Resurrecting the So-Called 'Depression Gene'::Genes May Play Role in Response to Adversity

Resurrecting the So-Called 'Depression Gene'::Genes May Play Role in Response to Adversity

  8:01:00 PM    Science Lover

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University of Michigan Health System researchers have found new evidence that our genes help determine our susceptibility to depression.

Our genes help determine our susceptibility to depression, 
new research suggests. (Credit: iStockphoto/
Nicholas Belton)

Their findings, published online in the Archives of General Psychiatry, challenge a 2009 study that called the genetic link into question and add new support to earlier research hailed as a medical breakthrough.

In the summer of 2003, scientists announced they had discovered a connection between a gene that regulates the neurotransmitter serotonin and an individual's ability to rebound from serious emotional trauma, such as childhood physical or sexual abuse.

The journal Science ranked the findings among the top discoveries of the year and the director of the National Institute of Mental Health proclaimed, "It is a very important discovery and a real advance for the field."

That excitement was dampened in 2009, however, after the research was called into question by a study published in the Journal of the American Medical Association. The New York Times reported that analysis, which examined results from 14 different studies, showed the initial findings had "not held up to scientific scrutiny."

Srijan Sen, M.D., Ph.D, an assistant professor of psychiatry at the University of Michigan Medical School, and his colleagues are presenting a new, broader analysis of the follow-up studies to date. The U-M team examined 54 studies dating from 2001 to 2010 and encompassing nearly 41,000 participants -- making it the largest analysis of the serotonin gene's relationship to depression.

"When we included all the relevant studies, we found that an individual's genetic make-up does make a difference in how he or she responds to stress," says Sen.

The U-M analysis supports previous findings that individuals who had a short allele on a particular area the serotonin gene had a harder time bouncing back from trauma than those with long alleles.

Rudolf Uher, Ph.D., a clinical lecturer at the Institute of Psychiatry in London, says the U-M research will help cut through the debate about the genetic connection and refocus the field on making new advances to help those affected by mental illness.

"The major strength of the analysis is that it is the first such work that included all studies that were available on the topic," Uher says. "And it gives a very clear answer: the 'short' variant of the serotonin transporter does make people more sensitive to the effects of adversity."

The authors of the initial study from 2003 were also excited by the U-M team's results.

"Their careful and systematic approach reveals why the JAMA meta-analysis got it wrong," says Terrie Moffitt, Ph.D., a professor at Duke University and one of the authors of the 2003 study. "We hope that the same journalists who were so hasty to publish a simplistic claim in 2009 will cover this more thoughtful new analysis."

When the U-M team restricted their analysis to the 14 studies included in the 2009 JAMA paper, they also failed to find a genetic link, suggesting to Sen that the scope of the analysis, not the methodology, was responsible for the new findings.

The U-M analysis found robust support for the link between sensitivity to stress and a short allele in those who had been mistreated as children and in people suffering with specific, severe medical conditions. Only a marginal relationship was found in those who had undergone stressful life events.

But that's also common sense. Different stressful life events may have very different effects, Sen says. For instance, there is no reason to think that the effects of divorce, at a biological level, would be similar to the effects of losing your home or being physically assaulted.

Still, the study results don't mean that everyone should run out and get a genetic test; additional susceptibility from having a short allele is only one factor among many that determine how an individual responds to stress, Sen says.

Additional research will help to map an individual's genetic profile for depression.

"This brings us one step closer to being able to identify individuals who might benefit from early interventions or to tailor treatments to specific individuals," Sen says.

Funding: The research was supported by grants from the National Institutes of Health, University of Michigan Depression Center and Studienstiftung des Deutschen Volkes.

Additional U-M Authors: Margit Burmeister, Ph.D., Kerby Shedden, Ph.D., former graduate student Katja Karg

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ADHD Is a Genetic Disorder Children With ADHD More Likely to Have Missing or Duplicated Segments of DNA

ADHD Is a Genetic Disorder Children With ADHD More Likely to Have Missing or Duplicated Segments of DNA

  10:23:00 AM    Science Lover

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New research provides the first direct evidence that attention-deficit/hyperactivity disorder (ADHD) is a genetic condition. Scientists at Cardiff University found that children with ADHD were more likely to have small segments of their DNA duplicated or missing than other children.

In a new study, children with ADHD were more likely to have small segments of their DNA duplicated or missing than other children. (Credit: iStockphoto/Zmeel Photography)

The study also found significant overlap between these segments, known as copy number variants (CNVs), and genetic variants implicated in autism and schizophrenia, proving strong evidence that ADHD is a neurodevelopmental disorder -- in other words, that the brains of children with the disorder differ from those of other children.

