[00:00:13]
>> All of us. Are. There it's like. So. Yes. You are. Thankful All right well thank you for having me and thanks to the organizers for inviting me I'm always excited to come over to attack I sort of feel out of place but I'm very happy to be around everyone so the plan today is to since I know it's a diverse audience that we're going to go through a number of things I was saying if anyone knows this fox and hedgehog parable I'm definitely a fox I like to do a lot of things and like to investigate a lot of different areas rather than one area only so we're going to go through a lot of things that the lab and I myself are very interested in in terms of how we can understand how individuals move and when they lose the ability to move how we might be able to develop effective strategies to make them move better.

[00:01:54]
I guess the other ground rose you can interrupt me at any time I plan to go relatively quickly because there's a number of things I'd like to show you and of course I put the sort of the coolest things at the end which I always like every talk of they do that and that's poor form I apologize in advance but we'll get there so.

[00:02:10]
And again trying to be better about this I want to make sure that I acknowledge my collaborators and the lab itself basically doing all this work I'm sort of now I get to brag about a lot of the things that some of the trainees do in the lab so let's see generally we're going to go through 3 chapters today and I'm going to point to this one because they told me that's what's on the the sort of set and I will sorry for those who are looking at the screen you won't get the luxury of the pointer but I think you'll be able to follow We're going to start with very quickly talking about how we think about the conceptualization of motor skill learning and how we may be able to characterize and promote motor skill learning in healthy individuals the 2nd part of the talk is really going to be talking about how we use these perturbation imaging approaches and I'll go from right off the bat all tell you when we're mostly thing and pervasive what we're thinking about and then the last part of the talk we'll be talking about sort of our next frontier and how we're trying to develop better technologies to concurrently image and modulator the system and in this case our system is the cortex and primarily motor cortex but also sensory So last 2nd I had to put in a video just to motivate this so is anyone a cup stacker competitive Cup soccer then you know this field the couple of people know it so hopefully this will actually work this is William Morrow he was the record holder in cup stacking So you'll see William here know.

[00:03:42]
So William is going to his job is basically to organize and sequence the stack these cups together. And so you can see he's quite good at it he has his group groupies in the back very excited about this he broke the record they said he couldn't break the 5 2nd mark he did it so point is that's an impressive motor skill achievement as you can see by the other vigils and that didn't happen just by accident he was not born a champion Cup Sachar right he had to learn how to actually do this or in a talk a little bit sort of at a high level how he got to that point so that's the 1st part how we think about this is we think about that essentially any change in behavior is underpinned by memory formation that's underpinned by neuroplasticity that's induced in a specific brain region and the most potent driver of neural plasticity is experience we still don't have a real drug or medicine that we can actually elicit the same degree of neural plasticity that experience can so if you remember anything from this talk you've had experience some type of neuro plastic change because you've created a memory about the information that was presented the other thing that's important of course doesn't show up here for the 1st time of all the time switches to talk which is great because then I can do fill in the blanks so these are the stages of memory formation and we're really in a focus on this interim stage which is consolidation so great consolidation that's the important thing that happens after the information is acquired or encoded and this is an important process where we can either stabilize the information that was acquired or we can actually even show evidence of enhancing that offline after the information has been acquired there's also things like a razor where you forget where there's transference where you transfer to another type of information or even integrating with previously acquired information how do we know that learning is occurred there has to be some sort of retrieval So we have to show time over time that there's a persistence of this information that's been acquired and just so you know after you retrieve you actually have to reconsolidate the information so that's actually an active process it turns out that each time you retrieve a memory reconsolidate in there can be slight changes in that over time so.

[00:05:53]
Again to reiterate the point the brain adapts and reorganizes in response to experience whether it be intensive juggling where we see structural changes in areas that are important for visual motor integration in the Post your product or text whether it's a mobilization after a fracture you can actually see maladaptive changes or cortical shrinking as someone has a fracture in their arm and they're not allowed to move it for a couple weeks so this is actually going to come become important later when I talk about some of the work of my graduates in their King who's actually trying to use this phenomenon to maybe booster potentiate plasticity and it turns out even in individuals who have had neurologic injury like stroke which is our primary patient population of interest that you can actually see reorganization as a result of the stroke both local to where the lesion has occurred but also into interconnected areas and that you can modify this reorganization through experience dependent class city buses rehabilitation So that's the very very very quick and fast start and then to everyone Ok so far.

[00:06:59]
So basically today and every day our lab is really interested in how can we measure and model a meaningful neuroplastic change after injury or in disease in humans in vivo non-invasively and our favorite way to do this is something called transcranial magnetic stimulation is of her own familiar heard of transcranial magnetic stimulation has everyone seen it.

