right so how does uh neuromodulation for pain worker so we first need to consider the fact that with all forms of neuromodulation there is something called dose and what we tend to have a pretty good understanding of what we mean by dose when we talk about drugs as in you're going to take two tablets a day and each tablet has so many milligrams of the active ingredient sometimes in the case of neuromodulation there seems to be confusion about what we actually mean by dose but there shouldn't be any confusion because it's actually very well defined neuromodulation dose are those features of the device that impact how much energy is delivered into the body or in the case of electrical stimulation that impact how electricity flows through the body now that sounds like a bit of an abstract definition but can we can reduce it to just two very simple things want to prescribe neuromodulation dose you need to one indicate where you place the electrodes on or near one part of the body there's the first aspect of prescribing neuromodulation dose and the second part is you need to indicate the waveform that you are playing into those electrodes so for example I can put a round electrode on my forehead and another one on my arm and I can apply a one volt signal fluctuating at one Hertz to those electrodes for a minute and that information fully defines the neuromodulation dose now um the neuromodulation dose is important because it determines how energy is delivered to the body which neurons are exposed to that energy and how they respond to that energy and so the behavioral consequences the position of the electrodes is especially important to influence uh impact which neurons we stimulate if I put an electrode here on my arm I'm going to feel tingling in this region and not in that region because the energy is being guided around the electrodes here so the position of the electrode has a very strong effect on which neurons are influenced the intensity that we apply to those electrodes and the waveform whether the intensity is fluctuating one time per second or 100 times per second we'll have a strong influence on how we change that neuronal activity do we make those neurons more active less active do they change how they process information so once again it's the position and it is the waveform that we're playing to those electrodes that together matter now once you recognize this there's a couple core layers the first one is if you have two neuromodulation devices that provide the same dose to the body they are indistinguishable to the body now they might have a different color or um um a different brand name on them but as far as the body goes as far as the cells in the body go those two devices are identical so that also means that if you want to innovate in neuromodulation you want to create a more effective or new neuromodulation therapy you must be innovating in neuromodulation dose you're either coming up with a new place for the electrodes or you're coming up with a new waveform in order to play to them and and this is this is literally a billion dollar question there have been companies that have been generated and have generated tremendous value to patients just by changing one aspect of electric position or changing one aspect of waveform now this this seems really overly trivial then by all means go out and and do it but it's actually not trivial because in fact there are many possible um um options of dose that you can think of right there's so many places you can put the electrode there's so many possible waveforms that you could apply um which one is really the magic recipe now there are things other than neuromodulation dose that certainly matter the user interface the battery life of the device things that might affect the um safety of the device that's unrelated to the dose per se so all those things matter it's not to diminish the importance of things other than neuromodulation dose but we do need to think of neuromodulation dose as something um special for the purpose of of adjustment now as I already mentioned you know there are many possible Doses and in fact each neuromodulation device can provide many possible doses so you have a neuromoduline shade device and it has 10 possible frequencies and 10 possible intensities and 10 possible electric locations so you multiply all those options together and you realize that each neuromodulation device is actually giving you more possibilities than you have time to test in any given patient and so from the constellation of doses that is made available by each given device and each device will have its own constellation of doses we need to select the right one for the right patient at the right time and the way we do that is dose instructions dose instructions are the manual that come with the device the tip that you heard from your friend all the information you're getting that allows you to take that device and adjust the dose adjustment knobs adjust the electric position in order to get the outcomes that you want so now you have a scheme that really shows you uh to first order how normal modulation works you have your neuromodulation device and that device is providing a dose energy that is going into the patient's body it is affecting the neurons in that body and that is what's driving any kind of Behavioral or any kind of clinical outcomes now because the device has many possible doses to pick from right we need dose instructions the dose instructions you're saying all right start at this intensity then go up to this point see what happens then try this frequency see what happens and tune it until you get the options that you want but we need those instructions to guide us