The Mental Health Social Worker

Macho’ masculine stereotype not healthy for relationships

Can lead to serious disease in adulthood

Findings in Rats Could Explain Women’s Increased Vulnerability to Disorders

A study in rats has revealed striking gender differences in the brain’s stress response that could shed light on women’s proneness to mood and anxiety disorders. Female rat brain cells were more sensitive to a key stress hormone than males’, which could adapt to the hormone in a way female cells couldn’t.

In the male brain under stress, many of the hormone’s receptors retreated into the cell, making the brain less stress reactive. A molecular dance unique to the male brain, between the receptor and an enabling protein, accounted for its resilient adaptation. By contrast, in the female brain under stress, receptors remained exposed on neuron membranes and the brain stayed sensitive to the hormone.

“Although more research is necessary to determine whether this translates to humans, these findings may help to explain why women are twice as vulnerable as men to many stress-related disorders,” explained NIMH grantee Rita Valentino Ph.D., of The Children’s Hospital of Philadelphia.

A team of researchers led by Valentino and Debra Bangasser, Ph.D., reported on their discovery online June 15, 2010 in the journal Molecular Psychiatry.

Background

An understanding of why women experience more stress-related mental disorders like depression and PTSD has until now eluded science.

Corticotropin releasing factor (CRF), which acts as both a hormone and a neurotransmitter, is likely a key player. In response to a stressor, CRF binds to receptors on cells in an alarm center deep in the brainstem, called the locus ceruleus. This telegraphs heightened emotional arousal throughout the brain via the chemical messenger norepinephrine. Such hyper-arousal can be adaptive for brief periods, but not if it becomes chronic. Runaway CRF is a core feature of depression.

Previous studies suggested that this alarm system is more sensitive to CRF and stress in the female brain. To pinpoint how this works at the level of cells and molecules, Valentino, Bangasser and colleagues used antibodies and an electron microscope to see how the CRF receptor responds in male versus female rats — both unstressed and after exposure to a stressful swim.

Results

Even in the absence of any stress, the researchers found the female stress signaling system to be more sensitive from the start. CRF receptors had stronger connections, or coupling, with relay proteins inside the cell than those of male rats. So it took lower levels of CRF to activate neurons in the unstressed females compared to males. CRF levels that had no effect in males turned on cells in female rats.

After stress, CRF receptors remained exposed on the neuronal membrane in the female rat, allowing CRF to persist in its effect. In the stressed male rat, the receptors interacted with internal proteins called arrestins, enabling some to retreat into the cell’s interior, where they couldn’t bind with the hormone. Such receptor internalization helped the male brain adapt its sensitivity to the stressor. Although the arrestin proteins are present in the female neurons, the receptors did not interact with them.

Significance

In females, certain brain cells are more sensitive to CRF and less able to adapt to too much CRF. The greater coupling of CRF receptors to relay proteins and their inability to internalize could translate into a lower threshold for stress-induced activation of the alarm system. This could increase risk for chronic activation and impair the brain’s ability to cope with high levels of CRF, as occurs in depression and PTSD, say the researchers. The study is the first to uncover sex differences at the level of receptor signaling, according to Valentino.

What’s Next?

The next step is to examine the male and female CRF receptors for structural differences that might account for the functional differences, said Valentino. Since most rodent models of mood and anxiety disorders use males exclusively, the new findings of gender differences in stress signaling mechanisms call for a more gender-balanced approach — especially for disorders that disproportionately affect females. The gender differences in stress signaling should also be factored-in as medication treatments based on blocking the CRF receptor are developed, say the researchers.

Molecular Dance of CRF Receptors

When the going gets tough inside a locus ceruleus neuron, it’s the female brain that acts “macho.” In response to a stressor, receptors for the stress hormone CRF remained exposed on the neuronal membrane in the female rat — taking the full hit. This increased CRF binding heightened the brain’s stress reactivity. By contrast, in the stressed male rat, CRF receptors danced with internal proteins called arrestins (green), which enabled some to retreat into the cell’s interior, where they couldn’t bind with CRF. This adaptation — unique to the male brain — toned-down the neuron’s stress sensitivity. Lack of such receptor internalization in the female brain could translate into impaired ability to cope with high levels of CRF — as occurs in depression and PTSD.

Source: Debra Bangasser, Ph.D., The Children’s Hospital of Philadelphia

Electron microscope photo of unstressed male rat brain locus ceruleus (left) shows CRF receptors (black spots with arrows) on the cell membrane. Following exposure to a stressor (right), receptors have retreated into the interior of the cell (black spots without arrows). Such receptor internalization enables the male brain to regulate its sensitivity to stressors. This adaptation does not occur in the female brain, which could account for increased vulnerability to stress-related disorders.

Source: Debra Bangasser, Ph.D., The Children’s Hospital of Philadelphia

Reference

Sex differences in corticotropin-releasing factor receptor signaling and trafficking: potential role in female vulnerability to stress-related psychopathology. Bangasser DA, Curtis A, Reyes BA, Bethea TT, Parastatidis I, Ischiropoulos H, Van Bockstaele EJ, Valentino RJ. Mol Psychiatry. 2010 Jun 15. [Epub ahead of print]PMID: 20548297

WASHINGTON, DC, July 28, 2010- How do you talk to a young child about their fear of starting school, getting a new babysitter, or moving to a new area? As adults, we know that change is a part of life, but very often young children yearn to keep things as they are. It helps them feel safe. A new picture book, “Harry the Happy Caterpillar Grows” by Cindy Jett  addresses how to help children when they fear change.

