Neurotonics: a PT team blog

"Translational Pain Research: From Mouse to Man"

2011-11-19T11:56:00.000-08:00

"Translational Pain Research: From Mouse to Man" is a 2010 book, freely available at Pubmed, edited by Lawrence Kruger at UCLA School of Medicine and Alan R. Light, at University of Utah, published by CRC Press in Boca Raton, Fla. I stumbled on it while searching for material on visceral afferents. The entire third chapter is all about these usually-skipped-over neurons.

I'm still working through chapter 1 by C. Richard Chapman, on complex systems and painful multi-system disorders, with 17 more to go. Excellent book so far.

I plan to revive this blog with a series of posts about this book, whatever thinking it gives rise to, whatever may pertain to being a manual therapist.

That old bugbear, fibromyalgia

2010-03-24T13:51:00.000-07:00

Lately I dropped in to Textbook of Pain to see what it had to say about fibromyalgia, or as it is commonly referred to, FM. I found out quite a lot I never knew before, actually.

I already knew that people who are diagnosed with FM hurt - the main complaint is body pain. Careful differential diagnosis comes first; serious major depressions, panic and anxiety disorders are ruled out. Next, apparently there is more than one kind of FM, primary and secondary. They look and act a lot alike so clinical reasoning is key: Existence of a prior condition means the FM must be treated as secondary:

1. Rheumatoid arthritis - 30% of patients will also likely have FM
2. Systemic Lupus Erythematosus - 40%
3. Sjögren's Syndrome - 50%

What "secondary" means, is that patients will have two kinds of pain at once, and treatment of the primary condition must be managed in a way that won't aggravate the pain from the secondary FM. Furthermore, one kind of pain might be well-managed and the other not. For example, "increasing the dosage of antirheumatic medications in the absence of active inflammation may have little effect on the pain amplified by FMS." There are issues with steroid treatment - e.g., patients withdrawing from steroid treatment for their RA might find the FM pain increasing temporarily with each decrease in glucocorticoid dosage. This is a surprise in that primary FM has not been helped with glucocorticoid.

Various infectious and inflammatory conditions such as Hep C, TB, syphilis, and Lyme disease, are associated with FM. FM, and aches and pains from subacute bacterial endocarditis could be confused.

Primary FM is referred to these days as a "disorder of abnormal sensory processing of sensory information within the CNS, exhibiting a limited array of recognized objective physiological and biological abnormalities."

1. Mountz et al 1995: CT scans showed abnormally low regional cerebral blood flow in thalamic nuclei and other pain processing brain structures, correlated with spinal fluid substance P levels.
2. Gracely et al. 2002: fMRI evidence for augmented pain processing in brain
3. abnormal spinal cord "wind-up"
4. In over 60% of cases, there exists a temporal relationship to a physical trauma or febrile illness and FM onset.
5. Evidence relating FM to actual muscle abnormality or pathology is weak, scant, inconclusive, or completely missing, in both invasive and non-invasive testing compared to healthy controls.

At a neurochemical level, findings support the concept of objective pain amplification. Various pro-nociceptive substances, and a few anti-nociceptive substances, have been examined.
One of the pro-nociceptive substances is Substance P (P for pain):
1. Russell 1998: Elevated levels of Substance P found in cerebral spinal fluid of patients diagnosed with FM
2. Vaeroy et al 1988, Russell 1998, Mountz et al 1995: average concentrations of Substance P in CSF found to be 2 to 3-fold higher in FM than in healthy controls. Substance P levels in saliva, serum or urine were not elevated.
3. Cerebral spinal fluid contains an esterase for breaking down Substance P - this substance was normal, not deficient, so the elevated levels of Substance P must be because the body makes more than the esterase can take care of.
4. Substance P is elevated in other conditions such as rheumatic diseases with or without FM (Russell, unpublished).
5. In painful OA of the hip, levels of Substance P returned to normal after hip replacement.
6. Tsigos et al 1993, Sjostrom 1988: In chronic low back pain, and diabetic neuropathy, cerebral spinal fluid Substance P levels are lower than normal. (So go figure...)

Another substance is nerve growth factor, elevated in CSF of those who have primary but not secondary FM (Giovengo et al 1999). It may even be NGF that is responsible for elevated levels of Substance P, whereas in secondary FM, the primary condition (arthritis etc.) itself may be responsible.

Cytokines called interleukins were found to be elevated, specifically IL-8 and IL-6. IL-8 is stimulated by Substance P.

G-protein-coupled receptors were found to not be able to inhibit intracellular cyclic AMP production by adenylate cyclase - more cyclic AMP was found floating around. This is being considered as a cause of the allodynia characteristic of FM.

Apparently there is no opioid deficiency; levels of Dynorphin A are found to be normal.

Serotonin levels, however, are lower. Numbers of active FM tender points correlated nicely with concentrations of serotonin in body serum (Wolfe et al 1997b).

Noradrenaline levels might be low; concentration of methoxyhydroxyphenylglycol, the inactive metabolite of noradrenaline, was found to be significantly lower than normal in FMS cerebrospinal fluid (Russell et al 1992).

Up to 35% of patients with FM, when tested using hypoglycemic hyperinsulinaemic clamp procedures, show inadequate responsiveness, or excessive response to feedback inhibition, of the hypothalamic-pituitary portion of the HPA axis (Adler et al 1999). This shows exaggerated adrenocorticotropic hormone response to insulin-induced hypoglycemia or stressful exercise and indicates poor tolerance for physiological stress.

Women are more commonly affected than men, and FM onset is often perimenopausal. About 30% of female FM patients are prematurely menopausal due to surgical removal of female reproductive organs. Forty-four % of female FM patients have premenstrual syndrome and pain which cycles in phase with their menstrual cycle (Anderberg et al 1998). It is thought that these differences are less a feature of estrogen and more to do with serotonin (Nishizawa et al 1997).

Sleep is a problem in FM. Deep stage IV non-REM sleep is when human growth hormone is released. It stimulates the liver to produce a long half-life peptide called insulin-like growth factor-1, found to be deficient in FM (Bennett et al 1997). It has been hard to develop a treatment based on administering this, even though it helps; growth hormone therapy is expensive at $1000/month.

Iyengar et al 2005: in a study of 80 multi-case families, 8 genetic markers were detected.

Who isn't afraid of Alzheimer's?

2010-03-23T00:36:00.000-07:00

I have found microglia interesting to learn about in the past, and have written here, here, here, here, and here, about their proposed relationship to pain.

Yesterday I saw a news story about researchers in Germany who carefully studied the relationship between microglia and neurons undergoing Alzheimer-like changes in mice, Dangerous custodians: Immune cells as possible nerve-cell killers in Alzheimer's disease,
and was immediately intrigued.

An advance online publication of the paper, Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer's disease, is freely accessible, at least for now.

That stressed neurons exude the chemokine, fractalkine, or that this substance attracts microglia, isn't fresh news. Like a bunch of little cellular opportunists, microglia catch the "scent" and begin moving toward it. Like any bunch of scavengers converging on a picnic, in this case, the amyloid-β forming and piling up, they also secrete/excrete (while gorging and multiplying, I suppose). What they signal/secrete/excrete isn't really explained, but what is news, is that it, or else just the sheer numbers of microglia converging, apparently sickens the affected neurons even more, kills them, according to this story.

In the paper, the authors, Fuhrmann etal., state,

"In Alzheimer's disease, microglia represent a double-edged sword. On the one hand, microglia can have a beneficial effect by secreting neurotrophic factors and phagocytosing amyloid beta (Aβ)², the latter of which remains controversial³. On the other hand, microglia may also be neurotoxic⁴. Little is known about the neurotoxic role of microglia in Alzheimer's disease. Human peripheral blood monocytes that are stimulated with Aβ induce neuron loss in vitro⁵. Neurons cultured without microglia are resistant to Aβ-induced neurotoxicity⁶."

The authors decided to interfere, genetically, with the receptors in the microglia that allow them to sense fractalkine; CX₃CR1,

"the unique receptor for fractalkine/CX₃CL1, which is expressed in neurons and presumably acts as a membrane-bound adhesion molecule and/or cleaved chemoattractant and is important for recruiting CX₃CR1-expressing microglia to injured neurons^{9, 10}."

They managed to show that it was definitely the microglia causing the neuron death, not any other factor. Furthermore, knocking out the ability of microglia to "smell" fractalkine didn't seem to interfere with their ability to clear the amyloid material associated with Alzheimer's. Moreover, the same treatment of the microglial receptor gives inconclusive results in other kinds of conditions - only in Alzheimer's does it seem to be a helpful intervention.

Supplementary information for this paper.

Fuhrmann, M., Bittner, T., Jung, C., Burgold, S., Page, R., Mitteregger, G., Haass, C., LaFerla, F., Kretzschmar, H., & Herms, J. (2010). Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer's disease Nature Neuroscience DOI: 10.1038/nn.2511

Multiple sclerosis and news buzz about it

2009-11-28T10:45:00.000-08:00

I must admit that as a young PT student and newly minted PT who thought I was coming down with whatever new thing I learned about, or had the opportunity of meeting/treating people who had x or y condition, MS probably freaked me out the most. Of late, a very nice massage therapist I know personally, ended up with this diagnosis.

How wonderful that this ailment is currently being highlighted as a condition which could be, potentially at least, reversible with a simple surgical procedure. Who'd have thunk? After all these decades?

Here are the news stories I've come across so far:

CTV W5 The Liberation Treatment
Medpage Radical MS Theory Stirs Interest
BBC: Multiple sclerosis 'blood blockage theory' tested

Nov. 30/09
Edit: I'm back in this post to add a link to Dr. Zamboni's website, Fondazione HILARESCERE.
Some of his papers can be found there. At least for now.

Ego tunnels, conscious entities, virtual bodies and so on.

2009-11-26T09:18:00.000-08:00

I have yet to read the book by Thomas Metzinger, The Ego Tunnel, but it's in the cart. Meanwhile I came upon a blog post, two in fact, by Peter Hankins at Conscious Entities blog, that set off a little speculative burst in my own brain.

Part I, and Part II.

In particular, this got my attention;

"There are many interesting details in this account, quite apart from its value as part of the overall argument. Metzinger briefly touches on four varieties of autoscopic (self-seeing) phenomena, all of which can be related to distinct areas of the brain: autoscopic hallucination, where the subject sees an image of themselves; the feeling of a presence, where the subject has the strong sense of someone there without seeing anyone; the particularly disturbing heautoscopy, where the subject sees another self and switches back and forth into and out of it, unsure which is ‘the real me’; and the better-known OBE."

It makes sense to me that multiple self-constructions/constructions of self would exist, given that there are many different body representations all throughout the brain, not just the big S1 map stretched over the top of the cortex, the famous one Wilder Penfield mapped out, and I didn't realize there were names already ascribed to the elicitation of their specific distortions..

A body misperception can be the absence of a familiar body sense just as well as it can be one that's displaced onto a mannequin or onto someone or something else entirely, or floating above.. in each case there will be a corresponding shift in neural traffic flow, the brain not operating in its own familiar manner, and part of it noticing that shift and confabulating predictive perceptual fantasies as to possible reasons why. As in the Charlie Rose Brain Series Part II, in which all the various visual perceptual distortions were touched on, body sense is subject to perceptual distortion. The science on this is younger, but is definitely happening, mostly in Europe, mostly referred to as research of virtual bodies, rubber hand illusions, etc etc. discussedmany times on this blog. It's all very fascinating, and likely to have a lot to do with learning to handle human pain issues much more adeptly with fewer drugs at some point.

Meanwhile, it won't be a bad idea to practice feeling your own normal body better, practice using normal brain pathways, strengthen them so that your brain maps don't get all out of whack some day, and in some misguided attempt at trying to locate body parts, make them spasm or make them hurt to be able to find them more easily - the neurological equivalent of lighting flares to see along a dark path.

Other reading:
1. Book review at Naturalism.org

Moving a humanantigravity suit around

2009-11-08T10:38:00.000-08:00

I confess that my usual perspective on the nervous system is from outside in - I consider what happens when I put my hand on someone else's body part, and consider ensuing movement output as a consequence, as a nervous system's direct response.. there's almost always that idea of my inputting some sort of talented (or not) sensory input - first. That's how my treatment brain works - it uses the "operator"/"interactor" model, by default, usually, and my conceptualizations end up being informed by it.

I've been away from clinical work for over 4 months now, and my brain is learning to think in different ways. So, when I think of "movement" now, I'm seeing it in more abstract terms. Lately several papers and blogposts about movement have come to my attention. I don't know how they synthesize, yet.. but I'm paying attention to the process, at least. I'd like to outline a few thoughts about them, bearing in mind the role of the brain as predictor, oscillator, simulator. First though, I'm going to just link them here.

1. The Brain in its Body: Motor Control and Sensing in a Biomechanical Context The Hournal of Neuroscience

2. Podcast interview of Barrett Dorko by Rod Henderson, May '09

3. A sensory source for motor variation Nature

4. Physiologically impossible movement of phantom limbs explained at Body in Mind blog (Lorimer Moseley)

5. Tiny Laser-scanning Microscope Images Brain Cells In Freely Moving Animals Science Daily

6. Two Wrongs Make a Right – Abnormal Brain Circuitry May Stop Abnormal Movement BrainBlogger

7. A head of time: For the first time, neuroscientists find brain cells that keep track of time with extreme precision. MIT - Everything gets a timestamp.

8. NOI Notes on Movement as Antigen David Butler's blog/newsletter

9. Primate anterior cingulate cortex: where motor control, drive and cognition interface. 2001

Moving into a robotic hand

2009-10-21T13:55:00.000-07:00

Here is another wonderful Mindhacks post: Inhabiting a robot hand Thank you Mindhacks.

This relates to all the posts here to do with robotics, haptics, virtual bodies, virtual body manipulation through mirror therapy or video, and rubber hand illusions. NOI twittered about the Mindhacks post in conjunction with Graded Motor Imagery, the virtual treatment they are promoting. Definitely worth boosting here as well.

Forty Years of Neuroscience

2009-10-21T13:51:00.000-07:00

I want to thank MindHacks for constructing such an informative post. Here it is, complete with all its links to Journal of Neuroscience.
Around the Brain in Forty Years.

Self-amputation

2009-10-10T06:42:00.000-07:00

There must be dozens of stories of this. A few years ago Oprah had as a guest a young woman who, trapped in a car which had gone off a bridge, hidden from view and possible rescue, self-amputated a leg to escape. About 5 years ago a young man hiking in the Grand Canyon became trapped when a rock tumbled and pinned his hand. He cut off the hand to escape.

It really makes one wonder what pain is, exactly.

In this story from yesterday (twittered by Mo of Neurophilosophy), a young man's leg was pinned by a concrete girder. He managed to cut most of it off himself, but a friend nearby had to help break the bone.

His brain decided the threat to his ongoing existence was greater than any threat from any upcoming nociception. It was capable of downregulating its own sensory input enough to allow him to remain conscious and focused and on task, as it realized this was its organism's only shot at surviving. In this way the seemingly impossible becomes possible, without loss of consciousness, and in spite of what must be a large loss of blood.

Fractals, brains, Pi

2009-09-18T00:51:00.000-07:00

A fellow-traveler on SomaSimple found this blogpost, Fractal Thoughts on Fractal Brains by David Pinkus, an interesting sequence of thoughts spurred by an open access article, Broadband Criticality of Human Brain Network Synchronization.

The word "fractal" always conjures up in my mind an image of the Norwegian coastline, then another little tidbit that always has stuck with me, about pi,

"Pi also appears as the average ratio of the actual length and the direct distance between source and mouth in a meandering river (Stølum 1996, Singh 1997)."

From the blogpost:

"The design, results and context for this study are very sophisticated, and the implications are quite abstract. So I’m going to do my best to be clear. First the context: Many natural systems exhibit fractal organization and behavior. A fractal is a branchlike structure. Think of a tree: (1) Trees have many more small branches than large ones. This characteristic is also sometimes called a “power-law” or “inverse power law” or a “1/f” organization. Each of these terms means that there are exponentially more small branches compared to big ones. (2) Trees are “self-similar,” meaning that small branching patterns resemble larger ones. This characteristic is also sometimes called “scale invariance” or “scale free” because no matter the size you are looking at, the general branching shape is the same. (3) The complexity of tree branching patterns can be quantified. Fractals are called “fractals” because they exist in fractional dimensions. A line fits perfectly in one-dimension. A plane (like a piece of paper) fits in two-dimensions. Fractals fit in between a line and a plane (or in the real world between two and three dimensions). More simply, because they are so complex, with huge numbers of tini tiny branches, trees never quite reach three dimensions. If you put them in a box, there will always be some space left over.

You may quickly recognize that many other natural structures besides trees are fractals: Neurons, rivers, the respiratory system, the circulatory system, geological fault lines, snow-flakes, and so on."

As if fractal form doesn't sound complex enough, there is fractal behaviour, apparently:

"Natural systems also produce fractal behavior over time or in dynamics. Earthquakes are a common example. There are many more small earthquakes than large ones (which is nice by the way). Other examples include the size of extinction events in animal species, numbers of academic publications (a few researchers do huge amounts of work and the rest of us do just a little), numbers of hits to web-sites, wait times in stop-and-go traffic, and word usage in literature (i.e., zipf’s law)."

Fractals as verbs as well as nouns. I've often thought of the brain as more verb than noun.

The kinesthetic senses

2009-09-10T07:47:00.000-07:00

This paper came to my attention yesterday: The kinesthetic senses by Uwe Proske and Simon Gandevia, in Australia. By some refreshing turn of events, it is open access. It provides an historical backdrop to nearly everything we as physical therapists are about. We are all about restoring this function, kinesthesia, to people in whom it would seem to have gone missing. We always have been. Without good kinesthesia, motor control goes offline. When motor control goes off line, so does maximal function.

The paper begins with a brief intro to kinesthesia. It states at the outset that muscle and skin receptors account for most of the receptor input that helps the brain make motor choices. It specifically states,

"Peripheral receptors which contribute to kinaesthesia are muscle spindles and skin stretch receptors. Joint receptors do not appear to play a major role at most joints."

Wow. Right there, we can see a huge erosion under the sea shore of one of the defining organizational principles of orthopaedic manual therapy, which is that getting to and wiggling or popping the right joint in the right way will jumpstart a better motor output. Orthopaedic manaual therapy (and chiro) have used this idea to build themselves and have perpetuated it for decades, for a century. It's just not valid. It was a false hypothesis, and finally research has begun to trickle out that suggests this is the case.

After a brief description of the contribution of muscle spindle receptors to the kinesthetic senses, Proske and Gandevia begin to discuss receptors found in skin:

"Concerning the possible contribution to kinaesthesia from other receptor types, the summary view is that while a good case has been made for some cutaneous receptors, the evidence is less convincing for joint receptors. The cutaneous receptor most likely to subserve a kinaesthetic role is the skin stretch receptor, the slowly adapting Type II receptor served by Ruffini endings (Chambers et al. 1972; Edin, 1992). For kinaesthesia at the forearm, stretch of skin over the elbow during elbow flexion can provide information about both position and movement. Movement illusions generated by stretch of skin of the hand and over more proximal joints, when combined with muscle vibration were greater than when either stimulus was applied on its own (Collins et al. 2005). The authors made the point that this was not just a matter of skin input facilitating the muscle input and that cutaneous input generated by skin stretch contributed to kinaesthesia in its own right. More recent observations have shown that skin input can also have an occluding action. Signals from local, rapidly adapting receptors evoked by low-amplitude, high frequency vibration can impede movement detection (Weerakkody et al. 2007).(....)
While joint receptors were first thought to be all-important in kinaesthesia, the present-day view is that their contribution at most joints is likely to be minor. Typically they respond to joint movement, but often with response peaks at both limits of the range of joint motion (Burgess & Clark, 1969). They are now thought of as limit detectors. However, there are examples in the literature of responses across the full range of joint movement (Burke et al. 1988) and here joint receptors may play a role under circumstances in which input from muscle and skin is not available (Ferrell et al. 1987). "

My bolds.

This paper is an important one for manual therapists who seek to understand how it is that "light" manual techniques seem to do as well to help patients' brains connect up in terms of improved, observable motor output, as heavy joint-based, manipulative or mobilizing ones.

Proske, U., & Gandevia, S. (2009). The kinaesthetic senses The Journal of Physiology, 587 (17), 4139-4146 DOI: 10.1113/jphysiol.2009.175372

Mirror therapy by David Butler

2009-08-14T19:07:00.000-07:00

A not so rambling thought from AK - "A new integrative theory for cortical pyramidal neurons"

2009-08-12T09:39:00.000-07:00

This is a blogpost I want to take apart carefully and fully appreciate, look up all the papers referenced, as well as the paper under discussion, see how it might relate top parietal lobes, body sense, kinesthetic constructs, exteroception, body work, manual treatment for pain.
A New Integrative Theory for Cortical Pyramidal Neurons.

Thank you for this, AK.

Mo on the "Connectome": "Not so fast"

2009-08-11T08:32:00.000-07:00

Mo from Neurophilosophy linked to an article, Not so fast, written for seedmagazine.com re: his perspective on the ambitious project of mapping all the pathways and connections there are in the brain.

He says confounding factors include neuroplasticity, ignoring the functions of neuroglia, and ordinary small-scale variations that occur:

"the connectome apparently ignores the phenomenon of neuroplasticity.

Plasticity refers to the brain’s ability to physically alter its structure in response to experience. Far from being immalleable, as was once thought, the brain is a highly dynamic organ. Neurons can sprout new connections within minutes of a given stimulus, and entire neural pathways can be rerouted so that function is recovered after a brain injury.

The connectome also disregards the functional importance of neuroglial cells, another class of cells which are found in the nervous system and which outnumber neurons by at least 10 to 1. Once thought to merely provide structural and nutritional support for neurons, glia have, in recent years, come into their own as key players in the brain. As well as performing the roles initially ascribed to them, glia carry out a whole host of other vital functions, including monitoring neuronal health, identifying damaged neurons, and regulating synaptic plasticity. They are also known to be capable of communicating not only with one another, but also with neurons. A map of brain connectivity cannot therefore be complete without taking glia into account.

Finally, although the large-scale connections are very similar among individuals, there are significant variations at smaller scales."

My bold.

Single cells, memory, learning

2009-08-02T08:10:00.000-07:00

Ever since I read Seth Grant's paper on synaptic evolution last year, which discusses proteomics at the level of synapses and how we have synaptic proteins in common with yeast, I've been thinking about synapses as gateways to information flow, controlled by proteins that are common to multiple life forms. It caught my full attention that we have synaptic proteins in common with yeast.

Last night I read "Microbes exploit groundhog day" in Nature's July issue. Excerpt:

"The proposal that microorganisms can associate a stimulus with an appropriate response to a future environment might seem far-fetched. After all, without cognition, microorganisms rely on simple regulatory networks to sense and respond to their environment. A canonical example of gene-regulation, the response of Escherichia coli to the sugar lactose, illustrates why it seems surprising that such networks can be used to anticipate environmental changes."

The write-up discusses a paper by Mitchell et al., Adaptive prediction of environmental changes by microorganisms (same issue).

"The insight of Mitchell et al., building on previous work, was to realize that the connection between stimulus and response can be offset in time. For example, if a non-lactose sugar consistently follows the availability of lactose, selection might favour the evolution of a regulatory network that directly links the presence of lactose to the expression of the non-lactose-utilization genes. This network would serve to 'prime' cells conferring an advantage by preparing them to use the non-lactose sugar in anticipation of its imminent availability and thereby reducing the lag time characteristic of de novo activation of response genes. Mitchell et al. call this mechanism adaptive anticipatory conditioning."

A clever experimental design was employed to examine the responses of E. coli and baker's yeast, Saccharomyces cerevisiae, to an environment simulating what each organism would ordinarily find in a typical higher intestinal tract (higher in lactose and low in maltose), compared to lower part of the tract (low in lactose and higher in maltose). Mitchell et al. found that "microorganisms can interpret their environment and respond in a way that provides a benefit only in following a future environmental change." A few wrinkles remain, but "one message is clear" -

"The regulatory networks that link environmental stimuli to microbial responses are complex and can evolve rapidly. The potential for microorganisms to offset responses from environments in which those responses are useful provides both a warning and an opportunity for researchers involved in testing the functional significance of links between stimuli and responses."

Possibly related, in some way, somewhere down the road, are these two recent tidbits from New Scientist:

1. Memristor minds: The future of artificial intelligence by Justin Mullins. It discusses artificial intelligence and a "fourth" ingredient, "memristor" (in addition to resistor, capacitor and inductor):

"Chua had anticipated the idea that memristors might have something to say about how biological organisms learn. While completing his first paper on memristors, he became fascinated by synapses - the gaps between nerve cells in higher organisms across which nerve impulses must pass. In particular, he noticed their complex electrical response to the ebb and flow of potassium and sodium ions across the membranes of each cell, which allow the synapses to alter their response according to the frequency and strength of signals. It looked maddeningly similar to the response a memristor would produce. "I realised then that synapses were memristors," he says. "The ion channel was the missing circuit element I was looking for, and it already existed in nature."
To Chua, this all points to a home truth. Despite years of effort, attempts to build an electronic intelligence that can mimic the awesome power of a brain have seen little success. And that might be simply because we were lacking the crucial electronic components - memristors." - (my bold)

2. Evolution's third replicator: Genes, memes, and now what? by Susan Blackmore. She comments (excerpts):

"We humans have let loose something extraordinary on our planet - a third replicator - the consequences of which are unpredictable and possibly dangerous.

What do I mean by "third replicator"? The first replicator was the gene - the basis of biological evolution. The second was memes - the basis of cultural evolution. I believe that what we are now seeing, in a vast technological explosion, is the birth of a third evolutionary process. We are Earth's Pandoran species, yet we are blissfully oblivious to what we have let out of the box."

"Billions of years ago, free-living bacteria are thought to have become incorporated into living cells as energy-providing mitochondria. Both sides benefited from the deal. Perhaps the same is happening to us now. The growing web of machines we let loose needs us to run the power stations, build the factories that make the computers, and repair things when they go wrong - and will do for some time yet. In return we get entertainment, tedious tasks done for us, facts at the click of a mouse and as much communication as we can ask for. It's a deal we are not likely to turn down."

