Dr. David Borsook - When Pain Gets Stuck: Abnormal Brain Systems Define Pain Behavior

We'll go ahead and get started. It's my great pleasure to introduce our speaker today, Doctor David Borsuk. Um, Doctor Borsuk completed his undergraduate medical degree and PhD in South Africa. And he came here and did his neurology residency at Boston City Hospital followed by a pain fellowship at MGH. Uh, he founded and continues to lead the pain and imaging neuroscience group which spans, uh, Boston Children's Hospital, MGH, and McLean Hospital. Uh, he's director of the Center for the Pain and the Brain and is a professor of anesthesia here at Harvard Medical School. He's currently an attending physician of the headache, in the headache program at Boston Children's. Uh, he has a very long and distinguished, I should say, a long and very distinguished research career in the field of pain. Uh, he's held numerous NIH grants, um, has mentored many clinicians and scientists, and, uh, has over 250 peer-reviewed publications. His current scientific interests include Um, we are focused on the understanding, uh, of pain neurocircuitry in healthy individuals and its alterations and treatment in the context of chronic pain disorders. Please join me in welcoming, welcoming him this morning. So good morning. Um, I, I don't know many people here, which is actually unfortunate but uh somehow some of us in the research community are tucked away, uh, sort of working on some of the processes that an academic institution demands. It's interesting for me that I'm in the Judah Voltman Auditorium because I met Doctor Volcan of, of Volker, sorry, Judah, um, in 1979. Uh, when I did a rotation here in, in surgery and, um, It's always interesting to meet a giant at the time and in retrospect in terms of an individual who's led led a field. So I, um, I, I also didn't note that today that surgical colleagues would be here and um I'm, I'm hoping to actually talk about something that is really important in the OR and hopefully of interest to you. So my, my aim today is to, to, to accomplish two things. One is uh to actually introduce you to People in our group who've contributed to our enterprise, uh, especially while being here at Children's. And the second is to give you some insights through some of the work we've done over time uh related to the theme of when pain gets stuck. And just parenthetically, it's those patients whose pain gets stuck. that receive inappropriate treatment because we keep giving treatment to something or someone where we're not uncoupling a process. And from a brain systems point of view, the lack of uncoupling is because of what has become termed in, in, in the literature now of centralization of pain. So all these complexities that clinicians may or may not hate in a patient of depression and anxiety. And, and, and other processes are part of this brain morphing into a new uh process. So when I was head of the pain program at MGH, um, One of our interests was on systems plasticity and I was Uh, on rounds and came across this patient who had had his his left arm amputated, um, 4 hours before and he had this phenomenon described by a neurologist in San Diego of touching the phantom limb. In other words, when you brushed him at 45 or 6 in red, he felt As if you were brushing the dorsum of his hand, right, his missing hand. And uh this was um obviously amazing to me, uh, to see it in action, but even more amazing to the patient. He was actually out of, you know, really nervous about this, this process. Anyway, we took him to the scanner and um We brushed him at 12, and 3 and asked, you know, are there any common areas activated, and this is non-specific area in somatosensory 2, and this is an activation using FMR and it represents a statistical increase in blood flow in that area. relative to, to baseline. Um, and then these are coronal sections through the brain. And then when we did it on the affected side, shown enlarged here, there was an activation in the somatosensory cortex that corresponded to his hand. So this is what really turned me on about the power of imaging and the opportunity to use this uh in, in disease states, uh, in drug development. And uh as NIH is trying to push this theme in biomarker, um, biomarker use. So, uh, these are the 6 themes if we have time and you don't throw me out before getting to the end of this lecture that I hope to cover. Uh, in introducing our group, I just wanted to give you a sense of the kind of work that, uh, we're currently involved in. Um, and then a brief history of pain, uh, and, and imaging, uh, and then getting into this theme of, uh, when pain gets stuck, uh, focusing on a program that we're very excited about, and that is, um, evaluating non-susception or pain activation while under surgery slash while under anesthesia. So, Um, with that, um, these individuals I'm introducing are in alphabetical order. And I hope I haven't left anyone out. Um, but, uh, Dusica joined us and, and got a K08, a perfect score on the NIH grant, um, looking at Um, the ontogeny of opioid effects. Uh, she's only one of two individuals I've been involved with who's managed to get a perfect score at NIH and obviously this theme is very of great interest in terms of opioid effects, uh, on, on the brain. Nadia um invited herself to our group and uh uh managed to get a, a K-25 with us uh and she's interested in, in imaging um spinal cord myelitis and has really led the group in imaging peripheral nerve when it's damaged, uh, in, in this case with ankle sprain. As a predictor of ongoing pain that you can actually look in, in the body of the nerve and see changes based on, on, on imaging. Um, a colleague who's taken some time off to start a family and will be back, uh, from, she's actually from, uh, uh, Portugal, um, has been interested in placebo, uh, in children, particularly as it relates to migraine. Um, And Duncan Hodgkinson joined us from UCL, an instructor now. Um, he's, uh, helped with, uh, actually led our migraine program but has actually been a leader in, in terms of adapting and defining autonomic changes in the magnet, which is no small challenge and, and, and, and is one of the leaders in that domain um in, in the world. Alyssa La Belle, who's known to the department, um, And, and someone I've known for decades, um, actually has been working on um a couple of things, but she received this Migraine Research Foundation Impact Award, the second to receive such an award, um, uh, since it, uh, it started. And, and her interest is in, you know, what happens to the brain when uh uh particularly kids. Uh, start having a few headaches and then boom, they have ongoing headache. There's some kind of switch that goes on and that's what she's, um, she's doing. Uh, Eric, uh, has actually, uh, worked with us since he was a postdoc and uh has led the field in the cerebellum in pain and has actually worked with surgeons at Dana-Farber in terms of uh what happens when particular areas of the cerebellum are removed and how that affects uh pain processing. And is also interested in a Uh, the use of, um, confocal microscopy of the cornea, which as it turns out, uh, is actually a marker, a biomarker of all pain uh conditions that you actually see these changes of nerve loss that's shown at the bottom here in the intact cornea versus the cornea that's, uh, uh, affected in this case, post-LASIK at many months, uh, producing chronic, uh, chronic pain. Uh Ke Pen joined us a year or so ago and has been working on something that I'm gonna spend more time on and that is our ability now to measure the nociception while under anesthesia. And the reason we think that's important is because this nociceptive barrage that is hard to define without a marker like this contributes to increased postoperative uh opioid use and uh potentially the uh the uh Onset of chronic neuropathic pain and just FYI chronic neuropathic pain after surgeries occurs in 15 to 50% of all surgeries and of that group, about 25% have severe ongoing pain. And so the theme of blocking pain at a surgical event and, and, and, and inhibiting chronicity is, is a major, a major issue in our healthcare process. And then Christine joined us recently. She's a psychologist, uh, the K23 Award, um, looking at those themes that I listed up there and um she, she, uh, brings to us the psychological uh uh focus which is obviously in kids is, uh, is hugely important. Um, Nick Todd is from the Brigham. He, um, we have a, he, he has a K08 with us, and he, he's doing. Um, we're looking at uh the use of focused ultrasound to deliver drugs at specific parts of the brain. I think this has been derived from a major program at the Brigham in terms of treating tumors. And so far as is as shown in the bottom, uh, you may be able to see that if you actually have the blood-brain barrier closed versus open, you have decreased, um, activation as shown by FMRI and this is a horizontal slice through a mouse brain with an inhibitory neurotransmitter, uh, GABBA. And then uh I think finally uh Jamon uh Upadja has joined us recently as an associate director and um, clearly he's still a little confused as you can see he hasn't actually defined his role, but these are his areas of interest. Uh, he was actually a fellow with us in the early 1800s uh and uh we're delighted to have him, have him on board. There are also been people in the anesthesia domain that have helped us with specific projects and they're listed here and I just wanted to acknowledge them because without uh clinic clinicians and if I had known this was also a surgical um meeting, I would have listed some of the surgeons who've helped us as well, particularly in orthopedic surgery and in cardiac surgery. So with that, uh, what about pain getting stuck? And so the, the theme is that Uh, it's kind of like watching, uh, an epoxy, uh, set that in the pain field, there are, there's a lot of evidence to indicate that if you treat, um, pain chronification early, you have a much better chance of, of, of dealing with it. But once pain is set, it's much harder to undo. And so getting pain unstuck. Uh, is, is a very difficult thing. And I'll show you an example where we, patients have been under ketamine coma to actually, uh, uh, unstick pain and, and what we think happens is that you actually redo or allow for connections to take place in the brain, uh, that uh were inhibited uh before. And, and this theme, uh, and I use the example, I mean, there are many examples of different types of pain, you know, from back pain, post-surgical pain, stroke, migraine, etc. But the theme is something along the lines of this, as I mentioned, after surgery, depending on which papers you read, 15 to 50% have chronic pain. But you have a surgical incident, there's, there's pain post-operatively, and the question is, Does it go on and then maintained post-sur post-surgically uh in, in a chronic state. And, and, and that issue is of interest because the surgical event is a defined place and, and time. So in fact, there's an opportunity here uh to actually try and block that ongoing uh process where pain continues uh uh uh in, in many patients, but, but not all. And so when we look at brain systems, we can actually look at a couple of things in in a relatively short time, including brain chemistry, changes in gray matter, uh, and changes in altered networks as well and these structural changes in nerve tracks. And in terms of brain function, if we took any of you and put you in a magnet and just measured brain function, we would see these low Of low frequency oscillations of the brain that can be defined in terms of specific networks. And if we took you then in, in 6 months, it would be the same assuming nothing has happened to you. If you're in a disease state, those patterns are very different. If you have drugs on board, those patterns are also very different. And in terms of changes in in gray matter volume, Uh, what happens, we think at least based on a couple of papers in animal work, is that dendritic tree complexity, uh, is changed. So with decreased volume, it's akin to a tree in summer with lots of tree leaves on it and a tree in winter with no leaves. So the, the weight of, of that area is actually uh uh diminished. And so if we look at the history of where we've come from, Um, you know, the first paper, actually I was still a resident in neurology at the time, uh, was, uh, in 1991 where people looked at pain stimulus and showed that the anterior cingulate uh was activated to pain. And, and for those in, uh, uh, neurosurgery, at least, uh, there'd be neurosurgical interventions for lesioning. The anterior cingulate for pain control, and many of them were done through MIT and, and MGH, um, and, and some still continue to be done. Uh, and we, we're now beginning to understand why that's the case. And that has gone forward to, to define what we now define a call the pain connectome, which is just a, a, a series of connections throughout the brain that define our pain state. And um Related to that, um, uh, you know, early work showed, um, this is from our group looking at specific activation along a tract, the somatosensory tract, and now we can not only see changes in brain volume within this tract but also predict as in the case of migraine from the German group Arnie May and and company can actually predict based on the volume of the nucleus and the trigeminal nucleus, um. Uh, where the patients will go on, uh, to have migraine attacks, uh, or chronify. Uh, one of our lucky strikes was defining the reward center in, in pain and aversion, and it, it happens to be the nucleus succumbens and hithertofore had been the area involved in addiction. Um, and now this was the aversive equivalent of reward. And what's been so interesting in more recent papers as exemplified by this paper is that you can actually look at brain connectivity between two regions in this case, the accumbens. And the medial prefrontal cortex that predicts the persistence of, of the pain state. Um So what about preventing pain before it starts and this is a surgical anesthesia event. And um this uh process is sort of uh uh we published this in the Annals of Surgery. Um, and Uh, basically, what whatever patient you have has all these domains of, of the, of contributions to what happens, uh, during anesthesia surgery and then afterwards. And basically, following nerve damage, you may have and during surgery, you may have sensitization of the brain because of the barrage of ongoing nociceptive uh activation and I'll show you some data on that. And then if it's allowed to continue, uh, as I mentioned before, there is this theme of, of centralization of, of pain. Um. So I'll just use an example from animal work, but the same theme exists in human studies that if you anesthetize an animal and then provide a nociceptive process of electrical or heat, um, you can see activation in the very pain pathway that you would see when the animal is awake. So in this case, it shows in a cross-sectional uh of the of a of a rat brain activation in the primary somatosensory cortex. So the, the question is, uh, many inhalational or most inhalational anesthetics are not analgesic. And the question is, how do we know, uh, under surgery about two themes that currently are, um, interpreted in a clinical sense and it may be, you know, of interest to actually have a marker or biomarker for it. And those two themes are not just event-related pain, you know, whether it's a cut. But once you've made a cut, inflammatory processes are immediate and you have ongoing pain. And so can we measure both event-related pain as well as ongoing pain, uh, under, under surgery. And so, um, actually through a chance meeting with uh David Bose at MGH's office was next door to me. We started this program of looking at near infrared spectroscopy to define uh measures. Uh, um, uh, of, of pain or nociceptive activation where basically you, you shine, you have an optode and you shine light in and you measure reflection, reflection of light and, and on top here, and then you get a signal that is dependent on the difference between Uh, oxy and reduced hemoglobin in terms of the wavelength difference shown between these two points, and you get a signal that you analyze. But with respect to nerves, if you look at the spatial and temporal domain relative to other things, especially EEG for example, and FMRI, it actually spans a large component of both domains in that sense. And so What I'm gonna focus you on are two areas of the brain that we that we've been focused on. One is the somatosensory cortex where pain, we know pain is activated in animal and human studies. And the other is um the prefrontal cortex, uh, where pain is integrated in terms of emotional processing. And so using this and if you just focus on, on the right, on the red lines, um, if you use brush versus heat, uh, with brush, there's a single vent and with heat, there's a double peak uh and that double peak has been seen in Uh, FMRI studies and that basically you can differentiate between a noxious and noxious heat in a, in a, in a, in a pretty robust way. And if you provide graded heat where pain levels are high, and then below pain levels, you see this disappearance of from the double to the single uh uh uh um peak, and, and that's over the cortex where we know pain is actually produced. So we've done 3 sets of experiments that have sort of enhanced our confidence that we may be onto something. And that relates to measures in the frontal or prefrontal cortex where in healthy subjects following a painful stimulus, you see this decrease in The signal in patients who are sedated, undergoing colonoscopy, but where you can see them cringe when their colon is insufflated. Uh, so you have a a marker, but they're, they're unconscious or sedated. And then, um, in anesthetize patients and work done here with uh cardiac surgery and um or cardiology and cardiac sur cardiology and also um Um, and the, the anesthesia team and Barry Kuzman has, has helped us with that. And so we've been interrogating this and, and look at it in the following way, whether you're awake or asleep, you get the signal. And, and the question is, you know, what does the signal mean? And Kerr just uh um got the front, front cover of, of a journal on uh progress in neurobiology, um. looking at all the data that has come together in terms of understanding the polar or prefrontal cortex of which is a medial and lateral component and how this may contribute to our understanding of pain. And so, in, in summary, most pain imaging studies show this area to be activated, but few have interpreted it in in any way. And so when we've looked at it in this way, it's actually connected to Many parts of the brain. And, and not only that, it's connected in a robust way to many of those resting state networks uh that define uh behaviors such as the somatosensory cortex or a somatosensory network or cognitive uh network. And so looking at this theme, once while we could get activation to painful stimuli, you know, what happens when you give them an analgesic and of which morphine is the gold standard. And