The research, published in the journal The Lancet, was largely funded by the Wellcome Trust, with additional support from Action Medical Research, the Medical Research Council and the European Union.

"We hope that these findings will help overcome the stigma associated with ADHD," says Professor Anita Thapar. "Too often, people dismiss ADHD as being down to bad parenting or poor diet. As a clinician, it was clear to me that this was unlikely to be the case. Now we can say with confidence that ADHD is a genetic disease and that the brains of children with this condition develop differently to those of other children."

ADHD is one of the most common mental health disorders in childhood, affecting around one in 50 children in the UK. Children with ADHD are excessively restless, impulsive and distractible, and experience difficulties at home and in school. Although no cure exists for the condition, symptoms can be reduced by a combination of medication and behavioural therapy.

The condition is highly heritable -- children with ADHD are statistically more likely to also have a parent with the condition and a child with an identical twin with ADHD has a three in four chance of also having the condition. Even so, until now there has been no direct evidence that the condition is genetic and there has been much controversy surrounding its causes, which some people have put down to poor parenting skills or a sugar-rich diet.

The team at Cardiff University analysed the genomes of 366 children, all of whom had been given a clinical diagnosis of ADHD, against over 1,000 control samples in search of variations in their genetic make-up that were more common in children with the condition.

"Children with ADHD have a significantly higher rate of missing or duplicated DNA segments compared to other children and we have seen a clear genetic link between these segments and other brain disorders," explains Dr Nigel Williams. "These findings give us tantalising clues to the changes that can lead to ADHD."

The researchers found that rare CNVs were almost twice as common in children with ADHD compared to the control sample -- and even higher for children with learning difficulties. CNVs are particularly common in disorders of the brain.

There was also significant overlap between CNVs identified in children with ADHD and regions of the genome which are known to influence susceptibility to autism and schizophrenia. Whilst these disorders are currently thought to be entirely separate, there is some overlap between ADHD and autism in terms of symptoms and learning difficulties. This new research suggests there may be a shared biological basis to the two conditions.

The most significant overlap was found at a particular region on chromosome 16 which has been previously implicated in schizophrenia and other major psychiatric disorders and spans a number of genes including one known to play a role in the development of the brain .

"ADHD is not caused by a single genetic change, but is likely caused by a number of genetic changes, including CNVs, interacting with a child's environment," explains Dr Kate Langley. "Screening children for the CNVs that we have identified will not help diagnose their condition. We already have very rigorous clinical assessments to do just that."

Dr John Williams, Head of Neuroscience and Mental Health at the Wellcome Trust, which has supported Professor Thapar's work for ten years, says: "These findings are testament to the perseverance of Professor Thapar and colleagues to prove the often unfashionable theory that ADHD is a brain disorder with genetic links. Using leading-edge technology, they have begun to shed light on the causes of what is a complex and often distressing disorder for both the children and their families."

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Mental Maturity Scan Tracks Brain Development

Mental Maturity Scan Tracks Brain Development

  9:26:00 PM    Science Lover

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Five minutes in a scanner can reveal how far a child's brain has come along the path from childhood to maturity and potentially shed light on a range of psychological and developmental disorders, scientists at Washington University School of Medicine in St. Louis have shown.

Researchers have shown that functional brain 
networks have the potential to help physicians 
probe psychiatric and developmental disorders. 
In this graphic, the brain regions that are important 
to assessing the maturity of the brain are shown as 
spheres, with the size of the sphere representing the 
region's relative importance. Different sphere colors 
identify brain regions as members of different
functional networks. The orange connections 
strengthen and the green connections weaken as the 
brain progresses toward adulthood. (Credit: 
Image courtesy of Washington University 
School of Medicine)

Researchers assert in Science that their study proves brain imaging data can offer more extensive help in tracking aberrant brain development.

"Pediatricians regularly plot where their patients are in terms of height, weight and other measures, and then match these up to standardized curves that track typical developmental pathways," says senior author Bradley Schlaggar, MD, PhD, a Washington University pediatric neurologist. "When the patient deviates too strongly from the standardized ranges or veers suddenly from one developmental path to another, the physician knows there's a need to start asking why."

Schlaggar and his colleagues say a new way of looking at brain scanning data may be able to provide similar guidance for monitoring and treating of patients with psychiatric and developmental disorders.