Additional resources:

1. BrainScience Podcast #51 Dr. Seth Grant on Synapse Evolution

Michael Merzenich's video on re-wiring the brain

2009-07-02T13:00:00.000-07:00

This is an excellent overview on brain development and neural plasticity.
Merzenich is a pioneer in research on the topic and in finding practical ways to work with it, e.g., his development of cochlear implants.

1. Michael Merzenich's blog, On the Brain

2. BrainSciencePodcast #54 with Dr. Ginger Campbell, Interview with Michael Merzenich on Neuroplasticity

Four ways neuroplasticity operates

2009-05-22T11:03:00.000-07:00

I picked up a book this morning called Neural Plasticity and Disorders of the Nervous System, by Aage R. Møller, who works in Texas.

On page 17 he has listed these four ways neuroplasticity operates:

"1. By (functional) changes in synaptic efficacy, the extreme of which is unmasking of dormant synapses, or masking of efficient synapses.

2. By reducing or modifying protein synthesis and proteinase activity in nerve cells.

3. By creation of new anatomical connections (sprouting of axons and dendrites) or elimination of existing connections or by altering synapses morphologically.

4. By elimination of nerve cells (apoptosis)."

Additional reading:

1. A quick search of blogposts re: neuroplasticity on Deric Bownd's Mindblog
2. A quick search of blogposts re: neuroplasticity on Mo's Neurophilosophy blog (and some others).
3. A quick search for neuroplasticity on this blog, Neurotonics.
4. A related blogpost, System Proteomics

Fabulous Interactive Brain Science Site: Genes2Cognition

2009-05-19T19:09:00.000-07:00

I have added a new link to the menu to the right, Genes2Cognition. Very impressive, one of the best I've ever seen. You can click on ANY of dozens of balloons, drag them around, click on them to bring up deeper levels of information. I picked "Perception" which led to "Cognition" which led to "Inattentional Blindness" which led to a wonderful short little video I had seen before, connected to a TED talk by Michael Shermer, which disappeared... but now looks like it's back!

You can take a look at brain parts, look into different levels of the brain, turn it all around, flip it upside down or look into it through the top.

You can click on and explore different conditions, or different functions.

I found the G2C site at the brain portion of the Dana Foundation website. I found the brain portion of the Dana Foundation website by clicking on the main page. I found the main page by clicking on the link provided by Deric Bownds in his new post, Arts and the Brain. Thank you Deric!

Apotemnophilia

2009-05-17T12:07:00.000-07:00

Recently I read the article Brain Games by John Colapinto in the New Yorker. It's a wonderful portrait, 13 or so pages long, of V.S. Ramachandran, the father of mirror therapy for phantom limb pain (according to me, at least). It provides the reader with a biographical account of Ramachandran, glimpses into his childhood, how he thinks (like Sherlock Holmes), a window into his personal life (can't remember his wife's birthday, forgets where he parked the car), and an account of his professional trajectory through life, how he ended up with a dinosaur fossil named after him, discussions of his interest in mirror neurons, synesthesia, ichthyology.

Lately he's been studying a patient, dubbed for the article, "Arthur Jamison". I am going to provide excerpts from the article now, direct quotes:

"Jamieson is seventy years old and lives in the Midwest. He is a physician and an amateur cellist, and has been married for forty-seven years. He also suffers from a rare and bewildering condition called apotemnophilia, the compulsion to have a perfectly healthy limb amputated--in his case, the right leg, at mid-thigh."

"After interviewing several apotemnophiliacs--Jamieson is the ﬁfth person with the disorder whom he has studied--Ramachandran was struck by the fact that all of them said they became aware of the compulsion in early childhood, that it centered on a particular limb (or limbs), that they could draw a line at the exact spot where they wanted the amputation to occur, and that they attached little or no erotic signiﬁcance to the condition. Furthermore, none rejected the limb as "not belonging" to them, as some stroke victims do in the case of a paralyzed arm or leg, and as Ramachandran had predicted they might. Instead, they said that the limb over-belonged to them: it felt intrusive. "If you talk to independent apotemnophiliacs, they say the same bloody things," Ramachandran told me. " 'The line for cutting is here.' 'It started in early childhood.' 'It's over-present.'
They're not crazy.""

"Asked where he would make the cut line for the amputation, Jamieson unhesitatingly drew an index ﬁnger across the middle of his right thigh. As to whether he felt that his leg didn't "belong" to him, Jamieson was emphatic. "Somehow, for me, that just doesn't compute, that kind of language," he said. "I have always been fascinated by amputation and wished that I had one. Why? Who the hell knows?"

"Ramachandran and other researchers have shown that the brain is what scientists call "plastic"--it can reorganize itself. Not only are different regions of the brain engaged inongoing communication with one another, with the body, and with the surrounding world; these relationships can be manipulated in ways that can reverse damage or dysfunction previously believed to be permanent. Ramachandran's work with patients at U.C.S.D. has led to one of the most effective treatments for chronic phantom-limb pain and to a new therapy for paralysis resulting from a stroke. (In both instances, his treatment involves only a ﬁve-dollar household mirror.) It has also provided suggestive insights into the physiological cause of such mystifying syndromes as autism."

"In the seventies, Michael Merzenich became expert at using microelectrodes to map the sensory cortex of monkeys. In one experiment, he mapped a monkey's hand area in the brain, then amputated its middle ﬁnger. Some months later, he remapped the monkey's hand and discovered that the brain map for the missing ﬁnger had vanished and been replaced by maps for the two adjacent ﬁngers, which had spread to ﬁll the gap. The results, published in the Journal of Comparative Neurology in 1984, were decisive proof that the brain can reorganize itself--at least across very short distances of one to two millimetres."

"After interviewing Jamieson in his ofﬁce, Ramachandran led him to a lab for a Galvanic Skin Response, or GSR, test, which would reveal how Jamieson's legs reacted to a mild pain stimulus... David Brang, one of Ramachandran's graduate students, attached a sensor to the middle two ﬁngers of Jamieson's right hand using a Velcro strap. The sensor would measure the reaction of Jamieson's sympathetic nervous system by monitoring the sweat on his ﬁngers. With a sterilized pin, Brang pricked Jamieson's legs at random points, waiting a few seconds between each prick. A scrolling graph on the computer screen registered Jamieson's responses.

The unaffected leg--the left one--and the right leg above where he wished to have it amputated showed a normal response: the graph at ﬁrst shot upward with each prick, but with further pricks it ceased to rise, then began to ﬂatten out, indicating that Jamieson's nervous system was getting used to the stimulus. But when Brang pricked Jamieson anywhere on the leg below the amputation line, his nervous system responded with increasing distress, the graph climbing higher and higher with each prick.

The experiment seemed to support Ramachandran's theory about the disorder. He believed that people with apotemnophilia had a deﬁcit in the right superior parietal lobule, where the body-image map is assembled. According to this notion, Jamieson was missing the neurons in the map that corresponded to his right leg from the mid-thigh down. He had normal sensation in the unwanted part of his leg--he felt the pin prick. But when the pain signal travelled to the right superior parietal lobule there was nothing in the body-image map to receive it.

"So there's a big discrepancy--a clash--and the brain doesn't like discrepancies," Ramachandran said."When a discrepancy comes in, it says, 'Shit! What the hell is going on here?,' and it kicks in and sends a message to the insular part of the brain, which is involved in emotional reactions--so you're getting this crazy GSR." In apotemnophilia sufferers, the discrepancy causes a feeling of distress that is no less agonizing for being below the level of conscious awareness.

In the past two years, Ramachandran has tested four other apotemnophiliacs using MEG brain scans. "You touch them anywhere in the body and the right superior parietal lobule lights up, as you would expect," Ramachandran said. "But if you touch him here"--he gestured to a point on Jamieson's leg below the amputation line--"nothing happens." Ramachandran said that the experiment needed to be repeated by other researchers, but, he added, "This takes a spooky psychological phenomenon and, as Shakespeare said, gives it a 'habitation and a name.' " Furthermore, the ﬁndings suggested to Ramachandran a possible method for alleviating the oppressive sensations in the unwanted limb.

Later, he asked Jamieson to stand in a corner of his ofﬁce and placed a three foot-high mirror in front of him, in such a way that in place of his right leg Jamieson saw his left, which he held bent at the knee. Jamieson gazed into the mirror. "Astonishing," he said. For a moment, the leg looked "right.""

This is fascinating stuff. I was reminded of reading Michael Gershon's book The Second Brain, about the gut and enteric nervous system, how if neural crest cells didn't make it in to colonize the large intestine, Hirschsprung's Disease (Megacolon) is the unfortunate result. So much depends on exquisite timing during embryological unfoldment. Miss one little beat and some batch of baby neurons won't exist, and the resulting human organism can end up with major deficit. It can affect the body, and maybe, as in the case of Apotemnophilia, one's sensory perception of one's body.

As I checked out Apotemnophilia online, I saw it was quite consistently coupled with notions of a sexualized nature with heavy overtones of psychiatric implications.

About this, Colapinto writes:

"Jamieson, who was born and raised in New York City, ﬁrst remembers having an unusual relationship with his right leg when, at around the age of seven, he was waiting for a bus. He found himself thinking that if he stuck out his leg it would be crushed and severed by the bus. "What came to me was not 'No, I don't want to do that' but 'How would I ever explain this?' " he told Ramachandran. In recounting his childhood memories, he said, "One of the things that's astonishing to me is how clear these recollections are."

"These things are very salient," Ramachandran said... "It's interesting to contrast these very clear-cut descriptions with these vague, Freudian notions about this whole phenomenon--that it's primarily connected with sexual stuff."

"Yeah," Jamieson said with disgust. "I've got no desire to cozy up to anyone with a stump. It's psychobabble.""

That it could be due to some embryologic formation error makes more sense. The thigh is actually the last part of the leg to form. Feet (in the form of ectodermic limb buds) poke out first, from the body wall. As toes begin to form, these feet, already containing vasculature and neural structure, begin to lengthen away from the body wall, and the "lines" of supply (vasculature) and communication (nerves) must grow to keep pace. Within the lengthening limb buds, bones begin to condense from cartilaginous masses which have formed from prior condensations of mesoderm; neural and vascular structures must simultaneously penetrate these condensations. Pathways of sensation of a limb to a brain include not just large diameter fibers from skin, but also many sorts of receptors, some very tiny, which report on all sorts of tissue, including vascular tissue (nervi vasorum). Some of these report on the sensory nerves themselves (nervi nervorum). Lots end up just inside the spinal cord, while others get all the way up as far as the insular cortex (1). The brain uses information coming in from many parallel kinesthetic channels(3) as well as visual ones, to construct its sense of self and body awareness/embodiment, to learn who is touching its organism, how it feels about that, what salience to assign in that moment. Apparently some sort of reverse processing occurs between afferents that go to the somatosensory cortex and those that go only to the insula(2). Apparently those going to the left insula are processed differently from those which go to the right (4).

All it would take would be some little screw-up in neural crest implantation into either the limb itself or else at the other end, in the brain itself (it would seem that quite a bit of "peripheral" "nerve", from neural crest, goes all the way into the brain, into some of its very touchy touch processing areas), so I can see how neural crest mishaps could be connected with body perception problems. Perhaps neural crest abnormality might become a target of investigation for body perception disorders some day.

1. Unmyelinated tactile afferents signal touch and project to insular cortex (Olausson et al.)
2. Unmyelinated tactile afferents have opposite effects on insular and somatosensory cortical processing. (Olausson et al.)
3. Unmyelinated afferents constitute a second system coding tactile stimuli of the human hairy skin. (Olausson et al.)
4. Coding of pleasant touch by unmyelinated afferents in humans. (Löken et al.)

Neuroplasticity with Michael Merzenich

2009-05-17T07:57:00.000-07:00

A friend and fellow PT, Jon Newman, recently sent me a link to a TED video released for public viewing only in April, it seems - Michael Merzenich on rewiring the brain. If you have ever wondered what neuroplasticity is, check this out. It runs about 23 minutes and I guarantee you'll come away with a deeper grasp of what the brain is and does.

Here is an excerpt I thought was particularly interesting:

"Now, one of the characteristics of this change process is that information is always related to other inputs or other information that's occurring in immediate time, in context. And that's because the brain is constructing representations of things that are correlated in little moments of time, and that relate to one another in little moments of successive time. The brain is recording all information and driving all change in temporal context.

Now, overwhelmingly, the most powerful context that occurred in your brain, is "you". Billions of events occurred in history that are related in time to your "self" as the receiver, your "self" as the actor, your "self" as the thinker, your "self" as the mover.

Billions of times, little pieces of sensation have come in from the surface of your body, that are always associated with "you," the receiver, and result in the embodiment of "you". "You" are constructed. Your "self" is constructed from these billions of events; it's constructed, it's created in your brain and it's created in the brain by physical change. This is the marvelously constructed thing that results in individual form, because each one of us has vastly different histories, and vastly different experiences, that drive into us this marvelous differentiation of self, of personhood."

I love this video. It makes me glad I picked the sort of work I did. I quite like the idea that when I put my hands on someone else, I'm helping them learn more about who they are, helping that brain add to its construction of "self" outside of a pain construction (if I'm careful, and I am). I like that I'm adding more "little pieces of sensation" to their temporally correlated process of embodied self, minus nociceptive input, i.e., more "danger" signals. Yeah, I can live with that.

I also like the idea that I learn more about/add to my own self-construct at the same time, as "little pieces of sensation" from my own skin (on my hands) enters my brain and is temporally correlated to what is already in there.

What is already in there? Circuitry routes, billions of neurons, receptor sites on them (lots and lots of receptors that can change to different ones, alter what they are sensitive to, thanks to "synaptic plasticity") and transmitters. There are convergence zones and arborizations, ascending and descending fibers, switchback and feed forward stations, and lots of somatotopic representational areas (brain maps of body parts). There is brain behaviour, and parts or areas that light up for pain as well as for other functions on fMRI, a vastly complex ecosystem, embedded within another outer ecosystem called the "body," with which it is completely integrated, both of which must exist co-mingled and learn to help each other within the greater outer planetary ecosystem, via a construct called "self."

Additional Reading

1. Michael Merzenich's TED bio
2. A page from my website, About Pain

Older blogposts on Neuroplasticity

1. Neuroplasticity (Dec 11, 2007)
2. Learning (Dec 12, 2007)
3. History of Neuroplasticity (Dec 12/2007)
4. Paradigm (Dec 16, 2007)
5. About mirror therapy (Dec 16, 2007)
6. Get your game on, ease your pain (Dec 17, 2007)
7. The devil is in the details (Dec 18, 2007)
8. A few types of Learning (Dec 18, 2007)
9. Cart ruts: More about UN-doing something (Dec 29, 2007)
10. And it's about brain parts: like hippocampus (Dec 30, 2007)
11. Function only (January 15 2008)
12. Smart prosthetics, smart nerves, smart brains (February 10, 2008)
13. Nervous System Basics VIII: PLASTICITY (May 10, 2008)
14. More about neurogenesis (June 7, 2008)
15. "Dialogues in Clinical Neuroscience" online (August 23, 2008)

"Higher" emotions have neural correlates too

2009-05-11T10:35:00.000-07:00

Check out this post at Deric Bowds Mindblog, Brain correlates of self-transcendent emotions, based on this paper by a group which includes the Damasios: Neural correlates of admiration and compassion.

Bownds writes:

"Antonio and Hanna Damasio and collaborators have now observed brain activities associated with our internal loftier emotions that transcend self-interest, such as elevation and admiration. These are hard to measure because they don't correlate obviously with facial expressions or body language."

Writers at PNAS (again, from Deric's blogpost) provide an overview, put the paper into context:

"Emotion research has something in common with a drunk searching for his car keys under a street lamp. ‘‘Where did you lose them?’’ asks the cop. ‘‘In the alley,’’ says the drunk, ‘‘but the light is so much better over here.’’ For emotion research, the light shines most brightly on the face, whose movements can be coded, compared across cultures, and quantified by electromyography. All of the ‘‘basic’’ emotions described by Paul Ekman and others (happiness, sadness, anger, fear, surprise, and disgust) earned their place on the list by being face-valid. The second source of illumination has long been animal research. Emotions that can be reliably triggered in rats, such as fear and anger, have been well-studied, down to specific pathways through the amygdala. But emotions that cannot be found on the face or in a rat, such as moral elevation and admiration, are largely abandoned back in the alley. We know they are there, but nobody can seem to find a flashlight. It is therefore quite an achievement that Immordino-Yang, McCall, Damasio, and Damasio managed to drag an fMRI scanner back there and have given us a first glimpse of the neurological underpinnings of elevation and admiration."

My bold.
Here is the abstract of the paper itself;

Abstract

In an fMRI experiment, participants were exposed to narratives based on true stories designed to evoke admiration and compassion in 4 distinct categories: admiration for virtue (AV), admiration for skill (AS), compassion for social/psychological pain (CSP), and compassion for physical pain (CPP). The goal was to test hypotheses about recruitment of homeostatic, somatosensory, and consciousness-related neural systems during the processing of pain-related (compassion) and non-pain-related (admiration) social emotions along 2 dimensions: emotions about other peoples' social/psychological conditions (AV, CSP) and emotions about others' physical conditions (AS, CPP). Consistent with theoretical accounts, the experience of all 4 emotions engaged brain regions involved in interoceptive representation and homeostatic regulation, including anterior insula, anterior cingulate, hypothalamus, and mesencephalon. However, the study also revealed a previously undescribed pattern within the posteromedial cortices (the ensemble of precuneus, posterior cingulate cortex, and retrosplenial region), an intriguing territory currently known for its involvement in the default mode of brain operation and in self-related/consciousness processes: emotions pertaining to social/psychological and physical situations engaged different networks aligned, respectively, with interoceptive and exteroceptive neural systems. Finally, within the anterior insula, activity correlated with AV and CSP peaked later and was more sustained than that associated with CPP. Our findings contribute insights on the functions of the posteromedial cortices and on the recruitment of the anterior insula in social emotions concerned with physical versus psychological pain.

I deliberately bolded the bit about the anterior insula, because of how involved it seems to be in pain production or at least pain perception.

Smart Prosthetics - Again

2009-04-19T15:56:00.000-07:00

Eric Robertson at PT Think Tank posted about this about week ago. Check out the video. Wonderful stuff.

Related posts:

1. Scott Mackler

2. Smart Prosthetics, Smart Nerves, Smart Brains

3. More Smartness

4. Monkey Robotics

5. Monkey intentions and control of a robot arm

The ABCDEFGHI of Persisting Pain

2009-03-12T12:08:00.000-07:00

Here is a link to a write-up I did recently on the topic:

The ABCDEFGHI of Persisting Pain.

I hope it is helpful to anyone who has any.

"Scans for Back Pain Ineffective"

2009-02-07T16:12:00.000-08:00

Tara Parker-Pope published this article yesterday in the NYT: Scans for Back Pain Ineffective

She can say that again. Not only does the scanning or imaging process do nothing whatever for the "pain", it may result in misleading interpretations of the imaging; well-meaning people may consider or resort to treatments that reinforce the problem rather than help the pain experience to disappear.

Excerpts:

"Researchers from Oregon Health and Science University in Portland reviewed six clinical trials comprised of nearly 2,000 patients with lower back pain. They found that back pain patients who underwent scans didn’t get better any faster or have less pain, depression or anxiety than patients who weren’t scanned. More important, the data suggested that patients who get scanned for back pain may end up with more pain than those who are left alone, according to the report published this week in the medical journal Lancet."

"The problem, say researchers, is that back scans can turn up physical changes in the back that aren’t really causing any problem."

“You can find lots of stuff on X-rays and M.R.I.’s like degenerative disks and arthritis, but these things are very weakly correlated with low back pain,” said study author Dr. Roger Chou, associate professor of medicine at Oregon Health. “We think we’re helping patients by doing a test, but we’re adding cost, exposing people to radiation and people may be getting unnecessary surgery. They start to think of themselves as having a horrible back problem and they stop doing exercise and things that are good for them, when in reality, a lot of people have degenerative disks and arthritis and have no pain at all.”

I completely agree. In addition to unnecessary surgery, they may be getting unnecessary manipulation and other "treatment" which is focused on supposedly misbehaving mesodermal derivatives instead of helping the ectodermal derivatives (i.e., skin, nerves, brain, embedded "I"- illusion) all learn to get along better.

Swiss neuroprostheses explorations

2009-01-12T10:07:00.000-08:00

Over at the BrainSciencePodcast forum, a listener, jezcentral, contributed this link:

Launching of EPFL Center for Neuroprostheses

Excerpt:

"What's a neuroprosthesis? It's a device made up of sensors, connections and electronic chips that are embedded in the body to repair certain neurological deficiencies. Recent progress in artificial retinas and man-machine interfaces that permit communication or action via thoughts alone gives us a glimpse of the possibilities the future might hold for improving the lives of the handicapped. The new Center will concentrate on six main themes: vision (retinal implants), hearing (cochlear implants), mobility (cortical and spinal implants), non-invasive man-machine interfaces (piloting at distance, robotics), the micro-and nano-fabrication of implants, and neuronal coding (signal processing, sensors).
The Center will be inaugurated on January 1, 2009, and will formally be part of EPFL's School of Engineering, in collaboration with the School of Life Sciences and the School of Computer and Communication Sciences. This project also opens the door to fruitful collaborations with other institutions in the Lake Geneva area, such as University of Lausanne and the Cantonal Hospital (CHUV)), University of Geneva and its hospital (HUG), and the regional biomedical industry."

Other posts on how prolific neuroresearch appears to be in Switzerland:
1. Virtual Body Experience
2. Something in Swiss water?
3. More from Lausanne: Mapping the structural core of the human cerebral cortex
4. Smelling someone else's alarm bells

On a related topic, related in terms of collaborative projects done by teams of people, in this case by a private backer, reader Kent sent me a link to Piece of Mind, from the Economist.

Excerpt:

"When we first put the mouse-brain atlas online free, it was met by the research world with suspicion. People wondered what the catch was. Scientific research has long been a solitary endeavour—one researcher, one microscope. Findings are protected so that discovery credit can be clearly defined and awarded. This is a successful model and will continue to be.
However, the Human Genome Project demonstrated a different path: multiple teams working collaboratively towards a common goal (...) We wanted the mouse atlas to be free and available for all to use as the basis for foundational research and discovery.

A new generation of implantable pacemakers for the brain will be widely used to treat everything from depression to addiction and Parkinson’s disease

If we thought it would be a hit right out of the gate, we were slightly wrong. It took a while for people to trust that it really was free to use. No one believed in a free lunch.

Now, things have changed. Today we have many scientists using the atlas for their research into Alzheimer’s, bipolar disorders, Down’s syndrome, Parkinson’s, fragile x mental retardation and epilepsy. The atlas is also giving scientists insight into alcoholism, obesity, sleep, hearing and memory.

The greatest testament to what we did was that researchers of spinal-cord diseases, trauma and disorders approached the institute and asked us to create a spinal-cord atlas, which is now close to completion. We will launch the first phase of a human-brain atlas, a four-year project, in 2010.

Like the Human Genome Project, the Allen Brain Atlases and Spinal-Cord Atlas have helped democratise the scientific landscape. When you can log on to a map of gene expression from anywhere in the world, more people can enter the scientific conversation. The result is a massive saving in time, since without the atlas each researcher could spend a lifetime trying to gather complete gene-expression data for his or her work."

Nothing but good will come out of this, I'm sure. Seth Grant, who recently decoded human synapse proteomics, used free genomic data bases to arrive at new perspectives on how evolution of the nervous system has proceeded. (Here is a blog post about that.) Listen to Ginger Campbell's BrainSciencePodcast #51 interview with Dr. Grant. (It was my pleasure to transcribe the interview - the transcription is linked to the podcast shownotes.)

More about Locus Ceruleus

2008-12-17T11:43:00.000-08:00

Deric Bownds at Mindblog posted about this new article today: Modafinil Shifts Human Locus Coeruleus to Low-Tonic, High-Phasic Activity During Functional MRI. Not exactly a catchy title, but what the abstract implies is pretty exciting - LC seems to be involved in cognition.

Cognition? Cognition. Fascinating.

Here is the abstract, viewable by clicking on Deric's post, How a cognition enhancing drug works.

"Models of cognitive control posit a key modulatory role for the pontine locus coeruleus–norepinephrine (LC-NE) system. In nonhuman primates, phasic LC-NE activity confers adaptive adjustments in cortical gain in task-relevant brain networks, and in performance, on a trial-by-trial basis. This model has remained untested in humans. We used the pharmacological agent modafinil to promote low-tonic/high-phasic LC-NE activity in healthy humans performing a cognitive control task during event-related functional magnetic resonance imaging (fMRI). Modafanil administration was associated with decreased task-independent, tonic LC activity, increased task-related LC and prefrontal cortex (PFC) activity, and enhanced LC-PFC functional connectivity. These results confirm in humans the role of the LC-NE system in PFC function and cognitive control and suggest a mechanism for therapeutic action of procognitive noradrenergic agents."

Thank you so much for bringing this to this reader's avid attention, Deric. I was interested in the pain-downregulating capacity of LC, its role in sleep, and its extensive connection to everything else in the brain. Now it looks like there may be a direct link between it and actual, functional cognition, not just anatomical noradrenergic pathways between it and parts of the brain one might be forgiven for having assumed were involved in actual, functional cognition.

Here is a link to posts I made earlier in the year, about locus ceruleus.

It has become one of those brain part names that leaps out at me, as does the insula.

More about virtual bodies

2008-12-02T09:45:00.000-08:00

In reference to More about glia, and a Neurophilosophy post on Moseley:

Today's post is short, because Mo has already written it. :-D He's called it The body-swap illusion.

In it Mo explains new work by Henrik Ehrsson, now in Stockholm, the paper If I Were You: Perceptual Illusion of Body Swapping, by Valeria Petkova and Henrik Ehrsson.

Thanks Mo, thumbs up for a great post.

