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Stress

Linda Van Aelst. Photo from CSHL

By Daniel Dunaief

Different people respond to the same level of stress in a variety of ways. For some, a rainy Tuesday that cancels a picnic can be a minor inconvenience that interrupts a plan, while others might find such a disruption almost completely intolerable, developing a feeling of helplessness.

Scientists and clinicians have been working from a variety of perspectives to determine the cause of these different responses to stress.

From left, graduate student Nick Gallo, Linda Van Aelst and Postdoctoral Researcher Minghui Wang. Photo by Shanu George

Cold Spring Harbor Laboratory Professor Linda Van Aelst and a post doctoral researcher in her lab, Minghui Wang, recently published a collaborative work that also included graduate student Nicholas Gallo, postdoctoral researcher Yilin Tai and Professor Bo Li in the journal Neuron that focused on the gene Oligophrenin-1, which is also implicated in intellectual disability.

As with most X-linked diseases, the OPHN1 mutation primarily affects boys, who have a single X chromosome and a Y chromosome. Girls have two X chromosomes, giving them a backup gene to overcome the effect of an X-linked mutation.

In addition to cognitive difficulties, people with a mutation in this gene also develop behavioral challenges, including difficulty responding to stress.

In a mouse model, Wang and Van Aelst showed that the effect of mutations in this gene mirrored the stress response for humans. Additionally, they showed that rescuing the phenotype enabled the mouse to respond more effectively to stress.

“For me and [Wang], it’s very exciting,” Van Aelst said. “We came up with this mouse model” and with ways to counteract the effect of this mutated analogous gene.

As with many other neurological and biological systems, Oligophrenin1 is involved in a balancing act in the brain, creating the right mix of excitation and inhibition.

When oligophrenin1 was removed from the prelimbic region of the medical prefrontal cortex, a specific brain area that influences behavioral responses and emotion, mice expressed depression-like helpless behaviors in response to stress. They then uncovered two brain cell types critical for such behavior: the inhibitory neurons and excitatory pyramidal neurons. The excitatory neurons integrate many signals to determine the activity levels in the medial prefrontal cortex.

The inhibitory neurons, meanwhile, dampen the excitatory signal so they don’t fire too much. Deleting oligophrenin1 leads to a decrease in these inhibitory neurons, which Van Aelst found resulted from elevated activity of a protein called Rho kinase.

“The inhibitor keeps the excitatory neurons in check,” Van Aelst said. “If you have a silencing of the inhibitory neurons, you’re going to have too much excitatory response. We know that contributes to this maladaptive behavior.”

Indeed, Wang and Van Aelst can put their metaphorical finger on the scale, restoring the balance between excitation and inhibition with three different techniques.

The scientists used an inhibitor specific for a RhoA kinase, which mimicked the effect of the missing Oligophrenin1. They also used a drug that had the same effect as oligophrenin1, reducing excess pyramidal neuron activity. A third drug activated interneurons that inhibited pyramidal neurons, which also restored the missing inhibitory signal. All three agents reversed the helpless phenotype completely.

Japanese doctors have used the Rho-kinase inhibitor fasudil to treat cerebral vasospasm. which Van Aelst said does not appear to produce major adverse side effects. It could be a “promising drug for the stress-related behavioral problems” of oligophrenin1 patients, Van Aelst explained in an email. “It has not been described for people with intellectual disabilities and who also suffer from high levels of stress.”

From left, graduate student Nick Gallo, Linda Van Aelst and Postdoctoral Researcher Minghui Wang. Photo by Shanu George

Van Aelst said she has been studying this gene for several years. Initially, she found that it is a regulator of rho proteins and has linked it to a form of intellectual disability. People with a mutation in this gene had a deficit in cognitive function that affected learning and memory.

From other studies, scientists learned that people who had this mutation also had behavioral problems, such as struggling with stressful situations.

People with intellectual difficulties have a range of stressors that include issues related to controlling their environment, such as making decisions about the clothing they wear or the food they eat.

“People underestimate how many [others] with intellectual disabilities suffer with behavioral problems in response to stress,” Van Aelst said. “They are way more exposed to stress than the general population.”

Van Aelst said she and Wang focused on this gene in connection with a stress response.

