Chapter 12. Psychopathology: Biological Basis of Behavioral Disorders
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|By Ann Graybiel and Kyle Smith For children and adults who have conditions such as obsessive-compulsive disorder (OCD), Tourette syndrome or autism, repetitive thoughts and actions can occur even if the individuals do not want them to. In OCD a thought that repeats again and again—“my hands are dirty, my hands are dirty”—can recur in a habitual way. Such conditions occur in people from different countries and cultures, suggesting that they represent a core dysfunction related to an imbalance between behaviors. These problems appear to reflect disturbances in brain circuits that are different from, but allied with, the normal habit circuits. Researchers in our group and that of Susanne Ahmari at the University of Pittsburgh have tested whether these OCD circuits can be controlled. Our lab group stimulated the neocortex and striatum in mice that were genetically engineered to have OCD-like traits. These mice groom themselves excessively, especially around the face. In the lab we mimicked a problem that people with OCD often have because they react excessively and repetitively to some trigger stimulus in the environment. We conditioned the mice to learn that after a tone sounded a drop of water would fall on their noses about a second later. We also performed the same routine with normal (“control”) mice. The OCD-like mice started by just grooming when the water drop came, but then began to start grooming in response to the tone alone, and kept grooming all the way through when the drop fell. The control mice learned to suppress this early grooming, which after all was a wasted effort because the water drop came later. The OCD-like mice groomed compulsively every time the external cue sounded. Using optogenetics—a technique that controls the activity of brain cells by shining light on them—we then excited a pathway that connects a small region in the cortex with the striatum. The pathway has been implicated in suppressing behaviors. This treatment immediately blocked the compulsive early grooming in the mutant mice! Yet when the water drop came, they could groom normally. And the optogenetic stimulation did not affect other normal behaviors such as eating; it selectively blocked the compulsive aspect of behavior. © 2014 Scientific American
Kevin Loria Music was among the least of Mr. B's concerns. As a 59-year-old Dutch man living with extremely severe obsessive compulsive disorder for 46 years, he had other things on his mind. His OCD was so severe it led to moderate anxiety and mild depression. Not only was his condition extreme, but it was also resistant to traditional treatment. It got so bad that he opted to receive an implant to stimulate his brain constantly with electricity — a treatment, called deep brain stimulation (DBS), that has been shown to successfully treat OCD in the past. It worked, but had a very peculiar side effect. As researchers write in a study published in the journal Frontiers in Behavioral Neuroscience, it turned Mr. B. into a Johnny Cash fanatic, though he'd never really listened to The Man in Black before. Mr. B. had listened to the same music for decades, but was never a devout music lover. He was a Rolling Stones and Beatles fan (with a preference for the Stones), and listened to Dutch music as well. But just months after flying to Minneapolis and having two sets of electrodes tunneled into his brain for the shock therapy, he had a mind-blowing run-in with the song "Ring of Fire" playing on the radio. Something about Cash's deep bass-baritone voice resonated with him at that moment. His life had already changed. After the surgical implants and therapy, his OCD had gone from extremely severe to mild, and his depression and anxiety were at a level lower than mild. But when he heard Cash croon, another change began. Mr. B. bought all the Johnny Cash music he could find and stopped listening to anything else — no more Beatles, no more Stones, no more Nederpop. Instead, he played Cash all the time, and especially loved the songs from the '70s and '80s. "Folsom Prison Blues," "Ring Of Fire," and "Sunday Morning Come-Down" are his favorites. They make him feel like a hero, he told doctors. © 2014 Business Insider, Inc.