[00:07:21]
Not everyone so hopefully Now videos work you may recognize the participant this is Dr Kay's are actually in our department as well but what I'm doing here is I'm holding a figure of a coil this is connected to basically a large capacitor when I triggered the system it sends an electrical current through magnetic wire you create a magnetic field this main that it field passes through the skull relatively an attenuated and induces these electrical currents.

[00:07:47]
In the underlying tissue in this case the motor cortex and as you can see when I stimulate her arm moves or twitches and really the workhorse of T.M.'s work is this m.e.p. there this motor of all potential that's a listed when we stimulate the motor cortex. Of course in the t.m.s. comes into flavors you when it's applied in isolation either single or non sort of repetitive pulses it's used as an investigative tool and you can actually probe different pathways in the areas that you're stimulating whether it be excited or an editorial in her cortical circuits or it is general cortical motor excitability if you applied in a repetitive pattern way you can actually modulator the activity in the underlying area that you're stimulating So it's 2 different areas that we're going to talk about both during the course of the socket and in fact the next part of the target and why I brought this to the forefront is that this is been used now for over 30 years really to probe cortical processing on airline behavior.

[00:08:48]
So one of my favorite papers I actually dusted off my old Speaking of the universe in Minnesota I went back and was trying to figure out why I was doing this in the 1st place I've been here now over 5 years and you start to think about what you're actually doing and why you're doing it and I went back and I realized that I was just fascinated by this idea that we could use this type of paradigm to probe the cause a little contributors to learning and we could really find out what areas of the brain are active when during that period of memory formation that support learning and this is a really really cool study that was done way back in early 2000 looking at using to mass in a repetitive way to try and disrupt activity in the motor cortex after an individual had trained on a certain task in this case a very classic 0 action time task and the measure of that is the skill score which will come back which is basically how well can you perform on a patterned sequence a pattern element.

[00:09:43]
Versus a random sequence so basically it accounts for a general motor performance improvement and looks at sequence specific morning and what they found is that if you apply to mass in that period after acquisition so during the consolidation phase you actually see a forgetting and a razor the memory suggesting that the primary motor cortex is cosily involved in memory consolidation for Syria action time pass a sequence specific learning.

[00:10:11]
Interestingly which is not part of the stock but another thing that I was interested in my dissertation is that sleep actually prevents this or razor from happening so you actually we have some rescue capability of sleep so of course what I try to do in my ph d. I tried to replicate that and look towards more goal directed movements that might be more related to what a patient might do after their injury such as a stroke in this case it was just a simple continues tracking task where they actually had to follow a pattern that was presented on the screen and we did the same thing we applied low frequency or disruptive T.M.'s after they had practiced the task the same on a practice time and it turns out we do inhibit the area we do inhibit primer cortex we see enhanced inhibitory activity in that area but we didn't see any influence on the ability to consolidate this and in fact even enhance this task so it suggests that not all tasks are created the same and there is a functional there's a sort of a individualisation of what brain regions are involved in motor learning at different periods during that memory formation phase.

[00:11:21]
What was interesting to us which we followed up in subsequent studies I don't have the time to talk about today is that the magnitude of inhibition that was experience through the stimulation or one might call it the effectiveness of the stimulation was correlated with how much change in their performance there was the more effective stimulation in this case actually the better they get at a retention of the labor intensive.

[00:11:42]
Ok So that is just a sort of starting place on where we're thinking about how we can look at the stages of memory formation I know I'm older learning and how we might probe the cortical contributors to that ability to learn and now we've got a little bit more excited later on thinking about what could we actually use stimulation to promote positive changes in cortical activity that may enhance skill learning and so this technique we like a lot in the lab which is called paired associative stimulation which is now pairing single T.M.'s pulses to the motor cortex time locked to a purple stimulus to a perforated nerve and in this case the median nerve in this case innovating the abductor policies brevis in the thumb and what you see if you do this at the right time i.e. trying to induce what we think of as a human analogue of Spike time independent plasticity you actually get an elevation and the excitability of the motor cortex following the stimulation so in this case that's what you're seeing here before the stimulation these are the responses you elicit like you saw on the video you see the simulations deliver for 10 minutes or so and after you get this persistent elevation of responsiveness in the motor cortex in this paired stimulation paradigm what's interesting about this and for those of you who are studying their apostasy may be at a semantic level or and not in a human level it actually shows very similar properties to what we know in terms of classical synaptic plasticity rules it evolves quickly it only takes 10 minutes to induce this it is reversible so you can see at 24 hours it goes back to baseline so it's not a permanent shift it's a transition and a handful of excitability it persist beyond stimulation so the stimulation is completed but we see this persistence of effect and it falls out Follistim porous if you get the timing wrong if you have asynchronous arrival of that after an input with the critical simulation you actually see the opposite effect you see a depression of cortical except.

