November 28, 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.

November 01, 2012

Study: Use of antipsychotic drugs improves life expectancy for individuals with schizophrenia

Results of a Johns Hopkins study suggest that individuals with schizophrenia are significantly more likely to live longer if they take their antipsychotic drugs on schedule, avoid extremely high doses and also regularly see a mental health professional. Psychiatrists have long known that people with schizophrenia who stick to a drug regimen have fewer of the debilitating delusions and hallucinations that are hallmarks of this illness. But there have been concerns about whether some of the known side effects of the medications — increased risk of cardiovascular disease and diabetes, for example — carry higher mortality risks, the researchers say. "We know that antipsychotic medications reduce symptoms, and our study shows that staying on reasonable, recommended doses is associated with longer life," says Bernadette A. Cullen, M.B., B.Ch., B.A.O., MRCPsych, an assistant professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine, and leader of the study published in Schizophrenia Bulletin. "The same is true for going to see a psychiatrist or therapist," she says, noting that regular visits to a mental health professional are one way to monitor and encourage drug-use compliance, but also in and of themselves increased survival in this vulnerable population. Cullen and her colleagues analyzed data collected between 1994 through 2004 on 2,132 adult Maryland Medicaid beneficiaries with schizophrenia. The researchers reviewed how much medication the patients took, how regularly they took it and how often they visited a mental health professional. The goal of the study was to review how adherence to the 2009 pharmacological Schizophrenia Patient Outcomes Research Team (PORT) guidelines was associated with mortality in this population. Comparing data from year to year, the researchers found that among those patients who had 90 percent or better compliance with their medication schedules, the risk of death was 25 percent lower compared to those who were less than 10 percent compliant. Over the decade-long study period, taking medication did not increase the risk of death and there was a trend towards reducing the mortality rate. In addition, the researchers found that each additional visit per year to a mental health professional was linked to a 5 percent reduction in risk of death overall LSW Continuing Education Cullen's study did not rule out all links between increased mortality and antipsychotic drugs. For example, her team found that people who took high doses of first-generation antipsychotic medication daily (1500 mg or greater chlorpromazine equivalents) were 88 percent more likely to die. She says mortality rates possibly increased in this group because first-generation antipsychotics have been associated with cardiac disease risks, and among those who died while taking the larger doses, 53 percent died of cardiovascular disease. "These drugs work very well, but there is clearly a point of diminishing returns," she says. "You rarely need to be on extremely high doses." Among those whose information was reviewed, the most common cause of death was cardiovascular disease (28 percent); unintended harm, including suicide, was responsible for 8 percent. "If people are taking their medications, they usually have fewer symptoms and are able to be more organized in other areas of their lives," says Cullen, director of community psychiatry at The Johns Hopkins Hospital. "We believe they are then more likely to make appointments with their primary care doctors, to stay on top of other illnesses they may have and to regularly take diabetes, blood pressure or cholesterol medication that they may require to stay healthy. We also believe that they are more likely to be socially engaged and have a healthier lifestyle." "If your illness is under control, you can do a lot more," she adds. Cullen says the study clearly lays out the value of mental health providers to individuals with schizophrenia. Those who saw therapists or psychiatrists were more likely to survive, regardless of whether the individual also took his or her antipsychotic medication on a regular basis, she says. This finding is crucial, she says, given that Maryland Medicaid officials are considering capping the number of mental health visits allowed each year, something the data now suggest is potentially detrimental to survival. Cullen notes that adherence to a medication regimen and moderate first-generation antipsychotic dosing are both part of the 2009 PORT recommendations designed to guide treatment. ### The study was supported by a grant from the National Institutes of Health's National Institute of Mental Health (R01MH074070). Other Johns Hopkins researchers involved in the study include Emma E. McGinty, M.S.; Yiyi Zhang, Ph.D.; Susan dos Reis, Ph.D.; Donald M. Steinwachs, Ph.D.; Eliseo Guallar, M.D., Dr.PH.; and Gail L. Daumit, M.D., M.H.S. For more information: