Good afternoon, everybody, and welcome to session 1501, Moving the Needle on Myofascial Pain Syndrome, Integrated Advancements in Clinical and Pain Strategies, Pain Sciences with Management Strategies. My name is Jay Shah. Before I continue, I just was asked to read this statement. We are aware that due to the high volume of CME, in high participation, there is a lag in transferring your participation data to the online learning portal for certain sessions. Rest assured that your participation in all sessions is recorded. We are currently working on the back end to speed up the data transfer. The Academy will send a notification to all registrants once the process is updated and all data has been transferred. It's a pleasure to be here, and I thank the Academy for inviting us, my colleagues and I, John Serbel and Antonio Stecco, to do this session. And what we hope to show you is that since Trevelyn Simon's original studies and publications, we've made considerable advancements in our understanding of myofascial pain syndrome. I have nothing to disclose except that I'm thrilled to be a part of this multidisciplinary team led by Dr. Lynn Gerber, and we're a multi-institutional and multidisciplinary team, and two of my colleagues, as I mentioned, will be lecturing in this session with me. We affectionately call ourselves the myofascianatos. So what is myofascial pain? As you know, this is a common and often overlooked pain condition that may be acute, but more commonly chronic, involves the muscle and surrounding connective tissue, such as the fascia. Symptomatically, patients describe this aching, deep, diffuse, and difficult to localize pain, and it's often referred some distance away from the trigger point, as you can see in this example of two distinct trigger points in the sternocleidomastoid muscle. According to Trevelyn Simon's, trigger points are central to the diagnosis of the syndrome. However, trigger points are commonly found in asymptomatic individuals, the so-called latent trigger points. As you know, latent trigger points are commonly found in pain patients with active trigger points, and some nodules are not tender at all. So how do we explain that? And historically, traditionally, myofascial pain was considered more of an acute or local musculoskeletal pain, involving primarily peripheral sensitization. So when a trigger point became active and was associated with spontaneous pain, most clinicians thought of it as mostly a peripheral problem, self-limiting, and with a little tincture of time and some local treatment, the pain would subside whether the trigger point went away or not. Now, central sensitization is signified, of course, by chronic pain, which is associated with disuse, depression, disability, and central sensitization syndrome is what it's called now. So what I hope to show you is that there's actually a lot of overlap between what is considered this more peripheral local problem and chronic central pain. And so a more advanced, recent understanding is that trigger points are a source of persistent bombardment into the dorsal horn. And by doing that, it will lead to further sensitization of the horn. And as you know, there is descending non-modulatory mechanisms, which will have an effect on the dorsal horn. And this will lead to either amplification of the receptive field or decrease in the receptive field, depending upon the circumstances that are happening both peripherally, centrally, and systemically. So we understand that there's a spectrum of sensitization. Now, we also know that the limbic system is preferentially activated by any source of persistent bombardment from muscle tissue. And it doesn't care how it's activated, whether it's through emotional stimuli or physical stimuli, somatic, visceral, etc. The patient will experience fear, anxiety, stress, etc. And as we know, there is this dynamic modulation occurring between the lamina and the spinal cord and these higher brain centers. There's also a critical structure in the rostral ventral medulla where we have these on and off cells. And this is a supraspinal gate that can either facilitate information or inhibit it. So if you have a circumstance where the on cells are dominating, this will lead to superspinal sensitization of the spinal cord, such that now even innocuous inputs coming into the dorsal horn can be perceived as painful. And this can allow us to understand how the receptive field of pain can start to expand. So why do I say all this? Because NIDAM has demonstrated in two elegant studies that patients with upper trapezius myofascial pain syndrome have increased limbic system activity. And they had decreased activity in the contralateral dorsal hippocampus, that part of the brain that's involved in down-regulating stress. So this shows us that there is this connection between these trigger points and the central nervous system. So we did a study led by Dr. Gerber back in 2015, where we looked at a cohort of subjects with chronic cervical pain, the trigger point, and those healthy subjects without. And we showed that a combination of soft tissue palpation, cervical range of motion, algometry, and self-reports could successfully distinguish subjects with cervical pain from those without. And we showed that compared to the no pain group, the group with cervical pain, secondary to active trigger points, had a lower PPT, they had poorer health status, more depression, fatigue, confusion, and mood disturbance, greater disability, more restriction in side bending, more latent trigger points, and more sleep disruption. So take a look at number three. What does that tell you? Limbic system dysfunction. So we concluded that a so-called local pain syndrome has significant associations with mood, health-related quality of life, and function. So as you know, trigger points are identified by physical examination and careful palpation of a taut band, and then upon palpating that taut band, reproducing the patient's symptomatic pain over that hyper irritable area. Now, we, of course, are looking not just at the symptoms, but we want to seek objective measures and reproducible findings. So our team uses pain pressure threshold as a way of clinically measuring discrete local candidates and as an outcome measure in treatment trials. And as you know, when you compare latent trigger points to active trigger points, we see that active trigger points are significantly more tender, and an active trigger point is more tender than a non-trigger point in that taut band, which is more tender than the normal muscle outside. And we see the same relationships in muscles harboring latent trigger points. So again, we see the spectrum of sensitization. What could be the underlying reason for this? Well, in 2005 and 2008, we did microdialysis studies simply using Trevell and Simon's criteria with digital palpation, and we found and demonstrated and confirmed that objective biochemical data validate the diagnostic distinction that clinicians make among active, latent, and uninvolved muscle. But interestingly, the unique biochemical milieu of substances that we identified, such as inflammatory mediators, neuropeptides, catecholamines, and cytokines are fascinating because they're involved with inflammation, neurogenic sensitization, persistent pain, and intracellular signaling. So Dr. Mensah has also demonstrated that, and I quote him here, that trigger points are not merely a perfect phenomenon. The input from these active trigger points leads to hyperacidability of central neurons that manifests in allodynia, hyperalgesia, and pain referral. And why is this? Because of upregulation of substance P and glutamate and opening up NDA receptors, and that these central changes are mainly based on an increase in the synaptic efficacy of central connections that are being induced by that nociceptive input. So if we put it together, we can take a look now and understand that when we identify an active trigger point, we're finding a coterie of substances that has this inflammatory profile, and each of these biochemicals can bind to the local nociceptor, sending increased signals near the dorsal horn. Just prior to the dorsal horn is the dorsal ganglion, which is releasing neuropeptides in two directions. Orthodromically, it's going to cause more and more sensitization, right? Antidromically, right, you're going to see increased release of substance P and CGRP down the nerve segment into the peripheral tissue. And how do we know this is relevant in active trigger points? Because it's elevated there. But please understand that it not only sensitizes that muscle, but anything that that nerve innervates, so the myotome, sclerotome, and dermatome. And this will lead to expansion of the receptive field of pain. And as we discussed earlier, there's dynamic modulation occurring here. So we can start to look at this myofascial pain syndrome as a type of neuromusculoskeletal pain. Neuro because the nervous system is clearly involved, as Dr. Serbell is going to discuss in much more detail. So we know that neurogenic inflammation occurs in neuropathic pain, osteoarthritis, inflammatory pain, and complex regional pain syndrome. And what's fascinating about it, of course, is that as it's increased, it can lead to more and more sensitization and pain in the peripheral tissue for sure. So here are some key questions to ask. What's the role of the muscle in this syndrome? What's the role of the trigger point? What causes activation of a trigger point? And is the trigger point the primary pathology or a secondary physical sign? What's the role of the nervous system and brain, especially when it becomes painful? So what are the changes that are occurring in the nociceptor along the peripheral nerve, into the spinal cord, into the brain? And Dr. Stetko is going to talk in exquisite detail about the fascia and the role the fascia can play when it becomes dysfunctional. So these are all critical questions to ask moving forward. Let's focus on the muscle. So we know that muscle pain is due mainly to the binding of three biochemicals, bradykinin, prostaglandin, serotonin. And also we have receptors for acidic pH, the vanilloid receptors. And Dr. Mensah has shown that the bradykinin receptor actually undergoes a conformational change from B2 to B1. So this is important because this is associated with a lower refractory period. So this area becomes more sensitized. Now, this is also associated with more neurogenic inflammation. So you start to see that the condition is now developing for more local tenderness. Now, he's also shown that when you have elevated levels of bradykinin and serotonin, it leads to the upregulation of receptors for protons. So this area can become even more sensitized. So again, this is critical to understand moving forward. So let's now look at the spinal mechanisms underlying CSENS facilitation and somatovisceral interactions. So Mensah has demonstrated that any source of muscle input will do what? It will lead to sensitization, and that sensitization can spread extra segmentally, such that what we can see now is this phenomenon where sensitization is spreading up and down the spinal cord, quite remote from the original source of input. So this is important to understand now as it relates to not just trigger points, but any source of persistent bombardment. But the bottom line is the sensitization occurring centrally, and you have increased neurogenic inflammation, as we said, and as we talked about this extra segmental sensitization. So we can appreciate then that a patient can develop a trigger point, a quadratus lumborum muscle on one side. With persistent bombardment, you'll see this extra segmental spread, contralateral spread of inflammation in the cord, and mirror image pain on the opposite side. But please understand that this information can also spread extra segmentally, so the patient can develop pain here and on the opposite side as well, depending on which segments are affected and whether those segments have loss of inhibition due to previous musculoskeletal visceral conditions. So with persistent bombardment, we also see besides CSENS, we see dysfunctional loss of inhibitory neurons, creation of facilitated segments, and this is all due to what's been called activity-dependent neuroplasticity. So if we look at to our osteopathic colleagues, they have shown us very clearly, and now we have the scientific evidence to support that with persistent bombardment, we see ventral horn outflow, lateral horn outflow, which will activate the autonomic ganglia, and the phenomenon of a dorsal root reflex, which will increase the neurogenic inflammation and tenderness in the tissue. So putting it together, here you can see input coming in from a joint, leading to activation of the anterior horn, and that will affect the myotome of that segment, L3-L4. It'll also affect the dermatome, so if one were to do a pinch and roll test, either paraspinally or segmentally across the tissue, or one were to use a pinwheel