I don't know what more evidence could be found to support the idea that the perceptual brain is in charge of autonomic outflow than to persuade it by means of illusion, both visual and tactile, that it was responsible for maintaining the bodily integrity of a mannequin, then physically threaten the mannequin and measure autonomic alarm as represented by evoked skin conductance response (SCR).

UPDATE Dec 16: Rubber hands feel real for amputees. Thank you again, Mo from Neurophilosophy.

More about glia, and a Neurophilosophy post on Moseley

2008-11-28T11:05:00.000-08:00

I saw a nice post by Mo, on Lorimer Moseley's work with pain research, called Distorting the body image affects perception of pain. Well-deserved recognition in my opinion - thumbs up to Mo. Lorimer Moseley's work has been discussed on this blog, HumanAntiGravitySuit, and Neurotopian several times, as has work done by others involving virtual bodies, body maps, alteration of pain experience, mirror therapy, etc.

A poster at Somasimple contributed this rather nice, very readable, up-to-date and open access article on glia, by Ben Barres, in Neuron, called The Mystery and Magic of Glia: A Perspective on Their Roles in Health and Disease. Enjoy!

Other posts mentioning Glia:
Microglia and Pain: A Manual Therapy Perspective (series)

Posts mentioning Moseley:
1. FABQ and physical therapy
2. The devil is in the details

Posts mentioning virtual bodies:
1. Something in Swiss water?
2. Just UN-do it
3. The user illusion
4. Haptic vest
5. Visual feedback
6. Virtual body experience

Posts mentioning mirror therapy:
Look in the menu to the right side of this blog. Or go to Neurotopian and use the search function, enter "Mirror Therapy" or just click on the menu item and get Matthias' blogpost series on the topic. (While you're at it, re-read his "Pain for Dummies" series.)

Scott Mackler

2008-11-03T06:50:00.000-08:00

The PT site Evidence in Motion posted about Scott Mackler, a neuroscientist with ALS. As it turns out, Scott Mackler is married to a PT researcher, Lynn Snyder-Mackler.

The CBS video, Brain Power, features brain-computer interface technology; Scott, unable to move anything but his mouth, eyes, and thoughts, can select letters from a screen by focusing on a particular letter that he wants: when a random flash highlights that particular letter, his thought, "That's the one I want," and whatever change in electrical potential that his selection creates, effectively communicates itself to the computer through an array of electrodes gelled to his scalp through a cap, and pegs the letter into a window. Then he can move on and peg the next letter. In this way, Scott can express himself and continue work as a neuroscientist.

(Thoughts move. Thoughts are verbs, not nouns. They move - they don't just sit there, being mere nouns. This is one good way that "feeling of certainty" discussed by Robert Burton in his book, On Being Certain, pays off! I am quite certain about that. Almost entirely certain, in fact.)

Also featured in the video we see monkey brain/robot arm interface technology, and an implant into the motor cortex of Cathy, a woman with locked-in syndrome, which gives her an opportunity to communicate with others, control a wheelchair, play music, and adjust the temperature and light level in her home, by moving a computer cursor across a screen, using only her thoughts about moving her hand.

Related blog posts:

1. Smart Prosthetics, Smart Nerves, Smart Brains
2. More Smartness
3. Monkey Robotics
4. Monkey intentions and control of a robotic arm
5. Ginger Campbell's podcast #43, interview with Robert Burton about his book, On Being Certain
6. Harriet Hall's review of the same book

November 4 Update:

7. Mo's Neurophilosophy post about this same topic - Brain Power

VIRTUAL SYMPOSIUM ON PAIN

2008-10-13T13:33:00.000-07:00

This post is about the up-coming webinar series sponsored by the Canadian Physiotherapy Association and its new Pain Science Division (of which I am a exec. member and one of the founders). An internet approach to current, up-to-the-minute meta-education about pain is being integrated into and embraced by the PT profession in Canada, and I couldn't be more happy about it.

I've had a chance to preview the first webinar, and I can assure you the program will shine in both form and content. The content is not overly difficult - it is easy to follow if you have any medical background. Even if you do not, you can take your time with the material and look up the words you don't know with google. Enter the word "define" (but no quote marks) followed immediately by a colon (like this -> :) and the word you want to look up.

For example, if you wanted to look up the word "nociception" to find out the meaning, you would go to google and enter:

define: nociception

Google will take you to a list of possible meanings.

The technical side of the webinar series is speedy and interactive. You can click on pretty much anything from anywhere, from menus listed on the side or as new menus present themselves. Each module will be accessible for an entire week, can be viewed multiple times, and by more than one individual. A discussion forum will operate, where individuals can log in, ask questions, discuss, and help develop answers for other participants' questions, perhaps from their own specialized level of expertise.

Because this is an internet event and is mostly in virtual time, anyone on the planet can participate (if they use English). Only the last (fourth) session will be in real time, probably sometime during the last week of November.

Every conscious human awareness who is embedded in a physically alive body will have to deal with their own pain circuitry at some time or other during their life span. Pain can be hell, but the more prepared we are, the more we can do about our own response to it at the time. Anyone from any walk of life, therefore, is invited. This is the PT profession, reaching out not only to its own members but to the world, offering everyone some well-organized, coherently-presented and useful basic information on a potentially unpleasant matter that either does or will affect us all.

GO HERE TO REGISTER.

Reframing epidermis as part of the sensing nervous system

2008-09-20T06:19:00.000-07:00

Dermatologists are busily investigating that with which they are concerned - skin. The epidermis: a sensory tissue, by Boulais and Misery, is a 2008 paper providing an overview of information that has accumulated to date.

Abstract:
"The skin is an efficient barrier which protects our bodies from the external environment but it is also an important site for the perception of various stimuli. Sensory neurones of the peripheral nervous system send many primary afferent fibres to the skin. They pass through the dermis and penetrate the basement membrane to innervate epidermal cells or remain as free endings. Nerve fibres are clearly involved in somatosensation. However, they are not always so numerous, for example in distal parts of the limbs, and some kinds of sensors can be at a distance of hundreds of micrometers from each other. The skin can detect patterns at a very fine and smaller scale, which suggests that nerve terminals are helped by epidermal sensors. All epidermal cells (keratinocytes, melanocytes, Langerhans cells and Merkel cells) express sensor proteins and neuropeptides regulating the neuro-immuno-cutaneous system. Hence, they must play a part in the epidermal sensory system. This review will consider the epidermal components of this forefront sensory system and the stimulations they perceive. The epidermis can be considered a true sensory tissue where sensor proteins and neurone-like properties enable epidermal cells to participate in the skin surface perception through interactions with nerve fibres."

Consider that skin is an organ, a continuous half inch or so thick membrane layer around the entire body, held on by connective tissue filaments, many millions of them, some thick and tubular, through which pass neural fascicles on their way to skin, and others (most) spider web thin. Skin is heavy. The BodyWorlds exhibit states that skin is equal in weight to the skeleton. If you are an obese person, you could well be carrying around skin that weighs as much or more than the rest of you does.

What does it do, other than be a burden? Well, a lot of things, but from a thermodynamic perspective, the skin is there to regulate temperature/promote heat loss. It's useful to remember that life is more a verb than a noun. The human body (any mammal body, but we'll look at our own body) is essentially a 100-trillion cell highly-controlled furnace operation reducing the oxygen gradient of the planet's atmosphere in order to produce carbon dioxide (in more ways than just metabolically.. but they are beyond the scope of this discussion). Plenty of heat is produced in this transformation, and must be eliminated from the multi-cell organism we are. Skin has 10 times the amount of blood flow than it needs to maintain its own existence (Gray's). So, its biggest job is to be a radiator/heat regulator for the entire organism.

It is also useful, I think, to remember (always) that ectoderm builds the body (if "life promotion" is going to be found in anything, it will be in ectoderm- I'm almost sure about that). Ectoderm builds the body in such a way that it kicks off layers, layers that seem to range from least "communicative" to most "communicative." It's first "cells" are germ cells, which lie completely dormant until stimulated. The next layer is mesoderm, which in addition to being the next least communicative, has to grow most of the body, 98% of it - all the bones and muscles and so on we are more familiar with. Next, it builds brain, spinal cord, and PNS- very very communicative. Lastly, what's left of the ectoderm encircles the entire body in a layer of lively communicative non-neural cells, which, even though they are non-"neural," strictly speaking, are still highly communicative, maybe the most communicative of all.

The neuro-immune-cutaneous system (NICS) refers to the communication system skin cells use in their efforts to keep the body as safe as possible through appropriate communication of environmental conditions. Here are some of the points made in the paper:

1. Epidermal cells connect the skin to the mind through a complex communication network, tightly related to the neuroendocrine and the immune systems.

(I would have used the word "perception" instead of "mind," but that's just me being picky, probably.. Had they used the word "perception," it would have been easier to include all the other mammals whose fur rises in fury or fright, reptiles and even invertebrates like cuttlefish and octopuses who can change their color to match their surroundings. I suspect our proclivity to blush or blanch is part of this system rather than primarily something to do with "mind," whatever that is.. all critters can be safely assumed to have perceptual capabilities, but I expect few will be found to be able to deduce meaning from perceptions with something called "mind.")

2. Langerhans cells and mast cells bridge the gap between neuroendocrine and immune systems in the skin. They participate in endocrine function through metabolism of vitamin D, production of neurohormones. They affect the permeability of blood vessels, are implicated in wound healing, pruritus (itching) and other dermatological disorders like psoriasis.

3. Epidermal cells act on the nervous system at local and central levels:
- 30 to 40% of dermatological patients also have psychological problems (understandable if you were being tortured by your own skin...)
- modulate the sensory information of touch or "pain." After ultraviolet (UV) exposure, they lead to a decrease in the pain threshold and immunomodulatory effects through pro-opiomelanocortin (POMC)-peptide release.

4. Brain can act on skin:
- can affect cutaneous functions in an efferent manner to stimulate target tissues; for example during neurogenic inflammation ("pain"-ful).

The authors go on to explain NICS further:

1. NICS consists of a common language shared by sensory neurones, keratinocytes, melanocytes, Langerhans cells and Merkel cells, with the neuromediators as letters. These powerful molecules are widely involved in skin physiology and the response to a stimulus.

2. Skin cells are able to recognize the relevant biological signals transmitted through neuromediators with high specificity because they synthesize the receptors themselves. Such neuroendocrine capabilities are critical for the activity of the NICS.

3. In the NICS, it is currently understood that:
- substance P (SP) plays a key role in pain sensitization and leads to mast cell degranulation
- POMC and derivatives are immunomodulators
- neurotrophines, like the nerve growth factor (NGF), are mitogenic proteins which also stimulate nerve fibre sprouting, regulate neuropeptides synthesis and probably take part in psoriasis
- catecholamine acts as an inflammatory factor

4. Acetylcholine, calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP) and neuropeptide Y (NPY) seem to act differentially, depending on the skin environment.

5. Therefore, the NICS acts locally, at the level of the neurogenic inflammation, but it is also considered to affect the whole organism via the endocrine and neurocrine pathways

6. "Until now, the concept of NICS mainly described the effects of the nervous system on skin cells through the presence of synapses, neurotransmitters and specific receptors in the skin. We now know that the epidermis also appears at the forefront of the sensory system, as revealed by new data on the sensory abilities of epidermal cells."

My bold. The authors carefully break down the picture by explaining which sensory proteins are made by which cell and commonly transducted by which size nerve fiber. They discuss the TRP (transient receptor protein) family, in particular TRP vanilloid 1 (TRPV1). It turns out that these receptors function exactly the same no matter which surface of the body they happen to be on - out in the epidermis of the body or that of the tongue - they are the equivalent of what we could perhaps call the nervous system's "weather" channels, sensing temperatures and tastes/ "tasting" temperatures both comfortable and noxious, and their fluctuations.

More about TRPV1:

1. is the most characterized receptor and probably the most expressed within the epidermis

2. TRPV1 is highly expressed in neurones involved in pain transmission and neurogenic inflammation (C and Aδ-fibres)

3. also shows a strong immunoreactivity in keratinocytes from the upper and the basal layers of the epidermis

4. In humans, the temperature responsiveness ranges from – 10 to 60 °C

5. plays a major role in the detection of temperatures over 42 °C and acidic conditions below a pH of 6.6

6. has the ability to bind capsaicin, the molecule which confers spiciness to chili peppers, with high affinity.

7. TRPV1 activation evokes sensations ranging from warmth to burning pain, as well as piquant taste

8. Consequences of its activation vary according to the context.
- once activated by capsaicin, the TRPV1 channel first leads to calcium influx and neuropeptide release.
- the lasting calcium influx, with too high intracellular calcium concentrations, leaves the neurone desensitized, thus it loses its ability to induce the release of neuropeptides such as SP, which is co-localized
- This is responsible for a transient insensitivity, which is exploited by dermatologists to induce analgesia or anti-inflammatory effects.

TRPV2 channel is heat-gated, strongly expressed in Aδ-fibres; it is activated for temperatures above 53 °C, warns of a burn.

TRPV3 channel is camphor sensitive, found in sensory neurones and keratinocytes of the inner boundary of the epidermis, is activated by heat from 31 °C to 39 °C.

TRPV4 channel is present in keratinocytes and Merkel cells, exhibits an apparent threshold of about 27 °C, and reacts to hypo-osmolarity.

TRPM8 (melastin cation channel) is menthol-sensitive and transduces cold; it "gates at temperatures below 30 °C. TRPM8 is expressed almost exclusively in a subpopulation of C-fibres representing 10% of the sensory neurones."

"TRPA1, a member of the TRP ankyrin-repeats family has been reported to be activated below 18 °C, so it may also participate in the cold responsive behaviour."

About touch:

The authors state that there is no firm model yet. They discuss three possible models:

1. high speed channels convert stimuli into an electrical signal (this is what is thought to occur in hair cells of the organ of Corti (hearing) because of their remarkable transduction speed)

2. ion channels are tethered to the cytoskeleton or extracellular matrix

3. a mechanosensory protein initiates a second messenger cascade leading to the opening of the ion channels, thus producing depolarization

Re: the third model, in research done with invertebrates two mechanosensitive proteins have been discovered, MEC-4 and MEC-10. These belong to the Degenerin/Epithelial sodium channel family, or Deg/ENaC. "This family is characterized by common N and C terminals, two membrane-spanning sequences and a large extracellular loop with 14 conserved cysteins. The receptors are organized into homo- or heteromultimers of 4 to 9 subunits, forming nine voltage-insensitive Na+ permeable channels in mammals. Thus the mechanosensitive Deg/ENaC is composed of α, β, γ and δ ENaC, the acid-sensing ion channel (ASIC), the brain Na+ channel 1 (BNC1 or ASIC2), the dorsal root acid-sensing ion channel (DRASIC or ASIC3), the brain-liver-intestine amiloride-sensitive Na+ channel (BLINaC) and the ASIC4, which is not proton-gated despite its name."

Although there is still some conflicting data and gaps, and the work done on invertebrates has yet to be perfectly aligned with mammal models, these proteins are found produced by pacinian and Meissner corpuscles, lanceolate endings of hair follicles and the neurites contacting to Merkel cells, mechanosensory neurones of the dorsal root and trigeminal ganglia and hair cells of the inner ear.

Going back to the TRP family, TRPV4 rescues mechanosensory deficit in C. elegans (worm), TRPC1 are stretch-sensitive ion channels gated by membrane deformation, mutated TRPA1 attenuates mechanical responsiveness, NOMPC (analogue to TRPN1 in Xenopus) is implicated in the somatosensation of Drosophila and is newly found in the vertebrate zebrafish, where it behaves as a mechanically-gated ion channel in sensory hair cells. TRPV4 can do two things: it is expressed in the Merkel cell-neurite complexes, anatomical structures composed of the association of mainly Aβ-fibres and Merkel cells, which play a key role in the slowly adapting type I mechanoreception; furthermore, "TRPV4 is highly expressed in non-sensory tissues too. There, TRPV4 is believed to control the systemic fluid balance by its osmolarity-sensitive capability."

Sensor proteins also include purinergic receptors, thought to participate in many cutaneous phenomena. "They are involved in cell growth, differentiation, neuronal regeneration, wound healing, inflammation, etc." There are two types of these receptors grouped according to the ligand they bind:

1. P1 receptors bind adenosine and are divided into 4 subtypes

2. P2 receptors, which bind ATP, ADP, and UTP, are divided into ionotropic P2X receptors and metabotropic G protein-coupled P2Y receptors.

"Keratinocytes express both the P2Y receptors, implicated in the mobilisation of intracellular calcium stores in response to noxious stimulation, and the P2X ion channel. The latter is involved in the initiation of afferent signals on sensory neurones and plays a key role in sensing tissue-damaging and inflammatory stimuli. Immunohistochemical investigation into Merkel cells has revealed expression of P2Y2 receptors, which could argue for a putative role of this channel in mechanoreception."

The paper goes on to discuss sensory nerve endings. It is worth remembering that single nerve cells span the entire distance between skin and spinal cord. They can be various sizes and have varied degrees of myelination and neuropeptide expression, and convey varied information. Functional properties are not strictly related to morphological aspects. However:

1. "it is currently accepted that cutaneous large myelinated Aβ-fibres of low-threshold are suited to be mechanoreceptors which feel pressure, stretch or hair movement."

2. Unmyelinated C-fibres and lightly myelinated Aδ-fibres are often thermoreceptors which respond to heat and cold with different thresholds of activation.

3. Nociceptors, containing opioid receptors, are mainly high-threshold C-fibres and Aδ-fibres which transduce painful sensations.

4. A pruritus-specific pathway was recently defined - the pathway processing the itch is functionally and anatomically separate from the pain pathway.

"The itch pathway implies its own subgroup of peripheral, mainly mechano-insensitive, C-fibres in the skin. In the central nervous system, histaminergic spinal neurones transduce the itch sensation initiated by dedicated pruriceptors, to the thalamus. The pruriceptors are activated by histamine which consistently provokes pruritus, and rarely pain. However, other inflammatory molecules such as prostaglandin E2, serotonin, acetylcholine, bradykinin or even capsaicin may induce a moderate itching sensation. Thus a complex interaction exists between the pain and the itch pathway. - Scratching that induces pain is well-known to inhibit the pruritus and conversely, the inhibition of pain-processing by µ-opioïd can generate pruritus. Therefore, the distinction between cutaneous fibres is not easy and disrupting criteria are frequently evoked, like nociceptive signalling, normally particular to Aδ and C-fibres, with the conductance speed of Aβ-neurones.
- Further investigations have revealed that Aβ-fibres can phenotypically switch into fibres expressing SP whereas normally, SP is only contained in a subpopulation of small C and Aδ-fibres involved in pain perception. This occurs following nerve injury but also after inflammation. Thus the peripheral endings of primary sensory neurones participate in neurotransmission. But they also participate in the immune response by the release of proinflammatory peptides, from unmyelinated C-fibres or myelinated Aδ-fibres, leading to the set of changes referred to as neurogenic inflammation."

5. Two kinds of nociceptor have been identified based on their ability to bind isolectin B4 (IB4). "Those which bind IB4 are usually small diameter non-peptidergic neurones involved in acute pain." But:
- "only half of them seem to answer to noxious stimuli, with the remainder containing less mechanosensory C-fibres
- Within the epidermis, nerve viability and sensitivity can be modulated by neurotrophic factors secreted by epidermal cells."
- IB4-negative neurones containing SP and CGRP are NGF-responsive, small diameter nociceptors
- IB4-positive neurones, which lack such neuropeptides, respond to glial-derived neurotrophic factor (GDNF)
- NGF (nerve growth factor) produced in large quantities by keratinocytes increases nociceptive-neurone survival while brain-derived neurotrophic factor (BDNF) decreases the activation threshold of mechanosensory Aβ-fibres
- neurotrophin-3 (NT3) enhances the innervation by slow adapting mechanosensory neurones.

6. Cutaneous neurites play a major role in the sensory behaviour, but there is much evidence suggesting a modulation of their sensitivity by epidermal cells:

- stimulated cutaneous sensory neurones induce action potentials, but also the release of neurotransmitters, which modulate inflammation, cell growth or pruritus.

- Such neuronal modulations of cutaneous properties regularly bring heterotrimeric G proteins into play at the beginning of the metabolic cascade, and endopeptidases at the end, for termination of the response degrading the messengers

Fascinating stuff. The paper goes on to discuss each type of skin cell separately in detail, which I won't bring here as I am more interested in the overall picture of touch and what occurs neurologically as a result, which of course involves neurochemistry.

Here are tidbits from the conclusion:

- Ion channels have been discovered on epidermal cells: TRP, purinergic and Deg/ENa channels are putative transducers of touch, thermal sensation and nociception, as shown in invertebrate models and knockout mice. Thus they must start the signalling of the stimulus at the molecular level, based on their thermo-dynamical properties.

- Merkel cells are excitable cells containing the molecular components of synaptic connections so they should transduce the stimuli synaptically.

- "The mechanisms of communication between keratinocytes, Langerhans cells or melanocytes and sensory neurones are more mysterious. They are non-excitable cells with no molecular basis of synaptic connections. Paracrine function is supposed, but the mediator used to transmit rapid stimuli as fast as they occur must exhibit the characteristics of a neurotransmitter. It must be specific enough to carry a unique signal and quickly degraded to transmit a short stimulation. We have started to gain insight into this phenomenon so that some non-peptidic candidates are now being considered, like calcium, which can activate neighbouring cells, once released by keratinocytes."

This is reminiscent of glial communication.

Finally: "Acceptance of the epidermis as a sensory and endocrine tissue as part of the NICS has increased, as some authors define skin as spread brain. However, the relationship between skin and brain, although fascinating, remains poorly understood."

I don't think it is beyond understanding if one considers ectodermal behavior - it is the layer that would seem to be in charge of who knows what and when and how much, like a general manager. It seems to like taking "membran-eity" and playing with it, seeing how small it can fold up a single epithelial membrane (brain) and how much surface area it can cover (skin). Ectoderm is like the protective sensing membrane boundary of single cell creatures that ended up inheriting the job of figuring out how to cover monstrous multi-cell creatures. I think it did a brilliant job of it.

Reference:
Online version of the whole paper (caution: format errors are displayed in table 2).

Related posts:
System Proteomics

Boulais N, Misery L (2008). The epidermis: a sensory tissue Eur J Dermatol , 18, 119-127 DOI: 10.1684/ejd.2008.0348

Smelling someone else's alarm bells

2008-08-30T10:53:00.000-07:00

Deric Bownds Mindblog has a post, Do our noses sniff danger in the air? on a recently investigated cluster of cells in the tips of mammalian noses (including humans, it is posited) called the Grueneberg ganglion.
From Science, Aug 2008:

"Grueneberg Ganglion Cells Mediate Alarm Pheromone Detection in Mice
Julien Brechbühl, Magali Klaey, Marie-Christine Broillet*

Alarm pheromones (APs) are widely used throughout the plant and animal kingdoms. Species such as fish, insects, and mammals signal danger to conspecifics by releasing volatile alarm molecules. Thus far, neither the chemicals, their bodily source, nor the sensory system involved in their detection have been isolated or identified in mammals. We found that APs are recognized by the Grueneberg ganglion (GG), a recently discovered olfactory subsystem. We showed with electron microscopy that GG neurons bear primary cilia, with cell bodies ensheathed by glial cells. APs evoked calcium responses in GG neurons in vitro and induced freezing behavior in vivo, which completely disappeared when the GG degenerated after axotomy. We conclude that mice detect APs through the activation of olfactory GG neurons.

Department of Pharmacology and Toxicology, University of Lausanne, Bugnon 27, CH-1005 Lausanne, Switzerland."

"Dialogues in Clinical Neuroscience" online

2008-08-23T19:38:00.000-07:00

A reader, Kent Schnake, sent me a link that looks very good - it's to Dialogues in Clinical Neuroscience, which appears to be open access, for past issues, anyway.

Here is a link to the 2004 issue on neuroplasticity. In it is an article by Fred Gage, downloadable.

Here are some posts that have included discussion of Fred Gage's work:

1. Nervous System Basics VIII: PLASTICITY
2. History of Neuroplasticity

Microglia and Pain: A Manual Therapy Perspective IV

2008-08-06T09:09:00.000-07:00

In reference to Microglia and Pain: A Manual Therapy Perspective:
Part I
Part II
Part III

REFERENCES:
1. Rock BR et al; Role of Microglia in Central Nervous System Infections. (open access) Clinical Microbiology Reviews, October 2004, p. 942-964, Vol. 17, No. 4
2. McMahon s and Koltenburg M; Wall and Melzack’s Textbook of Pain 5th Ed. Churchill Livingstone (September 21, 2005)
3. Ramachandran VS (ed); Encyclopedia of the Human Brain. Academic Press; 1st edition (June 2002): Stoll G et al; Microglia Vol. 3. pp 29-41; Angevine JB; Organization of the Nervous System Vol 3 pp 313- 371; Brown AM and Ransom BR; Neuroglia Overview Vol 3 pp 479- 491
4. Verkhratsky A and Butt A; Glial Neurobiology. Wiley 1 edition (Sept. 2007)
5. Kettenmann H; The brain’s garbage men. Nature Vol 446 Apr. 2007
6. . Piao ZG et al; Activation of glia and microglial p38 MAPK in medullary dorsal horn contributes to tactile hypersensitivity following trigeminal sensory nerve injury. PAIN 121 (2006)
7. Echeverry S et al; Characterization of cell proliferation in rat spinal cord following peripheral nerve injury and the relationship with neuropathic pain. PAIN 135 (2008)
8. Coull JAM et al; BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438 (Dec. 2005)
9. Tsuda M et al; P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 424 (Aug 2003)
Piao, Z.G. (2006). Activation of glia and microglial p38 MAPK in medullary dorsal horn contributes to tactile hypersensitivity following trigeminal sensory nerve injury.. Pain, 121(3), 219-231.

