Melzack & Katz, Pain. Part 17f: Chrousos and Gold and stress

The paper, Pain.

Part 17: The stress of it all Part 17b: Stress and adrenals Part 17c: Women, pain, and stress Part 17d: Stress, aging, and pain Part 17e: Stress and aging, keeping hippocampal dendrites fluffed up

SEE ALL PREVIOUS BLOGPOSTS IN THIS SERIES LISTED AT THE END

Hello again - I'm back from the hiatus on this blog, after an exhausting (to me anyway, an introvert) workshop teaching adventure in Eagan Minnesota. Here is a picture of the class. (It could use a bit of cropping. You can see balloons on the floor.. I use those as teaching tools.) 

DNM workshop Eagan Minn. July 26-28/13

So, back to business - back to the wonderful luscious paper I've been blogging about for months already, Melzack and Katz's paper, Pain. 

We left off in the middle of the subsection, Pain and stress, in the l-o-n-g section, Beyond the gate.  We were at these two paragraphs, 

"The cortisol output by itself may not be sufficient to cause any of these problems, but rather provides the conditions so that other contributing factors may, all together, produce them. Sex-related hormones, genetic predispositions, psychological stresses derived from social competition, and the hassles of everyday life may act together to influence cortisol release, its amount and pattern, and the effects of the target organs.

“These speculations are supported by strong evidence. Chrousos and Gold70 have documented the effects of dysregulation of the cortisol system: effects on muscle and bone, to which they attribute fibromyalgia, rheumatoid arthritis, and chronic fatigue syndrome. They propose that they are caused by hypocortisolism, which could be due do depletion of cortisol as a result of prolonged stress. Indeed, Sapolsky71 attributes myopathy, bone decalcification, fatigue, and accelerated neural degeneration during aging to prolonged exposure to stress."

We were about to investigate reference #70, 

Chrousos GP, Gold PW. The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis.JAMA 1992, 267:1244–1252.

..........

Who is G.P. Chrousos?

George P Chrousos is at the Athens University Medical School. According to Wikipedia, 

SOURCE
George P Chrousos

"Dr. Chrousos is among the 250 most prominent clinical investigators in the world. He has authored more than 1100 scientific publications, has edited 29 books and his work has been cited over 65,000 times. According to the ISI, he is the highest cited Clinical Pediatrician and Endocrinologist in the world." 

Here is his university profile. Here is his bio on Wikipedia. He is affiliated with King Saud University as well, apparently. 

Melzack certainly seems to like that 1992 paper, even though Chrousos has published a lot more since. Here are 87 free papers he has authored or co-authored. 

Who is P.W. Gold? 

Here is a short profile page about him. At least, I'm pretty sure that's him. 

It's a really common name, and a bunch of links to do with gold medals/jewellery/competitions etc. come up, annoyingly, so he's a bit hard to find amongst all the google clutter.  

SOURCE
Philip W Gold 

Add to that, he seems to keep very low profile. No bio. Wikipedia doesn't seem to know about him. 

He has published extensively as well; here are 20 free papers that will keep you busy.  Here is something from 11 years ago that looks interesting. 

....................... 

Anyway, now that we know who is who and where they are at, what they do, etc., let's unravel that old paper they wrote together 21 years ago that Melzack is still so fond of. I happen to have it open just now. 

Compared to that Gliopathy paper where we were stuck on a fogbound island for more than a week during the writing of section 14 of this massive missive, because the material was almost brand new to me.., this one is more like a lovely intellectually stimulating stroll through a museum with plenty of signage and context. It's one of those papers that digs back to the origins of everything, doesn't assume you already have a background in an entire field of research consisting mostly of things named with capital letters, greek letters, numbers and hyphens all in different combinations, which without Wikipedia, you'd be completely lost. Yeah, I guess I still feel cognitively traumatized a little by that brave attempt to learn new stuff while blogging about it. 

Anyway, we move on. The authors say,

"In the present overview, we shall attempt to provide a historical perspective on the concept of stress, to review current ideas regarding the neurophysiological and biochemical events that are set into motion during stressful situations, and to suggest how vulnerability to several major disease entities, such as affective illnesses and chronic inflammatory processes, reflects dysregulation of the stress response."

In describing and defining stress they say:

"Living organisms survive by maintaining an immensely complex dynamic and harm-onius equilibrium, or homeostasis, that is constantly challenged or outright threatened by intrinsic or extrinsic disturbing forces or stressors. The steady state required for successful adaptation is maintained by counteracting/reestablishing forces, or adaptational responses, consisting of an extraordinary repertoire of physical or mental reactions that attempt to counteract the effects of the stressors in order to reestablish homeostasis. In this context, we define stress as a state of disharmony, or threatened homeostasis. The adaptive responses can be specific to the stressor or can be generalized and nonspecific. The latter can be stereotypic and generally occur only if the magnitude of the threat to homeostasis exceeds a certain threshold."

Let's think about that for a moment. Just that. 

Let's think about how sensitive to perturbation the nervous system is, under ordinary circumstances. 

Let's think about how it requires a certain amount of stress just to learn. E.g., about gliopathy maybe.. 

Let's think about how, if stress is necessary to learn, there is inside the system all these evolved mechanisms to use stress, in small doses, to learn more about the world, but to protect the organism from an excess of stress, "an extraordinary repertoire of physical or mental reactions that attempt to counteract effects of the stressors in order to reestablish homeostasis." 

By making the organism feel the urge to do something different, give it the idea that it wants to walk away or close the book or click off the paper or turn off the news reports or leave facebook or stop writing for awhile, go to the bathroom or go get something to eat or go for a walk.

What if you can't change your actions, behaviour, context or environment, whenever you want to? What if you can't change the people around you? 

How about if you had endured a life like the one this woman did not survive? There was no escape, and even her doctor was forced to watch her die in one of the worst ways he could imagine, because of wishes of (probably) guilt-laden-but-helpless family members who didn't know any better and couldn't let go. It's the human default foible - her life had been living hell and all her offspring could think to do was prolong it unnecessarily based on nothing but dissociated and futile hope; they hadn't seen her enjoy any of it and hoped maybe she could; but prolonging her life just made more hell for her. They weren't thinking of her, they were acting from their own disheveled and confused and merged emotional states. According to me. 

Living a life that has been filled with inescapable stress prepares no one who might be involved for much of a peaceful exit from it.  

.................

Previous blogposts

Part 1 First two sentences Part 2 Pain is personal Also Pain is Personal addendum., Neurotags! Pain is Personal, Always.

Part 3a Pain is more than sensation: Backdrop Part 3b Pain is not receptor stimulation Part 3c: Pain depends on everything ever experienced by an individual

Part 4: Pain is a multidimensional experience across time

Part 5: Pain and purpose

Part 6a: Descartes and his era; Part 6b: History of pain - what’s in “Ref 4”?; Part 6c: History of pain, Ref 4, cont.. : There is no pain matrix, only a neuromatrix; Part 6d: History of Pain: Final takedown Part 6e: Pattern theories in the history of pain Part 6f: Evaluation of pain theories Part 6g: History of Pain, the cautionary tale. Part 6h: Gate Control Theory.

Part 7: Gate control theory has stood the test of time: Patrick David Wall;  Part 7b: Gate control: "The theory was a leap of faith but it was right!"

Part 8: Beyond the gate: Self as mayor Part 8b: 3-ring circus of self Part 8c: Getting objective about subjectivity

Part 9: Phantom pain - in the brain! Part 9b: Dawn of the Neuromatrix model Part 9c: Neuromatrix: MORE than just spinal projection areas in thalamus and cortex Part 9d: More about phantom body pain in paraplegics

Part 10: "We don't need a body to feel a body." Part 10b: Conclusion1: The brain generates its own experience of being in a body Part 10c:Conclusion 2: Your brain, not your body, tells you what you're feeling Part 10d: Conclusion 3: The brain's sense of "Self" can INclude missing parts, or EXclude actual parts, of the biological body Part 10e: The neural network that both comprises and moves "Self" is (only)modified by sensory experience

Part 11: We need a new conceptual brain model! Part 11b: Intro to a new conceptual nervous system Part 11c: Older brain models just don't cut it Part 11d: The NEW brain model!