[00:13:41]
So the unanswered question that we try to answer is that if you sort of exogamous Lee trying to induce neural plasticity using paired associate stimulation does it have any effect on motor learning in motor performance. So this is Jackie Palmer she's a talented post-doc in the lab who really helped bring this sort of study to fruition and what we see is that after we do the stimulation and it's not really important for the purposes of this talk other than we're looking at the gram line and the dotted line and you can see immediately after stimulation we get this heightened response in the motor cortex we see this enhanced of excitability So we know that we're getting some change in the activity in the region and then after they do that we have them actually practice on the Syria action time.

[00:14:26]
And we look and see how their performance changes and it turns out that the stimulation didn't have any influence on how well they could perform after the stimulation occurred so there was no at least in real time evidence of a behavioral effect. What was quite exciting and it fascinating to us is that we had these individuals come back one week later and we just had them perform the task again and it turns out the individuals who receive the paired associate stimulation the Neuromodulation protocol they actually showed an enhancement without any subsequent practice on the task of their ability to perform the task whereas the individuals who received a control stimulation paradigm they actually show evidence of significant forgetting so this is to suggest that these paradigms that value enormous of the story of facts it's really important to look not only at the performance within a session but also at the retention because again Alternately what we're really interested in is the persistence of this change.

[00:15:22]
Ok so then that's all great but not everyone has access to all electrical stimulators not everyone has access to transcranial magnetic stimulation especially individuals in the clinic so can we develop other ways that are low cost or modulators that don't actually require electromagnetic induction. So we were inspired by a work that was done actually in the early 2000 as well using sort of our mobilization to try and restrict sensory input and motor output and so on the study they had individuals mobilized for 12 hours and then they evaluated how well they could do a pointing task and you can see the trajectories are clearly more variable after the immobilisation and what they showed is that this was highly correlated with the change and excitability in this case of this amount of sensory area that they were targeting or think they're targeting with this immobilization condition suggesting there may be a link between a mobilization induced Neuromodulation and change in behavior for that that's I think what's important to appreciate is that when we're talking about these 2 must be based measures of excitability these just sort of twitches in the muscle that doesn't necessarily mean we're talking about plasticity So the individuals in a fall of study looked at can you actually change the amount of plasticity you can induce with this paired associate stimulation paradigm as a function of whether or not an individual is immobilized before that and so it turns out that if you mobilize someone and then perform pass you see a heightened response so you actually see an enhancement of the past like a fact and that's 7 straight here so this would be for a before and after.

[00:17:04]
Pass but before the immobilisation condition you can see an elevation of responsiveness So there's a heightened excitability then the individuals were immobilized and what you see is the now they have them do the past paradigm again and they show a further elevation that surpasses what you saw baseline So there seems to be an sort of a bi directional facto process induction as a function of mobilization suggesting that these.

[00:17:29]
Neuromodulation interventions are probably acting on similar subsets. So that's what Erin is undertaking in her graduate right now is actually looking at can we because partly we know now that there is a neurophysiological fact of immobilization and there appears to be a short term trans in effect on motor performance but we have no idea if it does anything with learning so what she's interested in is can we actually induce formalisation changes and excitability turns out that preliminary data suggest that we can that you have a greater amount of cortical inhibition after the mobilization compared to non immobilisation period of equivalent time yeah.

[00:18:13]
Sure yeah yeah thanks for the question so during the mobilization it's essentially 6 hours where they are wearing a sling and they have what's called a finger control and it's actually the same it that's used in the constrained use movement therapy studies that have been shown in stroke to be officious sufficient to restrict input and so they wear that continuously for 6 hours and then we bring them back to the lab and so they're allowed to go about their normal daily activities they're just asked to maintain their arm in the sling in the finger control and in turn then they take it off during Yes but we but we don't allow them to do much movement when they get in they have to be seated and then then we take the apparatus up and so we confirm that that actually does reduce the amount of activity during the mobilization mission so this is the immobilized group and this is the non a moment as Arman activity counts and this is the Melissa of sewing that we actually reduce the amount of activity in that arm and it seems to be that there is a relationship between this reduction in activity that we see as Asian and the amount of inhibition that we that we induce.

[00:19:18]
So that's Ok fine but the exciting thing I think the thing that has the most relevance for what we're interest in lab is a sort of functionally relevant plasticity is can we actually show evidence that there's a change in the amount of learning that occurs so in this case similar to the study paradigm before but instead of our to mass after the stimulation we actually have them be immobilized and what you see at least preliminarily is that there is an elevation of the amount of learning that occurs or there's greater retention in the group that was immobilized after training versus the group that was not suggesting that it might be able to augment these processes of consolidation that are current and potentially enhanced the effect of the training intervention Ok so that's chapter one how are we doing time is good questions on the other questions.

