Astrocytes identified as target for new depression therapy

Tufts neuroscientists find that starry brain cells can be used to mimic sleep deprivation BOSTON (January 23, 2013) — Neuroscience researchers from Tufts University have found that our star-shaped brain cells, called astrocytes, may be responsible for the rapid improvement in mood in depressed patients after acute sleep deprivation. This in vivo study, published in the current issue of Translational Psychiatry, identified how astrocytes regulate a neurotransmitter involved in sleep. The researchers report that the findings may help lead to the development of effective and fast-acting drugs to treat depression, particularly in psychiatric emergencies. Drugs are widely used to treat depression, but often take weeks to work effectively. Sleep deprivation, however, has been shown to be effective immediately in approximately 60% of patients with major depressive disorders. Although widely-recognized as helpful, it is not always ideal because it can be uncomfortable for patients, and the effects are not long-lasting Marriage and Family Therapist Continuing Education During the 1970s, research verified the effectiveness of acute sleep deprivation for treating depression, particularly deprivation of rapid eye movement sleep, but the underlying brain mechanisms were not known. Most of what we understand of the brain has come from research on neurons, but another type of largely-ignored cell, called glia, are their partners. Although historically thought of as a support cell for neurons, the Phil Haydon group at Tufts University School of Medicine has shown in animal models that a type of glia, called astrocytes, affect behavior. Haydon's team had established previously that astrocytes regulate responses to sleep deprivation by releasing neurotransmitters that regulate neurons. This regulation of neuronal activity affects the sleep-wake cycle. Specifically, astrocytes act on adenosine receptors on neurons. Adenosine is a chemical known to have sleep-inducing effects. During our waking hours, adenosine accumulates and increases the urge to sleep, known as sleep pressure. Chemicals, such as caffeine, are adenosine receptor antagonists and promote wakefulness. In contrast, an adenosine receptor agonist creates sleepiness. "In this study, we administered three doses of an adenosine receptor agonist to mice over the course of a night that caused the equivalent of sleep deprivation. The mice slept as normal, but the sleep did not reduce adenosine levels sufficiently, mimicking the effects of sleep deprivation. After only 12 hours, we observed that mice had decreased depressive-like symptoms and increased levels of adenosine in the brain, and these results were sustained for 48 hours," said first author Dustin Hines, Ph.D., a post-doctoral fellow in the department of neuroscience at Tufts University School of Medicine (TUSM). "By manipulating astrocytes we were able to mimic the effects of sleep deprivation on depressive-like symptoms, causing a rapid and sustained improvement in behavior," continued Hines. "Further understanding of astrocytic signaling and the role of adenosine is important for research and development of anti-depressant drugs. Potentially, new drugs that target this mechanism may provide rapid relief for psychiatric emergencies, as well as long-term alleviation of chronic depressive symptoms," said Naomi Rosenberg, Ph.D., dean of the Sackler School of Graduate Biomedical Sciences and vice dean for research at Tufts University School of Medicine. "The team's next step is to further understand the other receptors in this system and see if they, too, can be affected." ### Senior author, Phillip G. Haydon, Ph.D., is the Annetta and Gustav Grisard professor and chair of the department of neuroscience at Tufts University School of Medicine (TUSM). Haydon is also a member of the neuroscience program faculty at the Sackler School of Graduate Biomedical Sciences at Tufts. Additional authors are Luke I. Schmitt, B.S., a Ph.D. candidate in neuroscience at the Sackler School; Rochelle M. Hines, Ph.D., a post-doctoral fellow in the department of neuroscience at TUSM; and Stephen J. Moss, Ph.D., a professor of neuroscience at Tufts University School of Medicine and a member of the neuroscience program faculty at the Sackler School. Hines DJ, Schmitt LI, Hines RM, Moss SJ, Haydon PG. Translational Psychiatry. "Antidepressant effects of sleep deprivation require astrocyte-dependent adenosine mediated signaling." (2013) 3, e212; doi:10.1038/tp.2012.136. Published online 15 January 2013. This research was supported by award number R01MH095385 from the National Institute of Mental Health, part of the National Institutes of Health, as well as by award number R01NS037585 from the National Institute of Neurological Disorders and Stroke, both of the National Institutes of Health. Dustin Hines was partially funded by the Heart and Stroke Foundation of Canada. Haydon is co-founder and president of GliaCure Inc., which has licensed a pending patent application filed by Tufts University claiming compounds that modulate the signaling cascades, and related methods of use, described in this paper. About Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences at Tufts University are international leaders in innovative medical education and advanced research. The School of Medicine and the Sackler School are renowned for excellence in education in general medicine, biomedical sciences, special combined degree programs in business, health management, public health, bioengineering and international relations, as well as basic and clinical research at the cellular and molecular level. Ranked among the top in the nation, the School of Medicine is affiliated with six major teaching hospitals and more than 30 health care facilities. Tufts University School of Medicine and the Sackler School undertake research that is consistently rated among the highest in the nation for its effect on the advancement of medical science. If you are a member of the media interested in learning more about this topic, or speaking with a faculty member at the Tufts University School of Medicine or another Tufts health sciences researcher, please contact Siobhan Gallagher.

