Our brains are made of the same stuff, despite DNA differences

Gene expression databases reveal “consistent molecular architecture”

Despite vast differences in the genetic code across individuals and ethnicities, the human brain shows a “consistent molecular architecture,” say researchers supported by the National Institutes of Health. The finding is from a pair of studies that have created databases revealing when and where genes turn on and off in multiple brain regions through development counselor ceus

“Our study shows how 650,000 common genetic variations that make each of us a unique person may influence the ebb and flow of 24,000 genes in the most distinctly human part of our brain as we grow and age,” explained Joel Kleinman, M.D., Ph.D., of the National Institute of Mental Health (NIMH) Clinical Brain Disorders Branch.

Kleinman and NIMH grantee Nenad Sestan, M.D., Ph.D. of Yale University, New Haven, Conn., led the sister studies in the Oct. 27, 2011 issue of the journal Nature.

“Having at our fingertips detailed information about when and where specific gene products are expressed in the brain brings new hope for understanding how this process can go awry in schizophrenia, autism and other brain disorders,” said NIMH Director Thomas R. Insel, M.D.

Both studies measured messenger RNAs or transcripts. These intermediate products carry the message from DNA, the genetic blueprint, to create proteins and differentiated brain tissue. Each gene can make several transcripts, which are expressed in patterns influenced by a subset of the approximately 1.5 million DNA variations unique to each of us. This unique set of transcripts is called our transcriptome – a molecular signature that is unique to every individual. The transcriptome is a measure of the diverse functional potential that exists in the brain.

Both studies found that rapid gene expression during fetal development abruptly switches to much slower rates after birth that gradually decline and eventually level off in middle age. These rates surge again as the brain ages in the last decades, mirroring rates seen in childhood and adolescence, according to one of the studies. The databases hold secrets to how the brain’s ever-changing messenger chemical systems, cells and development processes are related to gene expression patterns through development.

For example, if a particular version of a gene is implicated in a disorder, the new resources might reveal how that variation affects the gene’s expression over time and by brain region. By identifying even distant genes that may be turning on and off in-sync, the databases may help researchers discover whole modules of genes involved in the illness. They can also reveal how variation in one gene influences another’s expression.

Prefrontal cortex

Kleinman’s team focused on how genetic variations are linked to the expression of transcripts in the brain’s prefrontal cortex, the area that controls insight, planning and judgment, across the lifespan. They studied 269 postmortem, healthy human brains, ranging in age from two weeks after conception to 80 years old, using 49,000 genetic probes. The database on prefrontal cortex gene expression alone totals more than 1 trillion pieces of information, according to Kleinman.

Among key findings in the prefrontal cortex:
Individual genetic variations are profoundly linked to expression patterns. The most similarity across individuals is detected early in development and again as we approach the end of life.

Different types of related genes are expressed during prenatal development, infancy, and childhood, so that each of these stages shows a relatively distinct transcriptional identity. Three-fourths of genes reverse their direction of expression after birth, with most switching from on to off.

Expression of genes involved in cell division declines prenatally and in infancy, while expression of genes important for making synapses, or connections between brain cells, increases. In contrast, genes required for neuronal projections decline after birth – likely as unused connections are pruned.

By the time we reach our 50s, overall gene expression begins to increase, mirroring the sharp reversal of fetal expression changes that occur in infancy.

Genetic variation in the genome as a whole showed no effect on variation in the transcriptome as a whole, despite how genetically distant individuals might be. Hence, human cortexes have a consistent molecular architecture, despite our diversity.


In previous studies, Kleinman and colleagues have found that all genetic variations implicated to date in schizophrenia are associated with transcripts that are preferentially expressed in the fetal brain. This adds to evidence that the disorder originates in prenatal development. By contrast, he and his colleagues are examining evidence that genetic variation implicated in affective disorders may be associated with transcripts expressed later in life. They are also extending their database to include all transcripts of all the genes in the human genome, examining 1000 post-mortem brains, including many of people who had schizophrenia or other brain disorders.

Multiple brain regions

Sestan and colleagues characterized gene expression in 16 brain regions, including 11 areas of the neocortex, from both hemispheres of 57 human brains that spanned from 40 days post-conception to 82 years – analyzing the transcriptomes of 1,340 samples. Using 1.4 million probes, the researchers measured the expression of exons, which combine to form a gene’s protein product. This allowed them to pinpoint changes in these combinations that make up a protein, as well as to chart the gene’s overall expression.

Among key findings:
Over 90 percent of the genes expressed in the brain are differentially regulated across brain regions and/or over developmental time periods. There are also widespread differences across region and time periods in the combination of a gene’s exons that are expressed.

Timing and location are far more influential in regulating gene expression than gender, ethnicity or individual variation.

Among 29 modules of co-expressed genes identified, each had distinct expression patterns and represented different biological processes. Genetic variation in some of the most well-connected genes in these modules, called hub genes, has previously been linked to mental disorders, including schizophrenia and depression.