[00:20:27]
Yeah so the question is do we do we think that the immobilisation is just changing the variability in terms of the amount of activity that one undergoes Yes so with that's that's essentially one of the these sort of features of this that we think there are so it's probably not just a direct change at the semantic level in terms of modifying the sort of the threshold for firing but it's probably related to this idea of how much plasticity gets induced over the period of a day like this say experience is a driver plus a city so if an individual is not allowed to actually experience then it's expected that you're going to not have the same please save the amount of variability in that experience on a person to person basis but we haven't really thought about too much about how we can might characterize the variability say in or the stability of performance so that a trial to trial changes that that these individuals are more consistent in their performance or and that's manifest as a mean improvement versus they're actually just better but it's still the same on a variable it's something that we're thinking about and looking at because.

[00:21:27]
Ok so I think that was sufficient time for you all to read this and I don't have to go through it Ok So part 2 now this is the part that was sort of our bread and butter in the lab and what we're really interested in as a as a therapist physical therapist I'm really interested in this is where all our work is trying to go it's really great to be able to play with the nervous system and raise it and lower it and all that is quite cool but if it doesn't meaningfully change behavior then we're not so interested it's just sort of a cool party trick however we're really interested in is can we actually leverage that into changing outcomes for individual patients and so here is a video it's a little bit old it was actually recorded in the lab that I have now so this is now one of our therapist those Wolf who is part of a multi-center randomized control trial looking at the effects of this constraint induced movement therapy the gold standard right now of the therapeutic interventions for individuals with Post Road product arm impairment and so what you'll see is this individual he's just asked to try and lift a lid to a pot with his arm that was affected by the stroke and what he's saying is not so important it's just watch his movement of his left arm the stork affected experiment and this is at the beginning prior to the therapeutic intervention so this sort of a baseline assessment.

[00:22:55]
So he clearly has difficulty performing the task due to the impairments the residual parents and I should mention that this individual is well beyond the period of time where we think there is heightened recovery potential So he's in the chronic phase of recovery after stroke so in this individual we call it persistent disability or persistent impairment but it's really permanent at this point so he's not going to see a huge amount of change just going about his daily life and so he was enrolled in this trial and I'll show you an after video of him momentarily.

[00:23:29]
This is a big problem you all probably have someone either your family or friend route that has been affected by a stroke and to varying degrees the screw the friendly thing is that the prevalence is expected to increase by 20 percent and the medical costs are predicted to triple due to the aging population ages a huge risk factor for stroke the thing is with the good news is we're getting better at helping these individuals survive the stroke so less individuals are dying after their stroke but that means now there's more individuals who have survived that have rehabilitation needs that are going on Met because the same advances in rehabilitation recovery have not paralleled the treatment advances in acute stroke management like t.p.a. for example so what we have is an increasing number of stroke survivors who have unmet rehabilitation and so that's really the next chapter is how can we actually meaningfully improve recovery for these individuals will start so now I showed you this schematic a little bit earlier and we've added a real learning piece so not only do you have learning new skills we have real learning of old skills after the stroke which underlie this recovery of function and again experience is a very potent driver of that that's the constrained use movement therapy is based upon is really dosing of high high doses of repetitive track practice for these individuals tasks of it so after a stroke we see that there are not only Again I meant to this earlier changes around the area of in part but also in distinct connected regions.

[00:24:58]
And what was very exciting way back in the early ninety's is that rehabilitation could actually change the brain before that in terms of stroke rehabilitation people got better sometimes sometimes they didn't and we had really no good way of knowing what the therapy was actually doing so we had very little idea however Raney knew those groping Kansas experiments really do strokes in the motor cortex and looked at if you give these individuals sort of monkey rehab versus spontaneous recovery the motor maps the you look at electrical stimulation of these this amount of copy it's very different if a monkey had received this task specific rehabilitative training versus if they were just allowed to spontaneous or cover however again these animals never got to sort of their pre-mortal level to function and that's really our big idea or big goal is how can we try and get individuals to that point but there is a problem this individual stroke here this is diffusion tensor imaging reconstructing the cortical spinal bilaterally and what you can easily appreciate is that this individual had full disruption of their cortical Spinal Tap meaning no matter how much reorganization happens in the cortex there's going to be very little effect on behavior because the wiring is no longer there so for this individual it's very challenging as a matter of fact if you do if you perform to mass on this individual you stimulate them no matter how hard you stimulate no matter how Tommy how many times you stimulate you are not serious spots.