Part 12: Action! 12b: Examining the motor system, first pass. 12c: Motor output and nervous systems - where they EACH came from Part 12d... deeper and deeper into basal ganglia Part 12e: Still awfully deep in basal ganglia Part 12f: Surfacing out of basal ganglia Part 12g: The Action-Neuromatrix 

Part 13: Pain and Neuroplasticity Part 13b: Managing neuroplasticity

Part 14: Side trip out to the periphery! Part 14b: Prevention of pain neurotags is WAY easier than cure Part 14c: PW Nathan was an interesting pain researcher  Part 14d: Brain glia are from neuroectoderm and PNS glia are from neural crest Part 14e: The stars in our headsPart 14f: Gleeful about glia Part 14g: ERKs and MAPKs and pain Part 14h: glia-fication of nociceptive input 14i: molecular mediators large and small Part 14j: Neurons, calling glia (over, do you read?) Part 14k: Glia calling glia, over. Do you read? Part 14l: satellite cell and neuron cell body interactions, and we're outta here!

Part 15: Prevention of neurobiological hoarding behaviour by dorsal horn and DRG glia is easier than clutter-busting after the fact

Part 16: Apples are to fruit as cows are to animals as nociceptive input is to pain

Interlude: The non-monolithic brain: "You don't need a body to feel a body"- Melzack

I'm up in the middle of the night so I thought I would do something useful (in my own mind at least), i.e., blog anyway, even after I said I wasn't going to.. but this one isn't about the current theme of stress and pain, the section I've been blogging about in the paper, Pain. 
This is one that I've been wanting to do on a tangential topic and for whatever reason, in the middle of the night, while preparing to teach a workshop, in a hotel room, in an insomniatic mood, my brain picks this time for this post. So, what the hey.. here we go.. (there is nothing pressing first thing in the morning - I can sleep in, so I don't have to stay in bed and try to force myself to sleep when I'm wide awake with all this stuff rolling around wanting to be written down).

Melzack's quote
Remember how Melzack said,  "You don't need a body to feel a body"? (I don't remember which blogpost that was in, or paper it was from, but I made a picture. Here it is. )

By me. 

Lately, and serendipitously, I've seen some things in my internet travels and stumbles-upon that might pertain to this.

Deep cortical layers are activated directly by thalamus
The first thing was a paper by Constantinople & Bruno, Deep Cortical Layers Are Activated Directly by Thalamus, about how information going to the somatosensory cortex is processed in two batches in two places within the layers, unlike what people previously thought, that it was processed in one batch by all the layers working together. I wrote about processing here, Part 11c, and included the picture from the paper, also below:

From Constantinople & Bruno 2013
SOURCE

Emx2, Pax6, Joan Stiles, Brain Development
The second thing was a video that Ginger Campbell shared, Joan Stiles talking about brain development.  Great video. About minute 30:35, she describes the genetic battle for territory-building between the two main genes that help the cortex develop, Emx2, and Pax6. It's been worked out what happens if one of them is slightly more influential than the other. Here is a screenshot of a cartoon shown in the video that depicts this:

SOURCE, Joan Stiles, Brain Development, minute 30:35

Novel 'Top-Down' Mechanism Repatterns Developing Brain Regions

The third thing, was this, from just the other day, from La Jolla, news that provided the tipping point for planning this post. By manipulating Pax6, researchers were able to manipulate development of the main somatosensory representational map in the brain. 

Excerpt:

"In order to study cortical layout, O'Leary's team altered a regulatory gene, Pax6, in the cortex in mice. In response, S1 became much smaller, demonstrating that Pax6 regulates its development. They found that the shrinkage in S1 subsequently affected other regions of the brain that feed sensory information into the cortex, but more interestingly, it also altered the body maps in these subcortical brain regions, overturning the idea that once established, these brain regions could only be changed by external experience. They dubbed this previously unknown phenomenon "top down plasticity."
"Top-down plasticity complements in a reverse fashion the well-known bottom-up plasticity induced by sensory deprivation," says O'Leary.
"Normally, the body map in S1 cortex mirrors similar body maps in the thalamus, the main switching station for sensory information, which transmits somatosensation from the body periphery to the S1 cortex through outgoing neural "wires" known as axons. In the newly discovered top-down plasticity, when S1 was made smaller, the sensory thalamus that feeds into it is also subsequently reduced in size.
"But the story has a more intriguing twist. "According to our present knowledge about the development of sensory circuits, we anticipated that all body representations in S1 would be equally affected when S1 was made smaller," says O'Leary. "It was a surprise to us that not only was the body map smaller, but some parts of it were completely missing. The specific deletion of parts of the body map is controlled by exaggerated competition for cortical resources dictated by S1 size and played out between the connections from thalamic neurons that form these maps in the cortex."