The story is about a caterpillar that has a fantastic life full of games, friends, school and leaf eating. He is stunned when, one day at caterpillar school, he learns that he is expected to  build a chrysalis and become a butterfly. Harry vows to remain a caterpillar forever, as his friends build their chrysalises and move on.  Eventually, Harry  learns to accept change as a necessary part of life, and  joins his friends as a butterfly. There are tips in the back of the book to help parents and educators use the story as a vehicle to talk to kids about their feelings, teach them coping strategies, and help them view change in a more positive light.

The book is beautifully illustrated by Kathy Voerg. It  is appropriate for children ages 4-10. It is part of New Horizon Press’s “Let’s Talk” series for young children.

Cindy Jett is a licensed clinical social worker. She has a masters degree from the National Catholic School of Social Service, and has had a psychotherapy practice in Washington, DC for ten years.

Contact:

Cindy Jett, LICSW

cindyjett@hotmail.com

http://harrythehappycaterpillar.com

By Michele Hoos, Health.com

(Heath.com) — As recently as 10 years ago, doctors advised women with bipolar disorder not to have children. While that thinking is now dated, bipolar women often face tough decisions about how to handle their medication during pregnancy.

Most drugs prescribed for bipolar disorder carry some risk of birth defects, yet women who discontinue medication risk relapsing into a manic or depressive episode; during the postpartum phase the relapse rate is as high as 50 percent to 70 percent, by some estimates.

(more…)

A U.S. Air Force suicide prevention program is associated with reduced suicide rates among Air Force personnel during times in which the program was rigorously implemented and monitored, according to an NIMH-funded study published online ahead of print May 13, 2010, in the American Journal of Public Health.

(more…)

ARLINGTON, Va. (July 1, 2010) – People with serious mental illness lose significantly more years of potential life than the general population, according to research presented in the July issue of Psychiatric Services, a journal of the American Psychiatric Association. Years of potential life lost, or YPLL, which is based on U.S. life expectancy in the year of death, is a widely used measure of premature mortality.

(more…)

NIH Grantees Eye Neuroprotective Mechanism for Alzheimer’s

Scientists have discovered a compound that restores the capacity to form new memories in aging rats, likely by improving the survival of newborn neurons in the brain’s memory hub. The research, funded in part by the National Institutes of Health, has turned up clues to a neuroprotective mechanism that could lead to a treatment for Alzheimer’s disease.

“This neuroprotective compound, called P7C3, holds special promise because of its medication-friendly properties,” explained Steven McKnight, Ph.D., who co-led the research with Andrew Pieper, M.D., Ph.D., both of University of Texas Southwestern Medical Center, Dallas. “It can be taken orally, crosses the blood-brain barrier with long-lasting effects, and is safely tolerated by mice during many stages of development.”

(more…)

By Faith H. Robinson, CNN

(CNN) — Every Friday morning, students walk into an art class in Atlanta, Georgia. Some look dazed, uncertain in their environment, as if it’s vaguely familiar but they can’t fully recognize where they are — until they sit down and begin to draw.

The moment their brushes hit the paper, their faces light up. Using bright colors — yellows, oranges, greens, purples — they begin to transfer the images from their minds. Sometimes they paint what they want and sometimes they draw the highlighted centerpiece of the day. One week it’s vegetables, another week it’s hats. As their artworks progress, they look happy, smiling and glancing at their teachers for approval. They’re not the only ones who are pleased.

(more…)

By Elizabeth Landau
CNN.com Health Writer/Producer

Some guys sound tough – and according to a new study, that may a good way of predicting whether they really are.

Results  in the current Proceedings of the Royal Society B found that people can accurately evaluate the upper-body strength based on men’s voices from four different populations and language groups. The voice samples came from the Tsimane of Bolivia, Andean herder-horticulturalists from Argentina, and college students from the United States and Romania.

(more…)

Lack of quality long-term relationships related to poorer well-being.

Few youths with early-onset schizophrenia who are treated with antipsychotic medications for up to a year appear to benefit from their initial treatment choice over the long term, according to results from an NIMH-funded study. The study was published online ahead of print May 4, 2010, in the Journal of the American Academy of Child and Adolescent Psychiatry.

Background

The NIMH Treatment of Early Onset Schizophrenia Study (TEOSS) included 116 youth between 8 and 19 years old, diagnosed with early onset schizophrenia spectrum disorder (EOSS). The TEOSS team randomly assigned the children to eight weeks of either olanzapine (Zyprexa) or risperidone (Risperdal)—both new generation atypical antipsychotics—or to the older conventional antipsychotic molindone (Moban). Response rates after eight weeks of treatment were comparable among the three medications. The results were reported in September 2008.

After the initial 8-week trial, 54 of the 116 participants entered the maintenance treatment phase in which they continued their initial medication and were monitored for up to 44 more weeks of treatment. Only 14 participants completed the additional 44 weeks of treatment.

