Longterm potentiation and nociception

As I scanned through Edge.org's question for 2012, I came upon this: Todd Sacktor's essay on "Elementary Particles of Memory", his contribution to the question,  2012: What is your favorite deep, elegant, or beautiful explanation? 

Excerpt:

The key molecule maintaining LTP is a persistently active enzyme, called PKMzeta. Together with the molecules maintaining LTD that are still being determined, these elementary molecules store most forms of memory. Without the persistent strengthening of synapses by PKMzeta, the ongoing physiological process of LTP at the synapse collapses, and most long-term memories are erased. The animal returns to a "blank slate," with just its genetic inheritance of behavior.

LTP= longterm potentiation. It's a process by which synaptic connections between neurons are strengthened. 

LTP is a persistent strengthening of synaptic connections triggered by a brief episode of high-frequency activity of those connections... The key molecule maintaining LTP is a persistently active enzyme, called PKMzeta... PKMzeta is an unusual form of protein kinase. Once made when LTP is triggered, PKMzeta is active all the time, rather than being turned on and off in response to other molecules. When mutations occur in genes for kinases that render them active all the time, they promote uncontrolled growth in cells, leading to cancer. However, the change in the gene that encodes PKMzeta also restricts the formation of the persistently active kinase to neurons. Because mature neurons are tethered to thousands of other neurons through their synapses, they cannot possibly divide and are remarkably resistant to forming cancers (most brain tumors in adults originate from glial cells, which readily divide). By restriction to cells that communicate but cannot divide, a mutation signaling continual growth, potentially deadly to an organism, was used to maintain long-term memory.

Isn't that remarkable. Here is a paper by him, from 2008: 

PKMzeta, LTP maintenance, and the dynamic molecular biology of memory storage.

ABSTRACT: How memories persist is a fundamental neurobiological question. The most commonly studied physiological model of memory is long-term potentiation (LTP). The molecular mechanisms of LTP can be divided into two phases: induction, triggering the potentiation; and maintenance, sustaining the potentiation over time. Although many molecules participate in induction, very few have been implicated in the mechanism of maintenance. Understanding maintenance, however, is critical for testing the hypothesis that LTP sustains memory storage in the brain. Only a single molecule has been found both necessary and sufficient for maintaining LTP--the brain-specific, atypical PKC isoform, protein kinase Mzeta (PKMzeta). Although full-length PKC isoforms respond to transient second messengers, and are involved in LTP induction, PKMzeta is a second messenger-independent kinase, consisting of the independent catalytic domain of PKCzeta, and is persistently active to sustain LTP maintenance. PKMzeta is produced by a unique PKMzeta mRNA, which is generated by an internal promoter within the PKCzeta gene and transported to the dendrites of neurons. LTP induction increases new PKMzeta synthesis, and the increased level of PKMzeta then enhances synaptic transmission by doubling the number of postsynaptic AMPA receptors (AMPAR) through GluR2 subunit-mediated trafficking of the receptors to the synapse. PKMzeta mediates synaptic potentiation specifically during the late-phase of LTP, as PKMzeta inhibitors can reverse established LTP when applied several hours after tetanization in hippocampal slices or 1 day after tetanization in vivo. These studies set the stage for testing the hypothesis that the mechanism of LTP maintenance sustains memory storage. PKMzeta inhibition in the hippocampus after learning eliminates the retention of spatial memory. Once the PKMzeta inhibitor has been eliminated, the memory is still erased, but new spatial memories can be learned and stored. Similar results are found for conditioned taste aversion when the inhibitor is injected in the insular neocortex. Thus PKMzeta is the first molecule found to be a component of the long-term memory trace.

Hmn. Insular cortex. That little brainpart, important in pain processing, in salience processing, shows up again. 

Anyway.

So... find something that messes with LTP and maybe.. "memory" could be erased? ... but I am way ahead of myself. Let me start again. 

A few days ago, this story came out of Nature | News: High-dose opiates could crack chronic pain. People in Vienna have found a way to reverse longterm potentiation in spinal cord synapses, at least in rat models. Here is the abstract of their paper,  Erasure of a Spinal Memory Trace of Pain by a Brief, High-Dose Opioid Administration:

Painful stimuli activate nociceptive C fibers and induce synaptic long-term potentiation (LTP) at their spinal terminals. LTP at C-fiber synapses represents a cellular model for pain amplification (hyperalgesia) and for a memory trace of pain. μ-Opioid receptor agonists exert a powerful but reversible depression at C-fiber synapses that renders the continuous application of low opioid doses the gold standard in pain therapy. We discovered that brief application of a high opioid dose reversed various forms of activity-dependent LTP at C-fiber synapses. Depotentiation involved Ca²⁺-dependent signaling and normalization of the phosphorylation state of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. This also reversed hyperalgesia in behaving animals. Opioids thus not only temporarily dampen pain but may also erase a spinal memory trace of pain.

So, what they did was, took rats, gave them 'chronic pain', i.e., allowed longterm potentiation to develop in their spinal cord synapses such that the second-order neurons conveying nociceptive afferent information to the rats' poor little brains, presumably their insular cortices, along with some other destinations probably, got way better at their jobs. Then, the researchers figured out what dose, and what kind, of opioid it took to reverse all the longterm potentiated changes. It turned out to be something called remifentanil, a "potent ultra short-acting synthetic opioid analgesic drug",  "given to patients during surgery to relieve pain and as an adjunct to anesthetic."

(A bit further down in the Wikipedia link is this interesting comment: 

Doses listed in the package insert from its manufacturer are much higher than those used in actual clinical practice

Huh. Gee, why not use it according to directions?)

Yes, pain would be a good thing to be helped to forget. Great place to start. 

There are only three neurons between anywhere on the surface of a vertebrate (or beneath its surface, I suppose..), and said vertebrate's brain. Clearly the junctions are the right place to target. Clearly opioids can help with pain, both prevention and, apparently, according to this, cure. It looks as though Sacktor may have been looking at the second link in the chain. The Vienna people looked at the first link.

I looked in the Vienna paper to see if PKMzeta figured in at all - the authors say they took a look:

We thus asked whether PKMz in spinal cord also plays a role for the maintenance phase of LTP (22, 23) after LFS. PKMz inhibitor ZIP had, however, no obvious effect on the maintenance of LFS-induced LTP within the observation period of 6 hours (fig. S2D).

22. M. N. Asiedu et al., J. Neurosci. 31, 6646 (2011).

23. T. C. Sacktor, Nat. Rev. Neurosci. 12, 9 (2011).

 It looks like they didn't see what Sactor found, or else they found something else:

Depending on the type of conditioning stimulation, distinct forms of LTP [longterm potentiation] are induced at C-fiber synapses, which affect different groups of postsynaptic neurons (13, 24) and involve signaling pathways that overlap only partially (13, 24, 25). 
We therefore tested whether OID [opioid-induced depotentiation] can also be achieved for other forms of established spinal LTP. We induced LTP by conditioning high-frequency stimulation (HFS, 100 Hz; fig. S3A) of sciatic nerve fibers or by subcutaneous capsaicin injections (fig. S3C). 
The latter selectively activates nociceptive nerve fibers, which express the transient receptor potential channel subfamily V member 1 (TRPV1). Remifentanil also fully reversed these forms of LTP (after HFS,  depotentiation was from 158 ± 8% to 99 ± 9%, n=12,P<0.001; after capsaicin,  depotentiation was from 170 ± 16% to 100 ± 13%, n=5, P<0.001;fig.S3, B and D), demonstrating that OID applies to various forms of activity-dependent LTP at C-fiber synapses.

My comments inside square brackets.

It's probably worth mentioning that if that first synapse, the one in the dorsal horn, can be affected, then the second-order neuron, the one that not only carries the info straight up but can turn into a signal amplifier blasting the info through the thalamus into all the third-order neurons that go to the sensory cortex, insular cortex, anterior cingulate cortex, like a lawn sprinkler on steroids, or a finger over the end of a garden hose increasing the distance and force of the spray, will be diminished to mere leakage. Then the brain will be able to ignore the ordinary light tapping or tinking of rain (nociception) on the roof, instead of a continuous thunderous pounding driving rainstorm day in and day out. Yes, one could still distract oneself (not register it as "pain") but it would probably be a lot harder than if the noise level could just be turned way down again to ordinary levels.


From the Viennese paper:

LTP is a synaptic model for some forms of hyperalgesia (26). We therefore asked whether OID has any relevance for behaving animals. Sub- cutaneous injections of capsaicin quickly led to mechanical hyperalgesia at the injected hindpaw (Fig. 4). The same dosage regimen of remifentanil that caused OID significantly attenuated capsaicin- induced hyperalgesia (Fig. 4A). Not surprisingly, the behavioral hyperalgesia was reversed only partially by the opioid treatment because additional peripheral and central mechanisms contribute to capsaicin-induced hyperalgesia (27, 28). PP1 inhibitor calyculin A fully blocked the attenuation of hyperalgesia by remifentanil (Fig. 4B), suggesting that depotentiation at nociceptive C fibers may erase a memory trace of pain[sic - at this point it's still only nociception]. LTP is expressed in ascending nociceptive pathways, which are relevant for the aversive components of pain. It will thus be interesting to explore whether opioids may also reverse the tonic-aversive state of pain (29). Taken together, the present and our previous data (3) demonstrate that activation of spinal MORs triggers distinct, bidirectional, and state-dependent synaptic plasticity in naïve versus potentiated C-fiber synapses. Remifentanil activates Ca2+-dependent signaling pathways, leading to activation of PP1 and PKC. At potentiated synapses, this normalizes the phosphorylation state [i.e., reverses the energy efficiency gained, makes them work harder again, makes them more "naive" again] of GluR1 at Ser831 and that of GluR2 at Ser880 and thereby depotentiates synaptic strength in C fibers. The presently identified reversal of synaptic LTP in nociceptive pathways provides a rationale for novel therapeutic strategies to cure rather than to temporarily dampen some forms of pain with opioids.

All "synaptic learning" seems to be about, really, in the case of pain, is a ratcheting of energy efficiency, such that the nociceptive neurons take advantage of a chemically altered "gain" in synaptic "strength" so that they can do their job with less fuel, perhaps. Economy of means. The Vienna people have figured out how to reverse that in a rat model, at the first synapse: it seems to me that Sactor's work has had to do with the second synapse upstairs in the brain, that he has not directly involved himself in LTP of the nociceptive system. 


Anyway, those are just some ramblings I've strung together from two recently read pieces of work that sound like maybe they talk about the same thing, LTP, but when I look close, I can't see that they actually do. I need to read the Vienna paper several more times, but so far it still looks like there's a gap between pain science and other neuroscience. It might help if people doing 'pain' science at the first synapse would stop calling it "pain science" and instead would call it "nociception science."