André Aleman & Damiaan Denys According to the World Health Organization, almost 1 million people kill themselves every year. That is more than the number that die in homicides and war combined. A further 10 million to 20 million people attempt it. Suicide is one of the three leading causes of death in the economically most productive age group — those aged 15–44 years — and rates have risen since the economic crisis triggered by the banking crash in 2008 (see 'Suicide rates in Europe'). For example, the number of suicides per year in the Netherlands rose by 30% between 2008 and 2012, from 1,353 to 1,753. In the United States, the average suicide costs society US$1.06 million according to the US Centers for Disease Control and Prevention. Despite its enormous societal impact, little progress has been made in the scientific understanding or treatment of suicidal behaviour. We do know that up to 90% of suicides occur in people with a clinically diagnosable psychiatric disorder1. Large epidemiological studies have shown mental disorders, particularly depression and alcohol addiction, to be major risk factors2. And there is compelling evidence that adequate prevention and treatment of such disorders can reduce suicide rates2. But psychiatry has long neglected the topic. Other than as symptoms of borderline personality disorder and mood disorders, suicide, suicide attempts and suicidal thoughts were not listed in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). The DSM-5 (published last year) does not code suicidal behaviour — the most prominent emergency in psychiatry in primary care. Suicidality is perceived as a medical complication rather than as a disorder in its own right. © 2014 Nature Publishing Group
Link ID: 19642 - Posted: 05.21.2014
Dr Lucy Maddox There has been much heated debate in recent weeks about whether cognitive behavioural therapy for psychosis has been totally over-egged. One stance is that Nice (the National Institute for Clinical Excellence) has recommended a treatment with little or no evidence base. Another is that CBT is a helpful intervention for many people experiencing psychotic-like phenomena. But what is CBT for psychosis? What does it look like? And how can knowing this help us to understand the issues being argued about? Psychosis is an umbrella term for a collection of symptoms. These symptoms get classed as "positive" or "negative", which is not to infer that some are good and some are bad, but rather to capture the fact that some of the symptoms add something new and others take something away. Positive symptoms are those that add an unusual experience of some kind, eg seeing things that others can't (hallucinations) or strongly believing things that don't make sense to others (delusions). Negative symptoms involve something being taken away from the person, eg a lack of enjoyment (anhedonia), motivation (avolition), or a lack of emotion. Whilst a recent meta-analysis has shown only limited evidence for the effectiveness of CBT for psychosis and suggested that previous results are inflated, we should be cautious about using this one meta-analysis to chuck out CBT for psychosis. Among other potential holes that could be poked in its conclusions is the fact that the analysis uses psychotic symptoms as the only outcome measure for effectiveness, which might not be the best or only thing we should be looking at. Many other reviews and individual studies do report reductions in psychotic symptoms from CBT for psychosis, including delusions and hallucinations and some of the brain processing correlates of these positive symptoms (eg Kumari et al 2011). Perhaps more interestingly though, they also report benefits from CBT in domains other than the psychotic symptoms themselves. (eg Wykes et al, 2009). © 2014 Guardian News and Media Limited
Link ID: 19639 - Posted: 05.20.2014
by Laura Sanders An injectable form of a newer, more expensive schizophrenia drug works no better than an older drug, scientists report May 21 in the Journal of the American Medical Association. In a randomized clinical trial of 311 people with schizophrenia, injections of paliperidone palmitate failed to alleviate schizophrenia symptoms just as often as did injections of haloperidol decanoate, a drug that’s been around for decades. A single injection of paliperidone palmitate, a second-generation antipsychotic, costs about $1000 in the United States. An injection of haloperidol costs only about $35. The two drugs caused different side effects: In some patients, haloperidol led to muscle tremors and restlessness and paliperidone palmitate caused weight gain. Knowledge of these different side effects — and not differences in effectiveness — might be useful in deciding which drug a person ought to take. © Society for Science & the Public 2000 - 2013.