Carl Zimmer wrote a wonderful blogpost two days ago, about how this was done, Mouseunculus: How the brain draws a little you. Note Pax6, the gene mentioned by Stiles in the video. Implications for autism apparently. 

Not quite sure how all this fits together, but I think it does fit somehow with Melzack's point, that you don't need a body to feel a body, and has implications for other phenomena besides autism, like xenomelia, mirror therapy, all kinds of things to do with pain and perception and manipulation thereof. 

There is the internal regulation system/critter brain being phylogenetically a lot older and fairly independent of cortex (other than perhaps as an annoying stressor to it, much of the time..), so already we know the brain isn't monolithic, but this is a new way of seeing how function slices up into different levels of processing and awareness, and maybe some day, clever treatment. False memories are now being implanted into mice, at least the latest buzz says so.. It would be cool if some day a false memory of "no back pain ever" could be implanted into people with back pain, for instance... 

OK, end of insomnia post. Back to where we left off in Melzack & Katz's paper, later. 

Melzack & Katz, Pain. Part 17e: Stress and aging, keeping hippocampal dendrites fluffed up

The paper, Pain.

Part 17: The stress of it all Part 17b: Stress and adrenals Part 17c: Women, pain, and stress Part 17d: Stress, aging, and pain

SEE ALL PREVIOUS BLOGPOSTS IN THIS SERIES LISTED AT THE END

Synopsis from yesterday

Stress is a Goldilocks, paradoxical kind of thing. You need a bit of it to learn anything, because the brain can't learn anything unless it's exposed to glucocorticoids, it seems. No stress at all and you could end up smart as an eggplant. 

Too much of it for too long though, you end up soaked in glucocorticoids, the cortisol will chew away at your physicality, and your hippocampus won't be able to control the hypothalamus. It will be the physiological equivalent of microphone squeal.

If the hippocampus can't tell the hypothalamus, "Thank you very much, I got it, I've learned what to do in this situation next time, so you can stop with the glucocorticoids already", the hypothalamus, like a dripping faucet, will just keep pouring the stuff out, which will just keep killing more and more of the body and prevent new baby cells from being born and raised in the hippocampus, which will make the hypothalamus drip faster, etc., etc. ... and then we will age very very quickly. 

All of a sudden.

Reflection

I remember this happening to me at about age 37. For no very clear externally blameable reason, I suddenly began to feel as though I was under inescapable stress. I went grey, needed glasses, became peri-menopausal, gained thirty pounds and began crying for no reason, out of the blue. In the space of just a couple months with no change in life on the outside, on the inside I felt a huge cave-in happen, and my physicality changed, just like that. After struggling for about a year on my own, I finally went for some psychotherapy, dealt with a few personal issues, and whether that helped or it was merely coincidental, I started to feel better and my inside life went on again. I chalked it up to one of those depressive episodes I get once in awhile and just live through. It was the worst one ever, though. The one I survived few years ago was pale by comparison.  

[Never ever managed to lose the extra weight - it must be my cortisol blotter.]

Exercise

If you don't "move it" you'll lose a lot of brain power in the hippocampus, which, by the sound of it, relies on neurogenesis and neuroplasticity to regulate other things, because, again by the sound of it, maybe its neurons just wear out and need replacing. Exercise makes brain-derived neurotrophic factor, BDNF. BDNF helps new baby brain cells develop, but even more strategically, it helps already existing brain cells develop more dendrites, and already existing dendrites develop a thicker, fluffier, spinier surface area. More surface area, better communication. 

SOURCE

................

Melzack and Katz continue, in the section to do with pain and stress: 

"The cortisol output by itself may not be sufficient to cause any of these problems, but rather provides the conditions so that other contributing factors may, all together, produce them. Sex-related hormones, genetic predispositions, psychological stresses derived from social competition, and the hassles of everyday life may act together to influence cortisol release, its amount and pattern, and the effects of the target organs."

