Sunday, June 29, 2014

Fabbro & Crescentini: "Facing the experience of pain: A neuropsychological perspective."

Most of the time my mental life feels like I'm in an undertow being dragged through time toward open sea - it's OK,  I've learned that I can breathe just fine deep under the pressure of all this mental water: Once in awhile, though, I feel like a surprise current lifts me up into sunshine and oxygen. 

This paper is like that surprise current. In fact, it's like the outline of the book I would always have written but never did, because what would have been the point, who would give a (you know)...  the grand finale of the book would have been how to touch people who have pain, or something totally and equally mundane and presumptuous, in that most of my outer life has to do with that and only that, and most people already think they already know how to do that, and they're right and wrong at the same time, and have all kinds of reasons why they think they're right and I'm wrong, and a lot of the time I think I must be wrong, while at least some of the time I think they are, and so on and so forth..  so it's gets exhausting trying to figure out how to surface by myself. Which is why I like to be part of SomaSimple where the regulars all joke about how dead we all already are...

Then someone posts a paper to SomaSimple, and it turns out to be absolutely the medicine I never even knew I needed.

The paper is about pain. Here is the abstract. Facing the experience of pain: A neuropsychological perspective. 

"Pain is an experience that none of us would like to have but that each one of us is destined to experience in our lives. Despite its pervasiveness, the experience of pain remains problematic and complex in its depth. Pain is a multidimensional experience that involves nociception as well as emotional and cognitive aspects that can modulate its perception. Following a brief discussion of the neurobiological mechanisms underlying pain, the purpose of this review is to discuss the main psychological, neuropsychological, cultural, and existential aspects which are the basis of diverse forms of pain, like the pain of separation from caregivers or from ourselves (e.g., connected to the thought of our death), the suffering that we experience observing other people's pain, the pain of change and the existential pain connected to the temporal dimension of the mind. Finally, after a discussion of how the mind is able to not only create but also alleviate the pain, through mechanisms such as the expectation of the treatment and the hope of healing, we conclude by discussing neuropsychological research data and the attitude promoted by mindfulness meditation in relation to the pain. An attitude in which, instead to avoid and reject the pain, one learns to face mindfully the experience of pain."

One has to look past the typical error these authors and almost everybody else makes, referring to "pain receptors" instead of nociceptors or conflating the meanings into each other interchangeably.

It's set up with 8 sections, possibly reflective of a Buddhist eight-fold path arrangement, possibly reflective of an eight-week mindfulness training program for pain, or maybe both. Ultimately it's about mindful acceptance of pain, any kind of pain, including existential angst. The authors point out in section 7, "The pain of change" (my favourite!) that the culture we're in does nothing to alleviate certain incorrect perceptions about physical and psychological existence. They more less say, the culture promotes illusion by reinforcing the false idea that objects are permanent (they can't be - everything is subject to entropy, everything burns in the fire eventually); furthermore the culture does us no favour by feeding us fairytales about what happens after - that only messes up our heads more, leaving us less capable of helping ourselves to combat our own suffering in the here and now. 

Here is the synopsis:

1. Pain is inevitable. There is pain of all kinds in all creatures, e.g., anxiety of separation from caregiver seen in baby chicks. 

2. Neuroanatomy, discussion of medial & lateral ascending nociceptive systems, and descending control systems. 

3. Section 7 specifically: After a comment related to how hard it has been for science to study consciousness, the authors describe brain evolution, describe the "blocks" (building blocks, not impediments) inside the brain and their generally accepted function. Basic neuroanatomy. Triune brain type stuff. 

4. A definition: 
"Many authors believe that consciousness is the world that appears every morning when we wake up after a, more or less unconscious, sleep. When the world appears, two “entities” are manifested to consciousness: on the one hand the objects that populate the world and on the other the subject (the self) who observes and interacts with them. Both the objects in the world and the self are arranged in space and, as we have seen for humans, also in time [90–92]. Now we begin to think that the objects, the self, the space and the time may not be real, but only “mental constructs”." 

5. A long section supporting that view with references.

6. Description of a "basal block"  "consisting of a spinal cord, the brain stem (with a well-developed and layered optic tectum), the hypothalamus, the oldest portions of the cerebellum, and some telencephalic structures (e.g., diencephalon, olfactory lobe)" - all vertebrates have this. It's the oldest part. It provides a rudimentary "sense of self". Vision developed.

