Category: Stress

A new article in The Quarterly Review of Biology helps explain why the immune system often makes us worse while trying to make us well.

The research offers a new perspective on a component of the immune system known as the acute-phase response, a series of systemic changes in blood protein levels, metabolic function, and physiology that sometimes occurs when bacteria, viruses, or other pathogens invade the body. This response puts healthy cells and tissue under serious stress, and is actually the cause of many of the symptoms we associate with being sick.

"The question is why would these harmful components evolve," asks Edmund LeGrand (University of Tennessee, Knoxville), who wrote the paper titled with Joe Alcock (University of New Mexico). The researchers contend that answer becomes clear when we view the acute-phase response in terms of what they call "immune brinksmanship."

The immune brinksmanship model "is the gamble that systemic stressors will harm the pathogens relatively more than the host," LeGrand said. The concept, he explains, is akin to what happens in international trade disputes. When one country places trade sanctions on another, both countries' economies take a hit, but the sanctioning country is betting that its opponent will be hurt more.

"One of our contributions here is to pull together the reasons why pathogens suffer more from systemic stress," LeGrand said.

The acute-phase response creates stress in several ways. It raises body temperature and causes loss of appetite and mild anemia. At the same time, certain vital nutrients like iron, zinc, and manganese are partially sequestered away from the bloodstream.

Some of these components are quite puzzling. Why reduce food intake just when one would expect more energy would be needed to mount a strong immune response? Zinc is essential for healthy immune function. Why pull it out of the bloodstream when the immune system is active? The benefits of a stressor like fever are fairly well known; heat has been shown to inhibit bacterial growth and cause infected cells to self-destruct. But what hasn't been clear is why pathogens should be more susceptible to this stress than the host.

LeGrand and Alcock offer some answers. For an infection to spread, pathogens need to multiply, whereas host cells can defer replication. Replication makes DNA and newly forming proteins much more susceptible to damage. It also requires energy and nutrients — which helps explain the benefits of restricting food and sequestering nutrients.

The act of invading a body also requires bacteria to alter their metabolism, which can make them more vulnerable to all kinds of stress, including heat.

Another reason pathogens are more vulnerable to stress is that the immune system is already pummeling them with white blood cells and related stressors at the site of the infection. That means that pathogens are already under local stress when systemic stressors are piled on. "In many ways, the acute-phase response reinforces the stress inflicted on pathogens locally at the infection site," LeGrand said.

As the term "brinksmanship" implies, there's an inherent risk in a strategy that involves harming oneself to hurt the enemy within. This self-harm leaves the body more vulnerable to other dangers, including other infections. Additionally, it is possible for the immune stressors to do more damage than required to control the pathogens.

"But in general, systemic stressors when properly regulated do preferential harm to invaders," LeGrand said. Viewed this way, it's not surprising that natural selection has utilized the stressful parts of the acute-phase response in mammals, reptiles, fish, and even invertebrates.

 A new study concludes that men who experience persistently moderate or high levels of stressful life events over a number of years have a 50 percent higher mortality rate.

In general, the researchers found only a few protective factors against these higher levels of stress — people who self-reported that they had good health tended to live longer and married men also fared better. Moderate drinkers also lived longer than non-drinkers.

"Being a teetotaler and a smoker were risk factors for mortality," said Carolyn Aldwin, lead author of the study and a professor of human development and family sciences at Oregon State University. "So perhaps trying to keep your major stress events to a minimum, being married and having a glass of wine every night is the secret to a long life."

This is the first study to show a direct link between stress trajectories and mortality in an aging population. Unlike previous studies that were conducted in a relatively short term with smaller sample sizes, this study was modified to document major stressors — such as death of a spouse or a putting a parent into a retirement home — that specifically affect middle-aged and older people.

"Most studies look at typical stress events that are geared at younger people, such as graduation, losing a job, having your first child," Aldwin said. "I modified the stress measure to reflect the kinds of stress that we know impacts us more as we age, and even we were surprised at how strong the correlation between stress trajectories and mortality was."