Link ID: 19638 - Posted: 05.20.2014
By ABIGAIL ZUGER, M.D. Sweet revenge comes in many delectable forms, among them the receipt of accolades for work long scorned. And then to get to tell the whole story at length and without a single interruption — small wonder that the Nobel laureate Dr. Stanley B. Prusiner, a renowned neurologist at the University of California, San Francisco, writes with a cheerful bounce. Once disparaged, his scientific work is now hailed as visionary, and his memoir takes the reader on a leisurely and immensely readable victory lap from then to now. In the process, two stories unfold. The first is the progress of Dr. Prusiner’s thinking on the transmissible proteins he named prions (PREE-ons) in 1982, starting with his first experiments on an obscure disease of sheep and ending with the most recent work linking prions to an array of human neurological catastrophes, including Alzheimer’s disease. The science is convoluted, like the proteins, and for the uninitiated the best way to achieve a rudimentary grasp of the subject is to hear it the way Dr. Prusiner tells it, from the very beginning. But a parallel narrative turns out to be equally fascinating: perhaps not since James D. Watson’s 1968 memoir “The Double Helix“ has the down and dirty business of world-class science been given such an airing. Dr. Watson raised eyebrows with his gossipy account of the serious task of unraveling the genetic code — and he was working in genteel postwar Britain at the time, with experimental science still at least in theory a gentleman’s game. That illusion is long gone: The stakes are considerably higher now, the competition fierce, the pace frantic, and Dr. Prusiner, 71, revisits quite a few of the battles that punctuated his long research career. He was an underachiever in high school and then an achiever in college and medical school, captivated by the laboratory early on. He finished his medical training on the neurology wards in San Francisco, where he met the patient who would set the course of his career: a slim, tanned 60-year-old woman from Marin County who was having trouble unzipping her golf bag. Months later she was dead of Creutzfeldt-Jakob disease, one of several related and invariably fatal neurological diseases (mad cow among them) that leave the brain of the affected human or animal riddled with holes, a useless sponge. © 2014 The New York Times Company
Link ID: 19632 - Posted: 05.19.2014
|By Beth Skwarecki The protein family notorious for causing neurogenerative diseases such as Parkinson's—not to mention mad cow—appears to play an important role in healthy cells. “Do you think God created prions just to kill?” muses Eric R. Kandel of Columbia University. “These things have evolved initially to have a physiological function.” Kandel's work on memory helped to reveal that animals make and use prions in their nervous systems as part of an essential function: stabilizing the synapses involved with forming long-term memories. These natural prions are not infectious, but on a molecular level they chain up exactly the same way as their disease-causing brethren. (Some researchers call them “prionlike” to avoid confusion.) Now neuroscientist Kausik Si of the Stowers Institute for Medical Research in Kansas City, Mo., one of Kandel's former students, has shown that the prion's action is tightly controlled by the cell and can be turned on when a new long-term memory needs to be formed. Once the prion's chain reaction gets started, it is self-perpetuating, and thus the synapse—where neurons connect—can be maintained after the initial trigger is gone, perhaps for a lifetime. But that still does not explain how the first prion is triggered or why it happens at only certain of the synapses, which play a crucial role in forming memories. Si's work, published February 11 in PLOS Biology, traces the biochemistry of this protein-preservation process in fruit flies, showing how the cell turns on the machinery responsible for the persistence of memory—and how the memory can be stabilized at just the right time and in the right place. © 2014 Scientific American
Eleven years on, I still remember the evening I decided to kill my baby daughter. It's not something you're supposed to feel as a new parent with a warm, tiny bundle in your arms. But this is how postnatal depression can twist your logic. At the time it made perfect sense. Catherine was screaming, in pain. She had colic, there was nothing I could do about it. If an animal were in this much pain you'd put it out of its misery, so why not a human? Postnatal depression can have this kind of effect even on the most reasonable woman, yet you won't find much about it in baby books. We're expected to love our kids the moment they pop out, even while the memory of the labour pains is still raw. I knew a baby would be hard work, of course, but I expected motherhood to be fulfilling. As it happened I had a wonderful pregnancy, followed by a quick and easy birth. But the problems started soon after. Catherine wouldn’t feed, her blood sugar levels tumbled and I ended up bottle-feeding her, in tears, in a hospital room filled with posters promoting the breast. I was a Bad Mother within 48 hours. Things were no better after the first month. This was meant to be a joyous time, but all I seemed to feel was rage and resentment. In pregnancy all the attention had been on me, and suddenly I was a sideshow to this wailing thing in a crib. I was tired, tetchy and resentful. My daughter had rapidly become a ball and chain. My freedom was over. I kept hoping this was just the “baby blues” and that it would soon pass, but things only got worse. When colic set in, for around five hours each evening Catherine would scream, her face a mix of red and purple rage. No amount of pacing, tummy-rubbing or soothing words could stop this tiny demanding creature. So one night, alone with her in her room, I decided it would be best to put her out of her misery. © 2014 Guardian News and Media Limited
