Early childhood depression alters brain development

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"The brains of children who suffer clinical depression as preschoolers develop abnormally, compared with the brains of preschoolers unaffected by the disorder, according to new research at Washington University School of Medicine in St. Louis. Their gray matter -- tissue that connects brain cells and carries signals between those cells and is involved in seeing, hearing, memory, decision-making and emotion -- is lower in volume and thinner in the cortex, a part of the brain important in the processing of emotions. The new study is published Dec. 16 in JAMA Psychiatry. "What is noteworthy about these findings is that we are able to see how a life experience -- such as an episode of depression -- can change the brain's anatomy," said first author Joan L. Luby, MD, whose research established that children as young as 3 can experience depression. "Traditionally, we have thought about the brain as an organ that develops in a predetermined way, but our research is showing that actual experience -- including negative moods, exposure to poverty, and a lack of parental support and nurturing -- have a material impact on brain growth and development." The findings may help explain why children and others who are depressed have difficulty regulating their moods and emotions. The research builds on earlier work by Luby's group that detailed other differences in the brains of depressed children. Luby, the Samuel and Mae S. Ludwig Professor of Child Psychiatry, and her team studied 193 children, 90 of whom had been diagnosed with depression as preschoolers. They performed clinical evaluations on the children several times as they aged. The researchers also conducted MRI scans at three points in time as each child got older. The first scans were performed when the kids were ages 6 to 8, and the final scans were taken when they were ages 12 to 15. A total of 116 children in the study received all three brain scans. "If we had only scanned them at one age or stage, we wouldn't know whether these effects simply were present from birth or reflected an actual change in brain development," said co-investigator Deanna M. Barch, PhD, head of Washington University's Department of Psychological and Brain Sciences in Arts & Sciences. "By scanning them multiple times, we were able to see that the changes reflect an actual difference in brain maturation that emerges over the course of development." The gray matter is made up mainly of neurons, along with axons that extend from brain cells to carry signals. The gray matter processes information, and as children get older, they develop more of it. Beginning around puberty, the amount of gray matter begins to decline as communication between neurons gets more efficient and redundant processes are eliminated. "Gray matter development follows an inverted U-shaped curve," Luby said. "As children develop normally, they get more and more gray matter until puberty, but then a process called pruning begins, and unnecessary cells die off. But our study showed a much steeper drop-off, possibly due to pruning, in the kids who had been depressed than in healthy children." Further, the steepness of the drop-off in the volume and thickness of the brain tissue correlated with the severity of depression: The more depressed a child was, the more severe the loss in volume and thickness. The researchers determined that having depression was a key factor in gray matter development. In scans of children whose parents had suffered from depression -- meaning the kids would be at higher risk -- gray matter appeared normal unless the kids had suffered from depression, too. Interestingly, the differences in gray matter volume and thickness typically were more pronounced than differences in other parts of the brain linked to emotions. Luby explained that because gray matter is involved in emotion processing, it is possible some of the structures involved in emotion, such as the brain's amygdala, may function normally, but when the amygdala sends signals to the cortex -- where gray matter is thinner -- the cortex may be unable to regulate those signals properly. Luby and Barch are planning to conduct brain scans on even younger children to learn whether depression may cause pruning in the brain's gray matter to begin earlier than normal, changing the course of brain development as a child grows. "A next important step will involve determining whether early intervention might shift the trajectory of brain development for these kids so that they revert to more typical and healthy development," said Barch, also the Gregory B. Couch Professor of Psychiatry. Luby said that is the main challenge facing those who treat kids with depression. "The experience of early childhood depression is not only uncomfortable for the child during those early years," she said. "It also appears to have long-lasting effects on brain development and to make that child vulnerable to future problems. If we can intervene, however, the benefits might be just as long-lasting." ### Funding from the National Institute of Mental Health and the National Institutes of Health Blueprint of the National Institutes of Health (NIH), grant numbers R01 MH66031, R01 MH084840, R01 MH090786, R01 MH098454-S, U54 MH091657, 2R01 MH064769-06A1, PA-07-070 NIMH R01 5K01MH090515-04 and T32 MH100019. Luby JL, Belden AC, Jackson JL, Lessov-Schlaggar CN, Harms MP, Tillman R, Botteron K, Whalen D, Barch DM. Early childhood depression and alterations in the trajectory of gray matter maturation in middle childhood and early adolescence?. JAMA Psychiatry, published online Dec. 16, 2015. http://jamapsychiatry.com doi:10.1001/jamapsychiatry.2015.2356 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 sixth 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." For more information on depression and other mental health related topics,please visit Aspira Continuing Education Online Courses