Aldwin said that previous studies examined stress only at one time point, while this study documented patterns of stress over a number of years.

The study, out now in the Journal of Aging Research, used longitudinal data surveying almost 1,000 middle-class and working-class men for an 18-year period, from 1985 to 2003. All the men in the study were picked because they had good health when they first signed up to be part of the Boston VA Normative Aging Study in the 1960s.

Those in the low-stress group experienced an average of two or fewer major life events in a year, compared with an average of three for the moderate group and up to six for the high stress group. One of the study's most surprising findings was that the mortality risk was similar for the moderate versus high stress group.

"It seems there is a threshold and perhaps with anything more than two major life events a year and people just max out," Aldwin said. "We were surprised the effect was not linear and that the moderate group had a similar risk of death to the high-risk group."

While this study looked specifically at major life events and stress trajectories, Aldwin said the research group will next explore chronic daily stress as well as coping strategies.

"People are hardy, and they can deal with a few major stress events each year," Aldwin said. "But our research suggests that long-term, even moderate stress can have lethal effects."

Michael Levenson, Heidi Igarashi, Nuoo-Ting Molitor and John Molitor with Oregon State University and Avron Spiro III with Boston University all contributed to this study, which was funded by the National Institute on Aging as well as an award from the U.S. Department of Veterans Affairs.

Journal Reference:

1. Carolyn M. Aldwin, Nuoo-Ting Molitor, Avron Spiro, Michael R. Levenson, John Molitor, Heidi Igarashi. Do Stress Trajectories Predict Mortality in Older Men? Longitudinal Findings from the VA Normative Aging Study. Journal of Aging Research, 2011; 2011: 1 DOI: 10.4061/2011/896109

Children whose mother or father is affected by bipolar disorder may need to keep their stress levels in check. A new international study, led by Concordia University, suggests the stress hormone cortisol is a key player in the mood disorder. The findings published in Psychological Medicine, are the first to show that cortisol is elevated more readily in these children in response to the stressors of normal everyday life.

"Previous research has shown that children of parents with bipolar disorder are four times as likely to develop mood disorders as those from parents without the condition," says senior author Mark Ellenbogen, Canada Research Chair in Developmental Psychopathology at Concordia University and a member of the Centre for Research in Human Development. "The goal of our study was to determine how this is happening."

Cortisol, the telltale hormone

Ellenbogen and colleagues had previously shown that cortisol levels in children with a parent affected by bipolar disorder were higher than kids whose parents were unaffected by the condition. The current study measured cortisol levels in these same individuals during chronic and episodic stress periods. In both circumstances, children of parents with bipolar disorder showed a greater increase in cortisol than those of parents without the disorder.

"Our study demonstrates that affected children are biologically more sensitive to the experience of stress in their natural and normal environment compared to unaffected peers," says Ellenbogen. "This higher reactivity to stress might be one explanation of why these offspring end up developing disorders and is a clear risk factor to becoming ill later on."

"We think we might be beginning to understand where we can intervene to actually prevent this increased sensitivity from developing," continues Ellenbogen. "We believe this sensitivity develops during childhood and our suspicion is that if you could teach both parents and their offspring on how to cope with stress, how to deal with problems before they turn into larger significant stressors and difficulties, this would have a profound impact."

About cortisol: Cortisol is a hormone that is produced by the body in response to anxiety and researchers use cortisol to monitor the biological response to stress.

About bipolar disorder: Bipolar disorder, which is also known as manic depression, is a treatable illness marked by extreme changes in mood, thought, energy and behavior. Bipolar disorder is also known as manic depression because a person's mood can alternate between mania (highs) and depression (lows). These changes in mood, or "mood swings," can last for hours, days, weeks or months.

This work was supported by the Canadian Institutes of Health Research, the Social Sciences and Humanities Research Council of Canada and the Fonds du Québec en Recherche sur la Société de la Culture.