Telltale similarities in expression profiles with genes previously implicated in schizophrenia and autism are providing leads to discovery of other genes potentially involved in those disorders.

Sex differences in the risk for certain mental disorders may be traceable to transcriptional mechanisms. More than three-fourths of 159 genes expressed differentially between the sexes were male-biased, most prenatally. Some genes found to have such sex-biased expression had previously been associated with disorders that affect males more than females, such as schizophrenia, Williams syndrome, and autism.


The Sestan study was also funded by NIH’s National Institute on Child Health and Human Development, National Institute on Neurological Disorders and Stroke, and National Institute on Drug Abuse. Data for the Sestan study are posted at www.humanbraintranscriptome.org and at http://www.developinghumanbrain.org, as part of a larger ongoing study, BrainSpan, funded by NIMH under the American Recovery and Reinvestment Act to create an Atlas of Human Brain Development.

The Kleinman study data on genetic variability are accessible to qualified researchers at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000417.v1.p1, while the gene expression data can be found at http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc5GSE30272. In addition, BrainCloud, a web browser application developed by NIMH to interrogate the Kleinman study data, can be downloaded at http://www.libd.org/braincloud.


Our brains are all made of the same stuff. Despite individual and ethnic genetic diversity, our prefrontal cortex shows a consistent molecular architecture. For example, overall differences in the genetic code (“genetic distance”) between African -Americans (AA) and caucasians (cauc) showed no effect on their overall difference in expressed transcripts (“transcriptional distance”). The vertical span of color-coded areas is about the same, indicating that our brains all share the same tissue at a molecular level, despite distinct DNA differences on the horizontal axis. Each dot represents a comparison between two individuals. The AA::AA comparisons (blue) generally show more genetic diversity than cauc::cauc comparisons (yellow), because caucasians are descended from a relatively small subset of ancestors who migrated from Africa, while African Americans are descended from a more diverse gene pool among the much larger population that remained in Africa. AA::cauc comparisons (green) differed most across their genomes as a whole, but this had no effect on their transcriptomes as a whole.
Source: Joel Kleinman, M.D., Ph.D., NIMH Clinical Brain Disorders Branch


Individual genetic variation likely affects the expression of genes. For example, across all ages and ethnicities studied, expression of a gene called ZSWIM7 stays low, medium or high in the prefrontal cortex, depending on which of three versions (A/A, A/G, G/G) is inherited. The versions are created by a tiny variation in the letters of the genetic code (DNA) at a location in the gene called rs1045599.
Source: Joel Kleinman, M.D., Ph.D., NIMH Clinical Brain Disorders Branch


Overall gene expression plummets 5-fold in infancy and 90-fold in childhood from its prenatal peak. The decline levels-off during the middle years, but expression surges again in the last decades of life, as the brain ages. Note: The fetal/infant graph at left is based on a different scale than the lifespan graph at right, so the two are not visually comparable.
Source: Joel Kleinman, M.D., Ph.D., NIMH Clinical Brain Disorders Branch


Males show more sex-biased gene expression. More genes differentially expressed (DEX) between the sexes were found in males than females, especially prenatally. Some genes found to have such sex-biased expression had previously been associated with disorders that affect males more than females, such as schizophrenia, Williams syndrome, and autism. Eleven of the brain areas shown are in the neocortex (NCX), or outer mantle.
Source: Nenad Sestan, M.D., Ph.D., Yale University Department of Neurobiology and Kavli Institute for Neuroscience


Profiling developmental processes. The expression data can be used to create trajectories for the expression of genes involved in particular processes, such as the development of synapses (structures that underlie communication between neurons). These expression trajectories can be compared for different regions, such as the NCX and cerebellar cortex (CBC).
Source: Nenad Sestan, M.D., Ph.D., Yale University Department of Neurobiology and Kavli Institute for Neuroscience

References

Colantuoni c, Lipska BK, Ye T, Hyde TM, Tao R, Leek JT, Colantuoni EA, Elkahloun AG, Herman MM, Weinberger DR, Kleinman JE. Temporal Dynamics and Genetic Control of Transcription in the human prefrontal cortex. Nature 2011. Oct 27

Kang HJ, Kawasawa1YI, Cheng F, Zhu Y, Xu X, Li M, Sousa1 AMM, Pletikos M, Meyer KA, Sedmak G, Guennel G, Shin Y, Johnson MB, Krsnik Z, Fertuzinhos MS, Umlauf S, Lisgo SN, Vortmeyer A, Weinberger DR, Mane S, Hyde TM, Huttner A, Reimers M, Kleinman JE, Šestan N. Spatiotemporal transcriptome of the human brain. Nature 2011. Oct 27.

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National Survey Dispels Notion that Social Phobia is the Same as Shyness

Source: NIMH

Normal human shyness is not being confused with the psychiatric anxiety disorder known as social phobia, according to an NIMH survey comparing the prevalence rates of the two among U.S. youth. The study was published online ahead of print October 17, 2011, in the journal Pediatrics.

Background

Social phobia is a disabling anxiety disorder characterized by overwhelming anxiety and excessive self-consciousness in everyday social or performance situations. Critics of the diagnosis have suggested that psychiatrists and pharmaceutical companies publicize social phobia, also known as social anxiety disorder, in order to increase sales of psychotropic medications, especially among youth. In addition, some have debated whether social phobia is just a “medicalization” of a normal variation in human temperament.

In response, Marcy Burstein, Ph.D., and colleagues at NIMH examined the rate of normal shyness among youth and its overlap with social phobia using data from the National Comorbidity Survey-Adolescent Supplement (NCS-A), a nationally representative, face-to-face survey of more than 10,000 teens aged 13-18 sponsored by NIMH. Social phobia was assessed using standard diagnostic criteria set by the American Psychiatric Association's Diagnostic and Statistical Manual (DSM-IV). To assess shyness, teens were asked to rate how shy they felt around peers that they did not know well.

Results of the Study

The authors found that while about half of youth identified themselves as shy, only 12 percent of shy youth also met criteria for social phobia in their lifetime. Moreover, among youth who did not identify themselves as shy, about 5 percent met criteria for social phobia, suggesting that social phobia and shyness are not necessarily directly related. Rather, the presence of social phobia may be independent of shyness in some instances.

In addition, those with social phobia were consistently more likely to also have another psychiatric disorder in their lifetime, like depression or a behavior or drug use disorder, compared to those who identified themselves as shy. Those with social phobia also showed higher levels of impairment in work or school, or among family or peers, though they were no more likely to be receiving professional treatment than those who were shy.

Finally, rates of prescribed medication use were low for all groups. Only about 2.3 percent of those with social phobia were taking the antidepressant paroxetine (commonly used to treat anxiety disorders), while 0.9 percent who described themselves as shy were taking it. In addition, those with social phobia were no more likely to be taking any prescribed psychiatric medication compared to the other groups.

Significance

The results suggest that social phobia is not simply shyness that has been inappropriately medicalized. Rather, social phobia affects a minority of youth and only a fraction of those who consider themselves to be shy. In addition, despite the greater disability that youth with social phobia experience and the greater likelihood that they will have another disorder, they are not more likely to be getting treatment compared to their peers, questioning the notion that these youth are being unnecessarily medicated continuing education for counselors

Citation

Burstein M, Ameli-Grillon L, Merikangas M. Shyness versus social phobia in U.S. youth. Pediatrics. Online ahead of print Oct 17, 2011.

Continued Use of Stimulants for ADHD Likely Does Not Increase Risk for Hypertension, but May Affect Heart Rate

Source: NIMH

Chronic use of stimulant medication to treat attention deficit hyperactivity disorder (ADHD) in children does not appear to increase risk for high blood pressure over the long term, but it may have modest effects on heart rate, according to follow-up data from the NIMH-funded Multimodal Treatment Study of Children with ADHD (MTA). The study was published online ahead of print Sept 2, 2011, in the American Journal of Psychiatry continuing education for counselors

Background

The MTA was the first major multi-site trial comparing different treatments for ADHD in childhood. The initial results of the 14-month study, in which 579 children were randomly assigned to one of three intensive treatment groups (medication management alone, behavioral treatment alone, a combination of both) or to routine community care, were published in 1999. The researchers found that medication management alone or in combination with behavioral therapy produced better symptomatic relief for children with ADHD than just behavioral therapy or usual community care.

After the study ended, participants returned to community treatment and were free to pursue whatever treatment course they wished. MTA researchers gathered follow-up data from MTA study participants at 2, 3, 6, 8, and 10 years after study entry.

ADHD is often a chronic condition that continues into adolescence, so some children take stimulants for years. Because stimulants can affect the heart, doctors are concerned about the possible risks for rapid heart rate, hypertension (high blood pressure) or other cardiovascular effects after many years of use. But studies have been inconsistent about whether the effects are long-lasting.

For this most recent data analysis, Benedetto Vitiello, M.D., of NIMH, and MTA colleagues examined the MTA follow-up data to determine if there was an association between chronic use of stimulant medication and changes in blood pressure or heart rate over a 10-year period.

Results of the Study

At the end of the 14-month study, children who were randomized to stimulant treatment in the study had, on average, higher heart rates compared to the children who were randomized to non-medication or community care. Heart rates for the children who continued to take stimulants after the end of the study were slightly elevated at subsequent checks, but they did not have an abnormally elevated heart rate (e.g., tachycardia).

The researchers concluded that stimulant medication did not appear to increase the risk for abnormal elevations in blood pressure or heart rate over a 10-year period. However, because some epidemiological studies have indicated that even modest elevations in heart rate may increase a person’s lifetime risk for cardiovascular problems, the persistent effect of continuous stimulant treatment on heart rate should not be dismissed.

Significance

The results of this study indicate that the effect of stimulants on heart rate can be detected even after years of use, suggesting that the body does not get completely used to it. However, after 10 years of treatment, researchers found no increased risk for hypertension. In addition, none of the children reported any adverse cardiovascular events over the 10-year period.

