the brain were activated by pictures of appetizing food such as chocolate cake compared to bland food such as rice or broccoli and non-food items such as staplers.

“In our study, we found that people with the MC4R mutation responded in the same way as normal weight people, while the overweight people without the gene problem had a lower response,” said lead researcher Agatha van der Klaauw, MD, PhD, of the Wellcome Trust-MRC Institute of Metabolic Science at Addenbrooke’s Hospital in Cambridge, U.K. “In fact, the brain’s reward centers light up when people with the mutation and normal weight people viewed pictures of appetizing foods. But overweight people without the mutation did not have the same level of response.”

The scans revealed that obese people with the MC4R mutation had similar activity in the reward centers of the brain when shown a picture of a dessert like cake or chocolate as normal weight people. The researchers found that, in contrast, the reward centers were underactive in overweight and obese volunteers who did not have the gene mutation. This finding is intriguing as it shows a completely different response in two groups of people of the same age and weight.

“For the first time, we are seeing that the MC4R pathway is involved in the brain’s response to food cues and its underactivity in some overweight people,” van der Klaauw said. “Understanding this pathway may help in developing interventions to limit the overconsumption of highly palatable foods that can lead to weight gain.”

To address the obesity epidemic, the Cambridge team is continuing to study the pathways in the brain that coordinate the need to eat and the reward and pleasure of eating

A study published in the American Journal of Geriatric Psychiatry indicates that middle-aged adults with a history of problem drinking are more than twice as likely to suffer from severe memory impairment in later life.

The study highlights the hitherto largely unknown link between harmful patterns of alcohol consumption and problems with memory later in life – problems which may place people at a high risk of developing dementia.

The study was carried out by researchers from the University of Exeter Medical School with support from the NIHR Collaboration for Leadership in Applied Health Research and Care South West Peninsula (NIHR PenCLAHRC).

The research team studied the association between a history of alcohol use disorders (AUDs) and the onset of severe cognitive and memory impairment in 6542 middle-aged adults born between 1931 and 1941. These individuals participated in the Health and Retirement Study in the US.

Participants were first assessed in 1992 and follow-up assessments took place every other year from 1996 to 2010.

A history of AUDs was identified using the CAGE* questionnaire (short for Cut down, Annoyed, Guilty, Eye-opener). Where participants registered a history of AUDs their chances of developing severe memory impairment more than doubled.

The study was led by Dr Iain Lang. He commented: “We already know there is an association between dementia risk and levels of current alcohol consumption – that understanding is based on asking older people how much they drink and then observing whether they develop problems. But this is only one part of the puzzle and we know little about the consequences of alcohol consumption earlier in life. What we did here is investigate the relatively unknown association between having a drinking problem at any point in life and experiencing problems with memory later in life.”

He added: “This finding – that middle-aged people with a history of problem drinking more than double their chances of memory impairment when they are older – suggests three things: that this is a public health issue that needs to be addressed; that more research is required to investigate the potential harms associated with alcohol consumption throughout life; and that the CAGE questionnaire may offer doctors a practical way to identify those at risk of memory/cognitive impairment and who may benefit from help to tackle their relationship with alcohol.”

Dr Doug Brown, Director of Research and Development at Alzheimer’s Society said: “When we talk about drinking too much, the media often focuses on young people ending up in A&E after a night out. However, there’s also a hidden cost of alcohol abuse given the mounting evidence that alcohol abuse can also impact on cognition later in life. This small study shows that people who admitted to alcohol abuse at some point in their lives were twice as likely to have severe memory problems, and as the research relied on self-reporting that number may be even higher.

"This isn’t to say that people need to abstain from alcohol altogether. As well as eating a healthy diet, not smoking and maintaining a healthy weight, the odd glass of red wine could even help reduce your risk of developing dementia."

* The CAGE asks four questions (and the acronym comes from words in each question: Cut down, Annoyed, Guilty, Eye-opener):

1. Have you ever felt you should cut down on your drinking?
2. Have people annoyed you by criticising your drinking?
3. Have you ever felt bad or guilty about your drinking?
4. Have you ever had a drink first thing in the morning to steady your nerves or get rid of a hangover (eye-opener)?

A team of scientists has identified the neurons used in certain types of motion detection—findings that deepen our understanding of how the visual system functions.

“Our results show how neurons in the brain work together as part of an intricate process used to detect motion,” says Claude Desplan, a professor in NYU’s Department of Biology and the study’s senior author.

The study, whose authors included Rudy Behnia, an NYU post-doctoral fellow, as well as researchers from the NYU Center for Neural Science and Yale and Stanford universities, appears in the journal Nature.

The researchers sought to explain some of the neurological underpinnings of a long-established and influential model, the Hassenstein–Reichardt correlator. It posits that motion detection relies on separate input channels that are processed in the brain in ways that coordinate these distinct inputs. The Nature study focused on neurons acting in this processing.

The researchers examined the fruit fly Drosophila, which is commonly used in biological research as a model system to decipher basic principles that direct the functions of the brain.

Previously, scientists studying Drosophila have identified two parallel pathways that respond to either moving light, or dark edges—a dynamic that underscores much of what flies see in detecting motion. For instance, a bird is an object whose dark edges flies see as it first moves across the bright light of the sky; after it passes through their field of view, flies see the light edge of the background sky.

However, the nature of the underlying neurological processing had not been clear.

In their study, the researchers analyzed the neuronal activity of particular neurons used to detect these movements. Specifically, they found that four neurons in the brain’s medulla implement two processing steps. Two neurons— Tm1 and Tm2—respond to brightness decrements (central to the detection of moving dark edges); by contrast, two other neurons— Mi1 and Tm3—respond to brightness increments (or light edges). Moreover, Tm1 responds slower than does Tm2 while Mi1 responds slower than does Tm3, a difference in kinetics that fundamental to the Hassenstein-Reichardt correlator.

