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March 18, 2012
Computer-Based Treatment Eases Anxiety Symptoms in Children
Small Clinical Trial Supports Larger Scale Testing
A computer-based training method that teaches a person with anxiety to shift attention away from threatening images reduced symptoms of anxiety in a small clinical trial in children with the condition. The results of this first randomized clinical trial of the therapy in children with anxiety suggest that the approach warrants more extensive testing as a promising therapy.
Background
As many as a quarter of 13- to 18-year-olds have met the criteria for an anxiety disorder at some point. Currently available treatments—including cognitive behavioral therapy and medication—relieve symptoms of anxiety in about 70 percent of children treated. Most children with clinical anxiety do not receive treatment, partly because of difficulties in access to care, including distance and financial resources. Scientists are searching for additional approaches, including therapies that do not involve medication with its associated side effects counselor ceus
A treatment called attention bias modification (ABM) has emerged from the observation that people with anxiety unconsciously pay more attention than others to anything that seems threatening. One way of detecting such a bias is a dot probe test. In the test, people view a computer screen on which angry and neutral faces are flashed briefly, adjacent to each other. After the faces disappear, a test image of dots appears where either one or the other face was, and the person has to respond by pushing a button. People with anxiety consistently respond more quickly to dots that appear where the angry face was located.
ABM presents patients with an exercise similar to the dot probe test, but the dots always appear where the neutral face was, and thus consistently draw the attention of the participant to this non-threatening image. A recent meta-analyses of ABM in adults by some of the same investigators who carried out this work suggested its potential as a treatment.
This Study
Researchers at Tel Aviv University (TAU) in Israel carried out a clinical trial on ABM as an outcome of a three-year collaboration with scientists at the National Institute of Mental Health and the University of Maryland, College Park, Maryland. Yair Bar-Haim of TAU led the study, which appears in the American Journal of Psychiatry. The study enrolled 40 children, 8 to 14 years old, who had sought help for anxiety. For children receiving ABM, after faces appeared on a screen, two dots appeared on the screen; children had to determine whether the dots were side by side, or one above the other. In every case, dots appeared only where the neutral face had been. There were also two control groups: in the first, dots appeared equally frequently where angry and neutral faces appeared; in the second, the only faces that appeared throughout were neutral, so the dots always appeared in the location of a neutral face. The object of the second control group was to help confirm that any therapeutic effect was from the ABM training, and not from desensitizing the children to threatening faces. Children in the study were randomly assigned to receive treatment, or to be in one of two control groups. All children had four training sessions over 4 weeks, with 480 dot-probe trials per session.
Although the trial was small, there was a “reasonably robust” decrease in the severity of anxiety, according to the authors. Following ABM, both the number and severity of symptoms were reduced.
Significance
An important feature of ABM, says NIMH author Daniel Pine, is that it addresses the fundamental neurological function underlying anxiety: attention. Changes in attention happen very quickly—in milliseconds. “We know from neuroscience that if you want to change behaviors that happen very quickly, you have to practice. You can’t just tell someone how to drive, or throw a ball. You have to practice,” says Pine.
Longitudinal studies that follow children into adulthood suggest that most chronic mood and anxiety disorders in adults begin as high levels of anxiety in children. In fact, childhood anxiety is as important in predicting adult depression as it is for adult anxiety. The ability to influence attention biases early in development might provide a powerful means of prevention for both of these disorders later in life. The approach requires no medication and in practical terms, the computer-based nature of ABM lends itself to large-scale dissemination, in a medium children are comfortable with. Larger-scale trials will be able to provide more information on the efficacy of the treatment in children and how it works to reduce symptoms of anxiety.
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Reference
Eldar, S., Apter, A., Lotan, D., Perez-Edgar, K., Naim, R, Fox, N.A., Pine, D.S., and Bar-Haim, Y. American Journal of Psychiatry. 2012 Feb 1;169(2):213-30.
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March 11, 2012
NIH-funded study defines treatment window for HIV-positive children infected at birth
HIV-positive children older than 1 year who were treated after showing moderate HIV-related symptoms did not experience greater cognitive or behavior problems compared to peers treated when signs of their infection were still mild, according to a study funded by the National Institutes of Health. But both groups of HIV-positive children lagged behind HIV-negative children in these areas, suggesting that the first year of life may present a critical treatment window for minimizing impairments in brain development due to HIV ceus for social workers
“Especially in children, we must always weigh the benefits of early treatment for HIV infection against the risks, which can range from long-term toxicity or drug resistance to scarcity of the supply of medications in regions with limited health care resources,” noted Thomas R. Insel, M.D., director of the National Institute of Mental Health (NIMH), part of NIH. “Knowing the parameters of appropriate care can assist providers in making difficult treatment decisions for this vulnerable population.”
As part of the NIH-funded Pediatric Randomized Early vs. Deferred Initiation in Cambodia and Thailand (PREDICT) trial, researchers assessed 284 HIV-positive children ages 1-12 who had mildly weakened immune systems but no severe symptoms of HIV infection. The children were randomly assigned to receive treatment immediately or to have treatment deferred until they began to show moderate signs of HIV-related illness.
At follow-up almost 3 years later, very few children in either group had progressed to AIDS. Children who received deferred treatment performed as well as those treated immediately on tests measuring intelligence, memory, and hand-eye coordination. However, both groups scored lower on these tests and had more behavior problems than HIV-negative children who took part in the PREDICT study. Though the study did not assess the children’s actual educational needs, the difference in test scores would place many HIV-positive children at a lower functional level than their HIV-negative peers, indicating they may need additional resources or special schooling.
“These findings suggest that the window of opportunity for avoiding neurocognitive deficits by treating HIV infection may only occur earlier, in infancy,” noted Pim Brouwers, Ph.D., who oversees NIMH-funded research on HIV/AIDS among children and adolescents and also served as a co-investigator on neurodevelopmental outcomes of the PREDICT study.
The results of the PREDICT study were presented at the 19th Conference on Retroviruses and Opportunistic Infections at the Washington State Convention Center in Seattle. The PREDICT study was sponsored by the National Institute of Allergy and Infectious Diseases, with further neurological analysis of the study participants supported by NIMH and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, all parts of NIH.
The ClinicalTrials.gov identifier for the PREDICT study is NCT00234091.
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The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website.
About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.
March 03, 2012
Antidepressant-suicide link in youths absent in new analysis
Drugs also found effective in reducing suicidal behavior in adults, elderly
In 2004, concerns about antidepressant drugs increasing suicidal thoughts and behaviors in young patients prompted the FDA to issue a rare "black box warning." Now, a new analysis of clinical trial data finds that treatment with the antidepressant fluoxetine did not increase — or decrease — suicidality in children compared to placebo treatment.
An analysis built on data from 41 trials and more than 9,000 patients also found that two different popular antidepressant drugs were effective at reducing suicidal behavior and depressive symptoms in adult and geriatric patients. The findings are published online Feb. 6 in the journal Archives of General Psychiatry Alcoholism and Drug Abuse Counselors Continuing Education
The failure to replicate the link between antidepressants and suicide should reassure doctors about prescribing these drugs to depressed patients, said first author Robert Gibbons, PhD, professor of medicine, health studies, and psychiatry at the University of Chicago Medicine.
"The key finding here, when we re-analyze all the patient-level longitudinal records in these studies, is that antidepressants neither increase nor decrease suicidal thoughts or behavior in children," Gibbons said.
The FDA decision on the black box warning was based on retrospective data from 25 clinical trials of newer antidepressant medications, including the serotonin reuptake inhibitor drug fluoxetine, marketed as Prozac or Sarafem. A meta-analysis combining adverse event data (primarily based on self reports of suicidal thoughts) from the trials revealed a small, but significant, increase in suicidal thoughts and behavior in children and young adults up to the age of 25.
For the new analysis, Gibbons and colleagues from the University of Illinois at Chicago, the University of Miami and Columbia University obtained individual-level, longitudinal clinical trial data — some of it unpublished — from pharmaceutical producers and a large National Institute of Mental Health collaborative study of fluoxetine and venlafaxine. The data included weekly screening of each trial subject for depression and suicidal thoughts, allowing researchers to compare the effect of drug or placebo over time on these measures.
In the analysis of the adult and geriatric trials testing fluoxetine or venlafaxine, both antidepressants were found effective in reducing suicide risk and depression symptoms. These two effects were also found to be statistically associated, suggesting that the drugs reduced suicidality by alleviating depression. Therefore, Gibbons said, effective treatment of major depressive disorder is important for a patient's safety.