[00:26:26]
And this is again sort of an experimental verification of what we see in many of these individuals who have dense heavy police after the stroke because they they don't have the ability even if they are sending the signals they're not going to make it not dissimilar to complete spinal cord injury.

[00:26:42]
So this turns out to be an important prognostic indicator for individuals after a stroke if acutely you see an individual this is one of the reasons actually I went back to school to get my peaches I worked in acute hospital setting and individuals would have a stroke and some of them could not move their on that was suspected by the start and they would ask me well I get movement of my arm back and unfortunately up all I could say was I don't know probably not all of it but if you're a patient that's not very informative is it so it turns out that if you measure it this is some work that was has been developed over the years in New Zealand that if you measure simple measures of strength of shoulder abduction and finger extension if individuals have poor strength you still don't know if that's because there's a there's sort of posts stroke inflammation so in a 4 there's a number of factors that could be contributing to that however if you perform to Mass on these individuals after and you can elicit a response so you actually do get a response here that's a positive prognostic indicator that suggests that the neural substrate is sufficiently intact for the signal to get from motor cortex to the preferred and that means that you're expected to even have potentially a good outcome versus individuals if you cannot of the response you expect to have limited or poor recovery a product arm function.

[00:28:01]
So this is quite helpful for their pissed as well as for patients and families in terms of clinical decision making thinking about what is realistic for an individual to achieve the challenges is that we don't know if this will actually translate to other health care systems this is was all developed in New Zealand very different health care system so Mary Alice.

[00:28:22]
Is actually doing this now in fact as I was walking over here the i.r.b. approval letter came through so that was great so she's actually going into Emory Hospital and Grady and is going to do this we're going to evaluate these individuals and to see if it does actually if using to mask and improve our ability to predict where an individual is going to be in 36 months after their stroke because again these assessments are taken very early and so the reason I so this table is that actually has profound implications for how you might deliver your therapy so if an individual is expect to have complete recovery your therapeutic intervention is going to be very different than someone who's predicted out none are poor right that's pretty clear so invite me back in a few years if you're interested and there will actually be a better speaker too so have her tell you all about this very quickly how do we drive our process if we believe there are pluses is important for learning and the recovery function how do then when do we deliver it and really how we've done it is dosing and this is not surprising a process I mean it's that you increase the dose you tend to increase the main into effect in fact the time intensive nature of this intervention so this is based on the dosing effect so intensive rehabilitation many many tasks are petitions and after that period of time months of this intervention here's the same individual remember his left arm is the one affected by the stroke and he's pretending to do a cooking show actually years of he's very interested in cooking.

[00:30:18]
Agree so it is great but it's still not normal if it's improved and this is hundreds of hours of practicing of functional tasks specific rehabilitation we know from the literature that it takes thousands the movements in pop science you hear about this you know 10000 hour rule right is that the amount of dosing to effect permanent sort of plateau based.

[00:30:45]
Improvement is quite high the big problem is in rehabilitation we see like a fraction of that so we're kidding ourselves in the clinical community to think that we're actually optimally driving neuro plastic change with our current interventions. So that that identifies a problem for us from a clinical perspective so the question is and I think some of you in this room with your interest in this you're part of the solution as well is how can we actually augment currently best practice therapies because we know they're there insufficient.

[00:31:19]
So there's now we have technologies I won't get into that today really I want to focus on Neuromodulation approaches that might be able to augment responses to training of typical therapies so now we just update a little bit and we talk about and I.V.'s are noninvasive brain stimulation as a way to potentially augment the mechanisms of neural plasticity to enhance memory formation learning to promote recovery of function.

[00:31:46]
And so this is been done for at least 20 years now and in looking at conventional paradigms like r t m s being able to target either down regulated if the lesion or stroke affected excitability or down regulate exaggerated contribution or nonsmoker affected excitability. And this is all born out of this model that was created from early work showing that this bilateral activation patterns when individuals are trying to read perform movements with their product arm and so this idea that you have local and global cortical reorganization they have decreased If solution and increased consciously so excited billeted creating this imbalance between the hemispheres right and that this imbalance may impart be one of the contributors to this persistent permanent motor impairment we know that it's mediated by these direct except it's very transferable projections of project on inhibitory enter and that then influence the primal Salo put but this is the key is that it depends on the level of impairment that actually this imbalance may be.

[00:32:53]
Modulating by how much impairment initialize and the structure reserve an individual demonstrates so the point here is that a stroke is a stroke is a stroke that this model is only so good as who it fits and it doesn't fit ever so we're trying to now take a sort of homogenous intervention.