Microglia and Pain: A Manual Therapy Perspective III

2008-08-06T06:50:00.000-07:00

In reference to Microglia and Pain: A Manual Therapy Perspective I, and Microglia and Pain: A Manual Therapy Perspective II:

The Dorsal Horn and Microglia

What role do microglia play in pain? Dorsal horns are the laminated posterior areas of the spinal cord where incoming sensory info is handled. Secondary neurons within the cord, actual CNS neurons, deal with it from then on. At the junction between the incoming sensory neurons and the secondary ascending neurons, there are, yes, you guessed it, microglia hanging around, waiting for a chance to “activate” and move along novel chemo-attractive gradients, substances released into the parenchyma by the presence of inflammation(6) and hypoxia(3), among other things(1), including nerve compression.

Once “activated” they “feed,” increase their populations, leave behind chemical “litter.” These chemicals “inhibit” the secondary ascending fibers. Inhibition? That’s good, isn’t it? Well, maybe not - if your job as a secondary ascending neuron is to be a bottle-neck, and your “bottleneck” function becomes inhibited by microglial activation, the brain is more likely to be confronted by too much nociception, too rapidly, and will need to allocate new resources to learn to downregulate it somehow.

What stimulates microglia at a spinal cord level? The Textbook of Pain chapter states, nerve “damage” such as spinal nerve ligation, chronic constriction injury, or rhizotomy. These are factors associated with neuropathic pain definitions, moreso than neurogenic. But remember the overlap. McMahon et al go on to say:
1. “..synaptic connections between neurons are in a continual state of change highly dependent on the activity not only of the pre- and postsynaptic neurons but also of the surrounding glia.
2. ..continual interplay of various modulatory processes serves to produce synaptic modifications (plasticity) that underlie physiological processes such as learning and memory.
3...common molecular pathways that produce these normal forms of plasticity also lead to pathological processes characterized by excessive excitation, including …pain.
4. In the dorsal horn, central sensitization is a form of excessive excitatory synaptic response in nociceptive transmission neurons, which leads to an increased gain of the pain transmission system and pain hypersensitivity.
5. Our knowledge of the molecular mechanisms of pain plasticity in the dorsal horn is rapidly growing.
6. Future advances will provide new insights into the neurobiological basis of pain, and we anticipate that these will provide the basis for novel types of analgesics and of new diagnostic and management strategies beyond what is presently envisaged.”

The story isn’t over yet, but it’s probably safe to say that whatever makes a synapse in the dorsal horn behave in a manner outside the norm is likely to gain the attention of microglia in the cord. They are thought to be responsible for mechanical allodynia that comes along with central sensitization, based on studies that carefully manipulated the P2X4 receptor they express9. Furthermore, whatever helps a synapse in the dorsal horn recover its ability to conduct business as usual, will likely help decrease central sensitization. It may be that the future of pain control will be in the hands of whoever can find the means to keep the microglial population in check and not allow them to gain the upper hand.

<<<<<<<<<<<<<<<<< >>>>>>>>>>>>>>>>>>>>>>

The fourth post will contain references and links to these three content posts.
All pictures/links have been added for the blog and did not appear in the article.
(Picture of dorsal horn was adapted from Nature Neuroscience)

Microglia and Pain: A Manual Therapy Perspective: Part II

2008-08-05T06:17:00.000-07:00

In reference to Microglia and Pain: A Manual Therapy Perspective: Part I:

Glial functions

In general, glia keep things running smoothly. Astrocytes make sure the synapses are working properly - duties include the regulation of ions to maintain optimal chemical stability in the extracellular fluid, sopping up and storing excess neurotransmitters such as glutamate, buffering K+, and storing glycogen, feeding the neurons with it when a burst is suddenly needed in a given region. They occupy physical space between neurons and capillaries, keep the blood supply and the neurons apart from each other. Oligodendrocytes in the CNS, and their cousins, the Schwann cells in the periphery, manufacture and maintain myelin coverage of their respective neurons. There are other kinds that do other jobs. (See image below and to right, modified from an article, The Dark Side of Glia (Science May 2005).)

Microglia are the smallest of the glia, and (in my opinion) the most mysterious, not just because of their unconventional origins, but also their behaviour; mostly they just sit there, inactive, sessile, not bothering anything, making up 5-15% of the total glial population. Yet they sense everything, and are capable of “activation,” generating a big response to altered environment, which sometimes works well (to take care of invaders) and sometimes not so well (from a pain point of view). They have many kinds of ion receptors - when their environment provides them with sufficient chemical provocation, they change their morphology and begin to mobilize, amoeba-style, drawn to sites of infection or where damage has occurred, where the blood-brain barrier has been breached by injury or vascular failure.

In the brain they act the way macrophages do in the outer body, absorb invaders and corpses, but there is a not-so-good side to all this: the nervous system is generally not used to having these little creatures moving around in it, and sometimes seems to have trouble adapting when they become active. Why should this be?

It is easier to understand if we consider what happens in an ecosystem when scavengers find sustenance in it:

1. First, they will reproduce rapidly. Think of flies on a carcass - soon there are many more flies buzzing around. In the brain and spinal cord, microglia, like the single-cell “creatures” they are, reproduce enormously when times are good - from their perspective. But the CNS, the spinal cord, is an enclosed space, without a lot of room for a burgeoning population of microglia, no matter how small they may be.

2. Microglia and their population explosion alter the chemical environment the nervous system has been used to. Think of excretion (flyspecks) left in their wake - the nervous system is already injured, and now it must adapt to a new chemical environment (polluted in a sense) on top of everything else. Substances released include cytokines, chemokines, trophic factors etc., some of which the neurons can use like “fertilizer” to grow with, others of which merely irritate them.

3. When this sort of “plasticity” occurs in the spinal cord, nociception becomes upregulated.

4. When the brain is exposed to such upregulation, depending on context, it might not succeed in successfully downregulating it back to normal.

The rest of this piece will concern itself with points 3 and 4.

Neurogenic and Neuropathic Pain

In Wall and Melzack’s Textbook of Pain (5th ed.) is a discussion about defining neuropathic as opposed to neurogenic pain. Microglial activation is associated with neuropathic pain which is in turn associated with neuronal damage. In general, from our perspective, we could consider neurogenic pain as more easily downregulated with manual therapy, because there is no irreversible nerve damage - the neurons and dorsal horn can recover. What we do with our contact, both verbal and manual, likely assists nervous systems to increase descending modulation to help decrease perceived pain. Possibly this is sufficient for a system with mere neurogenic pain to right itself, and microglial populations presumably go back to normal levels eventually.

(Image modified from Textbook of Pain 5th Ed.)

Neuropathic pain, or pain felt in the context of actual neuronal or dorsal horn damage due to injury, infection, or ongoing metabolic insult, is less likely to right itself with manual therapy - in fact, manual therapy may worsen matters instead. Luckily for us, at a glance it would seem that there is more neurogenic pain in the population than there is frank neuropathic pain. In the book, the authors conclude that there is no real dividing line yet - that there is a big area of overlap. This is frontier land. We must learn optimal ways to sort out the two main kinds of pain, in the clinic, based on close listening to a patient’s pain history, or risk adding to pain felt by some.

Microglia and Pain: A Manual Therapy Perspective: Part I

2008-08-04T18:30:00.000-07:00

I am going to post, in digestible blogpost-sized chunks, a piece I've written for an ortho newsletter, which I'm pleased to report has been accepted by the editor for inclusion sometime in the fall.

MICROGLIA AND PAIN: A MANUAL THERAPY PERSPECTIVE

 

"The human nervous system is a hierarchy, culminating in the brain, of 100 billion or more neurons of 10,000 types, 1-10 trillion neuroglial cells, 100 trillion chemical synapses, 160,000 km of neuronal processes, thousands of neuronal clusters and fibers tracts, hundreds of functional regions, dozens of functional subsystems, 7 central regions, and 3 main divisions. All of these parts form a coherent, bodily pervasive, diversified, complex epithelium with interdependent connectivity of neurons, mostly neither sensory nor motor but anatomically and functionally intermediate. The key organizing principles of the system are centralization and integration. The nervous system performs two roles: regulation and initiation. In the first, it counteracts: responsively and homeostatically, gathering stimuli from outside and inside the body (including the brain), assessing their short-term and long-range significance, generating activity from faster breathing to stock trading, even to functional plasticity in learning or after brain damage. In the other, it acts: endogenously… replacing one state of neural activity with another, generating activity from doing nothing at all to creative thinking and extraordinary achievement... Although the divisions and regions of the nervous system are identical in all normally developed humans, their genetic specification and personal history are unique, as are the permutations and combinations of their unified function. Each human nervous system is unprecedented. The work of each… is unpredictable, ever-different, surprising, startling, at times horrifying, but not infrequently magnificent." - Jay B. Angevine, Nervous System Organization, Vol.3 of Encyclopedia of the Human Brain

Introduction

Learning about pain can take a manual therapist down strange new paths.

Were manual therapy a city, one would find oneself on a comfortably broad avenue that constitutes all the accumulated wisdom of manual therapy - one would see a large population of peers moving around, or camped along both sides of the street. One can live one’s whole life here, and never venture beyond the edge of town.

In a very short paper I want to take you not just past the edge of town, but way out into the country-side, some of it still wild frontier. I want to try to convey, as Jay Angevine’s quote above conveyed to me, a sense of the vastness of what we must begin to learn to map in our own minds, if we are to ever understand what it is we deal with every day of our lives as we confront pain in our patients. For pain certainly stems from processes within the system described above.

Glia are not all of a kind

From a neuroresearch perspective, the brain/CNS gets most of the attention; spinal cord and peripheral nerves are considered as tentacles out from it. The body itself (the 98% of our physicality that is non-neural, non-neuronal) is mostly ignored - it is not part of the nervous system - instead it viewed as that which is acted upon by the nervous system. This seems backwards to us, at first, but in time this perspective starts to make sense. (After awhile, from a pain standpoint, it is the only perspective that makes sense.)

What is in the brain? Neurons and glia – lots of glia, lots of blood vessels. Neurons, even at 100 billion strong, are outnumbered at least ten to one by various kinds of glia. Neurons are huge compared to glia. Because glia are much smaller, it takes many more of them to make up a good half of brain volume. And microglia are the smallest of all, equal in numbers to neurons.

Where do glia come from? They form from the same precursor cells as neurons do, for the most part. The origins of microglia, however, are still a bit murky. Conventional thought has them as being from the early embryonic hemopoietic system, invading the brain early on before the blood-brain barrier is properly in place, then kept at bay via chemically controlled conditions by the other glia, just waiting to “activate.” Other researchers (a minority) think that they come from the same precursor cells as neurons and the other glia. This debate is still not quite settled, but it is agreed that they function as the nervous system’s “immune system.”

More on proteins

2008-08-01T07:25:00.000-07:00

In reference to System Proteomics:
On Carl Zimmer's blog, The Loom, I found Your Yeasty Network. His post references this open access paper:Protein Complex Evolution Does Not Involve Extensive Network Rewiring, by van Dam and Snel in the Netherlands. They are trying to determine relationships within something they term an "interactome." Zimmer loves the illustration (see his link).

Although the paper doesn't refer to protein complexes at synapses specifically, I should think anything that has to do with evolution of protein complexes will have to do with protein complexes at synapses.

Inside his post Zimmer refers to another of his posts, Carrying ancient history in the gut - here, he examines the differences between the protein complexes of yeast (more complex) and giardia (simpler).

I now pronounce you....

2008-07-16T15:35:00.000-07:00

In the book "The Brain That Changes Itself" by Norman Doidge the author recommends that those of us who help others by bringing about change in the nervous system call ourselves Neuroplasticians. A great name! But, what kind of neuroplastician am I?

In "Musicophilia," Oliver Sacks describes going to a concert and seeing the crowd move in unison to the music and being overtaken by the urge to move himself as well. He said it was as if the music joined together the nervous systems of the entire audience as one. He called it Neurogamy, which means the joining of 2 (or in the case of the concert, many) nervous systems. Sacks goes on to describe how this is one of the many amazing qualities of music.

I began to think about other examples of Neurogamy. Diane has often spoken of 2 nervous systems interacting during the patient encounter and I can also recall David Butler describing the patient's nervous system is processing you just as yours is processing them. It seems important for happy Neurogamy to take place during therapy. But what about unhappy Neurogamy? There are plenty of unhappy marriages in the world, why would the marriage of nervous systems be any different? Driving in traffic. A similar task forces a neurogamous relationship with strangers who have limited communication abilities with eachother. When this relationship is bad we see road rage.

I think that we could come up with many characteristics of good and bad Neurogamy that would be useful in the context of therapy. In the meantime, I'm happy to have thought of a name for my breed of Neuroplastician. We are clinical neurogamists!

Engineers are interested in skin

2008-07-05T12:24:00.000-07:00

For years I've been talking and promoting skin stretch as a not just a good avenue for kinesthetically influencing another human nervous system, but as probably one of the best ways:

1. the easiest, because skin is already out there, the first thing one "touches", and is already set up neurologically, connecting that person's brain with/for contact with environment

2. most practical, because it is the most highly innervated and therefore sensitive, and doesn't require much physical strength or special leverage from a practitioner

3. strongest neurologically, in terms of response elicited for effort made, and results gained for time spent.

It's the easiest way to stimulate physiologic nonconscious movement for the person's own brain to then harness into pain relief of ordinary uncomplicated mechanical pain or stiffness. I've worked this way for a couple decades now. (Elsewhere I've referred to this as "dermoneuromodulation", and to dermoneuromodulation as a major feature of "human primate social grooming.")

Earlier today I found a paper by some mechanical engineering students at Stanford who seem awfully interested in skin stretch. I think they are investigating haptic capacity - maybe they want to build better robots which can carry tea in expensive china without either
a) spilling tea, or;
b) dropping and breaking the china.

It's by Bark et al., and called Comparison of Skin Stretch and Vibrotactile Stimulation for Feedback of Proprioceptive Information; it can be found online (here's an html version I found).

I very much admire the way in which engineers simply read, absorb, accept things that are obvious at face value, and move on to develop cool applications based on research. My profession is so determined to seem scientific on the one hand, yet is so mired in "traditional" ways of applying manual therapy that it won't let go of visualizing everything backwards, from the joints out. See the attached Shaffer paper. (At least it does actually mention cutaneous receptors as maybe being somewhat important for balance and equilibrium...)

But generally, trying to get my own profession interested in the sensitivity and handling of skin is very difficult. It would rather contemplate bones, joints, muscles, and in general, innervation of mesoderm, rather than realize that the brain of a patient is always going to register skin contact first, at multiple levels which will react accordingly.

The Bark paper is loaded with excellent references to do with skin stretch and how it might apply to haptic possibilities for mechanical devices. See at bottom.

Additional Reading:

Shaffer SW, Harrison AL; Aging of the Somatosensory System: A Translational Perspective. (15-page pdf) Physical Therapy Vol 87 No 2 Feb 2007
.

From the Bark paper:
[1] K. Bark.Preliminary results from skin stretch perception tests,http://bdml.stanford.edu/twiki/bin/v...ontesting,2007.

[2] K. Bark, J. Savall, and R. Holop. Measuring skin stretch strain, http://bdml.stanford.edu/twiki/bin/v...roperties,2007.

[3] J. Biggs and M. Srinivasan. Tangential versus normal displacements of skin: Relative effectiveness for producing tactile sensations. In 10th International Symposium on Haptic Interfaces for Virtual Environment and Teleoperator Systems, pages 121–128. IEEE ComputerSociety, 2002.

[4] D. Caldwell, N. Tsagarakis, and C. Giesler. An integrated tactile/shear feedback array for stimulation of finger mechanoreceptor. International Conference on Robotics and Automation, pages 287–292, 1999.

[5] D. F. Collins, K. M. Refshauge, G. Todd, and S. C. Gandevia. Cutaneous receptors contribute to kinesthesia at the index finger, elbow,and knee. Journal of Neurophysiology, 94:1699–1706, May 2005.

[6] B. Edin and N. Johansson. Skin strain patterns provide kinaestheticinformation to the human central nervous system. Journal of Physiology, (487):243–251, 1995.

[7] B. B. Edin. Cutaneous afferents provide information about knee joint movements in humans. The Journal of Physiology, (531.1):289–297,2001.

[8] B. B. Edin. Quantitative analyses of dynamic strain sensitivity in human skin mechanoreceptors. Journal of Neurophysiology, 92:3233–3243, 2004.

[9] F. Freybergery, M. Kuschel, B. Farber, M. Buss, and R. Klatzky. Tilt perception by constant tactile and constant proprioceptive feedback through a human system interface. In Second Joint EuroHaptics Conference and Symposium on Haptic Interfaces for Virtual Environment and Teleoperator Systems, March 2007.

[10] M. Fritschi. Design of a tactile shear force prototype display. Inhttp://www.touch-hapsys.org, page Work package 6, 2003.

[11] E. Gardner and J. Martin. Coding of Sensory Information, chapter 21,pages 411–429. Principles of Neural Science. McGraw-Hill, fourth edition, 2000.

[12] E. Gardner, J. Martin, and T. Jessell. The Bodily Senses, chapter 22,pages 431–450. Principles Of Neural Science. McGraw Hill, fourth edition, 2000.

[13] G. D. Garson. Univariate glm,anova,and ancova”from statnotes:Topics in multivariable analysis. In http://www2.chass.ncsu.edu/garson/pa...htm,volume2007, page 1, 2007.

[14] G. M. Goodwin, D. I. McCloskey, and P. B. C. Matthews. The contribution of muscle afferents to kinesthesia shown by vibration induced illusions of movement and by the effects of paralysing joint afferents. Brain, 95(4):705748, 1972.

[15] V. Hayward and M. Cruz-Hernandez. Tactile display device using distributed lateral skin stretch. In Proceedings of the Haptic Interfaces for Virtual Environment and Teleoperator Systems Symposium, volume ASME DSC-69-2, pages 1309–1314. ASME IMECE2000.

[16] R. Johannson. Skin Mechanoreceptors in the Human Hand: Receptive Field Characteristics, pages 159–170. Sensory Functions of the Skin in Primates, with special reference to Man. Pergamon Press Ltd.,Oxford,, 1976.

[17] L. Jones, M. Nakamura, and B. Lockyer. Development of a tactile vest. In Proceedings of the 12th International Symposium on Haptic Interfaces for Virtual Environment and Teleoperator Systems. IEEE,March 2004.

[18] K. J. Kuchenbecker, N. Gurari, and A. M. Okamura. Effects of visual and proprioceptive motion feedback on human control of targeted movement. In IEEE International Conference on Rehabilitation Robotics, pages 513–524, June 2007.

[19] R. H. LaMotte, M. A. Srinivasan, C. Lu, P. S. Khalsa, and R. M. Friedman. Raised object on a planar surface stroked across the fingerpad: Responses of cutaneous mechanoreceptors to shape and orientation. Journal of Neurophysiology, 80:2446–2466, 1998.

[20] V. Levesque and V. Hayward. Experimental evidence of lateral skin strain during tactile exploration. In Proc. Eurohaptics, July 2003.

[21] J. Luk, J. Pasquero, S. Little, K. E. MacLean, V. Levesque, and V. Hayward. A role for haptics in mobile interaction: Initial design using a handheld tactile display prototype. In Proc. of the ACM 2006 Con-ference on Human Factors in Computing Systems, CHI 2006, pages171–180, 2006.

[22] D. Mahns, N. Perkins, V. Sahai, L. Robinson, and M. Rowe. Vi-brotactile frequency discrimination in human hairy skin. Journal of Neurophysiology, 95:1442–1450, March 2006.

[23] Y. Makino and H. Shinoda.Selective stimulation to superficial mechanoreceptors by temporal control of suction pressure. In Haptic Interfaces for Virtual Environment and Teleoperator Systems, WorldHaptics Conference, pages 229–234, March 18-20, 2005.

[24] G. Moy and R. Fearing. Effects of shear stress in teletaction and human perception. In Proceedings of the 1998 ASME Dynamic Systems and Control Division, ASME International Mechanical Engineering Congress and Exposition, volume DSC-Vol. 64, pages 265–272, November 1998.

[25] A. Murray, R. Klatzky, and P. Khosla. Psychophysical characterization and testbed validation of a wearable vibrotactile glove for telemanipulation. Presence: Teleoperators and Virtual Environments, 12(2):156– 182, April 2003.

[26] M. Pare, H. Carnahan, and A. Smith. Magnitude estimation of tangential force applied to the fingerpad. Experimental Brain Research,142:342–348, 2002.

[27] I. Summers, P. Dixon, P. Cooper, D. Gratton, B. Brown, and J. Stevens. Vibrotactile and electrotactile perception of time-varying pulse trains.Journal of Accoustical Society of America, 95(3):1548–1558, March1994.

[28] H. Tan, R. Gray, J. J. Young, and R. Traylor. A haptic back display for attentional and directional cueing. Haptics-e, 3(1), June 2003.

[29] H. Tan, A. Lim, and R. Traylor. A psychophysical study of sensory saltation with an open response paradigm. In In Proceedings of the Ninth (9th) International Symposium on Haptic Interfaces for Virtual Environment and Teleoperator Systems, American Society of Mechanical Engineers Dynamic Systems and Control Division, volume 69-2,pages 1109–1115, 2000.

[30] Q. Wang, V. Hayward, and A. M. Smith. A new technique for the controlled stimulation of the skin. In Proceedings of the Canadian Medical and Biological Engineering Society Conference, CMBEC, September 9-11, 2004.

Study notes

2008-07-05T09:06:00.000-07:00

I've been back in that Angevine chapter in Vol 3 of Encyclopedia of the Human Brain, and compiled some study notes along with pictures I found here and there by using Google images.

Here they are - perhaps they are of some use:

Nervous System Basics: Main Divisions

Nervous System Basics: Major Regions

Nervous System Basics: Organizing Principles

More from Lausanne: Mapping the Structural Core of Human Cerebral Cortex

2008-07-01T06:44:00.000-07:00

This paper (open access) has just been published online: Mapping the Structural Core of Human Cerebral Cortex. Researchers in Switzerland are finding ways to combine imaging techniques to deepen understanding of how the brain functions at rest and at work.

AUTHOR SUMMARY
"In the human brain, neural activation patterns are shaped by the underlying structural connections that form a dense network of fiber pathways linking all regions of the cerebral cortex. Using diffusion imaging techniques, which allow the noninvasive mapping of fiber pathways, we constructed connection maps covering the entire cortical surface. Computational analyses of the resulting complex brain network reveal regions of cortex that are highly connected and highly central, forming a structural core of the human brain. Key components of the core are portions of posterior medial cortex that are known to be highly activated at rest, when the brain is not engaged in a cognitively demanding task. Because we were interested in how brain structure relates to brain function, we also recorded brain activation patterns from the same participant group. We found that structural connection patterns and functional interactions between regions of cortex were significantly correlated. Based on our findings, we suggest that the structural core of the brain may have a central role in integrating information across functionally segregated brain regions."

The various images represent information gained from various kinds of investigative technique produces - this image (from the paper) is a computer integration/ combination..

July2: Back inside this post for a moment to drop a link from Mo's post at Neurophilosopy about this topic. Please go and read it - it contains much more analysis on the paper and the implications of the research, and links to this amazing picture of white matter tracts in the brain. The three main classifications of white fibers (association, commissural and projection) are clearly visualized:

Microglial origin

2008-06-30T18:22:00.000-07:00

Continuation of the Glia series:
Here is what the authors on the topic in Encyclopedia of the Human Brain, Guido Stoll, Sebastian Jander and Michael Schroeter have to say on the topic, p. 34 Vol 3:

"ORIGIN OF MICROGLIA
The origin of ramified microglia has been a long-standing controversial issue, although most authorities would accept that microglia are bone marrow derived and belong to the monocyte/macrophage lineage. The observation that the decline of blood-derived amoeboid cells (macrophages) in the CNS during the first postnatal weeks was accompanied by a dramatic increase in the number of ramified microglia was suggestive for a transition of amoeboid cells into resident ramified microglia. Based on morphological grounds, however, transitional forms between these brain macrophages and resting microglia could not be detected in the developing brain. Moreover, in an attempt to directly address the issue of transition, young mice received bone marrow transplants from transgenic mice, thereby allowing the distinction between host and donor cells in tissues. In these chimeric animals only 10% of parenchymal microglia in the CNS displayed the transgenic signal. In adult animals attempts to directly demonstrate the replacement of ramified parenchymal microglia from bone marrow-derived precursors have so far yielded inconclusive results. Ramified microglia in the adult CNS are an extremely sessile cell population exhibiting virtually no turnover from circulating monocytic precursor cells. In contrast to the parenchymal microglia, the perivascular microglia are definitely bone marrow derived and regularly replaced in the adult CNS as demonstrated by use of chimeric rats by Hickey and Kimura.

The view that parenchymal microglia are bone marrow derived has been challenged. Based on their finding that astroglial cultures initiated from newborn mouse neopallium contained bipotential progenitor cells that could give rise to both astrocytes and microglia, Fedoroff and colleagues put forward the idea that parenchymal microglia are of neuroectodermal origin as are all other glia. This view was further supported by the observation that the majority of microglia lacked the transgenic signal after bone marrow transplantation as described previously. Despite the uncertainty about their origin, microglia share most surface molecules with bone marrow-derived monocytes/ macrophages."

Neuroectoderm is a term researchers are using to replace 'neural crest derived tissue'.
I found a little picture of Fedoroff in a 2007 newsletter from U of Sask. (12 page pdf), a picture taken way back in 1963, and featured as an archival photo.

A written description below identifies Fedoroff as the man standing in the photo.
Alas, I was unable to retrieve the reference cited, which is in a book:
Fedoroff S (1995). Development of microglia. In Neouroglia (H. Ketterman and B.R. Ransom, Eds.), pp 162-181. Oxford University Press, NY.

I couldn't find very much that has been published on the topic, or any other papers by Fedoroff that discuss neuroectodermal origin of microglia.

The three chapter authors appear to be quite busy.. here is another chapter they have written elsewhere.

Monkey intentions and control of a robotic arm

2008-06-28T08:20:00.000-07:00

In a brief departure from a current catch-up I'm doing on glia, I want to catch up some old posts, thoughts, themes and developments to do with the brain as movement simulator.