By RONI CARYN RABIN For decades, scientists have embarked on the long journey toward a medical breakthrough by first experimenting on laboratory animals. Mice or rats, pigs or dogs, they were usually male: Researchers avoided using female animals for fear that their reproductive cycles and hormone fluctuations would confound the results of delicately calibrated experiments. That laboratory tradition has had enormous consequences for women. Name a new drug or treatment, and odds are researchers know far more about its effect on men than on women. From sleeping pills to statins, women have been blindsided by side effects and dosage miscalculations that were not discovered until after the product hit the market. Now the National Institutes of Health says that this routine gender bias in basic research must end. In a commentary published on Wednesday in the journal Nature, Dr. Francis Collins, director of the N.I.H., and Dr. Janine A. Clayton, director of the institutes’ Office of Research on Women’s Health, warned scientists that they must begin testing their theories in female lab animals and in female tissues and cells. The N.I.H. has already taken researchers to task for their failure to include adequate numbers of women in clinical trials. The new announcement is an acknowledgment that this gender disparity begins much earlier in the research process. “Most scientists want to do the most powerful experiment to get the most durable, powerful answers,” Dr. Collins said in an interview. “For most, this has not been on the radar screen as an important issue. What we’re trying to do here is raise consciousness.” Women now make up more than half the participants in clinical research funded by the institutes, but it has taken years to get to this point, and women still are often underrepresented in clinical trials carried out by drug companies and medical device manufacturers. © 2014 The New York Times Company
by Nathan Collins There's a new twist in mental health. People with depression seem three times as likely as those without it to have two brain lobes curled around each other. The brains of people with depression can be physically different from other brains – they are often smaller, for example – but exactly why that is so remains unclear. In humans, some studies point to changes in the size of the hippocampi, structures near the back of the brain thought to support memory formation. "There are so many studies that show a smaller hippocampus in almost every psychiatric disorder," says Jerome Maller, a neuroscientist at the Monash Alfred Psychiatry Research Centre in Melbourne, Australia, who led the latest work looking at brain lobes. "But very few can actually show or hypothesize why that is." Maller thinks he has stumbled on an explanation. He had been using a brain stimulation technique known as transcranial magnetic stimulation as a therapy for antidepressant-resistant depression. This involved using fMRI scans to create detailed maps of the brain to determine which parts to stimulate. While pouring over hundreds of those maps, Maller noticed that many of them showed signs of occipital bending. This is where occipital lobes – which are important for vision – at the back of the brain's left and right hemispheres twist around each other. So he and his colleagues scanned 51 people with and 48 without major depressive disorder. They found that about 35 per cent of those with depression and 12.5 per cent of the others showed signs of occipital bending. The difference was even greater in women: 46 per cent of women with depression had occipital bending compared with just 6 per cent of those without depression. © Copyright Reed Business Information Ltd.
By Pippa Stephens Health reporter, BBC News An anti-depressant drug could be used to slow the onset of Alzheimer's disease, say scientists in the US. Research into 23 people, and transgenic mice, found citalopram hampered a protein which helps to build destructive plaques in the brains of Alzheimer's patients. Scientists said they hoped the study could help prevent the disease. Experts said the study was "interesting" and that using an approved drug could be beneficial. Alzheimer's disease is the most common cause of dementia, affecting around 496,000 people in the UK. It affects the brain through protein plaques and tangles which lead to the death of brain cells, and a shortage of chemicals important for transmitting messages. Symptoms include loss of memory, mood changes, and problems with communication and reasoning. Researchers at the University of Pennsylvania and Washington University School of Medicine carried out the study between 2012 and 2014. They bred mice with Alzheimer's disease and looked at the levels of the peptide - or protein component - amyloid beta (AB), in the brain. AB clusters in plaques which, alongside the tau protein, are thought to trigger Alzheimer's. After giving the mice citalopram, the level of AB fell by 25%, compared to the control group, with no anti-depressant. And after two months of anti-depressants, the growth of new plaques was reduced, and existing plaques did not grow any further, the study said. But it noted the drug could not cause existing plaques to shrink, or decrease in number. BBC © 2014