The researchers do note that the effect on heart rate may be clinically significant for individuals who have underlying heart conditions. Therefore, children taking stimulants over the long-term should be monitored regularly for potential cardiovascular complications.

Citation

Vitiello B, Elliott GR, Swanson JM, Arnold E, Hechtman L, Abikoff H, Molina BSG, Wells K, Wigal T, Jensen PS, Greenhill LL, Kaltman JR, Severe JB, Odbert C, Hur K, Gibbons R. Blood pressure and heart rate in the multimodal treatment of attention deficit/hyperactivity disorder study over 10 years. American Journal of Psychiatry. Online ahead of print Sept 2, 2011.

Biology, Not Just Society, May Increase Risk of Binge Eating During Puberty

Source: Kelly Klump, Ph.D., Michigan State University

Biological changes associated with puberty may influence the development of binge eating and related eating disorders, according to a recent study on female rats conducted by NIMH-funded researchers. After puberty, the rats showed binge eating patterns that resemble those in humans, supporting the role of biological factors, since rats do not experience pressures to be thin or other psychosocial risk factors commonly associated with human eating disorders. The study was published online ahead of print on May 16, 2011, in the Journal of Abnormal Psychology.

Background
Among girls, symptoms of binge eating or bulimia nervosa often arise around puberty. Past research has largely focused on psychosocial roots for this association, but biological changes that occur during and after puberty are likely to have an effect as well.

Kelly Klump, Ph.D., of Michigan State University, and colleagues tested this theory in an animal model since animals do not experience psychological risk factors during puberty. They used a rat model that can distinguish between rats that are resistant to binge eating (BER) from those prone to binge eating (BEP), based on their individual eating habits.

For this study, the researchers studied binge eating risk from pre-puberty to adulthood in 66 female rats. In addition to their standard food, the rats were provided intermittent access to cake frosting, a highly enjoyable but nutritionally empty and high fat food.

Results
Over the course of development, all rats ate more frosting as they matured. However, a difference in frosting intake between BER and BEP rats emerged during puberty—no differences in frosting intake were observed in pre-puberty, but large differences were observed in puberty and adulthood (see Figure 1)

The researchers noted that rats in the BER and BEP groups ate similar amounts of the standard food and were similar in body weight. This suggests that the BEP rats were not overeaters generally, but were instead, prone to binge eat on high-fat foods only.

Significance
The findings reveal dramatic increases in binge eating proneness during puberty, suggesting that increases in binge eating and similar eating disorders during and after puberty in girls may be partially due to biological factors ceus for counselors

Similar to binge eating in humans, BEP rats ate much more of the high-fat food but did not increase their consumption of the standard food. Also, all rats preferred the high-fat food, regardless of developmental stage, which is similar to behaviors seen in girls; for example, girls tend to prefer candy over healthier treats at all ages. In both rats and humans, this behavior begins to diverge during puberty, with some consuming much more of the high-fat food than others.

Unlike humans, however, the percentage of binge eating rats (30 percent) was much higher than estimates in humans (3.5–19 percent). According to the researchers, this difference may indicate that binge eating in rats is a “pure” form of binge eating that is unmodified by psychosocial factors—such as social disapproval or guilt—that tends to decrease binge eating rates in humans.

What’s Next
More research is needed to develop and validate animal models of the cognitive and behavioral symptoms of eating disorders. Studies exploring the mechanisms underlying developmental changes that occur during puberty, for example the action of ovarian hormones, may also inform research on eating disorders.

Reference
Klump KL, Suisman JL, Culbert KM, Kashy DA, Sisk CL. Binge eating proneness emerges during puberty in female rats: A longitudinal study. J Abnorm Psychol. 2011 May 16. [Epub ahead of print] PubMed PMID: 21574664.

Source: Kelly Klump, Ph.D., Michigan State University

Adapted with permission from APA

Novel Model of Depression from Social Defeat Shows Restorative Power of Exercise

New Neurons Pinpointed as Central to Exercise Benefit

In a study in a mouse model that mimics the contribution of social stress to human depression, an environment that promotes exercise and exploration alleviated depressive behavior in the mice. The beneficial effect of activity depended on the growth of new neurons in the adult brain Continuing Education for Counselors

Background
In the 1990s scientists established that new neurons grow in the adult as well as the immature brain. The functions of neurogenesis, or new neuronal growth, are still being explored, but it is known that stress slows this growth in the hippocampus―a brain center involved in the formation of new memories―and that antidepressant treatment promotes it.

Previous research in animal models has also demonstrated that environmental enrichment―the addition of features in an animal's cage that provide opportunities for exercise and investigation―fosters resilience to stress and can alleviate the depression-like behavior that results from uncontrollable stress. Environmental enrichment has also been shown to promote hippocampal neurogenesis in animals.