among the many possible dosing options so how do we do that so we can take a step back here to 1965 which for me is really where I'm I would Mark the start of modern uh neuromodulation for pain and that is melzac and Walsh development of the gate control theory of pain it might be already familiar to you so I'm going to summarize it very briefly but in their paper they actually take a bit of a philosophical attack and they go back to Descartes a falaf French philosopher this is in the 17th century who had his own idea about um how pain works and the notion is that we start out here and we have some sort of um pain sensor some some part of the body that is sensitive in this case the Heat or pain perceptive perception and then there is a line now we know this would be an axon that goes from the leg up to the head and you can think of this line as sort of like ringing a bell in the head when we have pain we have this direct line to the brain and Bing that's how we perceive pain and Mel second wall started by sort of rejecting this notion of of a direct pathway and they instead replace that with this model that I'll summarize very briefly um and it's it's um it's actually rather straightforward once you grasp it which is I think partially why the gate control theory became so popular but they first said that look when pain information is traveling into the body it does not go straight to the brain it stops on the way in the spinal cord through a synapse and only then it's sent to the brain right and they're calling the axons the fibers that are transmitting the pain information these small diameter axons there are other axons these are larger diameter axons and they are not sensitive to pain they're sensitive to non-painful touch that information also goes through the spinal cord but it can travel directly to the brain as well so when we are touching and it's not painful we have this pathway and when we have pain we have this pathway so the key the first aspect of their idea is that you have two Pathways and they're both traveling through the spinal cord the second part of their pathway is this activation of the non-pinionful large axons will inhibit the transmission of painful information so what you can see here is that you have Painful information coming in and it needs to go through this T Cell as they called it before it goes up to the um brain and be felt and this is an excitatory pathway you have these large non-painful axons that are coming in sending that information to the brain but also going into the spinal cord where through this inhibitory synapse they block the transmission of painful information now this idea is very much analogous to um you know if you if you enter something and you rub it you kind of try rubbing it over so if you rub it it kind of feels better so the notion there is you have the painful stimuli coming and then you are um you're rubbing it in order to mask the sensation of pain where is that masking happening that masking is happening in the spinal cord that's where the junction is happening before the information is sent up now this is already a bit of a cartoonish simplification of the cartoonist simplification that melzak and wall developed and now we this this gate control theory has been studied for extensively the spinal cord has been studied uh much more extensively we've developed more and more intricate models of what's going on but for the purpose of what I want to describe to today I think this heuristic is sufficient you need to understand that there's two fiber types and the non-pable painful fiber type is blocking the transmission of the painful fiber type as travels through the spinal cord now this was a very Innovative idea uh as far as how pain Works uh but it was also very impactful because it led to a very specific suggestion of how we might treat pain essentially by mimicking that if you rub it it feels better with electrical stimulation so they directly and others follow the gate control theory with an invention of how to use electrical stimulation in order to control pain specifically using electrical stimulation to activate these large non-painful conducting fibers and therefore block the conduction of painful signal so what we're doing is we're applying electrical stimulation in such a way that we preferentially activate the large fibers that closes the gate this inhibitory synapse blocks the transmission of the painful stimulation and therefore you no longer feel pain now to make this work optimally you would want to stimulate the uh the part of the spinal cord where both these things are converging so that means that if you have pain coming from your right arm you'd want to stimulate the sensation large axons coming from the right arm and so on so you'd want to overlap as far as dermatome so now you see that they're very specific dose instructions that are consequence of gate control theory those dose instructions say find a part of body that hurts right you have chronic pain in this part of this body and place the electrodes somewhere on the bodies that you are activating the large axons the non-painful axons associated with that part of the body and apply enough juice enough stimulation to make them fire because when they're active right you're adding something but then that effect is one of inhibition now as a consequence however this pathway is also activated meaning you will feel it so the idea was that you should apply electrical stimulation in such a way that you feel non-painful tingling over the painful painful body part and that will block the pain from the body part just like rubbing it but now we're using electrical stimulation okay and that tingling that you get will