Modeling Gulf War illness: Knowing the cause of brain dysfunction is key to finding a cure

When hundreds of thousands of American troops deployed to the Persian Gulf in 1990 and 1991 in what is now called the First Gulf War, they were exposed to a variety of chemicals. These chemicals — especially when coupled with war-related stress — seem to still be affecting nearly 200,000 Gulf War veterans — or 25 to 32 percent of those who served — more than 25 years later, and the constellation of resulting symptoms has been termed Gulf War illness (GWI). This condition is characterized by central nervous system impairments — including cognitive and memory problems, mood dysfunction, sleep disorders and chronic fatigue — and systemic symptoms such as gastrointestinal problems and hypersensitive skin.

Using an animal model of GWI, researchers at the Texas A&M College of Medicine and the Central Texas Veterans Health Care System were able to demonstrate how GWI occurs, and their findings, which were published in the journal Frontiers in Molecular Neuroscience, hint at possible ways to mitigate some of the symptoms. This work was supported by grants from the Department of Veterans Affairs and Department of Defense and from the Texas Emerging Technology Fund.

The chemicals troops were exposed to in the Persian Gulf included pyridostigmine bromide, which was used as prophylaxis to prevent death in an attack with nerve gas agents. In addition, mosquito repellants, such as DEET, and pesticides, such as permethrin, were sprayed on their clothes and tents to keep potentially disease-carrying insects and rodents at bay. Some troops were also likely exposed to low levels of chemical warfare agents, due to demolition of Iraqi facilities storing those agents, and smoke from oil well fires.

Chemicals like DEET and permethrin can enter the brain through disruption of the blood-brain barrier, where they can inhibit the breakdown of a neurotransmitter called acetylcholine. “Essentially, they cause acetylcholine to build up in the brain, causing hyperexcitability of neurons as well as the death of some neurons, which leads to inflammation in the brain,” said Ashok K. Shetty, PhD, a professor in the Department of Molecular and Cellular Medicine at the Texas A&M College of Medicine, associate director of the Institute for Regenerative Medicine, research career scientist at the Olin E. Teague Veterans Medical Center, Central Texas Veterans Health Care System and senior author of the paper. “At the same time, troops were also taking pyridostigmine bromide, which can sequester the enzyme that breaks down acetylcholine, compounding the problem.”

To test the effects of such exposure, the researchers must first create an animal model. “We simulate what happened during the war,” Shetty said. “We give pyridostigmine bromide orally and apply DEET and permethrin dermally, and then expose them to a mild stressor. When you do that, these animal models develop the symptoms of GWI, such as cognitive and memory problems, and have chronic low-level inflammation in the brain.” Six months later — which is about 17 years in human terms — there was still evidence of persistent oxidative stress, even though they hadn’t been exposed to either chemicals or stress in the interim.

“Our data in animal models matches very well with what has been seen in patients,” Shetty said. They both had considerable systemic inflammation, which can be measured by levels of multiple pro-inflammatory cytokines in the blood serum. Pro-inflammatory cytokines circulate all over the body and cause systemic inflammation, which, in turn, can cause considerable problems in certain vulnerable regions of the brain such as the hippocampus. These problems include declined production of new neurons important for making new memories.

“We examined changes in a type of housekeeping cell in the brain, called microglia, and they indicated inflammation, which looked similar to what we see in aging individuals with memory problems and other cognitive impairments,” Shetty said. The animal models also had hyper-activated mitochondria (the ‘powerhouse’ of the cell), implied by increased expression of genes related to mitochondrial respiration — the process by which mitochondria transform stored energy into a form the cell can use. The researchers also found that many genes related to inflammation were upregulated. “Together, these findings raise the possibility that hippocampal dysfunction in GWI is one of the adverse outcomes of persistently elevated oxidative stress and inflammation at the systemic level,” he added.

Fortunately, antioxidants and anti-inflammatory compounds may be able to treat systemic inflammation, and it is possible such treatment would improve memory and mood function, Shetty said. The next steps are to test antioxidant and/or anti-inflammatory compounds on human veterans. For this, Shetty has established a collaboration with Dena Davidson, PhD, deputy director of research at the Veterans Integrated Service Network (VISN) 17 Center of Excellence for Research on Returning War Veterans in Waco, Texas, to purse clinical trials in GWI patients. Davidson and her team, along with Shetty, will begin a clinical trial funded by the Department of Defense in September to examine the efficacy of resveratrol in GWI patients. Shetty’s earlier research has shown that this compound may be able to help prevent memory loss occurring with aging. Additional studies completed recently in Shetty’s laboratory have also shown resveratrol as a promising compound for decreasing systemic and brain inflammation, as well as improving cognitive and memory function in animal models of GWI.