Results of the Study

Robert Findling, M.D., of Case Western Reserve University in Cleveland, and the TEOSS team reported that the participants’ treatment response tended to plateau during the follow-up, maintenance therapy period, such that most of the children did not improve beyond what they had already achieved during the initial eight weeks of treatment. In addition, most discontinued treatment during the maintenance phase, most commonly due to side effects such as weight gain, anxiety, increases in cholesterol levels, and other metabolic changes, regardless of which treatment they were receiving. None of the three medications appeared to be more effective than the others.

Significance

The findings suggest that few youths with EOSS continue treatment on the same antipsychotic medication over the long-term, with lack of effectiveness and adverse effects cited as the most common reasons for discontinuation. Most of those who initially responded to medication were able to at least maintain their initial improvements, but very few participants stayed on the medication through the 12-month study most frequently because of intolerable side effects.

What’s Next

The authors conclude that more effective and safer treatments need to be developed to treat children with EOSS.

Reference

Findling R. Johnson JL, McClellan J, Frazier JA, Vitiello B, Hamer RM, Lieberman JA, Ritz L, McNamara NK, Lingler J, Hlastala S, Pierson L, Puglia M, Maloney AE, Kaufman EM, Noyes N, Sikich L. Double-blind maintenance safety and effectiveness findings from the TEOSS. Journal of the American Academy of Child and Adolescent Psychiatry. Available online May 4, 2010.

Confirming results from earlier research, a clinical trial of treatment for major depression showed that the medication scopolamine, commonly used for motion sickness and as a sedative, could lift symptoms of depression within days, far faster than current antidepressants. Though the study was small, the magnitude of scopolamine’s effects in comparison with placebo suggests that this class of medications has potential for rapid treatment of depression.

Background

Currently available antidepressants typically require 3 to 4 weeks to take effect. In addition, despite a range of existing medications for depression, it’s estimated that 30 to 40 percent of patients do not respond at all to antidepressants. Developing new medications that act with alternative mechanisms to those already available—and more quickly—is an important goal of current research.

The most commonly used antidepressant medications affect signaling by serotonin, a neurotransmitter known to play a role in mood. Scopolamine interacts with cell receptors for another neurotransmitter, acetylcholine. Scopolamine is one of a class of compounds that block a specific type of receptor for acetylcholine (muscarinic receptors). Although various lines of research have suggested that acetylcholine-related activity plays a role in depression, to date, other neurotransmitter systems have been thought to be more central in the development of depression.

This Study

This study sought to replicate an earlier trial that demonstrated the ability of scopolamine to relieve symptoms of depression quickly in a group of patients with major depressive disorder or bipolar disorder. The current study focused on people with major depressive disorder. Like the earlier study, this one compared scopolamine with placebo, and was double-blind in that neither patients nor clinicians administering medication knew whether patients were receiving placebo or scopolamine (both were given intravenously).

After an initial treatment session in which all 22 patients in the trial received placebo once, half then received scopolamine three times, each treatment 3 to 5 days apart, and then placebo three more times, 3 to 5 days apart. The other half, after the initial placebo dose, received placebo three more times, then scopolamine three times. Patients receiving scopolamine first reported positive effects by the time they returned for a second dose 3 to 5 days later; many even reported improvement by the morning following treatment. After three treatments, their scores on a test for depression symptoms declined by 32 percent compared with 6.5 percent for placebo. These improved scores persisted until the end of the trial. Those receiving scopolamine after placebo had a 53 percent reduction in depression scores by the end of the clinical trial. Eleven of those in the trial experienced complete remission (one of those while on placebo).

Side-effects of scopolamine included drowsiness, dry mouth, light headedness, and blurred vision, but they were transient, resolving within hours.

Significance

Depression is a costly disease for both society and individuals. It is a leading cause of disability worldwide. For individuals and their family members, major depression is painful and frightening; depression is the predominant risk factor for suicide, the 11th leading cause of death in the U.S. The need for effective, rapid treatment alternatives is an urgent one.

While this is a small study, the difference between the response to scopolamine and placebo was statistically significant. By the end of the study 14 of the 22, or 64 percent of subjects, had achieved at least a 50 percent reduction in symptoms.

Subjects in the study reported short-term sedation but not euphoria with scopolamine. The antidepressant effects persisted weeks after the medication was no longer in the bloodstream. It is possible, according to the authors, that scopolamine’s antidepressant effects escaped notice earlier because it is usually used in smaller doses (such as for motion sickness) than in this study. The authors note the importance of replicating this work in larger groups of patients and developing more practical means of administering scopolamine. Further research will also provide information on the exact mechanism of action of the drug, a guide to development of additional new medications.

Dr. Maura Furey talks about her research with Scopolamine.

Read transcript.

References

Drevets, W.C. and Furey, M.L. Replication of scopolamine’s antidepressant efficacy in major depressive disorder: a randomized, placebo-controlled clinical trial. Biological Psychiatry 67:432-8, 2010.

Furey, M.L. and Drevets, W.C. Antidepressant efficacy of the antimuscarinic drug scopolamine. Archives of General Psychiatry 63:1121-1129, 2006.

