Awake Mental Replay of Past Experiences Critical for Learning

Blocking It Stumps Memory-Guided Decision-Making in Rats – NIH-Funded Study Awake mental replay of past experiences is essential for making informed choices, suggests a study in rats. Without it, the animals’ memory-based decision-making faltered, say scientists funded by the National Institutes of Health. The researchers blocked learning from, and acting on, past experience by selectively suppressing replay – encoded as split-second bursts of neuronal activity in the memory hubs of rats performing a maze task. “It appears to be these ripple-like bursts in electrical activity in the hippocampus that enable us to think about future possibilities based on past experiences and decide what to do,” explained Loren Frank, Ph.D., of the University of California, San Francisco, a grantee of the NIH’s National Institute of Mental Health (NIMH). “Similar patterns of hippocampus activity have been detected in humans during similar situations.” continuing education for social workers Frank, Shantanu Jadhav, Ph.D., and colleagues, report on their discovery online in the journal Science, Thursday, May 3, 2012. “These results add to evidence that the brain encodes information not only in the amount of neuronal activity, but that its rhythm and synchronicity also play a crucial role,” said Bettina Osborn, Ph.D., of the NIMH Division of Neuroscience and Basic Behavioral Science, which funded the research. Frank and colleagues had discovered in previous studies that the rhythmic ripple-like activity in the hippocampus coincided with awake mental replay of past experiences, which occurs during lulls in the rats’ activity. The same signal during sleep is known to help consolidate memories. So the researchers hypothesized that these awake ripple states are required for memory-guided decision-making. To test this in the current study, they selectively suppressed the ripple activity without disturbing other functions, while monitoring any effects on the animals’ performance in a maze task. Individual neurons in certain areas of the hippocampus become associated with a particular place. These place cells fire when the animal is in that place or – it turns out – is just mentally replaying the experience of being in that place. In the experimental situation, the rat needs to learn a rule to get a reward. It must remember which of two outer arms of a W-shaped maze it had visited previously and alternate between them – visiting the opposite arm after first visiting the center arm. The ripple activity occurs when rats are inactive during breaks between trials. Place cells associated with the maze fire in rapid succession and in synchrony with other neurons in the neighborhood. The same place cells fire in the same sequence as they did when the rat first walked through the maze – suggesting that the rat is mentally replaying the earlier experience, but on a much faster timescale. In the current study, an automatic feedback system shut down place cell firing, via mild electrical stimulation, whenever it detected ripple activity, thereby also preventing the replay of the maze memory. Without benefit of mental replay, rats’ performance on the maze task deteriorated. The impairment was in the animals’ spatial working memory – their ability to link immediate and earlier past experience to the reward. This ability was required to correctly decide which outside arm to visit after exiting the center arm during outbound trials. The researchers propose that awake replay in the hippocampus provides such information about past locations and future options to the brain’s executive hub, the prefrontal cortex, which learns the alternation rule and applies it to guide behavior. Even though the replay events in rats last just a fraction of a second, Frank notes that they are not unlike our own experience of memories, which tend to compress often lengthy events into snippets of just the highlights of what happened to us. “We think the brain is using these same ripple-like bursts for many things,” he explained. “It’s using them for retrieving memories, exploring possibilities – day-dreaming – and for strengthening memories.”

During breaks in trials when the rat was awake but inactive, areas in the brain’s memory hub emitted split-second bursts of ripple-like electrical activity (SWRs). This indicated that the rat was mentally replaying an earlier experience in the maze. Individual neurons in the areas become associated with a particular place. These place cells spike when the animal is in that place or – it turns out – is just mentally replaying the experience of being in that place. Embedded in the ripple-like signal above are place cells spiking in the same sequence as they did when the rat first walked through the maze. (Color-coded hatch marks match the path in the maze.) Rats’ performance in the maze task faltered when these awake mental replay events were blocked, revealing that they are important for memory-guided decision-making. Source: Shantanu Jadhav, Ph.D., University of California San Francisco In this YouTube clip, NIMH grantee Loren Frank, Ph.D., explains how rats mentally replay recent experiences in a maze. Reference Jadhav SP, Kemere C, German PW, Frank LM. Awake Hippocampal Sharp-Wave Ripples Support Spatial Memory. 2012, May 3, Science Express. 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.

