Tuesday, January 11, 2011

Stressed out! The powerful biology of stress - ABC Radio National – All In The Mind

ABC Radio National – All In The Mind

Stressed out! The powerful biology of stress

Presenter: Natasha Mitchell Producer: Natasha Mitchell/Anita Barraud

A little tension keeps us on our toes - we're biologically primed for it. But 'toxic' stress makes us physically sick, and powerful research is now revealing its potent impact on our developing bodies and brains. Don't miss two world leaders transforming our understanding.

Natasha Mitchell: And a happy new year on ABC Radio National Summer. Hope it's a fabulous 2011 for you and your kin, without the burden of stress. Although, let's admit it - stress is a fact of life. [Stress-news montage...]: The so called subprime mortgage crisis has sent world stock markets into a spin ... Domestic violence is on the rise, depression is on the rise, anxiety is on the rise, alcohol and drug use are on the rise, so the stress is starting to take its toll ... Tonight the biggest mortgage meltdown ... The thing that makes people most stressed out is when they don't feel like they have any control.

Bruce McEwen: The medical community has begun to accept the notion that for cardiovascular disease, for depression, for certain disorders, that there is a very clear inescapable link with stress. We're increasingly aware of the important role that inflammation plays. Inflammation is part of everything from cancer to Alzheimer's disease, to arthritis, to diabetes, to cardiovascular disease. you name it. And psychological stress elevates the inflammatory cytokines, just as an overload of calories, just as you know many of these things.

Tom Boyce: There is a kind of biological embedding if you will, a biological fingerprint that is left by experiences of growing up in disadvantage, and there are both short term changes in the biology of children who are exposed to those kinds of settings, but there appears to be longer term changes as well. They affect their development and may potentially affect things as distant as when they die, the chronic diseases they develop over the course of their adult life, that their mental health over the years of their adult life.

Natasha Mitchell: So is there a biology of misfortune? More on that provocative proposal later. We're talking stress, the all-pervasive feeling of worry, of burden, of overload and uncertainty. And crucially, of loss of control.
Last year the New York Times reported of three men, all in relatively good health, having heart attacks within weeks of being laid off from the steel mills in New York. 'I think the stress just got to him,' said Kim Smith of her 42-year-old husband Bob. Well today on the show - be blown away by what science is revealing about stress in the body and brain, in children, and in all of us. This is All in the Mind and I'm Natasha Mitchell.

Tom Boyce: I think of it as being almost kind of like an archaeological dig, if you will, you begin with the lived experience of the child, the adversity and stressful events that that child encounters, that is experienced by the child within circuitry of the brain. So we begin this archaeology by exploring what are the brain structures and functions that are changed by early exposure. Then you dig down a little further, a little smaller in scale and complexity and there are differences in the cellular level. in the communication between neurons within the brain, the kind of neuro-transmitter systems that are present in the brain. And then a little deeper are the sub-cellular kinds of processes like the epigenetic changes that we are now seeing that are also systematically different between low and high disadvantaged children.

Natasha Mitchell: And by epigenetic you are referring to not the genetics of a person but the cellular architecture that influences which genes are switched on and off in a body, which is very much affected, as we are finding out, by our environment, by what we are exposed to—our parenting, what we eat.

Tom Boyce: Exactly. The metaphor that I like to think about in this regard is when we move we pack all of our stuff in boxes, right? And boxes are great for moving from one place to another, but they're not very good for actually using the stuff that's in them. So we have to unpack these boxes of genes in order to use the genes, to express them, to have them guide the development of proteins that they code for. And epigenetics is this business of the packaging of the genome and the way in which it influences the expression of genes in a differential manner.

Natasha Mitchell: Paediatrician Professor Tom Boyce. And both my guests today think it's time policy makers took notice of biological evidence in their planning. First to the man whose research has really defined the study of stress. Professor Bruce McEwen from Rockefeller University is a neuroscientist and a neuro-endocrinologist. Well Bruce, welcome to the program.

Bruce McEwen: Thank you very much, it's good to be talking with you.

Natasha Mitchell: Stress operates paradoxically, doesn't it? In the one sense a modicum of stress keeps us on our toes; too much is a problem. I mean the brain reacts to stress but it also adapts to stress, doesn't it? Tell us about that paradox.