Trial of Non-Invasive Treatment Used New, Convincing Sham Control

Some depressed patients who don’t respond to or tolerate antidepressant medications may benefit from a non-invasive treatment that stimulates the brain with a pulsing electromagnet, a study suggests. This first industry-independent, multi-site, randomized, tightly controlled trial of repetitive transcranial magnetic stimulation (rTMS) found that it produced significant antidepressant effects in a subgroup of patients, with few side effects.

Active rTMS treatment accounted for remissions in 14 percent of antidepressant-resistant patients actively treated, compared to about 5 percent for a simulated treatment.

“Although rTMS treatment has not yet lived up to early hopes that it might replace more invasive therapies, this study suggests that the treatment may be effective in at least some treatment-resistant patients,” said Thomas R. Insel, M.D., director of the National Institute of Mental Health (NIMH), part of the National Institutes of Health, which funded the study.

Mark George, M.D., of the Medical University of South Carolina, Charleston; Harold Sackeim, Ph.D., and Sarah Lisanby, M.D., of Columbia University, New York City; David Avery, M.D., of the University of Washington, Seattle; William McDonald, M.D., of Emory University, Atlanta; and colleagues, report on their findings in the May 2010 issue of the Archives of General Psychiatry.

“This study should help settle the debate about whether rTMS works for depression,” said George, who led the research team. “We can now follow up clues suggesting ways to improve its effectiveness, and hopefully further develop a potential new class of stimulation treatments for other brain disorders.”

The treatment aims to jump-start underactive mood-regulating circuitry by targeting the top left front part of the brain with an electromagnetic coil that emits 3,000 pulses over a 37-minute session. It can be safely administered in a doctor’s office with few side effects — unlike more invasive brain stimulation treatments, such as electroconvulsive therapy (ECT) (See Background below).

Following a decade and a half of studies yielding mixed results, the FDA cleared an rTMS device for treatment of mildly treatment resistant depression in 2008, based on data submitted by the manufacturer. The field has been awaiting the results of the NIMH-funded multi-site trial to provide more definitive evidence of efficacy.

Lack of a convincing simulation control treatment that mimics transient tapping and twitching sensations produced by the magnet weakened confidence in findings of some previous rTMS studies. To address these concerns, the new study sought to blind patients, treaters and raters with a simulation control treatment that produced the same head-tapping sensation and scalp twitching as the active treatment. A metal insert below the magnet blocked the magnetic field from entering the brain, while electrodes touching the scalp delivered the tapping sensation. This simulation was so convincing that even the treaters could not confidently guess the randomization above chance level, according to the researchers.

A sample of 190 patients who had previously failed to respond to antidepressant medications received at least three weeks of randomized, controlled magnetic stimulations on weekdays for three weeks, with the rTMS magnet aimed at their brain’s left prefrontal cortex. Those who showed improvement received up to an additional three weeks of such blinded treatment.

Thirteen (14 percent) of 92 patients who received the active treatment achieved remission, compared to 5 (about 5 percent) of 98 patients who received the simulation treatment. Patients who received active rTMS were significantly more likely to reach remission, particularly if they had been moderately, rather than severely, treatment resistant. The remission rate climbed to nearly 30 percent in an open-label phase of this study in which there was no simulation control. George said this is comparable to rates seen in the STAR*D medication studies. However, the researchers note that “the overall number of remitters and responders was less than one would like with a treatment that requires daily intervention for three weeks or more, even with a benign side effect profile.”

Patients who responded to active treatment received up to three weeks of additional blinded, controlled rTMS until they achieved remission or stopped showing a meaningful response – so the number of responders did not differ significantly from the number of remitters. These patients who remitted then received a combination of medications intended to help maintain the treatment effect. Despite failing to respond to medications in the past, most remained in remission for several months.

Study participants who failed to improve during the blinded phase entered a course of open-label rTMS. Among those who had been in the active rTMS group, 30 percent achieved remission during this second phase. This suggests that some patients might require as many as 5-6 weeks of daily rTMS treatment, according to George. Most patients who remitted required 3-5 weeks of treatment.

“For treatment resistant-patients, we found that rTMS is at least as good as current medications or anything else we have available, except ECT,” said George. “Our current antidepressants do not work for many people.”

Since the rTMS treatment did not trigger any seizures or notable side effects, the researchers propose that higher levels of magnetic stimulation be used in future studies, as evidence suggests antidepressant effects of such stimulation are dose-dependent. Higher remission rates might also be attainable if rTMS were combined with medications, they suggest.

Using magnetic resonance imaging (MRI) scans of patients’ brains showing exactly where the magnetic coil was positioned, the researchers hope to confirm earlier findings suggesting that a more forward and to-the-side placement produces a larger therapeutic effect. They plan to report the results of the MRI analysis at the American Psychiatric Association meeting in late May.

Background

George, and colleagues, had earlier pioneered magnetic stimulation as a treatment for depression while at the NIMH intramural research program, beginning in the early l990s. They adapted a technology that NIH colleagues had developed for basic science studies to experimentally probe the brain. The prevailing brain stimulation therapy for treatment-resistant depression, ECT, involved a much more invasive, seizure-inducing procedure requiring general anesthesia in a surgical suite, with risk of memory loss. By contrast, rTMS could be administered to an awake, alert patient in an office setting, without a seizure or side effects — if it could be shown to work. Some skeptics argued, for example, that a seizure might be essential for a robust antidepressant effect.

In rTMS, a pulsing electromagnetic coil aimed at the brain area to be stimulated generates a magnetic field that passes readily through the skull, inducing an electrical current in the immediately adjacent brain tissue. By contrast, ECT requires a current sufficient to penetrate the skull’s resistance to electricity.

Since brain imaging studies by George and colleagues found that the brain’s left prefrontal cortex is under-activated in depression, their pilot rTMS studies targeted the magnet at this area, theorizing that the stimulation would likely be telegraphed to other mood-regulating areas via neural circuitry.

Following a course of such daily treatments over several weeks, some patients’ mood lifted while others did not change. In the years following these early studies, dozens of small, weakly controlled studies testing rTMS for depression have continued to report varied results, so skepticism continued.

Meanwhile, neuroscience advances have led to a proliferation of clinical trials testing rTMS as a potential treatment for a variety of other conditions — from tinnitus to schizophrenia. New, invasive brain stimulation treatments for depression have also appeared — including deep brain stimulation, vagus nerve stimulation and magnetic seizure therapy. Magnetic seizure therapy is a more robust version of TMS which produces a seizure on purpose and thus requires anesthesia and a similar setting as ECT. Sobering assessments of the current crop of antidepressants’ real-world effectiveness have also emerged from large-scale studies, such as STAR*D. These coincided with growing public demand for more effective, side effect-free treatments, sparking continued interest in rTMS.

Against this backdrop, the 2008 FDA clearance, or reclassification, allowed the marketing of an rTMS device for treatment of depression in mildly treatment-resistant patients, rather than for use in treatment of depression generally.

Reference

Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder. George MS, Lisanby SH, Avery D, McDonald WM, Durkalski V, Pavlicova M, Anderson B, Nahas Z, Bulow P, Zarkowski P, Holtzheimer PD, Schwartz T, Sackeim HA. Arch Gen Psychiatry. 2010 May.

New Neurons Pinpointed as Central to Exercise Benefit

In a study in a mouse model that mimics the contribution of social stress to human depression, an environment that promotes exercise and exploration alleviated depressive behavior in the mice. The beneficial effect of activity depended on the growth of new neurons in the adult brain.

Background

In the 1990s scientists established that new neurons grow in the adult as well as the immature brain. The functions of neurogenesis, or new neuronal growth, are still being explored, but it is known that stress slows this growth in the hippocampus―a brain center involved in the formation of new memories―and that antidepressant treatment promotes it.

Previous research in animal models has also demonstrated that environmental enrichment―the addition of features in an animal’s cage that provide opportunities for exercise and investigation―fosters resilience to stress and can alleviate the depression-like behavior that results from uncontrollable stress. Environmental enrichment has also been shown to promote hippocampal neurogenesis in animals.

This Study

This work, by Michael Lehmann and Robert Schloesser and colleagues in NIMH’s intramural research program, focused on the ability of environmental enrichment to reverse depressive behaviors caused by social defeat, a situation paralleling the social stresses that can trigger human depression. Past work in animal models has often used physical stressors such as electric shock, restraint, or forced exercise to create depressive behaviors. In addition, the scientists inserted a gene in mice that made it possible to selectively interrupt the growth of new neurons at a specific time and in a specific population of cells in the hippocampus, avoiding any spillover effects to other tissues.

Test mice in this study were housed across a partition in the home cage of a dominant, aggressor mouse. For 5 minutes per day, the partition was removed, allowing the “intruder” and dominant mouse to interact directly. After 2 weeks, the test mice consistently behaved submissively. The test mice were then divided and placed in either a spare environment, or one enriched with running wheels, and tubes of various shapes and sizes. Some of the mice assigned to either environment were a standard laboratory strain. Others had an inserted gene targeted to a population of hippocampal cells that give rise to new neurons; in mice with this transgene, the antibiotic valganciclovir is toxic to dividing cells so neurogenesis is prevented when the drug was added to the animals’ feed.

The nontransgenic test mice in the enriched environment, but not those in the more spartan cages, recovered from the submissive behavior seen after social defeat. The transgenic mice, in which neurogenesis was stopped, remained submissive, resembling the mice housed in the impoverished environment.

In tests to probe affect, or mood, the transgenic mice housed in the enriched environment also resembled mice housed in the impoverished environment in that they showed the same reduced inclination to explore, greater anxiety, and a less than normal interest in sweet solutions which mice usually prefer. Interruption of neurogenesis had no effects on the baseline health and behavior of the animals, so the lack of new neurons did not cause depression, but interfered with recovery.

Significance

This study demonstrates that psychosocial stress in mice can cause behavior resembling human depression, which environmental enrichment can ameliorate as long as neurogenesis is intact.

Key elements of this study included its use of a social stressor, more analogous to the social experiences that can contribute to human depression than the physical stressors often used in research. In addition, the use of the transgene in test animals enabled the scientists to control the interruption of neurogenesis with precision with respect to both timing and location and with no effects on neighboring cells.

According to author Michael Lehmann, “There are multiple avenues through which environmental enrichment can have a positive impact on depression. In this model we use a natural psychosocial stressor with relevance to social stress in humans, to induce depressive-like behaviors. We show that environmental enrichment can facilitate the recovery from social stress, and that adult neurogenesis is a requirement for the rehabilitating effects of enrichment.”

The authors suggest that neurogenesis may be central to the ability of an animal to update emotional information upon exposure to a novel environment. With neurogenesis impaired, they may be unable to integrate information on the features of a new, changed environment. The resulting cognitive distortions may trigger symptoms of major depression.

Research suggests that one important consequence of environmental enrichment is its impact on the function of the body’s stress response system. Animals in these enriched environments show positive effects on the physiology of stress resilience. In humans, successful antidepressant treatment is reflected in similar beneficial changes. Prior research has also linked neurogenesis with positive changes in the stress response system.

The authors also point out that in humans, physical exercise and positive psychosocial activity have beneficial effects on depression and stress resilience. Forms of entertainment that encourage mental activity, according to Lehmann, such as reading, video games, exercise and outdoor recreation could have longer lasting changes for many suffering from mild depressive symptoms than pharmacologic treatment, without the accompanying side effects.

Reference

Schloesser, R.J., Lehmann, M., Martinowich, K., Manji, H.K., and Herkenham, M. Environmental enrichment requires adult neurogenesis to facilitate recovery from psychosocial stress. Molecular Psychiatry online ahead of print, March 23, 2010, doi:10.1038/mp.2010.34.

Children who were born at less than 26 weeks of gestation have a higher risk for later impairments, a new study finds. Although advances in the neonatal intensive care have resulted in increased survival rates for these children, researchers who conducted a follow-up study of 219 extremely preterm children found that almost one-quarter had a psychiatric disorder at 11 years of age. The findings, which are reported in the May issue of the Journal of the American Academy of Child and Adolescent Psychiatry, show the most frequent psychiatric conditions were Attention-Deficit/Hyperactivity Disorder (12 percent), emotional disorders (9 percent), and Autism Spectrum Disorders (8 percent). The investigation also reports a threefold overall greater risk of subsequent mental health problems in those children born prematurely. (ScienceDaily, 4/25/10)

Many students are heavy users of the Internet, social media and cell phones, and showing symptoms similar to drug and alcohol addictions, according to a new study. Researchers asked 200 students to give up all electronic media for a 24-hour time period. Students were then asked to write about their feelings in regards to the experience. Many of the students expressed experiencing cravings and feelings of anxiety. Others said that they felt they were unable to function well without frequent access to their media sources. (Reuters, 4/23/10)

New Neurons Pinpointed as Central to Exercise Benefit

In a study in a mouse model that mimics the contribution of social stress to human depression, an environment that promotes exercise and exploration alleviated depressive behavior in the mice. The beneficial effect of activity depended on the growth of new neurons in the adult brain.

Background

In the 1990s scientists established that new neurons grow in the adult as well as the immature brain. The functions of neurogenesis, or new neuronal growth, are still being explored, but it is known that stress slows this growth in the hippocampus―a brain center involved in the formation of new memories―and that antidepressant treatment promotes it.

Previous research in animal models has also demonstrated that environmental enrichment―the addition of features in an animal’s cage that provide opportunities for exercise and investigation―fosters resilience to stress and can alleviate the depression-like behavior that results from uncontrollable stress. Environmental enrichment has also been shown to promote hippocampal neurogenesis in animals.

This Study

This work, by Michael Lehmann and Robert Schloesser and colleagues in NIMH’s intramural research program, focused on the ability of environmental enrichment to reverse depressive behaviors caused by social defeat, a situation paralleling the social stresses that can trigger human depression. Past work in animal models has often used physical stressors such as electric shock, restraint, or forced exercise to create depressive behaviors. In addition, the scientists inserted a gene in mice that made it possible to selectively interrupt the growth of new neurons at a specific time and in a specific population of cells in the hippocampus, avoiding any spillover effects to other tissues.

Test mice in this study were housed across a partition in the home cage of a dominant, aggressor mouse. For 5 minutes per day, the partition was removed, allowing the “intruder” and dominant mouse to interact directly. After 2 weeks, the test mice consistently behaved submissively. The test mice were then divided and placed in either a spare environment, or one enriched with running wheels, and tubes of various shapes and sizes. Some of the mice assigned to either environment were a standard laboratory strain. Others had an inserted gene targeted to a population of hippocampal cells that give rise to new neurons; in mice with this transgene, the antibiotic valganciclovir is toxic to dividing cells so neurogenesis is prevented when the drug was added to the animals’ feed.

The nontransgenic test mice in the enriched environment, but not those in the more spartan cages, recovered from the submissive behavior seen after social defeat. The transgenic mice, in which neurogenesis was stopped, remained submissive, resembling the mice housed in the impoverished environment.

In tests to probe affect, or mood, the transgenic mice housed in the enriched environment also resembled mice housed in the impoverished environment in that they showed the same reduced inclination to explore, greater anxiety, and a less than normal interest in sweet solutions which mice usually prefer. Interruption of neurogenesis had no effects on the baseline health and behavior of the animals, so the lack of new neurons did not cause depression, but interfered with recovery.

Significance

This study demonstrates that psychosocial stress in mice can cause behavior resembling human depression, which environmental enrichment can ameliorate as long as neurogenesis is intact.