In sum, these neurons process the two inputs that precede the coordination outlined by the Hassenstein–Reichardt correlator, thereby revealing elements of the long-sought neural activity of motion detection in the fly.

Johns Hopkins researchers say they have discovered a chemical alteration in a single human gene linked to stress reactions that, if confirmed in larger studies, could give doctors a simple blood test to reliably predict a person’s risk of attempting suicide.

The discovery, described online in The American Journal of Psychiatry, suggests that changes in a gene involved in the function of the brain’s response to stress hormones plays a significant role in turning what might otherwise be an unremarkable reaction to the strain of everyday life into suicidal thoughts and behaviors.

“Suicide is a major preventable public health problem, but we have been stymied in our prevention efforts because we have no consistent way to predict those who are at increased risk of killing themselves,” says study leader Zachary Kaminsky, Ph.D., an assistant professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. “With a test like ours, we may be able to stem suicide rates by identifying those people and intervening early enough to head off a catastrophe.”

For his series of experiments, Kaminsky and his colleagues focused on a genetic mutation in a gene known as SKA2. By looking at brain samples from mentally ill and healthy people, the researchers found that in samples from people who had died by suicide, levels of SKA2 were significantly reduced.

Within this common mutation, they then found in some subjects an epigenetic modification that altered the way the SKA2 gene functioned without changing the gene’s underlying DNA sequence. The modification added chemicals called methyl groups to the gene. Higher levels of methylation were then found in the same study subjects who had killed themselves. The higher levels of methylation among suicide decedents were then replicated in two independent brain cohorts.

In another part of the study, the researchers tested three different sets of blood samples, the largest one involving 325 participants in the Johns Hopkins Center for Prevention Research Study found similar methylation increases at SKA2 in individuals with suicidal thoughts or attempts. They then designed a model analysis that predicted which of the participants were experiencing suicidal thoughts or had attempted suicide with 80 percent certainty. Those with more severe risk of suicide were predicted with 90 percent accuracy. In the youngest data set, they were able to identify with 96 percent accuracy whether or not a participant had attempted suicide, based on blood test results.

The SKA2 gene is expressed in the prefrontal cortex of the brain, which is involved in inhibiting negative thoughts and controlling impulsive behavior. SKA2 is specifically responsible for chaperoning stress hormone receptors into cells’ nuclei so they can do their job. If there isn’t enough SKA2, or it is altered in some way, the stress hormone receptor is unable to suppress the release of cortisol throughout the brain. Previous research has shown that such cortisol release is abnormal in people who attempt or die by suicide.

Kaminsky says a test based on these findings might best be used to predict future suicide attempts in those who are ill, to restrict lethal means or methods among those a risk, or to make decisions regarding the intensity of intervention approaches.

He says that it might make sense for use in the military to test whether members have the gene mutation that makes them more vulnerable. Those at risk could be more closely monitored when they returned home after deployment. A test could also be useful in a psychiatric emergency room, he says, as part of a suicide risk assessment when doctors try to assess level of suicide risk.

The test could be used in all sorts of safety assessment decisions like the need for hospitalization and closeness of monitoring. Kaminsky says another possible use that needs more study could be to inform treatment decisions, such as whether or not to give certain medications that have been linked with suicidal thoughts.

“We have found a gene that we think could be really important for consistently identifying a range of behaviors from suicidal thoughts to attempts to completions,” Kaminsky says. “We need to study this in a larger sample but we believe that we might be able to monitor the blood to identify those at risk of suicide.”

The brains of children with autism are relatively inflexible at switching from rest to task performance, according to a new brain-imaging study from the Stanford University School of Medicine.

Instead of changing to accommodate a job, connectivity in key brain networks of autistic children looks similar to connectivity in the resting brain. And the greater this inflexibility, the more severe the child’s manifestations of repetitive and restrictive behaviors that characterize autism, the study found.

The study, published online July 29 in Cerebral Cortex, used functional magnetic resonance imaging, or fMRI, to examine children’s brain activity at rest and during two tasks: solving simple math problems and looking at pictures of different faces. The study included an equal number of children with and without autism. The developmental disorder, which now affects one of every 68 children in the United States, is characterized by social and communication deficits, repetitive behaviors and sensory problems.

“We wanted to test the idea that a flexible brain is necessary for flexible behaviors,” said Lucina Uddin, PhD, a lead author of the study. “What we found was that across a set of brain connections known to be important for switching between different tasks, children with autism showed reduced ‘brain flexibility’ compared with typically developing peers.” Uddin, who is now an assistant professor of psychology at the University of Miami, was a postdoctoral scholar at Stanford when the research was conducted.

“The fact that we can tie this neurophysiological brain-state inflexibility to behavioral inflexibility is an important finding because it gives us clues about what kinds of processes go awry in autism,” said Vinod Menon, PhD, the Rachel L. and Walter F. Nichols, MD, professor of psychiatry and behavioral sciences at Stanford and the senior author of the study.

Tracking shifts in connectivity

The researchers focused on a network of brain areas they have studied before. These areas are involved in making decisions, performing social tasks and identifying relevant events in the environment to guide behavior. The team’s prior work showed that, in children with autism, activity in these areas was more tightly connected when the brain was at rest than it was in children who didn’t have autism.

The new research shows that, in autism, connectivity in these networks that can be seen on fMRI scans is fairly similar regardless of whether the brain is at rest or performing a task. In contrast, typically developing children have a larger shift in brain connectivity when they perform tasks.

The study looked at 34 kids with autism and 34 typically developing children. All of the children with autism received standard clinical evaluations to characterize the severity of their disorder. Then, the two groups were split in half: 17 children with autism and 17 typically developing children had their brains scanned with fMRI while at rest and while performing simple arithmetic problems. The remaining children had their brains scanned at rest and during a task that asked them to distinguish between different people’s faces. The facial recognition task was chosen because autism is characterized by social deficits; the math task was chosen to reflect an area in which children with autism do not usually have deficits.

Children with autism performed as well as their typically developing peers on both tasks — that is, they were as good at distinguishing between the faces and solving the math problems. However, their brain scan results were different. In addition to the reduced brain flexibility, the researchers showed a correlation between the degree of inflexibility and the severity of restrictive and repetitive behaviors, such as performing the same routine over and over or being obsessed with a favorite topic.

“This is the first study that has examined how the patterns of intrinsic brain connectivity change with a cognitive load in children with autism,” Menon said. The research is the first to demonstrate that brain connectivity in children with autism changes less, relative to rest, in response to a task than the brains of other children, he added.

Guidance for new therapies

“The findings may help researchers evaluate the effects of different autism therapies,” said Kaustubh Supekar, PhD, a research associate and the other lead author of the study. “Therapies that increase the brain’s flexibility at switching from rest to goal-directed behaviors may be a good target, for instance.”

“We’re making progress in identifying a brain basis of autism, and we’re starting to get traction in pinpointing systems and signaling mechanisms that are not functioning properly,” Menon said. “This is giving us a better handle both in thinking about treatment and in looking at change or plasticity in the brain.”

Some people can handle stressful situations better than others, and it’s not all in their genes: Even identical twins show differences in how they respond.

(Image: iStockphoto)

Researchers have identified a specific electrical pattern in the brains of genetically identical mice that predicts how well individual animals will fare in stressful situations.

The findings, published July 29 in Nature Communications, may eventually help researchers prevent potential consequences of chronic stress — such as post-traumatic stress disorder, depression and other psychiatric disorders — in people who are prone to these problems.

“In soldiers, we have this dramatic, major stress exposure, and in some individuals it’s leading to major issues, such as problems sleeping or being around other people,” said senior author Kafui Dzirasa, M.D., Ph.D., an assistant professor of psychiatry and behavioral sciences at Duke University Medical Center and a member of the Duke Institute for Brain Sciences. “If we can find that common trigger or common pathway and tune it, we may be able to prevent the emergence of a range of mental illnesses down the line.”

In the new study, Dzirasa’s team analyzed the interaction between two interconnected brain areas that control fear and stress responses in both mice and men: the prefrontal cortex and the amygdala. The amygdala plays a role in the ‘fight-or-flight’ response. The prefrontal cortex is involved in planning and other higher-level functions. It suppresses the amygdala’s reactivity to danger and helps people continue to function in stressful situations.

Implanting electrodes into the brains of the mice allowed the researchers to listen in on the tempo at which the prefrontal cortex and the amygdala were firing and how tightly the two areas were linked — with the ultimate goal of figuring whether the electrical pattern of cross talk could help decide how well animals would respond when faced with an acute stressor.

Indeed, in mice that had been subjected to a chronically stressful situation — daily exposure to an aggressive male mouse for about two weeks — the degree to which the prefrontal cortex seemed to control amygdala activity was related to how well the animals coped with the stress, the group found.

Next the group looked at how the brain reacted to the first instance of stress, before the mice were put in a chronically stressful situation. The mice more sensitive to chronic stress showed greater activation of their prefrontal cortex-amygdala circuit, compared with resilient mice.

“We were really both surprised and excited to find that this signature was present in the animals before they were chronically stressed,” Dzirasa said. “You can find this signature the very first time they were ever exposed to this aggressive dangerous experience.”

Dzirasa hopes to use the signatures to come up with potential treatments for stress. “If we pair the signatures and treatments together, can we prevent symptoms from emerging, even when an animal is stressed? That’s the first question,” he said.

The group also hopes to delve further into the brain, to see whether the circuit-level patterns can interact with genetic variations that confer risk for psychiatric disorders such as schizophrenia. The new study will enable Dzirasa and other basic researchers to segregate stress-susceptible and resilient animals before they are subjected to stress and look at their molecular, cellular and systemic differences.

By studying the injuries and aptitudes of Vietnam War veterans who suffered penetrating head wounds during the war, scientists are tackling — and beginning to answer — longstanding questions about how the brain works.

The researchers found that brain regions that contribute to optimal social functioning also are vital to general intelligence and to emotional intelligence. This finding bolsters the view that general intelligence emerges from the emotional and social context of one’s life.

The findings are reported in the journal Brain.

“We are trying to understand the nature of general intelligence and to what extent our intellectual abilities are grounded in social cognitive abilities,” said Aron Barbey, a University of Illinois professor of neuroscience, of psychology, and of speech and hearing science. Barbey (bar-BAY), an affiliate of the Beckman Institute and of the Institute for Genomic Biology at the U. of I., led the new study with an international team of collaborators.

Studies in social psychology indicate that human intellectual functions originate from the social context of everyday life, Barbey said.

“We depend at an early stage of our development on social relationships — those who love us care for us when we would otherwise be helpless,” he said.

Social interdependence continues into adulthood and remains important throughout the lifespan, Barbey said.

“Our friends and family tell us when we could make bad mistakes and sometimes rescue us when we do,” he said. “And so the idea is that the ability to establish social relationships and to navigate the social world is not secondary to a more general cognitive capacity for intellectual function, but that it may be the other way around. Intelligence may originate from the central role of relationships in human life and therefore may be tied to social and emotional capacities.”