Prenatal exposure to insecticide chlorpyrifos linked to alterations in brain structure and cognition

While chlorpyrifos is no longer registered for household use in the US, it continues to be widely used around the world, as well as on many food and agricultural products throughout the US Even low to moderate levels of exposure to the insecticide chlorpyrifos during pregnancy may lead to long-term, potentially irreversible changes in the brain structure of the child, according to a new brain imaging study by researchers from the Columbia Center for Children's Environmental Health at the Mailman School of Public Health, Duke University Medical Center, Emory University, and the New York State Psychiatric Institute. The changes in brain structure are consistent with cognitive deficits found in children exposed to this chemical. Results of the study appear online in the April 30 PNAS. The new study is the first to use MRI to identify the structural evidence for these cognitive deficits in humans, confirming earlier findings in animals. Changes were visible across the surface of the brain, with abnormal enlargement of some areas and thinning in others. The disturbances in brain structure are consistent with the IQ deficits previously reported in the children with high exposure levels of chlorpyrifos, or CPF, suggesting a link between prenatal exposure to CPF and deficits in IQ and working memory at age 7 ceus for social workers The study also reports evidence that CPF may eliminate or reverse the male-female differences that are ordinarily present in the brain. Further study is needed to determine the consequences of these changes before and after puberty, the researchers say. Notably, the brain abnormalities appeared to occur at exposure levels below the current EPA threshold for toxicity, which is based on exposures high enough to inhibit the action of the key neurological enzyme cholinesterase. The present findings suggest that the mechanism underlying structural changes in the brain may involve other pathways. According to the lead author, Virginia Rauh, ScD, Professor at the Mailman School of Public Health and Deputy Director of the Columbia Center for Children's Environmental Health, "By measuring a biomarker of CPF exposure during pregnancy, and following the children prospectively from birth into middle childhood, the present study provides evidence that the prenatal period is a vulnerable time for the developing child, and that toxic exposure during this critical period can have far-reaching effects on brain development and behavioral functioning." "By combining brain imaging and community-based research, we now have much stronger evidence linking exposure to chlorpyrifos with neurodevelopmental problems," adds senior author Bradley S. Peterson, MD, Chief of Child & Adolescent Psychiatry, New York State Psychiatric Institute, and Director of MRI Research in the Department of Psychiatry, Columbia University Medical Center. In the current study, the researchers used MRI to evaluate the brains of 40 New York City children, ages 5 to 11, whose mothers were enrolled prenatally in a larger cohort study. Researchers compared 20 children with high exposures to CPF with 20 children with lower exposures; all exposures occurred prior to the EPA ban on household use of the chemical in 2001. They found brain anomalies were associated with the higher exposure. Since the 2001 ban, a drop in residential exposure levels of CPF has been documented by Robin Whyatt, DrPH, a co-author on the present study and Professor of Clinical Environmental Health Sciences and Co-Deputy Director of the Columbia Center for Children's Environmental Health at the Mailman School. However, the chemical continues to be present in the environment through its widespread use in agriculture (food and feed crops), wood treatments, and public spaces such as golf courses, some parks, and highway medians. People near these sources can be exposed by inhaling the chemical, which drifts on the wind. Low-level exposure can also occur by eating fruits and vegetables that have been sprayed. Although the chemical is degraded rapidly by water and sunlight outdoors, it has been detected by the Columbia researchers in many urban residences years after the ban went into effect. The study was supported by the National Institute of Environmental Health Sciences Grants 5P01ES09600, P50ES015905, and 5R01ES08977, as well as pilot funding through ES009089; EPA STAR Grants RD834509, RD832141, and R827027; National Institute of Mental Health Grants MH068318 and K02-74677; and the John and Wendy Neu Family Foundation. Additional co-authors included Frederica P. Perera and Megan K. Horton, Mailman School; Ravi Bansal, Xuejun Hao, and Jun Liu, Columbia University Medical Center; Dana Boyd Barr, Emory University; and Theodore A. Slotkin, Duke University.