“This really does demonstrate that when someone is exposed concurrently to a whole host of nasty chemicals even at low doses, there are consequences that are not going away,” Shetty said. “We hope that our research can help improve the quality of life in these veterans who were exposed while serving our country, and therefore are so deserving of whatever we can do to support them.”

 

Certain characteristics linked with ISIS anxiety

A new study examines the characteristics of individuals who are most likely to have anxiety concerning threats posed by ISIS.

In the study of 1007 adult Israelis, being female, having a lower socio-economic status, and having elevated levels of post-traumatic stress disorder (PTSD) symptoms were related to ISIS anxiety. Exposure to ISIS in the media and having low resilience were also linked to ISIS anxiety. Finally, the PTD-ISIS relationship was especially pronounced when the mental resources of resilience and optimism were low. Resilienceis defined mainly as a resource aimed at dealing with a current threat, while optimism is defined as a resource related to future outcomes.

“The findings may have important implications for addressing heightened anxiety in the event of elevated terrorist threats in terms of showing that exposure to ISIS media is detrimental to one’s mental health and increases ISIS anxiety beyond one’s level of general anxiety,” said Dr. Yaakov Hoffman, author of the Stress and Health. article. “Furthermore, the results may suggest that increasing one’s optimism and resilience may mitigate the ISIS threat sensitivity, especially in individuals with PTSD symptoms.”

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Deployment stress impacts well-being through different mental health issues for female and male vets

Experiencing stress-related mental health issues following deployment exposures increases risk of reduced well-being in other life domains in the years following military service for veterans. Gender plays an important role in these associations.

The findings, which appear in Clinical Psychological Science, have implications for better understanding the challenges female and male veterans face upon returning from service and may lead to ways care can be optimized with consideration of the role gender may play.

According to the researchers, previous studies have shown a relationship between the development of mental health issues, particularly PTSD, and decreased functioning and satisfaction with family and work for veterans. However, gender often has been overlooked as a variable, and the role of particular deployment stressors have not been extensively examined. “Our study illustrates the complex interplay between specific military exposures, mental health, and subsequent post deployment well-being between the genders,” explained lead author Brian Smith, PhD, assistant professor of psychiatry at Boston University School of Medicine and research psychologist in the Women’s Health Sciences Division, National Center for PTSD at VA Boston Healthcare System.

In this study, which was completed at the VA Boston Healthcare System, 522 male and female Iraq and Afghanistan War veterans completed two surveys. The first was completed within two years of separation from military service, and included questions about veterans’ military experiences as well as their current mental health. The second survey was completed approximately three and a half years later and included questions about functioning and satisfaction in the domains of work, romantic relationships and parenting.

The researchers concluded that each of the deployment stressors examined — warfare exposure, military sexual harassment and family stressors — had implications for veterans’ subsequent functioning and satisfaction in the areas of work and family. In addition, these exposures were often indirectly linked to functioning and satisfaction via mental health. Interestingly, the links differed between men and women. While PTSD symptoms played an important role for both genders, depression played a role as well, especially for female veterans. For example, PTSD linked all three deployment exposures and subsequent functioning and satisfaction in romantic relationships for men, while both PTSD and depression played significant roles for women. However, it is important to note that there were some similarities in risk as well. In the context of parenting, PTSD linked deployment exposures with reduced functioning for male and female veterans alike, and depression was the most important link in predicting lower satisfaction.

In addition, there was evidence for direct effects of military exposures on work and family quality of life. Again, some differences between males and females were found. For example, family stressors during deployment were directly associated with increased risk for parental impairment for female veterans, whereas for men the effect was only indirect through PTSD. These findings support the position that men and women may experience different military exposures and react in different ways. “This understanding of risk for reduced well-being, including the role of gender differences, may provide further important insight as to how to best cater post-military services to veterans’ unique needs following military service,” added Smith. “From a clinical perspective, these findings suggest that services aimed at addressing returning veterans’ reintegration into work and family life might pay particular attention to male and female veterans’ experiences while deployed, as well as their current mental health.”