be called paresthesia now once you have these dose instructions it turns out that there are actually several places where respecting those dose instructions you can place the electrodes now very natural places where the pain is occurring right so here you have red this is these small axons or the painful information being transferred up through the spinal cord here you have in Black the non-painful situation and this is where the gate is being closed you can see that by activating the dark fiber uh you will then close the gate and therefore the painful information will not be transmitted through and when you do that when you place an electrode on the surface of the body near where it hurts let's see back pain so you put the electrode on your back that is called transcutaneous electrical nerve stimulation or test but you can put the electrode somewhere else you could also insert an electrode through the skin with a small needle and place it below the skin right next to the nerve right so this would be percutaneous and so this is called percutaneous nerve stimulation or pns and the first people who actually tried it was this is the same wall from the gate control theory so wall collaborated with sweet and in 1967 which is just shortly after they actually invented git control theory they validated gate control theory uh using peripheral nerve stimulation and they also did it with hands so there's a very strong link between the creation of the theory of game control and the development of Technology to leverage it for the for therapeutic purposes and they're doing this both um on themselves and on pain patients well it didn't just stop there another location where you could stimulate uh is actually right here so this should be on the borsal columns the axons of the spinal cord as they travel up now you say but that seems like well it's sort of too late right it's after where the gate happens except these axons conduct both ways so you will be stimulating here and now be transmitting both to the brain producing this paresthesia that tingling and the kid you'll travel back towards the spinal cord and here the gate will form and so that will block um the transmission of pain and this was demonstrated by a clinician shealy and two Engineers Mortimer and reswick in 1967 right after gate control theory and they were aware of it and they acknowledged it as part of their motivation to develop this so this is now what we now call spinal cord stimulation that's and they're also calling it a dorsal cord stimulation um and you can stimulate it another place as well so you can stimulate uh at the dorsal root so right where these axons are entering the spinal cord this is something that we call a dorsal root stimulation now or or drg but all these ideas derive from gate control theory and respect very similar dose instructions they're all typically in their original form producing paresthesia over the painful region because if you rub it it feels better and so now we have again the schematic as I showed you before here's our neuromodulation device and the dose instructions are are explaining where we should place it and you can see that the theory inspired the dose instructions right the gate control theory led to Specific Instructions that inspired all these devices tens pns spinal cord stimulation um so then we have devices now that insert electrodes in certain locations we have dose instructions that go with those devices uh make sure you increase the intensity and place the electrodes in such a way that you produce tingling over that body part and this now produces an outcome in these techniques extremely successful but the question I have for you is this given the success right what did that success prove when you run a clinical trial with spinal cord stimulation what is it that the clinical trial is actually validating right is it validating the device and the dose instructions or is it validating the theory if the clinical trial is positive or even if the case series or the patient experience is positive does the fact that this was successful prove that the theory was right or rather that this intermediary the device and the dose instructions are right and obviously I have I think I have the answer here so we need to talk about more about how mechanisms drive device design and what I already showed you is that a single Theory such as gate control theory which is associated with producing paresthesia over the painful region can actually to multiple different devices in multiple different dose instructions such as spinal cord stimulation or tens but in fact even within one of those such as spinal cord stimulation there are different variances one group may look at gait control theory and develop spinal cord stimulation uh with 50 hertz stimulation that's the waveform but another group may look at gate control theory and develop spinal cord stimulation with 100 Hertz of stimulation or there may be slight variations in the size of electrodes that they use so the point is that a single Theory can lead to multiple and distinct device and dose instructions so that's one important idea that I think we could already see now new theories emerge for example one theory that emerged was that perhaps the way to control pain was not through the the mechanism by which we could control pain it's not by somehow adding this tingling thing but rather by stimulating in such a way that we shut down the transmission of painful activity altogether we essentially block those fibers that are carrying the painful activity we shut them down and so this was called you know this was has been developed in quite a bit of sophistication um some rings all that and I'm just calling