The study involved 144 Vietnam veterans injured by shrapnel or bullets that penetrated the skull, damaging distinct brain tissues while leaving neighboring tissues intact. Using CT scans, the scientists painstakingly mapped the affected brain regions of each participant, then pooled the data to build a collective map of the brain.

The researchers used a battery of carefully designed tests to assess participants’ intellectual, emotional and social capabilities. They then looked for patterns that tied damage to specific brain regions to deficits in the participants’ ability to navigate the intellectual, emotional or social realms. Social problem solving in this analysis primarily involved conflict resolution with friends, family and peers at work.

As in their earlier studies of general intelligence and emotional intelligence, the researchers found that regions of the frontal cortex (at the front of the brain), the parietal cortex (further back near the top of the head) and the temporal lobes (on the sides of the head behind the ears) are all implicated in social problem solving. The regions that contributed to social functioning in the parietal and temporal lobes were located only in the brain’s left hemisphere, while both left and right frontal lobes were involved.

The brain networks found to be important to social adeptness were not identical to those that contribute to general intelligence or emotional intelligence, but there was significant overlap, Barbey said.

“The evidence suggests that there’s an integrated information-processing architecture in the brain, that social problem solving depends upon mechanisms that are engaged for general intelligence and emotional intelligence,” he said. “This is consistent with the idea that intelligence depends to a large extent on social and emotional abilities, and we should think about intelligence in an integrated fashion rather than making a clear distinction between cognition and emotion and social processing. This makes sense because our lives are fundamentally social — we direct most of our efforts to understanding others and resolving social conflict. And our study suggests that the architecture of intelligence in the brain may be fundamentally social, too.”

U of T researchers have found a missing link that helps to explain how ALS, one of the world’s most feared diseases, paralyses and ultimately kills its victims. The breakthrough is helping them trace a path to a treatment or even a cure.

“ALS research has been taking baby steps for decades, but this has recently started changing to giant leaps,” said Karim Mekhail, professor in the Faculty of Medicine’s Department of Laboratory Medicine and Pathobiology.  “The disease is linked to a large number of genes, and previously, every time someone studied one of them, it took them off in a different direction. Nobody could figure out how they were all connected.”

Mekhail and his team discovered the function of a crucial gene called PBP1 or ATAXIN2 that’s often missing in ALS, also known as Lou Gehrig’s Disease.  Learning how this gene functions has helped them connect a lot of dots.

“This is an extremely important finding that may help us to better understand and target the pathways involved in neurodegenerative disease,” said Lorne Zinman, professor of medicine at U of T and medical director of the ALS/Neuromuscular Clinic at Sunnybrook Health Sciences Centre. “The next step will be to determine if this finding is applicable to patients with ALS.”

The key lies in a peculiarity of the human genome. It starts with the DNA, the blueprint that contains all our genetic information. The DNA passes its information to the RNA, which floats off to make proteins that help run our bodies. However, without ATAXIN2, the RNA fails to float away. It becomes glued to the DNA and forms RNA-DNA hybrids, said Mekhail. These hybrids gum up the works and stop other RNA from fully forming. Pieces of half-created RNA debris clutter the cell, and cause more hybrids.

“We think the debris and hybrids are on the same team in a never-ending Olympic relay race,” said Mekhail. “Over time there’s a vicious cycle building up. If we can find a way to disrupt that cycle, theoretically we can control or reverse the disease.”

On that front, Mekhail made a very surprising discovery: reducing calories to the minimum necessary amount stops the hybrids from forming in cells missing ATAXIN2. He and his team are studying whether a simple, non-toxic dietary restriction could be used with ALS patients, especially in the early stages or for those at risk of ALS.

Mekhail discovered the hybrids and missing genes in yeast cells and his results were published as the cover article for the July 28 edition of the journal Developmental Cell. Now his team is replicating this research on tissue from ALS patients – with very encouraging preliminary results.

“Within the next decade or two, I think there’s going to be a revolution in treatment for ALS and all kinds of brain disease,” he said. “These hybrids are going to play a role not just in ALS but in a lot of disease.”

Babies can learn what to fear in the first days of life just by smelling the odor of their distressed mothers, new research suggests. And not just “natural” fears: If a mother experienced something before pregnancy that made her fear something specific, her baby will quickly learn to fear it too — through the odor she gives off when she feels fear.

In the first direct observation of this kind of fear transmission, a team of University of Michigan Medical School and New York University studied mother rats who had learned to fear the smell of peppermint – and showed how they “taught” this fear to their babies in their first days of life through their alarm odor released during distress.

In a new paper in the Proceedings of the National Academy of Sciences, the team reports how they pinpointed the specific area of the brain where this fear transmission takes root in the earliest days of life.

Their findings in animals may help explain a phenomenon that has puzzled mental health experts for generations: how a mother’s traumatic experience can affect her children in profound ways, even when it happened long before they were born. 

The researchers also hope their work will lead to better understanding of why not all children of traumatized mothers, or of mothers with major phobias, other anxiety disorders or major depression, experience the same effects.

“During the early days of an infant rat’s life, they are immune to learning information about environmental dangers. But if their mother is the source of threat information, we have shown they can learn from her and produce lasting memories,” says Jacek Debiec, M.D., Ph.D., the U-M psychiatrist and neuroscientist who led the research.  

“Our research demonstrates that infants can learn from maternal expression of fear, very early in life,” he adds. “Before they can even make their own experiences, they basically acquire their mothers’ experiences. Most importantly, these maternally-transmitted memories are long-lived, whereas other types of infant learning, if not repeated, rapidly perish.”