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How fear can develop out of others’ traumas

What happens in the brain when we see other people experiencing a trauma or being subjected to pain? Well, the same regions that are involved when we feel pain ourselves are also activated when we observe other people who appear to be going through some painful experience. This is shown in a study from Karolinska Institutet in Sweden published in Nature Communications. But we are sensitive to different degrees to learning fear from other people and one explanation would appear to be found in the endogenous opioid system.

Seeing others express pain or anxiety can give us important information about things around us that are dangerous and should be avoided. Sometimes, however, we can develop fear of situations that, rationally speaking, are not dangerous. The opioid system is supposed to alleviate pain and fear but it does not work as effectively in all of us, which might be one of the reasons why some people develop anxiety syndrome merely by seeing others experience a trauma.

“Some people are over-sensitive to this form of social learning. Our study shows that the endogenous opioid system affects how sensitive we are and may explain why some people develop post-traumatic stress disorder (PTSD) merely by observing others who are experiencing traumatic events. After terror attacks, sensitive people might be afraid even if they themselves were not present,” says main author Jan Haaker, associated researcher at Karolinska Institutet’s Department of Clinical Neuroscience.

In a double-blind study, the researchers altered the brain’s internal chemistry in 22 healthy subjects by using a pharmaceutical substance to block the opioid system. 21 subjects were given an inactive placebo. The subjects then watched a video where other people were subjected to electric shocks.

The brain normally updates its knowledge of danger based on whether we are surprised, but when the opioid system was blocked, the people continued to react as if they were surprised even though they knew the electric shock would come. And the response was amplified even when they continued to watch other people being subjected to shocks. The response increased in regions of the brain such as the amygdala, the periaqueductal gray and the thalamus, which seems to indicate that the same functions as in self-perceived pain were involved. Communication also increased between these and other regions of the brain that were previously linked to the ability to understand other individuals’ experiences and thoughts.

“When the people participating in the experiment were themselves subjected to threatening stimuli that they had previously associated with other people’s pain, they perspired more and displayed more fear than those who had been given a placebo. This enhanced learning was even visible three days after the social learning episode,” says research team leader Andreas Olsson, senior lecturer at Karolinska Institutet’s Department of Clinical Neuroscience.

The study contributes to greater understanding of the psychology behind fear. The researchers hope that the new findings will eventually mean that people with anxiety conditions will be able to be given better, more individual-adapted clinical help.

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Emotional toll from mass trauma can disrupt children’s sense of competence

Traumatic events can have a profound effect on communities. Whether it is a terrorist attack or a natural disaster, such as a hurricane or tornado, the aftermath can have lasting effects, especially on children.

How children respond in the wake of mass traumatic events is related to their perceptions of competence — or how they view their ability to control a situation, said Carl Weems, professor and chair of human development and family studies at Iowa State University. An overwhelming challenge, such as a natural disaster, can disrupt the development of that sense of well-being.

In a paper published by the journal Applied Developmental Science, Weems and his colleagues evaluated perceptions of competence and symptoms of post-traumatic stress disorder in children and teens exposed to hurricanes Katrina and Gustav and the Deepwater Horizon oil spill. They found that children with higher levels of competence were overall more resilient and had fewer PTSD symptoms.

However, researchers found that competence and well-being declined for older youth, specifically between the ages of 8 to 12, following the oil spill. Weems says the findings do not explain why this is the case. He and his colleagues suspect older youth had a greater awareness, compared to younger children, of the oil spill’s impact on their family and community, which affected their well-being.

The damage from Hurricane Katrina was extensive and felt by everyone, regardless of age, said Weems, who lived in New Orleans at the time. Researchers characterized Hurricane Katrina as a traumatic event because it posed a direct threat to people’s lives. While the oil spill was devastating, it was different. Not as many lives were at risk and entire neighborhoods were not leveled as a result.

“The oil spill stress involved more family economic hardship. The impact was more subtle than Katrina,” Weems said. “That’s why we think we only saw an impact from the oil spill on older children because they understood what was happening to their family.”

In the paper, researchers explained that limited awareness of long-term consequences may have made it easier for younger children to rebound from the effect of the oil spill.