A Lorimer classic: "Reconceptualising Pain According to Modern Pain Science"

I saw this retwittered today - an earlier blogpost from Body in Mind (summer 2010 I think); I decided to bring it here, for the exercise, and for anyone who might have missed it at Body in Mind: Research into the role of the brain and mind in chronic pain.
Reconceptualising Pain According to Modern Pain Science was originally published in Physical Therapy Reviews 2007; 12: 169–178.

Abstract
"This paper argues that the biology of pain is never really straightforward, even when it appears to be. It is proposed that understanding what is currently known about the biology of pain requires a reconceptualisation of what pain actually is, and how it serves our livelihood. There are four key points:

(i) that pain does not provide a measure of the state of the tissues;
(ii) that pain is modulated by many factors from across somatic, psychological and social domains;
(iii) that the relationship between pain and the state of the tissues becomes less predictable as painpersists; and
(iv) that pain can be conceptualised as a conscious correlate of the implicit perception that tissue is in danger.

These issues raise conceptual and clinical implications, which are discussed with particular relevance to persistent pain. Finally, this conceptualisation is used as a framework for one approach to understanding complex regional pain syndrome."

Introduction:  (abbrev.)

"At first glance, pain seems relatively straightforward – hitting one’s thumb with a hammer hurts one’s thumb. Such experiences are easily understood with a structural-pathology model, which supposes pain provides an accurate indication of the state of the tissues. However, on closer inspection, pain is less straightforward. Much of the pain we see clinically fits into this less straightforward category, where pain cannot be understood as a marker of the state of the tissues. This paper argues that the biology of pain is never really straightforward, even when it appears to be."

Pain does not provide a measure of the state of the tissues

"In 1965, the gate control theory[2] was proposed to explain the variable response of animals to noxious stimuli. The theory proposed that noxious input was modulated at the spinal cord by other non-noxious input from the periphery, and by descending input from higher centres. That theory was interrogated in many animal experiments (see Wall and McMahon[3] for a review). A typical experiment would involve the insertion of recording electrodes into the nociceptors of the study animal, applying a defined injury and recording nociceptor activity. Finally, experimenters would record behaviours of the animal that implied that the animal was in pain. These behaviours might be relatively simple; for example, the reaction time of a withdrawal reflex. They might be relatively complex; for example, the ratio between time spent in a non-preferred environment (e.g. illuminated box) with a cool floor, and time spent in a preferred environment (e.g. dark box) with a heated floor.[4]
Two findings consistently emerged from those studies. First, the injury, or noxious stimulation, initiates the change in behaviour. Second, neither pain behaviour nor nociceptor activity hold an isomorphic relationship with the state of the tissues. By clearly demonstrating these things, those studies provided the first experimental evidence that pain does not provide a measure of the state of the tissues.
One limitation of animal experiments is that they do not tell us about pain. Human experiments, however, can. Although it is difficult to justify injuring human volunteers, it is possible to deliver non-harmful noxious stimuli, for example brief thermal, electrical or mechanical stimuli (see Handwerker and Kobal[5] for a review of various methods of experimentally inducing pain). By recording activity in nociceptors while simultaneously recording subjects’ pain ratings, experimenters have been able to evaluate the relationship between the state of the tissues (in the absence of tissue damage), activity in nociceptors, and pain.[6]
Human pain experiments corroborated both findings from the animal data. Specifically, noxious stimulation is necessary for nociceptor activity, which usually reflects the intensity of the stimulus, and nociceptor activation does not provide an accurate measure of the state of the tissues.[6] The human experiments went further because they showed that the relationship between pain ratings and nociceptor activation is variable. In fact, some authors have proposed that the notion of nociceptors is misleading because small diameter fibres (Aδ and C fibres) respond to very small (non-harmful) changes in the internal state of the body.[7] That said, some small diameter fibres are not responsive to small changes (so-called high-threshold neurons) and this sub-class of small diameter fibres may reflect what we call nociceptors. Regardless, it is clear that experimental studies do not show an isomorphic relationship between pain and nociceptor activity, nor between pain and the state of the tissues. Rather, they show a variable relationship that is modulated by many factors."

 

Pain is modulated by many factors from across somatic, psychological and social domains

"Anecdotal evidence that somatic, psychological and social factors modulate pain is substantial – sportrelated and war-related stories are common (see Butler and Moseley[8] for several examples). However, numerous experimental findings corroborate the anecdotal evidence (see Fields et al.[9] for a review of central nervous system mechanisms of modulation). Other factors that are known to modulate the pain evoked by a standardised stimulus include inflammatory mediators (increase nociceptor activity), tissue temperature (increased temperature increases nociceptor activity via summation), and blood flow (decreased blood flow increases nociceptor activity via summation induced by H+ ions). See Meyer et al.[6] for a review of peripheral mechanisms of modulation.
Experiments that manipulate the psychological context of a noxious stimulus often demonstrate clear effects on pain, although the direction of these effects is not always consistent. For example, a large amount of literature concerns the effect of attention on pain, and of pain on attention.[10–22] Despite the wealth of data, consensus is lacking: some data suggest that attending to pain amplifies it and attending away from pain nullifies it, but others suggest the opposite.
Anxiety also seems to have variable effects on pain. Some reports link increased anxiety to increased pain during clinical procedures[23–26] and during experimentally induced pain,[27] but other reports suggest no effect.[28,29] Relevant reviews conclude that the influence of anxiety on pain is probably largely dependent on attention.[28,30]
Expectation also seems to have variable effects on pain. As a general rule, expectation of a noxious stimulus increases pain if the cue signals a more intense or more damaging stimulus[22,31–35] and decreases pain if the cue signals a less intense or less damaging stimulus (see Fields[34] and Wager[36] for reviews). Further, cues that signal an impending decrease in pain, for example the process of taking an analgesic, usually decrease pain. Thus, expectation is thought to play a major role in placebo analgesia.[37,38]
The common denominator of the effect of attention, anxiety and expectation on pain seems to be the underlying evaluative context, or meaning of the pain. That is demonstrated by the consistent effect that some cognitive states seem to have on pain. For example, catastrophic interpretations of pain are associated with higher pain ratings in both clinical and experimental studies (see Sullivan et al.[39] for a review). Believing pain to be an accurate indicator of the state of the tissues is associated with higher pain ratings,40 whereas believing that the nervous system amplifies noxious input in chronic pain states increases pain threshold during straight leg raise.[41]
The social context of a noxious stimulus also affects the pain it evokes. Initiation practices and sadomasochistic sexual practices are two examples that highlight the importance of social context. Overall, the effects of social context are again variable but again seem to be underpinned by the underlying evaluative context, or meaning (see Butler and Moseley[8] for a review of pain-related data and Moerman[42] for exhaustive coverage of the role of meaning in health and medicine).
To review the very large amount of literature on somatic, psychological and social influences on pain is beyond the scope of this paper. However, it is appropriate, and clinically meaningful, to reiterate the theme that emerges from that literature: that the influences are variable and seem to depend on the evaluative context of the noxious input."

