Short version of the EMD/IND/MOD hypothesis by Rudger Alexander Kanding July 5, 2017 [Please find a printable version at the end of this page] Dear reader, this text presents a hypothesis for a disease mechanism that is possibly involved in a wide array of currently unexplained medical phenomena that are associated with musculoskeletal problems, dysregulation of the autonomic nervous system and mood changes. Phenomena explainable with this hypothesis include the functional somatic syndromes (e.g. fibromyalgia, irritable bowel syndrome, tension headache), the somatic symptom disorder, complex regional pain syndrome, myofascial pain, trigger points, and, surprisingly, the alcohol hangover and aging related health changes. The text is intended for both layman and readers with neuroscientific knowledge.
Part 1: Why brain ageing entails a chronic, tetanic muscle fibre strain When initiating a movement of your toe, a nerve signal originating from the so-called upper motor neuron in the brain, travels down deep into your spinal cord. There, the signal jumps to the lower motor neuron, travels to your toe muscles and your toe moves. Crucially, the activity of the lower motor neuron is controlled many times a second by blocking signals from a so-called inhibitory interneuron. The function of this inhibitory interneuron is to limit lower motor neuron activity in order to prevent muscle injury. In the disease tetanus, the bacterial toxin blocks the inhibitory interneuron. The normal, permanently ongoing spontaneous activity of the central nervous system (CNS) is now uncontrolled transmitted from the lower motor neuron to the muscle. This leads to severe muscle cramps that can tear off muscles and can break the spinal cord. Inhibitory interneurons (hereafter simply called ‘interneurons’) exist also and in the brain. Similar to the interneurons in the spinal cord, interneurons in the brain prevent the overactivity of other neurons. In this way, they control the activity of all kind of neuron groups that memorize e.g. motor programs, innate emotional memories (e.g. fear reactions), and also the many emotional memories one acquires throughout a lifetime. As described, the effect of the tetanus toxin has dramatic, often fatal consequences. This raises the question as to what happens when the many neurodegenerative influences the human brain is continually exposed to, lead to malfunction or even demise of interneurons in the brain. For simplicity I consider here only interneuron demise (hereafter called ‘IND’). Due to the outlined control function of interneurons, IND certainly entails a loss of control over neuron groups and the contained motor programs and memories. The effect of IND on these neurons groups is similar to the loss of control the tetanus toxin entails to the lower motor neuron. That means the baseline neural activity of the CNS is now transmitted in a stronger way through the neuron groups affected by IND, and this is equivalent to a slight, permanent activation of motor programs and memories. This process is hereafter called ‘memory overexpression’. Two important effects result from memory overexpression:
1
i) Released motor programs and the muscular reactions associated with released emotional memories have a slight ‘tetanic’ effect, lead to a slight, chronic muscle tension. ii) Additionally, released emotional memories cause a slight, chronic activation of the sympathetic nervous system. Compared to the millions of interneurons affected by the tetanus toxin, the daily occurring, normal IND affect only a very low amount of interneurons. The resulting consequences are therefore very weak and in the first place not perceivable by the affected person. Problems arise only when IND effects accumulate to a symptom causing level. Surprisingly, the accumulation of IND effects is mainly driven by the process of ageing, which regularly leads to demise of neurons. Solely in the neocortex 85000 neurons die by day through various effects of cell aging. Evidently, it is only a question of time, until the continual loss of interneurons through aging provokes symptoms. This happens e.g. when the resulting ‘tetanic’ muscle straining effect of IND is so strong, that single muscle fibres contract up to a level where pain receptors are triggered. Chronic pain evolves. Part 2 will show that in many cases accelerated brain ageing through subclinical inflammatory processes in the brain actually drives IND accumulation to a symptoms causing level. The drastic effects, that reduced interneuron activity exerts on muscular and sympathetic activity, can also experimentally be demonstrated in mice. For this purpose, a substance that transiently stops interneuron activity is injected into the so-called ‘lateral central amygdala’, a small brain structure that controls in mice, and likewise humans, the activity of innate and acquired emotional memories. This injection immediately induces a strong