Differences based on gender

Age was not the only factor to influence PTSD symptoms. In the study, girls were more likely to have higher rates of PTSD symptoms following disasters. Weems says this highlights the importance of interventions to promote competence and well-being among girls.

Researchers analyzed data from youth in five parishes or counties in the Gulf Region directly affected by Hurricanes Katrina, Gustav and the oil spill. More than 3,300 youth — 55 percent girls — between the ages of 8 and 18 were included in the study. Researchers had access to youth screenings and data collected prior to and after all three disasters.

Perceptions of competence and well-being were assessed through questions about the participants’ relationships with their parents and friends, their ability to solve problems or respond in emergencies and control actions, as well as how they feel about life. Researchers used surveys to measure symptoms of PTSD, and hurricane and oil spill exposure.

Treatment and intervention

Whether it is a terrorist attack, hurricane, tornado or wildfire, a natural disaster can profoundly affect a community with little warning. Weems says understanding how children respond to these situations can help researchers build appropriate interventions. Helping children face their fears and develop coping mechanisms to deal with those fears can improve resiliency.

In previous studies, Weems and his colleagues surprisingly found kids who experienced Katrina had stable PTSD before Gustav, but a significant decrease in PTSD symptoms after hurricane Gustav, which occurred three years later. Part of the reason why may be related to the successful evacuations and the fact few lives were lost during Gustav as a result, Weems said. In a way, Gustav made them face their fear.

Weems explained that cognitive behavior therapy is based on this principle of facing your fears through “exposure” to similar events or situations, and is an effective intervention for youth experiencing difficulty after trauma. It teaches youth that they have the competence to cope.

“We think Gustav may have provided a large scale, relatively more positive exposure for many, because people evacuated and the negative effects were less compared to Katrina. This helped children to develop a sense of competence and self-efficacy,” Weems said.

“When intervening after a disaster — whether it’s a hurricane or a tornado — you want to help kids actively cope and not avoid dealing with the situation or their feelings about it. By helping them develop their own sense of competence and well-being in dealing with bad things, you’ll develop more resilient children and prevent long-lasting problems.”

Weems cautions against pushing children too far, but helping them face their fears in a safe way. He recommends cognitive behavior therapy for youth with more serious difficulties following a traumatic event or natural disaster.

Previous work by Weems and colleagues found that children watching Gustav-related TV coverage was associated with their PTSD symptoms post-Gustav. Subsequent analyses revealed the relationship between TV viewing and post-Gustav symptoms of PTSD was significant only for children who had high levels prior to the hurricane. Parents of children with anxiety disorders such as PTSD should recognize the potential effects of media, Weems said.

“Parents don’t necessarily need to keep their kids from watching the coverage, but it is best that they’re not glued to the TV,” he said. “Parents should limit viewing and process the information with their kids.”

Veterans with PTSD have an increased ‘fight or flight’ response

Young veterans with combat-related post-traumatic stress disorder (PTSD) have an increased ‘fight or flight’ response during mental stress, according to new findings published this week in the Journal of Physiology.

The team at Emory University School of Medicine, led by Dr Jeanie Park, believe that this contributes to the increased risk of high blood pressure and heart disease in PTSD patients.

PTSD is prevalent in both military and civilian populations. The lifetime prevalence of PTSD in US adults is 7.8% and around 14% in post-9/11 veterans. PTSD patients are known to have a higher risk for developing high blood pressure and cardiovascular disease.

The researchers also found that veterans with PTSD had higher adrenaline levels and less control of their heart rate in response to blood pressure changes. While previous studies have suggested that the sympathetic nervous system- the ‘fight or flight’ response- of veterans is overactive, this study was the first to measure this increased activity directly and provide a potential mechanism behind this response.

Dr Park and her team took these measurements while the participants experienced two types of mental stress. First-person war images and sounds shown through virtual reality goggles recreated mental stress related to PTSD. Mental arithmetic elicited mental stress un-related to PTSD.

They studied the physiology of post-9/11 veterans, 14 of whom had PTSD and 14 who did not. They measured blood pressure, performed an electrocardiogram (EKG), and recorded sympathetic nerve activity directly in real-time using electrodes placed inside a large nerve. This technique is called microneurography and is considered the gold-standard method for assessing sympathetic nervous system activity in humans.