[00:33:14]
High frequencies stimulation to the motor cortex of the stroke affected hemisphere and all of these individuals in the red is where the stroke occurred different sizes different locations we think a bit naive to suggest that that is actually going to be a one size fits all approach that's going to positively model a neural plasticity an argument responses to therapies and in fact we showed this some years ago now is that we we did a study looked at this conventional one size fits all you have to start somewhere and it's a one size fits all approach to up regulating absolution all excitability this time in the system at a sensory cortex not motor cortex so we at least to try to get out of motor cortex and it turns out that in the active stimulation group individuals generally improved in their ability to perform the task but you can see there's variability.

[00:34:01]
Some showed remarkable sort of effects and responses and some showed pretty minimal and even maybe slightly no effect at all and it turns out that this variability could be explained about 72 percent of it and how much gray and white matter volume you had in the underlying tissue that you're trying to stimulate and that was only found in the active stimulation group there was no association in the sham stimulation group further suggesting that this is related to the effects of stimulation seems pretty intuitive if you don't have the substrate to stimulate it's hard to get a stimulation effect.

[00:34:38]
So we further gone on to try and again think about these ways we might be more sophisticated about individualizing Neuromodulation to induce positive neuro policy change we've shown that greater atmosphere coherence or this conic to Vittie between the motor cortical regions is enhanced after stroke and that it seems to be a state dependent effect we only see this exaggerated sort of coherence or this connecting between the hemispheres when they're active when they're actually producing.

[00:35:06]
A movement in this case is just a very simple sustained contraction. And it appears that there's a link between this exaggerated in our hemisphere inhibition and the amount of impairment have lower scores more impairments higher values more coherence between the hemispheres So the question is Is this a new potential biomarker target it fits with this inner hemispheric imbalance model we're able to actually directly measure how much activity is occurring between the hemispheres it seems to be associated with the amount of impairment an individual has it to us comes across as promising skeptical in the audience may not and that's great I'd love to hear more actually about that so we wondered is there a more promising Neuromodulation strategy than just simply stimulating the same region in everyone and just that single folk read it so I'm back in the literature looked and we found evidence where you can actually apply T.M.'s to the motor cortex bilaterally in a similar spite timing dependent plus the city paradigm where you're trying to optimize synchronous pre and post and after again this is very hand-waving because we're at the systems level right we're not looking at individual synapses but at a general at a systems level can we actually synchronize pre and post an attic activity and this is actually shown in healthy individuals about 10 years ago now to actually have an effect on not only the excitability in the target hemisphere it increases the excitability that's important to remember in the target hemisphere but also modifies the amount of interaction and the amount of inhibition between them misfires.

[00:36:51]
Further on the target and contra lateral to the target stimulation they actually show improvement in more motor performance and this is all in young healthy individuals so our goal is to try and translate that into individuals post rope so we essentially emulated the same exact paradigm the only thing we change at least at the outset was the population to be studied.

[00:37:14]
But then since we know that plus the city induction and by timing to process the timing it's crucial we found evidence in the literature that actually if you don't get the timing right you get an opposite effect so simply by shifting the timing by 10 milliseconds in terms of pairing stimulation between 2 cortical regions not dissimilar to what we're attack we were attempting to do can actually reverse the plus to do so basically the opposite of what one would hypothesize or an anti have been plasticity effect if you don't have the timing correct that scared us a little bit given that we know that after stroke individuals show varying levels of structural change so we have actually shown previously that there's reduced Mylan for example an individual's poster of well if there's reduced Mylan one would presume that those could be changes in signal conduction between regions so with that knowledge and with this work in healthy individuals we decided to go about trying to individualize the stimulation interval between the 2 pulses what we call the conditioning poles and the target pulse to try and optimize the arrival of the optimize the synchronous.

[00:38:21]
Pairing of these stimuli for each individual patient. So this is our sort of 1st attempt at individualisation of Neuromodulation and this is these are just examples of the timing between the stimuli and looking at individuals where you elicit the maximal response or the maximum amount of inhibition and using that interval then to guide the stimulation delivery versus So normally the standard one group the standard is 8 milliseconds between the 2 stimuli.

[00:38:55]
In these 2 individuals what we saw based on the maximum fact it would be 10 milliseconds more clear for the individual stroke and then the able bodied individual and when we do that when we actually individualized compared to that standard email say interval we see a heightened effect and we see the majority of individuals so a greater response to the individual ised condition versus the standard condition.

[00:39:22]
Yeah yeah so the question is the the range of end of the individual and so we limited it to what we know sort of from just the conduction time that anything before 5 milliseconds is not possible and then outside of say 25 milliseconds now you're engaging potentially other pathways in this inhibitory process so we limited it to between this 5 to 25 millisecond interval for this case once you get outside of that it gets a little bit murky on what you're actually so this we think is directly trance closely mediated inhibition.