This Study
This work, by Michael Lehmann and Robert Schloesser and colleagues in NIMH's intramural research program, focused on the ability of environmental enrichment to reverse depressive behaviors caused by social defeat, a situation paralleling the social stresses that can trigger human depression. Past work in animal models has often used physical stressors such as electric shock, restraint, or forced exercise to create depressive behaviors. In addition, the scientists inserted a gene in mice that made it possible to selectively interrupt the growth of new neurons at a specific time and in a specific population of cells in the hippocampus, avoiding any spillover effects to other tissues.

More on Mouse Behavior
Although "dominant and aggressive" may not sound like descriptors that apply to mice, male mice in the wild live apart from other males and they are intensely aggressive if housed together. In this study, male mice were allowed to interact directly for no more than five minutes at a time and were supervised to make sure one mouse did not injure or kill the other.
Mice naturally cover territory in the wild; if furnished with running wheels in a cage, they will, on their own, run the equivalent of as much as 6 to 10 kilometers in one day.
Stress―in this case social defeat stress―has unmistakable effects on the behavior of mice. Researchers use a variety of tests to describe changes in behavioral tendencies, including observing how boldly the mice explore an unfamiliar cage; how much time they will choose to spend in a dark (safe) vs. light (risky) compartment; and the extent to which they'll indulge their taste for something pleasant like sweetened water. Mice who have been the losers of repeated social defeats are visibly cautious and subdued, even in the judgment of observers who do not know whether they were winners or losers in a conflict.
Test mice in this study were housed across a partition in the home cage of a dominant, aggressor mouse. For 5 minutes per day, the partition was removed, allowing the "intruder" and dominant mouse to interact directly. After 2 weeks, the test mice consistently behaved submissively. The test mice were then divided and placed in either a spare environment, or one enriched with running wheels, and tubes of various shapes and sizes. Some of the mice assigned to either environment were a standard laboratory strain. Others had an inserted gene targeted to a population of hippocampal cells that give rise to new neurons; in mice with this transgene, the antibiotic valganciclovir is toxic to dividing cells so neurogenesis is prevented when the drug was added to the animals' feed.

The nontransgenic test mice in the enriched environment, but not those in the more spartan cages, recovered from the submissive behavior seen after social defeat. The transgenic mice, in which neurogenesis was stopped, remained submissive, resembling the mice housed in the impoverished environment.

In tests to probe affect, or mood, the transgenic mice housed in the enriched environment also resembled mice housed in the impoverished environment in that they showed the same reduced inclination to explore, greater anxiety, and a less than normal interest in sweet solutions which mice usually prefer. Interruption of neurogenesis had no effects on the baseline health and behavior of the animals, so the lack of new neurons did not cause depression, but interfered with recovery.

Significance
This study demonstrates that psychosocial stress in mice can cause behavior resembling human depression, which environmental enrichment can ameliorate as long as neurogenesis is intact.

Key elements of this study included its use of a social stressor, more analogous to the social experiences that can contribute to human depression than the physical stressors often used in research. In addition, the use of the transgene in test animals enabled the scientists to control the interruption of neurogenesis with precision with respect to both timing and location and with no effects on neighboring cells.

According to author Michael Lehmann, "There are multiple avenues through which environmental enrichment can have a positive impact on depression. In this model we use a natural psychosocial stressor with relevance to social stress in humans, to induce depressive-like behaviors. We show that environmental enrichment can facilitate the recovery from social stress, and that adult neurogenesis is a requirement for the rehabilitating effects of enrichment."

The authors suggest that neurogenesis may be central to the ability of an animal to update emotional information upon exposure to a novel environment. With neurogenesis impaired, they may be unable to integrate information on the features of a new, changed environment. The resulting cognitive distortions may trigger symptoms of major depression.

Research suggests that one important consequence of environmental enrichment is its impact on the function of the body's stress response system. Animals in these enriched environments show positive effects on the physiology of stress resilience. In humans, successful antidepressant treatment is reflected in similar beneficial changes. Prior research has also linked neurogenesis with positive changes in the stress response system.

The authors also point out that in humans, physical exercise and positive psychosocial activity have beneficial effects on depression and stress resilience. Forms of entertainment that encourage mental activity, according to Lehmann, such as reading, video games, exercise and outdoor recreation could have longer lasting changes for many suffering from mild depressive symptoms than pharmacologic treatment, without the accompanying side effects.

Reference
Schloesser, R.J., Lehmann, M., Martinowich, K., Manji, H.K., and Herkenham, M. Environmental enrichment requires adult neurogenesis to facilitate recovery from psychosocial stress. Molecular Psychiatry 2010 Dec;15(12):1152-1163. Epub 2010 March 23.

Study Reveals New Clues to How Depression May Develop

Activating neurons in a brain structure linked to disappointment increased depression-like behaviors in rats, while suppressing the neurons' activity reduced the behaviors, according to an NIMH-funded study. The findings help to explain previous research linking this brain structure to depression in humans and highlight a cellular process that hadn't been previously explored in mood disorders research. The study was published in the February 24, 2011, issue of Nature.

Background
Depression is one of the most studied mental disorders, with research honing in on brain structures, circuits, and biochemical processes critical to the development of the disorder. Yet many questions remain about how changes in the brain result in the observable symptoms and behaviors associated with depression. Counselor continuing education
To advance the science in this area, Bo Li, Ph.D., of Cold Spring Harbor Laboratory in New York, and colleagues, explored the role and connectivity of neurons in the lateral habenula (LHb) in rats that showed learned helplessness, a set of behaviors similar to symptoms of depression in people. The LHb is associated with how humans and animals experience disappointment or anticipate negative outcomes.

Results of the Study
The researchers found that LHb neurons receive input from many different brain regions involved in responding to stress. LHb neurons also connect out to many brain regions, such as the ventral tegmental area (VTA). The VTA helps to control reward-seeking behavior and may have a role in depression and other mood disorders.

LHb neurons in helpless rats were more responsive, such that communication signals to the VTA were more likely to be transmitted in the helpless rats than in control rats. In an attempt to moderate this phenomenon, the researchers tested the effects of deep brain stimulation (DBS), a surgical procedure currently being tested in humans for treatment-resistant depression. Applying continuous electrical stimulation directly to the LHb resulted in greatly reduced transmission to the VTA and a marked reduction in helpless behavior. The effects on transmission lasted only as long as the stimulation lasted. More intense stimulation resulted in stronger behavioral effects.

Significance
Although LHb activity was previously unstudied in the context of mood disorders, these findings suggest that this brain structure may actually play a central role in the development of depression.

What's Next
Further studies focusing on the molecular processes and signals underlying LHb activity in depression may reveal new targets for treatment development, according to the researchers. Such new treatments also may be able to reverse some forms of depressive disorders.

This study was supported in part by a Biobehavioral Research Award for Innovative New Scientists (BRAINS) from NIMH. Dr. Li was one of 12 researchers to receive this award in 2010.

New Approach to Reducing Suicide Attempts Among Depressed Teens

A novel treatment approach that includes medication plus a newly developed type of psychotherapy that targets suicidal thinking and behavior shows promise in treating depressed adolescents who had recently attempted suicide, according to a treatment development and pilot study funded by the National Institute of Mental Health (NIMH). The study, described in three articles, was published in the October 2009 issue of the Journal of the American Academy of Child and Adolescent Psychiatry. Continuing Education for Counselors
Background
Youth who attempt suicide are particularly difficult to treat because they often leave treatment prematurely, and no specific interventions exist that reliably reduce suicidal thinking and behavior (suicidality). In addition, these teens often are excluded from clinical trials testing depression treatments. The Treatment of Adolescent Suicide Attempters Study (TASA) was developed to address this need and identify factors that may predict and mediate suicide reattempts among this vulnerable population. A novel psychotherapy used in the study—cognitive behavioral therapy for suicide prevention (CBT-SP—was developed to address the need for a specific psychotherapy that would prevent or reduce the risk for suicide reattempts among teens. CBT-SP consisted of a 12-week acute treatment phase focusing on safety planning, understanding the circumstances and vulnerabilities that lead to suicidal behavior, and building life skills to prevent a reattempt. A maintenance continuation phase followed the acute phase.

In the six-month, multisite pilot study, 124 adolescents who had recently attempted suicide were either randomized to or given the option of choosing one of three interventions—antidepressant medication only, CBT-SP only, or a combination of the two. Most participants preferred to choose their intervention, and most (93) chose combination therapy. Participants were assessed for suicidality at weeks six, 12, 18 and 24.

Results of the Study
During the six-month treatment, 24 participants experienced a new suicidal event, defined as new onset or worsening of suicidal thinking or a suicide attempt. This rate of recurrence is lower than what previous studies among suicidal patients have found, suggesting that this treatment approach may be a promising intervention. In addition, more than 70 percent of these teens—a population that is typically difficult to keep in treatment—completed the acute phase of the therapy. However, many participants discontinued the treatment during the continuation phase, suggesting that treatment may need to include more frequent sessions during the acute phase, and limited sessions during the continuation phase.

The study revealed some characteristics that could predict recurrent suicidality, including high levels of self-reported suicidal thinking and depression, a history of abuse, two or more previous suicide attempts, and a strong sense of hopelessness. In addition, a high degree of family conflict predicted suicidality, while family support and cohesion acted as a protective factor against suicide reattempts. Other studies have found similar results, according to the researchers.

Significance
Although the study cannot address effectiveness of the treatment because it was not randomized, it sheds light on characteristics that identify who is most at risk for suicide reattempts, and what circumstances may help protect teens from attempting suicide again. In addition, the study found that 10 of the 24 suicide events occurred within four weeks of the beginning of the study—before they could receive adequate treatment. This suggests that a "front-loaded" intervention in which the most intense treatment is given early on, would likely reduce the risk of suicide reattempt even more.

What's Next
The effectiveness of CBT-SP—alone or in conjunction with antidepressant medication—will need to be tested in randomized clinical trials. In the meantime, because many suicide events occurred shortly after the beginning of the trial, the researchers suggest that clinicians emphasize safety planning and provide more intense therapy in the beginning of treatment. In addition, they note that therapy should focus on helping teens develop a tolerance for distress; work to improve the teen's home, school and social environment; and rigorously pursue coping strategies for teens who experienced childhood trauma such as abuse.