so this work done at MGH um shows basically random noxious and innoxious stimuli, which were presented at 30, 60, and 90 minutes after in a double-blind fashion of either a morphine or a placebo medication. And I'm just gonna summarize the the data below that basically we see. This deactivation, remember those curves that I showed for the three conditions were downgoing uh in the um frontal cortex and at around 60 minutes, it disappears and the same thing with the somatosensory cortex. And this profile of change in the brain without even asking the patient actually reflects the plasma levels of, of this drug when it's taken orally. And so not only did we have a morphine profile, but I'll tell you about data that we think is true also of remifentanyl under surgery. But our real issue is to be able to provide a little, a little box with a red or, or green light that the patient is having pain. And so not only can we see single volunteer changes, Uh, but group changes and we're working on sort of mathematical processes to actually, uh, define this in, in real time. And this is just a summary of the morphine data relative to brush, where morphine with pain flattens, shown in red, uh, and the same thing uh with Remifentanyl when cardiac ablation under anesthesia, uh, is, is present. So, uh, not shown here is recent work that um both uh Kerr and and Leno Besera who uh was with us, um, actually, he and I had worked together for over 20 years, um, had worked out a measure to look at ongoing pain. So not only will, will, can we now look at event-related pain where there's a cut or a pull or a twist uh or a movement, uh, but we can also look at an ongoing change of pain. And, and, and what we hope to do is be able to define the pain load in the perioperative. Space, whether it's during surgery or after surgery, and be able to correlate that with uh outcomes in terms of chronicity of pain, uh, opioid use, and, and so forth. And obviously, the idea is that if you have a measure, you can react to it and uh maybe block, you know, 80 to 90% of nociceptive activation events and maybe diminish uh the consequences post surgery. So in, in terms of Pain getting stuck. The theme I hope to, you know, presented is that if you prevent it or limit it early on, uh, you may not allow it to even go all the way to, to, to chronicity. But there's a theme in the neuroscience world, um, that has been promulgated by Bruce McEwen and others at Rockefeller on how allostatic load can contribute to the maintenance of disease state. And so thematically, you know, it's stress, and you can think of stress in psychological or physiological or other terms. Uh, and usually there's a behavioral response. So, you know, if you flick your hand or hurt your hand, there's an ouch and it goes away and your system adapts to it and everything's hunky-dory. However, if there is no adaptation to that process, then the systems become dysfunctional. And the dysfunctional state itself contributes to chronic pain. So an example may be uh you undergo surgery for a knee, uh, pain continues, you're scared of moving, you then become fearful or anxious, and so the anxiety domain contributes to the pain state and basically, you're in a freefall. And, and I think the best clinical example is like cardiac failure, you know, where you just uh wind down, uh, because there's no, no response to um getting it right. So we had published this paper in Neuron a while ago and I think it was the first in the pain field looking at um This concept of allostatic load in one disease that happened to be migraine. And I just want to give you some imaging examples of issues related to age, uh, hormones, and, and medications that can contribute to it. So just to make the theme really defined, uh, one of the major new concepts in the pain field is opioids, even given acutely, may contribute to pain chronification. So what we see in the pain clinic, certainly in, in the adult population more so because they're given more opioids, it seems, is that pain not only persists, but it, it gets worse and it's been termed, you know, um, opioid-induced hyperalgesia, which I think is a false term. It's actually opioid-induced brain systems decay that contributes in a similar way to the anxiety domain uh to this chronification. So here are a couple of themes to think about this work from, from University College London, uh Mariah Fitzgerald actually uh is is one of the more interesting papers I've seen in the paint field for the following reasons. And if I have it right, Basically, if you perform a common surgical uh model of neuropathic pain in, uh, in early postnatal days, these, these animals actually don't have pain behaviors or cannot be precipitated, um, until they're adults. So somehow, something has clearly changed in the brain. That persists, and they put it down to inflammatory molecules that are inhibited during a period of time and then come on. But we see this in kids now in terms of long-term v vulnerability to pain and anxiety and other issues. Um, and the worst of it may be suicide, but something, the point being is that age-dependent changes. have long-term consequences. And we're just beginning to understand those. We're, we're looking at, we, not we, the, the field is looking into this in terms of understanding how those processes may be defined and we have a program which is mostly a fundraising program of save the child's brain in terms of taking healthy young brains and when they have a process such as you know, concussion or Uh, post-surgical pain or migraine or what have you, how does this change over time into adulthood? In terms of um this theme of persistence, I think this was the first uh FMRI study um of children that came out of, uh, which was led by Alyssa La Bell and, and others here at Children, uh, where we scanned and looked at pain-related brain changes in patients who had complex regional pain syndrome. And then when they recovered. So it was a, it was a natural recovery. In other words, whatever happened, whether it was medication or a natural recovery, as it turns out in pediatric complex regional pain syndrome, most patients recover, whereas in adults, it's not the case. And the point being, with the study and not shown here is that even in the recovered patients, their brains were different. So they had no pain, but their, their brains were different