Fat-free See-through Brain Bares All

Method Enables 3-D Analysis of Fine Structure and Connections – NIH-funded Study Slicing optional. Scientists can now study the brain’s finer workings, while preserving its 3-D structure and integrity of its circuitry and other biological machinery. A breakthrough method, called CLARITY, developed by National Institutes of Health-funded researchers, opens the intact postmortem brain to chemical, genetic and optical analyses that previously could only be performed using thin slices of tissue. By replacing fat that normally holds the brain’s working components in place with a clear gel, they made its normally opaque and impenetrable tissue see-through and permeable. This made it possible to image an intact mouse brain in high resolution down to the level of cells and molecules. The technique was even used successfully to study a human brain. “CLARITY has the potential to unmask fine details of brains from people with brain disorders without losing larger-scale circuit perspective,” said NIH Director Francis S. Collins, M.D., Ph.D., whose NIH Director’s Transformative Research Award Program helped to fund the research, along with a grant from the National Institute of Mental Health NIMH. “CLARITY will help support integrative understanding of large-scale, intact biological systems, explained Karl Deisseroth, M.D., Ph.D., of Stanford University in California. “It provides access to subcellular proteins and molecules, while preserving the continuity of intact neuronal structures such as long-range circuit projections, local circuit wiring and cellular spatial relationships.” Deisseroth, Kwanghun Chung, Ph.D., and other Stanford colleagues report on their findings April 10, 2013 in the journal Nature. “This feat of chemical engineering promises to transform the way we study the brain’s anatomy and how disease changes it,” said NIMH Director Thomas R. Insel, M.D. “No longer will the in-depth study of our most important three-dimensional organ be constrained by two-dimensional methods.” Until now, researchers seeking to understand the brain’s fine structure and connections have been faced with tradeoffs. To gain access to deeply buried structures and achieve high enough resolution to study cells, molecules and genes, they had to cut brain tissue into extremely thin sections (each a fraction of a millimeter thick), deforming it. Loss of an intact brain also makes it difficult to relate such micro-level findings to more macro-level information about wiring and circuitry, which cuts across slices. In tackling this challenge, the researchers saw opportunity in the fact that the fats, or lipids, that physically support the brain’s working components, such as neurons and their connections, also block chemical probes and the passage of light. So replacing the lipids with something clear and permeable – that would also hold everything else in place – might make it possible to perform the same tests in an intact brain that previously could only be done with brain tissue slices. Deisseroth’s team infused into brain a high-tech cocktail, including a plastic-like material and formaldehyde. When heated, it formed a transparent, porous gel that biochemically integrated with, and physically supported, the brain’s working tissue – while excluding the lipids, which were safely removed via an electrochemical process. The result was a brain transformed for optimal accessibility. They called the new method Clear Lipid-exchanged Anatomically Rigid Imaging/immunostaining-compatible Tissue Hydrogel – CLARITY, for short. Using CLARITY, the researchers imaged the entire brain of a mouse that had been genetically engineered to express a fluorescent protein. A conventional microscope revealed glowing details, such as proteins embedded in cell membranes and individual nerve fibers, while an electron microscope resolved even ultra-fine structures, such as synapses, the connections between neurons. In a series of experiments using CLARITY in mouse brain, the researchers demonstrated that, for the first time, standard immune- and genetics-based tests can be performed repeatedly in the same intact brain. Tracer molecules, such as antibodies, can be readily delivered for staining tissue – or removed – leaving brain tissue undisturbed. The researchers found that CLARITY outperformed conventional methods across a range of previously problematic technical challenges. When they used CLARITY to analyze a post-mortem human brain of a person who had autism, even though it had been hardening in formaldehyde for six years, they were able to trace individual nerve fibers, neuronal cell bodies and their extensions. Free continuing education course material at Aspira Continuing Education Online Courses