"Basically, the results say that the mechanism by which the antidepressants affect suicide rates is by decreasing depression," Gibbons said. "It follows that if a treatment is not working for an individual, the risk for suicidal behavior and perhaps worse remains high."
To analyze the effects of antidepressants in children, the researchers used four trials of fluoxetine, which until recently was the only antidepressant approved for pediatric use. Once again, a reduction in depressive symptoms was observed in the drug-treated population compared to placebo. However, no significant change in suicide risk was detected between the two patient groups.
"I think that this paper supports the general idea that the effects of antidepressants in kids and adults are not really the same, since we don't see anything but beneficial effects of antidepressants in adults and geriatrics," Gibbons said. "In kids, we don't see a harmful effect, but we do see a disassociation between the beneficial effects on depression and the potential beneficial effect on suicide."
"This raises continued questions about what's going on in children," he continued. "Maybe children think about suicide in part because of depression, but also maybe due to other reasons not related to depression that are not affected by antidepressants."
Gibbons, who sat on the Food and Drug Administration panel that considered placing the black box warning on antidepressants, said he hoped the new results would reassure clinicians about the safety of the drugs. Previous research by his group found that the addition of the warning significantly reduced antidepressant prescriptions to both children and adults and correlated with a spike in suicide rates.
"I hope that the warnings will not prevent depressed children and adults from getting treatment for depression," Gibbons said. "The greatest cause of suicide is untreated or undiagnosed depression. It's very important that this condition be recognized and appropriately treated and not discarded because doctors are afraid to be sued."
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The paper, "Suicidal Thoughts and Behavior with Antidepressant Treatment," will be published online February 6th by Archives of General Psychiatry. In addition to Gibbons, authors include C. Hendricks Brown of the University of Miami, Kwan Hur of the University of Chicago, John M. Davis of the University of Illinois at Chicago, and J. John Mann of Columbia University. Funding for the research was provided by the National Institute of Mental Health and the Agency for Healthcare Research and Quality.
For more news from the University of Chicago Medical Center, follow us on Twitter at @UChicagoMed, or visit our Facebook page at facebook.com/UChicagoMed, our research blog at sciencelife.uchospitals.edu, or our newsroom at uchospitals.edu/news.
February 22, 2012
New brain connections form in clusters during learning
Researchers track structural changes during formation of new memories
SANTA CRUZ, CA--New connections between brain cells emerge in clusters in the brain as animals learn to perform a new task, according to a study published in Nature on February 19 (advance online publication). Led by researchers at the University of California, Santa Cruz, the study reveals details of how brain circuits are rewired during the formation of new motor memories ceus for social workers
The researchers studied mice as they learned new behaviors, such as reaching through a slot to get a seed. They observed changes in the motor cortex, the brain layer that controls muscle movements, during the learning process. Specifically, they followed the growth of new "dendritic spines," structures that form the connections (synapses) between nerve cells.
"For the first time we are able to observe the spatial distribution of new synapses related to the encoding of memory," said Yi Zuo, assistant professor of molecular, cell and developmental biology at UC Santa Cruz and corresponding author of the paper.
In a previous study, Zuo and others documented the rapid growth of new dendritic spines on pyramidal neurons in the motor cortex during the learning process. These spines form synapses where the pyramidal neurons receive input from other brain regions involved in motor memories and muscle movements. In the new study, first author Min Fu, a postdoctoral researcher in Zuo's lab, analyzed the spatial distribution of the newly formed synapses.
Initial results of the spatial analysis showed that one third of the newly formed synapses were located next to another new synapse. These clustered synapses tended to form over the course of a few days during the learning period, when the mouse was repeatedly performing the new behavior. Compared to non-clustered counterparts, the clustered synapses were more likely to persist through the learning sessions and after training stopped.
In addition, the researchers found that after formation of the second spine in a cluster, the first spine grew larger. The size of the spine head correlates with the strength of the synapse. "We found that formation of a second connection is correlated with a strengthening of the first connection, which suggests that they are likely to be involved in the same circuitry," Zuo said. "The clustering of synapses may serve to magnify the strength of the connections."
Another part of the study also supported the idea that the clustered synapses are involved in neural circuits specific to the task being learned. The researchers studied mice trained first in one task and then in a different task. Instead of grabbing a seed, the mice had to learn how to handle a piece of capellini pasta. Both tasks induced the formation of clustered spines, but spines formed during the learning of different tasks did not cluster together.
The researchers also looked at mice that were challenged with new motor tasks every day, but did not repeat the same task over and over like the ones trained in seed-grabbing or capellini-handling. These mice also grew lots of new dendritic spines, but few of the new spines were clustered.
"Repetitive activation of the same cortical circuit is really important in learning a new task," Zuo said. "But what is the optimal frequency of repetition? Ultimately, by studying the relationship between synapse formation and learning, we want to find out the best way to induce new memories."
The study used mice that had been genetically altered to make a fluorescent protein within certain neurons in the motor cortex. The researchers used a special microscopy technique (two-photon microscopy) to obtain images of those neurons near the surface of the brain. The noninvasive imaging technique enabled them to view changes in individual brain cells of the mice before, during, and after learning a new behavior.
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In addition to Zuo and first author Min Fu, the coauthors of the paper include UCSC graduate student Xinzhu Yu and Stanford University biologist Ju Lu. This research was supported by grants from the Dana Foundation and the National Institute of Mental Health.
February 15, 2012
Mom's Love Good for Child's Brain
School-age children whose mothers nurtured them early in life have brains with a larger hippocampus, a key structure important to learning, memory and response to stress LCSW Continuing Education
The new research, by child psychiatrists and neuroscientists at Washington University School of Medicine in St. Louis, is the first to show that changes in this critical region of children's brain anatomy are linked to a mother's nurturing.
Their research is published online in the Proceedings of the National Academy of Sciences Early Edition.
"This study validates something that seems to be intuitive, which is just how important nurturing parents are to creating adaptive human beings," says first author Joan L. Luby, MD. "I think the public health implications suggest that we should pay more attention to parents' nurturing, and we should do what we can as a society to foster these skills because clearly nurturing has a very, very big impact on later development."
The brain-imaging study involved children ages 7 to 10 who had participated in an earlier study of preschool depression that Luby and her colleagues began about a decade ago. That study involved children, ages 3 to 6, who had symptoms of depression, other psychiatric disorders or were mentally healthy with no known psychiatric problems.
As part of the initial study, the children were closely observed and videotaped interacting with a parent, almost always a mother, as the parent was completing a required task, and the child was asked to wait to open an attractive gift. How much or how little the parent was able to support and nurture the child in this stressful circumstance — which was designed to approximate the stresses of daily parenting — was evaluated by raters who knew nothing about the child's health or the parent's temperament.
"It's very objective," says Luby, professor of child psychiatry. "Whether a parent was considered a nurturer was not based on that parent's own self-assessment. Rather, it was based on their behavior and the extent to which they nurtured their child under these challenging conditions."
The study didn't observe parents and children in their homes or repeat stressful exercises, but other studies of child development have used similar methods as valid measurements of whether parents tend to be nurturers when they interact with their children.
For the current study, the researchers conducted brain scans on 92 of the children who had had symptoms of depression or were mentally healthy when they were studied as preschoolers. The imaging revealed that children without depression who had been nurtured had a hippocampus almost 10 percent larger that children whose mothers were not as nurturing.
"For years studies have underscored the importance of an early, nurturing environment for good, healthy outcomes for children," Luby says. "But most of those studies have looked at psychosocial factors or school performance. This study, to my knowledge, is the first that actually shows an anatomical change in the brain, which really provides validation for the very large body of early childhood development literature that had been highlighting the importance of early parenting and nurturing. Having a hippocampus that's almost 10 percent larger just provides concrete evidence of nurturing's powerful effect."
Luby says the smaller volumes in depressed children might be expected because studies in adults have shown the same results. What did surprise her was that nurturing made such a big difference in mentally healthy children.
"We found a very strong relationship between maternal nurturing and the size of the hippocampus in the healthy children," she says.
Although 95 percent of the parents whose nurturing skills were evaluated during the earlier study were biological mothers, the researchers say that the effects of nurturing on the brain are likely to be the same, for any primary caregiver — whether they are fathers, grandparents or adoptive parents.
The fact that the researchers found a larger hippocampus in the healthy children who were nurtured is striking, Luby says, because the hippocampus is such an important brain structure.
When the body faces stresses, the brain activates the autonomic nervous system, an involuntary system of nerves that controls the release of stress hormones. Those hormones help us cope with stress by increasing the heart rate and helping the body adapt. The hippocampus is the main brain structure involved in that response. It's also key in learning and memory, and larger volumes would suggest a link to improved performance in school, among other things.