Schlaggar, the A. Ernest and Jane G. Stein Associate Professor of Neurology, says he has sent children with obvious, profound psychiatric conditions for MRI scans and received results marked "no abnormalities noted."

"That's typically looking at the data from a structural point of view -- what's different about the shapes of various brain regions," he says. "But MRI also offers ways to analyze how different parts of the brain work together functionally."

Compare functional data to standardized models of how brain function or disease normally develops, Schlaggar says, and a range of new clinical insights becomes available.

Schlaggar and his colleagues use an approach to brain scanning called resting state functional connectivity. By correlating increases and decreases in blood flow to the various brain regions as subjects rest in the scanner, scientists determine which of these regions work together in brain networks.

In a study published in 2009, Washington University scientists showed that as the brain matures, these brain networks change. The overall organization switches from networks involving regions physically close to each other, which is the dominant motif in a child's brain, to networks that connect distant regions, the primary organizational principal in adult brains.

For the new study, lead author Nico Dosenbach, MD, PhD, a pediatric neurology resident at St. Louis Children's Hospital, took this and other distinctions that mark the transition from child to adult brain and adapted them for use in a technique for mathematical analysis called a support vector machine. The technique is employed in many contexts in science and economics and on the Internet.

"It's a way that mathematicians have developed for predicting something with high specificity and sensitivity when you have huge amounts of data instead of one really good measurement," Dosenbach explains. "Any one of these measurements doesn't tell you much, but if you put them together and use the right math to sift through and restructure them, you can get good predictive results."

Dosenbach used data from five-minute MRI scans of 238 normal subjects ranging in age from 7 to 30. The support vector machine analyzed approximately 13,000 functional brain connections and selected the best 200 produce a single index of the maturity of each subject. The data allowed scientists to predict whether subjects were children or adults, and roughly formed a curving line that tracks the path of normal functional brain development.

The researchers suspect patients with brain disorders will appear out of alignment with this normal developmental curve.

"The beauty of this approach is that it lets you ask what's different in the way that children with autism, for example, are off the normal development curve versus the way children with attention-deficit disorder are off that curve," Schlaggar says.

Schlaggar suggests that functional brain scans might be conducted on a group of children at risk but not yet suffering from a developmental disorder.

"When a fraction of them later develop that disorder, you can go back and construct an analysis like this one that will help predict the characteristics of the next child at highest risk of developing the disorder," he says. "That's very powerful both clinically and from the perspective of understanding the causes of these disorders."

This approach might enable treatment prior to onset of symptoms, Schlaggar says, and should help physicians more quickly and closely track the results of clinical trials of new therapies.

"MRI scans are expensive, so this may not be what we use for everyone right now," Dosenbach says. "But many children with these types of disorders already receive regular structural MRI scans, and five more minutes in the scanner won't add that much to the cost."

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Computer Program Detects Depression in Bloggers' Texts

Computer Program Detects Depression in Bloggers' Texts

  12:55:00 PM    Science Lover

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Researchers at Ben-Gurion University of the Negev (BGU) developed a software program that can detect depression in blogs and online texts. The software is capable of identifying language that can indicate the writer's psychological state, which could serve as a screening tool.

The software, developed by a team headed by Associate Professor Yair Neuman in BGU's Department of Education, was used to scan more than 300,000 English language blogs that were posted to mental health Web sites. The program identified what it perceived to be the 100 "most depressed" and 100 "least depressed" bloggers. A panel of four clinical psychologists reviewed the samples, and concluded that there was a 78 percent correlation between the computer's findings and the panel's.

Professor Yair Neuman will be presenting his BGU team's work at the 2010 IEEE/WIC/ACM International Conference on Web Intelligence and Intelligent Agency Technology in Toronto, Canada, August 31 -- Sept. 3, 2010. Prof. Neuman's findings will also be published in the conference's proceedings.

"The software program was designed to find depressive content hidden in language that did not mention the obvious terms like "depression" or suicide," explains Prof. Neuman. "A psychologist knows how to spot various emotional states through intuition. Here, we have a program that does this methodically through the innovative use of 'web intelligence.'"

For example, the program spots words that express various emotions, like colors that the writer employs to metaphorically describe certain situations. Words like "black" combined with other terms that describe symptoms of depression, such as sleep deprivation or loneliness, will be recognized by the software as "depressive" texts.

Originally conducted for academic purposes, the findings could potentially be used to screen for would-be suicides.

The software provides a screening process that raises an individual's awareness of his or her condition, enables mental health workers to identify individuals in need of treatment, and can then recommend they seek professional help. Because, "no one can actually replace excellent human judgment," says Neuman.