Bruce McEwen: Well I think the best way to start is to talk about the different ways we think of stress. There is positive stress when you rise to a challenge and generally are exhilarated because you are able to meet that challenge. And it means you have to have a good sense of yourself, a good sense of whether the risk is worth taking, good self-esteem and a good sense of control. And then there's tolerable stress, something really bad happens, say the loss of a job, a divorce, the loss of a loved one, but you have these internal resources and you have a social support system that can help you out. so you can weather the storm.
And then there's toxic stress—there you don't have the personal resources perhaps, you don't have the social support system and the favourite definition of stress is really something where you don't have control. And then the paradox about the body is that the body produces chemicals, hormones, like cortisol and adrenalin and we also produce inflammatory cytokines when we're stressed, it affects our metabolic hormones.

Natasha Mitchell: And those cytokines are key immune cells.

Bruce McEwen: Immune cells. but they are also produced by many other cells of the body and the brain and they are sort of really hormones in a way. The autonomic nervous system, our sympathetic and our parasympathetic systems, they help keep our heart rate balanced and also affect inflammatory processes, they affect metabolic processes. So there's this whole network of what we call 'allostasis', which is the active process by which the body adapts to a challenge, a stressful situation. The paradox is that when these chemicals are overproduced or under-produced, when this network is out of sync, then the body can show a wear and tear that we call 'allostatic load', it really is the price the body pays. Normally the adaptive response is 'turn it on' and 'turn it off'. If you can't turn it off or if you can't turn it on in sufficient amounts you have problems. and that's what leads over time to an accumulation of wear and tear that contributes to all of the diseases of modern life, whether it's obesity, diabetes, cardiovascular disease, arthritis, and even some of the degenerative brain diseases like Alzheimer's disease and so forth, are really products of this and are made worse by this imbalance.

Natasha Mitchell: And it was indeed Bruce McEwen who nearly 20 years ago now defined the concept of 'allostatic load' to describe this imbalance when the body's stress system, our classic fight or flight response, doesn't switch off. And you can imagine those situations, a boss constantly on your back, an angry relationship, a child growing up in a deprived home. And Tom Boyce is especially interested in this last scenario. As Professor of Paediatrics and Interdisciplinary Studies at the University of British Columbia in Vancouver, where he holds the BC Leadership Chair in Child Development. He and colleagues are doing some extraordinary work tracking stress hormones in kindy kids.

Tom Boyce: So there are two major stress response systems at the neuroendocrine level in the body. One is what we call the HPA axis which stands for the hypothalamic pituitary adrenal cortical axis, which outputs from the adrenal gland that sits on top of the kidney, cortisol. And cortisol has profound effects on the immune system, the cardiovascular system, the peripheral vasculature, the amount of glucose that's in the blood and so on. The second system is called the locus coeruleus norepinephrine system.

Natasha Mitchell: Say that fast after you've had a glass of wine.

Tom Boyce: Really... And it begins with this little nucleus that's in the brain stem and it's responsible for activating the autonomic nervous system which is the part of human biology that mediates the whole fight or flight response. The dry mouth, dilatation of the pupils in the eye, the sweaty palms and so on.

Natasha Mitchell: The beating heart, the sweating brow...

Tom Boyce: That's right, all of the things that we're all familiar with right. What we're finding in our work in the San Francisco bay area among kindergarten children is that kids who within their social groups are more subordinate, who kind of filter to the bottom of the social hierarchy within the group of children within their class, that they have higher levels of reactivity in both of those systems than do children who are dominant and at the top, the leadership, if you will, of the classroom. We think that a similar kind of thing happens among children of low social class families. A variety of work has shown that kids who are growing up in disadvantaged families have higher cortisol levels, higher cortisol reactivity, changes in immune system, that are greater among kids in disadvantage.

Natasha Mitchell: Just play that out a bit further, what does it mean to be subordinate in a kindy context, the kindergarten context? You've done some very interesting observational studies. haven't you. and then measuring cortisol levels in the saliva of those little kids. but what does it mean to be subordinate in a kindy hierarchy?