Like too much salt in the soup, it can ruin the entire batch.

" These speculations are supported by strong evidence. Chrousos and Gold70 have documented the effects of dysregulation of the cortisol system: effects on muscle and bone, to which they attribute fibromyalgia, rheumatoid arthritis, and chronic fatigue syndrome. They propose that they are caused by hypocortisolism, which could be due to depletion of cortisol as a result of prolonged stress. Indeed, Sapolsky71 attributes myopathy, bone decalcification, fatigue, and accelerated neural degeneration during aging to prolonged exposure to stress."

Hmmnn... hy-PO-cortisolism? Depletion? 

OK, I don't quite get this - it will require digging up and reading Chrousos and Gold to see what they are talking about. 

Chrousos GP, Gold PW. The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis.JAMA 1992, 267:1244–1252.

This might take awhile. Another place to land, rest from our ride down the river, get out and stretch. This looks like a nice safe place to tie up the boat for awhile. 

SOURCE

Blogus Interruptus
I'm off to teach in Minneapolis for a few days. I'll resume the blog-saga when I return, next week. 

..............

Previous blogposts

Part 1 First two sentences Part 2 Pain is personal Also Pain is Personal addendum., Neurotags! Pain is Personal, Always.

Part 3a Pain is more than sensation: Backdrop Part 3b Pain is not receptor stimulation Part 3c: Pain depends on everything ever experienced by an individual

Part 4: Pain is a multidimensional experience across time

Part 5: Pain and purpose

Part 6a: Descartes and his era; Part 6b: History of pain - what’s in “Ref 4”?; Part 6c: History of pain, Ref 4, cont.. : There is no pain matrix, only a neuromatrix; Part 6d: History of Pain: Final takedown Part 6e: Pattern theories in the history of pain Part 6f: Evaluation of pain theories Part 6g: History of Pain, the cautionary tale. Part 6h: Gate Control Theory.

Part 7: Gate control theory has stood the test of time: Patrick David Wall;  Part 7b: Gate control: "The theory was a leap of faith but it was right!"

Part 8: Beyond the gate: Self as mayor Part 8b: 3-ring circus of self Part 8c: Getting objective about subjectivity

Part 9: Phantom pain - in the brain! Part 9b: Dawn of the Neuromatrix model Part 9c: Neuromatrix: MORE than just spinal projection areas in thalamus and cortex Part 9d: More about phantom body pain in paraplegics

Part 10: "We don't need a body to feel a body." Part 10b: Conclusion1: The brain generates its own experience of being in a body Part 10c:Conclusion 2: Your brain, not your body, tells you what you're feeling Part 10d: Conclusion 3: The brain's sense of "Self" can INclude missing parts, or EXclude actual parts, of the biological body Part 10e: The neural network that both comprises and moves "Self" is (only)modified by sensory experience

Part 11: We need a new conceptual brain model! Part 11b: Intro to a new conceptual nervous system Part 11c: Older brain models just don't cut it Part 11d: The NEW brain model!

Part 12: Action! 12b: Examining the motor system, first pass. 12c: Motor output and nervous systems - where they EACH came from Part 12d... deeper and deeper into basal ganglia Part 12e: Still awfully deep in basal ganglia Part 12f: Surfacing out of basal ganglia Part 12g: The Action-Neuromatrix 

Part 13: Pain and Neuroplasticity Part 13b: Managing neuroplasticity

Part 14: Side trip out to the periphery! Part 14b: Prevention of pain neurotags is WAY easier than cure Part 14c: PW Nathan was an interesting pain researcher  Part 14d: Brain glia are from neuroectoderm and PNS glia are from neural crest Part 14e: The stars in our headsPart 14f: Gleeful about glia Part 14g: ERKs and MAPKs and pain Part 14h: glia-fication of nociceptive input 14i: molecular mediators large and small Part 14j: Neurons, calling glia (over, do you read?) Part 14k: Glia calling glia, over. Do you read? Part 14l: satellite cell and neuron cell body interactions, and we're outta here!

Part 15: Prevention of neurobiological hoarding behaviour by dorsal horn and DRG glia is easier than clutter-busting after the fact

Part 16: Apples are to fruit as cows are to animals as nociceptive input is to pain