Autism Risk Unrelated to Total Vaccine Exposure in Early Childhood

A child’s risk for developing an autism spectrum disorder (ASD) is not increased by receiving “too many vaccines too soon,” according to a new study published in The Journal of Pediatrics. Although previous scientific evidence has shown that vaccines do not cause autism, more than 1 in 10 parents refuse or delay vaccinations for their young children. A main safety concern of these parents is the number of vaccines administered, both on a single day and over the course of a child’s first 2 years of life. In the first study of its kind, researchers from the CDC and Abt Associates, Inc. compared vaccine records for over 1000 children born from 1994–1999, some of whom were later diagnosed with ASD. The researchers calculated the total number of vaccine antigens each child received between birth and age 2, as well as the maximum number of antigens each child received on a single day. The study found that the total number of vaccine antigens received was the same between children with ASD and those without ASD. Additionally, antigen number was also found to be unrelated to the development of two sub-categories of ASD—autistic disorder and ASD with regression LCSW Continuing Education The researchers concluded, “The possibility that immunological stimulation from vaccines during the first 1 or 2 years of life could be related to the development of ASD is not well-supported by what is known about the neurobiology of ASDs.”

NIH Study Shows People with Serious Mental Illnesses Can Lose Weight

People with serious mental illnesses such as schizophrenia, bipolar disorder and major depression can lose weight and keep it off through a modified lifestyle intervention program, a National Institute of Mental Health (NIMH)-funded study reported online today in The New England Journal of Medicine. Over 80 percent of people with serious mental illnesses are overweight or obese, which contributes to them dying at three times the rate of the overall population. They succumb mostly to the same things the rest of the population experiences—cardiovascular disease, diabetes and cancer. Although antipsychotic medications increase appetite and cause weight gain in these patients, it is not the only culprit. Like the general population, sedentary lifestyle and poor diet also play a part. Lifestyle modifications such as diet and exercise should work for these patients, yet they are often left out of weight loss studies. “People with serious mental illnesses are commonly excluded from studies to help them help themselves about their weight,” said Gail L. Daumit, M.D., of Johns Hopkins University, Baltimore, and the study’s lead author. “We’re showing that serious mentally ill patients can make successful, sustained changes with proper interventions.” This study could usher in new forms of weight loss treatment for people with serious mental illness. “Until now, obesity among those with serious mental illnesses has not received adequate attention,” said NIMH Director Thomas R. Insel, M.D. “People with serious mental illnesses need more attention to their physical health. This study provides convincing evidence these individuals can make substantial lifestyle changes and therefore should suffer fewer medical complications as they age.” Other factors that preclude people with serious mental illnesses from losing weight include memory impairments or residual psychiatric symptoms that impede learning and adopting new behaviors such as counting calories. Socioeconomics are also a factor as many can’t afford or can’t get to physical activity programs like fitness gyms. Some patients additionally suffer from social phobia or have poor social interactions, and are simply afraid to work out in a public area. Daumit’s group attempted to solve these issues by bringing the gyms and nutritionists to places most of these patients frequent—psychiatric rehabilitation outpatient programs. Under the trial name ACHIEVE, the researchers randomized 291 participants in 10 rehab centers around Maryland to receive the usual care, consisting of nutrition and physical activity information, or six months of intensive intervention consisting of exercise classes three times a week along with individual or group weight loss classes once a week. Both groups were followed for an additional year, during which the weight loss classes of the intervention arm tapered down but the exercise classes remained constant. The intervention arm included goals such as reducing caloric intake by avoiding sugar-sweetened beverages and junk food; eating five servings of fruits and vegetables daily; choosing smaller portions and healthy snacks; and moderate intensity aerobic exercise. Participants in the specially tailored weight loss program lost seven pounds more than the controls—and continued to lose weight and did not regain, despite the reduced frequency of classes and counseling sessions. In contrast, the general population tends to experience peak weight loss in the first six months and then rebound and gain part or all of their weight back. On average, each participant was on three psychotropic medications, with half on lithium or mood stabilizers, all known to cause weight gain. But no matter what they were on, they lost the weight. “We’re showing behavioral interventions work regardless of what they’re taking,” Daumit said. Her group is now looking for ways to spread the program. VIDEO Project Achieve is the first weight loss clinical trial to include people with serious mental illnesses. Reference Effects of a behavioral weight loss intervention in persons with serious mental illness. Daumit GL, Dickerson FB, Wang N-Y, Dalcin A, Jerome GJ, Anderson CAM, Young DR, Frick KD, Yu A, Gennusa III JV, Oefinger M, Crum RM, Charleston J, Casagrande SS, Guallar E, Goldberg RW, Campbell LM, Appel LJ. NEJM, March 21, 2013 Professional Counselor Continuing Education Grant number: MH080964 ### The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website. About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.