7. Mammals developed a "second block" - "considerable development of both the medial cerebral cortex (hippocampus, limbic lobe) and the lateral cortex (temporal lobe and parietal lobe)." These came with the ability to autonomously thermoregulate/be active in the nighttime. Hearing and smell evolved. A second level of representation of "self" formed - sounds and smells became paired with visual "imagination." 

8. A third level of representation developed with acquisition of language. Language however depends a lot, still, on visual imagery. 

9. Then, a little tutorial on how everything is a verb, not a noun. 

"At this point it is questionable whether in the outside world there are space, time, and objects. Albert Einstein believed that the concept of “object” was probably a creation of the human mind and of some other animal [111]. The idea that there are stable objects is operationally useful for moving through the world. If I refer to a particular book or a particular car it is not difficult to understand each other at the practical level. However, it is necessary to distinguish the practical level from the ontological level. For the Greek philosopher Heraclitus (535–475 BC) and for the Indian philosophical and psychological genius known as the Buddha (485–405 BC) objects do not really exist but there exist only processes. In this sense, a book, a car, a house originate (are built), show (last for a certain period of time), and then disappear. For Heraclitus and the Buddha all things behave like fire: originate, burn up, and then are extinguished [112,113]. Now we know that all entities known in the universe are, in effect, processes."

My bolds. Everything is subject to entropy, baby. Everything.

10. The authors go on: it isn't easy, being free to think of oneself as a "process" and not a "thing", particularly since the culture continually reinforces the idea that one is a "thing." 
"Moving from a worldview formed by “stable objects” to a worldview formed by processes is not easy. The confusion between a representation of the existing world composed of space, time, objects, and self and the ontological dimension has generated in humans what has been called the “pain of change”, or the pain of existence [114]. To consider the world as ontologically consisting of objects has encouraged humans to desire to possess and accumulate. Not only humans have been affected by the fear of change, which probably has its neurobiological origin in the pain of separation. Moreover, in current scientific and philosophical thinking, the idea has prevailed that the equilibrium is the ideal condition, while it is obvious that the biological and cultural life are based only on changes, or the progressive succession of one crisis after another. In thermodynamic, in fact, equilibrium corresponds to the “Heat Death” [115]. Humans have learned through culture and education to consider the processes as objects and, at a deeper level, to consider the self as an object of indefinite or eternal duration. Thus, the idea of separation from the self and the thought of one’s own death have become the primary sources of anguish [13]. Instead of changing the perspective, many cultures, especially the West, have developed a series of myths and stories to avoid the pain of change [116]."

That's it, in a nutshell. Our brain/mind becomes habituated to thinking processes served up by our culture that do not serve us well in the long run. I've often criticized the English language for not having enough verbs, and too many nouns, and for turning concepts into nouns as though they were something real instead of a symbol of a thought "process".. 
But I digress: back to the paper.

11. The authors continue:
"Starting with some typical human neuropsychological experiences (e.g., out of body experiences, OBEs), supernatural realities have probably been conceived in which the change is no longer present and the self (often referred to as soul) is eternal [117]. Instead of dealing with the pain with awareness, trying to stay with dignity in front of it, it was decided to adopt the strategy of avoidance and escape [118]. Unfortunately, the escape from a psychological problem does not extinguish the problem, but probably nourishes it [73,119]."

Exactly - religion was invented to serve the culture, not the humans processing, not the human processors, within it. Religion and culture have been allowed to dominate, keep terrified people terrified of life, and terrified of death, giving them stories instead of helping them integrate the simple facts of existence. We're here one minute, and the next we're gone. Religions colonize minds to the point of such complete dissociation that people are willing to "die" to support the very religion that dissociates them from having an intact psychology. Artificially installed, self-perpetuating, positive-feedback-loopy craziness. 
But again, I have digressed.

12. The last section is mostly a plug for mindfulness meditation, for pain - be it the pain of existence or physically perceived pain. 
"The attitude of mindfulness meditation in the treatment of pain is completely different from the so-called natural reactions. First of all, the universality of the conditions of illness, suffering and pain are recognized... Through mindfulness one learns to become aware of physical and/or psychological pain when it is present; moreover one also learns, slowly and with a lot of difficulties, to become aware of the impulses that arise in response to pain. Thus, instead of reacting, we learn to stand still and look carefully at all the sensations of pain and at what is happening in our minds. Not only we try not to run away from pain, but we also try to cultivate an attitude of kind reception of it, maintaining at the same time a slight smile on the lips and an attitude of non-attachment (letting go) [127–129]... [a bunch more neuroanatomy] ...   The courses of eight weeks of mindfulness meditation that are organized in a number of hospitals to cope with the pain are definitely a good starting point; however, the understanding of what mindfulness really is, is achieved only through a series of insights that come from a long and steady meditation practice [137–139]. In fact, according to Grant and Rainville, they are required at least 2000 h of practice (about eight years with a meditative practice of 1 h per day) to be able to develop some analgesic effects through meditation [140]. To mindfully face the experience of pain is therefore not at all easy, but it is possible."

OK, here I feel a bit of a departure.. I'd rather speed that up a bit.
I get that existence is, all by itself, painful and angst-ridden. I get that that's just life. There really isn't anything better to do with one's life than to get through as best you can, with whatever brain you've managed to grow in spite of whatever culture you may have ended up in, with all sorts of influences and circumstances well beyond your own control, and with a healthy attitude born from having separated existential wheat from cultural chaff, not buying the lies anymore, doing a thorough mental, emotional, psychological house-cleaning, tossing out all irrelevancies. I don't think you can get to my age and still be healthy if that hasn't been done at some point along the way.

But if it's physically perceived pain, well, there are some things I think we can do about that, if it's the kind that changes with movement or position or use. 

Having said that, I do recall a pain I once felt deep in my right hip, sort of pelvic floor, sort of buttock... I think it started up from trying to do abduction stretches or something. It lasted a long time. Months and months. I got some treatment for it, and it felt better, but still it was bad enough I couldn't sit on the floor cross-legged for very long.
I went to a meditation event. Lots of other people were in the room, sitting on the floor. I couldn't - I had to sit in a chair. We were asked to focus on any pain we felt, and send it "light". Whatever kind of pain didn't matter. I chose my crabby butt pain to focus on.
I remember what I was wearing, and I remember there was some tinkly sitar music CD playing. Wonderfully, surprisingly, all the residual pain suddenly vanished along with the movement impairment. So... 

It went away in a single afternoon, not after 2000 hours.

It went away in one distinct moment. I do distinctly remember how relieving that felt.
It never ever came back. Not in that part of my representational map, anyway.. 

Yay for my capable brain. I have no idea how it did that. I only care that it could, and did. 


Fabbro F, Crescentini C; Facing the experience of pain: A neuropsychological perspective. Phys Life Rev. 2013 Dec 19. pii: S1571-0645(13)00202-9

Wednesday, June 25, 2014

Suzana Herculano-Houzel has novel news about glia in the human brain

I'm way behind in my MOOC these days, but I'm still learning stuff - recently from the interchange between Peggy Mason and other students. Yesterday I spotted this blogpost in my news feed: 

Neurons outnumber glia? Yup, a fact learned from a MOOCer. (1) For the longest time the dogma has been that glia outnumber neurons by a ratio of 10:1. This woman says, no, that's not right

Why is this important to me? Because prominent pain theorists in my profession have been saying, number 1, that glia-neuron ratios in the human brain are more like 20:1 (from a lecture at NOI 2012, scroll down), and number two (and incidentally to this, but incorrectly according to me) that glia are immune cells, instead of glia are non-neuronal neural cells from the neural tube that can exhibit certain immune-like properties at times. Anyway, the gist of the argument is that glia are overwhelmingly numerous and can bother neurons instead of maintaining them.

Well, I don't think the "glia are immune cells" assertion was correct; now it looks like maybe the "overwhelming numbers" assertion is suddenly weaker. Bear in mind meanwhile, that I completely support the move away from biomechanical clinical reasoning in this profession, and toward nervous system-based reasoning, theory, practice methods, explanatory models, treatment models. 

Here are some more links.

This post in this thread

Here is a link to Suzana Herculano-Houzel's lab. Under a section titled "Dogmas that are no more" she states, 
there are not 10 times more glial cells than neurons in the human brain, but at most 1 glial cell to every neuron in the whole brain
Here is a link to the abstract of her paper about this. Not all brains are made the same: new views on brain scaling in evolution. (2)

Here is a link to her TED talk, What is so special about the human brain? 