Past animal studies have indicated that a nurturing mother can influence brain development, and many studies in human children have identified improvements in school performance and healthier development in children raised in a nurturing environment. But until now, there has not been solid evidence linking a nurturing parent to changes in brain anatomy in children.
"Studies in rats have shown that maternal nurturance, specifically in the form of licking, produces changes in genes that then produce changes in receptors that increase the size of the hippocampus," Luby says. "That phenomenon has been replicated in primates, but it hasn't really been clear whether the same thing happens in humans. Our study suggests a clear link between nurturing and the size of the hippocampus."
She says educators who work with families who have young children may improve school performance and child development by not only teaching parents to work on particular tasks with their children but by showing parents how to work with their children.
"Parents should be taught how to nurture and support their children. Those are very important elements in healthy development," Luby says.
Luby JL, Barch DM, Belden A, Gaffrey MS, Tillman R, Babb C, Nishino T, Suzuki H, Botteron KN. Maternal support in early childhood predicts larger hippocampal volumes at school age. Proceedings of the National Academy of Sciences Early Edition, Jan. 30, 2012. www.pnas.org/cgi/doi/10.1073/pnas.1118003109.
Funding for this research comes from grants awarded by the National Institute of Mental Health of the National Institutes of Health (NIH).
Washington University School of Medicine's 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
February 04, 2012
Gene Regulator in Brain’s Executive Hub Tracked Across Lifespan – NIH study
Mental illness suspect genes are among the most environmentally responsive
For the first time, scientists have tracked the activity, across the lifespan, of an environmentally responsive regulatory mechanism that turns genes on and off in the brain’s executive hub. Among key findings of the study by National Institutes of Health scientists: genes implicated in schizophrenia and autism turn out to be members of a select club of genes in which regulatory activity peaks during an environmentally-sensitive critical period in development. The mechanism, called DNA methylation, abruptly switches from off to on within the human brain’s prefrontal cortex during this pivotal transition from fetal to postnatal life. As methylation increases, gene expression slows down after birth.
Epigenetic mechanisms like methylation leave chemical instructions that tell genes what proteins to make – what kind of tissue to produce or what functions to activate. Although not part of our DNA, these instructions are inherited from our parents. But they are also influenced by environmental factors, allowing for change throughout the lifespan.
“Developmental brain disorders may be traceable to altered methylation of genes early in life,” explained Barbara Lipska, Ph.D., a scientist in the NIH’s National Institute of Mental Health (NIMH) and lead author of the study. “For example, genes that code for the enzymes that carry out methylation have been implicated in schizophrenia. In the prenatal brain, these genes help to shape developing circuitry for learning, memory and other executive functions which become disturbed in the disorders. Our study reveals that methylation in a family of these genes changes dramatically during the transition from fetal to postnatal life – and that this process is influenced by methylation itself, as well as genetic variability. Regulation of these genes may be particularly sensitive to environmental influences during this critical early life period.”
Lipska and colleagues report on the ebb and flow of the human prefrontal cortex’s (PFC) epigenome across the lifespan, February 2, 2012, online in the American Journal of Human Genetics.
“This new study reminds us that genetic sequence is only part of the story of development. Epigenetics links nurture and nature, showing us when and where the environment can influence how the genetic sequence is read,” said NIMH director Thomas R. Insel, M.D.
In a companion study published last October, the NIMH researchers traced expression of gene products in the PFC across the lifespan. The current study instead examined methylation at 27,000 sites within PFC genes that regulate such expression. Both studies examined post-mortem brains of non-psychiatrically impaired individuals ranging in age from two weeks after conception to 80 years old CADC I and II Continuing Education
In most cases, when chemicals called methyl groups attach to regulatory regions of genes, they silence them. Usually, the more methylation, the less gene expression. Lipska’s team found that the overall level of PFC methylation is low prenatally when gene expression is highest and then switches direction at birth, increasing as gene expression plummets in early childhood. It then levels off as we grow older. But methylation in some genes shows an opposite trajectory. The study found that methylation is strongly influenced by gender, age and genetic variation.
For example, methylation levels differed between males and females in 85 percent of X chromosome sites examined, which may help to explain sex differences in disorders like autism and schizophrenia.