By ANNE SAKER CINCINNATI — The psychologist Lynda Crane found that of the many injuries inflicted by schizophrenia, the greatest could be the pain of being forgotten. Just naming the illness somehow erased the person, something she learned when her 18-year-old son’s doctors said he had schizophrenia. Six years later, he committed suicide. “It took me a long time to come to terms with it,” Dr. Crane says. “Even I had a hard time understanding it, how this bright man, with a brilliant future, could suffer like this. One thing I learned was that as soon as you mentioned the word, people stopped seeing the person. They just saw the diagnosis and a collection of symptoms. Doug, my son, was forgotten.” For years Dr. Crane, a professor at the College of Mount St. Joseph in the western hills of Cincinnati, sought a way to enlighten her students and others about the ordinary people who live with schizophrenia despite its extraordinary burdens – the confused thinking, the delusions, the hallucinations, the anxiety and fear. Then she discovered a tool more commonly used among sociologists and anthropologists: oral history. Employing the device to examine schizophrenia has shifted her own perspective about a disease she thought she knew well. “People with schizophrenia do not lose their individuality, even when the illness is very severe,” Dr. Crane says. “What I discovered through oral history is that it’s not about schizophrenia. It’s about a complexity of life that is very hard to get at any other way.” For the past three years, on their own time and with no outside money, Dr. Crane and a fellow Mount St. Joseph psychologist, Tracy McDonough, have built the Schizophrenia Oral History Project. Other oral history collections have focused on diseases like AIDS or leprosy, but this is the first to focus on schizophrenia, they say. © 2014 The New York Times Company
Link ID: 19593 - Posted: 05.10.2014
by Clare Wilson IMAGINE you are a doctor before the advent of modern medical tests and your patient is gasping for breath. Is it asthma, a chest injury, or are they having a heart-attack? You don't know and have no idea how best to help them. Some would argue that's what it's like for doctors trying to diagnose mental health problems today. There are no blood tests or brain scans for mental illnesses so diagnoses are subjective and unreliable. The issue came to a head one year ago this month, with the latest edition of psychiatry's "bible", the Diagnostic and Statistical Manual of Mental Disorders. The US National Institute for Mental Health (NIMH) said the DSM-5 had so many problems we effectively need to tear it up and start again. The way forward, it said, is a new research programme to discover the brain problems that underlie mental illnesses. That research is now taking off. The first milestone came earlier this year, when the NIMH published a list of 23 core brain functions and their associated neural circuitry, neurotransmitters and genes – and the behaviours and emotions that go with them (see "The mind's 23 building blocks"). Within weeks, the first drug trials conceived and funded through this new programme will begin. While just a first draft, the list arguably represents the future of neuroscience-based mental healthcare. "This is the Rosetta stone for characterising human mental function," says Andrew Krystal at Duke University in Durham, North Carolina. Criticism of psychiatry has been growing for years – existing treatments are often inadequate, and myriad advances in neuroscience and genetics have not translated into anything better. Vocal opponents are not confined to the US. Last week, the new UK Council for Evidence-based Psychiatry launched a campaign claiming that drugs such as antidepressants and antipsychotics often do more harm than good. © Copyright Reed Business Information Ltd.
By Maggie Fox Treating psychiatric illnesses with antipsychotic drugs can greatly reduce the risk that a patient will commit a violent crime, researchers reported on Thursday. Their study, published in the Lancet medical journal, adds weight to the argument that severely mentally ill people need to get diagnosed and treated. Mental health experts agree that people with psychiatric illnesses such as schizophrenia are far more likely to become victims of violence than they are to hurt someone else. But Dr. Thomas Insel, director of the National Institute on Mental Health, also notes that people with severe mental illness are up to three times more likely than the general population to be violent. The question has been whether treatment lowers these risks. One high-profile case is that of Jared Loughner, a schizophrenia patient who shot and killed six people in Arizona and wounded several more, including then-congresswoman Gabrielle Giffords. Dr. Seena Fazel of Britain’s Oxford University used a Swedish national database to find out. Sweden keeps careful medical records, and has similar rates of both mental illness and violence to the United States. The only exception is homicide, where the U.S. has much higher rates than just about every other country. Fazel’s team looked at the medical records of everyone born in Sweden between 1961 and 1990. “We identified 40,937 men and 41,710 women who were prescribed any antipsychotic or mood stabilizer between Jan 1, 2006, and Dec 31, 2009,” they wrote. It worked out to about 2 percent of the population.
