In the Blogs: Stressed? This Dog May Help

By Michele Hollow 

Each morning, Cali, an 18-month-old Rhodesian Ridgeback, patiently waits for the K-12 students to pass through the doors of the Calais School in Whippany, N. J. As they walk by, Cali sniffs each one.

The students, about 85 in all, smile at the short-haired dog but know not to pet or distract her while she is working. Cali is a cortisol detection dog, trained to detect the stress hormone our adrenal glands secrete when we become anxious or stressed.

When we are agitated, cortisol levels in our bloodstream rise. It’s Cali’s job to let Casey Butler, her handler, know if a student’s cortisol levels are high. If they are, that student spends time talking with Ms. Butler and Cali to help defuse the stress. “The children feel safer with Cali around,” she explained. “They tend to open up more.”

Cali’s signals are so subtle that the students and other teachers waiting nearby rarely notice. But Ms. Butler, 25, pays close attention to see if Cali points with her nose and stares at a child.

Many of the students at Calais are on the autism spectrum; some have attention deficit disorder, oppositional defiant disorder and other challenges that can trigger anxiety and other difficult emotions.

Like most service dogs, Cali is extremely quiet and unassuming. “The students don’t like it when a dog jumps on them,” explained Ms. Butler, a health teacher who is a certified specialist in natural canine behavior rehabilitation and in animal adaptive therapy.

Cali was brought to the school last year from a local nonprofit called Merlin’s Kids that trains service dogs to work with special-needs children. “Some schools with a special-needs population have service dogs that visit and work with the students as a once-in-a-while activity,” said David Leitner, executive director of the Calais School. “We thought having a service dog on staff would benefit our students.”

It was a decision that was presented to the teachers and staff at the school, and met without opposition. “A lot of us know people with service dogs, and we have seen how beneficial they are,” said Diane Manno, the principal at Calais. “And in just a short time, we have seen how Cali has helped our students.”

When Cali spots an anxious student, and Ms. Butler asks the student whether he or she is feeling stressed, the typical response is “I’m O.K.” Ms. Butler counters by saying, “Cali told me otherwise.”

“They listen to her because Cali is nonthreatening, and they like being around her,” Ms. Butler said.

A ninth grader agreed. “Cali can help us cope with our problems so that we don’t have to get through it by ourselves,” she said. “She is loving, intuitive and goofy.”

A few weeks ago, in Ms. Butler’s office, Cali started pacing, alternately moving toward the door and nudging Ms. Butler. “She led me up one flight of stairs to the opposite end of the building, where we found a girl starting to have a meltdown,” she said.

Noticing Cali, the student asked if she could pet her. Ms. Butler told her not yet. “I first make sure Cali is safe,” she said. “Within a few minutes of seeing Cali, the student calmed down.” Only then does she reward students by letting them pet, brush and — sometimes — walk Cali.

It’s their uncanny sense of smell that allows dogs like Cali to detect rising cortisol levels in our sweat or breath, and identify a student having trouble even in a faraway classroom, said Nicholas Dodman, director of the Animal Behavior Clinic at Cummings School of Veterinary Medicine at Tufts University. “Humans have 12 million smell receptors in their nose. At the lowest estimate, dogs have 800 million. Scent hounds like beagles and bassets have up to four billion. A dog’s ability to smell odors is beyond our comprehension.”

“We are proud of ourselves when we drive past Burger King and can smell that they are cooking burgers,” he said. “Dogs can smell a burger being cooked in the next town. That is why dogs are used to detect melanomas, diabetes and other types of disease. It’s all about the sense of smell.”

Cali can also detect when a student is faking. “I’ve had students come into my office saying they don’t feel well,” Ms. Butler said. “It’s not uncommon for a student to want to miss a class or a test. If Cali doesn’t signal when she sniffs them, I send them back to the classroom.”

At the end of the school day, the students board the buses back home, and Cali goes home with Ms. Butler. In a few weeks a second service dog will join the crew, a beagle named Cleo, an occupational and speech therapy dog. The students will work with Cleo to improve their fine motor skills by opening and closing the buttons and snaps on her harness, and will practice their oral and social skills by reading to her.

The students are eagerly standing by.

In the News: Effects of Stress On Brain Cells Offer Clues to New Anti-Depressant Drugs

Structure of protein SGK1.Based on PyMOL rendering of PDB 2R5T.

May 6, 2013 in Neuroscience

Research from King's College London reveals the detailed mechanism behind how stress hormones reduce the number of new brain cells - a process considered to be linked to depression. The researchers identified a key protein responsible for the long-term detrimental effect of stress on cells, and importantly, successfully used a drug compound to block this effect, offering a potential new avenue for drug discovery.

The study, published in Proceedings of the National Academy of Sciences (PNAS) was co-funded by the National Institute for Health Research Biomedical Research Centre (NIHR BRC) for Mental Health at the South London and Maudsley NHS Foundation Trust and King's College London.

Depression affects approximately 1 in 5 people in the UK at some point in their lives. The World Health Organisation estimate that by 2030, depression will be the leading cause of the global burden of disease. Treatment for depression involves either medication or talking therapy, or usually a combination of both.

Current antidepressant medication is successful in treating depression in about 50-65% of cases, highlighting the need for new, more effective treatments.

Depression and successful antidepressant treatment are associated with changes in a process called "neurogenesis"- the ability of the adult brain to continue to produce new brain cells. At a molecular level, stress is known to increase levels of cortisol (a stress hormone) which in turn acts on a receptor called the glucocorticoid receptor (GR). However, the exact mechanism explaining how the GR decreases neurogenesis in the brain has remained unclear.