Key elements of this study included its use of a social stressor, more analogous to the social experiences that can contribute to human depression than the physical stressors often used in research. In addition, the use of the transgene in test animals enabled the scientists to control the interruption of neurogenesis with precision with respect to both timing and location and with no effects on neighboring cells.

According to author Michael Lehmann, “There are multiple avenues through which environmental enrichment can have a positive impact on depression. In this model we use a natural psychosocial stressor with relevance to social stress in humans, to induce depressive-like behaviors. We show that environmental enrichment can facilitate the recovery from social stress, and that adult neurogenesis is a requirement for the rehabilitating effects of enrichment.”

The authors suggest that neurogenesis may be central to the ability of an animal to update emotional information upon exposure to a novel environment. With neurogenesis impaired, they may be unable to integrate information on the features of a new, changed environment. The resulting cognitive distortions may trigger symptoms of major depression.

Research suggests that one important consequence of environmental enrichment is its impact on the function of the body’s stress response system. Animals in these enriched environments show positive effects on the physiology of stress resilience. In humans, successful antidepressant treatment is reflected in similar beneficial changes. Prior research has also linked neurogenesis with positive changes in the stress response system.

The authors also point out that in humans, physical exercise and positive psychosocial activity have beneficial effects on depression and stress resilience. Forms of entertainment that encourage mental activity, according to Lehmann, such as reading, video games, exercise and outdoor recreation could have longer lasting changes for many suffering from mild depressive symptoms than pharmacologic treatment, without the accompanying side effects.

Reference

Schloesser, R.J., Lehmann, M., Martinowich, K., Manji, H.K., and Herkenham, M. Environmental enrichment requires adult neurogenesis to facilitate recovery from psychosocial stress. Molecular Psychiatry online ahead of print, March 23, 2010, doi:10.1038/mp.2010.34.

In-Scanner Tasks Reveal Divergences with Overlapping Disorders

A series of imaging studies are revealing that the brain works differently in youth with bipolar disorder (BD) than in chronically irritable children who are often diagnosed with pediatric BD.

“This suggests that chronically irritable children may suffer from a syndrome distinct from BD and may require different treatments,” said Ellen Leibenluft, M.D., chief of NIMH’s Section on Bipolar Spectrum Disorders, which is conducting the studies.

Episodic vs. Chronic Irritability

Like BD in adults, some children have classic episodes of mania, with a distinct change in mood ­­ becoming more irritable or euphoric than usual – along with a simultaneous change in sleep, activity, and thought patterns. Instead of such clear-cut episodes interspersed with periods of normal mood or depression, many more children present with chronic, severe irritability. Whether these children also have pediatric BD has been at issue.

To capture these severely irritable children without clear episodes, Leibenluft and her colleagues have defined a syndrome they call severe mood dysregulation (SMD). Youth with SMD share certain overlapping features with their bipolar peers, such as poor frustration tolerance and impaired ability to recognize emotional facial expressions, but differ in symptoms, course, and pedigree.

Leibenluft’s team showed in earlier studies that children with BD tend to come from families with histories of the disorder and tend to carry the disorder into adulthood, while children with SMD don’t. Children with SMD are more prone to developing depression or anxiety disorders rather than BD as adults.

SMD is now embodied in the similar Temper Dysregulation Disorder with Dysphoria (TDD) category of the recently proposed psychiatric diagnostic manual revision (DSM-V), which cites the NIMH team’s studies in defining TDD. SMD/TDD is much more common than pediatric BD, affecting about 3.2 percent of children, but no less disabling.

Children with BD or SMD both tend to have attention deficit hyperactivity disorder (ADHD) symptoms, but children with just ADHD differ from those with SMD in not experiencing marked irritability, and from those with BD in not having episodes of mania or depression. To further clarify distinctions among these diagnoses, the NIMH researchers are using brain imaging to compare the workings of neural circuits in pediatric BD and these seemingly related disorders.

“We’re finding that the same clinical symptom, or behavioral deficit, may be mediated by more than one brain mechanism,” explained Leibenluft.

Reading Fear into Neutral Faces

Previous studies also suggested that children with BD have weakened connections between the amygdala, the brain’s fear hub, and other brain structures involved in processing facial emotion. These weakened connections may contribute to the children’s impaired ability to recognize emotional expressions.

In a follow-up study, reported in the January 2010 issue of the American Journal of Psychiatry, Melissa Brotman, Ph.D., Leibenluft and colleagues compared amygdala activity in children with ADHD, BD, SMD, and healthy controls while they rated emotion in neutral faces. Functional magnetic resonance imaging (fMRI) revealed that this task seemed to engage unique neural mechanisms in each syndrome.

For example, when rating how fearful the neutral faces appeared, the amygdala over-activated in ADHD, under-activated in SMD, and ­­ unexpectedly – activated normally in bipolar disorder relative to controls.

In previous such studies, children with bipolar disorder showed increased amygdala activity – and even in this study, they subjectively rated the neutral faces as more fearful than did controls. So the latter outcome may be a fluke. Still, the findings add to evidence of divergence between bipolar and SMD in the way the brain processes facial emotion.

Since studies have shown that depressed children have reduced amygdala activity, and SMD is a risk factor for adult depression, the researchers suggest that amygdala dysfunction in SMD might be a predictor of later depression.