compared with healthy controls. Um, And I just wanted to list here, and, and you can read it for yourselves that basically uh prevalence rates in terms of chronic pain in kids is, uh, is quite high. The second example are gender or sex differences, and this happens to be in, in migraine. Uh, but in chronic pain, there is a, a female preponderance. Uh, but here are examples for the same condition, same age, different sex, differences in positive in red and negative in blue, um, in terms of males, either greater or less than females, uh, for the same stimulus and for the same migraine state. In other words, they had migraines for the same duration, uh, uh, and so forth. And so, uh, you know, some, some of this relates to significant things. So for example, the responsivity or responses of the drug nalbufine in women and men are completely different. In women, it's analgesic and in men, it's hyperalgesic unless you give naloxone with it. And so these are themes that are clearly gonna come into practice of medicine in terms of uh how we uh Modify uh and treat patients. And then the last example is actually work that was done by Jamon a while ago. But uh we took a group of what we call white-collar addicts. These were patients who Got hooked at a party, maybe took a couple of medications after a dental procedure, um, had no history of addiction. They were screened by colleagues at McLean. Um, and, um, they were all on opioids for at least, uh, 1 year. And, and basically, there are two things I want to just give you an example of, um, but we looked at structures, structural changes, white matter changes, and functional changes. And I'll just give you examples of two. The first is, uh, changes in the amygdala, where in opioid-dependent patients, the volume of this area, which is very closely linked to a number of processes, including pain and fear, is different. So in these patients, at least one structure is significantly different in terms of its size. And if you think about the volume being down and those connections being lost, it means that cables between London and New York are cut and so only 3 people can speak at a time instead of millions because of these, these changes. And here's another example of changes in white matter. These cables that I mentioned, where in fact compared with healthy controls. There are all these abnormalities and what Jamon did is actually looked at individual subjects in red, the opioid-dependent patch patients versus the controls. And for each patient compared with their well-matched control, there were these uh significant, there were these differences. And not only were these differences present uh in these patients for whole brain, but the cable pathway from the amygdala. That went out to the rest of the brain was also different. So we could put a correlation between the, the owner of the originator of these cables uh uh was not sending out the same connections. And so you go back to that brain connectivity slide, and it means that something is amiss and not all is well in the state of Denmark. I just wanted to put this in, it's a little bit of an aside, um. But uh there has been this issue of where are we going with analgesics and uh a group of us have put this paper together in translational medicine, uh, but it's a really, it's a really problematic field and um as you may know, the director of NIH um brought together a, a, a, a group. I've been lucky enough to be part of that. Uh, where they really are looking and pushing for new analgesic, uh, new analgesics, not just to stop the opioid crisis, which has been the driver, but to stop the use of opioids in the clinic, which is a, a contributor to this. And so I'll just give you a few examples of how we've taken, uh, and looked at in animal models, uh, network alterations in an animal model with a colleague, um, Remy Burstein at, at the BI. Uh, where we can actually start looking at, um, things that you obviously can't do in, in humans. And there are other examples of what we've done, uh, in, in animal work. So what about some insights from the clinic and I've just chosen a couple, uh, one of which or two of which relates to just the natural history of the evolution or devolution of pain uh in post-stroke pain, and that's post thalamic stroke. So for those of you who may not have seen such patients, when you Have um particularly right-sided thalamic stroke, you have this burning pain usually affecting the whole of the, the left side of the body, uh, that is, it is essentially untreatable. Um, and, uh, but if you look at it that over, over a long time, most recover and, and some, uh, some don't. And the converse for hepatic, uh posttherpetic neuralgia, which has actually decreased thanks thanks to uh vaccinations, um. But the same theme exists that basically pain persists and in some patients, they are resistant to treatment and, and in, in many, they, they, they do respond. And so we've begun to look at this in, in a, hopefully a new way. This is a program run out of the pain program here at Children's at the Mayo Clinic, um, Uh, and we've taken patients who have complex regional pain syndrome that are admitted there and undergo a three-week treatment program where pharmacological interventions are essentially set aside and it's mostly psychological and um phys uh, you know, PT, and basically, uh, many of these patients and then another paper with uh with a colleague Laura Simons. Uh, shows that about 60 to 70% of patients respond and, and others don't, and they're resistant to this treatment. But if you take them as a group, and all we've done with these kids is put them in the magnet, ask them to lie down and measure those resting state networks, and we see that they are, uh, you know, all over the show and significantly different to healthy controls when they come in. And when they go out, there is sort of clearing of those abnormalities. And this happens to be for the salient network, but here's something that may be more uh easily understood that in the sensory motor network relating to pain, um, is also cleared up. So we're basically beginning to look at this with new technologies that are around to target specific treatments for each of these, uh, each of these domains, and hopefully that will take off soon. But you can look at it another way. You go into a supermarket and you scan, you know, you scan the product and