New evidence that chronic stress predisposes brain to mental illness

By Robert Sanders, Media Relations | February 11, 2014 BERKELEY — University of California, Berkeley, researchers have shown that chronic stress generates long-term changes in the brain that may explain why people suffering chronic stress are prone to mental problems such as anxiety and mood disorders later in life. myelin stained blue Myelin is stained blue in this cross section of a rat hippocampus. Myelin, which speeds electrical signals flowing through axons, is produced by oligodendrocytes, which increase in number as a result of chronic stress. New oligodendrocytes are shown in yellow. Image by Aaron Friedman and Daniela Kaufer. Their findings could lead to new therapies to reduce the risk of developing mental illness after stressful events. Doctors know that people with stress-related illnesses, such as post-traumatic stress disorder (PTSD), have abnormalities in the brain, including differences in the amount of gray matter versus white matter. Gray matter consists mostly of cells – neurons, which store and process information, and support cells called glia – while white matter is comprised of axons, which create a network of fibers that interconnect neurons. White matter gets its name from the white, fatty myelin sheath that surrounds the axons and speeds the flow of electrical signals from cell to cell. How chronic stress creates these long-lasting changes in brain structure is a mystery that researchers are only now beginning to unravel. In a series of experiments, Daniela Kaufer, UC Berkeley associate professor of integrative biology, and her colleagues, including graduate students Sundari Chetty and Aaron Freidman, discovered that chronic stress generates more myelin-producing cells and fewer neurons than normal. This results in an excess of myelin – and thus, white matter – in some areas of the brain, which disrupts the delicate balance and timing of communication within the brain. “We studied only one part of the brain, the hippocampus, but our findings could provide insight into how white matter is changing in conditions such as schizophrenia, autism, depression, suicide, ADHD and PTSD,” she said. The hippocampus regulates memory and emotions, and plays a role in various emotional disorders. Kaufer and her colleagues published their findings in the Feb. 11 issue of the journal Molecular Psychiatry. Does stress affect brain connectivity? Kaufer’s findings suggest a mechanism that may explain some changes in brain connectivity in people with PTSD, for example. One can imagine, she said, that PTSD patients could develop a stronger connectivity between the hippocampus and the amygdala – the seat of the brain’s fight or flight response – and lower than normal connectivity between the hippocampus and prefrontal cortex, which moderates our responses. “You can imagine that if your amygdala and hippocampus are better connected, that could mean that your fear responses are much quicker, which is something you see in stress survivors,” she said. “On the other hand, if your connections are not so good to the prefrontal cortex, your ability to shut down responses is impaired. So, when you are in a stressful situation, the inhibitory pathways from the prefrontal cortex telling you not to get stressed don’t work as well as the amygdala shouting to the hippocampus, ‘This is terrible!’ You have a much bigger response than you should.” white matter fibers in human brain White matter fiber architecture of the brain. Human Connectome Project. She is involved in a study to test this hypothesis in PTSD patients, and continues to study brain changes in rodents subjected to chronic stress or to adverse environments in early life. Stress tweaks stem cells Kaufer’s lab, which conducts research on the molecular and cellular effects of acute and chronic stress, focused in this study on neural stem cells in the hippocampus of the brains of adult rats. These stem cells were previously thought to mature only into neurons or a type of glial cell called an astrocyte. The researchers found, however, that chronic stress also made stem cells in the hippocampus mature into another type of glial cell called an oligodendrocyte, which produces the myelin that sheaths nerve cells. The finding, which they demonstrated in rats and cultured rat brain cells, suggests a key role for oligodendrocytes in long-term and perhaps permanent changes in the brain that could set the stage for later mental problems. Oligodendrocytes also help form synapses – sites where one cell talks to another – and help control the growth pathway of axons, which make those synapse connections. The fact that chronic stress also decreases the number of stem cells that mature into neurons could provide an explanation for how chronic stress also affects learning and memory, she said. Kaufer is now conducting experiments to determine how stress in infancy affects the brain’s white matter, and whether chronic early-life stress decreases resilience later in life. She also is looking at the effects of therapies, ranging from exercise to antidepressant drugs, that reduce the impact of stress and stress hormones. Kaufer’s coauthors include Chetty, formerly from UC Berkeley’s Helen Wills Neuroscience Institute and now at Harvard University; Friedman and K. Taravosh-Lahn at UC Berkeley’s Department of Integrative Biology; additional colleagues from UC Berkeley and others from Stanford University and UC Davis. The work was supported by a BRAINS (Biobehavioral Research Awards for Innovative New Scientists) award from the National Institute of Mental Health of the National Institutes of Health (R01 MH087495), a Berkeley Stem Cell Center Seed Grant, the Hellman Family Foundation and the National Alliance for Research on Schizophrenia and Depression. RELATED INFORMATION •Stress and glucocorticoids promote oligodendrogenesis in the adult hippocampus (2/11/14 Molecular Psychiatry) •Daniela Kaufer’s web site •Researchers find out why some stress is good for you (4/16/13 press release) For more information on this and other mental health topics, please visit Counselor CEUs