Brain Imaging Predicts Psychotherapy Success in Patients with Social Anxiety Disorder

Treatment for social anxiety disorder or social phobia has entered the personalized medicine arena—brain imaging can provide neuromarkers to predict whether traditional options such as cognitive behavioral therapy will work for a particular patient, reported a National Institute of Mental Health (NIMH)-funded study that was published in the January 2013 issue of JAMA Psychiatry. Background Social anxiety disorder (SAD)— the fear of being judged by others and humiliated— is the third most prevalent psychiatric disorder in Americans, after depression and alcohol dependence, according to the National Comorbidity Survey, a U.S. poll on mental health. This fear can be so strong that it interferes with daily life activities like going to work or school. If left untreated, some sufferers use alcohol, food, or drugs to reduce the fear at social events, which often leads to other disorders such as alcoholism, eating disorders, and depression. The NIMH claims that 6.8 percent of U.S. adults and 5.5 percent of 13- to 15-year-olds, the age of onset for this chronic disorder, are annually afflicted Social Worker Continuing Education Although psychotherapy and drugs, such as antidepressants and benzodiazepines, exist as treatments for SAD, current behavioral measures poorly predict which would work better for individual patients. “Half of social anxiety disorder patients have satisfactory response to treatment. There is little evidence about which patient would benefit from a particular form of treatment,” said John D. Gabrieli, Ph.D., lead author of the study. “Currently, there is no rational basis for prescribing one treatment over the other. Which treatment a patient gets depends on whom they see.” Enter personalized medicine, the use of genetic or other biological markers to tailor treatments to those who would actually benefit from them, thus sparing the expense and side effects for those who would not. Brain imaging could identify neuromarkers or targeted areas of the brain that could one day optimize treatment for individual patients. Neuromarkers are being used in other areas of mental illness, for instance, to predict the onset of psychosis in schizophrenia and the likelihood of relapse in drug addiction. In this study, Gabrieli, at the Massachusetts Institute of Technology in Cambridge, and his colleagues, used functional magnetic resonance imaging (fMRI) in 39 SAD patients before a 12-week course of cognitive behavioral therapy. The patients viewed angry versus neutral faces and scenes while undergoing fMRI examination (see first slide). Compared to neutral faces, angry faces convey disapproval and are likely to prompt excessive fear responses and negative connotations in SAD patients; cognitive behavioral therapy teaches these patients ways to downregulate their responses. The patients’ brain images were then compared to their scores on a conventional clinical measure, the Liebowitz Social Anxiety Scale (LSAS), a questionnaire which they took before and after therapy completion. Results of the Study SAD patients responded more to the images of faces and not scenes, which is characteristic for the social basis of this disorder. Patients whose brains reacted strongly to the facial images before treatment benefitted more from the therapy than those who reacted to these the least (see second slide). Specifically, changes in two occipitotemporal brain regions—areas involved in early processing of visual cues such as faces—correlated with positive cognitive behavioral therapy outcome. These neuromarkers predicted treatment outcome better than the currently used LSAS. Significance This study is the first of its kind to use neuroimaging to predict treatment response in SAD patients. Neuromarkers may become a practical clinical tool to guide the selection of optimal treatments for individual patients. Integration of neuromarkers with genetic, behavioral, and other biomarkers is likely to further refine the prediction. What’s Next A larger study comparing people with SAD with normal participants is needed to verify the results. fMRI studies using other facial expressions (disgust or fear) might be better predictors. Studies that look at other treatment options, such as drugs, are also needed to confirm which treatment is optimal. Researchers asked patients with social phobia to undergo functional magnetic resonance imaging (fMRI) while viewing images of neutral versus angry faces and scenes. The patients’ brains showed more activity when they viewed the faces. Source: Gabrieli Lab, MIT Patients with social phobia whose brains “lit” up the most, particularly in two regions towards the back of the brain that process what we see, responded the best to psychotherapy. Source: Gabrieli Lab, MIT Reference Doehrmann O, Ghosh SS, Polli FE, Reynolds GO, Horn F, Keshavan A, Triantafyllou C, Saygin ZM, Whitfield-Gabrieli S, Hofmann SG, Pollack M, Gabrieli JD. Predicting Treatment Response in Social Anxiety Disorder from Functional Magnetic Resonance Imaging. JAMA Psychiatry. January 2013. 70(1):87–97.