Peering inside the fearful brain

Debiec, who treats children and mothers with anxiety and other conditions in the U-M Department of Psychiatry, notes that the research on rats allows scientists to see what’s going on inside the brain during fear transmission, in ways they could never do in humans.

He began the research during his fellowship at NYU with Regina Marie Sullivan, Ph.D., senior author of the new paper, and continues it in his new lab at U-M’s Molecular and Behavioral Neuroscience Institute.

The researchers taught female rats to fear the smell of peppermint by exposing them to mild, unpleasant electric shocks while they smelled the scent, before they were pregnant. Then after they gave birth, the team exposed the mothers to just the minty smell, without the shocks, to provoke the fear response. They also used a comparison group of female rats that didn’t fear peppermint.

They exposed the pups of both groups of mothers to the peppermint smell, under many different conditions with and without their mothers present.

Using special brain imaging, and studies of genetic activity in individual brain cells and cortisol in the blood, they zeroed in on a brain structure called the lateral amygdala as the key location for learning fears. During later life, this area is key to detecting and planning response to threats – so it makes sense that it would also be the hub for learning new fears.

But the fact that these fears could be learned in a way that lasted, during a time when the baby rat’s ability to learn any fears directly was naturally suppressed, is what makes the new findings so interesting, says Debiec.

The team even showed that the newborns could learn their mothers’ fears even when the mothers weren’t present. Just the piped-in scent of their mother reacting to the peppermint odor she feared was enough to make them fear the same thing.

Even when just the odor of the frightened mother was piped in to a chamber where baby rats were exposed to peppermint smell, the babies developed a fear of the same smell, and their blood cortisol levels rose when they smelled it.

And when the researchers gave the baby rats a substance that blocked activity in the amygdala, they failed to learn the fear of peppermint smell from their mothers. This suggests, Debiec says, that there may be ways to intervene to prevent children from learning irrational or harmful fear responses from their mothers, or reduce their impact.

 From animals to humans: next steps

The new research builds on what scientists have learned over time about the fear circuitry in the brain, and what can go wrong with it. That work has helped psychiatrists develop new treatments for human patients with phobias and other anxiety disorders – for instance, exposure therapy that helps them overcome fears by gradually confronting the thing or experience that causes their fear.

In much the same way, Debiec hopes that exploring the roots of fear in infancy, and how maternal trauma can affect subsequent generations, could help human patients. While it’s too soon to know if the same odor-based effect happens between human mothers and babies, the role of a mother’s scent in calming human babies has been shown.

Debiec, who hails from Poland, recalls working with the grown children of Holocaust survivors, who experienced nightmares, avoidance instincts and even flashbacks related to traumatic experiences they never had themselves. While they would have learned about the Holocaust from their parents, this deeply ingrained fear suggests something more at work, he says.

An evolutionarily ancient and tiny part of the brain tracks expectations about nasty events, finds new UCL research.

The study, published in Proceedings of the National Academy of Sciences, demonstrates for the first time that the human habenula, half the size of a pea, tracks predictions about negative events, like painful electric shocks, suggesting a role in learning from bad experiences.

Brain scans from 23 healthy volunteers showed that the habenula activates in response to pictures associated with painful electric shocks, with the opposite occurring for pictures that predicted winning money.

Previous studies in animals have found that habenula activity leads to avoidance as it suppresses dopamine, a brain chemical that drives motivation. In animals, habenula cells have been found to fire when bad things happen or are anticipated.

"The habenula tracks our experiences, responding more the worse something is expected to be," says senior author Dr Jonathan Roiser of the UCL Institute of Cognitive Neuroscience. "For example, the habenula responds much more strongly when an electric shock is almost certain than when it is unlikely. In this study we showed that the habenula doesn’t just express whether something leads to negative events or not; it signals quite how much bad outcomes are expected."

During the experiment, healthy volunteers were placed inside a functional magnetic resonance imaging (fMRI) scanner, and brain images were collected at high resolution because the habenula is so small. Volunteers were shown a random sequence of pictures each followed by a set chance of a good or bad outcome, occasionally pressing a button simply to show they were paying attention. Habenula activation tracked the changing expectation of bad and good events.

"Fascinatingly, people were slower to press the button when the picture was associated with getting shocked, even though their response had no bearing on the outcome." says lead author Dr Rebecca Lawson, also at the UCL Institute of Cognitive Neuroscience. "Furthermore, the slower people responded, the more reliably their habenula tracked associations with shocks. This demonstrates a crucial link between the habenula and motivated behaviour, which may be the result of dopamine suppression."

The habenula has previously been linked to depression, and this study shows how it could be involved in causing symptoms such low motivation, pessimism and a focus on negative experiences. A hyperactive habenula could cause people to make disproportionately negative predictions.

"Other work shows that ketamine, which has profound and immediate benefits in patients who failed to respond to standard antidepressant medication, specifically dampens down habenula activity," says Dr Roiser. "Therefore, understanding the habenula could help us to develop better treatments for treatment-resistant depression."

A study involving nearly 27,000 older adults on five continents found that nearly 1 in 10 met criteria for pre-dementia based on a simple test that measures how fast people walk and whether they have cognitive complaints. People who tested positive for pre-dementia were twice as likely as others to develop dementia within 12 years. The study, led by scientists at Albert Einstein College of Medicine of Yeshiva University and Montefiore Medical Center, was published online on July 16, 2014 in Neurology®, the medical journal of the American Academy of Neurology.