SHY hypothesis explains that sleep is the price we pay for learning

MADISON — Why do animals ranging from fruit flies to humans all need to sleep? After all, sleep disconnects them from their environment, puts them at risk and keeps them from seeking food or mates for large parts of the day. Two leading sleep scientists from the University of Wisconsin School of Medicine and Public Health say that their synaptic homeostasis hypothesis of sleep or "SHY" challenges the theory that sleep strengthens brain connections. The SHY hypothesis, which takes into account years of evidence from human and animal studies, says that sleep is important because it weakens the connections among brain cells to save energy, avoid cellular stress, and maintain the ability of neurons to respond selectively to stimuli. "Sleep is the price the brain must pay for learning and memory," says Dr. Giulio Tononi, of the UW Center for Sleep and Consciousness. "During wake, learning strengthens the synaptic connections throughout the brain, increasing the need for energy and saturating the brain with new information. Sleep allows the brain to reset, helping integrate, newly learned material with consolidated memories, so the brain can begin anew the next day. " Tononi and his co-author Dr. Chiara Cirelli, both professors of psychiatry, explain their hypothesis in a review article in today's issue of the journal Neuron. Their laboratory studies sleep and consciousness in animals ranging from fruit flies to humans; SHY takes into account evidence from molecular, electrophysiological and behavioral studies, as well as from computer simulations. "Synaptic homeostasis" refers to the brain's ability to maintain a balance in the strength of connections within its nerve cells. Why would the brain need to reset? Suppose someone spent the waking hours learning a new skill, such as riding a bike. The circuits involved in learning would be greatly strengthened, but the next day the brain will need to pay attention to learning a new task. Thus, those bike-riding circuits would need to be damped down so they don't interfere with the new day's learning. "Sleep helps the brain renormalize synaptic strength based on a comprehensive sampling of its overall knowledge of the environment," Tononi says, "rather than being biased by the particular inputs of a particular waking day." The reason we don't also forget how to ride a bike after a night's sleep is because those active circuits are damped down less than those that weren't actively involved in learning. Indeed, there is evidence that sleep enhances important features of memory, including acquisition, consolidation, gist extraction, integration and "smart forgetting," which allows the brain to rid itself of the inevitable accumulation of unimportant details. However, one common belief is that sleep helps memory by further strengthening the neural circuits during learning while awake. But Tononi and Cirelli believe that consolidation and integration of memories, as well as the restoration of the ability to learn, all come from the ability of sleep to decrease synaptic strength and enhance signal-to-noise ratios. While the review finds testable evidence for the SHY hypothesis, it also points to open issues. One question is whether the brain could achieve synaptic homeostasis during wake, by having only some circuits engaged, and the rest off-line and thus resetting themselves. Other areas for future research include the specific function of REM sleep (when most dreaming occurs) and the possibly crucial role of sleep during development, a time of intense learning and massive remodeling of brain Counselor CEUs

