Saturday, August 03, 2013

Melzack & Katz, Pain. Part 17i: Pathophysiology of 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 Part 17f: Chrousos and Gold and stress Part 17g: Stress conceptualization through the ages Part 17h: Phenomenology and physiology of stress


We are still making our way carefully and patiently and non-stressfully through the twists and turns in Chrousos and Gold's 1992 overview paper on stress, one of Melzack's all time favourite references, so we can return to Melzack and Katz

Pathophysiology in the stress system
Stress response is supposed to happen, in response to an (extrinsic!) stressor, then be over with. Everything comes back to normal after; Selye asserted way back in 1936 that "severe chronic disease of any etiology could present with anorexia, loss of weight, depression, hypogonadism, peptic ulcers, and immunosuppression." He linked all these signs to increased and protracted production of CRH. 

Chrousos and Gold tried to work out how "melancholic depression" fit with this picture.
"The syndrome of melancholic depression also seems to represent dysregulation of the generalized stress response, which in this state seems to escape the usual counterregulatory elements that serve to make it a self-limiting process.
"Hence, the cardinal manifestations of melancholic depression are the hyper-arousal and redirection of energy that are extremes of the classic manifestations of the generalized stress response..  arousal becomes dysphoric hyperarousal and anxiety, and vigilance is turned into hypervigilance and insomnia.
“The dysphoria observed in melancholic depression may represent tachyphylaxis of the mesocorticolimbic system to chronic activation of the stress system.. cognition, memory, and attention are focused obsessively on depressive ideas, adversely influencing the ability of the individual to remember and focus on learning and solving practical, everyday, or pertinent problems.
“In this disease, assertiveness is often transformed into excessive cautiousness and anxiety. Moreover, decreased emphasis on feeding and reproduction, which is adaptive in the context of the generalized stress response, becomes maladaptive in the sustained anorexia, hypothalamic hypogonadism, and decreased libido that are the hallmarks of melancholic depression. Both the HPA axis and the sympathetic system appear chronically activated in this illness.
“Could increased and chronic CRH secretion explain the pathophysiological picture of depression? Such hypersecretion of CRH was shown in depression and was originally thought to be an epiphenomenon. Administration of CRH to experimental animals, however, with its profound effect on reproducing the stress response, suggests that CRH may participate in the initiation and/or propagation of a vicious cycle." - p 1248
I like that word, tachyphylaxis.
It means, everything is going along fine, predictably, then all of a sudden your brain decides to be overreactive to something it used to ignore. Or respond to weakly. Hmmn. I think that has happened to me a time or two.

Too much CRH
They also wondered about anorexia nervosa, panic anxiety, OCD, chronic active alcoholism/withdrawal from alcohol or narcotics, excercise-aholism, malnutrition, hyperthyroidism, and premenstrual tension syndrome. They pointed out that anorexics often showed evidence of hypersecretion of arginine vasopressin which delays extinction of behaviours. They pointed out that panic disorder, OCD and chronic obsessive exercising to the point of amenorrhea suggested lack of ability to slow down or stop a given behaviour; they noted that elite athletes tended to go through withdrawal if they had to discontinue exercising, which they wondered might be related to the sudden decrease in beta-endorphins, etc., involved in pleasurable aspects of the stress response, or maybe stress-induced activation of the mesocorticolimbic dopamine systems.
They mentioned that hyperthyroidism exacerbated endogenous depression.

Too little CRH
At the other pole, opposite from skinny anxious depressed over-exercising hyperthyroidal non-menstruating anorectics with their stress response mechanism turned on all the time, were two other categories; "atypical" depression, and Cushing's syndrome, "in which the clinical picture of polyphagia and weight gain, as well as fatigue, anergia, and excessive sleep, was, in fact, converse to that expected from CRH hypersecretion." - p 1249

Yup, it turned out that scant CRH was produced in patients with seasonal affective disorder, chronic fatigue syndrome, hyPOthyroid syndrome... Animals models supported the notion. So they went ahead and proposed that there might well be a problem with insufficient stress response and hypoarousal.

"Such hypoarousal may or may not be accompanied by dysphoria, perhaps owing to inadequate stimulation of the mesocorticolimbic system by the stress system." - p 1249  
These patients didn't necessarily feel depressed.. 