to check for hyperalgesia, one would see signs of sensitization. And the sclerotome can also be effective as well, such as bursa, ligaments, tendons, etc. Now, let's remember also, it's not just the joint, but the source of bombardment could be the muscle, it could be the viscera, and as we know, there are these wide dynamic range neurons, which make connections among these structures, allowing the spread of excitation. So we've also understood now, of course, that even if you eliminate the original source of bombardment, once the tissue, once the neuron is sensitized, this sensitization can persist, and so that's why we need to address this type of pain as a segmental dysfunction and treat the segment, not just the peripheral source, which could be the trigger point. So putting it together, you can see that persistent bombardment from the joint can affect, as we said, the lateral ventral horn, increase the dorsal root reflex, producing more neurogenic inflammation, and this can also affect the opposite side, and now the manifestations can then be in the muscle and the viscera, and either one of these could also serve as a source of the bombardment. So how do we now explain expansion of the receptive field of pain? So this is quite fascinating. Dr. Mensah and his group did a study where what they did here was you see a neuron connected to a receptive field. So what the black color is meant to signify is that this neuron only responds to noxious pressure within this local area. So noxious pressure outside this area, another neuron will be activated, but not this neuron, and if you apply light pressure or light touch here, this neuron will not be activated. So what they then did was they injected bradykinin into the tibialis anterior, and what did they observe? Within five minutes, this neuron, which only has a connection to this receptive field, can now be excited by receptive fields here and here, and he was very intrigued by this, and what he discovered was that yes, we do have so-called effective connections from neurons to receptive field. So this is that original neuron I showed you to its receptive field. Here's a neuron for this receptive field here, and we also have so-called latent or ineffective connections. How do you turn a latent or ineffective connection into an effective one? A powerful nociceptive bombardment, in this case injection of bradykinin. Now let's remember that this persistent bombardment, as we said, will lead to increased release of glutamate substance B. These substances, particularly the neuropeptides, can diffuse, and they can activate a neighboring neuron via this previously ineffective synapse. So now what can happen is this neuron can now be reached from that more remote receptive field. So now what happens is that gets activated, but what was even more intriguing, and that I'll show you more clinically relevant, is that in 15 minutes the original receptive field now begins to respond to even innocuous pressure. It becomes sensitized. Okay, and that's all that took us 15 minutes. So this can help us understand alidinia, hyperalgesia, and then of course what's most distressing to our patients is expansion of the receptive field of pain. So Dr. Mensah also emphasizes that even if you have two structures, such as the sacroiliac joint and the gastroxoleus or the Achilles tendon, that are very far apart structurally, there are mechanisms by which these two can communicate that are independent of, say, let's say a radiculopathy or something like that. Now he applies these considerations and looks at one of these classic trigger point referral patterns in the Travell and Simons manual. So let's say you have a patient that has first developed pain in their lower extremity in the gastroxoleus area, and then they've developed pain in their Achilles tendon, and then develop pain in the sacroiliac joint. So of course we want to rule out a radiculopathy, SI joint dysfunction, etc. Let's say we rule those out on a physical exam. But we see that there is a trigger point here that does refer pain in both those locations. What could be happening here? Well, so applying these considerations, Mensah makes this argument in terms of the model. He says that this trigger point could be the original source of bombardment, could be an active trigger point in the gastroxoleus, which is now sensitizing the L5-S1 segment. And as you can see here, this has ineffective connections to neighboring neurons. I'm showing the neurons for the SI joint initially in purple because the patient has not yet developed pain at this location. But because of this persistent bombardment and sensitization of those segments, now you have these ineffective synapses, which can become effective ones. And once they become effective ones, now that neighboring neuron can be activated. And the patient can start to complain of pain, even though the tissue is normal, the tissue and joint are normal, and there's no local, no susceptive activity going on here. So let's say you do a local treatment. Let's say you do a dry needling treatment, and you deactivate, but this is to pretend this is in the gastroxoleus, in the upper trapezius. You deactivate the gastroxoleus trigger point. Great. You've now turned that off as a source of bombardment. However, we still have a sensitized segment here, S2-S3, right? So how would you know it's sensitized? Because you could repeat the exam, and you would still see signs of segmental sensitization. And of course, this activity could have spread to L3-L4 segments, in which case it could involve the knee joint. It could also spread to the contralateral side as well. Now, this is a simple somatosomatic interaction, but this could also be a somatovisceral, such that now the patient could start to complain of pain, and a female patient could complain of pain in the endometrial tissue, for example. Or it could be in the pelvic floor musculature. So you start to understand now the potential applications of this model. So I just want to emphasize again what an amazing contribution Trevella and Simon's made to our specialty. This quote is from Dr. Simon. Since no medical specialty claims skeletal muscle as its organ, it's often overlooked. This was his sort of, those of you who heard Dr. Simon's lecture over the years, this was his sort of call to arms, to physiatrists, to embrace the muscle and integrate the muscle in our differential diagnosis of chronic pain syndromes. And also we owe so much to Janet Trevella, who published this paper