Surprising Rate of Women Have Depression After Childbirth

One in every seven women have significant depressive symptoms March 13, 2013 | by Marla Paul CHICAGO --- A surprisingly high number of women have postpartum depressive symptoms, according to a new, large-scale study by a Northwestern Medicine® researcher. This is the largest scale depression screening of postpartum women and the first time a full psychiatric assessment has been done in a study of postpartum women who screened positive for depression Depressive Disorders CE Course The study, which included a depression screening of 10,000 women who had recently delivered infants at single obstetrical hospital, revealed a large percentage of women who suffered recurrent episodes of major depression. The study underscored the importance of prenatal as well as postpartum screening. Mothers’ and infants’ health and lives hang in the balance. The lives of several women who were suicidal when staff members called them for the screening were saved likely as a result of the study’s screening and immediate intervention. “In the U.S., the vast majority of postpartum women with depression are not identified or treated even though they are at higher risk for psychiatric disorders,” said Northwestern Medicine lead study author Katherine L. Wisner, M.D. “It’s a huge public health problem. A woman’s mental health has a profound effect on fetal development as well as her child’s physical and emotional development.” Wisner is director of Northwestern’s Asher Center for the Study and Treatment of Depressive Disorders and the Norman and Helen Asher Professor of Psychiatry and Behavioral Sciences and professor of obstetrics and gynecology at Northwestern University Feinberg School of Medicine. She’s also a physician at Northwestern Memorial Hospital. “A lot of women do not understand what is happening to them,” Wisner said. “They think they’re just stressed or they believe it is how having a baby is supposed to feel.” The paper was be published in JAMA Psychiatry March 13. Wisner conducted the research when she was at the University of Pittsburgh. In the study, 14 percent of the women screened positive for depression. Of that group, 826 received full psychiatric assessments during at-home visits. Some of the key findings from those assessments: - In women who screened positive for depression, 19.3 percent thought of harming themselves. “Most of these women would not have been screened and therefore would not have been identified as seriously at risk,” Wisner said. “We believe screening will save lives.” Suicide accounts for about 20 percent of postpartum deaths and is the second most common cause of mortality in postpartum women. - Many women who screened positive for major depression postpartum had already experienced at least one episode of depression previously and, in addition, had an anxiety disorder. The study found 30 percent of women had depression onset prior to pregnancy, 40 percent postpartum and 30 percent during pregnancy. More than two-thirds of these women also had an anxiety disorder. “Clinicians need to know that the most common clinical presentation in the post-birth period is more complex than a single episode of depression,” Wisner said. “The depression is recurrent and superimposed on an anxiety disorder.“ - Of the women who screened positive for major depression, 22 percent had bipolar disorder, the majority of whom had not been diagnosed by their physicians. There is often a delay in correctly diagnosing bipolar disorder, which depends on identifying not only the depressed phase but the manic or hypomanic phase as well. But postpartum is the highest risk period for new episodes of mania in a woman’s life. “That’s a very high rate of bipolar disorder that has never been reported in a population screened for postpartum depression before,” said Wisner. “It is significant because antidepressant drug treatment alone can worsen the course of bipolar disorder.” In addition, women who have been pregnant in the past year are less likely to seek treatment for depression than women who have not been pregnant, previous research has shown. Maximizing a woman’s overall mental and physical health in pregnancy and after childbirth is critically important. “Depression during pregnancy increases the risk to a woman and her fetus,” Wisner said. “Depression is a physiological dysregulation disorder of the entire body.” Maternal prenatal stress and depression is linked to preterm birth and low infant birth weight, which increases the risk of cardiovascular disease. Depression also affects a woman’s appetite, nutrition and prenatal care and is associated with increased alcohol and drug use. Women with untreated depression have a higher body mass index preconception, which carries additional risks. When a new mother is depressed, her emotional state can interfere with child development and increases the rate of insecure attachment and poor cognitive performance of her child, Wisner said. Screening prenatal and postpartum are essential (Illinois requires mandatory screening for perinatal mental health disorders), but the health care field must develop cost effective and accessible treatment, Wisner emphasized. “If we identify patients we must have treatment to offer them,” Wisner said. The study was funded by grant RO1 MH 071825 from the National Institute of Mental Health of the National Institutes of Health.