LA BioMed researchers remain at the forefront of mental health initiatives

The month of May recognized as Mental Health Awareness Month LOS ANGELES (April 30, 2012) – With the month of May recognized nationally as Mental Health Awareness Month, the physician-researchers at the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center (LA BioMed) continue to be at the forefront of mental health initiatives, engaging in clinical trials to help find therapies and treatments for individuals who suffer from mood and anxiety disorders. According to the National Institute of Mental Health (NIMH), mental health concerns affect 1 in 10 Americans today, but fewer than 25 percent of people with a diagnosable mental disorder seek treatment. Ira Lesser, M.D., is a principal investigator at LA BioMed and Chair, Department of Psychiatry, at Harbor-UCLA. At LA BioMed, he has led a number of clinical trials on mood and anxiety disorders, including the largest ever conducted on depression – Sequenced Treatment Alternatives to Relieve Depression (STAR*D) – a study funded by the NIMH. LA BioMed was one of 41 clinical sites participating, enrolling the greatest number of individuals and was the highest primary care enrolling site in the country. "With a growing number of individuals being diagnosed with a mental health disorder, it's imperative that we educate these individuals as to the options available to them, and also encourage them to seek treatment," said Dr. Lesser. "At LA BioMed, we are working to develop treatments and therapies that will not only help to cure but also help individuals cope with their existing conditions in the long term." In addition to STAR*D, Dr. Lesser and his staff (Karl Burgoyne, M.D., Benjamin Furst, M.D., Deborah Flores, M.D.) are working on other clinical trials including Biomarkers for Rapid Identification of Treatment Effectiveness in Major Depression (BRITE) and Biomarkers for Outcomes in Late-Life Depression (BOLD). Working alongside Dr. Lesser is LA BioMed investigator Michele Berk, Ph.D., who is directing a multi-site, randomized clinical trial that tests the effects of dialectical behavior therapy (DBT) on teenagers who have attempted suicide or engaged in self-harm behaviors, such as cutting. Suicide now ranks as the third leading cause of death in the U.S. among youth ages 10-19. DBT has been shown to be effective in reducing suicidal behavior in adults with depression and personality disorders. Sponsored by the NIMH, this study is the first such clinical trial in the U.S. to test the effectiveness of DBT in adolescents. John W. Tsuang, M.D., in conjunction with Steven J. Shoptaw, Ph.D., from the UCLA Department of Family Medicine, is spearheading a Phase I clinical safety trial that for the first time examines the effects of Ibudilast when administered with metamphetamine (MA), an addictive stimulant that is closely related to amphetamine. Funded by the National Institutes of Health National Institute on Drug Abuse (NIDA), this study will help to determine the effects of Ibudilast - combined with relevant doses of MA - on heart rate and blood pressure, and whether or not Ibudilast alters the way in which the body absorbs, distributes, and metabolizes MA. The development of one or more medications to reduce MA abuse, when implemented with evidence-based behavioral and counseling interventions, would have obvious public health significance. Dr. Tsuang is hoping that following the initial safety trial, physicians will be able to utilize Ibudilast in treating patients with MA dependence to help them improve memory and reduce the damage done to their central nervous system due to MA abuse social worker continuing education About LA BioMed Founded in 1952, LA BioMed is one of the country's leading nonprofit independent biomedical research institutes. It has approximately 100 principal researchers conducting studies into improved treatments and cures for cancer, inherited diseases, infectious diseases, illnesses caused by environmental factors and more. It also educates young scientists and provides community services, including prenatal counseling and childhood nutrition programs. LA BioMed is academically affiliated with the David Geffen School of Medicine at UCLA and located on the campus of Harbor-UCLA Medical Center. For more information, please visit www.LABioMed.org

Dual medications for depression increases costs, side effects with no benefit to patients