called the Myofascial Genesis of Pain in 1952. And of course, she was ridiculed and the whole thing was poo-pooed in terms of a model of pain. But what I was fascinated by was her, the subtitle, Trigger Areas in Myofascial Structures Can Maintain Pain Cycles Indefinitely. So she knew nothing about neurogenic inflammation, central sensitization, wide dynamic range neurons, ineffective synapses, etc. It was all based on good clinical observation. And that was the key. So what our team is doing, as you will learn from my next two speakers, was using clinical and animal model research, biomarkers, and imaging to come up with more mechanism-based diagnostic criteria and identify treatment targets and objective outcome measures. So now I thank you very much for your attention. I will turn it over to my colleague, Dr. Serval. Share screen, just trying to get the screen up. Sorry for the technical difficulty. Can we have my presentation? Thank you, Dr. Shah, it's indeed a pleasure to be able to share some of my work at the University of Guelph regarding the mechanisms of myofascial pain. And so I want to pick up from Dr. Shah's concepts that he actually initiated here. The main problem in the field right now is that the definition and the pathogenesis of myofascial pain is still not fully understood. And a core disagreement still persists, as Dr. Shah mentioned, about whether myofascial pain is in fact a disease process or a collection of signs and symptoms, as we know as a syndrome. And we can extend this definition, and the problem really is that the integration of myofascial trigger points in this model actually can broaden this problem, is that disagreement still persists about whether the trigger point itself is the primary pathology in myofascial pain or a secondary physical sign. And so the theories of myofascial pain, the integrated hypothesis is one of the leading theories of myofascial pain, and the patient usually gives a history and onset of pain, whereby the activation of the trigger point is clinically associated with either an acute or chronic muscle overload injury. However, the integrated hypothesis doesn't align with many clinical observations. And the first being is that the trigger point itself is associated with a number of somatic and or visceral conditions in the absence of muscle injury. In the black here, we can see several concepts, several terms, osteoarthritis, hello? Okay, however, the integrated hypothesis does not align with many clinical observations, the first of which is that the trigger point itself is associated with a number of somatic and or visceral conditions in the absence of muscle injury. For example, here in black, I have several somatic conditions, osteoarthritis, migraine, and fibromyalgia that have been clinically associated with trigger points, but in the blue here, we see a growing number of clinical non-musculoskeletal or visceral conditions that have been associated with the clinical manifestation of trigger points, including psychological stress, chronic pelvic pain, and so on. And so these are in the absence of injury. Similarly, the trigger point itself, for those of you who have treated it manually, the trigger point does not in fact respond like an injured locus. For example, pressure on a trigger point does not induce a withdrawal reflex typically evoked by a local injury. Patients will also define these as good pain and would actually ask for more pressure during the manual therapy, which suggests that there isn't a local injury here, that perhaps there's some other mechanism involved. So at this point, my focus was redirected in my research program to ask the question of what other pathophysiologic mechanisms may be responsible then for the clinical manifestation of trigger points. And so a key study that we ran into early on in our investigation was a USANOVA study back in 2007 that discussed the idea of visceral cross-sensitization. And so what they did was they used an animal model of experimentally induced colitis. And within three days, they observed an increased inflammatory response in the bladder. They did not evoke an injury in the bladder, but they attributed this inflammatory response to a neurogenic inflammation that was triggered by central sensitization. And so we expanded this concept in our lab to ask the question of whether the primary pathology, does it really matter where the primary pathology resides? Can it reside in a somatic or a visceral tissue? And can this response, this neurogenic inflammatory response occur in both somatic and or visceral tissues? So in other words, is there a cross-sensitization mechanism here? And then by extension, could the myofascial trigger point then be the physiologic expression of neurogenic inflammation within somatic muscle tissue? And so we presented this theory. We published this back in 2010, the neurogenic hypothesis, which states that chronic myofascial pain then is the clinical manifestation of neurogenic inflammation subsequent to central sensitization as Dr. Shah just alluded to. And this is evoked by nociceptive inputs arising from a distinct primary pathology that resides within the common neurosegmental field of the affected muscle. So I outlined this mechanism here. If we introduce a primary pathology, we have two convergent pathways here, C-fibers, unmyelinated fibers. If we introduce a primary pathology here, be it somatic and or visceral, we evoke an orthodromic barrage of pain signals, which releases substance P and or any other pro-inflammatory neuropeptides into the dorsal horn to sensitize the segment. If this is allowed to persist, we evoke an antedromic response via this primary afferent depolarization mechanism and dorsal root reflexes. This effectively releases pro-inflammatory neuropeptides, predominantly substance P and CGRP into the peripheral tissues, creating a neurogenically mediated inflammatory response. And this was the mechanism that the Ustinova study highlighted. And so by extension, then, the neurogenic hypothesis also suggests that through these interneuronal pathways, we can also activate the alpha motor neuron pool. And so it's the coexistence of these two pathways, then, that creates the biological plausibility for the myofascial trigger point region. And using this model, we can now begin to explain some of those clinical observations that we couldn't explain using the integrated hypothesis. So the clinical relevance here is quite important to clinicians because I put both of the theories