Linked Brain Centers Mature in Sync

Imaging Reveals Underlying Unity Between Brain Structure and Development

Long-term neuroimaging studies show for the first time that areas of the brain that are wired together structurally and functionally also tend to mature in tandem over the course of development. The finding adds a new dimension to a picture that is emerging of how structure, function, and development of the brain are intertwined ceus for mfts

Background

Studies of brain development have shown that growth across the brain is not steady and uniform; some areas mature more quickly than others. These studies to date have not, however, examined whether areas of the brain that are linked functionally also develop in a coordinated way. It’s a challenging question because the developmental changes in brain anatomy that can be detected by neuroimaging unfold very slowly. Also, tempos of anatomical change differ from person to person, so comparing brain dimensions in different individuals at the same age can be misleading. The only way to approach this question is to track patterns of growth in the same individuals over many years.

This Study

To address this question, Armin Raznahan and colleagues at NIMH took advantage of a dataset that is unique in the world, consisting of records of brain growth measured by magnetic resonance imaging (MRI) of individuals from childhood to young adulthood. They studied changes in thickness of the outer layer of the brain, the cortex. In order to look for correlated anatomical change in connected parts of the brain, these investigators used records of cortical thickness from 108 individuals from ages 9 to 22. They focused on a well-defined and documented brain circuit: the default mode network or DMN. The DMN, a network identified by functional brain imaging, consists of nodes, or centers, in the brain that are active when someone’s mind is at rest, but quiet when the mind is focused on a task. In addition to tracking growth in the DMN, the NIMH investigators also looked at patterns of growth on the right and left side of the brain. There are extensive neuronal connections between the right and left hemispheres of the brain. Activation tends to be symmetrical and simultaneous within analogous parts on either side of the brain.

Results showed that there was a marked correlation in the rates of cortical thickness change between different points within the DMN when compared with the average correlation among thousands of other points across the brain. A similar pattern was seen among points in a second “task positive” network that is active while someone is carrying out goal-directed tasks; rates of change in cortical thickness within this second network also showed a pattern of coordinated maturing. Parts of the cortex involved in the integration and processing of incoming information and responses—the association cortex—were most likely to show correlated anatomical change with broad areas of the cortex. Similar correlations in change were not seen among parts of the cortex involved primarily in sensory input.

Correlations in anatomical change were also apparent between analogous centers on the right and left side of the brain, paralleling the symmetry in activation of these areas. Finally, the investigators looked at an area of the cortex (the frontopolar cortex) for which previous work had shown differences in the rate of maturation between males and females. This study found the same difference between males and females in maturation rate in this area. In addition, there were differences between the sexes in the degree to which thickness change in this area showed coordination with that of other areas of the cortex.

The coloring in this MRI scan reflects the extent to which changes in various areas of the maturing cortex correlate with similar changes over time in the default mode network, a network in the brain that is active when a person is at rest. Red indicates the highest degree of correlation—blue is the lowest. (Colors indicate correlation with one “node” within the default mode network, indicated by a circle in the image.)

Source: Armin Raznahan, Child Psychiatry Branch, National Institute of Mental Health


Significance

Neuroscientists are increasingly viewing the brain in terms of the development and function of neural circuits. According to Dr. Raznahan, this approach represents a sea change compared to the earlier emphasis on studying individual brain areas. In addition to the work reported here, recent studies of gene expression (activity) patterns in the brain suggest that genes that have roles in laying down connections between functionally related areas are also especially active during development.

In a high percentage of cases of mental disorders, the first symptoms emerge during youth; this is one piece of evidence that mental illnesses are disorders of development. Research on the relationships between brain connectedness and structural maturation can help provide a basis for future studies of how disruptions in the laying down of neural circuits in the brain during development can shape the structure and function of the adult brain and set the stage for mental illness. The authors point out in their paper that disorders that disrupt functional connections might also alter structural brain development. Comparing how development unfolds in individuals with and without disorders of mental health can offer clues to causes and targets for therapies. Finally, the findings on sex differences reported here can lend insight into the types of behavior seen during adolescence, especially risk-taking.

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 bd able to provide more information on the efficacy of the treatment in children and how it works to reduce symptoms of anxiety.

history of the 80s

history of the 80s

Pattern Recognition Technology May Help Predict Future Mental Illness in Teens

Pattern Recognition Technology May Help Predict Future Mental Illness in Teens


Source: NIMH

A technique combining computer-based pattern recognition and brain imaging data accurately distinguished teens at risk for mental disorders from those with low risk and may someday be useful in predicting risk in individuals, according to an NIMH-funded study published February 15, 2012, in the journal PLoS One.