Professor Carmine Pariante, from King's College London's Institute of Psychiatry and lead author of the paper, says: "With as much as half of all depressed patients failing to improve with currently available medications, developing new, more effective antidepressants is an important priority. In order to do this, we need to understand the abnormal mechanisms that we can target. Our study shows the importance of conducting research on cellular models, animal models and clinical samples, all under one roof in order to better facilitate the translation of laboratory findings to patient benefit."

In this study, the multidisciplinary team of researchers studied cellular and animal models before confirming their findings in human blood samples. First, the researchers studied human hippocampal stem cells, which are the source of new cells in the human brain. They gave the cells cortisol to measure the effect on neurogenesis and found that a protein called SGK1 was important in mediating the effects of stress hormones on neurogenesis and on the activity of the GR.

By measuring the effect of cortisol over time, they found that increased levels of SGK1 prolong the detrimental effects of stress hormones on neurogenesis. Specifically, SGK1 enhances and maintains the long-term effect of stress hormones, by keeping the GR active even after cortisol had been washed out of the cells.

Next, the researchers used a pharmacological compound (GSK650394) known to inhibit SGK1, and found they were able to block the detrimental effects of stress hormones and ultimately increase the number of new brain cells.

Finally, the research team were able to confirm these findings by studying levels of SGK1 in animal models and human blood samples of 25 drug-free depressed patients.

Dr. Christoph Anacker, from King's College London's Institute of Psychiatry and first author of the paper, says: "Because a reduction of neurogenesis is considered part of the process leading to depression, targeting the molecular pathways that regulate this process may be a promising therapeutic strategy. This novel mechanism may be particularly important for the effects of chronic stress on mood, and ultimately depressive symptoms. Pharmacological interventions aimed at reducing the levels of SGK1 in depressed patients may therefore be a potential strategy for future antidepressant treatments."

More information: Anacker, C. et al. 'A role for the kinase SGK1 in stress, depression and glucocorticoid effects on hippocampal neurogenesis' Proceedings of the National Academy of Sciences (PNAS) (May 2013) www.pnas.org/cgi/d… s.1300886110

Wiki on SGK1:

http://en.wikipedia.org/wiki/SGK

Adrenaline, Cortisol, Norepinephrine: The Three Major Stress Hormones, Explained

by Sarah Klein

Thanks to the work of our sympathetic nervous system, the "fight or flight" system that takes over when we're stressed, when you see your boss's name in your inbox late at night, your body reacts like there's a lion on the loose.

Behind the wide range of both physical and mental reactions to stress are a number of hormones that are in charge of adding fuel to the fire.

Adrenaline

What It Is: Commonly known as the fight or flight hormone, it is produced by the adrenal glands after receiving a message from the brain that a stressful situation has presented itself.

What It Does: Adrenaline, along with norepinephrine (more on that below), is largely responsible for the immediate reactions we feel when stressed. Imagine you're trying to change lanes in your car, says Amit Sood, M.D., director of research at the Complementary and Integrative Medicine and chair of Mayo Mind Body Initiative at Mayo Clinic.

Suddenly, from your blind spot, comes a car racing at 100 miles per hour. You return to your original lane and your heart is pounding. Your muscles are tense, you're breathing faster, you may start sweating. That's adrenaline.

Along with the increase in heart rate, adrenaline also gives you a surge of energy -- which you might need to run away from a dangerous situation -- and also focuses your attention.

Norepinephrine

What It Is: A hormone similar to adrenaline, released from the adrenal glands and also from the brain, says Sood.

What It Does: The primary role of norepinephrine, like adrenaline, is arousal, says Sood. "When you are stressed, you become more aware, awake, focused," he says. "You are just generally more responsive." It also helps to shift blood flow away from areas where it might not be so crucial, like the skin, and toward more essential areas at the time, like the muscles, so you can flee the stressful scene.

Although norepinephrine might seem redundant given adrenaline (which is also sometimes called epinephrine), Sood imagines we have both hormones as a type of backup system. "Say your adrenal glands are not working well," he says. "I still want something to save me from acute catastrophe."

Depending on the long-term impact of whatever's stressing you out -- and how you personally handle stress -- it could take anywhere from half an hour to a couple of days to return to your normal resting state, says Sood.

Cortisol

What It Is: A steroid hormone, commonly known as the stress hormone, produced by the adrenal glands.

What It Does: It takes a little more time -- minutes, rather than seconds -- for you to feel the effects of cortisol in the face of stress, says Sood, because the release of this hormone takes a multi-step process involving two additional minor hormones.

First, the part of the brain called the amygdala has to recognize a threat. It then sends a message to the part of the brain called the hypothalamus, which releases corticotropin-releasing hormone (CRH). CRH then tells the pituitary gland to release adrenocorticotropic hormone (ACTH), which tells the adrenal glands to produce cortisol. Whew!

In survival mode, the optimal amounts of cortisol can be life saving. It helps to maintain fluid balance and blood pressure, says Sood, while regulating some body functions that aren't crucial in the moment, like reproductive drive, immunity, digestion and growth.

But when you stew on a problem, the body continuously releases cortisol, and chronic elevated levels can lead to serious issues. Too much cortisol can suppress the immune system, increase blood pressure and sugar, decrease libido, produce acne, contribute to obesity and more.

"Ducks walk out of a lake, flap their wings and they fly off," says Sood. "When you face something stressful, particularly if it's not likely to repeat or doesn't have a huge long-term impact, you want to be able to shake it off and move on with life."

Of course, he adds, estrogen and testosterone are also hormones that affect how we react to stress, as are the neurotransmitters dopamine and serotonin. But the classic fight-or-flight reaction is mostly due to the three major players mentioned above.

Wikipedia: Dr. Stephen Porges' Polyvagal Theory

The Polyvagal Theory (gr. 'polus', “‘many’” + 'vagal', "'Vagus Nerve'") was proposed and developed by Dr. Stephen Porges, Director of the Brain-Body Center at the University of Illinois at Chicago.

The theory specifies two functionally distinct branches of the vagus, or tenth cranial nerve. The branches of the vagal nerve serve different evolutionary stress responses in mammals: the more primitive branch elicits immobilization behaviors (e.g., feigning death), whereas the more evolved branch is linked to social communication and self-soothing behaviors.

These functions follow a phylogenetic hierarchy, where the most primitive systems are activated only when the more evolved structures fail. These neural pathways regulate autonomic state and the expression of emotional and social behavior.

Thus, according to this theory, physiological state dictates the range of behavior and psychological experience. Polyvagal theory has many implications for the study of stress, emotion, and social behavior, which has traditionally utilized more peripheral indices of arousal, such as heart rate and cortisol level.

The measurement of vagal tone in humans has become a novel index of stress vulnerability and reactivity in many studies of populations with affective disorders, such as children with conduct problems and those suffering from borderline personality disorder.

Phylogenetic Subsystems/Stages

The vagus nerve is a primary component of the autonomic nervous system. Polyvagal theory outlines the structure and function of the two distinct branches of the vagus, both of which originate in the medulla.

More specifically, each branch is associated with a different adaptive behavioral strategy, both of which are inhibitory in nature via the parasympathetic nervous system (PNS).

The vagal system is in opposition to the sympathetic-adrenal system, which is involved in mobilization behaviors. According to polyvagal theory, these opposing systems are phylogenetically arranged.

The Dorsal Vagal Complex

The dorsal branch of the vagus originates in the dorsal motor nucleus and is considered the phylogenetically older branch. This branch is unmyelinated and exists in most vertebrates. This branch is also known as the “vegetative vagus” because it is associated with primal survival strategies of primitive vertebrates, reptiles, and amphibians. Under great stress, these animals freeze when threatened, conserving their metabolic resources.

The DVC provides primary control of subdiaphragmatic visceral organs, such as the digestive tract. Under normal conditions, the DVC maintains regulation of these digestive processes. However, prolonged disinhibition can be lethal for mammals, as it results in apnea and bradycardia.

The Ventral Vagal Complex

With increased neural complexity seen in mammals (due to phylogenetic development) evolved a more sophisticated system to enrich behavioral and affective responses to an increasingly complex environment.

The ventral branch of the vagus originates in the nucleus ambiguus and is myelinated to provide more control and speed in responding. This branch is also known as the “smart vagus” because it is associated with the regulation of sympathetic “fight or flight” behaviors in the service of social affiliative behaviors.

These behaviors include social communication and self-soothing and calming. In other words, this branch of the vagus can inhibit or disinhibit defensive limbic circuits, depending on the situation.

The VVC provides primary control of supradiaphragmatic visceral organs, such as the esophagus, bronchi, pharynx, and larynx. The VVC also exerts important influence on the heart.

When vagal tone to the heart’s pacemaker is high, a baseline or resting heart rate is produced. In other words, the vagus acts as a restraint, or brake, limiting heart rate. However, when vagal tone is removed, there is little inhibition to the pacemaker, and so rapid mobilization (“fight/flight”) can be activated in times of stress, but without having to engage the sympathetic-adrenal system, as activation comes at a severe biological cost.

Vagal Tone: A Physiological Marker of Stress

In order to maintain homeostasis, the central nervous system responds constantly, via neural feedback, to environmental cues.

Stressful events disrupt the rhythmic structure of autonomic states, and subsequently, behaviors. Since the vagus plays such an integral role in the PNS via regulation of heart rate, it follows that the amplitude of respiratory sinus arrhythmia (RSA) is a good index of PNS activity via the cardiac vagus.That is, RSA is a measurable, noninvasive way to see how the vagus modulates heart rate activity in response to stress. This method is useful to measure individual differences in stress reactivity.

RSA is the widely used measure of the amplitude of heart rate rhythm associated with rate of spontaneous breathing. Research has shown that amplitude of RSA is an accurate indicator of the efferent influence of the vagus on the heart. Since inhibitory effects of the VVC branch of the vagus allow for a wide range of adaptive, prosocial behaviors, it has been theorized that individuals with greater vagal tone are able to exhibit a greater range of such behaviors.

On the other hand, decreased vagal tone is associated with illnesses and medical complications that compromise the CNS. These complications may reduce one's capacity to respond to stress appropriately.

Clinical Applications of Polyvagal Theory and Vagal Tone

Vagal tone has been used in medical and psychological research to better understand the physiological underpinnings of various disorders.

For example, healthy human fetuses have a high variability in heart rate, which is mediated by the vagus. On the other hand, heart rate decelerations, which are also mediated by the vagus, are a sign of fetal distress.

More specifically, prolonged withdrawal of vagal influence on the heart creates a physiological vulnerability to the influence of the DVC, which in turn produces clinically relevant bradycardia. However, the onset of this deceleration is commonly preceded by transitory tachycardia, which is reflective of the immediate effects of VVC withdrawal.