In reference to blogposts The devil is in the Details (Dec 18/07), More on Learning (Dec 21/07), and The User Illusion, Dec. 22/07:

Today Deric Bownds Mindblog post featured a short piece about a big big topic:
Science Hack - monkey brain moving robotic arm. Readers can follow the links and find the great little video - as usual, a food reward proved to be the most effective for getting a monkey to neuroplasticize its brain... this monkey can't move its own arm but it learned to move the robotic one to reach food and put it into its own mouth. Remarkable. It appears that with the right motivation a brain can learn whatever it needs to.

Additional Reading:
Differences Between Intention-Based and Stimulus-Based Actions (12 page pdf)
.

About ASTROGLIA

2008-06-27T13:06:00.000-07:00

In reference to About Glia:

I just waded through the entire chapter on astroglia in Encyclopedia of the Human Brain. I discovered it was written by two researchers in France, Nicole Baumann and Danielle Pham-Dinh. The chapter is extensive (from p. 251-268 in Vol. 1) and I've still only scratched the surface of what is available in this large reference work on glia.

Here is the concluding section of their chapter:

"CONCLUSIONS
The importance of glia has become increasingly clear with the development of molecular biology and cell culture techniques. With technical progress, the roles of glia in neuronal migration in the development of neuronal pathways as well as in synaptic functions have bee deciphered. Increasingly, the molecules involved in developmental processes and in the adult are being identified; molecules necessary for the migration of neurons on radial glia or Bergmann* cells are made by neurons or glia with multiple interactions. Molecular studies of developmental mutants and human pathologies have led to the identification of the involvement of glia in numerous defects of migration that lead to microcephaly and other developmental diseases.

In many cases, axonal guidance seems to involve preformed glial pathways that may remain and create glial boundaries. Increasingly these neuroglial interactions are being identified in relation to neuronal functions. Because of their mobility and plasticity, glial cells appear to be increasingly involved in the functions of the cabled neuronal network. Synapses throughout the brain are ensheathed by astrocytes. Astrocytes help to maintain synaptic functions by buffering ion concentrations, clearing released neurotransmitters, and providing metabolic substrates to synapses. As recently reviewed, glia should be envisaged as integral modulary elements of tripartite synapses because they are now playing an active role in synaptic transmission and are fully involved in neuron-astrocyte circuits in the processing of information in the brain. They are indispensable in obtaining nutrients from the blood and helping to maintain the blood-brain barrier. For energy metabolism, these glial cells take up glucose from the brain capillaries and transform it into lactate and other fuels absolutely necessary for the neurons to function. The metabolic coupling between glia and neurons is increasingly obvious in view of the development of the methods of investigation, even in vivo; astrocytes contribute to the deoxyglucose signal in PET, which may give new insights into the interpretation of this signal in neurological and psychiatric disorders. Astrocytes are necessary to avoid the excitotoxic role of glutamate through the glutamate-glutamine cycle, which is pivotal, as are probably other neurotransmitter cycles. One of the recent developments is the way in which communication can occur through glial cells by calcium waves; this seminal discovery has been followed by a wealth of work demonstrating that calcium signaling can extend even to neurons and can be bidirectional. It is possible that astrocytes may provide new means of communication in the nervous system and new pathways not yet clearly defined. No doubt, there are enormous gaps to fill in relation to their functions in vivo; hints have been provided, for example, by the observation that they are modulated by circadian rhythms and hormonal states.

Although myelin repair and synaptic remodeling and regeneration can occur, many enigmas still remain, especially in humans, in which the factors may be different from those in the murine species. Thus, studies in primates and in vivo systems cannot be omitted at this stage in view of therapeutic implications.

The dysfunction of glial cells is possibly at the origin of many of the degenerative diseases of the nervous system and the major brain tumors (glioma). Although the neuroimmunological role of astrocytes as antigen presenting cells is still unclear in the CNS under in vivo conditions, their role in neurodegenerative diseases seems increasingly evident because they are implicated in the suppression of oxidative stress. No doubt, in the near future, we will understand more about the cross talk between glial cells and neurons in normal and pathological states. Already, abnormal astrocytes and oligodendrocytes appear to be involved in cognitive functions as evidenced from leukodystrophies related to oligodendrocyte or astrocyte genetic disorders. Recently the primary genetic defect of Alexander disease was demonstrated in astrocytes where mutations of GFAP lead to a secondary demyelinating disease, enlightening the pivotal role of astrocyte on oligodendrocyte and myelin maintenance.

Progress in neuroscience has shown that neurons and glia do not represent just the addition of independent compartments and that the cooperation of both cell populations is essential for development and functions of the nervous system. As mentioned by Peschanski, the time has come for "neurogliobiology" because neurons and glia (including astrocytes, oligodendrocytes and microglia) in the nervous system are indissociable partners."

Notes:
* Bergmann cells are a subtype of astrocyte located in the cerebellum; they help maintain synapse junctions between Purkinje cells and climbing fibers.

Additional reading:
1. Also by Nicole Baumann and Danielle Pham-Dinh: Biology of Oligodendrocyte and Myelin in the Mammalian Central Nervous System. They seem to be the go-to people for basic fundamentals on glia.
Baumann, N., Pham-Dinh, D. (2001). Biology of Oligodendrocyte and Myelin in the Mammalian Central Nervous System. Physiological Reviews, 81(2), 871-927.

About glia

2008-06-22T13:00:00.000-07:00

This is the first post of several I intend to make about glia, a class of neural (but not neuronal) cells that I really don't know enough about yet. Now, having become rather interested in synapses, I've come to see the need to know more about the cell basics.

I started out with the Encyclopedia of the Human Brain. In Volume 3, p. 480, I gained a sense of proportion. Glial numbers exceed neurons by a factor of 10 to 1. They account for 50% of the volume of the entire brain. Volume, not numbers. They are tinier.

p. 406, I learned a bit about four main types:

INTRODUCTION:
- Glia are far more abundant than neurons in the brain
- Glia of the brain and spinal cord are classified into four types:
1. astrocytes
2. oligodendrocytes
3. microglia
4. ependymal cells

Astrocytes
- are starshaped glial cells found in both gray and white matter
- have a role in the mechanical support of neurons
- contribute to metabolic regulation of the micro environment of the brain
- participate in its response to injury

Oligodendrocytes
- are confined mainly to white matter
- are responsible for the myelination of brain axons (as Schwann cells are in the PNS)

Microglia
- are small cells found in gray and white matter
- serve as the phagocytes of the brain
- migrate as necessary to damaged areas where they consume pathogens and neuronal debris

Ependymal cells
- line the ventricles of the brain
- at a specialized structure called the choroid plexus (one of which is found in each ventricle) they form a secretory epithelium that produces the CSF that fills the ventricles and bathes the entire CNS

There is some debate about their origins. For now I'm going to go with neural crest being their parent progenitor, but will bring the different opinions here later. Microglia pose the biggest departure, because they are scavengers, macrophagic in behavior, thought to come possibly from a hemopoietic source. However, I wouldn't put it past neural crest to be quite capable of making a version of brain cell that behaves just like a macrophagic cell that originates with mesoderm.

Further reading:

1. NIH Public Access: Glial cells: Old cells with new twists (2008) (mostly about oligodendrocytes)

2. Neurophilosophy: Nerve glue comes unstuck
- Background on Rudolf Ludwig Karl Virchow (who was responsible for suggesting that glial cells were merely filler, and whose other claim to fame was that washing one's hands to prevent spread of infection was not important.)

3. A Wikipedia link explaining membrane proteins, connexins (small) and connexons (larger, 6 connexins from each cell forming a gap junction between two cells)

4. Neurophilosophy: Starring role in the brain for astrocytes

5. Neurophilosophy: Astrocytes take center stage in brain function

6. Neurophilosophy: Getting a grip on cerebral bloodflow

7. Neurophilosophy: Six iconoclastic discoveries about the brain

(How can you tell I'm a huge Neurophilosophy fan?)

8. Fifty-eight page paper about oligodendroctyes by Nicole Baumann and Danielle Pham-Dihn: Biology of Oligodendrocyte and Myelin in the Mammalian Central Nervous System (2001)

(These two authors also have a chapter on astrocytes in Encyclopedia of the Human Brain)

Synapse Proteomics

2008-06-18T09:18:00.000-07:00

Lily Tomlin, in her comedic role as Trudy the bag lady, in the 1991 film Searching for Signs of Intelligent Life in the Universe, mentioned that she thought she likely suffered from a few "lapses in the synapses."

In all seriousness though, both Deric at Mindblog and Mo at Neurophilosophy have referred recently to work being done on synaptic complexity.

1. Deric's post, Increasing complexity of nerve synapses during evolution refers to this Nicholas Wade article in the New York Times, Brain Power May Lie in Complexity of Synapses, which looks at the possibility that the more complex the synapses are, the more brain power there is likely to be.
(Image from the Nicholas Wade NYT article, originally from the journal Nature Neuroscience.)
The NYT article looks at this paper, Evolutionary Expansion and anatomical specialization of synapse proteome complexity by Emes RD, Grant S, et al.

2. Meanwhile, Mo at Neurophilosophy wrote this blogpost: Synapse proteomics & Brain Evolution about the same paper.
.........................................

In the first part of a series of posts here called Nervous System Basics (see Part I), I wanted to draw attention to the fact that there are 100 billion neurons, 1-10 trillion glial cells, and 100 trillion chemical synapses.

This is just so hard to imagine (i.e., form a mental construct about). And those are just the numbers associated with the complexity due to numbers of microscopic-sized physical structures. Now add large numbers of complexities in the synapses themselves, at a molecular (beyond ordinary microscopic-sized) order of magnitude, and you might catch a glimpse of how complex our brains truly are.

HERE ARE SOME TAKE HOME POINTS

1. It's not just about brain size or numbers of neurons:
From the Wade NYT piece:

"A human brain... is three times the volume of a chimpanzee’s... (however) in fact the synapses get considerably more complex going up the evolutionary scale, Dr. Grant and colleagues reported online Sunday in Nature Neuroscience. In worms and flies, the synapses mediate simple forms of learning, but in higher animals they are built from a much richer array of protein components and conduct complex learning and pattern recognition..."

(From Mo's Neurophilosophy post:)

"a new study which used bioinformatics to compare the synapses of distantly related species suggests that size may not be the most important factor in human brain evolution after all. Instead, the new findings, which were published online in Nature Neuroscience on Sunday, suggest that it is an increase in the complexity and number of synapses that was crucial for the emergence of complex behaviours and cognition."

2. Each synapse has a role in adding complexity and therefore brainpower:

"If the synapses are thought of as the chips in a computer, then brainpower is shaped by the sophistication of each chip, as well as by their numbers. “From the evolutionary perspective, the big brains of vertebrates not only have more synapses and neurons, but each of these synapses is more powerful.." (- Wade quoting Dr.Grant)

(From Mo's post:)

"On the receiving end of the synapses of mammals, immediately beneath the membrane, there is a dense network of proteins called the postsynaptic density (PSD). The PSD contains more than 1,000 proteins, which can broadly be divided into 3 different classes: the components of around 12 parallel but converging signaling pathways.."

3. Synapses preceded nervous systems: (Wade again:)

"He included yeast cells in his cross-species survey and found that they contain many proteins equivalent to those in human synapses, even though yeast is a single-celled microbe with no nervous system. The yeast proteins, used for sensing changes in the environment, suggest that the origin of the nervous system, or at least of synapses, began in this way."

4. Synaptic problems ("lapses in the synapses") may be responsible for mental disorders (Wade again:)

"The roots of several mental disorders lie in defects in the synaptic proteins, more than 50 of which have been linked to diseases like schizophrenia, Dr. Grant said."

5. Synapses might "evolve" by 'tweaking' themselves? :

In Mo's post, there is a link to this page, on postsynaptic density or PSD. In it is stated the definition; "The postsynaptic density is a multiprotein complex containing membrane proteins, signaling molecules and core PSD proteins." Mo says,

"The PSD contains more than 1,000 proteins, which can broadly be divided into 3 different classes: the components of around 12 parallel but converging signaling pathways, with the components of each one clustered to form an enormous macromolecular complex; the cytoskeletal and scaffolding proteins which tether the complexes to precise locations at the membrane, in close proximity to the receptors which activate them; and the enzymes which regulate the movements and functions of the complexes and their individual components within the membrane.

The regulatory enzymes act by making minor modifications in the structure of the signaling pathway components. One apparently ubiquitous form of modification involves the addition of a small molecule called a phosphate group to a specific site on the target protein. This process, phosphorylation, is catalyzed by enzymes called a kinases. It is reversible, and acts like a switch - the phosphate groups can be removed by another group of enzymes called phosphatases, and the addition or removal of a phosphate group activates or inhibits a target protein.

These signaling pathways are incredibly complex - the enzymes all act on multiple targets, and differ in their effects on each. Furthermore, they are subject to the same regulatory mechanisms as the proteins they regulate. They too can have phosphate groups or other small molecules added or removed, and in some cases, activate or inhibit themselves by catalyzing modifications of their own structure."

(This is really clear, and I'd like to thank you Mo, for being such a good writer on such a difficult topic that even a regular person like me can catch a glimpse of some immense implications...)

6. Proteomics (i.e., the study of proteins) might help researchers unravel synaptic mysteries and reveal more about how the brain "works": (Mo again:)

"The interactions between these signaling pathways are very poorly understood, largely because researchers were until recently only able to investigate one or two of the components at any one time. This is where proteomics comes into its own, because it allows for simultaneous analysis of hundreds or thousands of molecules, enabling researchers to begin teasing apart the pathways and networks instead of plucking individual components out one at a time."

Additional Links/Reading:
1. Genes to Cognition program headed by Seth Grant
2. Grant S; Organization of brain complexity - synapse proteome form and function (2006, open access)
3. Genes2Cognition
4. Grant S; The synapse proteome and phosphoproteome: a new paradigm for synapse biology (2006, 5-page pdf)
5. Hensch TK, Fagiolini M; Excitatory-Inhibitory Balance: Synapses, Circuits, Systems (2003): Chapter 1, The Organization and Integrative Function of the Post-Synaptic Proteome, is by Grant S et al.
6. Ziff EB; Getting to synaptic complexes through systems biology (2006)
7. Short (5 minute) YouTube video: Neurons and Neuro-transmitters
8. Press release June 2009, from the Sanger Institute where Seth Grant works: Origins of the Brain: Complex Synapses drove brain evolution
9. Emes R and Grant SG et al; Evolutionary expansion and anatomical specialization of synapse proteome complexity, Nature Neuroscience, June 2008, open access 8-page pdf

More about neurogenesis

2008-06-07T20:40:00.001-07:00

There are some other posts here that include the topic of neurogenesis:
1. History of Neuroplasticity
2. And it's about brain parts: like hippocampus
3. Nervous Systems Basics VIII: PLASTICITY

Here is a new study on the matter; Spatial Relational Memory Requires Hippocampal Adult Neurogenesis.

Abstract: The dentate gyrus of the hippocampus is one of the few regions of the mammalian brain where new neurons are generated throughout adulthood. This adult neurogenesis has been proposed as a novel mechanism that mediates spatial memory. However, data showing a causal relationship between neurogenesis and spatial memory are controversial. Here, we developed an inducible transgenic strategy allowing specific ablation of adult-born hippocampal neurons. This resulted in an impairment of spatial relational memory, which supports a capacity for flexible, inferential memory expression. In contrast, less complex forms of spatial knowledge were unaltered. These findings demonstrate that adult-born neurons are necessary for complex forms of hippocampus-mediated learning.

(Thank you, Deric Bownds at Mindblog.)

The best general reader book I've found on the topic of neuroplasticity and neurogenesis is the one by Sharon Begley, Train Your Mind, Change Your Brain: How a New Science Reveals Our Extraordinary Potential to Transform Ourselves .

The best general reader book I ever found on the topic of spatial brainmaps is Sandra Blakeslee's book,The Body Has a Mind of Its Own: How Body Maps in Your Brain Help You Do (Almost) Everything Better. (This same author helped Ramachandran write his now-classic Phantoms in the Brain: Probing the Mysteries of the Human Mind.)

Both these authors' books have been discussed or the authors have been interviewed by Ginger Campbell at Brainscience Podcast; there are links to a discussion of Sharon Begley's book (episode 10), and Sandra Blakeslee's interview (episode 23, also #21), and others on neuroplasticity.

More reading:
1. The Reinvention of Self, a 2006 article by Jonah Lehrer in Seed about Elizabeth Gould's pioneering research into neurogenesis in marmosets

"Sky-blue place" IV: Descending modulation

2008-06-01T08:34:00.000-07:00

In reference to:
Locus Ceruleus: "Sky-blue place"
"Sky-blue place" II: Projections
"Sky-blue place" III: Input

This will be the last post in this series.
I think I've turned over most of the stones I could find learning about this cool little brain spot that seems to know just when to wake up the brain and when to be quiet.

I want to bring forward a few more juicy tidbits here, however, from Textbook of Pain 5th Ed.

1. The PAG (periaqueductal grey) and locus ceruleus seem to enhance one another's function: (p. 394:)

"Concurrent delivery".. (of "ethylketocyclazocine,""reported to have μ-agonist properties"), "at doses that together were less than injected in either site alone, produced a significant, naloxone-reversible increase in response latency. These observations were argued to reflect a synergic interaction between these two anatomically distinct systems (Bodnar et al 1991)."

If something is naloxone-reversible it means it has an opioid effect of some kind.

2. Anterior insular cortex projects to LC: (p. 127:)

"Dorsolateral pontine systems may also contribute to cortical control of spinal nociceptive transmission. Increasing GABA levels in the anterior insular cortex produces an analgesic effect that is blocked by intrathecal administration of α-adrenergic antagonists. Because this cortical region projects to the locus coeruleus as well as the RVM, it was suggested that inhibition of the insular outflow disinhibits noradrenergic neurons of the locus coeruleus (Jasmin et al 2003b). This could be through an action in the pons or via the RVM."

I missed this when I did the projections post.
(Note: RVM = rostral ventromedial medulla)

3. Linkage to affective states: (p. 234:)

"Chapman (2004) described how processing of nociceptive signals produces affect in multiple neurotransmitter pathways that project to the cortex. Noradrenergic, serotonergic, dopaminergic and acetylcholinergic fibres and pathways are involved. Drawing on an extensive literature on the biology of emotions (e.g. Gray 1987), noradrenergic pathways are recognized as linked most closely to negative emotional states. Of particular importance are nociceptive afferent systems operating and transmitting through the limbic brain-in particular the locus coeruleus, the dorsal noradrenergic bundle, the ventral noradrenergic bundle, and the hypothalamo-pituitary-adrenocortical axis-to all of the neocortex. These are not specific in their activation to nociception, but are also responsive to non-nociceptive, aversive emotional states. These systems are recognized as fostering survival by allowing biological vigilance to threatening and harmful stimuli, both external and internal. Chapman proposes that the affective dimensions of pain can best be conceptualized as involving a two-stage mechanism. The immediate experience would be akin to hypervigilance or fear, with this rapid response giving rise through efferent messages to visceral and other event-related, autonomic activity that creates a strong negative subjective experience and an affective response involving images and symbols."

4. Supraspinal analgesia: (p. 431:)

"Fibres descending from the RVM to the dorsal horn of the spinal cord are mostly serotonergic, enkephalinergic, glycinergic and GABAergic. The nucleus raphe magnus contained within the RVM and the noradrenergic nuclei (locus coeruleus, subcoeruleus, A5 and A7 cell groups) are major PAG relays for noradrenergic and serotonergic descending pathways, respectively, to the dorsal horn (Kwiat & Basbaum 1992). Rather than the RVM being a homogeneous population of serotonergic neurons, GABA- (and glycine-) releasing neurons are now thought to constitute a significant proportion of spinally projecting RVM fibres (Antal et al 1996). The pharmacology of noradrenergic and serotonergic modulation in the dorsal horn is complex but opioids can also interact with noradrenergic mechanisms and there are many studies showing that the effector mechanism and location for the major noradrenaline target receptor-the α2 adrenoceptor-is very similar to that of opioid receptors."

Here is a picture of where LC is to be found in the brain (see red arrow, image from Atlas of Functional Neuroanatomy and modified).

Look at how tiny it is. (I think if you click on the picture you can enlarge it some more.)

Here is a link to a set of notes I made on this little brain part.

Monkey Robotics

2008-05-30T08:08:00.000-07:00

Mo at Neurophilosophy posted this today: Monkey controls robotic arm with brain-computer interface. It's a great post, full of great links. Check it out.

Other posts here that refer to monkeys and/or robotics:
1. Smart Prosthetics, Smart Nerves, Smart Brains
2. More Smartness

"Sky-blue place" III: Input

2008-05-19T12:51:00.000-07:00

In reference to "Sky-blue place" II: Projections:

In the post referenced above I provided a very very sketchy list of all the places LC fibers go to, what they affect, i.e., which parts hear the "alarm."

I now have pages and pages of info on that, but finding out which bits feed into LC is a bit harder. I guess the pathways are a bit less well worked out.

The Appenzeller source lists a couple of places, nucleus paragigantocellularis lateralis (of the rostral ventrolateral medulla), and nucleus prepositus hypoglossi of the rostral dorsomedial medulla.

Nucleus paragigantocellularis lateralis (what a name!) corresponds neuroanatomically to the neurochemical localization of C1 and A1 epinephrine and norepinephrine-containing cell bodies near the ventral surface of the brainstem. Nucleus prepositus hypoglossi corresponds to the localization of C3 adrenergic neurones near the dorsal surface of the medulla bordering on the 4th ventricle. (Riveting, I know..)

Other than that, apparently LC receives neurons from itself, with collaterals. Appenzeller says, p. 162:

"Both external and internal perturbations can activate the locus ceruleus, the latter after sensory processing in the medullary nuclei. Thus, if a stimulus were perceived as novel, severe or threatening, locus ceruleus activation could foster transmission of the signal to higher brain centers, facilitating active attention and memory consolidation and further orienting the organism to the stimulus."

The brain can perturb its own LC. Maybe it's the LC that becomes activated during times of cognitive dissonance.

New Territory

I looked into those two medullary or brainstem nuclei, which took me into the reticular formation, from which I'm yet to emerge. It is not an easy place to grasp. Gray's Anatomy (39th) says, (p. 347):

"The brain stem contains extensive fields of intermingled neurones and nerve fibres, which are collectively termed the reticular formation. The reticular regions are often regarded as phylogenetically ancient, representing a primitive nerve network upon which more anatomically organized, functionally selective, connections have developed during evolution. However, the most primitive nervous systems show both diffuse and highly organized regions, which cooperate in response to different demands.

"The general characteristics of reticular regions may be summarized as follows. They tend to be ill-defined collections of neurones and fibres with diffuse connections. Their conduction paths are difficult to define, complex and often polysynaptic, and they have ascending and descending components that are partly crossed and uncrossed. Their components subserve somatic and visceral functions. They include distinct chemoarchitectonic nuclear groups, including clusters of serotoninergic neurones (group B cells), which synthesize the indolamine 5-hydroxytryptamine (serotonin); cholinergic neurones (group Ch cells), which contain acetyltransferase, the enzyme which catalyses the synthesis of acetylcholine; and three catecholaminergic groups composed of noradrenergic (group A), adrenergic (group C), and dopaminergic (group A) neurones, which synthesize noradrenaline (norepinephrine), adrenaline (epinephrine) and dopamine respectively as neurotransmitters."

This seems daunting, but in persevering, I am learning quite a bit about the reticular formation system(s). They are generally grouped into three systems, raphe or median, medial (just to be confusing) located between the raphe and lateral, the third.

Are the neurons coming or going to LC?

The raphe system seems to connect to LC, but are the neurons afferent or efferent? From Gray's:

"the dorsal raphe nucleus, in addition to sending a large number of fibres to the locus coeruleus, projects to the dorsal tegmental nucleus and most of the rhombencephalic reticular formation, together with the central superior, pontine raphe and raphe magnus nuclei."

However, another source, an online book, Basic Neurochemistry, in its page on serotonin, says:

"The raphe nuclei also receive input from other cell body groups in the brainstem, such as the substantia nigra and ventral tegmental area (dopamine), superior vestibular nucleus (acetylcholine), locus ceruleus (norepinephrine) and nucleus prepositus hypoglossi and nucleus of the solitary tract (epinephrine)."

Regarding pain modulation

In Gray's this tantalizing bit appears: "Raphe spinal serotoninergic axons originate mainly from neurones in the raphe magnus, pallidus and obscurus nuclei. They project as ventral, dorsal and intermediate spinal tracts in the ventral and lateral funiculi, and terminate respectively in the ventral horns and laminae I, II and V of the dorsal horns of all segments, and in the thoracolumbar intermediolateral sympathetic and sacral parasympathetic preganglionic cell columns. The dorsal raphe spinal projections function as a pain-control pathway that descends from the mesencephalic pain-control centre, which is located in the periaqueductal grey matter, dorsal raphe and cuneiform nuclei. The intermediate raphe spinal projection is inhibitory, and, in part, modulates central sympathetic control of cardiovascular function. The ventral raphe spinal system excites ventral horn cells and could function to enhance motor responses to nociceptive stimuli and to promote the flight and fight response."

To be continued.

References:
1. Atlas of Functional Neurology (2006) Hendelman W (p. 114-19)
2. Gray's Anatomy (39th ed.) p. 347-350
3. Handbook of Clinical Neurology: The Autonomic Nervous System Part I, Elsevier 2000, Appenzeller O., Vinken PJ, Bruyn GW, p. 155
4. Basic Neurochemistry (1999) Siegal G

Additional reading:
1. Brainstem (scholarpedia)

"Sky-blue place" II: Projections

2008-05-18T08:30:00.000-07:00

In reference to: Locus Ceruleus: "Sky-blue place";

Noradrenergic neurons of LC project to:

1. thalamus
-especially anteroventral nucleus

2. hypothalamus nuclei (although most noradrenergic projections in this area come from norepinephrine-containing cells in the medulla)
-paraventricular
-periventricular
-supraoptic
-dorsomedial

3. hippocampus
noradrenergic activation of the hippocampus may facilitate long-term memory of distressing events

4. septal area
-basal nucleus of the stria terminalis
-central and basolateral nuclei of amygdala
-olfactory bulb

5. cerebellum

6. neocortex

7. several brainstem nuclei thought to function as primary sensory or association centers

Some features of this projection system

Apparently the arborization is very extensive - very few cells project very widely. This means that this little sky-blue spot has a lot of leverage. It doesn't take very many cells to get a big effect if those cells have a multiply-branched communication system in place.

It must be emphasized that this system is entirely inside the brain and spinal cord. LC directs its messaging only to other brain parts. It stays away from the body department - leaves communication of alerting and alarming to a different system; it does not project much directly to sympathetic preganglionic neurons, and probably participates only indirectly in regulation of sympathoneural outflow. Its job seems to be to "alarm" the hypothalamus which in turn "alarms" the adrenals which then prepare the body for an encounter with danger.

It might seem roundabout to have different systems running different parts differently, but a lot of things in the nervous system work like this. Bits that evolved ahead of other bits kept their operating systems and merely linked up to or completely enclosed other systems. They all still work, in parallel, separately and together. And it's not so bad from an organism point of view. Better for survival to have many systems (in case one should be knocked out) than to rely completely on just one perfected one.

The LC doesn't just magically know what's going on outside - special senses are involved, and must register input which must in turn be relayed to the LC before the LC can perform its alarm bell duty. So, next, I'll address where the LC gets its information from.

NOTES

*Innervation that travels from one part of the brain to another part or parts.

**"Noradrenergic"refers to a neurotransmitter, noradrenaline, also called norepinephrine, that stimulates a nervous system out of ordinary function into super function. (Here is a wikipedia entry about it.) In the brain it is thought to be recycled out of another neurotransmitter called dopamine. In the body it is secreted by the adrenal glands (which sit on top of the kidneys).

REFERENCES

1. Handbook of Clinical Neurology: The Autonomic Nervous System Part I, Elsevier 2000, Appenzeller O., Vinken PJ, Bruyn GW, p. 155

Locus Ceruleus: "Sky-blue place"

2008-05-16T11:29:00.000-07:00

You must admit, the name is catchy.

I first read about this spot in the brain in a very entertaining and informative book called Beyond the Zonules of Zinn: a Fantastic Journey Through Your Brain, by David Bainbridge, a vet. I first heard about the book from Ginger Campbell of Brainscience podcast, in Episode 32.

Bainbridge, in his discussion about the tegmentum, has this to say about locus ceruleus;

"Also in this area is the wistful-sounding locus coeruleus, the "sky blue place." Its ethereal blue color probably results from the deposition of long chains of the chemical that its neurons release, norepinephrine. The coeruleus is in no way a restful place, however. It is probably important in driving the rest of your brain to be active when it needs to be, and it is involved in alertness, arousal, stress and ultimately panic. Its neurons send meandering tendrils to almost all other parts of your brain to jolt you into action - for example, it is almost certainly part of the fright-recognition pathway between the hillocks and the almonds. Intriguingly, it is also important in dreaming sleep - something to which we will return briefly in the final chapter of this book. Finally, and perhaps unsurprisingly when you consider what it does, many antidepressants are thought to act on areas with which the locus coeruleus communicates. Maybe depression is when the sky-blue place darkens into twilight."

I must admit I was captivated by the unabashedly poetic way he writes about this "sky-blue place" (along with everything else). He says elsewhere in the book that it was originally discovered and named by Félix Vicq d'Azyr, who was an anatomist, veterinarian, and personal physician to Marie Antoinette.

It sounded like a part that deserved to be checked out more deeply, and I'm glad I did. There are scads of interesting factoids about this brain part, which I will bring here to this blog over the next few days. Meanwhile, here is what is probably its main feature important from a pain perspective: it alerts the whole brain to novel stimuli via ascending (or rostrally projecting) fibers, while simultaneously dampening nociceptive relay neurons in the dorsal horn through descending (or caudally projecting) fibers. (Check out the image provided. Find LC, which is colored lime green in this image, not sky-blue. Trace the arrows projecting from LC. They go up and around the whole cortex, and down to the cord.)

This explains why, even if you have pain, if you were to see a bus coming at your toddler, you forget all about your pain, wouldn't even feel it probably, and would run out to snatch your toddler out of danger.

This makes the locus ceruleus sort of like a transmission that can change gears suddenly, or a switch box that can change the locus of one's attention in a flash. Kandel says (p. 895);

"The largest collection of noradrenergic neurons is in the pons in the locus ceruleus. Remarkably, although the locus ceruleus projects to every major region of the brain and spinal cord, in humans it contains only about 10,000 neurons on each side of the brain. The locus ceruleus maintains vigilance and responsiveness to novel stimuli. It therefore influences both arousal at the level of the forebrain and sensory perception and motor tone in the brain stem and spinal cord."

From the Encyclopedia, p. 639 Vol 3;

"LC activation can also produce potent anti-nociception by reducing the response of neurons of the dorsal horn of the spinal cord through the stimulation of α2- adrenergic receptors."

References:
1. Handbook of Clinical Neurology: The Autonomic Nervous System Part I, Elsevier 2000, Appenzeller O., Vinken PJ, Bruyn GW
2. Gray's Anatomy (39th ed)
3. Encyclopedia of the Human Brain
4. Principles of Neural Science 4th Ed (Eric Kandel)
5. Image provided courtesy of CNSforum Brain Explorer image bank

Additional reading:
1. Brainstem (Scholarpedia)

Nervous System Basics IX: CHEMICAL CODING

2008-05-11T07:02:00.000-07:00

Angevine's eighth and last organizing principle:

"Chemical Message Coding
The basic function of the nervous system, from which all others derive, is communication, performed (with unsung neuroglial support) by neurons. It depends on special electrical, structural,and chemical properties of these diversified cells with their long processes, on their exploitation and refinement of two basic protoplasmic properties, irritability and conductivity, on their external and internal neuronal morphology featuring multipolar shape and integrative design, almost infinite modes of dendritic and axonal branching, widespread, diversified connections, and specialized organelles, and on their use of chemical substances to encode, deliver and decipher messages of their own and other neurons.

Neural circuits are chemically coded. Neuroanatomy encompasses interneuronal connections and also chemical mediators and transmitters. Neuroactive substances comprise neurotransmitters, neuromodulators, and neurohormones. Their definition in contexts other than site of action, postsynaptic neuronal activity, and corelease of one or more additional neuroactive substances can be misleading. Neurotransmitters are small molecules acting swiftly, locally, and briefly on target cells. Neuromodulators are very small (peptides), regulating but not effecting transmission, and neurohormones are also small, with intrinsic activity mediated by neuronal and other cells, exerting slow, widespread, and enduring influence via the extracellular fluid or bloodstream.

Neurons releasing hormones are quasi-endocrine cells, liberating secretory products from axonal endings into the perivascular space to be conveyed to blood vessels and thence to target organs. The provincial concerns of neurophysiology and endocrinology have fused into neuroendocrinology, as psychoneuroimmunology has united psychobiology, molecular neurobiology, and immunology."

This area of study, neurophysiology, is something I haven't tackled yet to any large extent, still don't know the transmitters from the neurohormones from the chemical neuromodulators, but I'm working on it.

What I like about Angevine's little chemical coding summary is that it is succinct and clear.

Here is more, from Gray's Anatomy:

"Neurohormones
Neurohormones are included in the range of transmitter activities. They are synthesized in neurones and released into the blood circulation by exocytosis at synaptic terminal-like structures. As with classic endocrine gland hormones, they may act at great distances from their site of secretion. Neurones secrete into the cerebrospinal fluid or local interstitial fluid to affect other cells, either diffusely or at a distance. To encompass this wide range of phenomena the general term neuromediation has been used, and the chemicals involved are called neuromediators".

"Neuromodulators
Some neuromediators do not appear to affect the postsynaptic membrane directly, but they can affect its responses to other neuromediators, either enhancing their activity (increasing the immediate response in size, or causing a prolongation), or perhaps limiting or inhibiting their action. These substances are called neuromodulators. A single synaptic terminal may contain one or more neuromodulators in addition to a neurotransmitter, usually (though not always) in separate vesicles. Neuropeptides are nearly all neuromodulators, at least in some of their actions. They are stored within dense granular synaptic vesicles of various sizes and appearances."

"Neurotransmitters
Until recently the molecules known to be involved in chemical synapses were limited to a fairly small group of classic neurotransmitters, e.g. ACh, noradrenaline, adrenaline, dopamine and histamine, all of which had well-defined rapid effects on other neurones, muscle cells or glands. However, many synaptic interactions cannot be explained on the basis of classic neurotransmitters, and it now appears that other substances, particularly some amino acids such as glutamate, glycine, aspartate, GABA and the monoamine, serotonin, also function as transmitters. Substances first identified as hypophyseal hormones or as part of the dispersed neuroendocrine system of the alimentary tract, can be detected widely throughout the CNS and PNS, often associated with functionally integrated systems. Many of these are peptides: more than 50 (together with other candidates), function mainly as neuromodulators and influence the activities of classic transmitters."

More than 50. Looks like I'll be catching up on this for awhile. We must add to this the fact that ATP itself (the molecule which supplies metabolic energy) has been found to be a global (purinergic) neurotransmitter as well. Here is what Gray's Anatomy says about this recent upset to the way the data base on this was once arranged:

"The traditional concept of autonomic neurotransmission is that preganglionic neurones of both sympathetic and parasympathetic systems are cholinergic and that postganglionic parasympathetic neurones are also cholinergic while those of the sympathetic nervous system are noradrenergic. The discovery of neurones which do not use either acetylcholine or noradrenaline (norepinephrine) as their primary transmitter, and the recognition of a multiplicity of substances in autonomic nerves which fulfil the criteria for a neurotransmitter or neuromodulator, have greatly complicated neuropharmacological concepts of the autonomic nervous system. Thus, adenosine 5'-triphosphate (ATP), numerous peptides and nitric oxide have all been implicated in the mechanisms of cell signalling in the autonomic nervous system. The principal cotransmitters in sympathetic nerves are ATP and neuropeptide Y, vasoactive intestinal polypeptide (VIP) in parasympathetic nerves and ATP, VIP and substance P in enteric nerves."

My bold.

Geoffrey Burnstock, who has researched the autonomic nervous system for decades, suspected ATP long ago. Enough other researchers have drawn the same conclusion that it has become accepted, and he wrote a lengthy (140 page) detailed review paper on the history of the discovery. (Physiology and Pathophysiology of Purinergic Neurotransmission 2007).

He's currently (among other things) working on unraveling purinergic mechanosensory transduction and pain with a Swiss company, Roche Bioscience in Palo Alto. Here is an interview with this apparently irrepressible man.

Nervous System Basics VIII: PLASTICITY

2008-05-10T09:35:00.000-07:00

Angevine's 7th attribute is plasticity:

"Plasticity
Highly reliable in a healthy person, the human nervous system has inherent modifiability, though in adulthood this attribute cannot approach that in invertebrates (moths and snails) or certain other vertebrates (teleosts and amphibians). In mammalian development, neural plasticity is striking. In continues postnatally. Abnormal visual experience at certain sensitive periods profoundly affects ocular dominance and orientation columns in the visual cortex. If an eye is closed at birth, ocular dominance columns for the other eye enlarge at the expense of adjacent blind eye columns, with thalamic fibers arriving in the cortex expanding terminal fields into them. If, shortly after birth, visual stimuli are restricted for a few weeks or even days to stripes of one orientation, cortical cells develop a response preference to lines of that orientation.

In humans, PET imaging studies of cortical blood flow show that tasks requiring tactile discrimination activate visual cortex in people blind at birth or having lost sight in childhood. This suggests that cortical connections reorganize after blindness: that afferent fibers to nearby cortical areas serving polymodal sensory integration usurp the bereft visual cortex. Such plasticity may explain the well-known tactile acuity of the blind.

In later development, neural plasticity operates on many levels, as in fine-tuning circuits to changing body dimensions. Depth perception is recalibrated as the skull enlarges and interpupillary distance increases. Even in adulthood, plasticity persists. Vilayanur Ramachandran has shown that a stroke with a cottonswab on the cheek of a young man who had accidentally lost his left arm led him to feel touch on his missing left hand. Later, the whole hand could be mapped on his face. The findings suggest that the deprived somatosensory cortical region for the hand becomes innervated by fibers from the adjacent face areas and that secondary input to a cortical neuron's broad receptive field becomes functional when primary input is lost.

After injury to the CNS, intact neurons form new terminals, by axon sprouting, to replace those of other neurons lost to trauma and thus reoccupy vacated synapses. Such reactive synaptogenesis, the clinically proven effectiveness of long-range regrowth of PNS axons, and the evident potential for axon regeneration in the CNS (as in teleosts and amphibia) hold promise for circuit reestablishment. But in mammals, these factors are thwarted by myelin debris, glial scarring, usurpation of sprouts, unresponsive injured neurons, and complex central connections. Developmental neuroscience now focuses on the cerebral cortex. The human nervous system appears to learn very rapidly by using preconstructed circuits and by locking neurons into specific types and functions after cell origin."

About that last paragraph suggesting that deliberate neurogenesis is difficult in mammals, check out this new blogpost Growing new neurons by Kevin McHenry at painonline.com:

"Wernig et al in Proc Natl Acad Sci U S A May (2008) have achieved a real breakthrough. They have been able to convert fibroblasts to neurons. These converted cells form into neurons, glia, and even dopaminergic cells. There has always been concern that converted cells might form tumors, but these scientists painstakingly separated the cells turned into neurons from pluripotential cells with fluorescent stains."

Seems like ordinary cells can be turned into neurons if they can be recoded, using appropriate transcription factors, "Oct4, Sox2, Klf4, and c-Myc"

Also, work by Peter Eriksson and Fred Gage showed that neurogenesis is intrinsic to the human brain, even in elderly people on the brink of death (see this history module, The Growth of New Neurons in the Adult Human Brain).

Neuroplasticity has been a favorite topic on this blog. It's starting to dawn on a few of us PTs that this is what "improved outcomes", be they pain reduction or increased function, strength etc, have always been all about. Here are some old posts with extensive links:

1. Neuroplasticity Dec 11/07
2. Learning Dec 12/07
3. History of neuroplasticity Dec 12/07
4. About mirror therapy Dec 16/07
5. The devil is in the details Dec 18/07
6. A few types of learning Dec 18/07
7. Cart ruts: More about UN-doing something Dec 29/07
8. It's all about movement Dec 30/07
9. And it's about brain parts: like Hippocampus Dec 30/07
10. Function only Jan 15/08
11. Smart Prosthetics, smart nerves, smart brains Feb 10/08

Nervous System Basics VII: UNIFORMITY WITH VERSATILITY

2008-05-09T07:27:00.000-07:00

Here is Angevine's 6th attribute:

"Uniformity with Versatility
The vertebrate nervous system is accurately and reproducibly assembled. In animals of like genus and species it appears almost identical, although this is not absolute when genetic histories differ. Minor variations in the size of components and arrangements of cells are seen between species, striking ones between classes, orders and families. Yet basic regions and properties, cells and circuits, and overall organization are sufficiently alike to permit instant recognition off the basic brain plan and insights as to what these parts and cells contribute to function. Humans show increases in brain size and regional elaboration, numbers of neurons and prominence of certain connections, variations in cerebral sulcation, hemispheric asymmetry, and long projections."

Once nature came up with a way to do something at a cellular level and this cellular model survived all the predatory and thermodynamic slings and arrows, it became handed down more less intact. Neurons are highly useful, but expensive metabolically; once a working model became established it became highly conserved, replicated endlessly in all manner of species filling all manner of niches, each species phenotype using the basic neuron model in endlessly inventive ways.

As creatures evolved, bits got added to the nervous system, but nothing was ever really deleted from it. As a result, we share basic neuron structure design with animals that date back to the days prior to the division that occurred between vertebrates and our invertebrate cousins on the planet - everything considered "animal" has neurons, except for sponges. The list includes radially symmetric jelly fish, starfish, etc., insects... - all have neurons (i.e., we humans are not "special" for having neurons, but our neuron number and arrangement is - "specie-al" to humans).

As evolution proceeded our (really ancient animal) ancestors found their neuronally equipped selves becoming bilaterally symmetrical, better for getting a grip on the world to haul a little body physically perhaps, but requiring more hard drive to coordinate two sides. So the nervous system found itself clumped up a bit at one end. After that it was probably just more economical for special senses to evolve where there was already extra hard drive built in.

Everything after that, all the way to us, is a result of addition rather than truly different body plan. Apparently no other types of body plan were able to make it in the real world of predation and thermodynamic forces. So we share our bilaterally symmetric body plan with all other primates, quadrupeds, land vertebrates, and sea vertebrates including fish, who "invented" backbones and spinal cords, and everything else all the way back through time to whatever represents the fork in the road that led to worms on one side and fish ancestors on the other. Although worms lack a vertebral arrangement or any bones for that matter, they do have a bilaterally symmetric body plan, neurons, and a little "brain", up in front, to run all of it.

Additional reading:
1. Principles of Brain Evolution, Georg F. Streidter
2. Brain Architecture: Understanding the Basic Plan, Larry W. Swanson
3. Development of the Nervous System, Sanes, Reh and Harris

Nervous System Basics VI: PURPOSEFULNESS

2008-05-08T06:49:00.000-07:00

Angevine's fifth basic organizing principle, purposefulness:

"The Purposefulness of Neural Components
Every part of the nervous system has at least one function, often many more. Small parts of the CNS may play crucial roles, as in the extensive distribution and profound influence of axons from inconspicuous brain centers. The locus ceruleus ("blue spot") on each side of the fourth ventricle contains about 12,000 large melanin-pigmented neurons. These synthesize norepinephrine and release it in the cerebral cortex, cerebellum, and almost every other part of the CNS. Electrically, they are almost silent in sleep, hypoactive in wakefulness, and hyperactive in watchful or startling situations. They serve vigilance and attention to novel stimuli. They contribute, indirectly but no less crucially, to perceptual and cognitive functions. By contrast, immense structures make large but expensive contributions, as in the cognitive and motor abilities afforded us by the billions of neurons in our cerebral and cerebellar cortices."

I never have heard such attributes associated with the locus ceruleus before. Fascinating. Another tidbit on locus ceruleus, from Kandel, p. 483:

"...other descending inhibitory systems that suppress the activity of nociceptive neurons in the dorsal horn originate in the noradrenergic locus ceruleus and other nuclei of the medulla and pons. These descending projections block the output of neurons in laminae I and V by direct and indirect inhibitory actions. They also interact with endogenous opioid-containing circuits in the dorsal horn..."

So, locus ceruleus is involved in descending inhibition of pain. Doubly fascinating.

On another topic expanding from this organizing principle, i.e., preconscious genesis/control of conscious thought or action, of ordinary activities we "imagine" to be of our own "free will", much research has demonstrated that, in fact, non-conscious areas of the brain truly run all the decision making activities and simply provide us a grand illusion that we somehow have choice in what we are going to "do" in any given moment.

This can pose a problem if one's concept of the brain is
1. it is monolithic and singular, or
2. if one identifies conscious awareness with the brain itself
3. if one's experience is that when one wants to pick up one's hand, one can, and that's all there is to it.

It may seem odd that nonconscious parts of one's own brain control the behavior and timing of the "I" construct, instead of the other way round. Yet, this is more like how things actually are.

Antonio Damasio's book, The Feeling of What Happens, helps this all fall into place. Reading this book helped my own concept of the brain to change completely from thinking of it as some big homogenous blob up on the top of my body, to an appreciation of the brain as a community of discrete parts that communicate intensely and continuously, a predictor and simulator.

After reading this book, my image of the brain changed to one in which a main, nonconscious "brain", operating autonomously but with my best interests first and foremost, exists in space with two parts attached, a large mobile body attached to the back end, and something called "conscious awareness" affixed (sort of like a miner's head lamp, but easily swiveled) to the front end. The "brain" in the middle can coordinate these two parts easily. (It's a simplistic image but it works for me. In PT, it will take quite awhile before all of us switch from regarding the brain as that blob at the top of the body that is none of our business, to seeing the body as merely the big blob behind the brain, and the brain as the main focus of our interventions.)

There is a trail of research on the timing of conscious awareness as being an after-the-fact phenomenon leading back to Benjamin Libet's Time of conscious intention to act in relation to onset of cerebral activity (readiness-potential): the unconscious initiation of a freely voluntary act. Note the extensive citation list.

Deric Bownds spoke of it recently on MindBlog. Here is a more recent paper he mentioned: Unconscious determinants of free decisions in the human brain.

Additional reading:

1. Books by Benjamin Libet
2. Review of Mind Time, one of the books
3. Publisher comment on another Libet book, The Volitional Brain
4. An analysis of Libet's work by John McCrone

Nervous System Basics V: SPECIALIZATION

2008-05-07T08:24:00.000-07:00

Here is Angevine's 4th vantage point:

"Specialization
Reflecting its diverse tasks, the nervous system is specialized, from the single neuron to each brain region. Specialized subsystems analyze sensations. They differ in some ways, but data processing is progressive and networked in all. Neurons and the neuroglia have special shapes and roles, but both enjoy all criteria for cells and work in concert. Less obvious but equally specialized are subsystems for other functions: sleep-wakefulness, alertness, attention, affect, collating pages of a report, reading out loud from a book, self-awareness, brain damage control, and so on ad infinitum.

Ubiquitous specializations include those for high nerve conduction velocity (large axon diameter, thick myelin sheath), space-saving bundling (small-axon diameter, thin myelin sheath, shared sheaths), short latency response (monosynaptic reflex), staggered, persistent latencies (parallel side chaining of long-axoned neurons), dependability (neuron redundancy), feature analysis (parallel processing), effect monitoring (feedback circuits), and force multiplication (feed-forward circuits). The neurons performing such tasks and the neuroglia backing them up are as specialized as these many diversified services. For neurons and the neuroglia, form indeed reflects function."

I think each of these features listed in the second paragraph could be a book in itself; I will list them out again:
1. high nerve conduction velocity (large axon diameter, thick myelin sheath)
2. space-saving bundling (small-axon diameter, thin myelin sheath, shared sheaths)
3. short latency response (monosynaptic reflex)
4. staggered, persistent latencies (parallel side chaining of long-axoned neurons)
5. dependability (neuron redundancy)
6. feature analysis (parallel processing)
7. effect monitoring (feedback circuits)
8. force multiplication (feed-forward circuits)

Specialization also applies to microglia.

Additional reading from Scholarpedia:
1. neuron
2. neuronal cable theory
3. Rall model on cable properties of dendritic trees

Nervous System Basics IV: CENTRALIZATION

2008-05-06T05:23:00.000-07:00

Angevine's third basic organizing principle of the nervous system:

Centralization
"The key feature of the nervous system is centralization. It offers few circuits for local interactions of body parts. The CNS is almost always involved even if the distance, as from thumb to index finger, is slight. Intercession of the brain and spinal cord ensures integrated and coordinated activity.

Exceptions are instructive. The local cutaneous response to irritating stimuli (raking a blunt probe over the skin) has three components: local reddening (vasodilation from injury), wheal formation (transient edema from tissue fluid extrusion), and ensuing vasodilation (flare) with lowered thresholds and increased sensitivity to pain (pinprick). The flare and hyperalgesia represent an axon reflex. Nociceptive (pain) nerve endings are activated by substances released by injured tissue cells, and nerve impulses are conducted a short way centrally along nociceptive axons and then distally over branches of these axons to nearby arterioles, causing them to dilate. Advanced or primitive (it is sluggish, starting in about 20 sec. and developing fully in around 3 min), this reflex involves local nerve fibers only, not the CNS.

The "triple response" illustrates three concepts. Pain receptors sense chemical, as well as mechanical and thermal stimuli. Their sensitivity is increased by substances accumulating in the damaged area. Their response includes a neuroeffector component. They release substances (peptides) that initiate further events, providing further protection and favoring local tissue repair.

Studies in invertebrate neural systems show extensive local control of visceral function. Exceptions to central control are also found in the mammalian ANS. Near-normal interaction of bowel segments persists in the absence of CNS innervation. Sensory fibers from the gut exert feedback in intramural autonomic ganglia on visceral motor neurons regulating smooth muscle in the intestinal wall. The nervous system has pattern generators, both central and peripheral: systems with cellular, synaptic, and network properties (cyclic firing rhythms, reciprocal inhibition of cell pairs, leader and follower cells) that provide automated mechanisms for generating rhythmic movements (breathing, walking) or periodic activities (sleeping, waking). Regulated by neural (sensory feedback, volitional override) or neuroendocrine influences, pattern generators are pithy examples of neural endogenous activity."

This is a very instructive passage, particularly in its clear explanation of the peripherality of the axon reflex, but I would be so bold as to quibble with Angevine over his use of the term, "pain receptors." Some pain researchers part company with this terminology, preferring instead to refer to peripheral receptors that register chemical, mechanical and temperature stimuli which could be harmful (but aren't necessarily), as nociceptors, not "pain receptors." They are quite clear that strictly speaking, incoming information to the CNS is not "pain" until the brain decides it is, at which point it will make it so. It may seem a small point, but depending on context, the brain may choose to ignore nociception entirely to deal with a completely different, but from its perspective, more pertinent or immediate threat. Numerous examples of this are in the pain literature dating back to the Civil War. Also, the brain is capable of making "pain" in the absence of any noxious input (Derbyshire 2004).

Additional reading

For axon reflex:

1. Axon Reflex (3-page pdf)
2. Excerpts from book, Clinical Motor Electroneurography: Evoked Responses Beyond the M-wave on axon reflex
3. Axon reflex as discussed in book, Biology of Skin
4. Caselli A; Validation of the nerve axon reflex for the assessment of small fibre dysfunction JNNP 2006 (abstract)

For pain without nociception:

5. Derbyshire SW Cerebral activation during hypnotically induced and imagined pain 2004 (10-page pdf)

For pattern generators:

6. Hooper, SL Central pattern generators, 2000: 16-page pdf

Nervous System Basics III: UNITY

2008-05-05T08:16:00.000-07:00

Here is the second organizing principle of the human nervous system;

"Unity
As in epithelium, all parts of the nervous system are physically coherent and functionally linked by nerves, tracts, and specified cell to cell contacts. Potentially each part communicates with all others. Some connections are direct (a two-neuron, monosynaptic reflex), whereas others involve myriad interposed neurons. Though complex, neural circuits offer total connectivity: fast, body-wide communication. Nerve impulses may originate in sensory nerve endings in any part of the body or anywhere in the system itself. Responsive activity complements endogenous activity, which is always evident in the human nervous system with its startling capacity to generate patterns of behavior and initiate events on its own. Sensory impulses, triggered by PNS primary sensory neurons, race over its nerves to the CNS, there diverging to clusters of secondary sensory neurons. Analysis begins. New impulses pass to central neurons on which related messages converge, which is a recombinant process providing integration. Other messages on stimulus modality, intensity, location, affective quality, body position and movement, visceral activity, fatigue, experience, and expectations are all integrated. Huge numbers of impulses are generated; untold numbers of synapses are activated. Almost instantly, nerve impulses that will elicit bodily responses stream out of the CNS to muscles and glands."

David Butler PT says in his book, The Sensitive Nervous System, p. 19;

"Each neuron is studded with approximately 5000 spines on which other neurons connect. Most of these connections will be part of feedback loops from neighboring neurons. Only a small percentage will come directly from the associated sense organs. "Every neuron is plumbed into a sea of feedback" (McCrone 1997). This gives the nervous system a recursive structure that allows the system to repeat itself again and again.This will allow a continual check/recheck on its actions.

The numbers are hard to get a feel for and popular texts are useful to try to get the message over. Kotulak (1996) based on evidence from electron microscopy research, says that there are about 350 million connections in a pinhead size speck of brain tissue. But the big numbers are just the start. It is the combination of connections possible which is awesome. Edelman (1992) reasoned that there were more possible combinations of connections than positively charged particles in the universe. There must be an extraordinary density of coding behind connections and combinations, allowing patterns of activity which can all be replayed if needed or quickly adapted for future responses. Our ultimate behavior is a result of this coding. There is surely enough space for the memories of a lifetime including all painful experiences, their contexts, the actual and possible responses at the time and future responses."

A number as big as something in the entire universe is all packed up inside the human skull, every human skull. I very much like to remember this when I find myself bogged down by some little annoyance. It makes the small stuff go back to smallness.

References:
1. The Sensitive Nervous System (2006) David Butler PT
2. Inside the Brain, 1997, Ron Kotulak
3. Encyclopedia of the Human Brain 2002, edited by VS Ramachandran
4. The Dynamics of Brain Processing: Top-down Effects of Consciousness, 1997, John McCrone
5. Brilliant Air, Bright Fire, 1994, Gerald Edelman (lots of more recent books)

Nervous System Basics: Part II: UBIQUITY

2008-05-04T06:52:00.000-07:00

There are 8 considerations presented by the author on how to contemplate the nervous system. They are,
1. Ubiquity
2. Unity
3. Centralization
4. Specialization
5. Purposefulness
6. Uniformity with Versatility
7. Plasticity
8. Chemical Message Coding

This is the first. From p. 331, Vol III, Encyclopedia of the Human Brain, author Jay B. Angevine:

"Ubiquity
With 100,000 miles of nerve fibers the nervous system rivals the vascular system. Both pervade the body and function in harmony. By nerve impulses or circulating red and white cells, glucose, hormones and immune principles, they integrate body activity, protect the body, enhance its performance to met stress or demand, promote its growth and nutrition, and maintain its tone and vigor. The trunk and branches of both systems reflect body form. If either system and no other part of a person were visible, he or she would be recognizable. Density of innervation varies as the value of parts to sensory discrimination or motor control. In well-innervated areas (lips, fingertips) stimuli are sharply discriminated as to modality, intensity, and location, but in sparsely innervated areas (flanks, legs) these are less defined. Similarly, muscles vary in the ratio of motor neurons to muscle fibres. The higher the ratio, the more precise the control of the muscle and the movement it serves (a motor neuron may excite 2000 muscle fibers in a limb muscle or as few as 5 in extrinsic ocular muscles)."

I don't know what else to say. To me this is a beautiful image of a filamentous system which comprises only 2% of our physicality, but which regulates 100% of our function.

Nervous System Basics: Part I

2008-05-02T13:04:00.000-07:00

In this series of posts I intend to bring out information found in one (just one) section of the 4-volume Encyclopedia of the Human Brain, 2002, edited by V.S. Ramachandran.

The section in question is written by Jay B. Angevine at the U. of Arizona, and begins page 313 in Vol. 3. He states the nervous system has:

*100 billion neurons of 10,000 types,
*1-10 trillion neuroglial cells,
*100 trillion chemical synapses,
*160,000 km. of neuronal processes,
*thousands of neuronal clusters and fiber tracts,
*hundreds of functional systems,
*dozens of functional subsystems,
*7 central regions, and
*three main divisions.

One hundred and sixty thousand kilometers, or about 100,000 miles of nerve fiber: the Bodyworlds Exhibit states that there are 72.5 kilometers (45 miles) of nerves, which are macro bundles of many fibers.. and that seemed a big number...

Angevine says, "... all of these parts form a coherent, bodily pervasive, diversified, complex epithelium with interdependent connectivity of neurons", most of which are interneurons rather than sensory or motor. The key organizing principles are centralization and integration (although there are many others as we will find out).

The nervous system performs the dual roles of regulation and initiation.

"In the first, it counteracts: responsively and homeostatically, gathering stimuli from outside and inside the body (including the brain), assessing their short-term and long-range significance, generating activity from faster breathing to stock trading, even to functional plasticity in learning or after brain damage.

In the other, it acts: endogenously, not so homeostatically, replacing one state of neural activity with another, generating activity from doing nothing at all to creative thinking and extraordinary achievement, even taking steps toward understanding how itself, the nervous system, works."

Angevine examines the overall organization of the nervous system from a number of perspectives in this section that runs 58 pages, and here I will delve into the third of ten sections he outlines, basic organizing principles, of which there are 8. I want to give each one of these principles some time and thought here.

Transcript For BrainScience Podcast #31

2008-04-23T08:29:00.000-07:00

I have prepared a transcript of Dr. Ginger Campbell's Episode #31, Brain Rhythms with Györgi Buzsáki, with her permission.

You can read it here: Synchrony and Oscillation in the Brain.

The transcript was written to assist my own learning of the material in both the book and podcast. Here is a link to Brain Oscillations: Ten Part Series, on the same topic.

The ideas in the podcast are much easier to follow if one can read along as one listens; the intention of publishing this transcript is for it to be a listening/learning aid for anyone who wishes to dig deeper into understanding the presentation, and the book upon which it is based.

Encyclopedia of Dynamical Systems, in Scholarpedia

2008-03-29T09:01:00.000-07:00

Scholarpedia is a work in progress, of course, but it is a publically accessible site where anyone can go and get an explanation of a concept or overview of a field of study from the scholars themselves. In the little menu on the left, one finds "dynamical systems". Clicking on it takes you directly to Encyclopedia of dynamical systems, which is a very good resource for anyone mystified by how brains "work", and who would like to de-mystify themselves a little. The very first article in the "applications" list is Binding by Synchrony, by Wolf Singer at Max Planck Institute in Germany.

At the moment I'm working on Mechanoreceptors and stochastic resonance. It's well worth a read just for basic review of sensory organs in skin, if nothing else, but if you're a manual therapist who has always been curious about the meaning of 'stochastic resonance' and want to know more, this article might enlighten considerably.

Ten-part post series on brain oscillations

2008-03-24T13:08:00.000-07:00

I want to put a link up to a blogpost series I just completed at humanantigravitysuit, on brain oscillations, based on the Ginger Cambell brainsciencepodcast interview with Dr. György Buzsáki in Feb/08, based on his book Rhythms of the Brain.

The link to everything is called Brain Oscillations: Ten part series. I'll be posting it in the menu to the right, as well.

Something in Swiss water?

2008-03-14T07:13:00.000-07:00

I am starting to wonder what it is about Switzerland. In the past few months, three separate science projects jumped out at me, all Swiss and all brainy:

1. VIRTUAL BODY EXPERIMENTS:

These are described in the blog post Virtual Body Experience. The third was by Bigna Lenggenhager:

"Swiss scientist Bigna Lenggenhager induced virtual body illusions in her subjects, then had them move themselves out of position, then back into positions where they thought they had previously been, but which were in fact where their "virtual" bodies had been.

Her paper “Video Ergo Sum: Manipulating Bodily Self-Consciousness” was also published in the August 24, 2007, issue of Science."

Here is a related video.

2. BLUE BRAIN PROJECT:

This is a Swiss project headed by Henry Markram, in which an artificial "brain" is being painstakingly built. Jonah Lehrer writes,

"In the basement of a university in Lausanne, Switzerland sit four black boxes, each about the size of a refrigerator, and filled with 2,000 IBM microchips stacked in repeating rows. Together they form the processing core of a machine that can handle 22.8 trillion operations per second. It contains no moving parts and is eerily silent. When the computer is turned on, the only thing you can hear is the continuous sigh of the massive air conditioner. This is Blue Brain."

So far the project has managed to accurately simulate a single cortical column from a two-week old rat brain, only... but is still an amazing achievement. Here are media links.

3. PHYSIOTHERAPY THINKING:

A systematic review in press for Manual Therapy:

Paradigm shift in manual therapy? Evidence for a central nervous system component in the response to passive cervical joint mobilisation

Annina Schmid, Florian Brunner, Anthony Wright and Lucas M. Bachmannd
a Uniklinik Balgrist, Department of Physiotherapy, Forchstrasse 340, 8008 Zurich, Switzerland
b Uniklinik Balgrist, Department of Rheumatology, Forchstrasse 340, 8008 Zurich, Switzerland
c School of Physiotherapy, Curtin University of Technology, Perth, Australia
d Horten Center for patient-oriented research, University of Zurich, Switzerland
Received 28 February 2007; revised 30 November 2007; accepted 18 December 2007. Available online3 March 2008.

Abstract

Segmental neurological modulation, neural hysteresis and biomechanical effects have been proposed as mechanisms underpinning the effects of manual therapy. An increasing number of studies hypothesise activation of the central nervous system resulting in a non-segmental hypoalgesic effect with concurrent activation of other neural pathways as a potential mechanism of action. Whether this model is consistent with the current literature is unknown.

This systematic review aims to assess the consistency of evidence supporting an involvement of supraspinal systems in mediating the effects of passive cervical joint mobilisation.

We searched randomised trials in three electronic databases from inception to November 2007, without language restriction, and checked reference lists of included studies. We assessed study validity and extracted salient features in duplicate.

Fifteen studies met our inclusion criteria. The overall quality was high. We found consistency for concurrent hypoalgesia, sympathetic nervous system excitation and changes in motor function. Pooling of data suggested that joint mobilisation improved outcomes by approximately 20% relative to controls. This specific pattern suggests that descending pathways might play a key role in manual therapy induced hypoalgesia.

Our review supports the existence of an alternative neurophysiological model, in which passive joint mobilisation stimulates areas within the central nervous system.

Keywords: Treatment outcome; Cervical pain; Neck; Manipulation spinal; Joint mobilisation techniques; Physical therapy (speciality)"

Whatever the Swiss have going on there, I hope it doesn't lose any momentum, especially in view of the fact that it would appear brain consideration is making it all the way into Swiss PT culture, and out into the world of manual therapy. (Big smile)

Cultural Relativism and Postmodernism, what a team.

2008-03-04T13:46:00.000-08:00

"In the final session of the conference, Paul Shankman, associate professor of anthropology at UC Boulder, spoke about cultural relativism and its evolution from a powerful anthropological research tool, which asked researchers to temporarily suspend moral judgment in order to understand cultures on their own terms, to its "lapse into moral relativism and epistemological relativism." If each culture has its own way of knowing and its own completely unique set of values that others cannot understand, cross-cultural understanding is rendered impossible, said Shankman. Also, extreme relativism overly romanticizes culture and assumes that all cultural practices deserve respect simply because they are "out there."

"Used properly," concluded Shankman, "relativism can lead to better understanding and possibly greater objectivity. Misused, it can lead to moral paralysis and an end to a rational approach to cultural differences and similarities.""

The above is an excerpt from this aricle in the Skeptical Enquirer about cultural relativism.

I think you are quite right, Diane. Also, this helps make sense of why many of those demonstrating post modern thinking to justify adoption of pseudoscientific thinking demonstrate a peculiar phenomenon. No ideas are to be rejected because they are that particular person's "truth" while at the same time they will attack vigorously any who question the validity of the pseudoscience. If you assume that cultures cannot understand each other or make any objective observations of eachother then the person attempting to do so must be acting in an immoral manner.

Engulfed: To be or not to be

2008-03-02T09:59:00.000-08:00

In reference to What's in a Name:

Cory, you said,

"I stumbled upon a blog this week that has engulfed me. It is the science based medicine blog."

I find that site a good port in a storm. I linked it to my own blog awhile ago. It looks like an wonderfully informative effort by medical skeptics to uncover and examine pseudoscientific thinking in general and in their own profession specifically. I think the world, especially the internet world, needs all the help it can get in that regard.

Cory, you said,

"I wanted to explore the name Science based medicine. What is the difference between this and Evidence Based Medicine?"

It looks like the authors at Science-Based Medicine blog are burrowing straight into a similar topic at the moment.

Could some of the problem defining the boundary of what is and what isn't strictly "evidence-based" include issues stemming from cultural relativism?

Lynn Payer wrote a book that impressed me greatly at the time, called Medicine and Culture:

"A classic comparative study of medicine and national culture, Medicine and Culture shows us that while doctors regard themselves as servants of science, they are often prisoners of custom. The United States, England, Germany, and France have equivalent life expectancy rates, yet medical treatment differs enormously from country to country. A new foreword by the author examines the trend toward evidence-based medicine and addresses the substantial changes in medical culture since 1988, including the proliferation of alternative medicine and the changing face of medicine in the European Community since the fall of Communism."

It was from the perspective of a writer who noted that the treatment of one's medical "diagnosis" could change just by crossing a border.

All we can do, I think, from inside a designated profession, is ultimately rely on basic science to settle the arguments. About PT, we certainly have our own fires to put out, don't we? In the absence of a generally recognized theory of our work, lots of strange fluff can creep in, which may need close scrutiny on a regular basis.

If I could choose a way to conceptually unite PT globally, I think I'd pick Cott's Movement Continuum Theory, based on Hislop's pathokinesiology theory. It's stretchy enough to include movement from cellular through to social. From an article by Michael A. O'Hearn:

"Building on Hislop's pathokinesiology theory is the MCT as proposed by Cott et al.3 It was described with the purpose of being unique and central to physical therapy, as well as being broad and applicable to research and education while "subsuming" current middle-range theories. It is similar to pathokinesiology, being established on the principle that movement is essential for human life, taking place on a continuum from a cellular level to an individual's interaction with society. Physical therapy intervention can take place at one or several places along the interdependent continuum similar to Hislop's.1"

I've just finished a lengthy look at Buzsáki, learning a bit about his research on brain oscillations. Even they qualify as "movement", inherent in neurons. Seems to me that neuroscience has opened up vast new territory for PT to explore, adapt to, consolidate itself into.

Most of this post is straying off topic though, isn't it? In the end, in the clinic, when we are working with the patients, regardless of who we are, medical doctors or physiotherapists, we are people in a culture who have adopted a designation, a path that is trying to make scientific sense of the world. As an individual we can choose to just ride along, or else we can put a bit of personal thought and energy into looking at where that path is actually heading, help to steer it a bit. One of my favorite essays of all time is James Willis' The Sea Monster and the Whirlpool. In this essay Willis argues that in a profession where one finds oneself looking after others medically (and dare I say, physiotherapeutically), one must retain one's humanity, steering carefully between "Scylla", for Willis a two-headed sea monster, whose heads are Antiscience and Pseudoscience, on one side, and on the other, "Charybdis" the whirlpool of "Scientific Fundamentalism."

There, I think I've finally managed to get back on track with Sackett.

What's in a Name

2008-02-29T20:25:00.000-08:00

I stumbled upon a blog this week that has engulfed me. It is the science based medicine blog. It's authors include some of the various skeptic circles including Harriet Hall and Steven Novella among others. These are so many great conversations on this blog. But, I wanted to explore the name Science based medicine.

What is the difference between this and Evidence Based Medicine? Well, I believe little if you look at Sackett's discussion of what he meant by Evidence Based Medicine. EBM describes the use of research, clinical experience, and patient preference in clinical decision making.

All too often, however, EBM takes on an Evidence Only Medicine (as described by Nicholas Lucas) characteristic. This is where no decisions can be made without outcome based research to back it up. Of course this is a very narrow view and is impractical in the clinic.

I believe Sackett's ideas are better described by the term Science Based Medicine. This implies a decision making process consistent with the scientific method. Doesn't that sound more consistent with Sackett's aims?

Cory's new blog

2008-02-27T09:51:00.000-08:00

Just a quick post to point readers in the direction of Cory's new blog and webpage, Forward Motion (see permanent link to the right). Very nice site!

Getting past fear

2008-02-18T06:01:00.000-08:00

In reference to FABQ and physical therapy:

Cory, I have to confess up front that I've never used this questionnaire with any of my patients.

I completely concur with your conclusion:

Bottom line, change the belief about pain and you change the way a person behaves in response to pain. Change the behavior in response to pain and you can change the pain itself.

This post by Matthias also references Waddell's book and the biopsychosocial model, here.

The brain seems to be attracted to novelty, even if only the novelty of a new idea (it must find the "new idea" nonthreatening of course..). This ties in with Melzack's pain model, where the neuromatrix constantly folds in cognitive evaluative, sensory-discriminative, and motivational-affective inputs, to produce its outputs, one of which might be pain perception.

The other thing the brain finds convincing, possibly even more so, is illusion, whether visual (as with mirror therapy a la Ramachandran, or with videos a la Ehrsson and Lenggenhager and Blanke) or kinesthetic ("movement illusion" as per Collins et al) or perhaps both. (Here's a little study idea I had late last year..)

If the illusion is convincing enough to the brain, it doesn't seem to matter if the "mind" is convinced or not - people seem overwhelmingly capable of suspending any disbelief they may have. The mirror therapy is sufficient proof of that - the amputee patient is fully aware they are looking at their remaining limb move in a mirror image, yet the illusion still works. A large-scale trial of mirror therapy is currently underway at Walter Reed army hospital.

It looks to me like our PT work will just keep on evolving and get easier and easier, the more the brain/ nervous system comes to be understood and appreciated, the more we learn to understand how it perceives and constructs a reality for itself and the human body it is meshed with.

FABQ and physical therapy

2008-02-17T09:39:00.000-08:00

Another study on the FABQ (fear avoidance behavior questionnaire) in physical therapy was published in this month's JOSPT. The purpose of the study was to more specifically delineate the significance of the 2 portions of the test, look at predictive ability of each, and determine the score at which the test became predictive. Very exciting, I know.

The FABQ was developed by Gordon Waddell, of biopsychosocial model fame, and is as a test to determine the fear based pain behavior of patients. It is built on the premise that people in pain exist on a spectrum from "confronters" to "avoiders" when it comes to pain. Avoiders are more likely to continue to be in pain. It has been shown to be one of the better tools at identifying who is more and less likely to have their pain become long standing.

What I find missing from these studies, and this one is no different, is a lack of a description of what this actually means. Why would a person avoid pain and another confront it? The descriptions are usually left under the vague nature of "psychological issues."

One need only look toward Lorimer Moseley and Dr. Waddell for more. Dr. Moseley has shown us that beliefs about the nature of pain were discriminative in a group of people with experimentally induced pain of whose pain would continue. This adds to his research showing that educating the patient on pain physiology and thus giving them a more accurate understanding of pain, decreased their pain.

Waddell has shown that even the explanatory model of the clinician plays a role the persistence of pain.

Bottom line, change the belief about pain and you change the way a person behaves in response to pain. Change the behavior in response to pain and you can change the pain itself.

More Smartness II

2008-02-15T07:37:00.000-08:00

In reference to Smart Prosthetics, Smart Nerves, Smart Brains
In reference to More Smartness:

This morning I happened to see this on Deric Bownd's Mindblog: A non-invasive brain-machine interface?

In it he blogs about a study that used magneto- and electro-encephalographic recordings only, to differentiate out signals for moving hands, with up to 67% accuracy. Here is the abstract of Hand Movement Direction Decoded from MEG and EEG by Waldert et al:

"Brain activity can be used as a control signal for brain–machine interfaces (BMIs). A powerful and widely acknowledged BMI approach, so far only applied in invasive recording techniques, uses neuronal signals related to limb movements for equivalent, multidimensional control of an external effector. Here, we investigated whether this approach is also applicable for noninvasive recording techniques. To this end, we recorded whole-head MEG during center-out movements with the hand and found significant power modulation of MEG activity between rest and movement in three frequency bands: an increase for 7 Hz (low-frequency band) and 62–87 Hz (high- band) and a decrease for 10–30 Hz (β band) during movement. Movement directions could be inferred on a single-trial basis from the low-pass filtered MEG activity as well as from power modulations in the low-frequency band, but not from the β and high- bands. Using sensors above the motor area, we obtained a surprisingly high decoding accuracy of 67% on average across subjects. Decoding accuracy started to rise significantly above chance level before movement onset. Based on simultaneous MEG and EEG recordings, we show that the inference of movement direction works equally well for both recording techniques. In summary, our results show that neuronal activity associated with different movements of the same effector can be distinguished by means of noninvasive recordings and might, thus, be used to drive a noninvasive BMI."

Brain-machine interface research looks to be a red-hot field of endeavor. Anything that doesn't involve having to plug actual wires into actual brains is likely to have a higher chance of catching on as a widespread innovation. I am truly amazed at this kind of work. I look forward to finding out how much easier life may become for those who have had spinal cord injuries, stroke etc., and for the caregivers of these people, including those in my own profession involved in neurorehabilitation.

This paper was from last year; the link does not appear to have citations listed. The Nicolelis monkey/treadmill research was conducted this year. Here are more papers on Brain-Machine interface, from the wikipedia link to Miguel Nicolelis:

Lebedev, M.A., Carmena, J.M., O’Doherty, J.E., Zacksenhouse, M., Henriquez, C.S., Principe, J.C., Nicolelis, M.A.L. (2005) Cortical ensemble adaptation to represent actuators controlled by a brain machine interface. J. Neurosci. 25: 4681-4693.

Santucci, D.M., Kralik, J.D., Lebedev , M.A., Nicolelis, M.A.L. (2005) Frontal and parietal cortical ensembles predict single-trial muscle activity during reaching movements. Eur. J. Neurosci., 22: 1529-1540.

Carmena, J.M., Lebedev, M.A., Crist, R.E., O’Doherty, J.E., Santucci, D.M., Dimitrov, D.F., Patil, P.G., Henriquez, C.S., Nicolelis, M.A.L. (2003) Learning to control a brain-machine interface for reaching and grasping by primates. PLoS Biology, 1: 193-208.

Nicolelis MA (2003) Brain-machine interfaces to restore motor function and probe neural circuits. Nat Rev Neurosci. 4: 417-422.

Wessberg J, Stambaugh CR, Kralik JD, Beck PD, Laubach M, Chapin JK, Kim J, Biggs SJ, Srinivasan MA, Nicolelis MA. (2000) Real-time prediction of hand trajectory by ensembles of cortical neurons in primates. Nature 16: 361-365.

Hi Cory!

2008-02-14T00:03:00.000-08:00

Response to: New Neurotonics Team Member

Hi Cory!

Welcome to the family. ;-)
Glad you agreed to join our blog.

As I've just announced on my blog I have to take a little break from contributing - my brain just doesn't let me write meaningful stuff at the moment.

And since I don't want to compromise quality I will just relax for a few weeks. I will however be reading everything you two write in the meantime! ;-)

Glad to be here

2008-02-13T15:16:00.000-08:00

In reference to New Neurotonics Team Member:

Thanks Diane. I'm excited to be able to contribute and hope I am up to the standards of excellence that you and Matthias have established.

New Neurotonics Team Member

2008-02-13T11:41:00.001-08:00

In reference to New PT Team Blog:

I'm pleased to announce that Cory Blickenstaff, a PT in the state of Washington, owner of a new, thriving solo PT practice and dad of a new baby boy, will be joining us here at Neurotonics presently, our third author. A link will be up soon.

Cory is a longtime member and moderator at SomaSimple, the one and only public neuroscientific PT discussion forum in existence so far, to my knowledge.

Welcome Cory. We look forward to conversing and posting with you here.

More Smartness

2008-02-10T13:31:00.000-08:00

In reference to Smart Prosthetics, Smart Nerves, Smart Brains:

From the wikipedia link on haptic technology, check out the virtual back that gives osteopathic students feedback on their handling. Hopefully it will help them learn to have lighter touch. I see the virtual back has no nerves associated with it. There is also a link to a site about a robotic hand which looks promising.

I found some more links that have to do with the bionic arm:

1. Here is Todd Kuiken, the surgeon who performed the nerve transplant.
2. Here is Claudia Mitchell, the girl with a new left arm.
3. Here is Jesse Sullivan, the man who had nerve transplantation, with Dr. Kuiken.
4. Here is more about Jesse Sullivan, and we are also introduced to the work of Miguel Nicolelis, a Brazilian researcher.

"Some of the most innovative research is being done by Miguel Nicolelis, a neurologist at Duke. He has bypassed the muscle system entirely. His experiments are based on directly reading the firing of neurons in the brains of monkeys. Neurosurgeons implanted an electrode with tiny wires into the surface of an animal's brain, and then connected them to a computer."

5. He was able to train a monkey to walk on a treadmill, put implants in her brain, which picked up her intent to walk, to send signals to a robot in Japan, which in turn walked on a treadmill. All in real time. Check it out. This is quite amazing to me.

Smart Prosthetics, Smart Nerves, Smart Brains

2008-02-10T06:20:00.001-08:00

In reference to Learning (Dec 12/ 2007):

Matthias said:

If you look at a genius like Dean Kamen - a great inventor - you will see what I mean.
He is creative and simply doesn't give up.

I watched his 5 minute TED talk and was impressed.

Lately a reader, Kent, sent me this Nov 07 article from BBC news on a parallel development in the UK. It explains how a bionic arm can "feel" - it can't really; there is no way to literally hook a brain up to a device that can be put on and taken off, despite innovations in haptic technology (see here for an old post called Haptic Vest). In this case the amputees "learned" to "feel" their prosthetic arm through sensory nerve transplant from arm to chest wall. They learned to discriminate sensation of their chest skin from that of their "hand".

Fortunately the (very very cool!) original paper by Todd Kuiken et al. is open access. Take a look at the graphics depicting the amazing amount of sensory discrimination the two subjects were able to attain. They relearned their way out of numbness, essentially. The male subject had lost both upper limbs and the female subject had lost her left upper limb. It took awhile, but the sensory nerves to arm/hand transplanted into the chest skin eventually turned back on and their brains rewired for appropriate data collection. Interesting about subcutaneous fat being removed - this moved skin closer to muscle, stimulating the nerves more with underlying muscle movement.

Abstract

Amputees cannot feel what they touch with their artificial hands, which severely limits usefulness of those hands. We have developed a technique that transfers remaining arm nerves to residual chest muscles after an amputation. This technique allows some sensory nerves from the amputated limb to reinnervate overlying chest skin. When this reinnervated skin is touched, the amputees perceive that they are being touched on their missing limb. We found that touch thresholds of the reinnervated chest skin fall within near-normal ranges, indicating the regeneration of large-fiber afferents. The perceptual identity of the limb and chest was maintained separately even though they shared a common skin surface. A cutaneous expression of proprioception also occurred in one reinnervated individual. Experiments with peltier temperature probes and surface electrical stimulation of the reinnervated skin indicate the regeneration of small diameter temperature and pain afferents. The perception of an amputated limb arising from stimulation of reinnervated chest skin may allow useful sensory feedback from prosthetic devices and provides insight into the mechanisms of neural plasticity and peripheral regeneration in humans.

This is yet another example of how profound neuroplasticity can be, quite apart from how capable the human brain is of incorporating objects into its brain maps (see Place Cells and Grid Cells Part I and Part II).

Stopping Disc Spin

2008-02-06T08:05:00.000-08:00

Paul Mintken gathered together a lot of articles to support his statement that imaging of funny looking discs and pain do not correlate particularly well. You can read his post here.

A good post, but I have a wee issue with this first statement:

"I just don’t know if we are ever going to be able to isolate the pain generator in the majority of patients with low back pain."

Um, how about the nervous system Paul?

Physical THERAPIST

2008-01-31T06:44:00.000-08:00

In response to Feedback All Over Again:

Matthias, your post reminded me of (one of my many) recurring thoughts:

1. We are called Physical Therapists

2. Many within the profession want us to be strictly PHYSICAL therapists

3. I say we need to remain physical THERAPISTS.

Ideally we can fluctuate between our two poles smoothly and as needed, but I never want the therapeutic capacity our name implies to become defined strictly just by what we do with only our hands, i.e., physically. I'm sure robots will come along that will be precise about delivering physical forces to joints, etc. - they'll likely produce more quantifiable data than we ever have!

Instead, I want us to keep the human aspect, remain a profession that can continue to learn and evolve and adapt as science does - the more we understand the brain, the easier it should be for this profession we are part of to move into fully developing our empathic and genuinely therapeutic side. If one can learn to funnel "feeling" (i.e. therapeutic regard) through one's interview style, therapeutic presence, and hands, while retaining ethical conduct, remaining therapeutically boundaried and scientific accountable, now, THIS is therapy.

If we recognize that all pathways must be accessed/treated simultaneously, the profession will be in good shape in the future.

Feedback All Over Again

2008-01-31T00:48:00.000-08:00

Response to: Getting a handle on back pain

Hi Diane!

I think this passage from the article is the most important:

From the perspective of the brain, there are two distinct types of pain. The first type of pain is sensory. When we stub our toe, pain receptors in the foot instantly react to the injury, and send an angry message to the somatosensory cortex, the part of the brain that deals with the body. This is the type of acute pain that doctors are trained to treat. The hurt has a clear bodily cause: if you inject an anesthetic (like novocaine) into the stubbed toe, the pain will quickly disappear.
The second pain pathway is a much more recent scientific discovery. It runs parallel to the sensory pathway, but isn't necessarily rooted in signals from the body. The breakthrough came when neurologists discovered a group of people who, after a brain injury, were no longer bothered by pain. They still felt the pain, and could accurately describe its location and intensity, but didn't seem to mind it at all. The agony wasn't agonizing.

This strange condition - it's known as pain asymbolia - results from damage to a specific subset of brain areas, like the amygdala, insula and anterior cingulate cortex, that are involved in the processing of emotions. As a result, these people are missing the negative feelings that normally accompany our painful sensations. Their muted response to bodily injury demonstrates that it is our feelings about pain - and not the pain sensation itself - that make the experience of pain so awful. Take away the emotion and a stubbed toe isn't so bad.

Chronic pain is the opposite of pain asymbolia. It's what happens when our brain can't stop generating the negative emotions associated with painful sensations. These emotions can persist even in the absence of a painful stimulus, so that we feel an injury that isn't there. It's like having a permanently stubbed toe.

Doctors have traditionally focused on the bodily aspects of chronic pain. They assume that a healed body is a painless body. If a patient has chronic back pain, for example, then he is typically prescribed painkillers and surgery, so that the pain signals coming from his spinal nerves are stopped. But the dual pathways of pain mean that this approach only treats half of the pain equation. Unless you find a way to treat the emotional pathway, then the chronic pain will continue.

It might not be the perfect description of chronic pain - but it is very helpful to explain the connection between emotional states and pain - and why there is no "imaginary" pain.
All pain is real since it is always constructed in the brain.

Using fMRI to provide visual feedback is overkill. It's nice to see that feedback therapy works regardless of which type of feedback you give to the brain - put in the case of chronic (low back pain) it's much easier to do with tactile stimulation.

What I don't like about this type of therapy is it's reliance on high-tech.
After all: what good is this type of therapy if only a very small percentage of people can benefit from it?

If you want high-tech - think of our brains. Organic computers that are able to change, to evolve, to learn. We have to realize that our brains are the most high-tech "gadgets" out there so to speak - and use them accordingly.

I completely agree with Ian that we should start focusing inwards more. It's cheaper, more efficient in the long run (because if you work on yourself you learn for life) and puts responsibility and control back into the hands of the patient.

Getting a handle on Back Pain

2008-01-30T09:29:00.000-08:00

Here are some good, written-for-the-public, articles on the old topic of back pain and a new high-tech twist on its alleviation. Article 1 is by Jonah Lehrer, author of the blog Frontal Cortex and an editor for Seed Magazine: The Psychology of Back Pain.

The article uses the word "mind"(Christof Koch would probably not approve); however, the gist of it is that if a person with chronic low back pain can access a way to visualize the regions of the brain involved in and perpetuating/fueling the "central sensitization" of the body zone involved, i.e., viewing their own brain on an fMRI screen, they can learn to reduce the back pain in a top-down manner. Excerpt from the last page of the article:

"Christopher deCharms, PhD, a lead author on Dr. Mackey’s paper, is trying to take this therapeutic approach mainstream. He has started a company called Omneuron, which makes the experimental treatment available to a wider audience. A standard session goes like this: A patient lies in a brain scanner while experiencing pain, and he watches as his brain flares up in agony. He sees the smear of neural activity that makes him suffer. Then, with the help of a trained therapist, the patient learns how to consciously turn off the specific brain areas that correlate with the chronic pain. After a few sessions, the awful symptoms begin to fade away. The pain is no longer permanent. It’s a real-world example of mind over matter."

Another general-reader article, called Seeing Your Pain, by Emily Singer, discusses Omneuron's work in a bit more detail.

I found these two articles linked into a thread called "The Psychology of Back Pain", at SomaSimple.com.

Both these articles but especially the second (all the way through) emphasize doing something with basic visualization;

1. Turn attention inward (in this case, with the help of a huge expensive MRI visual feedback machine, which provides an outside, visible "fixation" point; associative "learning" takes place)

2. Create a visible "thought object" (as per Antonio Damasio) to hold in one's attention, in this case a visual image that represents one's "pain" (in this case, it's a red spot on a screen flickering in a part of the brain that brain research has identified as being associated with persistent pain, therefore as close to "real", as closely associated as it's possible to get, probably - boosting the all important "trust" factor)

3. Find ways to "deconstruct" the now-'visible' "thought object", the visualization of the pain, the "source" of it.

I guess this works (finally) for those who can't just go ahead and do a facsimile of this on their own. In fact, I wonder if one could find correlations between low back pain and lack of imagination? Image-ination? Ability to form visual images?

We already know that the brain can't tell the difference between something "real" and something "illusory". It will respond to a sufficiently convincing image and downregulate pain successfully, as Ramachandran's mirror work for phantom limb pain has shown.

MRIs are still pretty expensive to use as feedback devices. As Ian S. pointed out in the thread,

"sitting still and learning to meditate costs $0... I think the interventions are interesting but fit in with the culture of high tech solutions to what are low tech approaches (paying attention / learning to take responsibility / reducing threat )."

Function Only

2008-01-15T07:32:00.000-08:00

In response to Vicious Circles:

I don't think you have to worry Matthias, about falling off your functionalist track when studying brain parts. ;)

Brain parts can't do much in isolation - they need to grow up with and be constantly stimulated by other brain parts in order to do anything, plus they seem to need to have that nice steady stream of 10,000 new neurons a day folded into the mix to keep the entirety working well. It seems to me that brain as a whole is much less about "parts" and much more about "function" than the rest of the body:

1. Some "parts" can take over for other "parts" in a pinch.. I met a young woman a few years ago who had had a hemispherectomy for extreme epilepsy as a young child. The remaining half had taken over function quite readily.

2. Constraint induced movement therapy (CIMT) can retrain remaining parts of the brain to take over from parts that have been wiped out by stroke. (For more on this you can listen to Ginger Campbell's podcast interview with Edward Taub, the originator of this form of therapy, in her brain science podcast #28.)

It seems to me that neuroplasticity is such a feature that it likely may have been and in many cases likely still is a confusing factor for researchers who really, really want to find direct relationships between brain parts and functions.

I know where you're coming from - I'm a PT too. We started out being taught structure - "This is the knee joint. It bends thusly. It is covered in cartilage to make movement smoother." Etc etc...

What helped get me out of this structuralist mind set training was embryology. The physicality of the body we deal with as PTs is a blend of mesodermal and ectodermal derivatives (well, endodermal too, but we don't deal directly with or concern ourselves with endoderm much.)

We get taught all about the mesodermal derivatives (overwhelmingly!) in school: mesoderm derivatives account for 98% of the whole body. Their structure IS their function.. unfortunately the educators don't realize what they are doing to our poor brains! :D

Direct ectodermal derivatives, by contrast, account for only 2% of the body's mass - and that includes outermost layer of skin, brain, spinal cord, and all the 45 miles of nerves that lace throughout all that mesoderm. We have a brain 5 times BIGGER than needed to operate a mammal our size - and still, direct ectodermal derivatives account for only 2% of mass! That's tiny!

However (and this is a very clear distinction), direct ectodermal derivatives use 16%-20% of all the oxygen taken in. (Streidter, Principles of Brain Evolution) That's huge! The nervous system and the rest of the body are clearly out of proportion here. Big, big difference physiologically.

This is still astonishing to me, every time I think of it. What a busy system. What a huge oxygen sink our brains are, so big and so busy. So "functional". Function is its business - brain "structure" is less relevant by comparison. In fact, sometimes when I remember that fact that humans have a brain 5 times bigger than necessary for operating a mammal our size, I wonder if its high-maintenance oxygen-neediness contributes to most of our problems..

Anyway, back to the point - I don't think brain parts can be classified into "this part does this, and that part does that" as easily as the rest of the body can. And everyone, at all times, will do well to remember that correlation does not = causation. One notes when reading papers that the authors are usually very careful to skirt around declarative statements such as, "the x part is responsible for y." Instead they say something like, "Y was found to be associated with abc waves in the z frequency when neurons in the x part were stimulated" or "when the animal exhibited x behavior." That way, they can describe a relationship between parts and function, but don't run the risk of sounding prematurely categorical or final.

You said:

"If you think about patients with chronic pain it all starts making sense:
pain leads to stress - stress leads to gray matter loss in the brain (not just in the hippocampus) - thereby limiting the amount of neurons you have to be able to learn something new. It really is a vicious circle. Scary stuff."

But, maybe stress can also lead to pain... or maybe neuron loss in the brain can lead to less adaptation to stress which might lead to pain... I don't think anyone has it figured out for sure yet. It's really all one great big circle of function/adaptation. As Quinter et al. have said, pain seems to be an aporia. (Not that we can't do something to help!)

One thing we can take comfort in (as PTs) is that movement appears to be associated with better brain function as well as all sorts of other health benefits. Motion is lotion for the brain/nervous system, not just the joints. :)

Vicious Circles

2008-01-14T07:31:00.000-08:00

Response to: Hippocampus

Diane - I have to admit that I haven't done much research on specific brain structures yet. I guess I'm so far out on the purely functionalist track that anything having to do with structure scares me to death. ;-)

However - when it comes to the brain things might be different after all.
I found another interesting article about the effects of severe stress on hippocampal volume.

If you think about patients with chronic pain it all starts making sense:
pain leads to stress - stress leads to gray matter loss in the brain (not just in the hippocampus) - thereby limiting the amount of neurons you have to be able to learn something new. It really is a vicious circle. Scary stuff.

I wonder if an increase in hippocampal volume is universal, i.e. can these new neurons then be used for other tasks as well or are they built for one task only?

More on Motor Learning

2008-01-06T09:46:00.000-08:00

I want to point readers in the direction of Frank Forencich at Exuberant Animal, and his article, Learning From the Inside Out.
Here is another about motivation in physical learning called Romancing the Body.

He has many other 2007 articles archived here, and other years here, for those interested.

And it's about brain parts: like Hippocampus

2007-12-30T17:34:00.000-08:00

In reference to It's all about movement:

From our PT perspective it's might be about movement, Matthias, freedom from pain, but I would propose that from a functional perspective there are other considerations, such as having good working brain parts, understanding their contributions to movement, to pain processing, or purpose having us move from A to B in the first place.

The hippocampus has been a riveting study focus for me this fall and winter. Buzsáki has worked for decades to understand brain waves, and noticed that theta waves, his favorite, seem to come from there. My impression from reading his book is that theta waves are like a drum beat setting a rhythm for all the other kinds of waves.

If I may, further to the discussion about types of memory, Learning to Memory, I want to post a link to a fascinating lecture video, a 2005 talk by Sue Becker from McMaster called The Role of the Hippocampus in Memory, Contextual Gating, Stress and Depression. It touches on Hebbian learning, neurogenesis, topics we took a look at in History of Neuroplasticity. Becker is building on this to examine what the learning rules might be, and build models for them. She describes the hippocampus as a large convergence zone, where information from lots of other parts is "coded". Neurogenesis takes place here. A constant supply of new neurons seem to be necessary for coding memories over time, over temporal gaps. If neurogenesis is slowed by stress, new connections have trouble being made. (Sapolosky has mentioned this as well.) New neurons remain plastic (able to make new connections) for longer than old ones.

Single cell recordings of spatial coding cells in the hippocampus have been made with human subjects, as they move about in a virtual world (prior to this only rats had been examined). She touches on spatial hemi-neglect, neglect of the left half of a person's environment following a type of stroke; she is working on building a model that can account for both "egocentric" (sensory/self) and "allocentric" (other/outside) spatial coding.

Her third area of investigation is the role the hippocampus as a comparer and coder of personal behavior. This brings in the role of context. The hippocampus is crucial for determining context of a situation, and allow you to react appropriately in a stressful condition. Here we come back to producing movement again. If the hippocampus isn't working, how will you know what movement to choose? The hippocampus may exert a modulatory effect on other parts of the brain.

Also, here is a link to one of Ginger Campbell's brain science podcasts (Episode #3) which discusses Eric Kandel's book, In Search of Memory. In episode #12 she discussed another book, Memory: From Mind to Molecules, by Larry Squire and Eric Kandel.

The internet is absolutely full of great information.

It's all about movement

2007-12-30T07:53:00.000-08:00

In response to: Cart ruts.

Diane, I think you described the basic thinking behind different forms of "movement therapy" quite well - it's not necessarily what one does - but how.
The focus has to be on the process of learning and creating the environment for learning - only then can the brain build new connections that it can use later on.

Yoga - if done right - is just one of the many forms of movement out there that has taken those principles and put them into a comprehensive system.
For those of you out there who want an alternative - here are some:

1) Somatics: based on the work of Feldenkrais - but shorter, faster and easier to do. The exercises in this book are great - plain and simple.

2) Feldenkrais: more complex than the Somatics stuff - but also great. You can start by doing just a few steps and working your way towards doing a whole session later on. Remember: it's all about learning something new. Break it down in smaller portions if you have to.

3) Ruthy Alon: also a Feldenkrais practitioner. Her book is a very good - on every level. She does a great job explaining why we move the way we do - what we can do better - and the principles behind "body learning". The exercises are also great - very easy to do.

4) Swimming: here and here. These two books are the best money can buy when it comes to a form of movement most are pretty familiar with. They concentrate on basic (and advanced) techniques - so swimmers at all levels will find something to work with. By breaking down the different swimming styles into small parts you can find out where your weaknesses are and work to correct them.

5) George Leonard: started with Aikido at the age of 40. Developed his own form of movement based body learning technique.

6) all the others. ;-)
Just think Alexander Technique, Dance in all shapes and sizes, .......

Fact is: do something - anything. ;-)

Cart ruts: More about UN-doing something

2007-12-29T10:36:00.000-08:00

In reference to Just UN-do it:

Some more thoughts have occurred to me since I wrote that post relating the activity of UN-doing to learning processes. (Perhaps this will turn into a start of the deconstruction of that interesting term either Feldenkrais or his student Hanna came up with, sensory-motor amnesia.)

First of all, we must remember that motor pathways or any other kind, once learned, are not really erased, but can be weakened or strengthened according to the tenets of neuroplasticity; if not entirely extinguished, they can at least be eclipsed by laying in new pathways over top. Receptors are constantly being torn down and new ones built, potentially sensitive to other substances (see extinction learning).

If you can introduce new behaviors or motor activities that counter others, this should in theory provide the brain with an opportunities to select options. "Not-doing" options can be reshuffled with/shuffled into "doing" options by executive function, and a movement created that is optimal in the moment. It may not be the fastest or most spectacularly athletic, but it should be at least sufficient to get the job done and not hurt - over a whole life span. I think yoga is a form of (non)exercise that (ideally, if done correctly) trains the brain for doing just that.

What does this mean? Think of a cart pulled by a horse. Think of the driver of the cart as the executive function of the brain, with access to information and ability to choose from a variety of options. Think of a cart rut on a grassy plain, a track that has been worn by repetition. Driving the cart deliberately in the rut every time might seem like the most sensible, efficient thing to do - after all the rut is smoother, in the straightest line from A to B, but the horse (brain) already knows it so well the driver ends up practicing monotony, being bored, daydreaming - which, on another level, are all ways of exercising self-reinforcing neuroplasticity (mental cart ruts) as well.

Remember, neuroplasticity can lead to bad habits just as fast as to good ones.
If the driver wants to exercise neuroplasticity s/he will do well to practice making new cart ruts deliberately.

A wise cart driver knows some things that horses may not; that boredom isn't good, that grass can re-grow and hide ruts (ruts can heal if left alone), that a new rut may be bumpy at first but will smooth with time, that taking a new route will not only assist nature by allowing regrowth of grass but will stimulate the horse to greater capacities as well, of observation and alertness.

Making new trails through the grass will require more deliberate attention and simultaneous quelling of ordinary anxiety, the kind the brain produces whenever you ask it to do a new thing. There will be some resistance, in other words, probably, from the brain/horse. In yoga, deliberate slow deep breathing easily overcomes this feeling. Practicing relaxing into each position three times (not in a row, but three times total in a single session) gives the executive function (cart driver) and the brain (horse) an opportunity to witness improvement necessary for positive feedback, which builds success, which in turn greatly enhances the learning.

Deliberately choosing new ways of moving/not-moving can build a better repertoire, a greater selection of cart ruts to choose from should external conditions change: for example, sticking with the metaphor a bit longer, if it rains hard, or the river floods and there is standing water on the grassy plain, some of the more well-worn (deeper) ruts may be too full of water and mud to be an efficient route anymore. If the driver has seen this possibility ahead of time, and has some other routes in mind to take instead, the load can still be delivered. Furthermore, if other ruts have been created and practiced, perhaps none of them will have become so deep as to be impassable in spite of bad weather or circumstances.

It is all about having taken some time to build in more options, just in case.
In terms of motor output (being able to do what you want to be able to do, on through a whole lifetime, without pain), building in options has to do with spending time with your body before any pain problem that might arise, and paying close attention to it, just out of curiosity.

If pain is already a feature in one's life, the good news is, one still can learn to "UN-do" un-useful movement patterns, or recover useful ones. Some special props or extra help might be needed, that's all.

Finally, I don't mean to make this post sound like some sort of long advert for yoga - there are many other movement therapy systems that can help achieve the same long term goals. You can make up a new one if you want! The key features are breathing, attending, enjoying, producing feedback for all systems, gaining information, and playing with the overall speed of an activity (especially slowing it way down), practicing something on the other side of the body for the novelty of it and to regulate pathway building.

A long series of now moments

2007-12-27T12:59:00.000-08:00

In reference to Memories vs: stories :

What bothers me most about memory is how misleading it can be.
Implanting false memories is in fact quite easy.

Matthias, so true.
(In this radio program, Elizabeth Loftus mentions how unpopular she and her research became.)

I think implanting false memories would fit with the illusion-of-truth type of implicit memory.

The program also goes into some detail about memory degradation, how in fact each time a memory is recalled, it has to be "recreated" in some ways. The participants talk about how the more a memory is repeated, the more it can potentially degrade. In effect the situation is that one doesn't really recall a "past" so much as one considers another reconstructed "now". Here is a link to an essay by Joseph LeDoux, explaining how his thinking on memory was changed by some work by Karim Nader that showed memory is reconstructed each time it is accessed.

This reminds me of Blakeslee's book, The Body Has a Mind Of It's Own. Even procedural memory (that of a skilled activity) can degrade. It may be more optimal to practice a movement (a golf stroke for example) mentally rather than physically, part of the time, to avoid an onset of dystonia.

So there we are. There is some sort of optimal amount to practice a behavior, to "learn" it well, to commit it to "memory": practicing it too much without enough rest will degrade it. Not knowing how to UN-do something and practice THAT as well, might be something to think about.

Memories vs. Stories

2007-12-27T09:45:00.000-08:00

Reply to: From Learning to Memory

What bothers me most about memory is how misleading it can be.
Implanting false memories is in fact quite easy.

It seems as if our brains only remember a condensed version of what happened and re-construct the details later during recall.

What I would like to know is just how specific this is in regards to motor memory?
Does our brain "make up" parts of a motor response? - or are those motor memories "perfect"?

And how and why do these patterns degrade over time? - a process best described by sensorimotor amnesia.

From Learning to Memory

2007-12-26T06:27:00.000-08:00

In reference to Just Do It:

We've talked quite a bit about all the various types of learning that exist, which, as Kandel pointed out, all occur at synaptic levels.

All this has made me think about memory. What's the point learning something if you can't remember it later? I've spent a number of weeks, months even, trying to soak up that Buzsáki book, Rhythms of the brain.

I found a footnote in it (p. 288) about the synesthetic memory of a Russian named Shereshevskii (which in his case was thought to have interfered with face recognition), explicit and implicit types, kinds of each, all of which use/are used by specific parts of the brain. It might be good to review these:

A. IMPLICIT: "previous experiences aid in the performance of a task without conscious awareness of these previous experiences (Schacter, 1987).

Types are:
a) Priming: "previous contact with something can implicitly aid in its subsequent recall or recognition", "can be conceptual or perceptual", "the remembered item is remembered best in the form in which it was originally encountered" (context is everything)

b) Illusion-of-truth effect: "a person is more likely to believe a familiar statement than a new one." (a danger for older people - they can become more easily preyed upon)

c)Procedural:"long-term memory of skills and procedures, or "how to" knowledge (procedural knowledge)." (linked to cerebellum and the basal ganglia function)

B. EXPLICIT (aka declarative memory): "conscious, intentional recollection of previous experiences and information", "some scientists suggest that episodic memory might be dependent on the right hemisphere, and semantic memory on the left hemisphere." (brain regions involved are medial temporal lobe; hippocampus and related areas of the cerebral cortex)

Types are:
a) Episodic: "memory of events, times, places, associated emotions, and other conception-based knowledge in relation to an experience."

b) Semantic: "memory of meanings, understandings, and other concept-based knowledge unrelated to specific experiences"

Neural structures involved in explicit memory:

"Most are in the temporal lobe or closely related to it, such as the amygdala, the hippocampus, the rhinal cortex in the temporal lobe, and the prefrontal cortex. Nuclei in the thalamus also are included, because many connections between the prefrontal cortex and temporal cortex are made through the thalamus.

The regions that make up the explicit memory circuit receive input from the neocortex and from brainstem systems, including acetylcholine, serotonin, and noradrenaline systems."

Evidence for the distinction between implicit and explicit
Brooks & Baddeley, 1976
Graf & Schacter, 1985, 1987
Jacoby & Dallas, 1981
Tulving, Schacter, & Stark, 1982

OTHERS:

Longterm memory: anything longer than 30 seconds, stored as meaning

Short term memory: stored only for about 20 seconds and discarded

Sensory memory: "ability to retain impressions of sensory information after the original stimulus has ceased" Two types:
1. Iconic: "short term visual memory (a sensory memory), named by George Sperling in 1960"
2. Echoic memory : "the auditory version of sensory memory"

(Thank you Wikipedia.)

Here is a very entertaining WNYC radio program on memory, from June 07. It discusses one more kind, creative memory.

More about memory in this program also, about 11 minutes in.