Tom Boyce: Any kindergarten teacher can tell you that within two weeks of 20 kids coming together in a classroom there will be a pecking order that is linear and transitive, with kids at the top and kids at the bottom. There are children who imitate each other, who defer to one child versus another, who automatically get to go to the head of the line instead of the back of the line. And this is something, if you think about it, we're all basically familiar with, not only from our adult experiences but from our childhood experiences. And it turns out that this ranking of children has certain things in common with the ranking that occurs within societies. And so we've been doing observational studies looking to see whether there are differences in things like stress reactivity, if there are differences in sort of pre-clinical psychiatric conditions, behaviour problems and differences in physical health problems as well. But there are other investigators: Sonia Lupien at McGill University is an example and this is Bruce McEwen's work as well showing that even basal levels of salivary cortisol are higher among kids who are from lower SES families. There may be changes over time and kids may sort themselves out in different ways as they go into adolescence and into young adulthood, but we think that there is a tendency at least at the group level for kids who start out high in HPA reactivity and basal secretion to stay there.

Natasha Mitchell: Now this is very significant because it has all sorts of effects down the track doesn't it? Tell us about the dental caries study that you did.

Tom Boyce: We realised at some point in our study of kindergarten children that one of the effects of cortisol over the longer term, when it's constantly secreted high such as in adults with Cushing's syndrome is that it causes a depletion of calcium in calcified tissues like bones. People with Cushing's disease get osteopenea and osteoporosis. We weren't going to study the bones of these kindergarten children because they are presumably all fine but we did realise within the next year they were all going to have teeth falling out, which is another calcified tissue.

Natasha Mitchell: You became the tooth fairy.

Tom Boyce: It was called the tooth fairy project, and we paid kids $10 a tooth, by the way as a little aside I think we paid them bit too much because when one of the teeth came back from the dental school and they said this is not a human tooth, this is a dog's tooth, so somewhere in Berkeley there's a dog missing a tooth. And we have in fact found that the kids who were more reactive in the HPA axis in fact had thinner and less dense enamel within the teeth that had been exfoliated. So we think that that may be part of the key as to why subordinate kids get more caries is because they have greater cortisol secretion and this comes out in the saliva and may change the enamel density and thickness.

Natasha Mitchell: And as we've heard higher resting levels of cortisol are also linked with elevated markers of inflammatory processes in the body which Tom Boyce says have also been recorded in disadvantaged kids and which point towards higher rates of cardiovascular disease, chronic pulmonary disease and mood disorders in adulthood.

This is All in the Mind on ABC Radio National abc.net.au/rn going global on Radio Australia and as podcast. I'm Natasha Mitchell. What about the brain? Bruce McEwen argues it's been neglected as the organ of stress and his work is revealing how significantly it can be remodelled. You'll remember leading neuroscientist Fred Gage on the show talking about our plastic organ of memory called the hippocampus deep inside the brain. Turns out it's very receptive to cortisol, in fact the stress hormone helps us remember better. But too much of a good thing, and in rats at least ……….

Bruce McEwen: We found that certain neurons in the hippocampus when under chronic stress their dendrites, these big trees that are the receiving points for information from other nerve cells, they shrink.

Natasha Mitchell: They're like around every brain cell there are these sort of sprouting limbs if you like and dendrites are what bring the signals in and some people would have heard that axons are what take the signals out. So what happens to those branching dendritic structures?

Bruce McEwen: In the hippocampus they shrink, and there are fewer connections. But then a colleague in India, Shona Chattarji, discovered that under the very same conditions of stress neurons in the amygdala were actually growing and forming new connections—which is an organ of fear and if it's overactive of anxiety—and the animal is becoming more anxious. Now there's another brain area called the prefrontal cortex.
Natasha Mitchell: Which is at the front of our brain, it's our executive brain in many senses, it helps us plan and prioritise that sort of thing.

Bruce McEwen: And it also governs our emotions, it keeps the amygdala in check and it helps to decide, along with the hippocampus which is very important for remembering where you are, the context of what is happening, it helps to decide whether these situations are worth paying attention to and it keeps the system from overreacting. And then with our collaborator John Morrison we discovered that there's a part of the prefrontal cortex in which these neurons are shrinking, the dendrites are shrinking and they're losing connections. So they are losing a very important input—it's a reversible process, if you stop the stress it will grow back.

Natasha Mitchell: Now what does that mean, what impact does that have on a person's behaviour or in this case a rat's behaviour?

Bruce McEwen: Well what we found is when the animal, the rat, is challenged with a complex task in which it has to shift the meaning of cues that predict where a food reward is, if the task is difficult, having either a lesion of the prefrontal cortex which other people did, or chronic stress, reduces mental flexibility. Their ability to shift is not totally gone, it's just much slower and less efficient.