For more:

"How your nervous system sabotages your ability to relate" an interview with Stephen Porges about his polyvagal theory by Ravi Dykema

http://www.nexuspub.com/articles_2006/interview_porges_06_ma.php

Allostatic load

Bruce McEwen.

From Wiki:

The term allostatic load, coined by McEwen and Stellar in 1993, is defined as the physiological consequences of chronic exposure to fluctuating or heightened neural or neuroendocrine response that results from repeated or chronic stress.

It is used to explain how frequent activation of the body's stress response, essential for managing acute threats, can in fact damage the body in the long run. Allostatic load is generally measured through a composite index of indicators of cumulative strain on several organs and tissues, but especially on the cardiovascular system.

The hormones and other physiological agents that mediate the effects of stress on the body have protective and adaptive benefits in the short run and yet can accelerate pathophysiology when they are over-produced or mismanaged; this kind of stress can cause hypertension and lead to heart disease. Constant or even irregular exposure to these hormones can eventually induce illnesses and weaken the body's immune system.

Adaptation in the face of stressful situations and stimuli involves activation of neural, neuroendocrine and neuroendocrine-immune mechanisms. This adaptation has been called "allostasis" or "maintaining stability through change", which is an essential component of maintaining homeostasis. The main hormonal mediators of the stress response, cortisol and epinephrine (adrenaline), have both protective and damaging effects on the body.

In the short run, they are essential for adaptation, maintenance of homeostasis, and survival “allostasis”. Yet, over longer time intervals, when called upon frequently, the resulting “allostatic load” exacts a cost that can accelerate disease processes. Allostatic load can be measured in physiological systems as chemical imbalances in autonomic nervous system, central nervous system, neuroendocrine, and immune system activity as well as perturbations in the diurnal rhythms, and, in some cases, plasticity changes to brain structures.

Four conditions that lead to allostatic load are:

Repeated frequency of stress responses to multiple novel stressors;
Failure to habituate to repeated stressors of the same kind;
Failure to turn off each stress response in a timely manner due to delayed shut down; and
Inadequate response that leads to compensatory hyperactivity of other mediators.
The effects of these forms of dysfunctional allostasis cause allostatic load and this, over time, leads to diseases. Allostatic load effects can be measured in the body. When tabulated in the form of allostatic load indices using sophisticated analytical methods, it gives an indication of cumulative lifetime effects of all types of stress on the body.

Brain Rules has the most succinct, clear-cut description of the harmful effects of chronic stress that I've read. I've decided that chronic stress will be the next focal point of my research. I'm particulary interesting in moderating/reducing the cortisol levels in my own system.

To start with, I found a book which I'll rush to the top of the to-read pile. It a great overview at a browse, even though the title is almost certainly pure hype -- unless by that, they simply mean that McEwen has redefined toxic chronic stress as allostatic load.

From Amazon: The End of Stress As We Know It by Bruce McEwen

"There's a whole new way to think about stress. Sure, some stress is inevitable, but being 'stressed out' isn't. In fact, we can learn to rechannel the powerful stress activators in our lives to make us even more effective. "Hamlet" spoke of 'suffering the slings and arrows of outrageous fortune.' These days we simply use the word 'stress' to describe that feeling. And if you ask ten random people if they feel stressed, chances are that at least nine will reply with a resounding, 'Yes!'

Indeed, the very way we use the word implies that we are its victims - as in, 'I'm under so much stress' or 'I'm completely stressed out.' There's now a better way to look at this picture, a way to move from victim to victor.

The first step is to look to the science behind it all because in the science lies a whole new message about stress. Science allows us to understand what the stress response is and why our bodies react the way they do. Like all living creatures, we're mapped to respond instinctually in certain ways, and generally for good reasons. We know, for example, that in times of emergency, we effortlessly shift into a different biological mode. Based on our perception of the crisis, our brains initiate the 'stress response' or the 'flight-or-fight reaction. ' Our attention becomes keenly focused. Our heart and lungs accelerate to ready us for action. Our glands mobilize extra energy resources and summon the immune system to battle stations. This whole process is Nature's way of empowering us to respond swiftly, sometimes dramatically, to sudden events, while remaining mentally alert and physically prepared to meet a challenge. 

But what if the crisis situation does not present us with a foe to be fought? Or if fleeing is not the answer? Too often in modern times, the situations that bring on the stress response require neither the fight nor flight response for which our bodies are genetically programmed. The stress response is nevertheless likely to kick in - just as it's programmed to do - even though it cannot help speed us toward a resolution. Deprived of its natural successful result, the very system that's designed to protect us begins to cause wear and tear on our bodies - actually bringing on illnesses as diverse and severe as asthma, diabetes, heart disease, ulcers, and increased susceptibility to colds and infections.

The good news is that there are definite things that we can do to prevent this process from ultimately taking this wrong turn. New research in brain functioning allows us to understand the reactions our bodies have to various stressful circumstances.That knowledge is power - the power to harness the energy stored within us and to channel it in positive ways. "The End of Stress as We Know It" leads us to a new appreciation of the mind - body connection so that we learn how to reduce stress and increase our overall sense of health and well-being-and even turn aside the slings and arrows of life."

An Interview with Stafford Lightman, Endocrinologist, Bristol University, England

Q:  What are the origins of the stress response?