There are a couple other situations humans find themselves in:
"This category of chronic CRH hyposecretion may also include some forms of obesity that are characterized by a hypoactive, hypo-serotonergic axis; subgroups of adult patients with the posttraumatic stress disorder, which was recently associated with decreased urinary free cortisol excretion and increased sympathetic system discharges in response to specific memories or stressors; and withdrawal from smoking, which was associated with decreased adrenaline or noradrenaline excretion and decreased plasma concentrations of epinephrine and cortisol. Decreased CRH secretion in the early period of nicotine abstinence could explain the hyperphagia and weight gain frequently observed in these patients." - p 1249
So, with decreased CRH secretion, people tended to be overweight - they over ate and under exercised. If they had been smokers and quit, they put weight on easily. Sounds like most of North America. Well, except for the hyper secretors off to their daily spin class. 

Chrousos and Gold added a last paragraph to this section to do with a rat model of autoimmune inflammatory disease in which hypofunctional CRH system is built in. 
"The defect of the CRH neuron in this animal is generalized, so that the CRH gene is hyporesponsive not only to any of the physiological inflammatory stimuli, but to neurochemical and environmental stimuli as well. Hence, Lewis rats show not only evidence of defective immune counterregulation, as a consequence of their deficient CRH neuron responsiveness, but also evidence of behavioral alterations compatible with decreased CRH synthesis and release in the central nervous system." p. 1249
Maybe this is why Melzack refers to this paper. If the brain doesn't register input as much of a threat it may not respond adequately. Maybe until it's way too late. Thus maybe are painful conditions linked. 

Chrousos and Gold include a nice succinct table summarizing all their ideas:


[I'm definitely mostly in the right column.]

Potential mechanisms of stress syndrome dysregulation
The last bit of this paper is some very nice brainy jazz improv by Chrousos and Gold. They propose that both hyper and hypo dysregulation of the stress response "involves a number of health problems of enormous impact to society." They reiterate that the system is nonspecific, is "meant to interact with internal and external perturbations in a quite similar manner." Therefore, "inappropriate adaptational responses could be maladaptive and act as stressors themselves," become part of a positive feedback loop. 

Individual variability in response to stressors could be a function of high or low sensitivity to stressors. 
"For normally active individuals, there is an optimal level of arousal, and potential shifts in the activity of the stress system in either direction could produce subjective discomfort or decreasing performance."

My bold... Well yeah, in an ideal world.. If somebody is tuned into their [not diseased or disabled so far] body, perfectly, all the time, no distractions, nothing to fret over, I should think awareness of one's own interoception could help keep everything in there on track... 

But... but... how well does this pan out in real life? People close to us that we depend on end up tragically dying, affecting us the rest of our lives, loved ones become ill and fade off into dementia, we ourselves are diagnosed with something serious and our whole life changes and now revolves around the chronic, maybe terminal illness, or we are involved in an accident while trying to have some fun for a change, and we are left permanently disabled by it, not to mention all the life sucked away simply having to recuperate, recover, undergo rehab. Sometimes three or four of these events occur all in the space of a year with some people. 

The vast Niagara Falls of stress that some people have had fall on their heads boggles my mind sometimes. Yeah, as a therapist I do take it on. Not directly, but over time, I sometimes find I have to get away from people completely for awhile. Not that I don't still want to try to help them, but sometimes, it just gets overwhelming, what people go through. My inner critical cognition usually pipes up with something like, "You are not a very strong person (me myself and I..) - you're being a selfish wimp. Look how easy and smooth your life is compared to theirs. Get back in there and keep helping." But my insular cortex and anterior cingulate cortex go, "Whoa there my friend, I canna give her more - she's creaking, the whole ship! Time to dry dock and look after the hull, scrape off all the barnacles or they'll eat all the way through and she'll sink and then she'll be of no use to anyone ever again. So back off and give her space to find some peace." 
[I love this critter brain of mine - it looks after me the best it can, bravely standing right up to the socially installed helper brain the way it does! I feel lucky that somehow, I ended up living a life that I can escape from, when and if I need to.]

The corollary of this is how sensitive and aware of the impact of their story on others people instinctively are. Not very many people go around boasting about how wonderful they are because they survived giant piles of imposed stress and ended up injured or with dead relatives or a son who shot himself or a daughter who became a drug addict or you name it plus they have to look after a grandchild with some bizarre disorder that requires non-stop attention plus they are dealing with a parent with failing health who tends to fall over and break his or her hips.. 