Using biomarkers to identify and treat schizophrenia

Researchers say lab-based tests may be boon to both clinicians and researchers In the current online issue of PLoS ONE, researchers at the University of California, San Diego School of Medicine say they have identified a set of laboratory-based biomarkers that can be useful for understanding brain-based abnormalities in schizophrenia. The measurements, known as endophenotypes, could ultimately be a boon to clinicians who sometimes struggle to recognize and treat the complex and confounding mental disorder. "A major problem in psychiatry is that there are currently no laboratory tests that aid in diagnosis, guide treatment decisions or help predict treatment response or outcomes," said Gregory A. Light, PhD, associate professor of psychiatry and the study's first author. "Diagnoses are currently based on a clinician's ability to make inferences about patients' inner experiences." continuing education for counselors Diagnosing and treating schizophrenia is a particularly troubling challenge. The disorder, which affects about 1 percent of the U.S. population or roughly 3 million people, is characterized by a breakdown of normal thought processes and erratic, sometimes dangerous or harmful, behaviors. "Schizophrenia is among the most severe and disabling conditions across all categories of medicine," said Light, who also directs the Mental Illness, Research, Education and Clinical Center at the San Diego VA Healthcare System. The precise cause or causes of schizophrenia are not known, though there is a clear genetic component, with the disorder more common in some families. Clinicians typically diagnose schizophrenia based upon inferences drawn from the patient's inner experiences. That is, their ability to describe what's happening inside their minds. "But even the best clinicians struggle with diagnostic complexities based on sometimes fuzzy clinical phenomenology," said Light. The clinical challenge is compounded by the fact that "many schizophrenia patients have cognitive and functional impairments," said Light. They may not be able to reasonably explain how or what they think. Light and colleagues investigated whether a select battery of neurophysiological and neurocognitive biomarkers could provide clinicians with reliable, accurate, long-term indicators of brain dysfunction, even when overt symptoms of the disorder were not apparent. These markers ranged from tests of attention and memory to physiological assessments of basic perceptual processes using scalp sensors to measure brain responses to simple sounds. The researchers measured the biomarkers in 550 schizophrenia patients, and then re-tested 200 of the patients one year later. They found that most of the markers were significantly abnormal in schizophrenia patients, were relatively stable between the assessments and were not affected by modest fluctuations in clinical status of the patient. Light said further research is required, including whether the endophenotypes can differentiate other psychiatric disorders, be used to anticipate patient response to different kinds of drugs or non-pharmacological interventions or even be used to predict which subjects are at high risk of developing a psychotic illness. "We believe this paper is an important step towards validating laboratory-based biomarkers for use in future genomic and clinical treatment studies of schizophrenia," Light said. ### Co-authors are Neal R. Swerdlow, Anthony J. Rissling and Marlena Pela, Department of Psychiatry, UCSD; Allen Radant, Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle; Catherine A. Sugar, Departments of Psychiatry and Biostatistics, UCLA; Joyce Sprock, Mark A. Geyer and David L. Braff, Mental Illness, Research, Education and Clinical Center, San Diego VA Healthcare System and Department of Psychiatry, UCSD. Funding for this research came, in part, from National Institute of Mental Health grants MH042228, MH079777 and MH065571 and the Department of Veterans Affairs.