A:  Stress is an extremely important protective mechanism for human beings, and in fact for all animals, because if you're being chased by a lion it's important to get away. In order to get away you need to give as much oxygen and as much sugar to your muscles to make them work as fast as they can, so your blood flow needs to go faster. When you're being frightened, your brain detects the danger, it sends signals down your spinal cord to your adrenal medulla to release adrenaline. The adrenaline increases the amount of sugar in your blood and increases your heart rate, and this helps your efficiency of getting away from the lion. Your brain also sends signals down to the pituitary gland, which releases another hormone which acts on the outside of the adrenal, the adrenal cortex, and that releases cortisol. Cortisol is also very important in keeping your blood sugar up, keeping your blood pressure up, and helping allow the body to have maximal exertion to get away from danger.

Q:  What happens to the body as a result of the stress response in the brain?

A:  One of the fascinating things that happens is [that] the body is being prepared only to use its really essential functions, so the muscles work well, the liver releases more sugar, for energy, but things are actually being turned off as well. Although the heart rate is going up and more blood is going round the body, parts of the body which aren't needed urgently are being turned off. The blood supply to the gut and areas like this is actually decreased, so your digestion diminishes—you don't need digestion when you're running away from a lion—obviously your sexual function is turned off, and a lot of the non-essential activities of the body just decrease so that you preserve the really essential ones to get away from the dangerous situation.

In a modern situation we don't have these same sorts of dangerous problems, but what we have are other very stressful situations. And the interesting thing, of course, is that your blood sugar goes up, your heart rate goes up and your blood pressure goes up, but you're not utilizing all of this, you're not running away, you're not having energy, so all of these hormonal responses are happening, but they're actually not being used.

Q:  When does the stress response become dangerous?

A:  The important thing about the stress response is it's adapted for short-term responses. It becomes dangerous when you get multiple stress responses, one after the other, or experience chronic stress that goes on for weeks or years. When that happens your levels of cortisol can be raised for very prolonged periods of time, and it can have lots of nasty effects on the body. It can damp down your immune system, for instance, so that you can't respond to diseases as well as you should. It can also have effects on the brain, actually decreasing the number of brain cells in certain parts of the brain and decreasing your memory. It also can affect your blood pressure, and it can affect the fats in the blood and make it more likely for you to have heart attacks and strokes. So when you have chronic stress, that's when stress becomes dangerous.

Q:  Can caring for people with chronic illnesses actually lead to illnesses in caregivers?

A:  There's been quite a lot of interest recently about what chronic stress can do to cause disease. We did a study on caregivers of patients with Alzheimer's disease…We've looked at their hormones and we find that their cortisol is indeed raised, so they have a hormonal stress response which is prolonged for a very long period of time. We've also looked at their immune function by giving them influenza vaccination, which is routinely given to elderly people, and we've found that their antibody response to the influenza vaccination is much poorer than equivalent people of the same age who aren't caring for a loved one with Alzheimer's or some other disease.

So it's clear that chronic stress does damp down the immune system. And other people have also shown that chronic stress can decrease your ability to heal wounds, so that if you've got small wounds they just don't heal as well. The body just doesn't function quite as well when you have large, high levels of cortisol circulating through it for long periods of time.

Q:  Has stress been linked to depression and other mental illnesses?

A:  It's quite clear that chronic stress is related with depression. Depression is a very major common disease in our society, and it is undoubtedly related to the chronic stress that we have in our society.

The ability of stress to cause depression as well as other problems like heart disease and high blood pressure are connected in an interesting way. [Patients who are depressed after a] heart attack are much more likely to die within the next few years than people who've had heart attacks and who aren't depressed. So again this depression, which is related to chronic stress, actually has a major effect on life expectancy.

Q:  Might there someday be a pill to reduce the effects of stress?

A:  We are involved in an intensive program to develop an anti-stress pill, and the only way we can do this really is to try and block the beginning of the pathway in the brain that causes the response to stress. And this happens at the hypothalamus, which makes a hormone called CRH. We're making a pill that blocks the effect of CRH, and therefore blocks all of the effects of stress on the body, including the effects of stress in causing an increase in cortisol. We're not designing a drug to give to everybody who's stressed. But this can be very important and hopefully should actually be an extremely useful treatment for … depression that's associated with severe stress.

The Lifetime Effects of Stress: Cortisol Pulses

30 March 2010

Professor Stafford Lightman and his team in the Laboratories for Integrative Neuroscience and Endocrinology are interested in how stress impacts upon human health throughout the lifespan – just how does it affect your body and the way it responds to disease?

Stress-related disease is a rapidly increasing feature of our society, but the mechanisms through which stress causes disease are poorly understood. It is an area of research that fascinates Stafford Lightman, who has been working on finding answers to some of these questions for many years. Recently he has been able to demonstrate that events that happen to you around the time of your birth, or even before you are born, can have epigenetic effects on your later life.

What that means is that while such events do not actually affect the genes themselves they can affect the way your genes function. So if you had a very stressful childhood, this can have long-lasting influences throughout the whole of your life.

Lightman has looked at these effects in rodents and has seen that if rats are stressed early on in their lives, this can change the way they produce their stress hormones throughout the rest of their lives. For example, if a mother rat neglects her pups, when those pups become adults and are examined to see how they respond to stress they have a much stronger response than pups that had caring mothers. In adult rats the levels of the stress hormone corticosterone in those stressed as pups goes much higher during a stressful event and lasts much longer than in rats that were well looked after as pups.

In humans the situation is much the same. If adult stress is superimposed on a stressful childhood, that combination not only means that are you more susceptible to stress in later life, but also that when you encounter a stressful situation your stress hormones – called cortisol in humans – dramatically increase. If these hormone levels are raised chronically for a long period of time, they can cause problems with the whole range of biochemical processes that occur within us and we become more susceptible to diseases such as depression, diabetes and hypertension, and also to memory loss. High levels of cortisol cause shrinkage of the hippocampus which can lead to poor memory function.