She points out in the paper that in some areas of the brain,  glial ratio is higher and in other areas (e.g., cerebellum) way lower. 

Here is a recent paper on this:  The glia/neuron ratio: How it varies uniformly across brain structures and species and what that means for brain physiology and evolution.(3)

"It is a widespread notion that the proportion of glial to neuronal cells in the brain increases with brain size, to the point that glial cells represent "about 90% of all cells in the human brain." This notion, however, is wrong on both counts: neither does the glia/neuron ratio increase uniformly with brain size, nor do glial cells represent the majority of cells in the human brain. This review examines the origin of interest in the glia/neuron ratio; the original evidence that led to the notion that it increases with brain size; the extent to which this concept can be applied to white matter and whole brains and the recent supporting evidence that the glia/neuron ratio does not increase with brain size, but rather, and in surprisingly uniform fashion, with decreasing neuronal density due to increasing average neuronal cell size, across brain structures and species. Variations in the glia/neuron ratio are proposed to be related not to the supposed larger metabolic cost of larger neurons (given that this cost is not found to vary with neuronal density), but simply to the large variation in neuronal sizes across brain structures and species in the face of less overall variation in glial cell sizes, with interesting implications for brain physiology. The emerging evidence that the glia/neuron ratio varies uniformly across the different brain structures of mammalian species that diverged as early as 90 million years ago in evolution highlights how fundamental for brain function must be the interaction between glial cells and neurons."

It makes total sense to me that it would be thus - the brain is an evolved phenomenon, not a done deal. It's not homogeneous, not a monolith - more like an ecosystem. 

This makes sense, looking back at the TRPv1 business about how TRPv1 receptors so heavily influence the blood brain barrier (5) in some parts of the brain (spinal cord and just about all the critter brain) but not other parts (cerebellum and frontal lobes).  According to this new information, one might see a pattern here: glia are not as numerous as previously supposed, glia form the blood brain barrier, the more there are in a given location the more affected they would become, presumably, and the less there are in a given region the less affected that region would be by something affecting the bloodbrain barrier. 

1. The Brain is Soooo Cool blog, Peggy Mason, post from June 17/2014

2. Herculano-Houzel S.; Not all brains are made the same: new views on brain scaling in evolution. Brain Behav Evol. 2011;78(1):22-36

5. Simon Beggs, Xue Jun Liu, Chun Kwan and Michael W Salter; Peripheral nerve injury and TRPV1-expressing primary afferent C-fibers cause opening of the blood-brain barrier. Molecular Pain 2010, 6:74

Friday, June 20, 2014

Interview with Patrick Wall

This is an old interview - Patrick Wall died in 2001 - but it's wonderful to hear his voice, his massive wisdom, through airwaves. 

I suspect the interview was edited to focus only on pain - there is a second guest whose field of expertise is vision, but the focus seems to be entirely on pain. 

It's about a half hour long. Well worth listening to. I'm on my third time through. 

Tuesday, June 17, 2014

TRPv1 receptors and aging

TRPV1 Pain Receptors Regulate Longevity and Metabolism by Neuropeptide Signaling
The sensation of pain is associated with increased mortality, but it is unknown whether pain perception can directly affect aging. We find that mice lacking TRPV1 pain receptors are long-lived, displaying a youthful metabolic profile at old age. Loss of TRPV1 inactivates a calcium-signaling cascade that ends in the nuclear exclusion of the CREB-regulated transcriptional coactivator CRTC1 within pain sensory neurons originating from the spinal cord. In long-lived TRPV1 knockout mice, CRTC1 nuclear exclusion decreases production of the neuropeptide CGRP from sensory endings innervating the pancreatic islets, subsequently promoting insulin secretion and metabolic health. In contrast, CGRP homeostasis is disrupted with age in wild-type mice, resulting in metabolic decline. We show that pharmacologic inactivation of CGRP receptors in old wild-type animals can restore metabolic health. These data suggest that ablation of select pain sensory receptors or the inhibition of CGRP are associated with increased metabolic health and control longevity.
Other than having to substitute (as usual) the word "nociception" for the word "pain" throughout, this is an absolutely fascinating paper, which presents all sorts of evidence in favour of the idea that TRPv1 receptors are one of the big causes of the evils of aging.
It makes some sense.. when nociceptors go off they start chain reactions in other nociceptors (peripheral sensitization) that encourages them to make more TRPv1 receptors.. all that. And the function of C fibres in the first place is to sit there and make CGR, Substance P, etc., and leak it strategically out into tissue as "growth factors" to help tissue heal, or keep on "growing".. But this paper takes it a step more - Too many TRPv1 receptors leads to more aging, and more inflammation.. inactivating CGRP receptors slows decline. Knocking out the TRPv1 receptor slows decline. Reverses it even. 
All over the inside of the body, organs, brain itself..