that blocking Theory now blocking Theory does not necessarily produce paresthesia because it's not based on activating the non-painful fibers it's simply based on shutting down the painful ones and so the blocking theory has actually led to the suggestion for different devices and different dose instructions for example using higher frequencies and those have then been tested uh with um their own distinct outcomes and in some cases very encouraging ones and so what we see here is that when one develops a new mechanistic Theory that can inspire new devices and new dose instructions which in turn might lead to better clinical outcomes now along with gate control theory and blocking theories I'm going to group a whole bunch of of work into something I'm going to call scrambling Theory which you can think of roughly as I'm just going to um send electrical signals into the nervous system in such a way that I interrupt the reliable transmission of information think about it as you have like a a line carrying data and you just sort of start zapping it so that whatever is starting at one end doesn't show up on the other end right whereas normally you have signal now it produced static so squaringly theory is based on the notion that when when pain is transmitted it's being transmitted with sort of an organized and some sort of organized way and by just zapping away at it we can scramble that information and so by the time whatever shows up on the other end reaches the brain the brain does not read that as pain it's reading it as something else or it doesn't register it uh at all now scrambling theory was a new Theory and it led to the suggestion that we might make specific types of new devices with different types of dose instructions and those of course could could also be tested but something interesting happened it turned out that some of the devices that already existed and were being used uh you know already on patients were claimed by scrambling theory meaning the scrambling finger people were looking at this existing technology which was invented normally based on blocking Theory and they were saying oh no no it's not blocking in fact it's working but it's not working because of blocking it's working because of scrambling or the scrambling Theory may suggest oh we have an idea for a device and dose instructions but once you consider that specific device and its dose instructions you realize it is similar to one suggested by gate control theory and this is just fine but it shows us that different theories can Inspire the same device and dose instructions or think about it Opposite a single device and dose instruction can be claimed by different theories and now we have new classes of theories that have been enveloped uh there are theories that are based on the fact that the stimulation is not acting necessarily the spinal cord but is also acting centrally since that we then that in that even when you're stimulating peripherally that information is being transmitted to the brain maybe that's where we're getting the anti-paint effects their ideas that I'm very interested in that have to do with not stimulating the neurons directly but stimulating the vasculature the blood vessels that surround those neurons so that is a new mechanism there are theories about stimulating glial cells another very important player in the nervous system and so you can see a situation where these new theories might Inspire new devices and new dose instructions but not necessarily right because a given uh device and dosage structure might be um claimed by specific Theory so now we go back to this question I asked earlier you have your neuromodulation device uh It's associated with particular dose instructions uh how you're essentially programming it we apply it applying a particular dose to a patient and you look at the outcome if the outcome is successful or if it's not let's say it's successful what have we shown Works what have we proven we've proven that the neuromodulation device and the dose instructions work we have not proven that the theory works right for the reasons I've just explained if the outcomes are not successful right that and we've shown that this particular device in this particular dose instructions don't work and it might suggest as a problem with the theory or it might suggest we didn't apply the theory correctly in designing a device and in designing dose instructions so it's important to realize that that um often when you get a device right now if a device is being provided to you by a rep and they're saying well this is the device these are the dose instructions to to use it and this is the theory that back backed it up that theory as a conjecture that theory is important that theory is what drove the creation of the device itself but it might be right or it might be wrong and the device may work or may not independent of them can ask an interesting question um I mentioned that with gate control theory the notion is that you need to produce paresthesia tingling over the part of the body that's painful and that tingling represents activation of these large axons and that's what leads to the therapeutic outcome so uh it's a tick you would ask a question but can we get based uh therapy of pain without paresthesia so let's think about that now the initial dose instructions I presented based on date Theory said place the electrodes over the painful part or at least over the axons associated with the painful part and apply stimulation in such a way that you activate the large axons the non-paint carrying axons and that this will produce paresthesia but why do you necessarily need to produce paresthesia might it be possible to activate