On the contrary, usually people (at least the ones I meet) are circumspect. You have to gently inquire to get the broader picture. They come in with pain, and they don't want to have it be connected with who they are and what they do 24/7 and who they're involved with and in what capacity... Inescapably. They might not want to know that stress affects cortisol levels and their desire to move around for pleasure. Maybe they no longer feel they are entitled to feel pleasure from life. From moving. They might not even remember that ordinary movement is supposed to feel good. They may have become so bogged down, just barely hanging on day by day that they don't recall the last time they experienced yes-ciception of any kind. Being in a body has become kinda beside the point, they are so busy caretaking other people through the chaos of mere existence, because they are good people and they think they have to sacrifice themselves to a social ideal. To be happy in the future or something. Or to earn respect. Or a ticket to an imaginary heaven.
They want pain to be some kind of detachable, objective problem that they can take in to get fixed. They do not want to have to own it. They don't want to see connections. Not right away anyway.
It takes some fancy accompanying sometimes, to reach the place where you can actually help somebody see how pain works. Mostly, I rely on what we both gleaned from careful listening during the interview, my little five-to-ten minute intro to nervous system function, then the most innocuous manual therapy I've ever come up with while still managing to be slightly provocative - i.e., skin stretching in various positions.

It's all a bit of a dilemma. As a PT, part of a supposed helping profession, it's a dilemma. There you are, posing as a member of a profession that prides itself on being optimistically able to rehab and return people back to productive lives, which blithely teaches students a biomedical model of pain, pretty much, focusing on "correcting" anatomy and movement thereof. The truth is, the more one learns about pain the more one can see how it's connected to everything in life, not the least bit detachable. Ignoring it isn't any kind of answer. Projecting it onto a body part doesn't work very well - it's not the least bit blameable on some body part or some innocent tissue. It's not objective. Not objectifi-able. Not at all. This is exactly what Melzack is being all counter-cultural about - he's saying, come on people, we must face the truth here. Pain is bio, and psycho, and social. Pain is always personal. And stress (also [mostly] social) is a huge piece. 

But I digress terribly. Back to Chrousos and Gold.
They say, page 1250,
"In both hyperactive and hypoactive individuals, the range of the optimum for sense of well-being and performance would be significantly curtailed. The dysphoric component of both extreme states may be explained, respectively, by hyperstimulation and tachyphylaxis or by inadequate stimulation of the dopaminergic reward system, whose activity is influenced accordingly by the stress system."
Nothing like suppression of the dopamine systems to make a person not feel like moving, make them want to roll up into a ball whenever they get the chance, or at the other extreme, hyperstimulation enough to make them unable to sit or lay still long enough to get anything yes-ciceptive out of a human primate social grooming session.
"... Patients with melancholic depression... who would be expected to express an enhanced response of the stress system when not depressed and while eucortisolemic, might be quite unresponsive to stimuli from the external world during a depressive episode. At that time, the heightened awareness of internal cues and painful memories, and concurrent activation of the stress system, could make the system refractory to stressors that would otherwise influence its activity. Conversely, a patient with panic disorder will frequently express panic at times of the day that the stress system is at the nadir of its function."
I don't know what "eucortisolemic" means.. I think it might mean hypercortisolemic. But I'm not sure. And google can't find an easy answer for me.

About PTSD: 
"These patients are typically in a basal state of stress system hypoactivity that, however, is associated with heightened responses of the stress system to certain stressors. More detailed studies will be needed before one knows exactly whether a disease state represents hypersensitivity or hyposensitivity of the stress system to stressors and whether situations exist in which, depending on the state, shifts could take place from one side of the dose-response curve to the other. Such a shift of the dose-response curve from the left extreme to the right extreme appears to occur during the early period of cocaine withdrawal." 
Does this mean post traumatic stress disorder is like addiction to harmful stress? I don't really understand that part. Plus it's from 1992. I imagine a lot of work has been done on it since then.

Edit: Aug 8/2013
Found a tidbit from earlier in the year on treatment for PTSD that I want to include: Virtual reality provides relief from soldiers' trauma. Just talking about the trauma didn't help as much as total immersion into it again, but all the while knowing it was just a video game. 
"Soldiers with PTSD either discussed their most traumatic experience over and over while looking at computer-presented images of similar scenes, or were immersed in virtual reality simulations, in which sights, sounds, vibrations and even smells could be tailored to their most traumatic memory."After nine weeks of treatment involving up to 18 sessions (each 90 minutes long), both groups showed similar reductions in their symptoms. But clear differences emerged when McLay examined them again three months later. By that time, the improvements in the group given traditional exposure therapy had largely disappeared. "But in the virtual reality therapy group the gains continued," McLay says."
Also, service dogs have been found to be helpful for PTSD symptom management. One critter brain helping another.