I know it's behind a paywall. Alas.

So, read No Pain, Big Gain on the paper, and this one, No Pain, Time Gained from Pain Research Forum.

If you can get it, it's good to read this one first: The Hallmarks of Aging, open access.

TRPv1 receptors, I gotta admit, they are pretty weird and powerful.. This open access paper, Peripheral nerve injury and TRPV1-expressing primary afferent C-fibers cause opening of the blood-brain barrier, from 2010, explains how they are able to open the spinal-cord-blood barrier for up to a week, but not just the spinal cord - brain too! Frontal lobes and cerebellum are spared, though, for some strange reason, which I'm sure will be made more clear as time goes on.. maybe to do with how the brain develops in the first place, before it grows those big blobs of cerebellum and frontal lobes.

This more recent paper, Central Terminal Sensitization of TRPV1 by Descending Serotonergic Facilitation Modulates Chronic Pain, explains how they are kept "fanned" by serotonin from nuclei in the medulla. Read Stephani Sutherland's post about it in order to fathom better what is implicated by this particular descending facilitation. Remember that thin C sensory neurons have one foot on the platform and the other on the train. I.e., one end out in the periphery and the other in the dorsal horn. A cell body in between, living in a dorsal root ganglion, responding to input at either end, presumably being stimulated to crank out even more TRPv1 receptors..

The Riera paper. It's amazing. Maybe some day it will be possible to go get a TRPv1-ectomy or something. Take a pill to block unwanted ravages of CGRP. 

I had not come across the concept "health-span" before. Clearly it's a more attractive proposition than mere "life-span."


1. Céline E. Riera, Mark O. Huising, Patricia Follett, Mathias Leblanc,  Jonathan Halloran, Roger Van Andel,  Carlos Daniel de Magalhaes Filho, Carsten Merkwirth, Andrew Dillin;  TRPV1 Pain Receptors Regulate Longevity and Metabolism by Neuropeptide Signaling. Cell, Volume 157, Issue 5, 22 May 2014, Pages 1023–1036

2. Kate Yandell; No Pain, Big Gain. The Scientist May 22, 2014

3. Michele Solis; No Pain, Time Gained; PainResearchForum Jun 4, 2014

4. Carlos López-Otín, Maria A. Blasco, Linda Partridge, Manuel Serrano, and Guido Kroemer; The Hallmarks of Aging. Cell. Jun 6, 2013; 153(6): 1194–1217.

5. Simon Beggs, Xue Jun Liu, Chun Kwan and Michael W Salter; Peripheral nerve injury and TRPV1-expressing primary afferent C-fibers cause opening of the blood-brain barrier. Molecular Pain 2010, 6:74

6. Kim YS, Chu Y, Han L1, Li M, Li Z, Lavinka PC, Sun S, Tang Z, Park K, Caterina MJ, Ren K, Dubner R, Wei F, Dong X; Central terminal sensitization of TRPV1 by descending serotonergic facilitation modulates chronic pain. Neuron. 2014 Feb 19;81(4):873-87

7. Stephani Sutherland;  Central TRPV1 Contributes to Neuropathic Hyperalgesia:

Friday, June 13, 2014

Heading to the UK in September

PhysioUK has invited me to teach in the UK. Here is a link to a "priority notification" webpage they have built, so that people can pre-register.

The dates will be Sept 20-23 for London, and another batch in Manchester (to be confirmed) the following week.

Thursday, June 12, 2014

Why language matters: "Avoiding Stupidity is Easier than Seeking Brilliance"

Sometimes it feels like the pile just grows higher and deeper with every year that passes.

What pile in particular?

The pile of cognitive bias and poor use of language - that pile.

Recently a blogpost appeared promoting a tissue-blaming and tissue-based manual therapy method that combines a kind of handling with a very botched explanatory model, historically so pounded into/conflated with the handling itself, that it would seem no one ever gave a fig about explaining it better. I replied a bunch of times, which has become a slideshow  now.. the conversation itself is still ongoing. A SomaSimple thread exists about it, too. 

Tissue-based targeting and tissue-based reasoning have GOT to be separated out, some day, from what we really do, which is try to help people with pain problems. (Before I die, I hope..)
Why? Who cares?

It matters because tissue-based referencing is noceboic to patients, that's why. Adriaan Louw says so.

It matters because patients don't care about tissue, they want to be able to move easier, or at least, not be afraid of moving even if their pain isn't the kind that responds to manual treatment. Bronnie Thompson says so. 

From this blogpost:

"In expert tennis, about 80 per cent of the points are won; in amateur tennis, about 80 per cent of the points are lost. In other words, professional tennis is a Winner’s Game – the final outcome is determined by the activities of the winner – and amateur tennis is a Loser’s Game – the final outcome is determined by the activities of the loser. The two games are, in their fundamental characteristic, not at all the same. They are opposites..." 
Think about it.

Eighty percent of professional games are won because the professional knows how to avoid mistakes.

Eighty percent of amateur games are lost, because one amateur makes more mistakes than the other does.
To win, all you have to do is make fewer mistakes!

In manual therapy terms, that might translate into not looking for, finding, or most of all not talking about postural defects, or bio-mechanical faults, to the patient, instead looking at only gross movement amounts and comfort levels instead.
Why not? Because "tissue faults" are misleading, and don't have anything to do with causing pain. Chances are higher that if they exist at all, they are a result of pain, not a cause, apart from any someone might have been born with.

The lesson to take away: Avoiding stupidity is easier than seeking brilliance.

One way to look at the mess manual therapy is in and always has been in would be to ignore the mess it's in and always has been in, with it's postural/structural/biomechanical/bio-medical/all the purely imagination-based cause-effect posthoc reasoning inherent in it. 

Yes, one could simply learn to ignore it. But I can't. Why not? Because I AM a manual therapist, and I want it to be better. 

That's why. 
For all the reasons I care about helping people who hurt. 
For all the reasons I hate when I get into pain myself (so fortunate that it's a very rare experience for me). 
For all the reasons that it matters in general for people in my profession to grow up intellectually and learn how to use their own brain instead of relying on manual therapy "culture" to do all their thinking for them or to have worked through all its own fallacious reasoning already. It hasn't, and it will never be able to, unless each of us does our own heavy lifting first.

And I don't care how many certifications someone has, or letters appear behind his or her name, or "big names" they can brag about treating. That sort of thing simply doesn't impress me any more.

Yesterday I was listening to the radio as I worked on a new image for my treatment manual. I learned that at McGill University, and for historic reasons unique to Canada, the law program prepares its students for the world by teaching civil law and common law simultaneously. It's done that way because it was noted that in the past, if one set of law was taught before the other in a linear manner, students would prefer whichever version they were taught first, that form would take over their brains, and from then on they would consider that form more important than the other form. So, the instructors decided to teach them simultaneously because both are equally important in Canada.

I thought about manual therapy, how it's taught operator-style to therapists, how that skews them into being egoists, thinking they have control over a process which in its essence is a dance between two nervous systems, equally, and over tissue targets that they can't even touch except via a blubber layer that slides all over the place and swiftly informs the brain about whatever is going on with its organism. So delusional.

What if manual therapy were taught from the start that it's about the dance, instead? 

I try hard to do that. I'm sure I fail, but I do try.

I learned a new word today - conspicuity. This idea backs up the law school at McGill's idea that you have to be careful how information is presented or students will end up skewed toward a particular cognitive bias. 

Conspicuity refers to an object's ability to catch a person's attention. When something is conspicuous it is easily visible. There are two factors which determine conspicuity: sensory conspicuity and cognitive conspicuity. Sensory conspicuity factors are the physical properties an object has. If an item has bright colors, flashing lights, high contrast with environment, or other attention-grabbing physical properties it can attract a person’s attention much easier. For example, people tend to notice objects that are bright colors or crazy patterns before they notice other objects. Cognitive conspicuity factors pertain to objects that are familiar to someone. People tend to notice objects faster if they have some meaning to their lives. For example, when a person hears his/her name, their attention is drawn to the person who said it. The cocktail party effect describes the cognitive conspicuity factor as well. When an object isn’t conspicuous, it is easier to be intentionally blind to it. People tend to notice items if they capture their attention in some way. If the object isn’t visually prominent or relevant, there is a higher chance that a person will miss it.

Gee, do you think that cognitive conspicuity could refer to learning tissue-based treatment models, instead of nervous system-based treatment models, as well?  I think so..

Wednesday, June 04, 2014

Mice, learned helplessness, navy seals, depression (in no particular order)

This morning Tord Helsingeng in Norway posted an interesting piece to the Dermoneuromodulation group on Facebook:

Stress and the susceptible brain(1), by Bethany Brookshire, aka Scicurious, about a paper(2).

Here's the story:
1. The objective is to unravel depression.
2. Mice were put into cages with floors that shocked they little tiny tender feets, randomly, for an hour. They had to endure this for two days straight. Then they were allowed a place to escape to.
3. Eighty percent (80%) of the mice dove for the escape route; 20% didn't bother. These ones also lost weight and didn't appear to have much fun anymore.
4. The 80% that escaped were considered "resilient", i.e., could "still change their behaviors in response to stress", while the 20% that didn't bother were considered "susceptible", and a model for depression.
5. Here is the abstract:
When facing stress, most individuals are resilient whereas others are prone to developing mood disorders. The brain mechanisms underlying such divergent behavioral responses remain unclear. Here we used the learned helplessness procedure in mice to examine the role of the medial prefrontal cortex (mPFC), a brain region highly implicated in both clinical and animal models of depression, in adaptive and maladaptive behavioral responses to stress. We found that uncontrollable and inescapable stress induced behavioral state-dependent changes in the excitatory synapses onto a subset of mPFC neurons: those that were activated during behavioral responses as indicated by their expression of the activity reporter c-Fos. Whereas synaptic potentiation was linked to learned helplessness, a depression-like behavior, synaptic weakening, was associated with resilience to stress. Notably, enhancing the activity of mPFC neurons using a chemical–genetic method was sufficient to convert the resilient behavior into helplessness. Our results provide direct evidence that mPFC dysfunction is linked to maladaptive behavioral responses to stress, and suggest that enhanced excitatory synaptic drive onto mPFC neurons may underlie the previously reported hyperactivity of this brain region in depression.

Tord wondered why. Excellent question. Why would susceptibility/depression/failure to run away from an obvious stressor be associated with stronger synaptic activity in the medial prefrontal cortex?

When I went to look up medial prefrontal cortex, I found this:

Though depression involves an overall reduction in brain activity, some parts of the brain are more affected than others. In brain-imaging studies using PET scans, depressed people display abnormally low activity in the prefrontal cortex, and more specifically in its lateral, orbitofrontal, and ventromedial regions. And the severity of the depression often correlates with the extent of the decline in activity in the prefrontal cortex.

Wait... my bold. Isn't "low" the opposite of "stronger"? 
Or maybe: if the synapses are stronger, they don't have to be as active to ferry around the same amount of information. So the brain can make do with less activity and still know what it's doing.
Also this:
One of the regions of the prefrontal cortex that is most affected both by depression and by the manic phase of manic depression is the ventromedial cortex (also known as the subgenual cortex, because it sits beneath the genua, or knee, of the corpus callosum). This area deep inside the frontal lobes, on either side of the centre line separating the two hemispheres, lets us switch from one kind of affect to another. It is also heavily involved in feelings of pleasure and positive reinforcement.

Wait... pleasure?
Isn't this a contradiction? Would the 20% of mice who grimly stuck out the foot shocks be enjoying it?

I couldn't find anything about a dorsomedial prefrontal cortex in Brain from Top to Bottom, so I googled.. found this:

The PFC can be divided into ventromedial and dorsolateral regions, each of which is associated with posterior and subcortical brain regions. The ventromedial PFC (vmPFC) has reciprocal connections with brain regions that are associated with emotional processing (amygdala), memory (hippocampus) and higher order sensory processing (temporal visual association areas), as well as with the dorsolateral PFC (dlPFC). The dlPFC has reciprocal connections with brain regions that are associated with motor control (basal ganglia, premotor cortex, supplementary motor area), performance monitoring (cingulate cortex) and higher order sensory processing (association areas, parietal cortex). The vmPFC is well suited to support functions involving the integration of information about emotion, memory and environmental stimuli, and the dlPFC to support the regulation of behaviour and control of responses to environmental stimuli....

According to the SEC framework, counterfactual reasoning about action versus inaction preferentially recruits the dorsomedial PFC (dmPFC). Several neuroscience studies have implicated the dmPFC in the continuous internal monitoring of action (Botvinick et al. 2004). Barch et al. (2001) report an extensive meta-analysis of functional imaging studies that included data from a broad range of action monitoring tasks (e.g. involving the inhibition of prepotent responses) that recruited the dmPFC. Along the same lines, Waltonet al. (2004) observed activity in the dmPFC when participants monitored the outcome of self-selected actions. These findings suggest that the dmPFC is critical for monitoring the addition versus subtraction of actions for counterfactual reasoning. 

So... trying to figure out the mice business, none of the authors are clear about which bit, ventral or dorsal, they are examining. Maybe in mice there isn't enough in there to subdivide. Or maybe there is and they didn't. 

I have yet to fathom all that, but in the back of my mind I keep thinking about Navy Seals, what they have to go through in their training, how the situation is designed to weed out anyone who caves to the stress, who can't take the combination of socially imposed stress and physical stress.

"If you want to change the world, start by making your bed."

(Then, find people to help you paddle, measure people by the size of their heart, not their flippers, get over being a sugar cookie, don't be afraid of circuses, learn to slide down an obstacle head first, punch sharks right in the nose, don't lose it in the darkest moment, when you're up to your neck in mud, sing, and don't ever ever ring the bell.)

Maybe those little mice were doing their own version of navy seal training. Maybe they were inhibiting their own behaviour because that way, they could "enjoy"(if that's the right word..) maintaining an internal locus of control. 
Maybe the mice that headed off for the escape hatch were being driven to it by the external locus of control, handlers, which in human terms might be the equivalent of external "society" - an Other-Determined locus of control. Maybe the 20% who stayed put were thinking, screw you, I'm going to stay right here - this isn't so bad, I'm used to it now. Those jerks think they can make me go toward that spot where 80% are going, but I'll show them I'm different/I'm tough/ I'm an individual/I'm no sissy/I can take whatever they dish out/eff them - how much worse could it get?

Speaking of mouse handlers, it has come up that mice respond to the sex of the handler. If the handler is male, mice will not exhibit the same sorts of behaviours as when the handler is female. I.e., they don't exhibit "pain" behaviours. Even their chemistry (descending modulation) is different. 
So there is another twist. We don't know what sex the handler is in the "depression model" study, not from the abstract at least..


1. Brookshire B; Stress and the susceptible brain. Scicurious ScienceNews blog June 3/2014

2. Wang M, Perove Z, Arenkiel BJ, Li, B; Synaptic Modifications in the Medial Prefrontal Cortex in Susceptibility and Resilience to Stress. The Journal of Neuroscience, 28 May 2014, 34(22): 7485-7492

5. Parrish S; 10 Life Lessons From a Navy Seal. Farnam Street blog, May 27/2014

6. Brookshire B; You smell, and mice can tell. Scicurious ScienceNews blog May 2/2014

7. BIM: Of Mice and Men - Jeff Mogil on Grimacing, BodyInMind blog May 21/2014

8. Robert E Sorge, Loren J Martin, Kelsey A Isbester, Susana G Sotocinal, Sarah Rosen, Alexander H Tuttle, Jeffrey S Wieskopf, Erinn L Acland, Anastassia Dokova, Basil Kadoura, Philip Leger, Josiane C S Mapplebeck, Martina McPhail, Ada Delaney, Gustaf Wigerblad, Alan P Schumann, Tammie Quinn, Johannes Frasnelli, Camilla I Svensson, Wendy F Sternberg, & Jeffrey S Mogil; Olfactory exposure to males, including men, causes stress and related analgesia in rodents. Nature Methods 11, 629–632 (2014)