here in apposition to one another. The integrated hypothesis suggests that the myofascial trigger point resides within this region of primary hyperalgesia and effectively is the cause of MPS, whereas the neurogenic hypothesis suggests that the trigger point resides within this region of secondary hyperalgesia, thereby representing an effect. And so again, this is critical to a clinician because it, again, defines where we look for the primary pathology. And so again, if this mechanism is true, then, we should see trigger points manifesting in segmental or regional patterns. And so this kind of theoretical framework basically informed my research program. And so the next question that we pursued was really, is there a common primary pathology that may be responsible for driving the pathophysiology of myofascial pain? And so again, knowing what we know, and Dr. Shah alluded to this quite elegantly, we know that the primary pathology needs to be persistent. So transient pathologies or injuries do not qualify or are not characteristic of persistent sensitization. So one of the most common conditions that we treat clinically that evokes persistent nociceptive inputs is osteoarthritis. So armed with the hypothesis, we moved into an animal model to examine some of these mechanisms. And so the first was that spine osteoarthritis may be a common primary pathology that drives the pathophysiology in clinical manifestation of chronic myofascial pain via these neurogenic mechanisms. And so what we did was we took a population of geriatric rats, an animal model, and then we looked for the association between naturally occurring lumbar spine OA at the L3, L5 levels in the rats, and examined for neurogenic inflammatory responses within the neurosegmentally linked quadriceps muscle. We published this recently in 2019. And what we saw was very interesting. In the aging rats or the aged population, we saw significant increases in substance P relative to young, healthy control animals. Similarly, we looked, and I'll speak to this a bit more later, but we looked for a pro-inflammatory biomarker downstream of substance P known as PAR2, again, significant increases in this aging population that were not observed in the young animals. And so this was an association study. We then decided to look at the causal relationship between spine OA and substance P expression within these neurosegmentally linked muscles. And so this study we experimentally induced using the surgical compression model for set compression at the L4 to L6 levels in the rat lumbar spine. And then we examined for the expression of substance P and pro-inflammatory biomarkers within the neurosegmentally linked quadriceps and used the biceps brachii as a control, as a non-segmental control. And we compared the expression of substance P between the two muscles. So any difference or any increase in the quadriceps substance P levels would necessarily suggest a very robust segmental mechanism. And so that's, in fact, what we found. Substance P in the quadriceps muscle was significantly increased bilaterally in the neurosegmentally linked quadriceps, but not within the biceps brachii, once again, demonstrating a neurosegmental neurogenic inflammatory response. And we know that this is important. Dr. Shaw has demonstrated increases in substance P in myofascial pain patients. And we know this is very important simply because of the powerful vasodilatory and pro-inflammatory mechanisms of substance P through its direct actions on immune cells. Similarly, proteinase-activated receptor 2, or PAR-2, is a well-established biomarker of inflammation. And we examined for this as well downstream of substance P. And once again, we saw increases at the neurosegmentally linked quadriceps bilaterally, but not in the biceps brachii. Once again, demonstrating a pro-inflammatory response downstream of substance P via these neurosegmental pathways. And so this is essentially a couple of studies that sort of highlights us moving into an animal model to understand the causal relationships. What are the clinical take-home messages? I think there's important insights here, both in the diagnosis and management of myofascial pain. Firstly, we know that we can treat peripherally, we can treat the myofascial trigger point to deactivate a segment through gating mechanisms. Activation of myofascial trigger points selectively activates large myelinated fibers that gate pain input from those segments. But at the same time, if we find persistent trigger points within these myotomes, we must also, as clinicians, be looking to rule out any primary pathologies residing within the neurosegmentally linked tissues. And very often we can identify both clinical and subclinical pathologies. So again, a very important concept to sort of adopt into our clinical practice is both treatment of the peripheral manifestation of sensitization, but also making sure that we rule out any primary pathologies that may be residing within the neuromeric field of that myotome. And with that, I want to thank you for your attention, apologize for the technical difficulties. I'll pass this along to Dr. Antonio Secco, who will discuss the role of the fascia in myofascial pain. Let me make sure that I have it. OK. So we are going to talk about the fascia component in myofascial pain syndrome. So what is fascia? Why fascia can be a critical component in myofascial pain? Fascia is a multiple-layer structure of connected tissue. So we published an article explaining that the fascia is not an irregular mesh like people thought in the past, but is a multiple-layer structure made by collagen fiber type 1, type 3. Normally, we have two or three layers. So if we try to see, for instance, like a leg, this is a peak, like it's a fresh sample, you see how each single structure glides. You see the gastrocnemius. You see the soleus. What it means? It means that between each muscle, there is two or more layers, and between the layers, there is loose connective tissue that allows the gliding. You can see, as a fresh sample, everything glides nicely, smoothly. If you try to do a dissection in an embalmed cadaver with formaldehyde, everything is stuck. It's rigid. It's like a piece of wood. Why is that? Why is such difference? Because the quality of the extracellular matrix change. If you try to do a dissection in a TINEL method, typical way to embalm, in particular in Austria, UK, in Australia, you can have like a body that have two years and still is extremely hypermobile. If