By Sandra G. Boodman, As the jet hurtled toward New York’s John F. Kennedy International Airport on New Year’s Day 2013, the clinical psychologist watched her 16-year-old daughter warily, praying there would be no recurrence of the girl’s inexplicable and bizarre behavior. The previous night, while walking down a street in Spain where the family had spent Christmas, the teenager suddenly began yelling that the traditional New Year’s Eve fireworks were actually bombs. On the flight home, the girl seemed entirely normal. Her mother thought the high school junior might have had a panic attack, stressed by her upcoming college search and impending wisdom teeth extraction. But the uneventful flight brought a short-lived relief. Five days later, the teenager was hospitalized for treatment of what appeared to be a severe psychotic break. And for the next six weeks, the news seemed to get worse as a more ominous diagnosis emerged — and with it the specter of death. “Every day seemed like a horror story,” said Carmen, a psychoanalyst who practices in New York and whose last name, along with that of her daughter, Mia, is being withheld at her request to protect her professional privacy. For Lara Marcuse, a neurologist at Mount Sinai Hospital in Manhattan who treated Mia during her hospitalization, those weeks were filled with tension and anxiety that deepened as she worried that the teenager might not survive her sudden illness. “If she was my age,” said Marcuse, who is 44, “Mia would either be dead, in a coma or in a state psychiatric center.” Instead Mia, now 18, has fully recovered. She recently had a part in her high school play, is anticipating graduation and looking forward to entering college in September. © 1996-2014 The Washington Post
Link ID: 19548 - Posted: 04.29.2014
By MATTHEW PERRONE WASHINGTON (AP) — The Food and Drug Administration announced Friday it will convene a public meeting in October to review the risks of psychiatric and behavioral side effects with Pfizer’s anti-smoking drug Chantix. The agency said in a federal notice it will convene its panel of psychiatric drug experts to discuss the pill’s risks and how to best manage them. Since 2009 Chantix has carried the government’s strongest safety warning — a ‘‘black box’’ label — because of links to hostility, agitation, depression and suicidal thoughts. The warning was added after the FDA received dozens of reports of suicide and hundreds of reports of suicidal behavior among patients taking the smoking-cessation drug. At that time, the FDA also required Pfizer to conduct additional studies to determine the extent of the side effects. A spokeswoman for Pfizer said Friday that the company recently submitted new data to the FDA comparing the drug’s psychiatric safety to placebo and other anti-smoking techniques. The FDA first began investigating potential side effects with Chantix in 2007, the year after the twice-a-day pill hit the market. The drug’s labeling tells patients to stop taking Chantix immediately if they experience agitation, depressed mood, suicidal thinking and other behavioral changes. Doctors are advised to weigh the drug’s risks against its potential benefits in helping patients quit smoking.