References
Vitiello B, Brent D, Greenhill L, Emslie G, Wells K, Walkup J, et al.. Depressive symptoms and clinical status during the treatment of adolescent suicide attempters. Journal of the American Academy of Child and Adolescent Psychiatry 2009;48(10):997-1004.

Brent D, Greenhill L, Compton S,Emslie G, Wells K, Walkup J, et al. The treatment of adolescent suicide attempters (TASA): predictors of suicidal events in an open treatment trial. Journal of the American Academy of Child and Adolescent Psychiatry. 2009;48(10):987-996.

Stanley B, Brown G, Brent D, Wells K, Poling K, Curry J, et al. Cognitive behavior therapy for suicide prevention (CBT-SP): treatment model, feasibility and acceptability. Journal of the American Academy of Child and Adolescent Psychiatry. 2009;48(10):1005-1013.

Get Fit and Be Active Your Way: Popular New Year's Resolutions

Be Active Your Way
A Guide for Adults

•Wondering about how much activity you need each week?
•Want to get physically active but not sure where to begin?
•Already started a program and would like tips on how to keep it up or step it up?

Written for men and women ages 18 to 64, this booklet is based on the 2008 Physical Activity Guidelines for Americans released by the U.S. Department of Health and Human Services. When reading, you'll want to pay special attention to the Advice to Follow boxes in this booklet. They offer you a quick snapshot of the latest information from these new guidelines.

Share this booklet with your family and friends so you can be active together!

What is physical activity?
Did you know?

•Some activity is better than none.
•The more you do, the greater the health benefits and the better you’ll feel.
Physical activity is any form of exercise or movement of the body that uses energy. Some of your daily life activities—doing active chores around the house, yard work, walking the dog—are examples.

To get the health benefits of physical activity, include activities that make you breathe harder and make your heart and blood vessels healthier. These aerobic activities include things like brisk walking, running, dancing, swimming, and playing basketball. Also include strengthening activities to make your muscles stronger, like push-ups and lifting weights.

The good news?
People of all types, shapes, sizes, and abilities can benefit from being physically active. If you have a disability, choose activities in this booklet that work for you. Talk with your health care team about the amount and types of activities that are right for your ability or condition.

Making Physical Activity a Part of Your Life

Doing More
"I started taking a 45-minute water aerobics class with a group of women from church. It's really a lot of fun, and I am getting in shape. I started out going 2 days a week, and now my goal is to make it to all 3 classes a week."
Congratulations! You are doing some regular physical activity each week and are ready to do more. You may be feeling the benefits of getting active, such as having fun with friends, sleeping better, and getting toned. Are you looking for ways to do more activities at a moderate level?

Here are 2 examples for adding more activity
1.You can do more by being active longer each time. Walking for 30 minutes, 3 times a week? Go longer—walk for 50 minutes, 3 times a week.
2.You can do more, by being active more often. Are you biking lightly 3 days a week for 25 minutes each time? Increase the number of days you bike. Work up to riding 6 days a week for 25 minutes each time.
Tip: If you have not been this active in the past, work your way up. In time, replace some moderate activities with vigorous activities that take more effort. These are explained in detail in Part 3. Counselor Continuig Education
Activities for stronger muscles and bones
Advice to follow:
Adults should do activities to strengthen muscles and bones at least 2 days a week.
Choose activities that work all the different parts of the body—your legs, hips, back, chest, stomach, shoulders, and arms. Exercises for each muscle group should be repeated 8 to 12 times per session.

Try some of these activities a couple of days a week:
•Heavy gardening (digging, shoveling)
•Lifting weights
•Push-ups on the floor or against the wall
•Sit-ups
•Working with resistance bands (long, wide rubber strips that stretch)
Tip: Some people like resistance bands because they find them easy to use and put away when they are done. Others prefer weights; you can use common grocery items, such as bags of rice, vegetable or soup cans, or bottled water.

For best success
•Team up with a friend. It will keep you motivated and be more fun.
•Pick activities that you like to do.
•Track your time and progress. It helps you stay on course. Fill in these forms to help set your activity goals. Before you know it, you'll be able to do at least 2 hours and 30 minutes of activities at a moderate level each week.
•Add in more strength-building activities over time. For example, you can do sit-ups or push-ups.

Shaping up
"My son and I play in a baseball league twice a week. On the days we play, I sleep much better at night. This makes me want to do more on other days. My son wants to lift weights together, and so we got some weights and work out in the basement."

Planning your activity for the week
Physical activity experts say that spreading aerobic activity out over at least 3 days a week is best. Also, do each activity for at least 10 minutes at a time. There are many ways to fit in 2 hours and 30 minutes a week. For example, you can do 30 minutes of aerobic activity each day, for 5 days.

On the other 2 days, do activities to keep your muscles strong. Find ways that work well for you.