you do a dissection in formaldehyde, the body is extremely rigid. What is the difference? The difference is due to the quality of the loose connective tissue. Formaldehyde make dry up and make very stiff, very viscous, the extracellular matrix. So the lubricant between layer. The TINEL method preserve the loose connective tissue between the layer. So the body, even if it's two years, is still hypermobile. If you try to take a look, for instance, at the intermuscular septa, you see the intermuscular septa have multiple layer, not just two or three like a normal deep fascia, muscular fascia, have seven, eight. And so you see how much gliding is possible. What is the function of this structure? To separate the deep compartment from the superficial compartment, at the same time to connect what is proximate from what is distally. So the fascia system is critical to allow the transmission force, but we will see also to allow coordination. But we don't have to forget that between the fascia layer, we have extracellular matrix, in particular, protoglycan and hyaluronan, hyaluronan or hyaluronic acid that is the chief component that is the really lubricant of the extracellular matrix. So who produced this substance? Well, we have published an article in 2016. Our group show up in the fascia. We have a specific cell, the fascia sites, like we wanted to call, like a sort of fiberglass that produce hyaluronan. And you see this cell have all around, all this fluid around is all hyaluronan. So inside the fascia, you have fibroblasts that produce collagen type one, type three, and fascia sites that produce hyaluronan, because we need both the component. We need the layer of collagen fiber, as well we need the lubricant that allow the gliding between and between the layer. So what can happen? It can happen that if you immobilize someone, you keep produce hyaluronan, but this hyaluronan, it can have a retention. It can accumulate in the endomysium, perimysium, epimysium, which in the fascia and the muscle. So in all the interface. So this is, at the beginning, it doesn't seem a bad situation or doesn't seem to have something wrong with the physiology of our body. In reality, there is something wrong that can happen because the hyaluronan is a non-Newtonian fluid. So if you increase the concentration of hyaluronan in a spread surface, so forget about capsule B compartment, but think about the tiny space between the fascia layer. Well, if you increase too much the concentration of the hyaluronan, hyaluronan can aggregate and you have an exponential increase of the viscosity. What it means? It means that the hyaluronan aggregate, this will change the behavior of the excess aromatics, making everything more viscous. So this aggregation, this reaction is well known. So we have an article since 2006, basically. We published this article in 2016 to try to explain better to the clinician this dramatic reaction. So if you have an exceed amount of hyaluronan in a spread surface, this can aggregate, can generate what the people call macromolecular crowding. This aggregation will increase the viscosity and consequently we have less lubrification, less tissues gliding. So that can explain easily why you have stiffness. The typical stiffness that people has, that they wake up in the morning, they feel stiff, they do some step and then the stiffness go away. Or you are sitting for a while and then you start to feel stiff when you wake up. But maybe after a while, the stiffness go away. But stiffness, it can also be related with pain. Why is that? Because fascia is very well innervated. We published an article, I didn't put right here, but last year we tried to evaluate the skin, what we call superficial fascia, deep fascia, muscle, tendon, ligament. And well, we were almost surprised because fascia have more innervation than tendon and ligament and more or less the same innervation of muscle. So it means it is an extremely well innervated structure that have rufinic corpuscle, pacinic corpuscle and a lot of free-ending nerves. So if you have a normal gliding, what do you have? You have a normal stimulation of the mechanoreceptor. So we have what we call proprioception. Because in our opinion, fascia is really the organ for proprioception, is the structure, the infrastructure that allow you to perceive the movement because it's in connection with the muscle, but at the same time is isolated. So you can perceive the movement is relative far away for the fulcrum from the bone. So the moment is very large and can perceive even better the movement in different direction in the space. But if you have a lack of gliding, the MRI will be the same, the ultrasound will be the same. But right here, you will irritate the mechanoreceptor. So you have a bombardment from here. You will have a sensitization from here, a peripheral sensitization. So this can lead to what we call myofascial pain. So so far, we never proved this hypothesis because we tried radiologically, surgically, but nobody was able to really prove this peripheral nociception damage. So what we try to do, we try to evaluate with a particular MRI, a very common syndrome like elbow pain, and we try to evaluate not just the muscle, but also the deep fascia in a different way with a specific MRI, what we call T1 row. So what is the particular characteristic of the elbow? Like the typical epicondylitis is something that occur on the lateral side of the elbow where everything converge. Because if we have a look right there, if you do a dissection, you will see that the muscle, the origin of the muscle, the capsule, the deep fascia, everything converge and fuse on the lateral side of the elbow. So at that level, you can call this structure, the origin of the muscle, you can call deep fascia, but this can be also part of the septa that go down in the intermuscular septa up to the capsule. So we try to focus attention in the deep fascia. It normally has a range between 0.5, 0.6 millimeter. So it's pretty tiny, but trust me, it's very rigid. This can carry a lot of weight because it's all collagen fiber in multiple direction. So it's able to carry weight in multiple direction, something that a ligament cannot because a ligament have all parallel collagen fiber. Well, let's have a look in the contralateral side, the pathological side, the patient have a symptom. So you see the deep fascia is clearly thicker than the other side. We get to almost one millimeter. Again, you see one millimeter right here, the intermuscular septa as well is alterated. Also the intermuscular septa right here. So as you call this structure, what is deep fascia, intermuscular septa, the tendon origin of the extensor, what is exactly that? I mean, let's call the fascial system, so like connected tissue that is located around and within the muscle. So the question is, is this one a fibrosis? Is this one an inflammation? What is exactly going on right here? Because if you do a color Doppler, you will not see an increase of the blue fluid because there is not clear inflammation. If you try to evaluate if it's really a fibrosis, so an exceed amount of tissue, it can seems with this MRI, but MRI has a major artifact. So if you have a different layer, one close to the other, the MRI as well, the ultrasound can pick up one major structure is not able to define three layer of dense connective tissue with an interface of loose connective tissue. So we are not really sure that we have an exceed amount of connective tissue type one type three. This can be just an increase of the space in the interface between layer of fascia. So to prove these hypotheses, we try to do a simple study and we try to apply a new MRI T1 row in this patient that have a typical symptom in the region of the elbow. So if we try to evaluate the elbow, okay, you see the brachial fascia, right here is the biceps. You see the forearm fascia, this is the biceps, a point of roses, okay? So this is the middle part, this is the lateral part. So you see, you clearly see the different collagen fiber. If we take a full sample right here, what are you going to see? You see one layer of collagen fiber, loose connective tissue, adipose cell, glycosaminoglycans, hyaluronan, another layer of collagen fiber, here dry up the loose connective tissue, but this is the third layer, loose connective tissue one more time. And this tiny layer is the epimysium. So what do you mean? If you do a flexion extension of the elbow, this angle will change, this layer will glide over this layer, and the muscle will contract in a third direction. So each single structure will glide in a different way. So try to imagine if the viscosity of this loose connective tissue will increase, become more sticky, what happen? That your elbow become rigid. The patient will come in your office and say, look, you know what, It's some weeks that my elbow is get the ridges. And if yesterday, you know, I ran to catch a glass that was falling down from the table, it was so painful. So you can do an MRI, you can do an ultrasound normally, but you will not see anything alterated. It can become thicker, this part. My fibrosis doesn't occur overnight. Fibrosis needs a long period of time. It needs like some insults that will stimulate the production of fibrosis. So most of the time, what you have? You have a change of the quality of the loose connective tissue that can happen overnight. So we focus the attention in the hyaluronic, because hyaluronic is really, is have the unique capacity to bind water. So water can be attaching all over both the side of hyaluronic. But hyaluronic can also self-aggregate. It can bind other proteins, human protein. So if the hyaluronic self-aggregate, like you see right here, and if it aggregate even other protein, like you see right here, the viscosity increase, and the shear rate of the hyaluronic, the shear rate of the hyaluronic viscosity increase, and the shear rate between layer will drop one to 10. So this will really make more viscous the loose connective tissue. So it will make more rigidity. And this rigidity obviously will make limitation, impair, and irritation of the mechanoreceptor. So going more microscopic point of view, here you see an aggregation of hyaluronic. So you see, this is all hyaluronic aggregate. The hole are where free water are present. So when hyaluronic aggregate, you see there is less space for water to bind hyaluronic, because hyaluronic all over here is aggregated. So what I mean, that you have like a sort of honeycomb, a sponge that have a large hole with a lot of structure that is built up that self-aggregate hyaluronic. So this is a normal hyaluronic. This is self-aggregate hyaluronic. So right here is like in 2D. This is 3D. You see, you have like a sponge with a small hole with a lot of septa of hyaluronic. So there is a lot of space, a lot of surface where water can bind hyaluronic. So the red is a primary water bound. The dark blue is second bind water. And the light blue as well is a free water. So if you have like a free hyaluronic, you have a lot of water that is bind with hyaluronic. So you have a really nice lubricant. But if the hyaluronic is self-aggregated, you have a sponge with big hole and with a small surface where the water can bind hyaluronic. And you have a lot of free water. So this sponge is definitely more rigid than this sponge. Because right here, there is less binding water and more self-aggregate hyaluronic. So T1 row can define if you have a free water or bind water. Are more free water you have, are more viscous is the loose-coated tissue. Are less free water you have, are more lubricant you have. So this is the amazing picture, the first picture that we get. So this is a normal MRI. You see the deep fascia sticker, but you don't really know what's going on there. With T1 row, you see there is an exceed amount of free water. So all the loose-coated tissue right here is very viscous. You see more close to the elbow, more close to the wrist. This is one patient, this is another patient. And again, you see that the deep fascia is really viscous. There is a high concentration of unbind water. So there is a lot of self-aggregate hyaluronic. So what we did, we decided to do a treatment. We started with a simple manual therapy because everybody know that manual therapy can improve the symptom, can improve the stiffness. So we applied manual therapy laterally. And this is pre-treatment, close to the elbow, close to the wrist. And this is after treatment. And see the lateral part of the elbow, of the forearm, the red is less. So it means that there is less free water, more bind water. So the quality of this lubricant is more fluid. Vice versa, as a control, we didn't touch the opposite side. You see the middle, the epitrochlea, the stiffness is the same. But this tells you a lot of information. First of all, it's not enough to treat this side of the pain because over time the body will increase the stiffness contralaterally to try to generate like a sort of balancing. So if you don't treat