Moving on: 
"Animal infants that are separated from their mothers, for instance, develop a syndrome characterized by hyperreactivity of the stress system to stressors and altered, "anxiety-like" behaviors throughout the rest of their lives."
Great.. break out the balloons and party hats. 
If you happened to be born in the 40's or 50's, in North America, the medical fad was, you were born in a hospital from a mother who was etherized, so her uterus had to work all by itself. And you ended up etherized too, obviously. First drug encounter imposed by one's social context. Great. Welcome to the planet, little baby. 
Then you were removed from your mother (maybe against her desire to bond, because paternalistic medical model of the day told the mom it was important to rest after having her body blown apart by birth), and so you woke up in a ward full of other crying babies, left there, mostly without any maternal contact, for days. How smart an idea was that? The first thing your baby brain learned, the first thing it neuroplasticized itself around,  was that life was full of nothing but being hungry tired cold and lonely amidst a deafening din of noisy woe, plus existential terror, because your mother's familiar body, the only thing you already "knew," was gone for stretches of time that felt like infinity, leaving you hungry and lonely and skin-starved. These days, if you happen to be born premature, add 15 nociceptive heel sticks for blood draw every day on top of all that.
But I digress yet again. 

Here is Chrousos and Gold's final paragraph:
"Based on the information presented on the physiological regulation of the stress system, one could postulate a number of potential biochemical defects that could, in theory, lead to basal or stressor-induced hyperactivity or hypo-activity of this system. Thus, increased CRH peptidergic, serotonergic, cholinergic, catecholaminergic, or thyroid hormone-mediated stimulatory activity, or decreased inhibitory activity of the CRH-peptidergic, gamma-aminobutyric acid/benzodiazepine, glucocorticoid-mediated, and opioid- or corticotropin- peptidergic influences on the stress system could result in diseases characterized by increased stress system activity.   
"The converse biochemical changes, on the other hand, would be expected in diseases characterized by hypoactivity of the stress system. We may be quite far from definitively elucidating the molecular defects responsible for a disease potentially attributable to a dysregulated stress system, such as depression, anorexia nervosa, or autoimmune disease. Moreover, it is likely that a combination of molecular defects and/or environmental events may be required for the expression of each of these illnesses. However, the theoretical framework for testing the hypothesis that a dysregulation in the stress system can lead to human disease has been set in place, with the potential for improved understanding, diagnosis, and treatment of these disorders."


Yeah, they were talking about categorical disorders, illnesses. 

But then there is life itself, in a body. 
Life, the ultimate terminal disease. 
I should think stress response, and a brain that has learned to mount a successful stress response to it, would all depend on pure luck, having picked a parental gene pool well, and then a favourable context, just like everything else. Whatever has been learned by a brain is what it will default to as "normal." 
Society is a stressor - I don't care what kind of society it is. Some are way worse than others, but all of them are going to be detrimental and supportive in different ways to different people at different ages, and having a connection to one is better than not having any at all, so there you go. There is no cure for social stress response induction. As human primates, we are stuck with life inside a troop. Not much option to go off and be a lone tiger or leopard. So we have to figure out how to set boundaries instead, then learn to not feel guilty about doing so. 
I know... it's hard to do retroactively, after you already took on way more than you can chew earlier in life in some fit of over-optimistic hormonal I-can-handle-whatever-life-dishes-me deluded state; only too late does it dawn on you that nothing you've taken on ever shrinks, instead responsibilities only ever seem to expand, and you find yourself hopelessly entangled in a bunch of other peoples' lives, so you do your best to keep your chin up. I get that. It's how we humans evolved. Long enough to reproduce, then evolution doesn't care.
I've heard that stress means you're living somebody else's life. What I really think is that life is stress, and finally you die of it, stress that is expressed one way or another, systems failure, etc. I mean, really there is no escaping stress. Or what comes at the end.
Not that there's anything inherently wrong with being made from stardust, recycled endlessly on the planet with which we interact with every breath we inhale and exhale and wholly subject to intersubjective illusion until finally we stop, or drop, having oxidized ourselves pretty much completely. It's just thermodynamics. It's just entropy. Everything in the entire universe is subject to it. 
It's all going to be OK. Really. Life will go on long after our particular ember of it has gone out.  



Tomorrow we will return to Melzack and Katz

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 7bGate 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 9cNeuromatrix: 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 10dConclusion 3: The brain's sense of "Self" can INclude missing parts, or EXclude actual parts, of the biological body Part 10eThe neural network that both comprises and moves "Self" is (only)modified by sensory experience

Part 11We 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 12gThe 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 14cPW Nathan was an interesting pain researcher  Part 14dBrain 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

No comments: