Runaway Vigilance Hormone Linked to Panic Attacks

Translational Experiments in Rats, Humans Suggest New Medication Target A study has linked panic disorder to a wayward hormone in a brain circuit that regulates vigilance. While too little of the hormone, called orexin, is known to underlie narcolepsy, the new study suggests that too much of it may lead to panic attacks that afflict 6 million American adults. "Targeting the brain's orexin system may hold promise for a new generation of anti-anxiety treatments," said Thomas R. Insel, M.D., Director of the National Institute of Mental Health (NIMH), part of the National Institutes of Health. "This is a good example of how translational experiments in rats and humans can potentially yield clinical benefits." NIMH grantee Anantha Shekhar, M.B., Ph.D., and colleagues at Indiana University and Lund University, report on their findings online Dec. 27, 2009 in the journal Nature Medicine. They showed that blocking orexin gene expression or its receptor prevented panic attack-like responses in rats. The study also revealed that panic disorder patients have excess levels of the hormone Alcoholism and Drug Abuse Counselors Continuing Education Background Orexin, also called hypocretin, is secreted exclusively in a circuit emanating from the brain's hypothalamus, known to regulate arousal, wakefulness and reward. Panic attacks can be experimentally-induced by infusing susceptible humans with a normally innocuous salt called sodium lactate. The salt similarly triggers panic-like anxiety behaviors in susceptible rat strains, suggesting that something is altered in their arousal circuit. Since sodium lactate activated orexin-secreting neurons in panic-prone rats but not in control rats, the researchers hypothesized that something might be orexin. Results of This Study The investigators first discovered that increased gene expression in orexin-secreting neurons correlated with increases in anxiety-like behavior in panic-prone rats following sodium lactate infusions. Using a technique called RNA interference, they then protected the panic-prone rats from developing anxiety behaviors following the infusions by first injecting them with a genetically-engineered agent that prevented orexin genes from turning on. Blocking orexin receptors with a drug that specifically binds to it also blocked the anxiety like behavior following the infusions. This mirrored effects, seen in both rats and humans, of benzodiazepine medications used to treat panic disorder. The excess sleepiness of narcolepsy, traced a decade ago to loss of orexin-secreting neurons in the arousal circuit, might seem to be an opposite state of a panic attack. However, the researchers demonstrated in rats that such sedation could not account for orexin's effects on anxiety. Also in rats, they traced orexin neurons to their end target to pinpoint the specific brain site that accounts for the anxiety effects, disentangled from cardio-respiratory components of the panic response. Finally, by measuring orexin in cerebrospinal fluid of 53 patients, the researchers showed that those with just panic disorder had higher levels of orexin than those with both panic disorder and depression. Significance Taken together, these results and other evidence suggest a critical role for an overactive orexin system in producing panic attacks, say the researchers. What's Next? Medications that block the orexin receptor may provide a new therapeutic approach for the treatment of panic disorder, they add. The research was also supported, in part, by NIH's National Center for Research Resources. Reference A key role for orexin in panic anxiety. Johnson PL, Truitt W, Fitz SD, Kelley PE, Dietrich A, Sanghani S, Traskman-Bendz L, Goddard AW, Brundin, L, Shekhar A. Nature Medicine.

Effects on Personality May Be Mechanism of Antidepressant Effectiveness

Results of a study of antidepressant treatment for major depression suggest that changes in personality traits seen in patients taking the drug paroxetine (Paxil) may not be the result of the medication’s lifting of mood but may instead be a direct effect of this class of drugs and part of the mechanism by which they relieve depression ceus for social workers Background People with a high level of the personality trait neuroticism—characterized by a tendency to experience negative emotions and moodiness—are more likely than others to develop depression. Neuroticism is one of five personality traits that psychologists use as an organizing scheme for understanding personality: the other four traits are extraversion, openness, conscientiousness, and agreeableness. People who take anti-depressants report lower levels of neuroticism and increased extroversion, in addition to a lifting of depression. The assumption has been that these changes in personality measures were the result, not the cause, of a lifting of depression. Studies in twins suggest that to a large degree the same genetic factors underlie both neuroticism and depression risk. Research also suggests that the neurotransmitter serotonin plays a role in the expression of both neuroticism and extraversion. The class of anti-depressant drugs to which paroxetine belongs—the selective serotonin reuptake inhibitors (SSRIs)—increase the neurotransmitter’s availability in the brain. This Study To test the relationship between SSRIs and personality, investigator Tony Tang and colleagues at Northwestern University, Evanston, IL, the University of Pennsylvania in Philadelphia, and Vanderbilt University in Nashville, TN, randomly assigned patients with major depressive disorder (MDD) to receive paroxetine (120 patients), placebo (60 patients), or cognitive therapy (60 patients). After 8 weeks, medication and cognitive therapy (CT) each proved more effective than placebo in reducing depression. In addition, measures of neuroticism (based on standard surveys) in the groups receiving medication or cognitive therapy dropped, while extraversion scores rose. The changes were striking; while patients receiving placebo also reported small changes in both traits, the changes in patients on paroxetine were four to eight times as large. Patients receiving paroxetine had much greater changes in personality traits than patients receiving placebo even when the degree of improvement in depression was the same. This suggested that the effects on personality traits were not the result of the drug’s lifting of depression. After accounting for decreases in depression in patients receiving CT, the improvement in extraversion, but not neuroticism, remained significant. In further comparison of paroxetine with placebo, patients who had initially taken placebo were given the option after 8 weeks to take paroxetine. During the placebo phase, there were small changes in neuroticism and extraversion; much greater changes occurred after 8 weeks on paroxetine. Finally, those patients on paroxetine with the greatest degree of change in neuroticism (but not extraversion) were least likely to relapse to depression; the degree of changes in personality in those receiving CT did not affect the chances of relapse. Significance While the neurochemical effects of SSRIs are known, how those changes act to reduce depression is not clear. These results contradict the prevailing assumption that changes seen in personality traits in patients taking SSRIs are a result of the drugs’ effects on depression. SSRIs may alter personality directly—and thus lift depression—or may act on a third factor that underlies both. CT may alter personality by a different path. Continued research on how these treatments work can provide a clearer understanding of the mechanism of action of SSRIs and how treatment can be best used to reduce depression and minimize relapse. Reference Tang, T.Z., DeRubeis, R.J., Hollon, S.D., Amsterdam, J., Shelton, R., and Schalet, B. Personality change during depression treatment. Archives of General Psychiatry 2009 Dec;66(12):1322-30.

Teens Who Recover from Hard-to-treat Depression Still at Risk for Relapse

Teens with hard-to-treat depression who reach remission after 24 weeks of treatment are still at a significant risk for relapse, according to long-term, follow-up data from an NIMH-funded study published online ahead of print November 16, 2010, in the Journal of Clinical Psychiatry. The long-term data reiterate the need for aggressive treatment decisions for teens with stubborn depression continuing education for social workers Background In the Treatment of Resistant Depression in Adolescents (TORDIA) study, teens whose depression had not improved after an initial course of selective serotonin reuptake inhibitor (SSRI) antidepressant treatment were randomly assigned to one of four interventions for 12 weeks: Switch to another SSRI-paroxetine (Paxil), citalopram (Celexa) or fluoxetine (Prozac) Switch to a different SSRI plus cognitive behavioral therapy (CBT), a type of psychotherapy that emphasizes problem-solving and behavior change Switch to venlafaxine (Effexor), a different type of antidepressant called a serotonin and norepinephrine reuptake inhibitor (SNRI) Switch to venlafaxine plus CBT As reported in May 2010, nearly 40 percent of those who completed 24 weeks of treatment achieved remission, regardless of the treatment to which they had initially been assigned. However, those who achieved remission were more likely to have responded to treatment early—during the first 12 weeks. After 24 weeks of treatment, the participants were discharged from the study and urged to continue care within their community. They were then asked to return for an assessment at 72 weeks. Results of the Study Of the 334 original TORDIA participants, about 61 percent had reached remission by week 72. Symptoms of depression steadily decreased after the initial 24 weeks of treatment. But at 72 weeks, many participants still reported having residual symptoms of depression, such as irritability, fatigue and low self-esteem. Those with more severe depression at baseline were less likely to reach remission. Those who responded early to treatment—within the first six weeks of treatment—were more likely to reach remission. Initial treatment assignment during the study did not appear to influence the remission rate or time to remission. However, of the 130 participants who had remitted by week 24, 25 percent had relapsed by week 72. Ethnic minorities tended to have a higher risk for relapse than whites. Significance Because more than one-third of the teens did not recover and the relapse rate was high, the authors conclude that more effective interventions early in the treatment process are needed. In addition, the higher risk of relapse for ethnic minorities suggests that cultural factors may influence the long-term course of depression and recovery, but it is unclear what those factors may be. What's Next The findings indicate that new methods are needed to accurately identify those who may not respond early in treatment so that patients unlikely to reach remission using a particular treatment may be offered alternative treatments earlier in the process. More data is needed, however, to be able to predict who might be more likely to remit and who may not. Reference Vitiello B, Emslie G, Clarke G, Wagner K, Asarnow JR, Keller M, Birmaher B, Ryan N, Kennard B, Mayes T, DeBar L, Lynch F, Dickerson J, Strober M, Suddath R, McCraken JT, Spirito A, Onorato M, Zelazny J, Porta G, Iyengar S, Brent D. Long-term outcome of adolescent depression initially resistant to SSRI treatment. Journal of Clinical Psychiatry.

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Rats recall past to make daily decisions

UCSF study offers path for studying learning, decision-making, PTSD UCSF scientists have identified patterns of brain activity in the rat brain that play a role in the formation and recall of memories and decision-making. The discovery, which builds on the team's previous findings, offers a path for studying learning, decision-making and post-traumatic stress syndrome. The researchers previously identified patterns of brain activity in the rat hippocampus, a brain region critical for memory storage. The patterns sometimes represented where an animal was in space, and, at other times, represented fast-motion replays of places the animal had been, but no one knew whether these patterns indicated the process of memory formation and recollection. In the journal Science this week (online May 3, 2012), the UCSF researchers demonstrated that the brain activity is critical for memory formation and recall. Moreover, they showed that the brain patterns through which the rats see rapid replays of past experiences are fundamental to their ability to make decisions. Disturbing those particular brain patterns impaired the animals' ability to learn rules based on memories of things that had happened in the past lsw ceus "We think these memory-replay events are central to understanding how the brain retrieves past experiences and uses them to make decisions," said neuroscientist Loren Frank, PhD, a associate professor of physiology and a member of the Keck Center for Integrative Neuroscience at UCSF, who led the research with Shantanu Jadhav, PhD, a post-doctoral fellow. "They offer insight into how a past experience can have such a profound effect on how we think and feel." The finding gives scientists a new way to investigate fundamental processes like learning and decision-making in animals and in people. It also may help shed light on memory disorders like post-traumatic stress disorder (PTSD), which is characterized by strong, disturbing and uncontrolled memories. WITHOUT LINKS TO THE PAST, RATS FACE INDECISION Seeking to understand how the recall of specific memories in the brain guides our thinking, Frank and his colleagues built a system for detecting the underlying patterns of neuronal activity in rats. They fitted the animals with electrodes and built a system that enabled them to detect a specific pattern, called a sharp-wave ripple, in the hippocampus. Whenever they detected a ripple, they would send a small amount of electricity into another set of electrodes that would immediately interrupt the ripple event, in effect turning off all memory replay activity without otherwise affecting the brain. The UCSF researchers knew that these sharp-wave ripples would be activated when the animals had to make choices about which direction to turn as they wended their way toward their reward: a few drops of sweetened condensed milk. These signals seem to be flashes of memory recall, said Frank, a rat's past knowledge flooding back to inform it on what had happened in the past and where it might go in the future. Squashing the sharp-wave ripples, the UCSF team found, disrupted the recall and subverted the rat's ability to correctly navigate the maze. This shows, said Frank, that the sharp-wave ripples are critical for this type of memory recall. Through these brain waves, the rat reprocesses and replays old experiences in a fleeting instant—lessons from the past essential for shaping their perception of the present. "We think these memory replay events are a fundamental constituent of memory retrieval and play a key role in human perspective and decision-making as well," he said. "These same events have been seen in memory tasks in humans, and now we know they are critical for memory in rats. We think that these fast-forward replays make up the individual elements of our own memories, which jump rapidly from event to event." Next, the team wants to tease out information about how the rats actually use these memory replay events to make decisions and how amplifying or blocking specific replay events will change the way an animal learns and remembers. They also think that these events could be important for understanding memory problems, as when stressful memories intrude into daily life. The article, "Awake Hippocampal Sharp-Wave Ripples Support Spatial Memory" by Shantanu P. Jadhav, Caleb Kemere, P. Walter German and Loren M. Frank is published by Science on May 4, 2012. After that date, the article can be accessed at: http://www.sciencemag.org This work was funded by grants from the Helen Hay Whitney Foundation and the National Institute of Mental Health, a component of the National Institutes of Health. Additional support was provided through a Wheeler Center Fellowship. UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.

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.