Background

Research on risk for mental disorders generally describes risk factors that apply to groups. To date, no biological measures can accurately predict an individual’s risk of future mental disorders.

Mary Phillips, M.D., of the University of Pittsburgh School of Medicine, and colleagues evaluated the use of computer-based techniques that automatically find patterns in data—these techniques are collectively called machine learning—with functional magnetic resonance imaging (fMRI) data. The researchers obtained fMRI data from 32 teens, half of whom had at least one biological parent diagnosed with bipolar disorder and were therefore at genetic risk for future psychiatric disorders. The other half of teens had no history of mental disorders either personally or in their immediate families.

The teens’ brain activity was assessed as they identified the gender of actors depicting various emotional facial expressions (happy, fearful, or neutral) in a series of photographs. Previous research has linked various mental disorders, especially depression and bipolar disorder, with abnormal patterns of brain activity during this task. Based on this fMRI data, the researchers used machine learning to calculate each participant’s odds for future mental illness social worker ceus

The participants were also assessed clinically and with fMRI at the start of the study, and clinically assessed again about two years later, on average. Long-term follow up is ongoing, with successive face-to-face assessments occurring every other year.

Results

Machine learning combined with fMRI accurately identified most of the healthy teens at genetic risk of future mental disorders vs. healthy teens with low genetic risk. Four of the 16 at-risk teens were misidentified as having low risk.

At the two-year follow up, none of the at-risk teens had developed bipolar disorder, but six were diagnosed with major depression or an anxiety disorder. Among all the at-risk teens identified through machine learning, these six had received the highest odds for belonging to the at-risk group.

Three of the four at-risk teens misidentified as belonging to the low risk group at the start of the study remained healthy at the second assessment. Clinical information for the fourth teen was not available at the time of follow-up.

Significance

Though still a very preliminary study, according to the researchers, machine learning combined with fMRI shows promise for predicting individual risk of developing future mental disorders, especially in at-risk populations.

The ongoing follow-up may also yield further insights into the relationship between depression, anxiety disorders, and bipolar disorder. Many studies have shown that bipolar disorder is often preceded by depression or anxiety disorders, and that these disorders may affect the course of subsequent bipolar disorder.

What’s Next

Larger studies using machine learning and fMRI will help to better define the extent to which pattern recognition techniques can accurately identify people at risk for future mental disorders. Research in this area may also inform early treatment or prevention efforts.

How stress influences disease: Carnegie Mellon study reveals inflammation as the culprit

PITTSBURGH—Stress wreaks havoc on the mind and body. For example, psychological stress is associated with greater risk for depression, heart disease and infectious diseases. But, until now, it has not been clear exactly how stress influences disease and health.

A research team led by Carnegie Mellon University's Sheldon Cohen has found that chronic psychological stress is associated with the body losing its ability to regulate the inflammatory response. Published in the Proceedings of the National Academy of Sciences, the research shows for the first time that the effects of psychological stress on the body's ability to regulate inflammation can promote the development and progression of disease continuing education for social workers

"Inflammation is partly regulated by the hormone cortisol and when cortisol is not allowed to serve this function, inflammation can get out of control," said Cohen, the Robert E. Doherty Professor of Psychology within CMU's Dietrich College of Humanities and Social Sciences.

Cohen argued that prolonged stress alters the effectiveness of cortisol to regulate the inflammatory response because it decreases tissue sensitivity to the hormone. Specifically, immune cells become insensitive to cortisol's regulatory effect. In turn, runaway inflammation is thought to promote the development and progression of many diseases.

Cohen, whose groundbreaking early work showed that people suffering from psychological stress are more susceptible to developing common colds, used the common cold as the model for testing his theory. With the common cold, symptoms are not caused by the virus — they are instead a "side effect" of the inflammatory response that is triggered as part of the body's effort to fight infection. The greater the body's inflammatory response to the virus, the greater is the likelihood of experiencing the symptoms of a cold.

In Cohen's first study, after completing an intensive stress interview, 276 healthy adults were exposed to a virus that causes the common cold and monitored in quarantine for five days for signs of infection and illness. Here, Cohen found that experiencing a prolonged stressful event was associated with the inability of immune cells to respond to hormonal signals that normally regulate inflammation. In turn, those with the inability to regulate the inflammatory response were more likely to develop colds when exposed to the virus.

In the second study, 79 healthy participants were assessed for their ability to regulate the inflammatory response and then exposed to a cold virus and monitored for the production of pro-inflammatory cytokines, the chemical messengers that trigger inflammation. He found that those who were less able to regulate the inflammatory response as assessed before being exposed to the virus produced more of these inflammation-inducing chemical messengers when they were infected.

"The immune system's ability to regulate inflammation predicts who will develop a cold, but more importantly it provides an explanation of how stress can promote disease," Cohen said. "When under stress, cells of the immune system are unable to respond to hormonal control, and consequently, produce levels of inflammation that promote disease. Because inflammation plays a role in many diseases such as cardiovascular, asthma and autoimmune disorders, this model suggests why stress impacts them as well."

He added, "Knowing this is important for identifying which diseases may be influenced by stress and for preventing disease in chronically stressed people."

Mothers and OCD children trapped in rituals have impaired relationships

News Release: Tuesday, April 10, 2012

A new study from Case Western Reserve University finds mothers tend to be more critical of children with obsessive-compulsive disorder than they are of other children in the family. And, that parental criticism is linked to poorer outcomes for the child after treatment.

Parent criticism has been associated with child anxiety in the past, however, researchers wanted to find out if this is a characteristic of the parent or something specific to the relationship between the anxious child and the parent.

“This suggests that mothers of anxious children are not overly critical parents in general. Instead they seem to be more critical of a child with OCD than they are of other children in the home,” said Amy Przeworski, assistant professor of psychology. She is the lead author of the study, “Maternal and Child Expressed Emotion as Predictors of Treatment Response in Pediatric Obsessive-Compulsive Disorder,” in the recent journal, Child Psychiatry & Human Development.

OCD is found in one in 200 children, according to the American Academy of Child and Adolescent Psychiatry. The psychological disorder overcomes individuals with repetitive thoughts that lead to anxiety, which is then acted out in exacting routines or behaviors that can range from foot tapping to eating rituals to school or bedtime preparations.

This research evolved from other studies that found parental criticism is associated with less success in therapy and a relapse of behavior.

“Parents’ criticism may be a reaction to the child’s anxiety. This research is not blaming the parent for the child’s OCD. But it does suggest that the relationship between parents and children with OCD is important and should be a focus of treatment. This means that parents can help children with OCD to get better.” Przeworski says.

“OCD sneaks up on the kids and parents,” Przeworski says.

The psychology professor, who specializes in anxiety disorders, says some parents become concerned when their children show some early warning signs for OCD:

• Rigidity in a child, with things routinely done or said in exactly the same way or order.
• Asking for reassurance many times in the day.
• Repetition of a task from tapping the foot, checking on the stove, washing hands that the child cannot stop when asked.
• Routines that have prescribed patterns or are excessive lengthy: An example is a two-hour shower or raw and chapped hands that look like the child is wearing red gloves.
• Bedtime or dinner rituals, where there is a prescribed order for eating food, placement of food on the plate, etc.
• Temper tantrums where the child goes beyond being stubborn but has anxiety associated with them.
• Children want symmetry in appearance or things around them.

Parents initially may think it is a phase, a habit or stubbornness. Over time, the behaviors become so exacting that the child and family members have to act in prescribed ways. Parents may end up criticizing the child in an effort to get them to drop obsessive-compulsive behaviors.

The researchers videotaped interviews with 62 mother-child pairs just before the child’s OCD treatment began. Children either had medication, therapy, a combination of the two, or a placebo. The children were between the ages of 7 and 17.

Because most mothers bring their children for treatment appointments, the researchers focused on the mother’s view of their children. Mothers were asked to give a five-minute description of their relationship with the child with OCD and the mother’s relationship with the sibling closest in age to the child with OCD. The researchers asked the children to describe their relationships with their mothers and fathers.

The researchers examined the presence of criticism and emotional over-involvement (over-protection or excessive self-sacrificing) in these descriptions. The tone of the OCD child and parent tended toward criticism, they said. The other sibling received more loving expressions. Parent criticism was associated with poorer child functioning after treatment.

Przeworski said treatment of OCD has good results, but many times parents misjudge these rigid routines as stubbornness or “just going through a phase” until the behavior takes over family life. Then parents realize the behavior requires therapy professional counselor continuing education

Collaborating with Przeworski were: Lori Zoellner from University of Washington; Martin E. Franklin and Edna B. Foa, University of Pennsylvania School of Medicine; and Abbe Garcia and Jennifer Freeman, Brown University. The study was supported with funds from the National Institute of Mental Health.