Journal Reference:

1. C. S. Ostiguy, M. A. Ellenbogen, C.-D. Walker, E. F. Walker, S. Hodgins. Sensitivity to stress among the offspring of parents with bipolar disorder: a study of daytime cortisol levels. Psychological Medicine, 2011; : 1 DOI: 10.1017/S0033291711000523

During the winter of 2008-2009, a three-week armed conflict in the south of Israel and the Gaza Strip named "Operation Cast Lead" resulted in hundreds of rocket and mortar attacks on Israeli civilian populations. During this time children and their families spent hours and days in shelters amid threats to their survival.

Although the psychological effects of children's health are well-documented, local resources aimed at alleviating the negative outcomes of mass trauma are often overwhelmed. In the face of human-made or natural disasters, the school setting and teachers empowered to serve as "clinical mediators" can provide crucial role in assisting children in coping with exposure to trauma.

In a study published in the April 2011 issue of the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP), researchers report on the effects of an Israeli, teacher-based stress resistance intervention implemented in grade schools before the rocket attacks that occurred during Operation Cast Lead, compared with a non-intervention but exposed control group. This is the first known study to evaluate psychiatric outcomes in children who received stress intervention before the onset of mass trauma.

Mr. Wolmer, and Drs. Hamiel and Laor, from the Tel Aviv-Brull Community Mental Health Center, Donald J. Cohen and Irving B. Harris Resilience Center for Trauma and Disaster Intervention, and Child Study Center at Yale University evaluated 1,488 fourth and fifth grade Jewish students from a southern Israeli city that had been exposed to the continuous rocket attacks during Operation Cast Lead. Participating schools, chosen because of their proximity to the Gaza Strip, provided teacher training in stress resistance which focused on resilience building rather than directly addressing trauma symptoms. The teacher-led intervention was implemented at six schools three months before the traumatic exposure.

Utilizing two rating assessments, the UCLA-PTSD Reaction Index and the Stress/Mood Scale, the children self-reported on the frequency of symptoms related to stress, fear, and mood changes in the previous month. These symptoms align with those found in children experiencing posttraumatic stress disorder (PTSD).

In the article titled "Preventing Children's Posttraumatic Stress After Disaster With Teacher-Based Intervention: A Controlled Study" Mr. Wolmer, and Drs. Hamiel and Laor, report that children who participated in the teacher-based intervention reported 50% fewer symptoms of posttrauma and stress as compared to the control group. For children with teacher-based intervention, the percentage of children meeting or exceeding the accepted cut-off score for PTSD was significantly lower, although mostly among boys.

Children with low socioeconomic status reported more symptoms of both scales than those with moderate and high socioeconomic status.

The researchers conclude, '"The teacher based, resilience-focused intervention is a universal, cost-effective approach to enhance the preparedness of communities of children to mass trauma and to prevent the development of PTSD after exposure."

In a related editorial Dr. Joan Rosenbaum Asarnow states, "The article by Wolmer et al. (1) provides a compelling example of the value of pairing public health/program innovations with strong evaluation designs. The need to provide the best public health and treatment programs requires that the best science be mobilized to maximize program effectiveness." Dr. Arsarnow continues, "Finding optimal approaches to combining these public health/program initiatives with state-of-the-art evaluations to inform science is a critical task for the field."

The study findings reported by Mr. Wolmer and colleagues were supported by grants from the Pritzker Family Foundation and the Irving Harris Foundation.

Journal References:

1. Leo Wolmer, Daniel Hamiel, Nathaniel Laor. Preventing Children's Posttraumatic Stress After Disaster With Teacher-Based Intervention: A Controlled Study. Journal of the American Academy of Child & Adolescent Psychiatry, 2011; DOI: 10.1016/j.jaac.2011.01.002
2. Joan Rosenbaum Asarnow. Promoting Stress Resistance in War-Exposed Children. Journal of the American Academy of Child & Adolescent Psychiatry, 2011; 50 (4): 320-322 DOI: 10.1016/j.jaac.2011.01.010

 Even relatively mild stress can lead to long term disability and an inability to work, reveals a large population based study published online in the Journal of Epidemiology and Community Health.