Van Aelst wanted to study the underlying cellular and molecular mechanism that might link the loss of function of oligophrenin1 with the behavioral response to stress.

At this point, Van Aelst hasn’t yet studied how the mutation in this gene might affect stress hormones, like cortisol, which typically increase when people or mice are experiencing discomfort related to stress. She plans to explore that linkage in future studies.

Van Aelst also plans to look at some other genes that have shown mutations in people who battle depression or other stress-related conditions. She hopes to explore a genetic link in the brain’s circuitry to see if they can “extend the findings.” She would also like to connect with clinicians who are studying depression among the population with intellectual disabilities. Prevalence studies estimate that 10 to 50 percent of individuals with intellectual disability have some level of behavioral problems and/or mood disorders.

Reflecting the reality of the modern world, in which people with various conditions or diseases can sequence the genes of their relatives, Van Aelst said some families have contacted her because their children have mutations in oligophrenin1.

“It’s always a bit tricky,” she said. “I don’t want to advise them yet” without any clinical studies.

A resident of Huntington, Van Aelst arrived at CSHL in the summer of 1993 as a post doctoral researcher in the lab of Michael Wigler. She met Wigler when he was giving a talk in Spain.

After her post doctoral research ended, she had planned to return to her native Belgium, but James Watson, who was then the president of the lab, convinced her to stay.

Outside of work, Van Aelst enjoys hiking, swimming and running. Van Aelst speaks Flemish, which is the same as Dutch, French, English and a “bit of German.” 

She is hopeful that this work may eventually lead to ways to provide a clinical benefit to those people with intellectual disabilities who might be suffering from stress disorders.

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There is a lot of stress in our lives these days. Stress envelops us. One man I know complained that even in his home, he does not feel stress free. When he puts on the television or radio, the now-commonplace partisan viewpoints surround him. And that is the least of it. The horrific shooting in a Pittsburgh synagogue, pipe bombs sent to at least 15 different targets perceived to be Democratic in nature throughout the United States, the shooting at a school in North Carolina and more make up some of the news just this past week. There seems to be no escape. Even conversation with customers or spouses inevitably touches on the daily stressful events.

Surely there have been times of even greater stress in our country. World War II comes immediately to mind. The Cold War, with regular air raids, was another. The Cuban Missile Crisis was yet another. But these were all threats from outside: from the Nazis, the Japanese, the Soviet Union. The stress today, whether rhetorical or physical, is domestic and aimed by Americans against other Americans. Worst of all, as political partisans denigrate opponents and gun violence becomes tragically routine, there doesn’t seem to be an end in sight.

Can we learn to manage the stress in our lives? The Harvard Women’s Health Watch advises that we can. In the August issue, published by a division of Harvard Medical School, physicians offer some information about stress and its effects. They also give some suggestions for coping with stress.

First the information. “It’s not uncommon to feel disorganized and forgetful when you’re under a lot of stress,” the article, “Protect your brain from stress,” explained. “But over the long term, stress may actually change your brain in ways that affect your memory.” Because stress can influence how the brain functions, including not only memory but also mood and anxiety, it can cause inflammation. This in turn can affect heart health. Thus stress has been associated with multiple chronic diseases of the brain and heart, according to Harvard physicians.

The brain is not just a single unit but a group of different parts that perform different tasks, according to the Harvard article. When one part is engaged, researchers believe that other parts may not have as much energy for their specialized functions. One example is if you are in a dangerous situation, the amygdala section takes over to ensure survival, while the energy level in parts having to do with memory or higher-order tasks recedes. Hence you might be more forgetful when stressed.

“There is evidence that chronic (persistent) stress may actually rewire your brain,” according to the research, as if exercising one section makes it stronger while other sections, like that having to do with more complex thought, take “a back seat.” Such brain changes may be reversible.

There are various kinds of stress. For example, one feels differently before taking a big test compared with that experienced in a car accident. More stress is worse, and long-term stress is generally worse than short-term stress, according to the physicians. Unpredictable stress is worse than stress that can be anticipated. Chronic stress can be more challenging than one that will end shortly. Feeling supported by others most likely mitigates stress effects.