Natasha Mitchell: It sort of makes sense of there are fewer dendritic arms receiving signals, those cells aren't as receptive to the signals that they receive, I guess.

Bruce McEwen: And then if we talk about translation, the graduate student who did this work Connor Liston, is also a medical student. He studied some of his fellow medical students studying for the board exam, the big exam.
Natasha Mitchell: A very stressful situation.

Bruce McEwen: And he used something called the perceived stress scale, which actually asks you questions about how much in control of your life you are in and what things are causing you to be stressed out. What he also did was to develop a human task which was very much like what he did with the rats, and they used functional brain imaging to define a circuit that was activated by this task. They could observe this circuit in these stressed students and they found that the more stressed out, the less efficient was the circuit, and they also showed an impairment on this behavioural task.

Now what they couldn't do was to look at the detail of the synaptic connections, but we believe that what we learned from the rat is translatable to the human. Now the good news is that when these students had taken the test and had a month off all these effects disappeared.

Natasha Mitchell: So they are reversible?

Bruce McEwen: Yes, so that emphasised the reversibility in the normal healthy brain. Now we're beginning to suspect that as the brain ages it may lose some of this resilience. Some of the work that we've been doing with Mark Kishiyama and Bob Knight, comparing low and high socioeconomic status kids, shows that there are systematic differences in the function of various circuitries within the brain. Mark's work has shown for example that there are differences in prefrontal cortical activation, the part of the brain that's out in front, behind the forehead. It appears that children from low socioeconomic status environments have greater vigilance, but at the expense of the ability to filter out kind of incoming stimuli.

And if you think about it it makes sense that kids growing up in poverty deal with far more in the way of threats, severe stressors that they have to be vigilant towards in order to protect themselves and often to survive. But it comes at the expense of developing the ability that also is located within the prefrontal cortex to discriminate between stimuli that are important and those that can be ignored.

Natasha Mitchell: Professor Tom Boyce. Obviously some children go on to succeed in the face of adversity, there are individual tales of resilience in this story about the biology of stress where the interplay of genetics, epigenetics and family environment probably play a part. That's an intense area of investigation for Tom's team now and their hypothesis is there's a group of adversity responsive genes—interesting.

Just on those shrinking dendritic branches of brain cells Bruce McEwen talked about, curiously, he thinks this could be the brain protecting itself from permanent damage by stress. For example in animals going into hibernation, the same dendrites can shrink in a matter of hours to conserve energy. But if the animals need to come out of their slumber to defend themselves, say, the dendrites rapidly grow back—isn't that amazing.

Interestingly your studies have revealed sex differences: that in male brains it seems that the reaction to stress is more severe than female brains. Give voice to that, I think that is interesting, there seems to be an inbuilt resilience that comes with oestrogen.

Bruce McEwen: Yes there is. Again from animal models we know that females do not show the same remodelling of their dendrites unless their ovaries are removed.

Natasha Mitchell: You don't see that same degree of shrinkage of the dendrites that branch into cells.

Bruce McEwen: Some of our recent work has shown that in females who have oestrogens on board there are changes in certain parts of the brain, especially in the prefrontal cortex and the amygdala that are produced by stress only when there are oestrogens on board. And we don't understand, there's actually the growth of nerve cells caused by stress. We don't know what this means functionally and what's even more interesting is that if you simply took a male, took the testes out and gave them oestrogens, you would not see the same responses as you would see in the male.

Natasha Mitchell: In the female.

Bruce McEwen: In the female, there is a period early in life, the period of sexual differentiation, the testes are producing testosterone that's programming the brain to be different and that's not happening in the female.
Natasha Mitchell: It's very interesting to contemplate that women might be more resilient, their brains might be more resilient to stress. You have to think about how that translates into behaviour.

Bruce McEwen: Well, but at the same time women are more prone on the average than men to anxiety and depressive disorders but……………

Natasha Mitchell: I wonder whether that's a protective response.

Bruce McEwen: I think it is. And men are more prone to conduct disorders and anti-social behaviour. The way I interpret it is that men and women take it out in a different way and, as you said, for the women this may be a protective response and I think in general women are more sensitive to the social environment on the average than many men are, there are obviously exceptions. Having a wife and three daughters and four granddaughters, and four grandsons as well, but I mean there are these very important and significant sex gender differences.