5 Most Common Mental Illnesses Share the Same Genes

From Autism to Depression: Largest Genetic Study Shows Mental Disorders Share Genetic Kinks --Associated Press Mental Illnesses Share Common DNA Roots, Study Finds --nbcnews.com An NIMH-funded study published online today in Lancet reveals that the five most common disorders—autism, attention deficit hyperactivity disorder, bipolar disease, schizophrenia, and major depression—all share similar genetic components. “These disorders that we thought of as quite different may not have such sharp boundaries,” said Dr. Jordan W. Smoller of Massachusetts General Hospital, one of the lead study authors. The results suggest that a rethink in how these disorders are defined might be in order. Rather than focusing on symptoms, which can be attributed to one or more disorder, physicians could one day start to rely on specific gene mutations or biologic pathways to make a formal diagnosis Aspira Continuing Education Online Courses And it also could lead to better treatments, said Dr. Bruce Cuthbert, director of the NIMH’s Division of Adult Translational Research and Treatment Development. “We are finally starting to make inroads where we have actual physiological mechanisms that we can target,” he said. “We can really start to understand the biology instead of having to guess at it.” Reference Cross-Disorder Group of the Psychiatric Genomics Consortium. Identification of Risk Loci with Shared Effects on Five Major Psychiatric Disorders: A Genome-wide Analysis. Lancet, published online February 28, 2013.

Mapping Brain Circuits Provides Clues to Schizophrenia, Earlier Detection of Psychosis