The relationship between pain and the state of the tissues becomes weaker as pain persists

"The nervous system is dynamic. This means that the functional properties of individual neurones and of synergies of neurones change in response to activity. To review all the changes that have been identified is beyond the scope of this paper and the expertise of this author. However, the nature of the changes can be summarised thus: that the neurones that transmit nociceptive input to the brain become sensitised as nociception persists, and that the networks of neurons within the brain that evoke pain, become sensitised as pain persists. The molecular and systems biology of these changes have been discussed at several levels.[8,43,44] The clinical manifestations of these changes are: hyperalgesia (formerly painful stimuli become more painful) and allodynia (formerly nonpainful stimuli become painful). These terms are used widely, most often in reference to tactile stimuli, but also in reference to movement and to thermal stimuli.
One aspect of the changes that occur when pain persists is that the proprioceptive representation of the painful body part in primary sensory cortex changes.[45–47] This may have implications for motor control because these representations are the maps that the brain uses to plan and execute movement.[48] If the map of a body part becomes inaccurate, then motor control may be compromised – it is known that experimental disruption of cortical proprioceptive maps disrupts motor planning.[49] The notion of distorted proprioceptive representation has been discussed with regard to its impact on motor control[50,51] and, more recently, in a theoretical way with regard to pain.[52] Although exceptions exist,[53] there is mounting evidence that changes in cortical representation occur in association with chronic pain, and it is feasible that these changes may become part of the problem.[46]"

Conceptualising pain as a conscious correlate of the implicit perception that tissue is in danger

"The biology of pain is complex. One response to this complexity is to develop clinically viable conceptual paradigms that incorporate what is now known about that complexity. One such paradigm that is gaining support is the neuromatrix theory (see Melzack[55] for a contextual review),[54] which conceptualises pain as one output of the central nervous system that occurs when the organism perceives tissue to be under threat. There are two important components of this conceptualisation.  First, there are other central nervous system outputs that occur when tissue is perceived to be under threat, and second, that it is the implicit perception of threat that determines the outputs, not the state of the tissues, nor the actual threat to the tissues (Fig. 1).
When tissue is under threat, a range of local and segmental responses occur. For example, inflammatory mediators are released, the body part is usually withdrawn via short and long latency reflex loops, there are rapid changes in blood flow and in the excitability of peripheral nociceptors (so-called peripheral sensitisation).[56] The nociceptive system transforms this threat into electrical activity in peripheral neurones. If this message of threat is then transmitted by spinal neurones to higher centres, the responses become more complex. For example, immune mediators are released into the blood stream,[57] voluntary and postural muscle activity are altered[58] and conscious knowledge of the threat (i.e. pain) may emerge. Within this context, pain will not emerge until the nociceptive input to the brain has been evaluated, albeit at an unconscious level (see Moseley[59] and Gifford et al.[60] for further discussion).
The second important component of the neuromatrix theory is that pain depends on the perceived degree of threat. This means that pain can be conceptualised as the conscious correlate of the implicit perception of threat to body tissues.[8,59] That psychosocial factors are very important in most chronic pain states is well established.[61–65] This paper argues that the mass of data regarding psychosocial factors can be gathered within the proposed conceptualisation that pain is one output of the central nervous system that occurs when the organism perceives tissue to be under threat. The conceptualisation has limitations and strengths. One limitation is that it does not attempt to describe the biology of implicit evaluation of threat, nor of how this might emerge into consciousness. In this sense it adds little to theories first proposed decades ago (see, for example, Hebb[66]). However, a strength of this conceptualisation is that it can easily be integrated into a clinical context where making sense of the influence of factors from across somatic, psychological and social domains is valuable."

Implications for clinical practice

"That pain does not reflect the state of the tissues, but rather is a conscious driver of behaviour aimed at protecting those tissues, has implications for clinical practice. One implication is that to base clinical reasoning on what is currently known about the biology of pain requires that the skills and knowledge of the clinician are broader than those related to anatomy and biomechanics. That is, the clinician must have a sound knowledge of diagnostic tools, tissue dynamics, healing and remodelling, peripheral and central sensitisation, and psychological and social factors that might affect the implicit perception of threat to body tissues. This information is readily available and there is evidence that clinicians can understand modern concepts with relatively limited training.[67] That said, it may be unrealistic to expect clinicians to keep uptodate with progress in knowledge across these areas. This points to a strength of the conceptualisation of pain as the conscious correlate of the implicit perception threat to body tissues because the clinician can use the conceptual model to guide treatment. That is, rather than know and understand all the evidence about which somatic, psychological and social factors have been demonstrated to modulate pain, and the nature of their modulation, the clinician can consider each factor in terms of what effect it might have on the implicit perception of threat. This conceptual model seeks to synthesize that wide body of evidence into a principle.
Another implication that is worthy of special mention is that patients should be helped to base their reasoning, about their condition and their pain, on similar information. This is important because teaching patients about modern pain biology leads to altered beliefs and attitudes about pain[40] and increased pain thresholds during relevant tasks.[41] Moreover, when education about pain biology is incorporated into physiotherapy management of patients with chronic pain, pain and disability are reduced.[68,69] A key objective of such education is to encourage patients to apply the same principle as that advocated for clinicians, summarised here as ‘what effect might this (factor) have on the implicit perception of threat’, or in patient-appropriate language, ‘how does this affect the answer to the question, how dangerous is this really?’.[8]"

(my bold - DJ)

Using this conceptualisation to understand CRPS and guide new options for management

"Complex regional pain syndrome (CRPS) is a debilitating condition that can occur after minor trauma, and sometimes without peripheral trauma, for example, post-stroke.[70] Much is known about the pathophysiology of CRPS, including facilitated neurogenic inflammation[71,72] and tissue hypoxia[73] at the injury site,[74,75] autonomic,[76] immune,[77–79] motor,[80,81] tactile[82–85] and proprioceptive[86] dysfunction (Fig. 2).
The syndromic pattern of signs and symptoms includes pain, hyperalgesia, allodynia, dystonia, swelling, abnormal blood flow, abnormal sweating, hair and nail growth. The sensitivity to provocation can be remarkable, for example, elicitation of pain, swelling and (anecdotally) blood flow changes in response to imagined movements[87] or when the patient receives visual input that the limb is being touched, even though it is not in fact being touched (‘dysynchiria’).[88] The wide-spread and multisystemic nature of the pathophysiology of CRPS implies that, although CRPS is usually initiated by peripheral insult, it is a disorder of the central nervous system.[75]
When one tries to make sense of such a multisystemic and exaggerated response to minor injury, the conceptualisation that pain is a conscious correlate of the implicit perception of the threat to body tissue can be useful. That pain is just one output by which the brain might try to protect the tissues – one aspect of a homeostatic response[89] – lends itself to CRPS because the other responses are so patent. That pain is a correlate of implicitly perceived threat to body tissue, rather than the state of the tissues, or the actual threat to the tissues, is particularly relevant to CRPS in the absence of any tissue or neural injury, for example, as a stress response.[90]
Each of the pathological findings that have been documented in patients with CRPS might be considered a protective response, whether it be an immune, motor, sensory, vascular, autonomic or conscious response. consistent with attempts to protect the part in question, by utilising immune, motor, sensory, vascular and autonomic systems as well as consciousness. Reducing the threshold for activation of these protective responses would seem a particularly effective way to protect the body part in question, for example making it so sensitive that even looking at it being touched activates a protective response.[88]
The challenge for those trying to understand CRPS according to this paradigm is to identify why the implicit perception of threat to body tissues is so exaggerated in some patients and in some situations, but not in others. Fundamental to the paradigm is that anything that modulates implicitly perceived threat should be relevant. That means that psychosocial factors, including anxiety, depression, attitudes and beliefs, social context or work status may all play an important role. Although patients with CRPS do not demonstrate a ‘typical’ psychosocial profile, psychosocial contributors are probably relevant in the majority of cases. Finally, there is initial evidence for a genetic contribution to CRPS,[91] but more data are required to clarify that possibility."

Clinical response to CRPS according to this paradigm

"If CRPS is an exaggerated protective response, then it seems sensible to devise treatment that aims first to find a baseline that is sufficiently conservative to not elicit the unwanted protective responses (to ‘get under the radar’), and second to expose the limb gradually to threat while continuing to avoid elicitation of the unwanted responses. This approach underpins graded motor imagery for CRPS,[92,93] whereby patients begin training by making left/right judgements of pictured limbs. It is known that this task activates cortical networks that involve representation of the limb and preparation for movement,[94] but this task does not activate primary sensory and motor cortices.[95] Graded motor imagery progresses from left/right laterality judgements to imagined movements, which do activate primary sensory and motor cortices,[95,96] and then to mirror movements. The order of these compo nents seems to be important in the effect on pain and disability in patients with chronic CRPS (Fig. 3).[1] In patients with acute (or anecdotally less severe) CRPS, it may be sufficient to begin training (conceptualised here as exposure to threat) with mirror movements.[97]
One of the key issues outlined earlier is that the nervous system changes when nociception and pain persist. There is a large amount of evidence that the cortical representation of the affected limb undergoes substantial changes in patients with CRPS[47,74,75,83,98–100] and these changes have been implicated in the maintenance of pathological pain syndromes (although see Moseley[53] for a word of caution).[46] If distorted cortical representation contributes to CRPS, then it would seem sensible to attempt to normalise cortical representation of the limb. This has been done in patients with phantom limb pain,[101] which is associated with changes in primary sensory cortex that are probably similar to those observed in CRPS (see Acerra et al.[102] for a review of common findings in phantom limb pain, stroke and CRPS). In that study with amputees, sensory discrimination training evoked normalisation of cortical representation, improvement in tactile acuity on the stump and reduction/elimination of phantom limb pain.[101] Increase in tactile acuity, normalisation of cortical representation and reduction in pain were positively related.
Finally, if CRPS reflects an exaggerated implicit perception of threat to body tissue, then it would seem sensible to attempt to reduce the perception of threat. One approach that has been studied extensively in other populations is the explanation to the patient of the underlying biology of their pain. Preliminary data from patients with CRPS appear promising,[103] but clinical trials are required."