So here is some advice from the Harvard publication on how to cope with stress. Establish some control over your situation such as by setting a routine. Get organized. Get a good night’s sleep — hard to do when stressed but going to bed and waking up at the same time each day helps, as does avoiding caffeine and creating a relaxing sleep environment. Get help, sooner rather than later. And try to change your attitude toward stress by striving for healthier responses to stress. Use its effects, if you can, to high power you to a goal. Like voting.

And I say, turn off the television and the instant news briefs on your cellphone for some quiet time each day.

United States Army Staff Sgt. Allen Pennington and Warrior Ranch Foundation Vice President Tony Simonetti spend time with Pennington’s horse Red. Photo from Warrior Ranch Foundation

When Marine Corps veteran StaceyAnn Castro first stepped into the round pen with a horse at Warrior Ranch Foundation, her guard was up.

Castro, who served in Operation Enduring Freedom from 2002 to 2004, and admittedly struggles with post-traumatic stress disorder, was face to face with a 1,400-pound Friesian horse named BlackJack during a July demonstration by the Mount Sinai and Islip-based nonprofit, which pairs military and first-responder veterans with rescue horses in need of rehabilitation and training.

Marine Corps veteran StaceyAnn Castro bonds with
Vet therapy: Mount Sinai’s Warrior Ranch helps heal
her horse BlackJack. Photo from Warrior Ranch
Foundation

The tough-as-nails veteran was attempting to engage BlackJack in basic ground exercises, but the horse was not budging. Its guard was up too.

“I soon realized it was because I was terrified of him,” Castro later said. “When you’re with these horses they feel everything you’re feeling, even the emotions you think you’re hiding from everybody else. You can’t hide them from a horse.”

Castro relaxed, and as she calmed down, so did BlackJack. The horse began to lick and chew — a reflex associated with the animal’s release of stress.

“By the end of the session, I wound up with a friend,” she said of BlackJack. “With the horses, you have someone you’re actually bonding with in your own private, silent language. It’s beautiful.”

Officially incorporated in June 2016, the Warrior Ranch Foundation has helped reduce the stress levels and PTSD symptoms of more than a dozen veterans still recuperating from a wide range of conflicts — from the Korean War to Vietnam War to the war in Afghanistan — by teaching them how to groom, feed and train troubled horses. And much like the veterans, the nine residential horses, mostly retired race and show animals that have been trained their whole lives to compete and perform in high-stakes settings, are learning to adapt to a new, more relaxed world.

Cathie Doherty spends time with horse Cody.
Photo from Warrior Ranch Foundation

“There’s a strong parallel between them and it’s amazing to see their emotional breakthroughs,” said Eileen Shanahan, the nonprofit’s founder and president. “While the race horses are trained to run, run, run, and as a result have emotional issues, the veterans are trained to go out there and do the best they can to protect and defend us. When they come back, they have to shut that off and that’s not so easy. We provide a safe haven for these humans and animals.”

Shanahan’s organization is the result of her lifelong love of country and horses. The Queens native, who shoots and produces television programs and commercials for a living, comes from a large military family with a father who served in the Marines, an uncle and brother in the Navy, nephews in the Army, as well as several first responders.

Although she mostly rode buses and subways growing up, Shanahan always admired horses from afar, seeing them as beautiful creatures.

When she got married and moved to East Quogue in the 1980s, she took up horseback riding and, 15 years ago, began adopting rescue horses and studying natural horsemanship — a variety of rapport-based horse training techniques.

United States Army Staff Sgt. Allen
Pennington with horse Red. Photo
from Warrior Ranch Foundation

For nearly a decade, she dreamt of providing this outlet for local veterans and finally launched it with the help of longtime friends and equestrians specialists. While the group currently works out of two private barns, the future plan is to turn Warrior Ranch into a national organization.

“We want to eventually help hundreds of veterans and horses because it really works,” Shanahan said, explaining that interactions like Castro’s is very common at the ranch. “A lot of times when they come here, the veterans have their arms crossed, but by the end of the day, they have ear-to-ear grins. A lot of them break down and cry and it’s so powerful to watch.”

Tony Simonetti, Warrior Ranch’s vice president and top horse trainer, has made a career of rehabilitating emotionally distraught horses and re-interacting them with their human counterparts, resolving more than 500 extremely difficult horse cases for people across the country. When asked his most memorable veteran-horse interaction within the organization, he talked about Army Staff Sergeant Allen Pennington, Warrior Ranch’s first soldier to go through the program, and Red, a 4-year-old, retired race thoroughbred.