Paradox of aging: The older we get, the better we feel?

Presently, there are about 40 million Americans over the age of 65, with the fastest-growing segment of the population over 80 years old. Traditionally, aging has been viewed as a period of progressive decline in physical, cognitive and psychosocial functioning, and aging is viewed by many as the "number one public health problem" facing Americans today. But this negative view of aging contrasts with results of a comprehensive study of 1,006 older adults in San Diego by researchers from the University of California, San Diego School of Medicine and Stanford University. Results of the Successful Aging Evaluation (SAGE) study – comprising a 25-minute phone interview, followed by a comprehensive mail-in survey – will be published in the December 7 online issue of the American Journal of Psychiatry. "While there is a growing public health interest in understanding and promoting successful aging, until now little published research has combined measures of physical health with cognitive and psychological assessments, in a large and randomly selected sample," said principal investigator Dilip V. Jeste, MD, Estelle and Edgar Levi Chair in Aging, Distinguished Professor of Psychiatry and Neurosciences, and director of UC San Diego's Stein Institute for Research on Aging, and the current President of the American Psychiatric Association (which was not involved in this study). The SAGE study included adults between the ages of 50 and 99 years, with a mean age of just over 77 years. In addition to measures which assessed rates of chronic disease and disability, the survey looked at more subjective criteria such as social engagement and participants' self-assessment of their overall health. "Sometimes the most relevant outcomes are from the perspective of the subjects themselves," said Jeste. The study concludes that resilience and depression have significant bearing on how individuals self-rate successful aging, with effects that are comparable to that of physical health. "Even though older age was closely associated with worse physical and cognitive functioning, it was also related to better mental functioning," said co-author Colin Depp, PhD, associate professor of psychiatry at UC San Diego School of Medicine. After adjusting for age, a higher self-rating of successful aging was associated with higher education, better cognitive function, better perceived physical and mental health, less depression, and greater optimism and resilience. Participants were asked to rate the extent to which they thought they had "successfully aged," using a 10-point scale and using their own concept of the term. The study found that people with low physical functioning but high resilience, had self-ratings of successful aging similar to those of physical healthy people with low resilience. Likewise, the self-ratings of individuals with low physical functioning but no or minimal depression had scores comparable to those of physically healthy people with moderate to severe depression. "It was clear to us that, even in the midst of physical or cognitive decline, individuals in our study reported feeling that their well-being had improved with age," Jeste said. This counterintuitive increase in well-being with aging persisted even after accounting for variables like income, education and marriage. Jeste suggests there's a take-away message for clinicians, which is that an optimistic approach to the care of seniors may help reduce societal ageism. "There is considerable discussion In public forums about the financial drain on the society due to rising costs of healthcare for older adults – what some people disparagingly label the 'silver tsunami.' But, successfully aging older adults can be a great resource for younger generations," he said. The findings point to an important role for psychiatry in enhancing successful aging in older adults. "Perfect physical health is neither necessary nor sufficient," Jeste said. "There is potential for enhancing successful aging by fostering resilience and treating or preventing depression." Aging and Long Term Care (Abridged) CE Course (3 hours) ### Additional contributors to this study include Gauri N. Savla, PhD, Wesley K. Thompson, PhD, Ipsit V. Vahia, MD, Danielle K. Glorioso, MSW, A'verria Sirkin Martin, PhD, Barton W. Palmer, PhD, David Rock, BA, and Shahrokh Golshan, PhD, UC San Diego; and Helena C. Kraemer, PhD, professor of biostatistics in psychiatry at Stanford University. This work was supported, in part, by NIMH grants T32 MH-019934 and P30 MH-066248, by NIH National Center for Research Support grant UL1 RR-031980, by the John A. Hartford Foundation, and by the Sam and Rose Stein Institute for Research on Aging.

Guide Offers a Blueprint for End-of-Life Conversation With Youth

Enlisting the advice of adolescents and young adults with serious illness, researchers at the National Institutes of Health have developed a guide to help young people and their families address issues surrounding end-of-life care. Voicing My CHOICES is the first guide designed to help adolescents and young adults express how they would like to be comforted, supported, and cared for in the course of serious illness, and how they would like to be remembered if they do not survive. The guide is aimed at helping families and health professionals open difficult conversations, and was written using language and questions tailored to the particular needs and preferences of young people. A paper in the November 2012 issue of the journal Pediatrics reported on a study in which young people with serious illnesses read and commented on pages from two existing advance care planning guides. The study found that adolescents and young adults do want to be involved in end-of-life planning. Almost all of the 52 participants in the study felt that having such a guide was helpful and important. Their comments on specific questions shaped the content of Voicing My CHOICES. Lori Wiener, Ph.D., director of the pediatric psychosocial support and research program at the National Cancer Institute, is lead author of the Pediatrics study and developed the prototype for Voicing My CHOICES that the young participants evaluated. She collaborated with Maryland Pao, M.D., clinical director of the National Institute of Mental Health, whose staff provides psychiatric consultation at NIH’s research hospital for patients of all ages with serious illness. Developing Voicing My CHOICES began with focus groups in which young people with serious illness endorsed the need for an advance care planning guide for persons their age. Out of this came a study, reported in 2008, in which a group of 20 adolescents and young adults living with cancer or perinatally acquired HIV disease were asked to read and evaluate the publication Five Wishes, an advanced directive for adults, along with additional topics identified during the focus groups. The study team used their feedback to create a new guide for young people called My Thoughts, My Wishes, My Voice. In the current study, youth reviewed pages from this publication and Five Wishes. Their comments were incorporated in the final Voicing My CHOICES. “Adolescents and young adults often stay silent, not sharing their fears—as they do not want to further upset their parents,” said Wiener. “And parents don’t bring up end-of-life issues for the same reasons.” The research studies showed, however, that teens and young adults are interested in these issues and value the opportunity to express their preferences. The guide also serves a developmental purpose. “At a stage of life where they would normally be seeking identity and a way to leave their mark on the world, they are in a situation where they can’t make decisions,” said Pao. Youth are concerned, she said, with how they will be cared for and remembered and, true to their age, about peer relationships. They want to be heard. Voicing My CHOICES includes questions about making medical care decisions and the types of life support a young person would or would not want. In response to comments, changes were made to make the language in Voices My CHOICES less technical, and to offer both yes/no and open-ended questions. Participants in the study endorsed a section in which they can indicate whether they would like to donate their body to science or have an autopsy, which speaks powerfully, said Wiener, to their sense of altruism and the need to find meaning in their experience Aging and Long Term Care CE Course “Adolescents and young adults can feel very frightened and alone when their bodies are no longer responding to medical interventions and decisions are being made around them,” said Wiener. “Allowing them to be involved in decisions, and to document how they wish to be remembered, enhances the trust in parent and medical provider relationships and provides them with the opportunity to give meaning to their life.” The product of a collaboration between clinical research teams representing two different areas of focus within NIH’s research hospital—pediatric oncology and psychiatry—Voicing My CHOICES can be used to help patients, families, caregivers, and health care providers. Voicing My CHOICES is available from Aging With Dignity (www.agingwithdignity.org), a nonprofit that provides the advanced directive document for adults, Five Wishes. References Wiener L, Zadeh S, Battles H, Baird K, Ballard E, Osherow J, Pao M. Allowing adolescents and young adults to plan their end-of-life care. Pediatrics. 2012 Nov;130(5):897-905. doi: 10.1542/peds.2012-0663. Epub 2012 Oct 8. Wiener L, Ballard E, Brennan T, Battles H, Martinez P, Pao M. How I wish to be remembered: the use of an advance care planning document in adolescent and young adult populations. Journal of Palliative Medicine. 2008 Dec;11(10):1309-13.