This first fMRI study to include children with SMD and the first to compare amygdala activation across these groups suggests that, despite some overlapping symptoms, the brain may be working differently in each disorder.

Amygdala (yellow area where lines intersect) over-activated in subjects with ADHD and under-activated in those with SMD while they rated the fearfulness of neutral faces.

Source: NIMH Section on Bipolar Spectrum Disorders

Slow to Recognize Emotion

In an earlier study, children with BD, SMD and controls were asked to label the emotion emerging as faces morphed from a neutral to full expression. Children with either BD or SMD took significantly longer than controls before recognizing fear, surprise, disgust and happy expressions, report Brendan Rich, Ph.D., Leibenluft and colleagues in the Spring, 2008 issue of Development and Psychopathology.

Since another NIMH study had found that this impairment is not shared by children with ADHD or other childhood disorders, the results suggest that the two disorders may be on a continuum in terms of their underlying biological and psychological causes. Yet, the impaired face labelling was linked to different psychosocial impairments in the two groups – perhaps also hinting at some differences in underlying brain mechanisms, suggest the researchers. It was associated with dysfunctional family relationships among children with SMD, in contrast to deficient social reciprocity skills among youth with BD.

Children with both bipolar disorder and SMD were slow to identify emotional facial expressions, such as disgust (above) as they morphed from neutral to full intensity.

Source: NIMH Section on Bipolar Spectrum Disorders

Accentuating the Negative

Although chronic severe irritability is the hallmark symptom of SMD, irritability is also common in youth with BD, both within and between manic and depressive episodes. Children with irritability tend to have difficulty coping with frustration. The NIMH researchers had shown earlier that when frustrated by negative feedback, youth with BD emit brain wave patterns signaling impaired attention.

To pinpoint the underlying neural circuitry, the researchers turned to an imaging technique called magnetoencephalography (MEG), which can detect even fleeting, millisecond events deep in the brain. Rich, Leibenluft and colleagues reported on the first MEG study of childhood BD online December 27, 2009 in the journal Depression and Anxiety. They scanned youth with the disorder and controls while they performed an attention task rigged to frustrate them by leading them to believe – for a time – that they were losing money won earlier (Ultimately, their winnings were restored).

As expected, youth with BD reported being more upset by the frustration-inducing negative feedback than did the controls. This irritability was associated with over-activation of an emotion-processing circuit centered on a brain area earlier implicated in BD called the anterior cingulate cortex (ACC).

Youth with BD showed greater activation than controls after negative feedback (losing money) in an area of the left ACC. By contrast, controls showed greater activation than bipolar youth after positive feedback (winning money) in an area of the right ACC.

Such over-activation in the left ACC likely reflects exaggerated attention and disproportionate thinking about their performance in response to negative feedback among bipolar youth, suggest the researchers. This would exacerbate irritability and frustration, perhaps distracting them from positive information.

Related studies show that children with either SMD or BD experience increased frustration in such attention tasks relative to controls, but the SMD and BD children differ in the way their brains process the tasks. The SMD children’s brains respond more like those of children with ADHD.

Left: Left anterior cingulate cortex (where lines intersect) over-activated in pediatric BD in response to negative feedback. Right: Right anterior cingulate cortex (where lines intersect) under-activated in pediatric BD in response to positive feedback. MEG data superimposed on MRI data.

Source: NIMH Section on Bipolar Spectrum Disorders

Different Circuitry May Call for Different Treatments

On the mistaken assumption that they have BD, many children with SMD have been prescribed anticonvulsant and antipsychotic medications. Such misdiagnosis can expose children unnecessarily to risks of serious long-term side effects with these agents, including weight gain, diabetes and heart disease.

Leibenluft’s team is conducting a clinical trial to test whether children with SMD might be better helped instead with treatments more appropriate for depression and anxiety – disorders more related to their illness – and their ADHD symptoms. After discontinuing their other medications, children in the study are first given a stimulant medication, followed by a randomized course of treatment with either an antidepressant or placebo.

“In many ways, this is the single most important study we’re doing, in terms of public health impact,” noted Leibenluft.

References

Amygdala activation during emotion processing of neutral faces in children with severe mood dysregulation versus ADHD or bipolar disorder. Brotman MA, Rich BA, Guyer AE, Lunsford JR, Horsey SE, Reising MM, Thomas LA, Fromm SJ, Towbin K, Pine DS, Leibenluft E. Am J Psychiatry. 2010 Jan;167(1):61-9. Epub 2009 Nov 16.PMID: 19917597

Face emotion labeling deficits in children with bipolar disorder and severe mood dysregulation. Rich BA, Grimley ME, Schmajuk M, Blair KS, Blair RJ, Leibenluft E. Dev Psychopathol. 2008 Spring;20(2):529-46.PMID: 18423093

A preliminary study of the neural mechanisms of frustration in pediatric bipolar disorder using magnetoencephalography. Rich BA, Holroyd T, Carver FW, Onelio LM, Mendoza JK, Cornwell BR, Fox NA, Pine DS, Coppola R, Leibenluft E. Depress Anxiety. 2009 Dec 27. [Epub ahead of print] PMID: 20037920