Spontaneous Gene Glitches Linked to Autism Risk with Older Dads

Non-Inherited Mutations Spotlight Role of Environment – NIH-Supported Study, Consortium ceus for nurses

Researchers have turned up a new clue to the workings of a possible environmental factor in autism spectrum disorders (ASDs): fathers were four times more likely than mothers to transmit tiny, spontaneous mutations to their children with the disorders. Moreover, the number of such transmitted genetic glitches increased with paternal age. The discovery may help to explain earlier evidence linking autism risk to older fathers.

The results are among several from a trio of new studies, supported in part by the National Institutes of Health, finding that such sequence changes in parts of genes that code for proteins play a significant role in ASDs. One of the studies determined that having such glitches boosts a child’s risk of developing autism five to 20 fold.

Taken together, the three studies represent the largest effort of its kind, drawing upon samples from 549 families to maximize statistical power. They reveal sporadic mutations widely distributed across the genome, sometimes conferring risk and sometimes not. While the changes identified don’t account for most cases of illness, they are providing clues to the biology of what are likely multiple syndromes along the autism spectrum.

“These results confirm that it’s not necessarily the size of a genetic anomaly that confers risk, but its location – specifically in biochemical pathways involved in brain development and neural connections. Ultimately, it’s this kind of knowledge that will yield potential targets for new treatments,” explained Thomas, R. Insel, M.D., director of the NIH’s National Institute of Mental Health (NIMH), which funded one of the studies and fostered development of the Autism Sequencing Consortium, of which all three groups are members.

Multi-site research teams led by Mark Daly, Ph.D., of the Harvard/MIT Broad Institute, Cambridge, Mass., Matthew State, M.D., Ph.D., of Yale University, New Haven, Conn., and Evan Eichler, Ph.D., of the University of Washington, Seattle, report on their findings online April 4, 2012 in the journal Nature.

The study by Daly and colleagues was supported by NIMH – including funding under the American Recovery and Reinvestment Act. The State and Eichler studies were primarily supported by the Simons Foundation Autism Research Initiative. The studies also acknowledge the NIH’s National Human Genome Research Institute, National Heart Lung and Blood Institute, and National Institute on Child Health and Human Development and other NIH components.

All three teams sequenced the protein coding parts of genes in parents and an affected child – mostly in families with only one member touched by autism. One study also included comparisons with healthy siblings. Although these protein-coding areas represent only about 1.5 percent of the genome, they harbor 85 percent of disease-causing mutations. This strategy optimized the odds for detecting the few spontaneous errors in genetic transmission that confer autism risk from the “background noise” generated by the many more benign mutations.

Like larger deletions and duplications of genetic material previously implicated in autism and schizophrenia, the tiny point mutations identified in the current studies are typically not inherited in the conventional sense – they are not part of parents’ DNA, but become part of the child’s DNA. Most people have many such glitches and suffer no ill effects from them. But evidence is building that such mutations can increase risk for autism if they occur in pathways that disrupt brain development.

State’s team found that 14 percent of people with autism studied had suspect mutations – five times the normal rate. Eichler and colleagues traced 39 percent of such mutations likely to confer risk to a biological pathway known to be important for communications in the brain.

Although Daly and colleagues found evidence for only a modest role of the chance mutations in autism, those pinpointed were biologically related to each other and to genes previously implicated in autism.

The Eichler team turned up clues to how environmental factors might influence genetics. The high turnover in a male’s sperm cells across the lifespan increases the chance for errors to occur in the genetic translation process. These can be passed-on to the offspring’s DNA, even though they are not present in the father’s DNA. This risk may worsen with aging. The researchers discovered a four-fold marked paternal bias in the origins of 51 spontaneous mutations in coding areas of genes that was positively correlated with increasing age of the father. So such spontaneous mutations could account for findings of an earlier study that found fathers of boys with autism were six times – and of girls 17 times – more likely to be in their 40’s than their 20’s.

“We now have a path forward to capture a great part of the genetic variability in autism – even to the point of being able to predict how many mutations in coding regions of a gene would be needed to account for illness,” said Thomas Lehner, Ph.D., chief of the NIMH Genomics Research Branch, which funded the Daly study and helped to create the Autism Sequencing Consortium. “These studies begin to tell a more comprehensive story about the molecular underpinnings of autism that integrates previously disparate pieces of evidence.”