Commenting on the study, Dr Park said: ‘To protect patients against high blood pressure and heart disease, we need to first understand how their physiology malfunctions. We can then identify potential treatments.’

‘This study looked specifically at veterans with combat-related PTSD, so the findings do not necessarily apply to non-veterans with PTSD, nor to patients with non-combat-related PTSD,’ she added.

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Afghanistan and Iraq veterans’ opioid use similar to that of civilians

Heavy rucksacks, parachuting out of helicopters, combat injuries, and stress result in chronic pain for many service members. In the United States, opioids are commonly prescribed to manage chronic pain, and overprescribing is a concern, particularly for veterans’ healthcare.

However, a new study published in Pain suggests that opioid use among Operation Enduring Freedom (OEF), Operation Iraqi Freedom (OIF), and Operation New Dawn (OND) veterans is roughly comparable to that of the general U.S. population.

“We found that use of opioids among OEF/OIF/OND veterans was characterized by use of moderate doses prescribed for fairly long periods of time,” said Teresa Hudson, Pharm.D., Ph.D., study author and research scientist at the Central Arkansas Veterans Healthcare System and University of Arkansas for Medical Sciences. “However, chronic use among this group of veterans appeared to be lower than that of veterans who served in other time periods.”

The first-of-its kind study looked at pharmacy claims data from the Veterans Health Administration and found that 23 percent of all OEF, OIF, and OND veterans were prescribed an opioid in a given year. Among veterans prescribed opioids, about two-thirds took them for short periods of time, and one-third took them chronically.

“Findings from this study suggest that opioid use patterns of OEF/OIF/and OND veterans are similar to those of the U.S. population and suggest that the opioid problem is not so much a VA problem, but rather, an American problem,” said Mark Edlund, M.D., Ph.D., study author and senior research scientist at RTI International.

The study found that PTSD, major depressive disorder, tobacco use, and rural residence were strongly associated with chronic opioid use. Pain severity also increased the odds of chronic pain use among Iraq and Afghanistan veterans.

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Orange essential oil may help alleviate post-traumatic stress disorder

About 8 percent of people will develop post-traumatic stress disorder at some point in their lives, according to the U.S. Department of Veterans Affairs, yet treatments for this debilitating condition remain limited. In a new study, mice exposed to orange essential oil after a stressful situation showed improvements in markers of stress and fear, suggesting essential oil may offer a nonpharmaceutical option to help alleviate PTSD.

Cassandra Moshfegh, research assistant in Paul Marvar’s laboratory at the George Washington University, will present the work at the American Physiological Society’s annual meeting during the Experimental Biology 2017 meeting, to be held April 22-26 in Chicago.

“Relative to pharmaceuticals, essential oils are much more economical and do not have adverse side effects,” said Moshfegh. “The orange essential plant oil showed a significant effect on the behavioral response in our study mice. This is promising, because it shows that passively inhaling this essential oil could potentially assuage PTSD symptoms in humans.”

Essential oils are aromatic compounds produced naturally by plants. Orange essential oil is typically extracted from the peel of the orange fruit. People use essential oils for therapeutic purposes by diffusing them into the air, applying them to the skin or ingesting them in foods or beverages.

The researchers tested the effects of orange essential oil using Pavlovian Fear conditioning, a behavioral mouse model used to study the formation, storage and expression of fear memories as a model for PTSD. Mice were exposed to the orange essential oil by passive inhalation 40 minutes before and after fear conditioning. Typically mice freeze in fear when they hear a certain audial tone later, a response that diminishes gradually over time.

Twelve mice received the tone by itself, 12 mice received water and fear conditioning, and 12 mice received an orange essential oil and fear conditioning. Mice exposed to orange essential oil by passive inhalation showed a significant reduction in freezing behavior and stopped freezing earlier than the water-exposed, fear-conditioned mice. They also showed significant differences in the types of immune cells present after fear conditioning. The immune system contributes to the inflammation associated with chronic stress and fear, so immune cells are a marker of the biochemical pathways involved in PTSD.

Preliminary results point to differences in the gene expression in the brain between the mice that were exposed to essential oil and those that were not, hinting at a potential mechanism to explain the behavioral results. Moshfegh said further studies would be needed to understand the specific effects of orange essential oil in the brain and nervous system and shed light on how these effects might help to reduce fear and stress in people with PTSD.