[00:40:02]
And so then the last thing I want to tell you is the other just example is that when we individualize not only do we get a heightened. Effect in terms of changes in excitability in the exclusion cortex we also get a stronger effect on behavior so individuals after they receive the individualized intervention so it enhanced skill to a greater extent that receive the standard they still improved with the standard compared to a sham stimulation but to a greater extent with individuals so we're actually following up on this now in a larger cohort to see if we these these are stable and they are retained over time this is just 30 minutes after the stimulation.

[00:40:42]
And so we've done this quite a lot I won't go into all the details suffice it to say that's sort of the main goal and we're trying to look at stimulation or and i.b.s. related paradigms to modulating activity as a way to maybe potentiate the recovery of function post.

[00:40:59]
So I hope I've convinced you to some extent that none of us a brain stimulation can be an assessment tool to evaluate changes in excitability and connectivity actually and that it could be used potentially as a promising Neuromodulation tool if you take into account all the challenges as it relates to what we know as a specific medicine.

[00:41:20]
So we're going to the last chapter and this is going to be a whirlwind I can see the the attention levels and waning substantially which is understandable that was a lot so this is like the 10 2nd because this is the this might be the coolest part I think so if you didn't if you don't care about stroke rehab you can come back and Ok so all these great things about T.M.'s It's so awesome we use it all the time.

[00:41:48]
But it's limited and the fact that we've known it's been limited since the day it started right we're trying to say something about cortical excitability by measuring in g. and a muscle. There's already a problem there right so we're saying this peak rate this peak to peak amplitude tells us about.

[00:42:08]
Cortical excitability very very amazing elegant work in the early ninety's actually localize the effects of stimulation to the cortex to some extent not fully but we still have to appreciate that there's going to be spinal excitability influences changes at the level of the muscle position of the muscle actually changing stress receptor activities so on and so forth so there's a number of factors that can influence this and make it not a one to one assessment of excitability The other problem is we can only elicit a peripheral response from a select number of cortical regions so if you don't care about the motor cortex T.M.'s really isn't for you if you don't care about the visual cortex T.M.'s really isn't totally for you if you really care about connectivity as say a graph theoretical approach for example to miss really isn't for you right because we can only stimulate one or 2 reasons at a time so we thought we were really optimizing the technique by adding 2 coils some other groups the surface into 3 calls but that's about as far as it's gone in terms of focal stimulation but to appreciate the network level of interactions it's really difficult for a team asked to do that as terms of a probe So our solution is not the only solution there are a number of solutions but our solution to address a number of these limitations is to combine mass with e.g. in real time so this concurrent integration of T.M.'s with e.g. to be able to not only stimulate say the motor cortex and measure responses from the peripheral muscle we can also measure responses from the adjoining adjacent region but also we get responses in distant regions and we can actually measure that through space and time so for those of you very quickly again e.g. measuring protocol dynamics so this is also a benefit that we can actually measure it elicited activity directly from the reason that we're stimulating.

[00:44:03]
And I've shown you this what we do is we actually localize the anatomical reason I want to stimulate and so now it doesn't have to be motor cortex it can be anywhere you can do post your pride of cortex you can do temporal doors a lot of prefrontal cortex doesn't quite matter and actually helps if you put someone in the scanner and you get their anatomical image you can use you you can use standard m. and I coronets to try and find the exact spot that you want to target so now the options for stimulation location are have really sort of manifest of the mushroom and what we do when we stimulate is what all I want you to see here is just this is stimulating over the level of cortex stimulate over the right motor cortex and the difference between the 2 and the idea here is that we get a very rich sort of output of spatial temporal dynamics that we know exactly when the input was delivered and we can measure actually that input travel throughout the system.

[00:45:03]
And so you can see at 30 milliseconds the responses are quite different localized sort of on the front of central locations versus at 60 milliseconds it now appears to be more lateralized and this we can actually do a lot of fancy things to try and get into what this means and what that signal propagation over time actually is telling us but now we've at least opened the door to be able to have a new tool to assess cortical connectivity in health and in disease in response to training and looking at it over periods of time but this is this is sort of where we're going as a as a lab in terms of what we're looking at in characterizing their 0 plus the city and so we've done that after stroke we've shown that actually directly by direct stimulation response that I showed you earlier T.M.'s of all coherence is different after stroke we've actually looked at sort of the analog the Igi analog of any piece of this and we see that the profile of this vote response from cortical regions directly is actually also different so we confirm that what we would expect but now we have the data to show that and that it seems to be correlated with persistent impairment in chronic stroke and so our goal really is to measure cortical connectivity in stroke to be able to probe and really characterize these complex spatial temporal dynamics and have a really strong time lock probe to be able to do that have these event related dynamics rather than trying to characterize this over sort of a period of time say at rest or during an activity we can actually input signal and watch it move.