by Michael Slezak Could preventing the brain shrinkage associated with depression be as simple as blocking a protein? Post-mortem analysis of brain tissue has shown that the dendrites that relay messages between neurons are more shrivelled in people with severe depression than in people without the condition. This atrophy could be behind some of the symptoms of depression, such as the inability to feel pleasure. As a result, drugs that help repair the neuronal connections, like ketamine, are under investigation. But how this shrinkage occurs has remained a mystery, limiting researchers' ability to find ways of stopping it. Ronald Duman at Yale University wondered whether a protein called REDD1, which was recently shown to reduce myelin, the fatty material that protects neurons, was the key. To find out, his team bred rats unable to produce REDD1 and exposed them to a prolonged period of unpredictable stress. In normal rats, this stress resulted in depressive-like behaviour and brain shrinkage, but Duman's rats were unaffected. In contrast, rats engineered to overproduce REDD1 became depressed and had brain shrinkage, even without being stressed. What's more, injecting normal rats with a stress hormone boosted levels of REDD1 in the brain. Giving them a drug that blocked the production of stress hormones stopped them producing the protein, even when they were externally stressed. Taken together, the experiments show that REDD1 is necessary to produce the brain shrinkage seen in stressed rats, and that stress hormones are involved in its production – offering a possible way to prevent the shrinkage. © Copyright Reed Business Information Ltd
Link ID: 19532 - Posted: 04.24.2014
By Melissa Healy The nature of psychological resilience has, in recent years, been a subject of enormous interest to researchers, who have wondered how some people endure and even thrive under a certain amount of stress, and others crumble and fall prey to depression. The resulting research has underscored the importance of feeling socially connected and the value of psychotherapy to identify and exercise patterns of thought that protect against hopelessness and defeat. But what does psychological resilience look like inside our brains, at the cellular level? Such knowledge might help bolster peoples' immunity to depression and even treat people under chronic stress. And a new study published Thursday in Science magazine has made some progress in the effort to see the brain struggling with -- and ultimately triumphing over -- stress. A group of neuroscientists at Mount Sinai's Icahn School of Medicine in New York focused on the dopaminergic cells in the brain's ventral tegmentum, a key node in the brain's reward circuitry and therefore an important place to look at how social triumph and defeat play out in the brain. In mice under stress because they were either chronically isolated or rebuffed or attacked by fellow littermates, the group had observed that this group of neurons become overactive. It would logically follow, then, that if you don't want stressed mice (or people) to become depressed, you would want to avoid hyperactivity in that key group of neurons, right? Actually, wrong, the researchers found. In a series of experiments, they saw that the mice who were least prone to behave in socially defeated ways when under stress were actually the ones whose dopaminergic cells in the ventral tegmental area displayed the greatest levels of hyperactivity in response to stress. And that hyperactivity was most pronounced in the neurons that extended from the tegmentum into the nearby nucleus accumbens, also a key node in the brain's reward system.
Scientists have traced vulnerability to depression-like behaviors in mice to out-of-balance electrical activity inside neurons of the brain’s reward circuit and experimentally reversed it – but there’s a twist. Instead of suppressing it, researchers funded by the National Institutes of Health boosted runaway neuronal activity even further, eventually triggering a compensatory self-stabilizing response. Once electrical balance was restored, previously susceptible animals were no longer prone to becoming withdrawn, anxious, and listless following socially stressful experiences. “To our surprise, neurons in this circuit harbor their own self-tuning, homeostatic mechanism of natural resilience,” explained Ming-Hu Han, Ph.D External Web Site Policy., of the Icahn School of Medicine at Mount Sinai, New York City, a grantee of the NIH’s National Institute of Mental Health (NIMH) and leader of the research team. Han and colleagues report on their discovery April 18, 2014 in the journal Science. Prior to the new study, the researchers had turned resilience to social stress on and off by using pulses of light to manipulate reward circuit neuronal firing rates in genetically engineered mice – optogenetics. But they didn’t know how resilience worked at the cellular level. To find out, they focused on electrical events in reward circuit neurons of mice exposed to a social stressor. Some mice that experience repeated encounters with a dominant animal emerge behaviorally unscathed, while others develop depression-like behaviors.
By DORIS IAROVICI, M.D. “I think our experiment failed,” the young graduate student told me, referring to our attempt to take her off the antidepressant she’d been on for seven years. She was back in my campus office after a difficult summer break, and as she talked about feeling unsettled and upset, I wondered about the broader experiment playing out on college campuses across the country. Antidepressants are an excellent treatment for depression and anxiety. I’ve seen them improve — and sometimes save — many young lives. But a growing number of young adults are taking psychiatric medicines for longer and longer periods, at the very age when they are also consolidating their identities, making plans for the future and navigating adult relationships. Are we using good scientific evidence to make decisions about keeping these young people on antidepressants? Or are we inadvertently teaching future generations to view themselves as too fragile to cope with the adversity that life invariably brings? My patient had started medication as a college freshman, after she’d become depressed and spent much of her time in bed. She was forced to take a medical leave but improved quickly, returned to school and graduated. She married soon after and worked for a few years, feeling well all the while. Professional guidelines recommend six to nine months of medicine for first episodes of depression. But my patient had never been advised to stop taking it. She reluctantly agreed to my recommendation to taper off her antidepressant. © 2014 The New York Times Company
Link ID: 19502 - Posted: 04.17.2014