If stress hormone levels are raised for long periods we become more susceptible to diseases such as depression, diabetes and hypertension

Having established that stress hormones can have such effects, Lightman naturally asked the question – how does it happen? What he found was extremely interesting. It seems that cortisol is secreted in a circadian rhythm, which means that it has a peak level early in the morning and then decreases throughout the rest of the day. In humans, this peak occurs just before we wake up; cortisol is thus labelled as an ‘anticipatory hormone’ because it goes up in anticipation of what our body will need during the day. Since cortisol and corticosterone act on the liver to release glucose, this morning peak ensures that we have enough sugar in our blood to provide sufficient energy for us to function properly during the day. One fascinating outcome from Lightman’s studies is the fact that the circadian rhythm of cortisol and corticosterone is made up of multiple pulses that occur roughly every hour, so in fact hormone levels are going up and down all the time, especially in the morning in humans when cortisol levels are really high and the pulses are very big.

The relevance of these pulses is that they allow the body’s tissues to respond not just to the level of the hormones, but also to the frequency with which the hormone pulses occur. In fact, it is the basis of a digital signalling system. In arthritis, for example, the frequency of these pulses is doubled, allowing our natural hormones to moderate the disease process. Also, in patients with obstructive sleep apnea – an unpleasant condition in which people stop breathing for periods of a few seconds several times every night whilst they are asleep – the size of each individual cortisol pulse is markedly increased. This may well be one of the reasons why these patients develop high blood pressure, heart disease, diabetes and other stress-related disorders. Indeed, it is clear that in different physiological or pathological conditions not only do levels of hormones change but the frequency and pattern of their pulses change as well.

The next step for Lightman and his team was to look at the molecular biology of these pulses to try to understand what was going on at the cellular level. What they revealed is that every single pulse of corticosterone in rats is associated with a pulse of corticosterone receptors charging into the nucleus of the cell, binding on to DNA and making messenger RNA. Almost all cells in the body have these receptors which can be thought of as the ‘lock’ in a cell that is activated by the hormonal ‘key’ of corticosterone.  The messenger RNA that is made in response to these pulses is the signal for the production of new proteins by the cell and thus is vital for normal cellular function.

The circadian rhythm of cortisol and corticosterone is made up of multiple pulses that occur roughly every hour

The other important discovery was that different tissues in the body experience these pulses in different ways. The liver, for example, is extremely sensitive to pulses and so immediately responds to every individual pulse. Some parts of the brain, however, need two or three pulses before a response is generated. This is useful, as in a stressful situation you need your blood sugar levels to rise very quickly, while the brain may need more time for preparation before it wakes up. This research area is still in its infancy and its implications are not yet fully understood. However, what Lightman’s group does know is that these fluctuations or oscillations of hormones, which are going on all the time, allow us to have a system that reacts extremely fast in stressful situations. When confronted with a lion, for example, you want to have a really massive hormone response so that your brain focuses on how to escape and your blood sugar goes up so you have the energy to run away very fast.

But what does all this mean in today’s society where we are not often confronted by lions? “Now that we understand how these stress mechanisms work,” says Lightman, “we can begin to work out why some people appear to be at greater risk than others of getting diseases that are associated with stress. Furthermore, we will be much better positioned to design therapeutic ways of dealing with it. In the longer term we hope to be able to identify people who have had a particularly stressful childhood, for example, and provide them with advice that will protect them from developing the diseases to which they will be susceptible.” In the future, Lightman hopes to better understand what is called the epigenome – the way that past experiences have modified our cells, making us more vulnerable to certain diseases. “We will be able to look at people who, perhaps because of their childhood experiences, have had a change in their epigenome, which means that their genes respond more readily to stress, thereby putting them at more risk of getting certain diseases. Whether or not it’s a good or a bad thing, of course, one can argue about, but I think it will happen in the not-too-distant future. So personalised medicine won’t only be related to the genes you have – your genome – it will also be related to your epigenome.” Despite these fascinating results, there is still a great deal of work to be done investigating whether or not stress is a risk factor for all kinds of diseases. While we know, for instance, that there is a good correlation between being depressed and having a heart attack, we don’t know what mediates that. “Is it because the individual has a cortisol abnormality?” asks Lightman. “We know that people who are depressed have abnormal cortisol secretion. Is that the link?” Clearly the answer to these questions with regard to specific individuals would be extremely valuable.

To help further this work, Lightman and his team were thrilled to discover recently they had won a grant of £1.7 million from the Wellcome Trust. They will use these funds to look at how different patterns of stress hormones can affect genes in the brain and the liver, as well as how these patterns affect memory and the development of diseases such as diabetes. Undoubtedly they will have more answers in a few years’ time.

Insomnia Tied to Lack of Brain Chemical



"Gabba Gabba Hey" is a catchphrase associated with the punk rock band the Ramones. The phrase is included in the song "Pinhead" (1977), which contains the lyrics: "Gabba gabba, we accept you, we accept you, one of us." The song ends with: "Gabba gabba hey, gabba gabba hey!..."



By Aalok Mehta

December 24, 2008

Scientists have identified the first known brain chemical abnormality associated with insomnia: a substantial reduction in levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA).

Otherwise healthy people with insomnia have, on average, 25 to 30 percent less GABA in their brains than do normal sleepers, according to the new study, which appeared in the Nov. 1 issue of the journal Sleep.