(my bold - DJ - Learning to tell right body parts from left body parts, visually)

Conclusions

"Extensive experimental data corroborate anecdotal evidence that pain does not provide a measure of the state of the tissues and that pain is modulated by many factors from across somatic, psychological and social domains. It is now known that as nociception and pain persist, the neuronal mechanisms involved in both become more sensitive, which means that the relationship between pain and the state of the tissues becomes weaker and less predictable. One paradigm, which considers the current thought in pain biology, conceptualises pain as the conscious correlate of the implicit perception of threat to body tissue. This conceptualisation can be applied clinically to identify factors from across somatic, psychological and social domains that may affect the perceived threat to tissue damage. Further, it suggests approaches to treatment that target those factors. Evidence from clinical trials suggests that clinical strategies based on this conceptualisation can be effective in patients with disabling complex and chronic pain."

 (my bold - DJ)


LINK TO ORIGINAL BLOGPOST:

Reconceptualising Pain According to Modern Pain Science

Please go look at it, as there are helpful diagrams, acknowledgments and references I didn't copy over to here. While you are there, check out all the other excellent blogposts others have contributed. Body in Mind is one of the most thoughtful and clinically useful blogs on chronic pain to ever have graced the web.

Here is a recently posted, short, one-minute youtube video by Matthias Weinberger, showing mirror therapy for CRPS. 

What's my motivation?

The class I have been struggling with is going from bad to worse: I am learning my limitations.
Moi.

I do not personally have any real attraction to the geeky side of research, whether it be learning how to measure abstract things like pain, or even learning ABOUT the geeky side of pain research, such as learning what a criterion concurrent validity is compared to a convergent construct validity. Never have had. I simply have no hooks built in my brain, that could grab that information to work with it, even if I wanted to. Never went there. Never did that. Never was attracted. So, right now I'm asking myself how and why I ended up in this situation.

Ooh. The pain. I do not like finding out I do not have a nimble enough mind to even process the information let alone mentally manipulate the information let alone do assignments and exams about it. I feel trapped like a rabbit with one foot in a steel claw. I want to get out of here. If I make a move I just hurt myself and go nowhere.

So, I ask myself, why did I sign up for this?
I think I wanted to know about all of it, but I didn't really want to have to learn how to do it.

The instructor insists that this is the right way to learn to manage pain patients, and she may well be right, but managing pain patients this way is not really and never will be my focus.

I had an enormously long email conversation with her, and slowly, it has emerged as to what my focus might really be... It certainly differs from the one she has.  There is a certain clash of perspectives. In the end, all I am is a human primate social groomer who is always inquisitive about learning anything that will help me do my human primate social grooming better or more effectively by being able to explain. Furthermore, I'm convinced that having the story in the right ball park is also important, in the clinican mind and the patient mind.

Basically, to me, this boils down to being at least on the right kind of tissue, at least conceptually, i.e., somewhere in the nervous system, when discussing pain problems.

She is teaching a class on how to administer tests to patients to figure out what kind of pain they have. To do that, there are dimensions of testing one must learn about before administering.

It gets even more dicey than that. Here is the really scary part, from my point of view. The impression she gives me is that she would love to turn the whole PT profession into people like her. She has huge judgment against any use of pain science for information value only. She seems to want it to stay pure and unsullied, to boldly go into all the shades of grey, to measure them, to develop new conceptual tools that will calculate one colour of grey against another and measure them precisely in such neutral light that back in the sunshine one can still be confident that the scale one uses to gauge the grey shade one is looking for will still correctly identify it, even when its context has changed.

She said "nothing in research is black and white. Everything is grey. Clinicians want black and white all the time, but there isn't anything black and white." (Um, yeah... we already knew that, but we have to make decisions, and the best decisions are made when we can access the best information. Hello? Withholding information isn't helpful! And just because it will never be perfect or because it's only provisional or because it's still just a theory doesn't mean that it isn't closer than what we were working with before! LIFE IS A VERB, not a NOUN!)

She was discomfited at the very idea of pain research being distributed by people who are a lot less close up to it than she, who knows all about how many shades of grey there are and still may be. (Um, sorry, that started a couple decades ago. There was no spigot in place, so somebody built one. The amount of information that had piled up around pain, that was not getting into the minds of clinicians, was threatening to burst the dam and flood the profession far below. Some people thought it better to build some ways to drain some of it out to use to grow new food for thought. Um, so the profession could remain relevant on the ground and in the clinic and be more congruent with how science looks from there.)

She was discomfited by the idea that people were selling pain information to clinicians in workshops for money. (Um, you should see some of the other JUNK being sold - at least this is useful stuff, not JUNK!)

Everything in brackets, italicized, bolded and exclaimed, is my own emotional frustration with everything she expressed frustration about.

I can see her point - she loves the geeky side, and doesn't like to see any situation develop which could possibly misrepresent the careful effort she makes on behalf of the profession. I get it. I do. I think it boils down to intrinsic academic reluctance to take a stand or make a decision. I think some of that gets trained into people. Some of it is probably a character trait. It's good..., I mean, if we didn't have that, we'd have no science at all - all we'd have would be religion (and that would not be a good thing).  She says she is against dogma, so, another point for her.

