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.
Showing posts with label pain. Show all posts
Showing posts with label pain. Show all posts
Thursday, March 12, 2009
Wednesday, August 6, 2008
Microglia and Pain: A Manual Therapy Perspective IV
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
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)
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)
Tuesday, August 5, 2008
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.
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.
Monday, August 4, 2008
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
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.”
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.”
Sunday, June 1, 2008
"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:)
2. Anterior insular cortex projects to LC: (p. 127:)
I missed this when I did the projections post.
(Note: RVM = rostral ventromedial medulla)
3. Linkage to affective states: (p. 234:)
4. Supraspinal analgesia: (p. 431:)
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.
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.
Thursday, May 8, 2008
Nervous System Basics VI: PURPOSEFULNESS
Angevine's fifth basic organizing principle, purposefulness:
I never have heard such attributes associated with the locus ceruleus before. Fascinating. Another tidbit on locus ceruleus, from Kandel, p. 483:
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
"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
Friday, December 14, 2007
Virtual Body Experience
Check out the article, How to Excuse Yourself From Your Body, from the magazine Discover.
Swedish scientist H. Henrik Ehrsson devised a way to convince people's brains that what they were looking at, an image of their bodies projected in front of them, were in fact occupied BY them. He proved that the brains responded to the illusion "as if" it were real; he provoked measurable autonomic distress output by threatening to hit the "virtual" body with a hammer.
His study “The Experimental Induction of Out-of-Body Experiences” was published in Science, Aug. 24, 2007.
(See here for list of 30 of his articles.)
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.
How is this possible?
The Discover article says,
Experiment I:
Henrik Ehrsson, Karolinska Institute in Stockholm, Sweden
- 18 healthy individuals were seated. Their backs were filmed with a pair of video cameras while they wore goggles that
a)gave them a stereoscopic view of their backs
b)captured the video from both cameras.
- Ehrsson induced the illusion; he "repeatedly touched each person’s actual chest with one rod while, with another rod, he jabbed toward a point below and in front of the two cameras that corresponded to the “virtual chest” of the image projected into the goggles. With the shift in perspective through the goggles, subjects reported that they felt as though they were physically embodying a space six and a half feet behind where they actually were."
Experiment 2:
Ehrsson wanted to find out if the subjects would respond "as if" they were located in the illusory position.
- Sensors that monitor electrical conductance were applied to the subjects.
- The first experiment was duplicated.
- This time, "he swung a hammer toward the two cameras at a point corresponding to the center of the face of the camera-generated illusory body"...and, "the subjects’ skin showed a spike in electrical conductance—a sign of increased sweating and emotional arousal—and they reported immediate anxiety."
Experiment 3:
Bigna Lenggenhager et al., École Polytechnique Fédérale in Lausanne, Switzerland
- A camera was placed six and a half feet behind the back of each of 14 participants wearing 3-D video goggles.
- Their backs were stroked with a large pen; they could simultaneously see and feel their backs being caressed.
- The subjects were guided backward, then asked them to return to their previous position.
- "Participants overshot the distance by an average of 10 inches, moving closer to the position of their “virtual” bodies."
- The back of a mannequin's body was stroked, and the image projected into the subjects’ goggles. Subjects felt that the mannequin’s body was their body.
“We now understand how the brain combines information from the eyes and from the skin to compute or determine where the self is located in space,” Ehrsson says. Both experiments show how easily the brain can be tricked or how it “cheats,” he says, using memory and prior experiences to fill in data gaps."
Here is a youtube video about this. (Olaf Blanke, shown in the video, was Lenggenhager's team leader.)
Here is a link to Sandra Blakeslee's new book, The Body Has a Mind of its Own, which discusses these kinds of phenomena and attendant research in greater detail.
Just one additional thought for now.. why wouldn't this setup work for treating back pain? Someone could find 20 or so subjects with back pain, any old kind of back pain at all, acute, chronic, what have you, any age, any sort of work, any socioeconomic group... put the goggles on them, induce the illusion. Instead of getting the subjects to move forward and back or instead of eliciting threat responses from their autonomics, instead, the "virtual" backs, could be "treated". Or a film clip of the "virtual" back could be shown to move freely. I wonder if this illusion would be sufficient to get the subjects' brains to stop producing the pain output?
Dec. 29th '07: Back in to add a link to a youtube video on goggle-induced virtual reality games for phantom limb pain.
Swedish scientist H. Henrik Ehrsson devised a way to convince people's brains that what they were looking at, an image of their bodies projected in front of them, were in fact occupied BY them. He proved that the brains responded to the illusion "as if" it were real; he provoked measurable autonomic distress output by threatening to hit the "virtual" body with a hammer.
His study “The Experimental Induction of Out-of-Body Experiences” was published in Science, Aug. 24, 2007.
(See here for list of 30 of his articles.)
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.
How is this possible?
The Discover article says,
"While we navigate the world, our brains are constantly integrating sensory information gathered by sight, touch, and hearing. But sometimes the system goes haywire, and people experience the illusion that they are outside their physical bodies, floating above them and peering back from a distance of about 6 to 10 feet. These “out of body” experiences typically occur when people suffer strokes, epileptic fits, or migraines or are taking drugs. Two cognitive neuroscientists explored the boundaries of body perception by reproducing an out-of-body experience in the lab."