Emergency Department Suicide Screening Tool Accurately Predicts At Risk Youth

A set of four questions that takes emergency department nurses or physicians less than 2 minutes to administer can successfully identify youth at risk for attempting suicide, reported a study by National Institute of Mental Health (NIMH) researchers that was published in the December 2012 issue of the Archives of Pediatrics and Adolescent Medicine Aspira Continuing Education Online Courses Background Each year as many as 5 to 8 percent of U.S. children and young adults attempt suicide, according to the U.S. Centers for Disease Control and Prevention. In 2010, 4867 youths between ages 10 and 24 died by suicide, making it the second leading cause of death for people in this age group. Most individuals who die by suicide have visited a health care provider 3 months to 1 year before their death. Typically these patients saw an emergency department (ED) nurse and physician for some other health concern such as abdominal pain or headaches. These at-risk individuals often go unrecognized by ED staff who either lack the time or training to properly screen patients. The Joint Commission, a leading U.S.-based nonprofit healthcare accreditation organization, and the American Academy of Pediatrics have previously recommended the creation and use of suicide screening tools for adult and pediatric patient populations. To date there are no screening instruments to assess suicide risk in children and adolescents who visit EDs for medical or surgical reasons. “Many families use the emergency department as their sole contact in the healthcare system,” said Lisa M. Horowitz, Ph.D., M.P.H., lead author of the study. “Most people don’t show up to the emergency department and say ‘I want to kill myself.’ Rather they show up with physical complaints and do not discuss their suicidal thoughts. But studies have shown that if you ask directly, the majority will tell you. Nurses and physicians need to know what questions to ask.” Horowitz, a clinician and researcher with NIMH, and her colleagues developed a quick questionnaire that ED nurses and physicians could use to assess suicide risk among youth. Their study tested 17 candidate questions in 524 patients ages 10 to 21 years who visited one of three academically-affiliated pediatric EDs and had either psychiatric problems—suicidal ideation, intense anxiety, post-traumatic stress disorder—or medical/surgical concerns—gastrointestinal diseases, sickle cell anemia, cystic fibrosis. The questions—focusing on suicidal thoughts and behavior—were reviewed and revised by a panel of mental health clinicians, health services researchers, and survey specialists. The patients also completed one of two versions of the Suicidal Ideation Questionnaire (SIQ), the “gold standard,” 30-question suicide-screening tool that is used by pediatric and adolescent psychiatrists, but which is too long for ED visits and requires additional training. As part of the study’s safety plan, individuals whose responses indicated that they were at risk for attempting suicide were referred to mental health professionals—social workers, psychiatrists, psychologists—for further evaluation Suicide Prevention CE Course Results of the Study Of the 17 candidate questions, four (used as a set) stood out as having the most accuracy for predicting suicide attempts: current thoughts of being better off dead, current wish to die, current suicidal ideation, and history of suicide attempt. Positive responses to 1 or more of these 4 questions identified 97% of the youth at risk for suicide, regardless of whether these patients came in for psychiatric or general medical concerns. Based on results from the new questionnaire, 18.7% of the ED patients (98 of the 524) screened positive for suicide risk; most of whom had come to the ED with psychiatric concerns (84 of the 524). Elevated suicide risk was detected in 4.1% of the ED patients (14 of the 344) with medical/surgical concerns. Had it not been for the new screening tool, the suicide risk in these 14 patients most likely would have gone undetected. Significance The instrument based on these 4 questions, called the Ask Suicide-Screening Questions (ASQ), is the first time such a screen has been validated for pediatric and young adult patients evaluated in EDs for medical/surgical reasons. Although the number of these patients identified as high risk for suicide is small, the screen takes less than 2 minutes to administer. The tool is freely available and accessible online (pdf). What’s Next Additional research assessing the impact of suicidal screening in pediatric EDs on referral rates to mental health services and future suicidal behavior are needed. The accuracy of the ASQ among diverse demographic populations also needs examination. Additionally, a cost-benefit analysis for the screening tool is needed, as is research studying its use in other healthcare settings such as in-patient and out-patient care. Reference Horowitz LM, Bridge JA, Teach SJ, Ballard E, Klima J, Rosenstein DL, Wharff EA, Ginnis K, Cannon E, Joshi P, Pao M. Ask Suicide-Screening Questions (ASQ). A Brief Instrument for the Pediatric Emergency Department. Archives of Pediatrics and Adolescent Medicine. December 2012. 166(12):1170–1176.