Scientists have long suspected a link between GABA and insomnia. The neurotransmitter is known to help brain regions shut down by reducing electrical activity, and several common sleeping pills work by helping nerve receptors link to the chemical more efficiently. But the new study is the first to quantify GABA levels in the brains of insomniacs.

Because the GABA measurements were made during the day, the findings also lend further credence to the theory that insomnia is a “state of hyperarousal” extending throughout the waking hours rather than just a nighttime disease, the study authors wrote.

“The results suggest that insomnia is not just a sleep problem,” says principal investigator John Winkelman, a physician at Brigham and Women's Hospital, which is an affiliate of Harvard Medical School. “It’s a 24-hour-a-day problem.”

Mysterious disease

In many ways, insomnia remains largely a mystery to the medical community. “It’s the most common sleep disorder but the most poorly understood,” says Jerome Siegel, a psychiatry professor at the University of California, Los Angeles.

Part of the difficulty is that most people with insomnia also have other medical or psychiatric conditions, making it difficult to isolate the exact effects and possible causes of each one.

To get around this problem, Winkelman and his colleagues looked at 16 people with primary insomnia—that is, people free from any other known medical or sleeping conditions. About one-quarter of chronic insomniacs fall into this category.

Researchers collected data on the sleeping habits of the study participants using electroencephalography (EEG) and other monitoring devices. To measure GABA levels noninvasively, the scientists used a novel form of magnetic resonance spectroscopy, which uses magnetic resonance imaging to investigate brain tissue as well as structure. The team averaged GABA signals from the basal ganglia, thalamus and parts of the parietal, temporal and occipital lobes.

In addition to finding lower levels of GABA overall, Winkelman says, “one of the things that encouraged us we were on the right track was that in each of these sleep studies, the amount of wake time during the night was inversely correlated—highly—with GABA levels.”

Despite the promising results from those tests, Winkelman says much work remains to clarify the link between GABA levels and insomnia. “It could be that insomnia produces low GABA, or low GABA produces insomnia, or hyperarousal causes both,” he says. “We just don’t know.”

More details needed

Siegel, who has studied GABA release during sleep but was not involved with this study, echoed Winkelman’s caveat but was impressed by the findings and techniques used.

“This is sophisticated, elegant, cutting-edge work,” he says. “It’s one of the first, if not the first, to use this technique. I expect to see a lot more people using the technique they’re using.

“People with insomnia are not sleepy all the time,” he says. “People with chronic insomnia are more awake all the time. This may be what they are seeing with GABA levels.”

More work also is needed to identify the exact areas affected by these GABA levels. The neurotransmitter is one of the most common in the brain and can have opposing effects in different brain regions, including stimulating some areas that promote wakefulness.

Winkelman agrees. “We’re now trying to find out the specific areas of the brain that are active in insomniacs,” he says.

Stress and the hypothalamic-pituitary-adrenal axis

Here's an aha moment -- perhaps the HPA axis has a lot to do with my insomnia. Once more -- to the Wikipedia. This is a pretty dry, technical entry even by my standards. You might just want to skip it, unless you are stressed. I write some of these posts  just so I can nag Dr. R to "read my blog, dammit" and also maintain my amateur standing as a Proto-Aspie (formerly a Nerd, as in, "talk nerdy to me.")

The cortisol molecule. Don't you love these stick-and-ball molecular models? I do. I'd also like to see one for a McDonalds' Chicken McNugget.

The hypothalamic-pituitary-adrenal axis (HPA or HTPA axis), also known as the limbic-hypothalamic-pituitary-adrenal axis (LHPA axis) and, occasionally, as the hypothalamic-pituitary-adrenal-gonadotropic axis, is a complex set of direct influences and feedback interactions among the hypothalamus, the pituitary gland (a pea-shaped structure located below the hypothalamus), and the adrenal (also called "suprarenal") glands (small, conical organs on top of the kidneys).

The interactions among these organs constitute the HPA axis, a major part of the neuroendocrine system that controls reactions to stress and regulates many body processes, including digestion, the immune system, mood and emotions, sexuality, and energy storage and expenditure. It is the common mechanism for interactions among glands, hormones, and parts of the midbrain that mediate the general adaptation syndrome.

The key elements of the HPA axis are:

The paraventricular nucleus of the hypothalamus, which contains neuroendocrine neurons that synthesize and secrete vasopressin and corticotropin-releasing hormone (CRH). These two peptides regulate:
The anterior lobe of the pituitary gland. In particular, CRH and vasopressin stimulate the secretion of adrenocorticotropic hormone (ACTH), once known as corticotropin. ACTH in turn acts on:

The adrenal cortices, which produce glucocorticoid hormones (mainly cortisol) in response to stimulation by ACTH. Glucocorticoids in turn act back on the hypothalamus and pituitary (to suppress CRH and ACTH production) in a negative feedback cycle.

CRH and vasopressin are released from neurosecretory nerve terminals at the median eminence. CRH is transported to the anterior pituitary through the portal blood vessel system of the hypophyseal stalk and vasopressin is transported by axonal transport to the posterior pituitary.

There, CRH and vasopressin act synergistically to stimulate the secretion of stored ACTH from corticotrope cells. ACTH is transported by the blood to the adrenal cortex of the adrenal gland, where it rapidly stimulates biosynthesis of corticosteroids such as cortisol from cholesterol.