Different genes – and subsets of genes – methylate at different ages. Some of the suspect genes found to peak in methylation around birth code for enzymes, called methytransferases, that are over-expressed in people with schizophrenia and bipolar disorder. This process is influenced, in turn, by methylation in other genes, as well as by genetic variation. So genes associated with risk for such psychiatric disorders may influence gene expression through methylation in addition to inherited DNA.
Scientists worldwide can now mine a newly created online database of PFC lifespan DNA methylation from the study. The data are accessible to qualified researchers at: http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000417.v2.p1. BrainCloud, a web browser application developed by NIMH to interrogate the study data, can be downloaded at http://BrainCloud.jhmi.edu.
Two representative genes show strikingly opposite trajectories of PFC methylation across the lifespan. Each dot represents a different brain. Usually, the more methylation, the less gene expression.
Source: Barbara Lipska, Ph.D., NIMH Clinical Brain Disorders Branch
A representative gene showing how sex can influence levels of methylation across the lifespan. Each dot represents a different brain.
Source: Barbara Lipska, Ph.D., NIMH Clinical Brain Disorders Branch
Reference:
Numata S, Ye T, Hyde TM, Guitart-Navarro X, Tao R, Wininger M, Colantuoni C, Weinberger DR, Kleinman JE, Lipska BK. DNA Methylation Signatures in Development and Aging of the Human Prefrontal Cortex. American Journal of Human Genetics, 2011. Feb 2.
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The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website.
About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.
For the first time, scientists have tracked the activity, across the lifespan, of an environmentally responsive regulatory mechanism that turns genes on and off in the brain’s executive hub. Among key findings of the study by National Institutes of Health scientists: genes implicated in schizophrenia and autism turn out to be members of a select club of genes in which regulatory activity peaks during an environmentally-sensitive critical period in development. The mechanism, called DNA methylation, abruptly switches from off to on within the human brain’s prefrontal cortex during this pivotal transition from fetal to postnatal life. As methylation increases, gene expression slows down after birth.
Epigenetic mechanisms like methylation leave chemical instructions that tell genes what proteins to make – what kind of tissue to produce or what functions to activate. Although not part of our DNA, these instructions are inherited from our parents. But they are also influenced by environmental factors, allowing for change throughout the lifespan.
“Developmental brain disorders may be traceable to altered methylation of genes early in life,” explained Barbara Lipska, Ph.D., a scientist in the NIH’s National Institute of Mental Health (NIMH) and lead author of the study. “For example, genes that code for the enzymes that carry out methylation have been implicated in schizophrenia. In the prenatal brain, these genes help to shape developing circuitry for learning, memory and other executive functions which become disturbed in the disorders. Our study reveals that methylation in a family of these genes changes dramatically during the transition from fetal to postnatal life – and that this process is influenced by methylation itself, as well as genetic variability. Regulation of these genes may be particularly sensitive to environmental influences during this critical early life period.”
Lipska and colleagues report on the ebb and flow of the human prefrontal cortex’s (PFC) epigenome across the lifespan, February 2, 2012, online in the American Journal of Human Genetics.
“This new study reminds us that genetic sequence is only part of the story of development. Epigenetics links nurture and nature, showing us when and where the environment can influence how the genetic sequence is read,” said NIMH director Thomas R. Insel, M.D.
In a companion study published last October, the NIMH researchers traced expression of gene products in the PFC across the lifespan. The current study instead examined methylation at 27,000 sites within PFC genes that regulate such expression. Both studies examined post-mortem brains of non-psychiatrically impaired individuals ranging in age from two weeks after conception to 80 years old CADC I and II Continuing Education
In most cases, when chemicals called methyl groups attach to regulatory regions of genes, they silence them. Usually, the more methylation, the less gene expression. Lipska’s team found that the overall level of PFC methylation is low prenatally when gene expression is highest and then switches direction at birth, increasing as gene expression plummets in early childhood. It then levels off as we grow older. But methylation in some genes shows an opposite trajectory. The study found that methylation is strongly influenced by gender, age and genetic variation.
For example, methylation levels differed between males and females in 85 percent of X chromosome sites examined, which may help to explain sex differences in disorders like autism and schizophrenia.
Different genes – and subsets of genes – methylate at different ages. Some of the suspect genes found to peak in methylation around birth code for enzymes, called methytransferases, that are over-expressed in people with schizophrenia and bipolar disorder. This process is influenced, in turn, by methylation in other genes, as well as by genetic variation. So genes associated with risk for such psychiatric disorders may influence gene expression through methylation in addition to inherited DNA.