On the other hand, we have a profession full of clinicians who need better information about what it is we do and better stories with which to line our minds such that we can slide the better information out to patients. And the stories better be scientifically congruent with the information and congruent with the delivery by the profession to clinicians and by clinicians to each other and by clinicians to patients, or else the profession ends up anachronistic, or worse, deceiving the public.
EXAMPLE: I do not see any point in keeping clinicians in the dark about the nervous system and how it works. We aren't children. We shouldn't still be going around talking about something called "pain" as coming from muscles or bones or joints. It doesn't. Pain is something the brain makes out of raw data coming up from the body, but only if it has a "mind" to. It loves to tell itself stories. It can invent pain without sufficient information or even any information coming up from the body. (And no, don't go using that to blame patients for having pain. It's not them making it up. It's their brain, and they are trapped inside that brain, feeling the pain story, perceiving it even as their brain projects it.)

Anyway, here I still am, lying here with my little rabbit foot in the trap. I could chew the foot off, and would still have three feet left to run away on. I'd rather not lose a foot. Don't like making sacrifices.

There is a part of me (an ego part probably) freaked out about failing this class. After scoring an A (!) in the first class, which was all about learning what's going on in the nervous system. Learning the stories about what's going on in the nervous system. That's what I love learning about. Those stories are the ones I can explain to patients. That kind of thing I am definitely motivated to learn. This abstract, dry dull measurement stuff, not so much. I don't want some poor mark on my (pathetically irrelevant in any case) academic record. At least this ego part doesn't. It thinks people could come along and use it to judge me later. Now I remember why I hated going to university even though I loved learning information.

So, I'm forced to consider my options. Cognitive dissonance is so frickin' painful. Ow, my foot!

Lacking natural motivation for learning geeky methodological verificatory statisticality, I could force myself and could probably learn the material, but it would take me a lot longer than the time frame of 13 weeks. Even if I apply myself diligently 24/7 to nothing but the material (which I HAVE BEEN doing), I'm still going to lose. I don't know how to even begin to tackle the assignment, "Critical evaluation of a measure specific related to pain management". It's due at the end of March. No matter what I do, I'm convinced at this point that I'm gonna lose. I'm a dead woman.

From March 18, Pain-Topics.org News Research UPDATES: How to Make Practical Sense of Pain Research

Ronald Melzack: Pain Pioneer

 I attached this to the Facebook Page, Neuroscience and Pain Science for Manual Physical Therapists, and now here. Very nice little video about Melzack's life and work.

"Touch is good" - HumanPrimateSocialGrooming manual

In a recent SBM post, Mark Crislip discussed reflexology among other things.

He said,

“Monkeys, and other animals, groom each other often with a marked reduction in stress. Touch is good, and one doesn’t need to wrap it up in pseudoscientific nonsense for it to be beneficial.”

To which I replied, in the comment section,

"Thank you for saying that Mark; I’ve been saying the same thing for years. I call it “human primate social grooming.” Most human primate social grooming professions/professionals dislike the term, for some weird reason. Oh well.

Diane, human primate social groomer and manual therapist with a PT license to touch people."

Another commenter suggested that it was more succinct to use the term "pedicurist", which I took as an opportunity to explain the difference between operator model of human primate social grooming and interactor model of social grooming. So, I replied,

"Well, strictly speaking, any profession that is licensed to touch human beings for whatever reason including hair dressers, dentists, pedicurists and medicine, could all be considered human primate social groomers, I think.

It’s the “WHY-we-touch” that shakes the idea into layers, I think.

Those who touch to get a specific job done, like get a tooth out, get a toenail clipped or a callous scraped off, or hair cut, or appendix out etc., i.e., have an obvious, clear, objective purpose for both patient and practitioner to focus on; these practitioners have the option of being ’something more than just’ human primate social groomers. We could call these people “operator model” human primate social groomers.

Those who groom humans specifically to help them with nebulous perceptions and experiences of stress/pain, are (fundamentally) practitioners of what I would call the “interactor model” of human primate social grooming.

Could a desire to be more “operator” than “interactor”, to have some externalized reason for treating no matter how imaginary, i.e., a treatment “concept”, be a big reason *why* human primate social groomers (and now I’m talking about only the ones like me, interactor-model ones who touch to relieve stress and reduce pain perception/experience) made up (and still make up!) crazy ideas like acupuncture meridians? Trigger points? Subluxations? Untestable and unprovable? then go on to develop complicated ways of treating them?

I’m content just treating human primates with pain problems nowadays, supported by pain science and neuroscience, rather than trying to learn to treat crazy concepts some other groomer(s) invented once-upon-a-time for fun and profit. I guess this makes me a full-on, out-of-the-closet, interactor-model human primate social groomer on the lowest possible rung of the human practitioner hierarchy; oddly, though, I find it the most comfortable place to be, the most science-based, with the least distance to fall.

Diane, human primate social groomer and manual therapist with a PT license to touch people/many opinions on the matter"

I would add, any idea about anything anyone thinks they can affect below the surface of the skin must be put carefully through Occam's Mental Meat Grinder before being adopted as verifiable fact.