The new test diagnoses motoric cognitive risk syndrome (MCR). Testing for the newly described syndrome relies on measuring gait speed (our manner of walking) and asking a few simple questions about a patient’s cognitive abilities, both of which take just seconds. The test is not reliant on the latest medical technology and can be done in a clinical setting, diagnosing people in the early stages of the dementia process. Early diagnosis is critical because it allows time to identify and possibly treat the underlying causes of the disease, which may delay or even prevent the onset of dementia in some cases.

“In many clinical and community settings, people don’t have access to the sophisticated tests—biomarker assays, cognitive tests or neuroimaging studies—used to diagnose people at risk for developing dementia,” said Joe Verghese, M.B.B.S., professor in the Saul R. Korey Department of Neurology and of medicine at Einstein, chief of geriatrics at Einstein and Montefiore, and senior author of the Neurology paper. “Our assessment method could enable many more people to learn if they’re at risk for dementia, since it avoids the need for complex testing and doesn’t require that the test be administered by a neurologist. The potential payoff could be tremendous—not only for individuals and their families, but also in terms of healthcare savings for society. All that’s needed to assess MCR is a stopwatch and a few questions, so primary care physicians could easily incorporate it into examinations of their older patients.”

The U.S. Centers for Disease Control and Prevention estimates that up to 5.3 million Americans—about 1 in 9 people age 65 and over—have Alzheimer’s disease, the most common type of dementia. That number is expected to more than double by 2050 due to population aging.

“As a young researcher, I examined hundreds of patients and noticed that if an older person was walking slowly, there was a good chance that his cognitive tests were also abnormal,” said Dr. Verghese, who is also the Murray D. Gross Memorial Faculty Scholar in Gerontology at Einstein. “This gave me the idea that perhaps we could use this simple clinical sign—how fast someone walks—to predict who would develop dementia. In a 2002 New England Journal of Medicine study, we reported that abnormal gait patterns accurately predict whether people will go on to develop dementia. MCR improves on the slow gait concept by evaluating not only patients’ gait speed but also whether they have cognitive complaints.”

The Neurology paper reported on the prevalence of MCR among 26,802 adults without dementia or disability aged 60 years and older enrolled in 22 studies in 17 countries. A significant number of adults—9.7 percent—met the criteria for MCR (i.e., abnormally slow gait and cognitive complaints). While the syndrome was equally common in men and women, highly educated people were less likely to test positive for MCR compared with less-educated individuals. A slow gait, said Dr. Verghese, is a walking speed slower than about one meter per second, which is about 2.2 miles per hour (m.p.h.). Less than 0.6 meters per second (or 1.3 m.p.h.) is “clearly abnormal.”

To test whether MCR predicts future dementia, the researchers focused on four of the 22 studies that tested a total of 4,812 people for MCR and then evaluated them annually over an average follow-up period of 12 years to see which ones developed dementia. Those who met the criteria for MCR were nearly twice as likely to develop dementia over the following 12 years compared with people who did not.

Dr. Verghese emphasized that a slow gait alone is not sufficient for a diagnosis of MCR. “Walking slowly could be due to conditions such as arthritis or an inner ear problem that affects balance, which would not increase risk for dementia. To meet the criteria for MCR requires having a slow gait and cognitive problems. An example would be answering ‘yes’ to the question, ‘Do you think you have more memory problems than other people?’”

For patients meeting MCR criteria, said Dr. Verghese, the next step is to look for the causes of their slow gait and cognitive complaints. The search may reveal underlying—and controllable—problems. “Evidence increasingly suggests that brain health is closely tied to cardiovascular health—meaning that treatable conditions such as hypertension, smoking, high cholesterol, obesity and diabetes can interfere with blood flow to the brain and thereby increase a person’s risk for developing Alzheimer’s and other dementias,” said Dr. Verghese.

What about people who meet MCR criteria but no treatable underlying problems can be found?

“Even in the absence of a specific cause, we know that most healthy lifestyle factors, such as exercising and eating healthier, have been shown to reduce the rate of cognitive decline,” said Dr. Verghese. “In addition, our group has shown that cognitively stimulating activities—playing board games, card games, reading, writing and also dancing—can delay dementia’s onset. Knowing they’re at high risk for dementia can also help people and their families make arrangements for the future, which is an aspect of MCR testing that I’ve found is very important in my own clinical practice.”

Boston University School of Medicine researchers may have found a way to delay or even prevent Alzheimer’s disease (AD). They discovered that pre-treatment of neurons with the anti-aging protein Klotho can prevent neuron death in the presence of the toxic amyloid protein and glutamate. These findings currently appear in the Journal of Biological Chemistry.

Alzheimer’s disease is the most frequent age-related dementia affecting 5.4 million Americans including 13 percent of people age 65 and older and more than 40 percent of people over the age of 85. In AD the cognitive decline and dementia result from the death of nerve cells that are involved in learning and memory. The amyloid protein and the excess of the neurotransmitter, glutamate are partially responsible for the neuronal demise.

Nerve cells were grown in petri dishes and treated with or without Klotho for four hours. Amyloid or glutamate then were added to the dish for 24 hours. In the dishes where Klotho was added, a much higher percentage of neurons survived than in the dishes without Klotho.

"Finding a neuroprotective agent that will protect nerve cells from amyloid that accumulates as a function of age in the brain is novel and of major importance," explained corresponding author Carmela R. Abraham, PhD, professor of biochemistry and pharmacology at BUSM. "We now have evidence that if more Klotho is present in the brain, it will protect the neurons from the oxidative stress induced by amyloid and glutamate.