Experiment I:
Henrik Ehrsson, Karolinska Institute in Stockholm, Sweden
- 18 healthy individuals were seated. Their backs were filmed with a pair of video cameras while they wore goggles that
a)gave them a stereoscopic view of their backs
b)captured the video from both cameras.
- Ehrsson induced the illusion; he "repeatedly touched each person’s actual chest with one rod while, with another rod, he jabbed toward a point below and in front of the two cameras that corresponded to the “virtual chest” of the image projected into the goggles. With the shift in perspective through the goggles, subjects reported that they felt as though they were physically embodying a space six and a half feet behind where they actually were."
Experiment 2:
Ehrsson wanted to find out if the subjects would respond "as if" they were located in the illusory position.
- Sensors that monitor electrical conductance were applied to the subjects.
- The first experiment was duplicated.
- This time, "he swung a hammer toward the two cameras at a point corresponding to the center of the face of the camera-generated illusory body"...and, "the subjects’ skin showed a spike in electrical conductance—a sign of increased sweating and emotional arousal—and they reported immediate anxiety."
Experiment 3:
Bigna Lenggenhager et al., École Polytechnique Fédérale in Lausanne, Switzerland
- A camera was placed six and a half feet behind the back of each of 14 participants wearing 3-D video goggles.
- Their backs were stroked with a large pen; they could simultaneously see and feel their backs being caressed.
- The subjects were guided backward, then asked them to return to their previous position.
- "Participants overshot the distance by an average of 10 inches, moving closer to the position of their “virtual” bodies."
- The back of a mannequin's body was stroked, and the image projected into the subjects’ goggles. Subjects felt that the mannequin’s body was their body.
“We now understand how the brain combines information from the eyes and from the skin to compute or determine where the self is located in space,” Ehrsson says. Both experiments show how easily the brain can be tricked or how it “cheats,” he says, using memory and prior experiences to fill in data gaps."
Here is a youtube video about this. (Olaf Blanke, shown in the video, was Lenggenhager's team leader.)
Here is a link to Sandra Blakeslee's new book, The Body Has a Mind of its Own, which discusses these kinds of phenomena and attendant research in greater detail.
Just one additional thought for now.. why wouldn't this setup work for treating back pain? Someone could find 20 or so subjects with back pain, any old kind of back pain at all, acute, chronic, what have you, any age, any sort of work, any socioeconomic group... put the goggles on them, induce the illusion. Instead of getting the subjects to move forward and back or instead of eliciting threat responses from their autonomics, instead, the "virtual" backs, could be "treated". Or a film clip of the "virtual" back could be shown to move freely. I wonder if this illusion would be sufficient to get the subjects' brains to stop producing the pain output?
Dec. 29th '07: Back in to add a link to a youtube video on goggle-induced virtual reality games for phantom limb pain.
Wednesday, December 12, 2007
Learning
Diane, I think that one of the most important statements from that program is this:
If you develop good learning skills - you can apply those anywhere and everywhere - all your life.
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.
All geniuses throughout history have shown some or all of the same skills:
creativity, an ability for lateral thinking, the ability to make connections between seemingly unrelated fields (of science) - and disrespect for authority.
Only by letting your mind wander to places that don't exist - by freeing yourself from the constraints society and/or peer pressure impose upon you can you really become creative and innovative.
In this case it's more important to un-learn constraining patterns of behavior than to learn new ones!
So where does pain fit in?
Learn to observe yourself - use Metacognition to identify situations, thoughts, habits, .... that aren't helpful. Start today.
Because if you learn to develop this crucial skill to it's full potential, you can use it - as stated above - anywhere, everywhere, anytime.
You have to realize that chronic pain is (mostly) a learned condition. The brain learned to be in pain all the time on it's own - what's called maladaptive plasticity.
But - by learning how to learn - and thus making use of "good" neuroplasticity - one can unlearn chronic pain.
1. The focus, the inner attention, has to be on the process of learning the action, not the desired action itself.That means that you have to learn how to learn.
If you develop good learning skills - you can apply those anywhere and everywhere - all your life.
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.
All geniuses throughout history have shown some or all of the same skills:
creativity, an ability for lateral thinking, the ability to make connections between seemingly unrelated fields (of science) - and disrespect for authority.
Only by letting your mind wander to places that don't exist - by freeing yourself from the constraints society and/or peer pressure impose upon you can you really become creative and innovative.
In this case it's more important to un-learn constraining patterns of behavior than to learn new ones!
So where does pain fit in?
Learn to observe yourself - use Metacognition to identify situations, thoughts, habits, .... that aren't helpful. Start today.
Because if you learn to develop this crucial skill to it's full potential, you can use it - as stated above - anywhere, everywhere, anytime.
You have to realize that chronic pain is (mostly) a learned condition. The brain learned to be in pain all the time on it's own - what's called maladaptive plasticity.
But - by learning how to learn - and thus making use of "good" neuroplasticity - one can unlearn chronic pain.
Subscribe to:
Posts (Atom)