Scientists worldwide can now mine a newly created online database of PFC lifespan DNA methylation from the study. The data are accessible to qualified researchers at: http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000417.v2.p1. BrainCloud, a web browser application developed by NIMH to interrogate the study data, can be downloaded at http://BrainCloud.jhmi.edu.
Two representative genes show strikingly opposite trajectories of PFC methylation across the lifespan. Each dot represents a different brain. Usually, the more methylation, the less gene expression.
Source: Barbara Lipska, Ph.D., NIMH Clinical Brain Disorders Branch
A representative gene showing how sex can influence levels of methylation across the lifespan. Each dot represents a different brain.
Source: Barbara Lipska, Ph.D., NIMH Clinical Brain Disorders Branch
Reference:
Numata S, Ye T, Hyde TM, Guitart-Navarro X, Tao R, Wininger M, Colantuoni C, Weinberger DR, Kleinman JE, Lipska BK. DNA Methylation Signatures in Development and Aging of the Human Prefrontal Cortex. American Journal of Human Genetics, 2011. Feb 2.
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The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website.
About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.
January 31, 2012
Ethnic Disparities Persist in Depression Diagnosis and Treatment Among Older Americans
Older racial and ethnic minorities living in the community are less likely to be diagnosed with depression than their white counterparts, but are also less likely to get treated, according to a recent NIMH-funded analysis published online ahead of print December 15, 2011, in the American Journal of Public Health.
Source: iStock Photo
Background
Depression is a significant health concern for older adults, regardless of ethnic or racial status. Previous studies have found racial and ethnic differences in the diagnosis and treatment of depression among the general population.
Using 2001-2005 data from the nationally representative Medicare Current Beneficiary Survey (MCBS), Ayse Akincigil Ph.D., of Rutgers University and colleagues examined rates of depression diagnosis and treatment among older adults living in the community. The survey asked questions about health care use and costs, insurance coverage beyond Medicare, access to care, and use of services.
Results
The survey found that about 6.4 percent of whites, 4.2 percent of African Americans, and 7.2 percent of Hispanics were diagnosed with depression. Among those diagnosed, 73 percent of whites received treatment (either with antidepressants, psychotherapy or both), while 60 percent of African Americans received treatment and 63.4 percent of Hispanics received treatment. These kinds of diagnosis and treatment differences are consistent with previous studies, the researchers noted. They also noted pronounced differences in socioeconomic status and quality of insurance coverage across ethnicities. Fewer whites reported having low incomes than ethnic minorities. However, these differences did not appear to account for the disparities in diagnosis or treatment rates.
Significance
The findings are consistent with the notion that depression continues to be under-recognized and undertreated among older minorities. According to the researchers, future research should investigate cultural factors such as help-seeking patterns, stigma, and patient attitudes and knowledge about depression as potential factors contributing to the disparities. For instance, ethnic minorities may be less likely to seek help for a mood disorder, and those with lower incomes may have more difficulty gaining access to specialized health care. In addition, they may be more likely to seek help from nonmedical providers, such as pastors or lay counselors, according to the researchers. Other research has suggested that minorities tend to cite stigma or shame associated with having a mental disorder as a reason for not seeking help for depression.
Differences in diagnosis rates may also reflect the notion that African Americans tend to have a greater sense of distrust of doctors in general compared to white patients, said the researchers. In addition, minority patients also may be more likely to present with more physical aspects of depression such as sleep problems or pain, rather than mood or cognitive symptoms, which can complicate detection and diagnosis of depression.
What’s Next
The researchers suggest possible ways to minimize the disparities in depression diagnosis and treatment among older minorities. For instance, psychiatrists and other health care workers could be offered public financial incentives for practicing in poorer communities where depressed older people may go untreated. In addition, adding cross-cultural education into professional training opportunities for health care workers could further reduce disparities. In the meantime, promising approaches such as universal depression screening programs could be implemented, the researchers concluded Nursing CEUs
Citation
Akincigil A, Olfson M, Siegel M, Zurlo K, Walkup J, Crystal S. Racial and ethnic disparities in depression care in community-dwelling elderly in the United States. American Journal of Public Health. Online ahead of print Dec. 15, 2011.
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