Two regions in the brain have been linked to schizophrenia and psychosis, which may lead to earlier detection of this disorder and symptom, reported an imaging study funded by the National Institute of Mental Health (NIMH) that was published online last month in Biological Psychiatry. Background Patients with schizophrenia experience decreased activity in the prefrontal cortex ( blue, top figure) and excess activity in the basal ganglia (red, bottom figure). The greater the disconnect between these two regions, the higher the level of psychosis seen in these patients. Psychosis is a loss of contact with reality that usually includes false beliefs about what is taking place or who one is (delusions) and seeing or hearing things that aren’t there (hallucinations). Numerous medical problems can cause psychosis such as substance abuse, brain tumors, and certain mental disorders such as schizophrenia and bipolar disorder. Treatment approaches include hospitalization, antipsychotic drugs, and various psychosocial treatments. Too often, psychosis is not diagnosed or treated early enough. The longer this duration of untreated psychosis, the poorer the patient’s long-term functioning and response to treatment. In the United States, the average time between the first onset of psychotic symptoms and the initiation of treatment is about 110 weeks, or over 2 years. Disordered thinking and psychosis often go hand-in-hand in patients with the chronic brain disorder schizophrenia. A popular and long-standing theory in the field implicates the prefrontal cortex, the brain area just behind the forehead that normally supports higher-order capabilities such as prioritizing, categorizing, and strategizing. Damage to this area causes not only disordered thinking but also leads to psychosis from the excess release of the neurotransmitter dopamine into regions deep inside the brain. While this theory offers a compelling explanation for the co-occurrence of these two symptoms in schizophrenia, there have been only a small handful of studies that have directly supported this theory. Identification of the exact circuit(s) involved has so far remained elusive Professional Counselor Continuing Education “Schizophrenia is a very complex condition, involving a constellation of diverse symptoms. This diversity presents both a challenge and a constraint for figuring out the neurobiological root causes of schizophrenia. There is likely not just one lesion but a number of lesions that are present across different brain regions that are the proximal causes for these symptoms.” explained Jong H. Yoon, M.D., at the University of California, Davis, and lead author of the study. Yoon’s study focused on the prefrontal cortex and the basal ganglia. The basal ganglia is a subcortical collection of neuron clusters, including the ventral tegmental area and substantia nigra, which produce the majority of the brain’s dopamine, and the striatum, an important site of action of dopamine. Using functional magnetic resonance imaging (fMRI), the researchers examined the brain activity within the prefrontal cortex and basal ganglia of 18 individuals with schizophrenia and 19 healthy controls. The subjects completed a memory task in which they had to remember images of faces across a brief delay period to determine if subsequently presented faces were the same faces; it was hypothesized that patients with schizophrenia would have more difficulty performing this task. Results of the Study Patients with schizophrenia experienced excess activity in the substantia nigra, decreased activity in the prefrontal cortex, and diminished functional connectivity between these regions, suggesting that communication among these regions was out of sync. Additionally, the higher the level of connectivity between the substantia nigra and the striatum, the higher the level of psychosis seen in the patients with schizophrenia. Significance These findings suggest that the prefrontal cortex-basal ganglia circuit may be a common pathway linking cognitive deficits and psychosis in schizophrenia. It also points to a more widespread use of fMRI in diagnosis and treatment. Compared to other neuroimaging techniques such as positron emission tomography (PET), fMRI yields more detailed images, does not use radiation, and is relatively widely available since most university-based brain imaging centers have this technology. These findings could also lead to the creation of a better animal model of psychosis, of which there currently are few. Biomedical research has shown that early detection and intervention could preempt later stages of diseases. This concept of “treatment as prevention” is seen in the NIMH-supported North American Prodrome Longitudinal Study (NAPLS), which is using biological assessments, such as neuroimaging, to predict who will convert to psychosis and to develop new treatment and prevention approaches. Another NIMH study, Recovery After an Initial Schizophrenia Episode (RAISE), supports the development and testing of two complementary models for early intervention in schizophrenia. Research is also underway to identify genes and environmental elements associated with schizophrenia. What’s Next Because the study involved patients with established illness who are already on antipsychotic medications, it needs replication in patients with schizophrenia who are not medicated and/or in the early phases of illness. The study should also be performed in individuals at high risk of developing psychosis to see if these findings could help identify individuals in the earliest stages of illness when interventions to prevent or significantly ameliorate schizophrenia can be instituted. To obtain greater precision in localizing brain regions, the study also warrants replication with high-resolution fMRI. Furthermore, the techniques in this study could also be applied to other disorders that can have psychosis as one of its symptoms, such as mood disorders, and post-traumatic stress disorder. Reference Yoon JH, Minzenberg MJ, Raouf S, D’Esposito M, Carter CS. Impaired Prefrontal-Basal Ganglia Functional Connectivity and Substantia Nigra Hyperactivity in Schizophrenia. Biological Psychiatry, published online January 14, 2013.