Taking two medications for depression does not hasten recovery from the condition that affects 19 million Americans each year, researchers at UT Southwestern Medical Center have found in a national study. "Clinicians should not rush to prescribe combinations of antidepressant medications as first-line treatment for patients with major depressive disorder," said Dr. Madhukar H. Trivedi, professor of psychiatry and chief of the division of mood disorders at UT Southwestern and principal investigator of the study, which is available online today and is scheduled for publication in an upcoming issue of the American Journal of Psychiatry. "The clinical implications are very clear – the extra cost and burden of two medications is not worthwhile as a first treatment step," he said. In the Combining Medication to Enhance Depression Outcomes, or CO-MED, study, researchers at 15 sites across the country studied 665 patients ages 18 to 75 with major depressive disorder. Three treatment groups were formed and prescribed antidepressant medications already approved by the Food and Drug Administration. One group received escitalopram (a selective serotonin reuptake inhibitor, or SSRI) and a placebo; the second group received the same SSRI paired with bupropion (a non-tricyclic antidepressant); and a third group took different antidepressants: venlafaxine (a tetracyclic antidepressant) and mirtazapine (a serotonin norepinephrine reuptake inhibitor). The study was conducted from March 2008 through February 2009 LSW Continuing Education After 12 weeks of treatment, remission and response rates were similar across the three groups: 39 percent, 39 percent and 38 percent, respectively, for remission, and about 52 percent in all three groups for response. After seven months of treatment, remission and response rates across the three groups remained similar, but side effects were more frequent in the third group. Only about 33 percent of depressed patients go into remission in the first 12 weeks of treatment with antidepressant medication, as Dr. Trivedi and colleagues previously reported from the Sequenced Treatment Alternatives to Relieve Depression, or STAR*D, study. STAR*D was the largest study ever undertaken on the treatment of major depressive disorder and is considered a benchmark in the field of depression research. That six-year, $33 million study initially included more than 4,000 patients from sites across the country. Dr. Trivedi was a co-principal investigator of STAR*D. The next step, Dr. Trivedi said, is to study biological markers of depression to see if researchers can predict response to antidepressant medication and, thus, improve overall outcomes. ### Other UT Southwestern researchers involved in the study were Drs. Benji Kurian and David Morris, assistant professors of psychiatry; Dr. Diane Warden, associate professor of psychiatry; and Dr. Mustafa Husain, professor of psychiatry, internal medicine, and neurology and neurotherapeutics. Former UT Southwestern professor Dr. A. John Rush, now with the Duke-NUS Graduate Medical School in Singapore, and researchers from the University of Pittsburgh; Massachusetts General Hospital; Columbia University College of Physicians and Surgeons; the University of California, Los Angeles; Vanderbilt University; Harbor-UCLA Medical Center; Virginia Commonwealth University; and Columbia University Medical Center also contributed. The study was funded by the National Institute of Mental Health. Forest Pharmaceuticals, GlaxoSmithKline, Organon and Wyeth Pharmaceuticals provided the medications. Visit http://www.utsouthwestern.org/neurosciences to learn more about UT Southwestern's clinical services in neurosciences, including psychiatry. This news release is available on our World Wide Web home page at www.utsouthwestern.edu/home/news/index.html To automatically receive news releases from UT Southwestern via email, subscribe at www.utsouthwestern.edu/receivenews