According to the researchers, Klotho is a large protein that cannot penetrate the blood brain barrier so it can’t be administered by mouth or injection. However in a separate study the researchers have identified small molecules that can enter the brain and increase the levels of Klotho. “We believe that increasing Klotho levels with such compounds would improve the outcome for Alzheimer’s patients, and if started early enough would prevent further deterioration. This potential treatment has implications for other neurodegenerative diseases such as Parkinson’s, Huntington’s, ALS and brain trauma, as well,” added Abraham.

An experimental anti-inflammatory drug can protect vulnerable neurons and reduce motor deficits in a rat model of Parkinson’s disease, researchers at Emory University School of Medicine have shown.

The results were published Thursday, July 24 in the Journal of Parkinson’s Disease.

The findings demonstrate that the drug, called XPro1595, can reach the brain at sufficient levels and have beneficial effects when administered by subcutaneous injection, like an insulin shot. Previous studies of XPro1595 in animals tested more invasive modes of delivery, such as direct injection into the brain.

“This is an important step forward for anti-inflammatory therapies for Parkinson’s disease,” says Malu Tansey, PhD, associate professor of physiology at Emory University School of Medicine. “Our results provide a compelling rationale for moving toward a clinical trial in early Parkinson’s disease patients.”

The new research on subcutaneous administration of XPro1595 was funded by the Michael J. Fox Foundation for Parkinson’s Research (MJFF). XPro1595 is licensed by FPRT Bio, and is seeking funding for a clinical trial to test its efficacy in the early stages of Parkinson’s disease.

“We are proud to have supported this work and glad to see positive pre-clinical results,” said Marco Baptista, PhD, MJFF associate director of research programs. “A therapy that could slow Parkinson’s progression would be a game changer for the millions living with this disease, and this study is a step in that direction.”

In addition, Tansey and Yoland Smith, PhD, from Yerkes National Primate Research Center, were awarded a grant this week from the Parkinson’s Disease Foundation to test XPro1595 in a non-human primate model of Parkinson’s.

Evidence has been piling up that inflammation is an important mechanism driving the progression of Parkinson’s disease. XPro1595 targets tumor necrosis factor (TNF), a critical inflammatory signaling molecule, and is specific to the soluble form of TNF. This specificity would avoid compromising immunity to infections, a known side effect of existing anti-TNF drugs used to treat disorders such as rheumatoid arthritis.

“Inflammation is probably not the initiating event in Parkinson’s disease, but it is important for the neurodegeneration that follows,” Tansey says. “That’s why we believe that an anti-inflammatory agent, such as one that counteracts soluble TNF, could substantially slow the progression of the disease.”

Postdoctoral fellow Christopher Barnum, PhD and colleagues used a model of Parkinson’s disease in rats in which the neurotoxin 6-hydroxydopamine (6-OHDA) is injected into only one side of the brain. This reproduces some aspects of Parkinson’s disease: neurons that produce dopamine in the injected side of the brain die, leading to impaired movement on the opposite side of the body.

When XPro1595 is given to the animals 3 days after 6-OHDA injection, just 15 percent of the dopamine-producing neurons were lost five weeks later. That compares to controls in which 55 percent of the same neurons were lost. By reducing dopamine neuron loss with XPro1595, the researchers were also able to reduce motor impairment. In fact, the degree of dopamine cell loss was highly correlated both with the degree of motor impairment and immune cell activation.

When XPro1595 is given two weeks after injection, 44 percent of the vulnerable neurons are still lost, suggesting that there is a limited window of opportunity to intervene.

“Recent clinical studies indicates there is a four or five year window between diagnosis of Parkinson’s disease and the time when the maximum number of vulnerable neurons are lost,” Dr. Tansey says. “If this is true, and if inflammation is playing a key role during this window, then we might be able to slow or halt the progression of Parkinson’s with a treatment like XPro1595.”

Early life experiences, such as childhood socioeconomic status and literacy, may have greater influence on the risk of cognitive impairment late in life than such demographic characteristics as race and ethnicity, a large study by researchers with the UC Davis Alzheimer’s Disease Center and the University of Victoria, Canada, has found.

“Declining cognitive function in older adults is a major personal and public health concern,” said Bruce Reed professor of neurology and associate director of the UC Davis Alzheimer’s Disease Center.

“But not all people lose cognitive function, and understanding the remarkable variability in cognitive trajectories as people age is of critical importance for prevention, treatment and planning to promote successful cognitive aging and minimize problems associated with cognitive decline.”

The study, “Life Experiences and Demographic Influences on Cognitive Function in Older Adults,” is published online in Neuropsychology, a journal of the American Psychological Association. It is one of the first comprehensive examinations of the multiple influences of varied demographic factors early in life and their relationship to cognitive aging.

The research was conducted in a group of over 300 diverse men and women who spoke either English or Spanish. They were recruited from senior citizen social, recreational and residential centers, as well as churches and health-care settings. At the time of recruitment, all study participants were 60 or older, and had no major psychiatric illnesses or life threatening medical illnesses. Participants were Caucasian, African-American or Hispanic.

The extensive testing included multidisciplinary diagnostic evaluations through the UC Davis Alzheimer’s Disease Center in either English or Spanish, which permitted comparisons across a diverse cohort of participants.

Consistent with previous research, the study found that non-Latino Caucasians scored 20 to 25 percent higher on tests of semantic memory (general knowledge) and 13 to 15 percent higher on tests of executive functioning compared to the other ethnic groups. However, ethnic differences in executive functioning disappeared and differences in semantic memory were reduced by 20 to 30 percent when group differences in childhood socioeconomic status, adult literacy and extent of physical activity during adulthood were considered. 

“This study is unusual in that it examines how many different life experiences affect cognitive decline in late life,” said Dan Mungas, professor of neurology and associate director of the UC Davis Alzheimer’s Disease Research Center. 