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Reduction of post-traumatic stress symptoms associated with noninvasive technology

A closed-loop acoustic stimulation brainwave technology significantly reduced symptoms in people suffering from post-traumatic stress in a small pilot study conducted at Wake Forest Baptist Medical Center. The study is published in the April 19 online edition of the journal BMC Psychiatry.

“The effects of chronic stress are killing people and the medical profession has not yet found an answer for how best to treat them,” said Charles H. Tegeler, M.D., professor of neurology at Wake Forest School of Medicine, a part of Wake Forest Baptist. “We believe there is a need for effective, non-invasive, non-drug therapies for symptoms of post-traumatic stress, which is why we conducted this trial.”

Nineteen volunteers who reported high scores on the Post-traumatic Stress Disorder Checklist, civilian version (PCL-C), a commonly used symptom inventory, were included in this single-site study. Of those, 18 completed an average of 16 sessions over a total of 16.5 days, with eight days of actual visits to the office, Tegeler said.

The intervention, high-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM), focused on the brain, which is the organ of central command for managing responses to threat and trauma. Participants received a series of HIRREM sessions in which brain electrical activity was monitored noninvasively at high spectral resolution with software algorithms translating selected brain frequencies into audible tones in real time. Those tones were reflected back to participants via ear buds in as little as four milliseconds, providing the brain an opportunity for self-optimization of its electrical pattern.

As a closed-loop neurotechnology, the process did not require any conscious, cognitive activity by the participant, who merely relaxed and listened to the tones.

“It’s as if the brain can look at itself in an acoustic mirror, recalibrate its patterns towards improved balance and reduced hyperarousal, and can relax,” Tegeler said. HIRREM was developed by Brain State Technologies based in Scottsdale, Arizona, and has been licensed to Wake Forest Baptist for collaborative research since 2011.

Participants completed the PCL-C, and 12 also had continuous recording of blood pressure and heart rate, before and after the intervention sessions. Changes in temporal lobe high frequency asymmetry were analyzed from baseline assessment through the first four sessions, and again for the last four sessions. Autonomic cardiovascular regulation was evaluated with analysis of heart rate variability and blood pressure modulation before and after the intervention.

After the sessions, 89 percent (16 of 18) of the participants reported clinically meaningful decreases in symptoms of post-traumatic stress as indicated by a change of at least 10 points from their baseline PCL-C score, Tegeler said. In the entire study group, the average reduction in the PCL-C score was 24 points. There were no adverse events reported.

There is ample scientific evidence that there is some brain asymmetry associated with chronic stress. This study is important because it also showed that there was improved balance in brain pattern activity and significant improvement in the autonomic nervous system function, as measured by heart rate variability and blood pressure modulation. All are relevant to a state of chronic stress, which now seems to affect so many people, Tegeler said.

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Common antibiotic may help to prevent or treat PTSD

The common antibiotic doxycycline can disrupt the formation of negative associations in the brain, according to new research from UCL and the University of Zurich.

The study, published in Molecular Psychiatry, was a pre-registered, placebo-controlled, double-blind randomised controlled trial in 76 healthy volunteers.

In the first session, participants were given either doxycycline or a placebo and learnt to associate a certain colour with an electric shock. A week later they were shown the colours again, accompanied by a loud sound but no shocks, and their fear responses were measured.*

The fear response was 60% lower in participants who had doxycycline in the first session compared to those who had the placebo, suggesting that the fear memory was significantly suppressed by the drug. Other cognitive measures including sensory memory and attention were not affected.

“When we talk about reducing fear memory, we are not talking about deleting the memory of what actually happened,” explains lead author Professor Dominik Bach (UCL Wellcome Centre for Neuroimaging, Max Planck UCL Centre for Computational Psychiatry and Ageing Research and University of Zurich Division of Clinical Psychiatry Research). “The participants may not forget that they received a shock when the screen was red, but they ‘forget’ to be instinctively scared when they next see a red screen. Learning to fear threats is an important ability for any organism, helping us to avoid dangers such as predators. Over-prediction of threat, however, can cause tremendous suffering and distress in anxiety disorders such as PTSD.”

Post-traumatic stress disorder (PTSD) is a term for a broad range of psychological symptoms that can develop after someone experiences or witnesses a traumatic event. PTSD is caused by an overactive fear memory, and the new research shows that doxycycline can reduce the fear memory response in healthy volunteers.