Natasha Mitchell: So given stress radically reconfigures our developing brain and body, how can we help parents and policy makers start us off on the right path in life?

Bruce McEwen: If a person develops a good self-esteem, which is often as a result of proper parenting, and I mean a good attachment, then they're going to have this sense of themselves that takes risks in a very careful way and feels rewarded when they are successful. When you see a little kid learning to tie his or her shoes and beginning to be able to manage life for themselves you begin to realise how each of us builds up this confidence in our ability to do things. There are many life skills that are not higher intellectual functions, things that we are learning all the time, and if you don't have these skills you just are helpless in a sense.

Natasha Mitchell: I mean you make the case that genetics itself doesn't necessarily explain how we respond differently to stress, but how we perceive stress has a fundamental influence on the biology of stress in the body, doesn't it? Perception and biology being connected—I think that is incredibly powerful.

Bruce McEwen: It gets back to the idea that the brain is the central organ of stress and decides if something is threatening, decides what to do about it. There's—just getting back to self-esteem—there's a very interesting study at Magill, by Jens Pruessner , showing that people who have low self-esteem have a smaller hippocampus. They were doing something called the Trier Social Stimulation test, which is a public speaking challenge. You put a person in front of a bunch of strangers and you ask them to talk about something very personal. If any one of us did it you can be sure that at the first time our heart rate would be pounding and our cortisol would go up. You ask people to do this several times in a row, each time with a different group of strangers, and you know. a different task. Most people who have good self-esteem habituate, their cortisol is not as large the second time and maybe the fourth or fifth time the heart rate goes up but it's no big deal. But he identified a group of people that had very high levels of cortisol the first time and they never habituated. And when he did standard profiles of their personality they had low self-esteem, low locus of control, they just didn't have this confidence in themselves. And then at Magill they found they had a smaller hippocampus, which of course governs cortisol secretion, the HPA access, but it also governs many aspects of our brain function, as we've already discussed.

So this is provocative finding, it needs to be borne out, but it suggests that early life events, the ability to develop a sense of yourself, the ability to control your environment—and of course on top of that the ability to be socially active, to have friends, not to isolate yourself, and learn all these life skills and so on, is what contributes to our ability to be resilient. Or when we're in a situation where we have a lousy job or a lousy relationship, to have the courage to stop and do something different.

Tom Boyce: The biological research that we and others have been doing, our hope is that it becomes part of a much larger frame that catches the attention and drives within policy makers and legislators and so on, within societies in general, a new kind of sense of the critical importance of how we care for and look out for our children.

Natasha Mitchell: You could imagine it as a sort of measure of interventions, if you like, if you mention cortisol levels before and after an intervention with a community of vulnerable children. That's an interesting possibility isn't it?

Tom Boyce: It is indeed, employing some of these biological measures in the service of the development and sculpting of interventions that would be more effective. It's far easier to measure differences in brain function before and after an intervention at age 5 than it is to wait for the consequences of the changes in brain circuitry that happened decades later in life.

Bruce McEwen: All public policies are health policies: a housing policy, a tax policy, an education policy, they are all affecting our health because if you're worried about your finances you're going to be stressed out. If you can't find a job you're going to be stressed out. So there are many things that will lead to this psychological stress. And so what government does and what the private enterprise does, if they give people a chance to plan their own working schedules, with day care, with other family responsibilities if they are given release time to go to physical activity, to exercise they are happier and they are healthier.

So all of these policies are good for the business because it's more productive, it's also good for the employee.
Natasha Mitchell: And good for the brain, brain based policy.

Bruce McEwen: Yeah, brain based policy. I mean it means reorganising society as much as we can to de-emphasise the pressure on the success—unfortunately the mighty dollar—to realise there's a life we want to live too and it's not all the bottom line.

Natasha Mitchell: Well Bruce McEwen thank you for joining me and it's been great to have you on the show.

Bruce McEwen: It's been an honour and it's been a lot of fun as well to chat with you.

Natasha Mitchell: Professor Bruce McEwen from Rockefeller University and before him Professor Tom Boyce from the University of British Columbia. The full interview with Bruce McEwen is on the All in the Mind blog. Lots more science unravelled there. And join the discussion on the All in the Mind website, look for 'add your comment' on this week's story at abc.net.au/rn/allinthemind. And there's our Audioboo channel of course too. I'm Natasha Mitchell. Next week, the divided brain and Western civilisation!


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