“It shows that variables like ethnicity and years of education that influence cognitive test scores in a single evaluation are not associated with rate of cognitive decline, but that specific life experiences like level of reading attainment and intellectually stimulating activities are predictive of the rate of late-life cognitive decline. This suggests that intellectual stimulation throughout the life span can reduce cognitive decline in old age.”

Regardless of ethnicity, advanced age and apolipoprotein-E (APOE genotype) were associated with increased cognitive decline over an average of four years that participants were followed. APOE is the largest known genetic risk factor for late-onset Alzheimer’s. Less decline was experienced by persons who reported more engagement in recreational activities in late life and who maintained their levels of activity engagement from middle age to old age. Single-word reading — the ability to decode a word on sight, which often is considered an indication of quality of educational experience — was also associated with less cognitive decline, a finding that was true for both English and Spanish readers, irrespective of their race or ethnicity. These findings suggest that early life experiences affect late-life cognition indirectly, through literacy and late-life recreational pursuits, the authors said.

“These findings are important,” explained Paul Brewster, lead author of the study, a doctoral student at the University of Victoria, Canada, and a pre-doctoral psychology intern at the UC San Diego Department of Psychiatry, “because it challenges earlier research that suggests associations between race and ethnicity, particularly among Latinos, and an increased risk of late-life cognitive impairment and dementia.

”Our findings suggest that the influences of demographic factors on late-life cognition may be reflective of broader socioeconomic factors, such as educational opportunity and related differences in physical and mental activity across the life span.”

Researchers at UC San Francisco have discovered that endostatin, a protein that once aroused intense interest as a possible cancer treatment, plays a key role in the stable functioning of the nervous system.

A substance that occurs naturally in the body, endostatin potently blocks the formation of new blood vessels. In studies in mice in the late 1990s, endostatin treatment virtually eliminated cancer by shutting down the blood supply to tumors, but subsequent human clinical trials proved disappointing.

“It was a very big surprise” to find that endostatin, through some other mechanism, helps to maintain the proper workings of synapses, the sites where communication between nerve cells takes place, said Graeme W. Davis, PhD, Hertzstein Distinguished Professor of Medicine in the Department of Biochemistry and Biophysics at UCSF and senior author of the new study. “Endostatin was not on our radar.”

The findings were reported online July 24 in the journal Neuron.

Synapses are continually shaped and reshaped by experience, a phenomenon known as plasticity. But for those changes to be meaningful, said Davis, they must take place against a stable background, which paradoxically requires another form of change that he and colleagues call “homeostatic plasticity.” Just as we change our pace, slowing down or speeding up, to keep abreast of a running partner, neurons adjust aspects of their function at synapses to compensate for changes in their synaptic partners brought on by aging, illness, or other factors.

In an example of homeostatic plasticity, in the neuromuscular disease myasthenia gravis, as muscle cells become less responsive to the neurotransmitter acetylcholine, nerve cells ramp up their secretion of the neurotransmitter to keep the system in balance for as long as possible. Some researchers believe that in other disorders, including autism and schizophrenia, a failure in such homeostatic mechanisms keeps synapses from functioning properly.

In previous research Davis noticed that applying a toxin to a muscle cell in the fruit fly Drosophila melanogaster triggers homeostatic plasticity in the neuron that forms a synapse on that muscle cell: the neuron—which is called presynaptic, because it is “before” the synapse with the muscle cell—reliably releases more neurotransmitter, just as happens when muscle cells begin to malfunction in myasthenia gravis.

Davis has since built on this model of homeostatic plasticity by painstakingly knocking out Drosophila genes one by one and recording from presynaptic neurons to see which genes are necessary for the homeostatic response, because it is these genes that may be compromised in diseases affecting the process.

“So far we’ve tested about 1,000 genes this way, which has entailed close to 10,000 recordings,” Davis said.

Using this technique Davis and colleagues observed at one point that knocking out a gene called multiplexin significantly hampered homeostatic plasticity in presynaptic neurons. But because that gene helps to form a structural protein known as collagen—which in humans is a component of ligaments, tendons, and cartilage—the finding wasn’t immediately considered relevant to synaptic function.

The team learned that the multiplexin protein can be snipped by an enzyme to produce endostatin, so in experiments led by postdoctoral fellow Tingting Wang, PhD, they tested whether endostatin might play a role in homeostatic plasticity.

“Nobody picked up multiplexin to work on for a couple of years, because we didn’t think a collagen could be that interesting,” Davis said. “Then, when a new postdoc, Tingting Wang, came to the lab, we started thinking about it harder.”

When the group genetically deleted the portion of Drosophila multiplexin that forms endostatin, presynaptic neurons behaved normally, but homeostatic plasticity was severely compromised when toxin was applied to postsynaptic muscle cells. On the opposite side of the coin, when the team overexpressed endostatin at Drosophila synapses lacking multiplexin, homeostasis was restored, whether endostatin was expressed in muscle cells or presynaptic neurons.

The research team is unsure precisely how and where endostatin exerts its effects on homeostatic plasticity, but they believe that multiplexin is cleaved at the postsynaptic site to form endostatin, and that the endostatin signal is conveyed to the presynaptic neuron to alter its function. “Because so many people in the cancer world have studied endostatin, there is a great set of tools available” to study the protein, Davis said, so he expects his group to make rapid progress in addressing these questions.

“Despite its checkered history in cancer, we know endostatin is a signaling molecule and we know that the brain has a great deal of collagen—we just haven’t known what it does, and we certainly don’t know what endostatin’s receptors in the brain might be.” Davis said. “But it’s pretty exciting to think about a new signaling molecule with a profound role in the stabilization of the function of neural circuits.”