Moving a humanantigravity suit around

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

Fabulous Interactive Brain Science Site: Genes2Cognition

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!

Microglia and Pain: A Manual Therapy Perspective III

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

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

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 from Lausanne: Mapping the Structural Core of Human Cerebral Cortex

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:

About ASTROGLIA

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

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

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

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

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.

Nervous System Basics VIII: PLASTICITY

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

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

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

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

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

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

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.

Transcript For BrainScience Podcast #31

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.

Something in Swiss water?

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)