Most Children with Rapidly Shifting Moods Don’t Have Bipolar Disorder

Relatively few children with rapidly shifting moods and high energy have bipolar disorder, though such symptoms are commonly associated with the disorder. Instead, most of these children have other types of mental disorders, according to an NIMH-funded study published online ahead of print in the Journal of Clinical Psychiatry on October 5, 2010. Background Some parents who take their child to a mental health clinic for assessment report that the child has rapid swings between emotions (usually anger, elation, and sadness) coupled with extremely high energy levels. Some researchers suggest that this is how mania—an important component of bipolar disorder—appears in children. How mania and bipolar disorder are defined in children is important because rapid mood swings and high energy are common among youth. Furthermore, many experts believe that overdiagnosis and misdiagnosis of bipolar disorder in youth may play a role in the increasing numbers of children being diagnosed with and treated for bipolar disorder. In choosing proper treatment, it is important to know whether children with rapid mood swings and high energy have an early or mild form of bipolar disorder, or instead have a different mental disorder CADC I & II Continuing Education In the Longitudinal Assessment of Manic Symptoms (LAMS) study, Robert Findling, M.D., of Case Western Reserve University, and colleagues assessed 707 children, ages 6-12, who were referred for mental health treatment. Of the participants, 621 were rated as having rapid swings between emotions and high energy levels, described as "elevated symptoms of mania" (ESM-positive). Parents of the other 86 children did not report rapid mood swings. These participants were deemed ESM-negative. Results of the Study At baseline, all but 14 participants had at least one mental disorder, and many had two or more. Attention deficit hyperactivity disorder (ADHD) was the most frequent diagnosis, affecting roughly 76 percent in both the ESM-positive and ESM-negative groups. However, only 39 percent were receiving treatment with a stimulant, the most common medication treatment for ADHD, at the start of the study. Only 11 percent of those with rapid mood swings and high energy (69 out of 621) and 6 percent of those without these symptoms (5 out of 86) had bipolar disorder, meaning that only this small percentage had ever experienced a manic episode, as defined by the current diagnostic system. Of the children with rapid mood swings and high energy, another 12 percent (75 children) had a form of bipolar disorder that includes much shorter manic episodes. Compared to children without rapid mood swings and high energy, those with these symptoms: Reported more symptoms of depression, anxiety, manic symptoms, and symptoms of ADHD Had lower functioning at home, school, or with peers Were more likely to have a disruptive behavior disorder (oppositional defiant disorder and/or conduct disorder). Significance Given that 75 percent of ESM-positive youth did not meet the diagnostic criteria for any bipolar disorder, the researchers suggest that bipolar disorder may not be common among children who experience rapid swings between emotions and high energy levels. Nevertheless, children with these symptoms experience significant impairments due to mood and behavior problems. The researchers also noted that ESM-positive and ESM-negative youth were prescribed psychotropic medications—including antipsychotics—at similar rates. Further study may provide insight into how serious mental illnesses should be treated in children. What's Next The study participants will be re-assessed every 6 months for up to 5 years, allowing the LAMS researchers to determine which children with rapid mood swings and high energy develop bipolar disorder later in life. Such research may inform efforts to identify early markers or predictors of the illness as well as possible protective factors. Reference Findling RL, Youngstrom EA, Fristad MA, Birmaher B, Kowatch RA, Arnold E, Frazier TW, Axelson D, Ryan N, Demeter CA, Gill MK, Fields B, Depew J, Kennedy SM, Marsh L, Rowles BM, Horwitz SM. Characteristics of Children With Elevated Symptoms of Mania: The Longitudinal Assessment of Manic Symptoms (LAMS) Study. J Clin Psychiatr. Epub 2010 Oct 5.