Psychotropic Medications Are Prescribed Appropriately Among U.S. Teens, National Study Finds

Prescribed psychotropic medications are not being misused or overused among U.S. youth, according to a study using nationally representative data sponsored by NIMH. The study was published December 3, 2012, online ahead of print in the Archives of Pediatric and Adolescent Medicine. Background Psychotropic medications affect the brain chemicals associated with mood and behavior. Some studies and media reports have raised concerns about their use among youth. However, much of the concern stems from information found in anecdotal reports, small clinical samples, or insurance databases rather than on representative samples of U.S. youth with clinical assessments of emotional and behavioral disorders. Studies from regional community samples have found widely varying rates, which can lead to skewed perceptions. For example, different studies have found a wide range of stimulant medication use for attention deficit hyperactivity disorder (ADHD)—from 7 percent to 72 percent—likely due to methodological and regional differences. As a result, it has been difficult to get a clear, accurate understanding of medication use among youth. Kathleen Merikangas, Ph.D., of NIMH and colleagues collected information on specific medication use in the National Comorbidity Study-Adolescent Supplement (NCS-A), a nationally representative, face-to-face survey from 2004 of more than 10,000 teens ages 13 to 18.The teens were asked questions that helped to ascertain information about mental disorders and service use. A previous report published in October 2010 using data from the NCS-A indicated that about 20 percent of U.S. youth are affected by some type of mental disorder during their lifetime serious enough to affect their functioning. In this most recent analysis, the researchers examined patterns of prescribed medication use among youth who met criteria for a wide range of mental disorders. Psychotropic medications that were examined include antipsychotics, antidepressants, and stimulants Professional Counselor Continuing Education Results of the Study Among those youth who met criteria for any mental disorder, 14.2 percent reported that they had been treated with a psychotropic medication. Teens with ADHD had the highest rates of prescribed medication use at 31 percent, while 19.7 percent of those with a mood disorder like depression or bipolar disorder were taking psychotropic medication. Among those with eating disorders, about 19 percent were taking a psychotropic medication, and 11.6 percent of those with anxiety disorders reported taking medication. Very few youth reported use of antipsychotic medications. They were most frequently used by youth with severe bipolar disorder (1.7 percent) or a neurodevelopmental disorder such as autism (2.0 percent). Approximately 2.5 percent of teens without a diagnosed mental disorder were prescribed a psychotropic medication. Among these youth, 78 percent reported having a previous mental or neurodevelopmental disorder and associated psychological distress or impairment. Significance The data suggest that most adolescent youth who are taking psychotropic medications have serious behavioral, cognitive or emotional disturbances. The findings also showed that youth being treated by a mental health professional were more likely to be receiving appropriate medication as opposed to those being treated within general medicine or other settings. However, more research is needed on medication use among children younger than age 13. Reference Merikangas K, He J, Rapoport J, Vitiello B, Olfson M. Medication use in US Youth with Mental Disorders. Archives of Pediatric and Adolescent Medicine. Online ahead of print Dec 3, 2012.