“We have demonstrated a proof-of-principle for an entirely new treatment strategy for PTSD,” explains Professor Bach. “The theory is based on the recent discovery that our brains need proteins outside nerve cells, called matrix enzymes, to form memories. Matrix enzymes are found throughout the body, and their over-activity is involved in certain immune diseases and cancers. To treat such diseases, we already have clinically approved drugs that block these enzymes, including the antibiotic doxycycline, so we wanted to see if they could help to prevent fear memories from forming in the brain. Our results support this theory, opening up an exciting avenue of research that might help us to find treatments for PTSD.

“Using drugs to prevent PTSD would be challenging, since in the real world we don’t know when a traumatic event is about to occur. However, there is growing evidence that people’s memories and associations can be changed after the event when they experience or imagine similar situations. This is called ‘reconsolidation’, and we now plan to test the effect of doxycycline on reconsolidation of fear memories. If this is successful, we would hope to apply the technique to more clinically realistic models of PTSD within a few years.”

*In the first session, participants were given either doxycycline or a placebo and put in front of a computer. The screen would flash either blue or red, and one of the colours was associated with a 50% chance of receiving a painful electric shock. This happened 160 times, with the colours appearing in random order, so that participants learnt to associate the ‘bad’ colour with the shock.

A week later, under no medication, participants returned to repeat the experiment. This time there were no electric shocks, but a loud sound played after either colour was shown. Participants’ fear responses were measured by tracking their eye blinks, as this is an instinctive response to sudden threats. The fear memory response was calculated by subtracting the baseline startle response — the response to the sound on the ‘good’ colour — from the response to the sound when the ‘bad’ colour was showing.

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Disrupted brain pathway, altered stress hormones key to TBI impact differences in men, women

The brains of men and women are wired differently, and when it comes to traumatic brain injuries (TBI), women are more likely to develop subsequent neuropsychiatric disorders, like anxiety, depression and post-traumatic stress disorder. Until now, it’s been unclear why that is, but a new study by researchers at the Uniformed Services University of the Health Sciences (USU) provides that missing link — a potentially disrupted pathway in the brain.

The study, “Sex-dependent effects of mild brain blast injury on neuroendocrine stress response,” was funded by the Center for Neuroscience and Regenerative Medicine at USU. The findings will be presented at the upcoming Endocrine Society’s annual meeting by lead author Ashley Russell, a Neuroscience PhD candidate in the F. Edward Hebert School of Medicine at USU, and USU research assistant Elizabeth Shupe.

Almost every tissue in the body is affected by the interaction between the nervous and endocrine systems. They produce the hormones that regulate sleep, mood and metabolism. USU researchers, in collaboration with colleagues at Colorado State University, sought to better understand why it is that blast brain injuries have a different impact on women and men, specifically in the neuroendocrine system. They conducted hormonal, behavioral and anatomical studies measuring the integrity of the body’s major neuroendocrine system, the hypothalamic-pituitary-adrenal (HPA) axis. They found that a mild TBI can disrupt that system, and that alteration of stress hormones correlated with an increase in anxiety-like behavior in a sex-dependent manner. The researchers believe that uncovering the basic underlying neuroendocrine dysregulation will ultimately allow for better treatments.

Every year, about 1.5 million individuals are diagnosed with TBI, and in the military, blast brain injury is the most prevalent as a result of explosive devices used in modern warfare.

“Currently, there are no therapeutic measures to mitigate the effects of subsequent neuropsychiatric disorders after a TBI. However, these findings allow us to see how a mild TBI injury can disrupt the neuroendocrine system, which hopefully will lead to better treatment modalities and better support for our warfighters,” Russell said.

She added that these findings could also translate to other forms of TBI that may occur from a car accident or sports injury.

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Refugees with PTSD regulate stress differently

New Michigan State University research has found that refugees diagnosed with post-traumatic stress disorder regulate stress differently than those who don’t have the disorder, but may have experienced similar suffering.

PTSD is a mental health disorder that makes a person re-experience a traumatic event.

“What we discovered was that a gene associated with a person’s mental health became overactive in refugees with PTSD and wasn’t able to respond the right way when working with the body’s stress defense system,” said Bengt Arnetz, a professor of family medicine who led the study.