the bilateral agonist antagonist, this patient can maybe develop over time apitrochleitis after epicondylitis. And once again, here the muscle have no alteration. So all the problem is at the level of the deep fascia. And that was quite well correlated with the symptom. So we did something more to make sure that we are talking about the hyaluronic non-proteoglycan. We try to inject hyaluronic dase. So the human recombinant hyaluronic dase. It is the enzyme that metabolize hyaluronic acid. So this is a dramatic patient. It's a patient with spasticity. So you see the healthy side and the hemiplegic side with spasticity. You see the biceps, the triceps. So you see pre-injection, you see a full thickness alteration of the viscosity. You have an aggregation full thickness. Endomysium, perimysium, apimysium, all over there is an aggregation. And you see the shape of the muscle is different. Then we inject hyaluronic dase. And after the injection, after a few weeks, you see the amount of red is less. So there is less free water, more bind water. And so less stiffness. And by the way, there were more passive motion, but also an increase of active movement. So this was really interesting. And we are moving forward to get more and more data about that. You must see how the inject side went back almost as a control side. So we really improve the motion of that arm. In active motion was something that really surprised us. And on top of that, we prove the difference from here to here is all due to hyaluronic, not protoglycan because hyaluronic dase metabolize hyaluronic. So what is still remain is maybe protoglycan or portion of hyaluronic that the needle didn't reach. But what is even more interesting that this happened all over the body because we have a clear data that even liver before to get fibrosis, you have an increase of the viscosity. We call densification. So densification because you have an increase of the viscosity of the loose connective tissue. You have an exceed three, eight time increase of extra matrix in liver before to get to fibrosis. This process take years, but you can evaluate, you can collect data from that. So with T1 Rho, we get data from here. We know the same process happen in the kidney, even the heart. So this aggregation, this densification occur in the musculoskeletal system as well in the visceral organ. So T1 Rho is not so expensive. It's just a few minutes more than a normal MRI, but obviously even ultrasound can be useful tool. We published this article, this matrix to try to explain that with the stiffness and the ecogenicity, you can really understand what's going on in your patient. But just the ecogenicity is not because stiffness, it will allow you to understand between a trigger point derivation, between sarcopenia and later fibrosis in a spastic patient. So just to get all together. So here we see the trigger point. So the hypoecogenic area that is more stiff. Here we have the study about low back pain. People with the chronic low back pain, the fascia sticker, the thoracombar fascia sticker is more stiff. This is our study, people with chronic pain, the fascia sticker, and you see there is more black in the middle. So what is this black? What is this black, the exceed amount of black? Can be hyaluronan, that is a fluid self-aggregated. And these show you that more stiff the thoracombar fascia, more stiff the trigger point. More black is the trigger point, more black is a fascia with alteration. Thicker is the fascia, thicker is the fascia in chronic and neck pain. So you see all the body, all the people are getting similar results. So we are moving hopeful in a good direction. So thanks for all. And this article is open source, so everybody can download and have a look. Thanks a lot. Okay, thank you very much. And thank you for the assembly, for listening to our lecture. There are a couple of questions. Let's take them real quick. Antonio, if you can answer this question, are there any ultrasound studies looking at the thickness of the intermuscular septa? We study mostly the fascia in different parts of the body. We collect data also from the intermuscular septa. We are talking about, for instance, at the level of the leg between like a different compartment. It is much easier to study deep fascia even for quite of the imaging because the ultrasound will pick up more superficial information. So we decide to pick up deep fascia to get better data and more reliability data. Thank you. Another question is, what is the role of acupuncture in myofascial pain? So a dry needling is certainly a form of acupuncture. And in our studies, we've shown that dry needling improves range of motion. It improves the cervical rotation. It improves some of the symptoms related to the limbic system dysfunction that we talked about earlier. It actually decreases the size of the active trigger point when the pain is decreased along with that. So it's fascinating. One last thing I'll mention is that the paraspinal points that Andrew Fisher mentioned about for injection in order to target the medial branch of the posterior primary rami, those are the classic Watteau jaw G points in acupuncture. So one last quick question. This is for Dr. Serval. An interesting theory, though then one expected myofascial pain of superior trapezius, levator scapula, muscles would be more common in older adults as spinal OA and spondylosis is more prevalent in this population. And at least clinically, we see this pain syndrome more commonly in younger adults without substantial spondylosis. So this will be the last question because of time. Thank you, Dr. Serval. Yeah, I'll respond quickly to what you told too. But I think the key thing here is I mentioned in the presentation that we need to consider subclinical cases or conditions as well. So spondylosis is typically preceded by discopathy. And I think discopathy checks all the boxes for a primary pathology that could drive central sensitization. So I think many of these mechanisms operate subclinically and can manifest as trigger points. And very often occult tumors and other occult pathologies are identified in the early stages by the presentation of trigger points because we can palpate them in muscle. So it's something to consider in your diagnostic workup. Thank you very much, everyone. Thank you.

Myofascial Pain Syndrome

Trigger Points

Neurogenic Inflammation

Fascia

Central Sensitization

Limbic System

Somatosomatic Interactions

Proprioception

Hyaluronic Acid Accumulation

T1Rho MRI