the large axons that are carrying non-painful information in such a way that we don't necessarily feel it and so we can um we can create a different version of dose instructions based on the very same Theory and here there's been a slight modification where we're going to still place the electrodes in such a way that we activate the axons uh the large axons associated with the painful region and we're going to apply just enough electrical stimulation to activate them to close the gate but we're not going to apply so much that you feel it we're going to be right in this little sweet spot just enough to get them going right like rubbing it so gently that you don't feel the rubbing but you're still activating a small amount of the underlying large axons but enough to produce a benefit so this is a different kind of dose instructions and and we can be even still more specific right and this is in fact how things are done in practice we can say first try to place the electrodes where you want them right based on activating these large axons right so maybe it's on the periphery uh maybe it's somewhere on the spinal cord now it turns out you're often not sure you put the electrodes where you should have the instructions now say start increasing the intensity until the person feels paresthesia over that same body part and that's a great test that we put the electrodes in the right part because if you put it in some spinal cord we're trying to treat pain in the left arm but we turn up the intensity and they feel tingling in the right arm we didn't put the electrode in the right spot now we moved the electrode now they feel tingling in the left arm so now the electrode is in the right spot but now without moving the electrode step two decrease the intensity and decrease it just to the point where the tingling goes away now the electrode is still in the same spot and because the tingling just went away we presume that we're still activating some of these large axons not enough for the person to feel it right but enough to have a meaningful effect so this is a gate Theory derived dose instructions and you can see we used paresthesia along the way but the therapy itself does not have paresthesia so it is paresthesia free paresthesia inspired this is actually something that is currently done in practice it has shown to be successful even so by the way even so the fact that we have a theory and we develop those instructions based on it right doesn't prove that the theory is correct and now I need to introduce this notion of a biomarker I'm defining a biomarker as something that you measure from the patient it could be subjective like I feel tingling it could be objective like you measure something about it and you use that biomarker as part of your dose instructions here the biomarker is the person reporting paresthesia you're adjusting the intensity and you are asking them where they feel the tingling and that's that's how you get the right kind of dose the biomarker is the subjective report of paresthesia but what I want to emphasize it so so initially when gate control theory was developed and things were working so well and this was being used as a biomarker it seemed to prove that gate control theory was right clearly right you feel the paresthesia if you rub it it works the pain goes away and so people thought that because we're using paresthesia as a biomarker and because the clinical therapy was working that proved the underlying Theory but of course when they turn down the intensity a little bit to the point that they no longer felt paresthesia but the pain relief was still there it showed that this biomarker was not this was not strictly needed is maybe part of the Joseph adjustment process but it's not strictly needed and now you can ask the question well was it was then the sensation of paresthesia the biomarker at all or maybe it's something else and so what we're trying to see what I'm emphasizing here is as much as we continue to use um mechanisms in order to inspire the development of devices and dose instructions actual success of something can is a bit disjointed from from those um mechanisms and that's equally true when we're using biomarkers biomarkers are inspired by mechanisms but they are um not mechanisms so this is my definition of of a biomarker in neuromodulation so it is a subjective or objective measure uh that you get from each patient as you are tuning the dose you're getting this biomarker from them and you are using that biomarker as part of those instructions uh and so dose instructions are calling on the biomarker they're referencing the biomarker they're saying for example uh ask them about paresthesia if they don't feel it keep turning the intensity uh up and this process now forms a a loop so if you start with let's say one particular dose you apply it to the person that produces an effect and you ask about the effect right do you feel paresthesia do you not feel paresthesia and then based on their answer yes or no the dose instructions tell you what to do don't feel that don't feel it turn off the intensity they say oh I feel too much it actually hurts the dose instructions might say to turn it down and so in practice neuromodulation dose instructions are loops with biomarkers this is generally the case this is how dose and structures work but I want to remind you that even when we use a biomarker and even when using that biomarker ends up being a big success uh it does not prove it does not establish that that biomarker is a mechanism or not even suggested now you've also heard the term closed loop stimulation I think that is a very powerful and emerging approach all they mean by closed loop is that this thing uh is being done uh by a computer and not by person so the dose instructions have been loaded into a machine and the machine is running the dose instructions meaning it's reading the biomarker and the Machine is deciding how to update the dose obviously with with a higher level of supervision or typically by clinician now it's important also to realize that when we talk about biomarkers there are two different kinds of bar markers and and I don't want to get too much into this right now but it's really important to distinguish this um otherwise um I think the whole consideration of how we use biomarkers can become rather muddled a responsive biomarker is a bar marker that changes with stimulation so for example paresthesia as we increase intensity the person will at some point feel paresthesia and based on what they report readjust things maybe we have a way to image the brain and directly image the brain's pain State and we use that so these would be typically what you call responsive biomarkers they're not the clinical endpoint they're not the goal of the treatment it's a biomarker but nonetheless it responds to stimulation now there are other kinds of biomarkers which are predictive and they are by definition not responsive to stimulation or not responsive stimulation in the sense of how we use them in dose instruction Loops so an example of that might be image guided placement so we need to know where to place the electrode so we take an image of that person that image is now biomarker and we place the electrode according to this biomarker but their Anatomy is not going to change word stimulation or sometimes you'd see like patient stratification so uh you have a hundred patients and 50 get the high dose and 50 get the low dose because of some characteristics about them but those characteristics are not going to be changed by stimulation but they nonetheless are part of dose instructions I think without getting too much more into it it's important as you consider how biomarkers are used uh you consider these two things and then there's a Twist right there's always a Twist the twist is that in neuromodulation there are some biomarkers which respond to stimulation but they are predictive an example of that would be the example I gave you of paresthesia based adjustment where the therapy doesn't actually involve paresthesia so remember what happened in that case we applied the stimulation intensity and we increased the intensity until we produce paresthesia right but then the intensity is turned down to the point that you no longer have paresthesia what that means is that paresthesia is not necessary to produce the benefit paresthesia is something that we use on the road to get to the right dose right but it is not necessarily there when we produce the stimulation so this is a subtlety a deep subtlety but one a very profound importance if you are designing or trying to use neuromodulation with some sophistication and it goes back to this point uh the greater point that we shouldn't confuse biomarkers with mechanisms now um uh among biomarkers that have generated a lot of interest recently specifically in spinal cord stimulation is something called ecaps so here we have a cartoon and we're applying spinal cord stimulation to the dorsal columns and we're zapping it and when we're zapping it we're activating these white matter tracks of the dorsal column and these axons are now conducting activity both ways up towards the brain uh but also down the spinal cord and from the white matter into the inner gray matter and when that activity enters the inner gray matter um it activates a synapse or synapses and those synapses are what are presumed to close the gate and so the therapy doesn't simply derive from the activation according to gate Theory doesn't simply derive from the activation of these axons but from the fact that the activity is transmitted into the deeper gray matter of the spinal cords but simply the dorsal horn and there is where the gate closes now people discovered that if you take another pair of electrodes and record you can actually measure the activation of these axons you can measure you can measure this this volley of external activity as it travels from the stimulation site on its way into the deeper spinal cord and this volley is called an ecap an evoked because evoked compound because there's a bunch of neurons responsible action potential and it reflects white matter Activation so this is what the ecaps look like and every time you stimulate pop ecap pop e cap and this is a form of biomarker and there are now closed loop systems that measure ecap and these are now machines that will automatically based on the size of the ecap adjust how strong will you stimulate so closed loop systems using um this type of biomarker and you machine needs to do this by the way because of the how quickly the intensity is being adjusted now uh when you develop these systems if you develop a system that says in order for therapy to be effective you must produce ecaps of this kind of variety then ecaps are a responsive biomarker right they are assumed as part of the system design to be essential right and I'm phrasing it that way to kind of maybe um uh jiggle something in your brain that may suggest you know what if they're what if they're not necessarily predictive not necessarily responsive but predictive but when I want to focus on now is a different thing a question we've been very interested in which was well okay here you're recording this um white matter axon conduction but you're not really recording what's going on in here right you're recording the activity of the axons as it passes by but you're not directly recording the synaptic uh geek control mechanism well could we record from that as well and that's something we worked on for a while and the short answer is yes you can actually record from what's going on uh deep inside the spinal cord this is something that we um call esaps uh it's not necessarily uh trivial to do so you need to be more specific and intentional about how you do your stimulation and how you do your recording for example I mean one thing that is Trivial is instead of stopping to record a two milliseconds you know you need to keep recording because these esaps are slow they're slow waveforms they're long waveforms which is consistent with synaptic activity gate if you will being slower than the initial blast of axons acid Travels by so now we have esaps okay finally going all the way back to gate control theorem and as I mentioned right this is gate control theory you stimulate large axons that carry non-painful information that information is carried into the spinal cord where through a synapse it closes a gate so this is an inhibitory synapse that blocks the transmission I'm excitatory information and this was sort of the cartoon that that simulates the idea and here you have the gate now what's interesting is you know where did Mel Zach and Wall come up with this idea what I already mentioned they were um a bit of philosophers they were uh uh um melzak was actually a psychologist so they were thinking a lot about the theory of pain what pain even means but wall wall wasn't your physiologist he was an electrophysiologist his interest was actually from recording synapse from recording from synapses in the spinal cord and specifically he hypothesized that the gate is a synapse and it's a rather slow synapse all synapses in fact are rather slow compared to um the conduction of action potential so he said the synapse uh hear this inhibitory synapse is the gate and it is reflected in a slow potential uh that he recorded So if you look at Wall's publication record it's dominated by his interest in the spinal cords generation of these slow potentials so here you have this initial fast Spike that we now call the ecap and here you have the slow potential that we now call the esap and he said that this slow potential was what was marking the closing of a gate so it's interesting that the gate control theory itself uh derived from walls recording of slow potentials his inference that these slow potentials actually represent the gate and from there we got to devices and and dose instructions but slow potentials were there all along and so now I think it's interesting we are looking at them again so in summary we have a neuromodulation device which provides a dose to the patient and with the response that you get from the patient will will be governed by is the neuromodulation dose now each you have different devices to choose from to begin with but even each device has many many possible doses that you could you could possibly test too many to test on any given patient and so to kind of narrow down the range of which which um doses we should use we are given dose instructions the dose instructions tell us how to tune the dose for each per person depending on on the treatment goals and those those instructions will rely on biomarkers I mean how do you just how do you tune into that person you need a measurement from that person subjective or objective that you're using to do it right and this is where we see um those Loops now theories about what causes pain theories about how neuromodulation Works how the nervous system neurons glia blood vessels respond to electrical stimulation all this theory is is always in the background and it's always developing and this theory is what we collect in order to invent neuromodulation devices and dose instructions right you can't invent the device without the dose instructions I mean not not from the perspective of creating that therapy you want to create a therapy you need to have a device and you need to package it with dose instructions and those come from our theories however once uh and by the way there's rather diverse sources of where that theory can come from we saw it could come from a philosophy uh it could come from basic science experiments like recording slow potentials um or quick results from Clinical observation right it could result from from uh frustration with existing Therapies and fiddling uh in the clinical arena with parameters and then the realization uh that you've stumbled onto something uh important very often how how these interventions are um uh brought about but all these things come together uh in as as part of this background theory that Inspire us to create devices um and Associated dose instructions and then we test them we test them on one patient we test them on multiple in the clinical trials we try to make these trials pivotal leading to you know FDA success and reimbursement and all that process um and that process uh importantly uh validates the technology it validates the device it validates the dose instructions and just that it doesn't prove that the theory was right it maybe corroborates it right and to the extent that we are not happy with what we are seeing clinically right and since we're not happy then we go back to the well right and we think about what is deficient in the theory or what we didn't recognize in the theory and then we could invent the next generation of devices with their associate dose instructions and we test them right and that is how neuromodulation for families and if you're interested these are some references that you can look up regarding dose what dose means uh here's that pain gate control theory I mentioned and this is our work uh