It is well known that mental health problems are associated with long term disability, but the impact of milder forms of psychological stress is likely to have been underestimated, say the authors.

Between 2002 and 2007, the authors tracked the health of more than 17,000 working adults up to the age of 64, who had been randomly selected from the population in the Stockholm area.

All participants completed a validated questionnaire (GHQ-12) at the start of the study to measure their mental health and stress levels, as well as other aspects of health and wellbeing.

During the monitoring period, 649 people started receiving disability benefit — 203 for a mental health problem and the remainder for physical ill health.

Higher levels of stress at the start of the study were associated with a significantly greater likelihood of subsequently being awarded long term disability benefits.

But even those with mild stress were up to 70% more likely to receive disability benefits, after taking account of other factors likely to influence the results, such as lifestyle and alcohol intake.

One in four of these benefits awarded for a physical illness, such as high blood pressure, angina, and stroke, and almost two thirds awarded for a mental illness, were attributable to stress.

The authors say that it is important to consider their findings in the context of modern working life, which places greater demands on employees, and social factors, such as fewer close personal relationships and supportive networks.

These factors lead them to ask: "Are the strains and demands of modern society commonly exceeding human ability?" And they conclude that while mild stress should not be over-medicalised, their findings suggest that it should be taken more seriously than it is.

Journal Reference:

1. D. Rai, K. Kosidou, M. Lundberg, R. Araya, G. Lewis, C. Magnusson. Psychological distress and risk of long-term disability: population-based longitudinal study. Journal of Epidemiology & Community Health, 2011; DOI: 10.1136/jech.2010.119644

— The hippocampus, a brain region implicated in memory and interpreting environmental contexts, has been the focus of a controversy in posttraumatic stress disorder (PTSD).

Early MRI studies suggested that the volume of the hippocampus was reduced in some people with chronic PTSD. This observation was interpreted as suggesting that stress produced atrophy within the hippocampus, consistent with a body of research conducted in animals. Supporting this hypothesis, it appears that the same region of the hippocampus that is most-sensitive to stress effects in animals, the CA3 region, may show the greatest volume reductions in people with PTSD.

More recently, the non-traumatized identical twins of people with PTSD were shown to have smaller hippocampal volumes, suggesting that a small hippocampus might be a risk factor for PTSD. This hypothesis relates to the role that the hippocampus plays in drawing inferences about one's environmental context, such as evaluating the safety of the environment. The hippocampus also provides some inhibitory control of hypothalamic centers that control the levels of the stress hormone cortisol.

Now, a new study in Biological Psychiatry has found that larger hippocampal volume is associated with recovery of PTSD. Brigitte Apfel and colleagues used structural magnetic resonance imaging to study hippocampal volume in Gulf War veterans who recovered from PTSD in comparison to veterans with chronic PTSD and to control participants who never had PTSD. They found that recovered veterans had, on average, larger hippocampal volumes than those with chronic PTSD and similar volumes compared to the control participants.

"These results need to be interpreted with caution because we did not measure brain changes over time. However, the finding suggests that hippocampal damage in PTSD is reversible once the symptoms remit," explained Dr. Apfel. "If our finding can be confirmed, it might suggest that treatment of PTSD could be viewed as brain restoration rather than primarily a way to ease symptoms."

Does this finding help to resolve the conundrum of whether the hippocampus is a target of stress or a contributor to stress response?

This finding would appear to support the hypothesis that a small hippocampus is a risk factor for the persistence of PTSD, because people with larger hippocampi seemed better able to recover. This finding may be consistent with the observation that some gene variants associated with emotional resilience in response to stress are also associated with larger hippocampal volume. Alternatively, it is possible that smaller hippocampi reflect early life stress or other environmental factors that compromise resilience in adulthood.