freezing reaction, i.e. a strong whole body muscular contraction, which is accompanied by typical signs of sympathetic hyperactivity as e.g. increased blood pressure and increased heart beat rate (Ciocchi et al., 2010, p. 277). This experiment shows for one important emotional memory system that a loss of interneuron activity inside such a system indeed causes an overexpression of stored emotional memories, and that this overexpression is accompanied by strong physical reactions. It is therefore quite conceivable, that solely aging related IND in this small brain structure (~ 0.5 cm3), even when acting only on innate emotional memories, can affect enough memories to cause a level of memory overexpression that strains some muscle fibres up to a painful level. Importantly, around a dozen of brain structures use interneurons in a similar way as the lateral central amygdala in order to control emotional memories, and memories of physical reactions. All these brain structures are therefore sites of vulnerability where IND may cause the described effects. The presented model how aging induced IND causes symptoms is therefore far from being a pure hypothetical construct. It is actually well founded in existing neural mechanisms. And it certainly exists as a real phenomenon, under the preconditions that enough interneurons are affected and brain repair mechanisms are not able to counterbalance the resulting memory overexpression (see the scientific version for a discussion of these points). But long time before the chronic muscle strain entailed by IND causes pain symptoms, IND is here hypothesized to cause a very common, currently medically unexplained symptom, that can be found in all human beings after a certain age. Probably to the surprise of the reader, the hypothesized symptom consists in the very common facial wrinkles like “crow’s feet” and similar wrinkles that are mainly situated around the eyes and eyebrows. Such wrinkles are often treated by means of an injection of the famous botulinum toxin A (Botox) into the muscle band that lays below the wrinkles. Botox paralyzes the muscle, the muscle relaxes and no longer draws the overlaying skin together. Wrinkles reduce or disappear and in this way reveal their origin in chronic muscle strain. It is this muscle strain that is here hypothesized to be caused by aging induced IND. A google image search for ‘facial muscles’ and ‘botox before after’ gives a good impression of the treatment effect of Botox and of the relationship between the alignment of muscle bands and wrinkles. Note the quite obvious but nevertheless crucial and astonishing conclusions from this model for the origin of facial wrinkles: i) Facial wrinkles are caused by neuron demise, thus by brain damage (!). ii) In most cases, IND actually strains muscles in a two step procedure: First, IND releases emotional memories, and second, the released emotional memories chronically activate muscular reactions. Because of this
2
relationship to emotional memories, facial muscle tensions and the resulting wrinkles can be viewed as ‘psychosomatic’. iii) Consequently, and paradoxically, facial wrinkles can therefore be viewed as ‘psychosomatic’ symptoms that are caused by brain damage. In fact, countless medical phenomena are caused, triggered, or amplified by IND or similar mechanisms, see below. To be continued in part 2. Prospect: ● ●
●
● ●
●
● ● ●
A variant of the ‘Hocking hypothesis’ plays an even more important role. Together with IND, this effect causes ‘memory overexpression disorders‘ (MODs). In MODs, the kind and severity of symptoms caused by the overexpressed memories depends on three main factors: i) the amount, kind, and strength of the overexpressed memories; ii) the amount of the IND the memories were exposed to, determining the level of overexpression; iii) actual hormone and cytokine levels, modulating memory overexpression. The around 20 so-called ‘functional somatic syndromes’ (FSS), like fibromyalgia, tension headache, premenstrual syndrome, irritable bowel syndrome, etc, are MODs. The same is valid for the so-called ‘functional neurologic disorders’, and the ‘somatic symptoms disorders’ (formerly ‘somatoform disorders’). The concept of MODs is not entirely new. The posttraumatic stress disorder (PTSD) is well known to be an MOD. Consider the proverb ‘Every really new idea begins as a heresy’ and therefore don’t be shocked: not only facial wrinkles, but the whole process of aging and its symptoms is to a large extent an MOD. In the same way as facial wrinkles, aging symptoms as muscle shortening, muscle stiffness, muscle pain and even grey hair (see part 2) can therefore be viewed as partly ‘psychosomatic’. Surprisingly, research data shows that this view is also justified for aging symptoms in animals. Again don’t be shocked: The alcohol hangover is a transient MOD (alcohol damages interneurons) and therefore a ‘psychosomatic’ phenomenon (!). Therefore, to understand MOD symptoms, imagine having constantly the symptoms of your last heavy hangover. Often MOD symptoms are even worse and need to be treated with opioids. The same is valid for a part of the symptoms induced by other neurotoxic substances such as e.g. cancer chemotherapy agents. Again don’t be shocked: the amount of emotional memories that accumulate during a lifetime and propel MODs lays in the millions, in severe cases in the dozen of millions. A short proposition for MOD research (not intended for laymen): For MOD treatment, instead of memory reinhibition/extinction, depotentiation of associated dACC memories that sustain memory expression, is better (can take some time, even thousands of hours). How to do that? Answer the following question: What happens during crying (shedding tears) for a lost person, inhibition of the sadness or depotentiation of associated dACC memories? Is the sadness expressed during this process or does the sadness express itself? So what is the general process that leads to the depotentiation of dACC memories?
Part 2: Memory formation has an intrinsic effect of memory overexpression, entailing the same consequences as IND Consider the following mysterious phenomenon: When a rat receives a strong, but harmless strike on a muscle, a taut band of chronically tensioned muscle fibers evolves in the muscle. This band reduces in strength with the passage of time. But surprisingly, a residue remains for the rest of the animal's life (Huang et al., 2015). Often, a pressure sensitive muscle nodule forms, a so called trigger point (TP). Both phenomena, trigger points and taut bands (hereafter together abbreviated as “TPs”) do not only exist in animals, they are also ubiquitous in humans. Sometimes with a known origin, as e.g. resulting from misposture or from injury. But in most cases, no causal event can be identified.
3
The pain and the functional problems associated with TPs can be severe, up to chronic painful states as e.g. frozen shoulder syndrome or fibromyalgia. A related phenomenon, CRPS (complex regional pain syndrome), often even leads to suicide. Several competing hypotheses exist to explain TPs. But none of them are conclusive. In fact, nobody knows why TPs evolve and what is the mechanism which sustains them. One aspect of TPs is particularity stunning and motivates the here presented view on the phenomenon. A view with far-reaching and on the first sight somewhat frustrating implications. Consider that TPs entail an array of disadvantages, including muscle shortening, stiffness, and increased energy consumption in the chronically strained muscle fibres. As TPs are frequent in young individuals, thus in the time span of reproduction, the phenomenon should be under constant evolutionary pressure. Thus, in the course of more than 500 million years of muscle and nervous system evolution, genetic variations that reduce the prevalence of TPs should have been favoured, and the phenomenon should have disappeared. But, instead, it is still seen in all kind of mammals, e.g. dogs, horses, cats, rats, rabbits etc, and even in sharks. Is it conceivable that evolution did not find genetic variations that eliminate the TP problem? Take into account the stunning healing and recovery capacity of animal bodies after tissue injury, bone break, etc., and take into account the sophisticated mechanisms evolution invented for their realization. Taking all this into account, it is difficult to accept that evolution could not develop a remedy for the side effects of a harmless strike on a muscle. This contradiction suggests an interesting speculation: Evolution could have found a remedy for TPs, but actually did not use it because the elimination of the TP causing mechanisms would have entailed severe disadvantages that outweigh the advantages. Of what nature could this disadvantage be? One possible answer to this question is: TPs are an intrinsic side effect of a very important, indispensable and highly optimized mechanism. Changes in this mechanism, which would eliminate TPs, would therefore entail severe detrimental consequences, and therefore evolution dispensed with these changes. Here is a proposition for the possible nature of this mechanism: In 2010 and 2013, Marc Hocking, an Australian veterinarian, published a new TP hypothesis, which is to my best knowledge the first one that is in line with the above deliberations (Hocking, 2010, 2013). His hypothesis explains the TP phenomenon as a result of ancient memory systems that are located in the spinal cord and are evolutionarily preserved across many species. When triggered by a painful event, as e.g. a strike on a muscle, these memory systems provoke TPs as a side effect. In what way are the mechanisms proposed by Hocking in line with the above deliberations about evolutions role in the TP phenomenon? The fact that the memory systems mentioned by Hocking are ancient and evolutionarily preserved across species, actually means that these systems are highly optimized and deeply entrenched in the basic functioning of the spinal cord. This in turn indicates that these systems are indispensible and unchangeable, and therefore could not be adjusted by evolution to eliminate TPs. The EMD/IND/MOD hypothesis extends Hockings hypothesis to higher level memory systems on the basis of two crucial research results on memory systems in humans and animals: ● During sleep, past experiences are in a highly intelligent way reprocessed, thereby extracting and memorizing the gist of the experience. In parallel, unimportant things are deliberately forgotten, e.g. by pruning nerve contacts (synapses) that were created during past experiences. ● Painful experiences (physical as well as emotional) are never forgotten and will be memorized for the whole lifetime of an individual (this is known as at least for conditioned fear memories in animals). Selective forgetting is necessary, because otherwise problems arise due to overuse of memory systems. Such problems are seen for instance in people that can remember large parts of their lives in a video-like style (people with HSAM, highly superior autobiographic memory). Selective, strong remembering of painful events is likewise necessary, because it should never happen to an animal, even years or decades after a painful and potentially dangerous event, that the pertaining context is forgotten and a new encounter with a similar event is naively experienced. In fact, one part of the gist of a painful experience is “don’t forget it, and remember every detail, in order to improve future dealings with similar situations”, so point ii) is actually a necessary consequence of point i). [But note that it is necessary to ‘forget’ a painful event after it turned out to be no longer
4
important for the actual life situation. For this purpose nature uses a kind of quasi-forgetting, the so-called ‘extinction’. Please see the main text for further explanations.] The crucial aspect of these results of neuroscientific research is the following: In order to grasp the gist of a painful experience, not only the context, i.e. location, environmental characteristics, etc, has to be remembered. Additionally, in order to improve future reactions to similar situations, the whole body reaction of the animal has likewise to be remembered. Put simply, in order to optimize a second encounter of a pain trigger, obviously the body reaction during the first encounter has to be taken into account. Even if the first encounter took place years or decades ago. And every little detail has to be remembered, as it is not predictable which detail will turn out to be the decisive one for survival. Concerning the harmless strike a rat receives on a muscle, the rat has therefore to remember every little detail of the whole reaction to the event. The surprise, the pain, the environmental context, and the whole emotional, muscular and neuroendocrinal reaction over the whole time span the reaction takes place. Thus a ‘procedural memory’ comparable to a video-recording of the whole event takes place. In the first place, this proceeding seems not to exhibit any problematic character. However, on the level of neurons and synapses, a memory formation strengthens existing synapses and creates new ones. Crucially, the stronger the muscular and emotional reactions are, that have to be memorized, the stronger the involved synapses are strengthened. As the event to memorize endures for at least for some seconds, quite a lot has to be memorized, and certainly, millions of synapses are involved. Now, when considering that a strengthened synapse transmits an incoming neural signal in a stronger way to the target neuron, a possible mechanism for TP formation can be devised quite easily. First consider, that a normal ‘noise’ of neural activity constantly leaves the memory systems of the brain and travels towards the target systems, e.g. to the muscles. This noise originates from the baseline activity of the CNS that permanently passes the memory systems of the brain. Crucially, the normal noise increases after memory formation because the synapses that were strengthened during memory formation now transmit the baseline activity of the CNS in a stronger way to the target regions. To a certain extent, the newly stored memory ‘leaks’ through the memory system (but see the “notes” section below). This has in fact the same consequences as those resulting from interneuron demise (IND), described in part 1: a slight, permanent overexpression of memorized emotional and muscular reactions. These reactions finally reach the sympathetic and the muscles and exert there the same effects as IND, i.e. chronic muscle fibre tension and chronic activation of the sympathetic. When examining in more detail the concrete example of a strike on a muscle, notice that this event is followed by a strong contractile muscular reaction, that involves large parts of the skeleton musculature, but is particularly strong in the muscle where the strike takes place. As argued above, this muscular reaction has to be memorized in detail, in order to optimize future reactions to similar events. And as argued, this memory is constantly overexpressed after memory formation. And naturally, a permanently overexpressed memory of a contractile muscular reaction manifests as a permanent muscle contraction. The strongest overexpression takes place at the location of the strongest muscular reaction to the strike. And in most (but not all) cases, this will be the location of the strike. And there, the particularly strong memory overexpression could exert such a strong contractile effect that it possibly manifests as a taut band. This deliberation motivates a simple, but nevertheless astonishing conclusion: The taut band that forms after a painful event to a muscle, could be nothing else than a slight, permanent overexpression of the memories of the muscular reactions that were provoked by the painful event. [Please note, that both mechanisms on which TPs develop according to the presented deliberations, cannot be eliminated by evolution. The first mechanism, memory overexpression, cannot be eliminated by evolution, because it is an intrinsic property of neuronal network based memory systems. Dispensing with the second mechanism, the permanent remembering of painful events, certainly would entail severe deleterious effects to an animal, thus evolution could also not eliminate this mechanism. The presented model of TP origin is
5
therefore in line with the above developed evolutionary argument that regards TPs as a side effect of evolutionary old, highly optimized and indispensable (i.e. by evolution not eliminable) biological mechanisms.] When considering that painful events mean not only physically but also emotionally painful events and when considering that overexpressed emotional memories not only entail muscle fibre strain, but also entail mood changes and also activate the sympathetic, then a wide variety of phenomena can be explained. Here is a short sketch of some lines of thought: ●
●
●
●
●
The physical symptoms of the functional somatic syndromes (FSS) and the somatic symptom disorders (SSD, formerly somatoform disorders) can be explained by memory overexpression towards the muscles and the sympathetic. The often accompanying neurological and mood symptoms can be explained by memory overexpression toward higher brain regions. The crucial feature of the somatic symptom disorders, an abnormal suffering that seems inappropriate with respect to diagnostic examination results, is quite naturally explained by the fact that emotional and physical pain are processed in the same brain region (dACC). Consider first that the physical suffering induced by memory overexpression can already be horrible. The pain caused by a single, strongly overstrained muscle fibre can already be severe enough to be life threatening if not treated. Certainly, most SSD patients do not exhibit such strong pain, the example only aims to demonstrate that in many cases the pure physical suffering can already be substantial. Now remember that each emotional memory is only slightly overexpressed and that therefore a high amount of weak painful emotional memories (or a low amount of very intense ones) needs to be overexpressed in order to cause painful muscle strain. As a result, in addition to the suffering from physical pain, the overexpressed emotional memories induce a high amount of weak (or a low amount of strong) suffering in the dACC and thereby strongly amplify the physical suffering. The examining physician of course cannot diagnose the presence of this amplifying mechanism and perceives the characteristics of SSD, an inappropriate suffering with respect to the examination results. Because the presented mechanism can also amplify the suffering from medically explained symptoms, the mechanism is in line with the new SSD feature introduced in DSM-5, that SSD symptoms do not need to be medically unexplained. Many FSS patients report traumatic life events (causing very strong, painful emotional memories), or report emotional abuse or neglect (causing high amounts of somewhat weaker painful emotional memories). The emotional memories acquired in these ways could cause, by means of overexpression, the symptoms of FSS, and therefore these reports of the FSS patients support the view of the FSS as MODs. As the muscular reaction to a painful event may involve large parts of the skeleton musculature, the effects of subsequent memory overexpression should not only provoke TPs but also increase the general muscle tonus in the affected person. This prediction is in line with research data showing that a higher amount of TPs in persons is associated with an increased general muscle tonus (measured e.g. in the calf muscle).
Some notes: ● The evolutionary argument and the argument that memory formation leads on the basis of synaptic strengthening to memory overexpression (leakage), are currently on an informal level. In a future text version I’ll develop both lines of thought on a scientific level. ● The baseline activity of the CNS, that is here hypothesized to ‘leak’ through the memory system and to cause thereby memory overexpression, results from normal neuronal ‘noise’ and from the permanent transmission of sensory input signals to memory systems, where these signals are checked whether important reactions need to be elicited (this process takes place even during sleep). To be continued in part 3. Prospect:
6
●
●
●
●
●
The two points mentioned in the prospect of part 2, the view of the alcohol hangover as an MOD, and the assumption that millions or even dozens of millions of emotional memories can sustain MODs, are developed on a scientific level in the main text. Posttraumatic stress disorder (PTSD) is possibly an MOD. Current therapeutic approaches focus on a process called ‘extinction’ in order to inhibit (i.e. block) the traumatic memories. Two severe problems arise from this method: i) blocked memories can spontaneously reactivate, and PTSD symptoms return. Extinction therapy has to be repeated. This is frustrating, time consuming, and expensive. ii) If an MOD like fibromyalgia is caused by hundreds of traumatic events, e.g. experienced during childhood, then theoretically hundreds of extinction sessions are necessary to inhibit overexpressed memories. This is very difficult to realize, too time consuming, and expensive. These problems motivate research for a more effective method. Crucially, research on fear conditioning and extinction shows that, surprisingly, the activation of an emotional fear memory does not depend on its main storage site, the so-called ‘amygdala’. The activation of a fear memory is rather guided by activity of the brain region (dACC) that stores the suffering associated with an emotional memory. In order to understand the role of this brain region, note that in case of severe, intractable emotional or physical pain, this brain region is surgically destroyed, which leads to pain relief and sometimes to a complete loss of suffering, even though the pain is experienced as before the operation (!). Theoretically, for neuro-psychotherapeutic approaches, instead of extinction of painful memories, a depotentiation of the suffering part associated with a painful memory, should be more effective. Reinstatement of e.g. a traumatic memory as it can happen after an extinction based therapy, can no more happen after a ‘depotentiation’ therapy. And every suffering part of a painful memory that was depotentiated in such a way, should reduce the overexpression of the whole painful memory and thereby permanently reduce MOD symptoms. Neuroscience should therefore examine whether the proposed depotentiation is theoretically possible, and whether it is practicable in real life. For a proposition how to perform dACC memory depotentiation see home.arcor.de/spt (Sorry, I could not yet tackle an english version, therefore only this quite extensive German version exists. The main texts are “Heilungsbericht” and “Online-Buch”.).
References 1. 2. 3. 4.
Hocking, M. J. (2010). Trigger points and central modulation—a new hypothesis. J ournal of Musculoskeletal Pain, 18(2), 186-203. Hocking, M. J. (2013). Exploring the central modulation hypothesis: do ancient memory mechanisms underlie the pathophysiology of trigger points?. Current pain and headache reports, 17(7), 347. Huang, Q. M., Lv, J. J., Ruanshi, Q. M., & Liu, L. (2015). Spontaneous electrical activities at myofascial trigger points at different stages of recovery from injury in a rat model. Acupuncture in Medicine, 33( 4), 319-324. Ciocchi, S., Herry, C., Grenier, F., Wolff, S. B., Letzkus, J. J., Vlachos, I., ... & Müller, C. (2010). Encoding of conditioned fear in central amygdala inhibitory circuits. Nature, 468(7321), 277-282.
7