Cortisol is a major stress hormone and has effects on many tissues in the body, including on the brain. In the brain, cortisol acts at two types of receptor  -- mineralocorticoid receptors and glucocorticoid receptors, and these are expressed by many different types of neurons. One important target of glucocorticoids is the hypothalamus, which is a major controlling center of the HPA axis.

Vasopressin can be thought of as "water conservation hormone" and is also known as "antidiuretic hormone." It is released when the body is dehydrated and has potent water-conserving effects on the kidney. It is also a potent vasoconstrictor.

Book, books, and more books. I approve!

Important to the function of the HPA axis are some of the feedback loops:

Cortisol produced in the adrenal cortex will negatively feedback to inhibit both the hypothalamus and the pituitary gland. This reduces the secretion of CRH and vasopressin, and also directly reduces the cleavage of proopiomelanocortin (POMC) into ACTH and β-endorphins.
Epinephrine and norepinephrine are produced by the adrenal medulla through sympathetic stimulation and the local effects of cortisol (upregulation enzymes to make E/NE). E/NE will positively feedback to the pituitary and increase the breakdown of POMCs into ACTH and β-endorphins.





The major communication center for brain-body interaction, the hypothalamus works with the pituitary gland to regulate your body’s hormones. When you have a “stress response,” these two structures throw the adrenal glands into high gear for “fight or flight.” (Image credit: Kathryn Born)

 




Function:

Release of CRH from the hypothalamus is influenced by stress,physical activity, illness, by blood levels of cortisol and by the sleep/wake cycle (circadian rhythm). In healthy individuals, cortisol rises rapidly after wakening, reaching a peak within 30–45 minutes. It then gradually falls over the day, rising again in late afternoon. Cortisol levels then fall in late evening, reaching a trough during the middle of the night. An abnormally flattened circadian cortisol cycle has been linked with chronic fatigue syndrome, insomnia, and burnout.

Anatomical connections between brain areas such as the amygdala, hippocampus, and hypothalamus facilitate activation of the HPA axis. Sensory information arriving at the lateral aspect of the amygdala is processed and conveyed to the central nucleus, which projects to several parts of the brain involved in responses to fear. At the hypothalamus, fear-signaling impulses activate both the sympathetic nervous system and the modulating systems of the HPA axis.

Increased production of cortisol mediates alarm reactions to stress, facilitating an adaptive phase of a general adaptation syndrome in which alarm reactions including the immune response are suppressed, allowing the body to attempt countermeasures.

Glucocorticoids have many important functions, including modulation of stress reactions, but in excess they can be damaging. Atrophy of the hippocampus in humans and animals exposed to severe stress is believed to be caused by prolonged exposure to high concentrations of glucocorticoids. Deficiencies of the hippocampus may reduce the memory resources available to help a body formulate appropriate reactions to stress.
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Stress and disease:

The HPA axis is involved in the neurobiology of mood disorders and functional illnesses, including anxiety disorder, bipolar disorder, insomnia, post-traumatic stress disorder, borderline personality disorder, ADHD, major depressive disorder, burnout, chronic fatigue syndrome, fibromyalgia, irritable bowel syndrome, and alcoholism.[

Antidepressants, which are routinely prescribed for many of these illnesses, serve to regulate HPA axis function.

Experimental studies have investigated many different types of stress, and their effects on the HPA axis in many different circumstances. Stressors can be of many different type -- in experimental studies in rats, a distinction is often made between "social stress" and "physical stress", but both types activate the HPA axis, though via different pathways. Several monoamine neurotransmitters are important in regulating the HPA axis, especially dopamine, serotonin and norepinephrine (noradrenaline). There is evidence that an increase in oxytocin, resulting for instance from positive social interactions, acts to suppress the HPA axis and thereby counteracts stress, promoting positive health effects such as wound healing.

The HPA axis is a feature of mammals as well as other vertebrates. For example, biologists studying stress in fish showed that social subordination leads to chronic stress, related to reduced aggressive interactions, to lack of control and to the constant threat imposed by dominant fish. Serotonin (5HT) appeared to be the active neurotransmitter involved in mediating stress responses, and increases in serotonin are related to increased plasma α-MSH levels, which causes skin darkening (a social signal in salmonoid fish), activation of the HPA axis, and inhibition of aggression. Inclusion of the amino acid L-tryptophan, a precursor of 5HT, in the feed of rainbow trout made the trout less aggressive and less responsive to stress.However, the study mentions that plasma cortisol was not affected by dietary L-tryptophan.

Studies on people show that the HPA axis is activated in different ways during chronic stress depending on the type of stressor, the person's response to the stressor and other factors. Stressors that threaten physical integrity, are uncontrollable or involve trauma tend to have a high, flat diurnal profile of cortisol release with lower than normal levels of cortisol in the morning and higher than normal levels in the evening, resulting in a high overall level of cortisol release during the day. Controllable stressors on the other hand tend to produce higher than normal morning cortisol. Stress hormone release tends to gradually reduce as time passes since the stress occurred. In post-traumatic stress disorder there appears to be lower than normal cortisol, and it is thought that a blunted hormonal response to stress may predispose a person to develop PTSD.

Here's the cortisol feedback loop at work. Cool, right? It seems many of the health concerns of today are made worse by modern stress, diet, and lifestyle on our still Flintstones-like bodies.

Cortisol, also known more formally as hydrocortisone (INN, USAN, BAN), is a steroid hormone, more specifically a glucocorticoid, produced by the zona fasciculata of the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat, protein and carbohydrate metabolism. It also decreases bone formation. Various synthetic forms of cortisol are used to treat a variety of diseases.