Imaging Biomarker Predicts Response to Rapid Antidepressant

Signals Dysfunction in Brain System Targeted by Scopolamine – NIH Study A telltale boost of activity at the back of the brain while processing emotional information predicted whether depressed patients would respond to an experimental rapid-acting antidepressant, a National Institutes of Health study has found. NIMH’s Dr. Maura Furey talks about scopolamine research “We have discovered a potential neuroimaging biomarker that may eventually help to personalize treatment selection by revealing brain-based differences between patients,” explained Maura Furey, Ph.D., of NIH’s National Institute of Mental Health (NIMH). Furey, NIMH’s Carlos Zarate, M.D., and colleagues, reported on their functional magnetic resonance imaging (fMRI) study of a pre-treatment biomarker for the antidepressant response to scopolamine, Jan. 30, 2013, online in JAMA Psychiatry. Scopolamine, better known as a treatment for motion sickness, has been under study since Furey and colleagues discovered its fast-acting antidepressant properties in 2006. Unlike ketamine, scopolamine works through the brain’s acetylcholine chemical messenger system. The NIMH team’s research has demonstrated that by blocking receptors for acetylcholine on neurons, scopolamine can lift depression in many patients within a few days; conventional antidepressants typically take weeks to work. But not all patients respond, spurring interest in a predictive biomarker Alcoholism and Drug Abuse Counselors Continuing Education The acetylcholine system plays a pivotal role in working memory, holding information in mind temporarily, but appears to act by influencing the processing of information rather than through memory. Imaging studies suggest that visual working memory performance can be enhanced by modulating acetylcholine-induced activity in the brain’s visual processing area, called the visual cortex, when processing information that is important to the task. Since working memory performance can predict response to conventional antidepressants and ketamine, Furey and colleagues turned to a working memory task and imaging visual cortex activity as potential tools to identify a biomarker for scopolamine response. Depressed patients have a well-known tendency to process and remember negative emotional information. The researchers propose that this bias stems from dysregulated acetylcholine systems in some patients. They reasoned that such patients would show aberrant visual cortex activity in response to negative emotional features of a working memory task. They also expected to find that patients with more dysfunctional acetylcholine systems would respond better to scopolamine treatment. Before receiving scopolamine, participants performed a working memory task while their brain activity was monitored via fMRI. For some trials, it required that they pay attention to, and remember, the emotional expression (sad, happy, etc.) of faces flashing on a computer monitor. For other trials, they had to pay attention to only the identity, or non-emotional feature, of the faces. After scanning, and over the following several weeks, 15 patients with depression and 21 healthy participants randomly received infusions of a placebo (salt solution) and/or scopolamine. Mood changes were monitored with depression rating scales. Overall, scopolamine treatment reduced depression symptoms by 63 percent, with 11 of the patients showing a significant clinical response. The strength of this response correlated significantly with visual cortex activity during key phases of the working memory task – while participants were paying attention to the emotional content of the faces. There was no such correlation for trials when they attended to the identity of the faces. The findings suggest that acetylcholine system activity drives visual cortex activity that predicts treatment response – and that differences seen between depressed patients and controls may be traceable to acetylcholine dysfunction. Overall, patients showed lower visual cortex activity than controls during the emotion phase of the task. Patients showing activity levels most dissimilar to controls experienced the greatest antidepressant response to scopolamine treatment. Visual cortex activity in patients who didn’t respond to scopolamine more closely resembled that of controls. As hypothesized, the pretreatment level of visual cortex activity appears to reflect the extent of patients’ acetylcholine system dysfunction and to predict their response to the experimental medication, say the researchers. Preliminary evidence suggests that such visual cortex activity in response to emotional stimuli may also apply to other treatments and may prove to be a shared biomarker of rapid antidepressant response, according to Furey. The level of increased activity in left and right visual cortex (blue), while attending to emotional faces in a working memory task, predicted depressed patients’ responsiveness to the experimental antidepressant scopolamine. View from the back of the brain shows fMRI data superimposed on anatomical MRI scan data. Source: Maura Furey, Ph.D., NIMH Experimental Therapeutics and Pathophysiology Branch Working memory task: Over several trials, participants were required to attend to either the identity (non-emotional feature) or the emotion of a face, remember it during a 9 second delay, and match the feature to a subsequent face. Neural activity in the visual cortex elicited by the emotion trials predicted a patient’s subsequent responsiveness to scopolamine treatment. Source: Maura Furey, Ph.D., NIMH Experimental Therapeutics and Pathophysiology Branch References Potential of Pretreatment Neural Activity in the Visual Cortex During Emotional Processing to Predict Treatment Response to Scopolamine in Major Depressive Disorder. Furey ML, Drevets WC, Hoffman EM, Frankel E, Speer AM, Zarate CA. JAMA Psychiatry. 2013 Jan 30:1-11. doi: 10.1001/2013.jamapsychiatry.60. [Epub ahead of print] PMID:23364679 Cholinergic Modulation of Cognition and Emotion in Mood Disorders ### The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website. About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.