“[Allen’s] this big, rough and tough guy, and when the horse connected with him, I just saw all the stress he was holding inside bubble right up through his chest and then he just couldn’t keep himself composed,” Simonetti said. “He broke down and turned around and hugged that horse like it was his battle buddy. And I told him, ‘don’t feel bad about that. That’s what you’re here for.’”

During a testimonial on the Warrior Ranch website, Navy veteran Cathie Doherty, who was diagnosed with PTSD and put on medication for a number of years, said she was grateful to have attended a women veteran’s retreat at the nonprofit.

United States Army Staff Sgt. Allen
Pennington with horse Red. Photo
from Warrior Ranch Foundation

“It was really an amazing experience,” Doherty said. “I think it touched me much deeper than I imagined it would. I appreciated working with the horses and that I had to make a connection with them. I feel I was present in the moment. I didn’t care about my phone, I didn’t care what was going on around me. It was a beautiful experience for me.”

Castro said companionship with a horse might be more beneficial than a human’s.

“When you’re a veteran and you’re having a bad day, you don’t want to tell anybody, you don’t want to talk about it — you want to forget about it,” she said. “But I also don’t want to be alone and, so, when you’re there with the horse, and that horse knows what you’re going through and feeling, he feels it too. And because you love the horse and you don’t want the horse to feel that way, you’re going to try and make yourself feel better. It’s awe-inspiring.”

U.S. Rep. Lee Zeldin (R-Shirley), who served four years in the Army, visited the ranch in Mount Sinai with his family Oct. 7 and saw firsthand the value of the nonprofit.

“It doesn’t take more than a few minutes to see the positive effects that you’re having on these horses, and from these horses the veterans are getting love that they possibly have never experienced
before,” Zeldin said. “In a way, you’re directly coping with the symptoms of PTSD while also productively escaping the worst of it. It’s a great concept and I’d love to see Warrior Ranch grow into something a whole lot bigger than it already is.”

U.S. Rep. Lee Zeldin, fifth from left, meets with members of the Warrior Ranch Foundation. Photo from Warrior Ranch Foundation

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By David Dunaief

Now that spring has sprung, the pace of life tends become more hectic. Although some stress is valuable to help motivate us and keep our minds sharp, high levels of constant stress can have detrimental effects on the body.
It is very likely that there is a mind-body connection when it comes to stress. In other words, it may start in the mind, but it can lead to acute or chronic disease promotion. Stress can also play a role with your emotions, causing irritability and outbursts of anger, and possibly leading to depression and anxiety. Stress symptoms are hard to distinguish from other disorders but can include stiff neck, headaches, stomach upset and difficulty sleeping. Stress may also be associated with cardiovascular disease, with an increased susceptibility to infection from viruses causing the common cold and with cognitive decline and Alzheimer’s (1).
A stress steroid hormone called cortisol is released from the adrenal glands and can have beneficial effects in small bursts. We need cortisol in order to survive. Some of cortisol’s functions include raising the glucose (sugar) levels when they are low and helping reduce inflammation and stress levels (2). However, when cortisol gets out of hand, higher chronic levels may cause inflammation, leading to disorders such as cardiovascular disease, as recent research suggests. Let’s look at the evidence.

Inflammation
Inflammation may be a significant contributor to more than 80 percent of chronic diseases, so it should be no surprise that inflammation is an important factor with stress. In a recent meta-analysis (a group of two observational studies), high levels of C-reactive protein, a biomarker for inflammation, were associated with increased psychological stress (3).
What is the importance of CRP? It may be related to heart disease and heart attacks. This study involved over 73,000 adults who had their CRP levels tested. The research went further to suggest that increased levels of CRP may result in more stress and also depression. With CRP higher than 3.0 there was a greater than twofold increase depression risk. The researchers suggest that CRP may heighten stress and depression risk by increasing levels of different proinflammatory cytokines, inflammatory communicators among cells (4).
In one recent study, results suggested that stress may influence and increase the number of hematopoietic stem cells (those that develop of all forms of blood cells), resulting in specifically an increase in inflammatory white blood cells (5). The researchers suggest that this may lead to these white blood cells accumulating in atherosclerotic plaques in the arteries, which ultimately could potentially increase the risk of heart attacks and strokes. Chronic stress overactivates the sympathetic nervous system — our “fight or flight” response — which may alter the bone marrow where the stem cells are found. This research is preliminary and needs well-controlled trials to confirm these results.