Agent Reduces Autism-like Behaviors in Mice

Press Release • April 25, 2012

Agent Reduces Autism-like Behaviors in Mice Boosts Sociability, Quells Repetitiveness – NIH Study National Institutes of Health researchers have reversed behaviors in mice resembling two of the three core symptoms of autism spectrum disorders (ASD). An experimental compound, called GRN-529, increased social interactions and lessened repetitive self-grooming behavior in a strain of mice that normally display such autism-like behaviors, the researchers say. GRN-529 is a member of a class of agents that inhibit activity of a subtype of receptor protein on brain cells for the chemical messenger glutamate, which are being tested in patients with an autism-related syndrome. Although mouse brain findings often don’t translate to humans, the fact that these compounds are already in clinical trials for an overlapping condition strengthens the case for relevance, according to the researchers. “Our findings suggest a strategy for developing a single treatment that could target multiple diagnostic symptoms,” explained Jacqueline Crawley, Ph.D., of the NIH’s National Institute of Mental Health (NIMH). “Many cases of autism are caused by mutations in genes that control an ongoing process – the formation and maturation of synapses, the connections between neurons. If defects in these connections are not hard-wired, the core symptoms of autism may be treatable with medications.” Crawley, Jill Silverman, Ph.D., and colleagues at NIMH and Pfizer Worldwide Research and Development, Groton, CT, report on their discovery April 25th, 2012 in the journal Science Translational Medicine. "These new results in mice support NIMH-funded research in humans to create treatments for the core symptoms of autism,” said NIMH director Thomas R. Insel, M.D. “While autism has been often considered only as a disability in need of rehabilitation, we can now address autism as a disorder responding to biomedical treatments." social worker ceus Crawley’s team followed-up on clues from earlier findings hinting that inhibitors of the receptor, called mGluR5, might reduce ASD symptoms. This class of agents – compounds similar to GRN-529, used in the mouse study – are in clinical trials for patients with the most common form of inherited intellectual and developmental disabilities, Fragile X syndrome, about one third of whom also meet criteria for ASDs. To test their hunch, the researchers examined effects of GRN-529 in a naturally occurring inbred strain of mice that normally display autism-relevant behaviors. Like children with ASDs, these BTBR mice interact and communicate relatively less with each other and engage in repetitive behaviors – most typically, spending an inordinate amount of time grooming themselves. Crawley’s team found that BTBR mice injected with GRN-529 showed reduced levels of repetitive self-grooming and spent more time around – and sniffing nose-to-nose with – a strange mouse. Moreover, GRN-529 almost completely stopped repetitive jumping in another strain of mice. “These inbred strains of mice are similar, behaviorally, to individuals with autism for whom the responsible genetic factors are unknown, which accounts for about three fourths of people with the disorders,” noted Crawley. “Given the high costs – monetary and emotional – to families, schools, and health care systems, we are hopeful that this line of studies may help meet the need for medications that treat core symptoms.” Reference: Silverman JL, Smith DG, Rizzo SJS, Karras MN, Turner SM, Tolu SS, Bryce DK, Smith DL, Fonseca K, Ring RH, Crawley, JN. Negative allosteric modulation of the MGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism. April 25, 2012, Science Translational Medicine.

In a nationally representative survey of 12- to 17-year-old youth and their trauma experiences, 39 percent reported witnessing violence, 17 percent reported physical assault, and 8 percent reported a lifetime prevalence of sexual assault.

April 2012 Social Media Message

In a nationally representative survey of 12- to 17-year-old youth and their trauma experiences, 39 percent reported witnessing violence, 17 percent reported physical assault, and 8 percent reported a lifetime prevalence of sexual assault. With help from families, friends, providers, and other Heroes of Hope, children and youth can be resilient when dealing with trauma. Visit www.samhsa.gov/children to learn more. When looking at rates of exposure to traumatic events, a nationally representative survey reported that among 12- to 17-year-old youth, 39 percent reported witnessing violence, 17 percent reported physical assault, and 8 percent reported a lifetime prevalence of sexual assault.1, 2 ceus for social workers Research has shown that caregivers can buffer the impact of trauma and promote better outcomes for children, even under stressful times, when the following Strengthening Families Protective Factors are present: •Parental resilience •Social connections •Knowledge of parenting and child development •Concrete support in times of need •Social and emotional competence of children3 Use these sample messages to share this childhood trauma and resilience data point with your connections on Twitter and Facebook and via email. Twitter: 39% of 12- to 17-year-old youths have reported witnessing violence, learn more: http://1.usa.gov/Ie4UjT via @samhsagov #HeroesofHope Facebook: A national survey of 12- to 17-year-old youths found that 17 percent reported physical assault and 8 percent reported a lifetime prevalence of sexual assault. Learn more about the behavioral health impact of traumatic events on children and youth and pass it on to observe National Children's Mental Health Awareness Day: http://1.usa.gov/Ie4UjT

References: 1. Kilpatrick DG, Acierno R. (2003). Mental health needs of crime victims: Epidemiology and outcomes. Journal of Traumatic Stress.16(2),119–132. Retrieved from http://onlinelibrary.wiley.com/doi/10.1023/A:1022891005388/abstract . 2.Saunders BE. (2003). Understanding Children Exposed to Violence Toward an Integration of Overlapping Fields. National Crime Victims Research and Treatment Center. J Interpers Violence. 18(4) 356-376. Retrieved from http://jiv.sagepub.com/content/18/4/356.short . 3.Horton, C. (2003). Protective factors literature review. Early care and education programs and the prevention of child abuse and neglect. Center for the Study of Social Policy.