it tells you what it is. And so by understanding these different networks, we can scan. The patient and actually say, OK, maybe this particular network is mostly deranged, like cognitive changes occur in chronic pain. And so most of the treatment should therefore be directed in that way. And the hypothesis is that by doing So, it, it will get better. And so it's a much more targeted approach to integrative medicine than, than just um sending a patient to me, for example, which is not a good idea, as Doctor Lavelle knows. Um, so this was a patient and we've done a few Uh, we called it Breaking, breaking the brain's glue. She was a school teacher who was seen in Philadelphia, sent to us through the program that Alyssa was actually working at at the time. And, um, She had complex regional pain syndrome following a minor surgery, and this was her state before she went to Germany for one week's worth of ketamine coma. And uh I think some midazolam was thrown in as well. Uh, but these were her psychophysical measures with high pain ratings before and then after uh uh treatment. But this is an example, and it was in the early days of resting states. So pre-treatment, and she was, she got one of these resting states. There was no activity. She didn't have to think where there was no change in the um Singular cortex and then post-treatment when she was pain-free, was back at work, uh, came running into the clinic as opposed when we first met her on a, on a wheelchair. Uh, and this, this change is consistent with healthy controls. And so that is an example of um What we think is that we've done a number of patients now of unsticking uh this, this glue. Another example of beginning to, to dissect apart responders and non-responders is from the same group of patients, uh, not the same specific group as that, looking at our little nucleus, the nucleus accumbens, and basically showing that Patients who have a smaller nuclear succumbens, right, um, are non-responders and you can actually look at that area and how it connects or doesn't connect with other areas. And so this, another way of looking at this in a social sense is that these these patients are less susceptible to the benefits of rewarding stimuli. So they will not get the same uh good feeling out of going to a movie or doing uh things that are good for them as, as, as young patients. And so there, there are enormous implications of understanding the non-responder state beyond uh just this kind of work and I think one of the last slides talks to that. I've mentioned this issue of gray volume. I just want to make it again that basically within an area, uh, uh, say this red block here, you have many more connections when there's a robust and healthy synaptic complexity, um, and these neural networks are as healthy as a tree in summer, uh, whereas, uh, they're less, there, there are less cables talking to other parts of the brain when individual or groups of neurons um actually lose their dendritic complexity. So I'll end with a couple of themes that I hope you will take home. The first is that, you know, in chronic pain, brain circuits are changed. And in some of them, uh, it's hard to unchange them or or get them back to a regulated state. These brain circuits are complex and I think this thinking now put on the market by um a colleague in Toronto of the pain connectome, essentially a domain of intricate, intricate multiple circuits uh that are dysfunctional um and you can think about it as A computer board where you take out one chip and it may work, but it may not work as well. If you take out certain chips, you're in real trouble and you may have persistent pain. So one example of that is work done by Maurizio Faber at MGH where they looked at patients who had major depressive disease with no history of pain prior to the diagnosis. And in 62% of them, they presented with generalized pain. So you could argue perhaps that basically something had happened through the depressed process to change these circuits to provide the phenotype of this generalized pain. The second theme is this imbalance between systems, particularly reward and aversion, um. And um some have called this, you know, some like us have called it reward deficiency and anti-reward state, but you can think about it in terms of how pain load may drive that theme, as I just uh made an example of with depressed patients, but it can go the other way with chronic pain producing depression and perhaps suicide. And then these disruptive processes are also, you know, relate as I just alluded to, to a general a general state of the patient. So this is work done by Sophie Wilcox when she was with our group looking at um uh effective Pictures. So these pictures are divided into three groups, positive, neutral, and, and negative and compared them with healthy controls. And there was a greater level of activity in the brains of patients to a negative emotion. Remembering that migraine or a repetitive pain state is an attack and an aversive state. And so they're sensitized to this. So everything they see in the world relates to a different brain than you and I if we're not migraine sufferers, um, have in, in terms of how they're eval evaluated and how they benefit um from, from treatments in terms of correcting this. And then perhaps the most useful thing that I hope to convey to you today is this slide, um, and it's from colleagues, uh, at, um, At McGill and, and Cathy, Catherine Bushnell is now at NIH and it's a theme that I think Alyssa is looking at in terms of why do some patients just jump into a chronified state in that example of new daily persistent headaches. Why is it that fibromyalgia patients are in continued pain? And so one nice model is this one, and that is that there are these, there is this area in the brain, the periaqueductal gray, which if you gave a microliter of morphine into it, you could perform open heart surgery. In fact, the first paper that was published in this was in a rat doing exactly that. They Put a small amount of morphine in the peria periaqueductal gray. So it's a very powerful descending process. Maybe a better example is when you watch NFL football, if you are a watcher and you see these guys break their necks, legs and arms, and, and essentially they, they get up. So this system is activating it. It's the same thing when a deer is, is attacked and killed by a lion, uh, um. That basically they, they probably don't suffer much pain because of this. You can show a mouse, a cat, right? Or the smell of a cat and their analgesic systems just shoot up into the air in terms of um being analgesic to painful stimuli. So this system, which initially was put on the, on, on, on the market or the in the field by Howard Fields and colleagues at UCSF has now integrated areas above that in, in more rostral areas of the brain, particularly that anterior cingulate, which we talked about earlier, and their powerful uh processes that can inhibit pain. However, when you either have chronic pain or you have a genetic uh issue where you may not have as strong and modulatory system, you are susceptible to post-surgical pain. You're more susceptible even to fear and anxiety. And so this is, this is probably the most robust model in terms of understanding why some patients um get stuck, and, and others don't. So I've listed, you know, we've been very lucky with support. So this is not current support, but it's current, it's support since being at Children's, uh, that some of it was brought across from uh MGH and, and, um, McLean. Uh, we've had support from the DOD and we've been very lucky in terms of support from a number of, uh, foundations, including Um, the anesthesia Foundation. We are, have either set up or are setting up, uh, um, collaborations with uh people from various groups including, uh, uh, you know, foreign overseas programs, uh, the Veterans Affairs group, and people, uh, more locally. Uh, this is uh the whole group with, um, that includes our research assistants. And I just thought it would be, uh, also nice to list our integration and, and work with, um, Colleagues uh in anesthesia and as I said, if I'd known there was a surgical component here, I would have included the surgeons we work with um outside of Doctor Mali um at these other institutions. So I hope you got something out of this. It was fun to be here and thanks for your time. Look, I'd first like to thank you for presenting this fascinating work this morning. I, I'd like to say that none of us have seen patients that have their pain get stuck, um, but that's certainly happens to all of us, and we always wonder whether this patient is genetically prone to, to it, and you presented some information on that today or did I do this operation somehow differently, which is usually no. From a practical perspective, what, what are the, um, interventions we can try to utilize on patients following surgery, um, that's obviously going to elicit some pain that we can try to prevent the pain from getting stuck. I think you mentioned that actually opioids tend to accentuate the process, which is ironic because you'll often Figured that if we keep the patient more comfortable the first day after their surgery, then the length of the pain and the severity of the pain's always gonna be shortened. Yeah, what can we do? So, um, I can send you a paper that we wrote on the Wounded Warrior relating to pre and intra and post um. Uh, injury, which is essentially a much more rapid process than, than we have in surgery. And basically, there are a couple of things that um we, we actually are, uh, that could be done that I think could enhance surgery, the, the surgical intervention dramatically. And, and the first is pre-surgery, understanding, for example, where the patients have a high catastrophizing or low catastrophizing scale. And it's a word that I fought with my colleagues on. And while I think it doesn't mean anything biologically, it is one of the best measures of predicting poor outcome. The other thing that is happening now is understanding some genetic profiles. So for example, patients with some abnormalities with some uh potassium-related genes. Actually have a much higher chance of developing pain. So one can define patients ahead of time. The second thing which we're actually trying to push NIH towards, and I think they're doing it now, uh, is setting up a program to look at these themes, uh, including, um, early treatment. I think one of the problems in the reality of what happens is I come to you for surgery, you do a beautiful job. I go home, I'm really happy my heart's, you know, working or whatever. And then the sort of seeping event comes on. And I'm not sure exactly what it is, and it's tingling and I wait a week and I wait 1 month and I wait 5 months and oh, it's pain and I tried this medication. I think one of the big things that we can do without much effort is to tell patients, if you start developing these symptoms, we need to see you because At that point, it's much easier to treat. I'll give you a practical example. A patient, adult patients with complex regional pain syndrome are very difficult to treat if you see them late. The average time for a pain patient to come to an adult clinic is 17 months from the onset. So if you get patients early, you can do simple things like with these patients, just physical therapy. So I think the way to look at it is that uh most patients with a pain level of less than 7 out of 10, whatever that means is. You have a much better chance of getting them back on track. The longer they have that. Pain that persists, uh, the less likely it is. I, I, I think, you know, we need to essentially think of ourselves in two components, a microscope or a uh uh uh and looking at the patient like a FedEx unit, you know, you mark them at the beginning. In terms of high risk or low risk. They then not categorized in terms of treatment profiles, but there is an ongoing process to evaluate. And I think what we're seeing in the field with, you know, the use of Phone, phone information systems, the ability to track changes. And I, and I think when someone pulls together a pain tracker, which they may, may well be, uh, and basically at a certain, when certain things come together, alarms, uh, alarms go off, we will do much better. Um, you raised something that has been sort of hard for me to communicate because it, it's, um, It's sensitive. So for most surgeons, and tell me if I'm wrong, you know, you, you do a a great job, um, patients do well afterwards, but then your interactions with them after that time. Generally fades in, in, in many surgical processes. So you kind of as the primary interventionist, you, you lose track of them and I think that's part of the problem because they're not