Want to learn more about how to add physical activity to your life?
•Join a fitness group.
•Talk to your health care provider about good activities to try.
•Speak to the worksite wellness coordinator at your job.
•Visit www.healthfinder.gov and type "activity" in the search box.

Family Health: Holiday Health and Safety Tips

The holidays are a time to celebrate, give thanks, and reflect. They are also a time to pay special attention to your health. Give the gift of health and safety to yourself and others by following these holiday tips.

Wash your hands often.
Keeping hands clean is one of the most important steps you can take to avoid getting sick and spreading germs to others. Wash your hands with soap and clean running water for at least 20 seconds. If soap and clean water are not available, use an alcohol-based product.

Clean Hands Save Lives


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Stay warm.
Cold temperatures can cause serious health problems, especially in infants and older adults. Stay dry, and dress warmly in several layers of loose-fitting, tightly woven clothing.


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Manage stress.
The holidays don’t need to take a toll on your health. Keep a check on over-commitment and over-spending. Balance work, home, and play. Get support from family and friends. Keep a relaxed and positive outlook.


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Travel safely.
Whether you're traveling across town or around the world, help ensure your trip is safe. Don’t drink and drive, and don’t let someone else drink and drive. Wear a seat belt every time you drive or ride in a motor vehicle. Always buckle your child in the car using a child safety seat, booster seat, or seat belt according to his/her height, weight, and age.

Available through the CDC:
Extreme Cold: A Prevention Guide to Promote Your Personal Health and Safety

Impaired Driving

Keep Kids Safe on the Road

Stay Safe and Healthy in Winter Weather

Traumatic Brain Injury

Travelers’ Health


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Be smoke-free.
Avoid smoking and breathing other people's smoke. If you smoke, quit today! Call 1-800-QUIT-NOW or talk to your health care provider for help.


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Get check-ups and vaccinations.
Exams and screenings can help find problems before they start. They can also help find problems early, when the chances for treatment and cure are better. Vaccinations help prevent diseases and save lives. Schedule a visit with your health care provider for a yearly exam. Ask what vaccinations and tests you should get based on your age, lifestyle, travel plans, medical history, and family health history.

Available through the CDC:
Things to Do Before Your Next Check-Up

Family Health History Resources and Tools

Get Smart: Know When Antibiotics Work

Vaccines and Immunizations

Safety of 2010-2011 Flu Vaccines

Women: Stay Healthy at Any Age (AHRQ)

Men: Stay Healthy at Any Age (AHRQ)


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Watch the kids.
Children are at high risk for injuries that can lead to death or disability. Keep a watchful eye on your kids when they’re eating and playing. Keep potentially dangerous toys, food, drinks, household items, choking hazards (like coins and hard candy), and other objects out of kids' reach. Learn how to provide early treatment for children who are choking. Make sure toys are used properly.

Injuries among Children and Adolescents
Toy Safety Tips (CPSC)

Counselor Continuing Education
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Prevent injuries.
Injuries can occur anywhere and some often occur around the holidays. Use step stools instead of furniture when hanging decorations. Leave the fireworks to the professionals. Wear a bicycle helmet to help prevent head injuries.

Most residential fires occur during the winter months. Keep candles away from children, pets, walkways, trees, and curtains. Never leave fireplaces, stoves, or candles unattended. Don't use generators, grills, or other gasoline- or charcoal-burning devices inside your home or garage. Install a smoke detector and carbon monoxide detector in your home. Test them once a month, and replace batteries twice a year.

Bicycle Related Injuries

Carbon Monoxide (CO) Poisoning Prevention

Fall-Related Injuries during the Holiday Season- United States, 2000-2003

General Injury Related Information

Fire Deaths and Injuries: Prevention Tips

Fireworks-Related Injuries


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Handle and prepare food safely.
As you prepare holiday meals, keep you and your family safe from food-related illness. Wash hands and surfaces often. Avoid cross-contamination by keeping raw meat, poultry, seafood, and eggs (including their juices) away from ready-to-eat foods and eating surfaces. Cook foods to the proper temperature. Refrigerate promptly. Do not leave perishable foods out for more than two hours.

It's Turkey Time: Safely Prepare Your Holiday Meal

Seasonal Food Safety: Fact Sheets (USDA)


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Eat healthy, and be active.
With balance and moderation, you can enjoy the holidays the healthy way. Choose fresh fruit as a festive and sweet substitute for candy. Select just one or two of your favorites from the host of tempting foods. Find fun ways to stay active, such as dancing to your favorite holiday music. Be active for at least 2½ hours a week. Help kids and teens be active for at least 1 hour a day.

Alcohol: Frequently Asked Questions

Get Smart Entertaining

Healthy Weight

Be Physically Active in the New Year

Managing Diabetes During the Holidays

Physical Activity for Everyone


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Protect pets from rabies.
Pets are also considered family members by many. Keep them healthy. There are several things you can do to protect your pet from rabies. First, visit your veterinarian with your pet on a regular basis and keep rabies vaccinations up-to-date for all cats, ferrets, and dogs.