In the United States, there is a big problem of undiagnosed people suffering from depression. The usual screening process is an online questionnaire, which is a self-selective process. If a person is completing a survey, he already suspects a problem. With this software, it is possible to analyze proactively. If the blogger agrees, he will know whether or not he needs to seek professional counseling.

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Men and Women Respond Differently to Stress

Men and Women Respond Differently to Stress

  10:50:00 AM    Science Lover

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Age and gender play a major role in how people respond to stress, according to a new study on 20-to-64-year-olds. Published in the journal Psychophysiology, the investigation was led by scientists from the Université de Montréal and the Montreal Heart Institute in collaboration with colleagues from the Université du Québec à Montréal and McGill University.

"Our findings suggest that women who are more defensive are at increased cardiovascular risk, whereas low defensiveness appears to damage the health of older men," says Bianca D'Antono, a professor at the Université de Montréal Department of Psychiatry and a Montreal Heart Institute researcher.

Defensiveness is a trait characterized by avoidance, denial or repression of information perceived as threatening. In women, a strong defensive reaction to judgment from others or a threat to self-esteem will result in high blood pressure and heart rate. Contrarily, older men with low defensive reactions have a higher cardiovascular rates.

The study was conducted on 81 healthy working men and 118 women. According to Dr. Jean-Claude Tardif a Université de Montréal professor and Montreal Heart Institute researcher, the physiological response to stress in women and older men is linked to this desire of maintaining self-esteem and securing social bonds.

"The sense of belonging is a basic human need," says D'Antono. "Our findings suggest that socialization is innate and that belonging to a group contributed to the survival of our ancestors. Today, it is possible that most people view social exclusion as a threat to their existence. A strong defensive reaction is useful to maintain one's self-esteem faced with this potential threat."

As part of the experiment, participants completed four tasks of varying stress levels. The first task involved reading a neutral text on Antarctica's geography before a person of the same sex. The second and third tasks involved role-playing in which participants followed a script where they were sometimes agreeable and sometimes aggressive. The final task involved a non-scripted debate on abortion.

Heart rate and blood pressure were measured during each of these tasks as was the level of cortisol in saliva. Results showed that women and older men had elevated cardiovascular, autonomic and endocrine responses to stress -- all potentially damaging to their health. The research team cautions, however, that more studies are needed to evaluate the long-term effects of defensiveness and its association to stress response patterns in disease development.

This study was supported by the Canadian Institutes of Health Research and the Fonds de la recherche en santé du Québec.

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Obesity Now Poses as Great a Threat to Quality of Life as Smoking

Obesity Now Poses as Great a Threat to Quality of Life as Smoking

  1:13:00 AM    Science Lover

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As the US population becomes increasingly obese while smoking rates continue to decline, obesity has become an equal, if not greater, contributor to the burden of disease and shortening of healthy life in comparison to smoking.

In a new study, researchers calculate that the Quality-Adjusted Life Years (QALYs) lost due to obesity is now equal to, if not greater than, those lost due to smoking -- both modifiable risk factors. (Credit: iStockphoto)

In an article published in the February 2010 issue of the American Journal of Preventive Medicine, researchers from Columbia University and The City College of New York calculate that the Quality-Adjusted Life Years (QALYs) lost due to obesity is now equal to, if not greater than, those lost due to smoking -- both modifiable risk factors.

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People With Generalized Anxiety Disorder

People With Generalized Anxiety Disorder

  1:17:00 AM    Science Lover

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Scrambled connections between the part of the brain that processes fear and emotion and other brain regions could be the hallmark of a common anxiety disorder, according to a new study from the Stanford University School of Medicine. The findings could help researchers identify biological differences between types of anxiety disorders as well as such disorders as depression.

This image shows, in red, brain regions with stronger connections to the amygdala in patients with GAD, while the blue areas indicate weaker connectivity. The red corresponds to areas important for attention and may reflect the habitual use of cognitive strategies like worry and distraction in the anxiety patients. (Credit: Image courtesy of Stanford University Medical Center)

The study, which will be published Dec. 7 in the Archives of General Psychiatry, examined the brains of people with generalized anxiety disorder, or GAD, a psychiatric condition in which patients spend their days in a haze of worry over everyday concerns. Researchers have known that the amygdala, a pair of almond-sized bundles of nerve fibers in the middle of the brain that help process emotion, memory and fear, are involved in anxiety disorders like GAD. But the Stanford study is the first to peer close enough to detect neural pathways going to and from subsections of this tiny brain region.

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