picked up either electronically or some other way with this FedEx type marker to know where they are. So I, I think um in, in this paper on the Wounded Warrior, uh, we actually define all these issues, uh, marching along from the pre-morbid state, whether it's genetic or psychological or physical through the perioperative state, including this trying to measure pain under or not susceptive uh through to when pain gets stuck. Like what do you do when, when pain gets stuck? Because the real problem and, and it's probably not as big a problem in children. Is that in adults, uh, we almost commit a crime in those that are stuck because we try and try and try and become more and more interventional. And yet, uh, we don't have a market to say you are resistant to this treatment, you know, we, it's not, there's no point in doing 1000 of these. Maybe you need ketamine or ECT. I'm, I'm just being, um, You know, giving you two examples of things that can really shake the brain rather than going on and doing all these other things. I remember when um I was at MGH, a woman came to the clinic from Florida, um, and she had something like um 40 stellate blocks, right? And um it was before the internet and, and, and, and being able to look at information online and what have you. And I said to her, Um, did any of them help? And she said no. And I said, did you ask your doctor why he was, she, I don't know, he or she was doing it? And she said no. So it's an I mean, it's an an example of how aggressive treatments are, are, are sometimes, you know, just stupid. I don't know how else to put that. Additional questions for Doctor Borsak. They have a brilliant talk. Uh, you know, you mentioned this concept of overtreatment with pain therapy and In the context of biomarkers, uh, you know, particularly in children, imaging biomarkers, are there some semi-objective criteria for assessing what you just mentioned, and that is, are they being overtreated either at baseline, during surgery, after surgery, and are there some semi-objective criteria for assessing their recovery using biomarkers, particularly imaging biomarkers? It could be very complicated, right? Got depression, anxiety, neuropathic pain, um, musculoskeletal pain, CRPS, but there must be some objective criteria for assessing whether you're giving too much pain therapy and also what the recovery profile looks like. Yeah, so, uh, Tor Wega, who's in Colorado, has done a lot of work on trying to use machine learning to, to differentiate, and most of it's been done in acute pain and they've recently done some in chronic. I think if you look at, you know, the 4 or 5 papers that are out there, um, including the one that, that I mentioned from, from children's, uh, there are ways of marking whether someone is likely to develop pain. And um you know, I think part of this NIH initiative is to actually define that, um, but I think it's a lot can be done now, you know, basically, um, one could change the field very quickly by implementing some simple things. Um, you know, it would be nice in children, it's not the case as often as in adults, although it's, it's reasonably high that post-surgical pain is a problem. But if we had, or, you know, put out a system that after surgery, you know, everyone carries this, this thing on their phone or watch or what have you, that defines this, this change. We've been working with MIT on, on defining metrics for some of the things we've done, including predicting a migraine attack, um 12 hours before or up to 12 hours before an attack. And so, um, I think there are ways, there are ways of, of dealing with it. Um, there is another issue in the field, um, that, you know, what is healthy and what is rubbish, and, you know, as opposed to what we do in pain. And the reason I say that is because we do a lot of things for which there's no, uh, you know, uh, there are no studies that are robust and they don't have to be RTC studies. So what we, what we're trying to push now and working with Thorweger and, and someone in our group is this end of one study. That basically you can actually define that process. Um, but I didn't show you data where for the differentiation in drug effects, taking uh nalbuffeine with and without naloxone, you show a whole different network that is changed by the existence by the addition of naloxone in men that when you add naloxone, an analgesic pathway is present. Whereas when you just give nalbuffen, Um, which is a mixed opioid, uh, agonist. You see an uh uh uh uh analgesic profile, right? So, there are a lot of things that can be done. I think one of the problems um is that there's been no investment in defining the true biomarker utility of imaging. We had started a program in the um Uh, in, in, in the 90s with a couple of companies um to, to look at this and we start, we finished things with acute pain. We didn't do a chronic pain, and then they dropped it and we tried with FNIH, the Foundation for NIH and we couldn't get companies. It was when the markets all went down and so forth. And right now, FNIH and NIH and the companies are putting in millions of dollars to do this kind of thing. So there's a huge bio-market, um, uh, uh. Process, and believe it or not, one of the biggest problems, um, you know, going back to one of the questions you asked are simple things like phenotyping patients, you know, uh, clinically, In the pain field, overall, it's, it's hard and, and maybe it could be done much better. And, and without a phenotype, you know, how do you give a look at, at, at treatment efficacy. And so pharmaceutical companies, when they look at trials, and again, going back to Maurizio Faber who runs a, a, a clinical trial program at MGH, you know, rubbish in, rubbish out, essentially. So if you bring in patients who are not well phenotyped, um, You're not sure what you're really uh uh treating. And I think we're seeing the consequences of that in depression and anxiety medications where actually when it gets out after phase 3 trials and it's FDA approved, in fact, it's not as good as the, the trial alluded to. So I think your question is actually very Topical. It's, it's where we are and, and what we can do. And obviously, those of us in the imaging field, um, are maybe more excited than we should be, but we think we have something to offer. Doctor Borsak, thank you so much for sharing this with us this morning.