Switching Off a Specific Brain Region Can Alter Ingrained Habits in Rats

Ingrained habits in rats can be quickly broken—and reestablished—by targeting and switching off a specific site in the brain’s prefrontal cortex using a technique known as optogenetics, according to an NIMH-funded study published November 13, 2012, in the Proceedings of the National Academy of Sciences (PNAS). Background Studies have established that the prefrontal region of the brain is associated with habit formation and expression. It is also linked to emotion regulation and to regions in the brain that are associated with behavioral flexibility, which counteracts habit. Kyle Smith Ph.D., Ann Graybiel Ph.D., of the Massachusetts Institute of Technology, and colleagues, trained rats to run a T-shaped maze. At the decision point, the rats were cued to turn to either one side, where chocolate milk awaited them as a reward, or to the other side, where the reward was sugar water. Eventually, running the maze and responding to each cue correctly became a habit, and the rats continued to do so even after the rewards were removed. The researchers then returned the rewards but paired the chocolate milk with exposure to lithium chloride, which causes nausea. Once the rats realized the milk made them ill, they declined to drink it. However, they continued to run the maze and turn toward the chocolate milk side of the maze when cued, indicating that running in that direction when prompted had become a nearly automatic behavior. Results of the Study To determine whether the habit could be broken, the researchers then applied a technique known as optogenetics—in which a laser light is delivered to brain cells through optical fibers—to see if they could manipulate a specific region of the rats’ prefrontal cortex known as the infralimbic (IL) cortex. When the laser was turned on and the IL cortex was disrupted, the rats nearly instantaneously stopped running habitually toward the chocolate milk reward. Instead, they appeared to act more thoughtfully, running toward the other side, where the untainted sugar water awaited. Once the rats were broken of the habit of running automatically to the chocolate milk side, they began to develop a habit of always running to the other side, even when they were cued to run toward the chocolate milk, and even after the untainted chocolate milk was returned. But when the IL region was again disrupted optogenetically, the rats returned to their original habit of running to the chocolate milk side when cued to do so. Significance Control of a small part of the prefrontal cortex can change whether or not habits are expressed. An old habit can be blocked abruptly, and a new habit can override it. But if the new habit is then blocked, the old habit returns, thus lending credence to the notion that old habits die hard Social Worker Continuing Education In addition, the fact that habitual behavior can be altered if IL activity is disturbed suggests that the circuitry in this region of the brain is coordinating on some level with other brain regions that directly access circuits involved in behavioral flexibility, as well as addictive behaviors. What’s Next Although the optogenetic technique is too invasive to use in humans, it does have implications for potentially disrupting destructive habits. Targeting this specific region of the brain could lead to better ways of controlling addiction disorders or mental disorders in which habitual behaviors are out of balance, such as obsessive compulsive disorder. Reference Smith K, Virkud A, Deisseroth K, Graybiel A. Reversible online control of habitual behavior by optogenetic perturbation of media prefrontal cortex. PNAS. Nov 13, 2012. 109(46):18932-18937.