A major remaining question is whether treatment-related increases in hippocampal volume mediate aspects of the therapeutic responses to PTSD treatments. A prior study reported that six months of antidepressant treatment increased hippocampal volume in people with PTSD.

"It may be time to view hippocampal volume as both a modulator of stress resilience and as a target for the negative impact of stress and the positive effects of treatments," commented Dr. John Krystal, Editor of Biological Psychiatry. "This more complex view might explain how the negative effects of stress "feed forward" to worsen outcomes in the face of subsequent stressors, while treatments would similarly cumulatively promote resilience."

Journal Reference:

1. Brigitte A. Apfel, Jessica Ross, Jennifer Hlavin, Dieter J. Meyerhoff, Thomas J. Metzler, Charles R. Marmar, Michael W. Weiner, Norbert Schuff, Thomas C. Neylan. Hippocampal Volume Differences in Gulf War Veterans with Current Versus Lifetime Posttraumatic Stress Disorder Symptoms. Biological Psychiatry, 2011; 69 (6): 541 DOI: 10.1016/j.biopsych.2010.09.044

— In the case of post-traumatic stress disorder, not all symptoms are created equal. In an effort to better treat PTSD, a study published March 1 in the journal Psychiatric Services is the first to examine which problems associated with PTSD actually correspond to lower quality of life, as indicated by the patient's willingness to die sooner or to risk life-threatening treatment to relieve their symptoms.

PTSD is more costly than any other anxiety disorder. As many as 300,000 veterans returning from Iraq and Afghanistan currently have PTSD, with costs for their care estimated at $4 to $6.2 billion over the next two years.

"To our knowledge, this is the first study to ask actual patients with PTSD about their health preferences," said lead author Jason Doctor, associate professor of Pharmaceutical Economics and Policy at the USC School of Pharmacy. "These findings identify targets for treatment that may improve quality of life among people with PTSD."

The researchers found that, of four major symptoms associated with PTSD, not all were associated with a patient's immediate quality of life, even though those who sought treatment for PTSD expressed significant overall declines in mental health.

Distressing recollections of a traumatic event and avoidance of certain activities and thoughts — both commonly conceived of as dysfunctional behaviors — had little correlation to a patient's reported sense of well-being, according to the study.

However, symptoms tied to heightened arousal — such as trouble sleeping, irritability and vigilance — were associated with lower quality of life among PTSD patients. Anxiety and depression were also associated with lower quality of life.

"We conjecture that although avoidance is an important aspect of PTSD, its effect on quality of life may be limited because it is a coping strategy. Avoidance may be a dysfunction that improves, in the short term, subjective well-being," explained Doctor, who is on the research faculty of the Schaeffer Center for Health Policy and Economics at USC.

The researchers found that, on average, a patient with PTSD was willing to give up 13.6 years of his or her life to live unburdened by the symptoms of the disorder.

On average, those with PTSD were willing to accept a treatment with up to a 13 percent chance of immediate death in order to achieve total relief of PTSD symptoms.

Lori Zoellner of the University of Washington, Seattle, and Norah Feeny of Case Western Reserve University were co-authors of the study.

The researchers interviewed 184 persons seeking treatment for PTSD at two treatment sites in different regions of the United States. The research was funded by the National Institute of Mental Health.

Doctor et. al, "Predictors of Health-Related Quality-of-Life Utilities Among Persons With Posttraumatic Stress Disorder." Psychiatric Services: March 2011.

Journal Reference:

1. Jason N. Doctor, Lori A. Zoellner and Norah C. Feeny. Predictors of Health-Related Quality-of-Life Utilities Among Persons With Posttraumatic Stress Disorder. Psychiatr Serv, 62:272-277, March 2011 DOI: 10.1176/appi.ps.62.3.272

 Your emotional response to challenging situations could predict how your body responds to stress, according to research published this month in the journal Brain, Behavior, and Immunity.