Infection
Stress may increase the risk of colds and infection. Cortisol over the short term is important to help suppress the symptoms of colds, such as sneezing, cough and fever. These are visible signs of the immune system’s infection-fighting response. However, the body may become resistant to the effects of cortisol, similar to how a type 2 diabetes patient becomes resistant to insulin. In one study of 296 healthy individuals, participants who had stressful events and were then exposed to viruses had a higher probability of catching a cold. It turns out that these individuals also had resistance to the effects of cortisol. This is important because those who were resistant to cortisol had more cold symptoms and more proinflammatory cytokines (6).

Cortisol
When we measure cortisol levels, we tend to test the saliva or the blood. However, these laboratory findings only give one point in time. Thus, when trying to determine if raised cortisol may increase cardiovascular risk, the results are mixed. However, in a recent study, measuring cortisol levels from scalp hair was far more effective (7). The reason for this is that scalp hair grows slowly, and therefore it may contain three months’ worth of cortisol levels. The study showed that those in the highest quartile of cortisol levels were at a three-times increased risk of developing diabetes and/or heart disease compared to those in the lowest quartile. This study involved older patients between the ages of 65 and 85.

Lifestyle and the Cellular Level
Lifestyle plays an important role in stress at the cellular level, specifically at the level of the telomere, which determines cell survival. The telomeres are to cells as the plastic tips are to shoelaces; they prevent them from falling apart. The longer the telomere, the slower the cell ages and the longer it survives. In a recent study, those women who followed a healthy lifestyle — one standard deviation over the average lifestyle — were able to withstand life stressors better since they had longer telomeres (8).
This healthy lifestyle included regular exercise, a healthy diet and a sufficient amount of sleep. On the other hand, the researchers indicated that those who had poor lifestyle habits lost substantially more telomere length than the healthy lifestyle group. The study followed women 50 to 65 years old over a one-year period.
In another study, chronic stress and poor diet (high sugar and high fat) together increased metabolic risks, such as insulin resistance, oxidative stress and central obesity, more than a low-stress group eating a similar diet (9). The high-stress group was caregivers, specifically those caring for a spouse or parent with dementia. Thus, it is especially important to eat a healthy diet when under stress.
Interestingly, in terms of sleep, the Evolution of Pathways to Insomnia Cohort study shows that those who deal with stressful events directly are more likely to have good sleep quality. Using medication, alcohol or, most surprisingly, distractors to address stress all resulted in insomnia after being followed for one year (10). Cognitive intrusions or repeat thoughts about the stressor also resulted in insomnia.
Psychologists and other health care providers sometimes suggest distraction from a stressful event, such as television watching or other activities, according to the researchers. However, this study suggests that this may not help avert chronic insomnia induced by a stressful event. The most important message from this study is that how a person reacts and deals with a stressors may determine whether they suffer from insomnia.

Constant stress is something that needs to be recognized. If not addressed, it can lead to suppressed immune response or increased levels of inflammation. CRP is an example of an inflammatory biomarker that may actually increase stress. In order to address chronic stress and lower CRP, it is important to adopt a healthy lifestyle that includes sleep, exercise and diet modifications. A good lifestyle may be protective against cell aging when exposed to stressors.

References:
(1) Curr Top Behav Neurosci. 2014 Aug. 29. (2) Am J Physiol. 1991;260(6 Part 1):E927-E932. (3) JAMA Psychiatry. 2013;70:176-184. (4) Chest. 2000;118:503-508. (5) Nat Med. 2014;20:754-758. (6) Proc Natl Acad Sci U S A. 2012;109:5995-5999. (7) J Clin Endocrinol Metab. 2013;98:2078-2083. (8) Mol Psychiatry Online. 2014 July 29. (9) Psychoneuroendocrinol Online. 2014 April 12. (10) Sleep. 2014;37:1199-1208.

Dr. Dunaief is a speaker, author and local lifestyle medicine physician focusing on the integration of medicine, nutrition, fitness and stress management.  For further information, go to the website www.medicalcompassmd.com and/or consult your personal physician.