The methyl CpG binding protein 2 gene, or MECP2, helps control the normal function of nerve cells and plays an important role in mental health and the body’s ability to handle stress.

An individual’s stress defense system, known as the hypothalamic pituitary adrenocortical axis, or HPA, is activated when he or she is exposed to mental pressure or trauma and then calms down when the event is over. In refugees with PTSD, this built-in security system doesn’t respond correctly and continues to overreact.

The findings are being presented at the American Psychosomatic Society’s annual meeting on March 18.

It’s estimated that up to a quarter of the refugees entering the United States have PTSD.

“Often times, those who come to the U.S. in search of a better life have been exposed to severe stress in one way or another,” Arnetz said. “Some of this trauma can include coping with poor environmental conditions for many years and even violent situations as a result of war.”

The federally funded study looked at 66 male and female refugees from Syria who had arrived in the United States within a month’s time. Each were interviewed and given a validated medical survey to determine if they had PTSD.

The survey, known as the PTSD Checklist-Civilian included questions on socioeconomics, exposure to trauma, as well as symptoms associated with the disorder. Refugees with scores above 30 were classified as having PTSD and were compared to those with lower scores.

Researchers also took blood samples from study participants in order to analyze the MECP2 gene activity.

Arnetz said his findings provide important information that will help advance this type of research and assist individuals who are focused on aiding refugees once they arrive.

“Because refugees have typically experienced terrible environmental factors such as air pollution, as well as severe violence and trauma, it’s important to study the impact of these things on the brain and body’s physiology in order to optimize the health, well being and social integration of this population,” he said.

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PTSD risk can be predicted by hormone levels prior to deployment, study says

Up to 20 percent of U.S. veterans who served in Iraq and Afghanistan developed symptoms of post-traumatic stress disorder from trauma experienced during wartime, but new neuroscience research from The University of Texas at Austin suggests some soldiers might have a hormonal predisposition to experience such stress-related disorders.

Cortisol — the stress hormone — is released as part of the body’s flight-or-fight response to life-threatening emergencies. Seminal research in the 1980s connected abnormal cortisol levels to an increased risk for PTSD, but three decades of subsequent research produced a mixed bag of findings, dampening enthusiasm for the role of cortisol as a primary cause of PTSD.

However, new findings published in the journal Psychoneuroendocrinology point to cortisol’s critical role in the emergence of PTSD, but only when levels of testosterone — one of most important of the male sex hormones — are suppressed, researchers said.

“Recent evidence points to testosterone’s suppression of cortisol activity, and vice versa. It is becoming clear to many researchers that you can’t understand the effects of one without simultaneously monitoring the activity of the other,” said UT Austin professor of psychology Robert Josephs, the first author of the study. “Prior attempts to link PTSD to cortisol may have failed because the powerful effect that testosterone has on the hormonal regulation of stress was not taken into account.”

UT Austin researchers used hormone data obtained from saliva samples of 120 U.S. soldiers before deployment and tracked their monthly combat experiences in Iraq to examine the effects of traumatic war-zone stressors and PTSD symptoms over time.

Before deployment, soldiers’ stress responses were tested in a stressful CO2 inhalation challenge. “Healthy stress responses showed a strong cortisol increase in response to the stressor, whereas abnormal stress responses showed a blunted, nonresponsive change in cortisol,” Josephs said.

The researchers found that soldiers who had an abnormal cortisol response to the CO2 inhalation challenge were more likely to develop PTSD from war-zone stress. However, soldiers who had an elevated testosterone response to the CO2 inhalation challenge were not likely to develop PTSD, regardless of the soldiers’ cortisol response.

“The means through which hormones contribute to the development of PTSD and other forms of stress-related mental illness are complex,” said Adam Cobb, a UT Austin clinical psychology doctoral candidate and co-author of the study. “Advancement in this area must involve examining how hormones function together, and with other psychobiological systems, in response to ever-changing environmental demands.”

Knowing this, the scientists suggest future research could investigate the efficacy of preventative interventions targeting those with at-risk profiles of hormone stress reactivity. “We are still analyzing more data from this project, which we hope will reveal additional insights into risk for combat-related stress disorders and ultimately how to prevent them,” said Michael Telch, clinical psychology professor and corresponding author of the study.

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Materials provided by University of Texas at Austin. Note: Content may be edited for style and length.