Saturday, October 24, 2015

Very enteric gut glia

Whoa.. totally sidetracked today by some basic information about the enteric nervous system I previously did not know.  Stumbled across this paper: Imaging neuron-glia interactions in the enteric nervous system, full text (at least for now..).

(I confess to not knowing that enteric neurons had "glia." Well, ok, I figured they likely had very thin (probably) myelination. But "glia"?)  

Turns out that they do. 
From Boesnams et al.: "Enteric glial cells share several features with astrocytes." (Unlike Schwann cells, I guess.)

"The ENS develops from neural crest cells that migrate and proliferate extensively to eventually form a network of interconnected ganglia throughout the entire length of the gut."

From Sasselli et al: "All enteric neurons and glia are derived from neural crest cells (NCC)"

Here is a trust-worthy, basic info page:  Enteric NS

Note to self: Live long and learn something new every day.

1. Valentina Sasselli,  Vassilis Pachnis, Alan J. Burns;  The enteric nervous system. Developmental Biology Volume 366, Issue 1, 1 June 2012, Pages 64–73 (FULL TEXT)
2. Furness JB; Enteric nervous system. Scholarpedia 2007
3. Werend Boesmans, Michiel A. Martens, Nathalie Weltens, Marlene M. Hao, Jan Tack, Carla Cirillo, and Pieter Vanden Berghe; Imaging neuron-glia interactions in the enteric nervous system. Front Cell Neurosci. 2013; 7: 183 (FULL TEXT)

Friday, October 16, 2015

A snapshot down into the chasm

If you look around the internet for images that relate to "chasm", you will find a lot of them that look like this:

Online battles still rage, on facebook and blogpost, mostly polite but not always, about what it is we think we are really doing in manual therapy. Here is a recent example. One of the replies I made there forms the basis of this blogpost.

Those of us who still imagine we are directly affecting "tissues", and "tissues" are responding, directly, to our tender or not-so-tender ministrations, fall into the "majority" camp, I think. 
Some will remain "laggards" until they die. 
I would categorize both these groups as "operators," because they insert themselves into the process as direct agents of any change. ("It was all about me, and my magic hands, making your tissues behave themselves.")

Those of us who think the nervous system is involved and on top of the process, adapting like crazy to everything we are doing to it, exploiting the opportunity offered it physically to create descending modulation that will result in greater movement and less pain (because it's cheaper), fall into the first camp. I would categorize this group as "interactors," because they realize the process of manual therapy is a dance between two nervous systems having a silent but busy kinesthetic conversation. ("It's all about your brain, taking advantage of an opportunity to change all its motor output and ultimately, be able to move you around more efficiently with less effort, in a less expensive manner. My job is just to hold up a flashlight, metaphorically speaking, so it can see what to do next. I'm just a catalyst, leaving nothing behind, as your nervous system "corrects" its own self.")

What's really at the bottom of this cognitive chasm?

A cognitive glitch resting on a mistake about who/what is the real "agent" of change. 

Climbing down to the bottom of the chasm

Regardless of whether we consider ourselves interactors or not, another person's tissue is all supposed to feel "homogeneous"; when we find something under our inquisitive little manual therapy fingers that doesn't feel that way, we are drawn to palpating it; if we aren't careful our heads fill up with all sorts of assumptions, many of which are wrong, based on the fact that the "blumps" we feel tend to go away when handled, and that usually people feel better and can move easier after. Thus do practitioners end up developing operative conceptual hallucinations based on palpatory pareidolia.

How do we get over that chasm?

I don't know for sure, and maybe any bridge over it is completely a fantasy, because I have read that anyone's brain can only have one conscious thought at a time: but I think we can at least swing across that chasm back and forth by being able to think bottom-up (outside-in) and top-down (patient's brain, inside-out) at exactly the same time. 

Sound impossible? 
Part of the cognitive hack I used on myself was to think at a neuro-cellular level instead of a tissue level, i.e., subtract any cells that were not neural. That way I could boil it down to there being just three very fast-conducting neuronal cells between my hand and the patient as person. From skin cell to sense of self. Then from patient's brain back out again, to all end organs of the patient's NS, like "muscles." Like smooth muscle. Like efferent autonomic nervous system. That was my (as an operator) new way in. 

I comforted myself that all the processing going on in there included me/any contact I was making, that the patient's brain was adding my exteroceptive contact with it into all its own body schema, and that its "maps" don't all load simultaneously, because of different fibres and different fibre speeds. That depending how slowly and carefully I loaded, how long I stayed in one place, what angle I used, whether I loaded or unloaded with one hand, some blump or other I could feel with my other hand, the brain would try to take advantage of every little shift and change, and exploit the input to self-correct its output, incuding any pain output. 

Pain is an output. That is something you simply have to accept as valid. It's an idea that changes everything. It goes completely against all models of pain that are bio-medical. It's a verb, not a noun. 

The other part of the cognitive hack was to realize that if there were only three cells between another person's brain and my hand, there were ALSO only three cells between my hand and my brain, and that I had to learn to listen acutely to feedback from my hands to tell me what was going on in the other person's nervous system. I.e., not their "tissues." ... that person's brain was feeling me, and my movement, intention, acceptance, emotion, every bit as closely as I was feeling "it." 

I could still do my job without cluttering up my mind worrying about tissue. Bam, I found myself interacting. Not only interacting with another person's nervous system, but interacting with my own, as well. Then my mind blew even more at the notion that there were four entities all interacting in complex ways - two nervous systems and two people inside them. 

Only after I started becoming aware I was interacting did I see the chasm, that I had crossed over it, and that in retrospect, I'd been "operating." (1)

What do we really "know" about "tissue"?

Probably not as much as we think we do. Take the case of muscle. I don't know how it is out there these days in education, but when I learned about the nervous system, it was taught as an outflow system, with the muscles as end organs. Technically this is perfectly true: However, my PT ed. took place way back when pain science had not yet made it onto anyone's radar, and PT training ended up being all about muscle. How to poke, prod, strengthen, loosen, muscle. Very very bottom-up. Very tissue-based.  All about striate muscle. Smooth muscle was inside the body in organs - we didn't need to worry about any of that.
I honestly cannot recall pain ever being discussed. I endured a very narrow education about treating other humans, with all the emphasis on "physical" - the "therapist" part was not taught in any systematic way. We were supposed to just soak that up along the way by hanging out with more senior therapists during clinical training. They would supposedly "model" being a therapist, and we were supposed to implicitly copy them, I guess. 

Except that some of them annoyed the bejeebers out of me, and I had no intention of ever copying them or modeling myself after them.

Physiology was taught in a disconnected fashion. We took physiology along with med students and nurses, so we were drenched in the biomedical model. I remember there were lots of graphs, and that I had to kill a turtle, both of which did not please me. It was never explained how touching people might affect their physiology. 

From the other side of the chasm, manual therapy models still, to this day, do not seem to care much about physiology. They are still very heavily tissue-based and dualistic.
The sensory nervous system and autonomic nervous system are not regarded as important for being feedback for a brain, trying its best to move its organism around. They are never suspected as having any potential glitches or positive feedback loops manifesting as localized peripheral physiological problems.

Anyway, back to "blumps." 

Smooth muscle cells (e.g., in skin organ for sure, vessels, sphincters, tubes, ducts, even fascia..) will contract (in the skin organ at least) when exposed to products of nociceptive-capable peptidergic neurons, such as Substance P, neurokinin A, CGRP.
It's a cellular function, chemical, that presumably evolved to assist with wound healing.

Normally, these substances excreted in dribble-like, tonic fashion by nociceptive-capable neurons, are used as trophic factors by their target tissue, and any excess cleared away by ordinary circulation. (You will find this explained well in Peggy Mason's book, Medical Neurobiology. (2) )

Presumably the smooth muscle cells *won't* be unduly activated, or stay activated, unless circumstances oblige, such as:
1. A big phasic burst of substances are released: One nociceptor's high threshold is reached and it depolarizes, spewing its products all over in faster, higher-than-usual concentrations, and starts a neurogenic cascade that activates other processes that in turn activates more nociceptive neurons which go on to activate other processes, etc., a physiological positive feedback loop..
2. Maybe a tipping point is reached whereby contraction of smooth muscle cells in fascial tissue occurs faster than any counteracting process that would result in their relaxation, and a mini "compartment syndrome" establishes itself
3. The "compartment syndrome" becomes exacerbated by the paradoxical effect of the smooth muscle in vasculature being relaxed (vasodilated) by the same substances, so that more blood is brought in or else can't escape contributing to more pressure inside the compartment
4. Some minor glitch occurs, whereby the reciprocal efferent "commands" by the ANS (contract, no, relax, no, contract) don't complement each other to smooth out the behaviour of the tissue end organs. And the fascial smooth muscle cells stay contracted. 
5. Maybe nociceptive-capable neurons don't have to be involved at all - maybe it's simply confusion within subsets of sympathetic efferent commands (contract, no, relax) that cancel each other too well and don't allow tissues to change at all.

Is that a blump I feel? 

Could "blumps" simply be just small (benign, non-urgent, non-medical, widely distributed) priapic-like* states anywhere in the body and palpable within its thick outer blubber layer?

Do they deserve to be stabbed? Is there not a kinder way to deal with them?


I have not yet found any histological papers that discuss smooth muscle in the connective tissue coverings of nerve trunks; however, there is plenty out there on smooth muscle in vascular walls, and nerve trunks travel along with vessels and are full of vasculature. Drainage out of nerves (which have become mechanically deformed, through adverse use or not enough "normal" movement) can be a big problem: if substances that contract smooth muscle build up within neural tubes and tracts, it seems logical (if they contain smooth muscle cells) the entire 3-tube neurovascular system in any given nerve branch could be affected, contributing to more adverse neural tension, amplified nociceptive input, delayed clearing of substances from the intraneural and extraneural milieu. 
That could be one reason we can feel "strings" and cords. 
I think.
On the other hand, if just the smooth muscle cells in the vasculature that feed and drain nerve trunks were affected, by either mechanical distortion OR by lack of clearing of built-up products of nociceptors inside the nerve trunk (yes, nerve wrappings are self-innervated by nociceptive capable neurons), it would scarcely matter from a clinical standpoint - those palpable bungee cords and strings would still form, probably. I'm almost certain.

Bloated cranky nerves.

Currently I'm trying to find out if smooth muscle cells "let go" as a consequence of
1. being physically stretched  
2. a local spinal cord inhibitory neuronal reflexive process stimulated by contact through non-nociceptive large sensory fibres 
3. descending inhibition by higher centers 
4. All three combined.

If I had to bet..
..I'd bet the farm on smooth muscle deactivation/decontraction being *mainly* by descending inhibitory modulatory control, from more rostral areas, nuclei that Butler refers to as the "drug cabinet" in the brainstem, down to the dorsal horn. Dopaminergic, noradrenegeric, serotinergic, opioidal.

I know that large fiber input does boost spinal gate control of nociception via glycenergic inhibitory interneurons (there is direct evidence for that, at last, after 50 years: see Foster et al. ); I'm still looking for direct evidence that said inhibition of nociception can therefore lead directly to smooth muscle cell relaxation at a spinal cord reflexive level - that's an extra step.

Until such evidence shows up and accumulates, the 'least wrong' assumption is that good results from manual therapy are due to descending modulation of a favourable kind, and that non-specific effects/ "common factor" effects, are the ones in final charge over pain perception and physiological self-correction.

This lovely paper is just in: Mancini, Flavia; Beaumont, Anne-Lise; Hu, Li; Haggard, Patrick; Iannetti, Gian Domenico D. Touch inhibits subcortical and cortical nociceptive responses. Pain: October 2015 - Volume 156 - Issue 10 - p 1936–1944 - it's full text, at least for awhile.

It proposes that touch affects pain perception at a subcortical level. So, yay!

2. Mason, Peggy; Medical Neurobiology. Oxford University Press; 1 edition (May 19, 2011)

* Yes, I went there. 

Monday, October 12, 2015


I get it. Nothing in life is perfect. Everyone makes mistakes. I make mistakes.
But gee, I hate when scholars (who are supposedly held to higher academic standard) get careless and (OK, maybe inadvertently) mislead those of us who come along later and read their papers. 

I found another example of one of those little things in life that makes me want to tear my hair out, and am wondering to myself, is it me, being slightly obsessed about OneLittleThing among all the millions of ideas that are wrong in the world? or is it a real thing that sticks itself in my face repeatedly and I have not just the right, but an obligation, to complain? Even if it's only on a blog that nobody reads? 

The issue: referring to astroglia as immune cells.  Wrongly. 
This is not the first time this issue has reared its head in my face. 

I saw this, in a paper I had just started to read. 

(Erk... Astrocytes are NOT "innate, parenchymal immune cells of the CNS") 

I was taken aback.

The possibilities that existed were:
a) Another paper, another author, was telling me I had learned glia all wrong.
b) The author was wrong. 

So I decided to check the references. 

The Ransohoff paper  is very long and very carefully points out the history of the arguments re: family background of each kind of cell, and why the conclusion is that microglia are immune cells of mesodermal origin.
There is not much in there about astrocytes, other than a diagram that points out that they are non-neuronal brain cells of ectodermal origin. The paper is focused on microglia. 

I read the whole thing. 
And was reassured that I had learned embryology correctly, at least where glia come from.. it's kind of important to know, in the long run.. which is why, presumably, so many people have sat at lab benches spending their entire precious lives trying to figure it out and finally succeeded.

Lots of people tell me that it doesn't matter, that I shouldn't be bothered by what is of ectodermal origin and what is of mesodermal origin.
I disagree. Drawing a conceptual line between them has helped me hugely. 


I thought scientific peer review was supposed to catch mistakes like that. 
Maybe nobody cares, except me, and all the embryologists for whom it matters most directly. 

Anyway.. same with the other three papers, two of which are open access. Nothing about astrocytes. They are only about microglia.

So, my question is, Why on earth would Dimitris N. Xanthos and Jürgen Sandkühler use four references that have next to nothing to say about astrocytes, and are overwhelmingly about microglia, to back up a sentence in which they calmly state (incorrectly) that astrocytes are immune cells? 

I'm probably doomed to never know.

The paper with which I have an issue:

1. Xanthos DN, Sandk├╝hler J; Neurogenic neuroinflammation: inflammatory CNS reactions in response to neuronal activity. Nat Rev Neurosci. 2014 Jan;15(1):43-53. (abstract only)


The papers used as reference:

2. Ransohoff RM, Cardona AE; The myeloid cells of the central nervous system parenchyma. Nature. 2010 Nov 11;468(7321):253-62. (abstract only)

3. Kettenmann H, Hanisch UK, Noda M, Verkhratsky A.; Physiology of microglia. Physiol Rev. 2011 Apr;91(2):461-553 (FULL)

4. Adriano Aguzzi, Ben A. Barres, and Mariko L. Bennett; Microglia: Scapegoat, Saboteur, or Something Else? Science. 2013 Jan 11; 339(6116): 156–161 (FULL)
(Can't blame any of those papers..) 

5. Stephen D. Skaper, Pietro Giusti and Laura Facci; Microglia and mast cells: two tracks on the road to neuroinflammation. The FASEB j. vol. 26 no. 8 3103-3117 April 19 2012 (FULL)

Too bad the first two papers are behind paywalls, or one could follow along. In the Skaper paper #5,  “glia” are mentioned as if they were all the same; because of sentence construction, it is left unclear as to whether the author thinks they all are immune cells:  
“The emerging realization is that glia and microglia, in particular, (which are the brain's resident macrophages), constitute an important source of inflammatory mediators and may have fundamental roles in CNS disorders from neuropathic pain and epilepsy to neurodegenerative diseases.”  
That sentence could be misconstrued to mean that all glia are macrophages. Maybe it's just poor writing. Maybe it was this paper /that sentence specifically, that confused Xanthos and Sandk├╝hler. But still, you'd think the Ransohoff paper (#2) would have clarified things, and prevented them from making an erroneous declarative sentence, had they read it more carefully.

What to do? Accept that life is a confusing mess and then we die?
Can't do it. That is unacceptable. Somewhere somehow I have to blow gently on the tiny flame of hope, keep it alive, the hope that one day, science will be able to sort mess, discard mistake, hold up fact; that scholars and authors don't just pad out their own confirmation biases with references that don't even support their statements. 

But when I see a mistake about something I do "know," highlighted against the vast darkness of ignorance I still have, that we all still have, I worry about whether I should trust anything that particular individual says about anything.
And I blog, because it relieves despair and stress and anxiety a little bit. 
Not much though.