* The truth is, we can't literally touch anything but skin.
* The truth is, skin (cutis/subcutis, the actual organ of "skin") is thick. (It's also rubbery and full of physiology, busy-ology)
* The truth is, we can bend things around a bit, things that are located inside, beneath skin, but we cannot "touch" them - only if they are exposed, as in an operation, can we literally touch them.
* The truth is, we are probably mobilizing neural structure a lot more than anything else with manual therapy


Which means, when we treat, we are using our imaginations a LOT.
It's ok to use imagination, but it's not OK for one group of PT or manual therapy imagination users to claim higher scientific turf than some other group of PT or manual therapy imagination users.
Get real.
What do you think you're testing/treating? What you imagine you are touching/affecting, instead of what someone else imagines they are touching/affecting?? How is your science based on whatever you think you can "operate on" under the skin ever going to be more than more tooth-fairy science, based on some hypothesis which is implausible because you can't get your hands literally on the thing that you are trying to affect with your hands, and you cannot rule out the fact that the patient's brain/neuromatrix is being very attentive to you and anything you try to do to it with those same hands? Give me a break.


Adoption of an interactor model would slice the matter in several novel directions.
a) we would be more science-based.
b) it would place neuromatrix and biopsychosocial models of human pain/function/dysfunction ahead of orthopaedic and biomechanical and other (also largely pseudoscience) operator models.
c) it's already pretty hard to design experiments that can test aspects of manual therapy.
d) adopting an interactor model would make things even harder.
e) we would, however, as clinicians, be on much firmer scientific ground.
f) why strive so hard to build an evidence base, based on operator models of treatment that contain such implausible tissue-based hypotheses (biomechanical, craniosacral, myofascial, triggerpoint, joint-based, reflex zone, acupuncture, you name it) in the first place?
g) adoption of an interactor model would make things harder but also easier. We could work toward improving what already works, i.e., the verb of therapeutic contact, as a new social element of that individual's biopsychosocial, pre-existing landscape, the entry of oneself as a therapist, with a social-grooming interactor role, into that person's neuromatrix. Not have to try to substantiate the noun (and therefore, myth(!)) of some system for
- supposedly pushing a joint sideways and thereby supposedly decreasing nociceptive afferent stimuli, or
- supposedly bending a suture somehow and thereby supposedly squishing cerebral spinal fluid around thereby supposedly decreasing nociceptive afferent stimuli, or
- supposedly physically stretching fascia (of all things!), a tissue whose job is to keep an organism and its layers from falling apart..
- etcetcetc.....
h) what is the element common to both the operator model (even though the operators won't admit it) AND the interactors? Skin.
i) Which takes us all the way back round to the question, "What are we really handling?"

Answer: The surface of someone's body. All the representational maps stored in the brain of the individual we are touching. All the feelings, thoughts, beliefs, impressions, perceptions that individual has stored up over a life time. The person has the pain problem. We don't. The person has to fix his or her own pain problem. We have to try to help them.

It's that simple.

It's a grooming encounter and they have a pain nit they can't reach by themselves. They need someone outside to verify it, so they can begin to downregulate it. Maybe it's a little, buried, default primate social need our human primate brains still have. I don't know. But I know we don't have to press very hard for that. We only have to apply a bit of judicious and NON-nociceptive stimulus to that person, at the right speed, for the individual. They need to become more aware of their body and simultaneously less aware of their pain.

It's that simple.

Handling skin properly is simple: Do anything to it you want, just avoid hurting the person through it, and the person's brain will take care of all the rest. Bear in mind what I will now call the...

First Law of Human Primate Social Grooming: Do No Nocicepting

Stick to that law even if the patient seems to have a high nociceptive threshold, even if they "think" they should pay for gain with more pain, even if they kid around and act tough, even if they've been told by countless other treaters that it's OK, just suck it up. Don't get sucked into that movie, people. Stick to the First Law and you will never have to hold yourself responsible for having created a new chronic pain patient.

They are out there, you know... Life is a verb, not a noun. The brain is a verb, not a noun. It interacts continuously with its environment, both inner and outer. Those whose nervous systems aren't organized quite normally, who perhaps lack the means by which their cells can produce that absolutely crucial opioid receptor in quite the right synapse, or whose systems go haywire and produce way too much Substance P or some other excitatory substance which can jimmy the ordinary downregulatory system... those people are out there. Yes, they are rare, and yes, they might instinctively already "know" they don't tolerate rough-house well, but some of them may find their way into your clinic regardless. They only want what any patient wants - some professional interactive human primate social grooming from someone who will take them as a person and all their possible baggage into account while being in therapeutic contact with them, and leave them explicitly with the locus of control over the treatment. If it happens to be you, and you didn't interview them enough to pick up they aren't appropriate for your kind of manual treatment (or manual handling, period), don't set the context correctly, or you wander off into your own operator mentations inappropriately or at the wrong moment, or you haven't told your patient to tell you when your handling feels uncomfortable... congratulations![not] - chances are pretty high you may have just initiated another person to the (already too high) chronic pain population. Oops. You (and your treatment idea) became their tipping point. Now you'll have to live with that, and (much) worse, so will they. No one starts out thinking they'll end up in chronic pathophysiological pain - they just do. Don't play any role in making worse problems for people than they already have.

If you're going to be a human primate social groomer, for goodness sake be an intelligent one - think about stress reduction - get that person's stress levels down before you ever begin - set the stage. Make it easy for yourself, and for them. Make it clear they are in ultimate veto charge of you and your handling. Make it a habit to give them cognitive material in the form of pain education to work with. Human primates need that as part of the human primate grooming process; those big frontal lobes need information to chew on throughout the process. With stress levels down, the individual will be more apt to incorporate you and your contact into his or her body schema, and good things will have a better chance to result. Go slow - the slower you go the more that person's brain will be able to take in what's going on and use it best to help itself.

Additional reading:

1. Bennedetti: The Placebo and Nocebo Effect: How the Therapist’s Words Act on the Patient’s Brain