"People who reported high levels of anger and anxiety after performing a laboratory-based stress task showed greater increases in a marker of inflammation, than those who remained relatively calm," said Dr Judith Carroll, who conducted the study at the University of Pittsburgh. "This could help explain why some people with high levels of stress experience chronic health problems," she added.

The investigators asked healthy middle-aged individuals to complete a speech in the laboratory in front of video camera and a panel of judges. During the speech, they monitored the physical responses to the task and then afterwards asked them about the emotions that they had experienced.

"Most people show increases in heart rate and blood pressure when they complete a stressful task," explained Dr Carroll, "but some also show increases in a circulating marker of inflammation known as interleukin-6. Our study shows that the people who have the biggest increases in this marker are the ones who show the greatest emotional responses to the task."

"Our results raise the possibility that individuals who become angry or anxious when confronting relatively minor challenges in their lives are prone to increases in inflammation," explained lead author Dr Anna Marsland, an Associate Professor of Psychology and Nursing at the University of Pittsburgh. "Over time, this may render these emotionally-reactive individuals more vulnerable to inflammatory diseases, such as cardiovascular disease," she said.

The research, funded by the National Institute of Nursing Research, is part of a burgeoning field, known as Psychoneuroimmunology, which investigates the interactions between psychological processes and health. "This paper addresses a key question in psychoneuroimmunology — what explains individual differences in the inflammatory response to stress," said Dr Margaret Kemeny, a Professor at the University of California, San Francisco. "These findings suggest that the specific nature of the emotional response to the task may be a key predictive factor and set the stage for future work defining these pathways and addressing their clinical implications," she added.

Journal Reference:

1. Judith E. Carroll, Carissa A. Low, Aric A. Prather, Sheldon Cohen, Jacqueline M. Fury, Diana C. Ross, Anna L. Marsland. Negative affective responses to a speech task predict changes in interleukin (IL)-6☆. Brain, Behavior, and Immunity, 2011; 25 (2): 232 DOI: 10.1016/j.bbi.2010.09.024

An article published in a forthcoming issue of the Journal of Traumatic Stress is one of the first to provide evidence of the effectiveness of exposure therapy with active duty military service members suffering from posttraumatic stress disorder (PTSD). The study shows that virtual reality exposure therapy resulted in significant reductions in PTSD symptoms after an average of seven treatment sessions. Additionally, 62 % of patients reported clinically meaningful, reliable change in PTSD symptoms.

During the treatment the soldier repeatedly revisits the memory, and through the use of their imagination they safely access emotions related to the original traumatic experience. Revisiting the memory while safely emotionally engaged, reduces anxiety, and allows the engagement process to be comfortably repeated. Lead author Dr. Greg Reger, "We know that lengthy military deployments in stressful environments with exposure to multiple, potentially traumatic events can lead to the desire to emotionally 'unplug.' By using multi-sensory virtual reality that can be customized in real time, the provider can help activate the memory with relevant sights, sounds, vibrations, even scents that resemble aspects of the event that is haunting them."

A clinical trial with Vietnam veterans and World Trade Center survivors has shown that virtual exposure therapy is an innovative and effective form of treatment. The current research extends those findings to the population of military service members returning from deployments to Iraq or Afghanistan with PTSD.

Reger, "It is possible that virtual reality exposure therapy would provide a more appealing treatment option to a young, technologically savvy generation of service members and veterans. In addition, it is possible that a treatment option like virtual reality exposure would be viewed by some service members as less stigmatizing than traditional treatment approaches. If accurate, virtual reality exposure therapy might provide us with the opportunity to treat service members and veterans who may not otherwise seek help."

Journal Reference:

1. Greg M. Reger, Kevin M. Holloway, Colette Candy, Barbara O. Rothbaum, JoAnn Difede, Albert A. Rizzo, Gregory A. Gahm. Effectiveness of virtual reality exposure therapy for active duty soldiers in a military mental health clinic. Journal of Traumatic Stress, 2011; 1 DOI: 10.1002/jts.20574