[00:46:33]
And importantly we can measure it in the time domain or in the frequency domain so we can look at oscillatory activity like I mentioned before looking at what we think of as information propagation throughout the system or we can just look at how reactive a given area is to say get a sense of the level of damage to that area.

[00:46:52]
Ok so we're doing that the other sort of ongoing projects Jackie is actually doing this to look at the lower extremity So all of what I've talked about today in stroke has been the upper extremity of or there's a lot of balance impairments the decreased ability to walk after stroke and subject is really leading the way in trying to figure out how we could use this concurrent T.M.'s e g approach to be able to understand the cortical substrates of the walking dysfunction post row and then we're doing some fancy modeling with some collaborators at u.c.s.d. to try and again model this signal propagation of the t.m.s. a vote response so what I think is the clinical promise so again I hope I have already said this but really the key also with e.g. is that we can measure responses on biologically relevant times go so we can in theory get a real time.

[00:47:43]
Output or a readout of cortical connectivity using this approach so we know when things start and we have again millisecond resolution on our signal we may be able to actually figure out changes in that spatial temporal domain you need to a specific condition we can also look at different brain states really can work showed very early on that if you try and do teach us of o t g 2 in individuals in the minimally conscious state you get a very different output than an individual who's healthy and then very very exciting is now flipping it and using it to guide when we stimulate So the idea here would be we see xperience state stimulate we see why brain state don't stimulate so we can actually and this is been done now and in a lot of.

[00:48:31]
Seamen have done this and showed that if depending on if you stimulate on an up state or a down state of the rhythm you get very different effects. So again going back to earlier on this conventional one you know one location just do it at one frequency that's I think a bit antiquated I think this is the sort of the future is being able to use an individual's own brain brain signal not too dissimilar to the CIA approaches to trying guide how we moderate the system to be more effective in moderating the system and then lastly just that ability to probe non motor circuits so to be able to understand circuits that are not usually investigated with stand alone T.M.'s.

[00:49:13]
And then last but not least I have to give a plug to Lena and her former graduate student post Aiden who are working with Jackie to now I've talked about top down I've always said that I'm a self-proclaimed brain ist I'm really like about the brain and that's what I focus on but they they've developed this very elegant paradigm to use the balance perturbation platform to now induce a perturbation from the bottom up so these and Jackie is measuring in are measuring these of both e.g. responses to this to try and evaluate what we see in terms of cortical control balance post struck we have very little idea of any any control that's of all but we do see a signal and as a matter of fact that he's doing some nice work that she's currently in the process of writing a grant for is looking at localizing these evoked responses to a balanced perturbation in the brain to specific order to reason seeing that those in both responses differ in their anatomical location as a way to try and understand this reorganization Post wrote and where we might identify new therapeutic targets or new regions that we might want to intervene rather than again these classical motor cortex here you know maybe it's the motor cortex for patient a maybe it's the prefrontal supreme motor cortex area for patient b. and now we have this at least a way to increase the parameter space on how we might individualized or develop precision medicine based interventions to help our individuals So with that I'll just close and say I think that again I hope I've convinced you to some extent that although there is a lot of challenges that still need to be addressed I think that characterizing in positively Augmentin neural plasticity does hold promise for improving movement ability both in health and disease of course I'm more interested in disease but this could also be used for regular human augmentation in terms of performance and that we have these now noninvasive perturbation imaging tools that allow us to go.

[00:51:13]
It a really sophisticated window into what's happening beneath it so again there's a lot of limitations of human subjects research is a lot of challenges we're trying to characterize neural plasticity in excitability at a systems level but these I think improvements in the tools that we have available allows us to ask better questions and get better answers now and I think narrowing the gap between sort of very elegant basic science work and some more of our applied human and their science work and then I think also you know it doesn't just have to be when I think about perturbation imaging this last year is really opened my eyes to think that perturbation can be a number of things whether it's a mobilization we are actually perturbing the normal system by having an individual where a sling all day and not allowing them to actually interact with their environment normally or is it just a very brief perturbation of their balance that causes them sort term loss of their balance and we can actually measure the neural dynamics of that so I think it's a really exciting time to open up how we can use these perturbation imaging approaches to understand the cortical contributions to movement and so I did live up to the title even though I didn't think I would in the end so with that I'll put up the collaborators again and thanks to all of them for their input the funny agencies our research participants and members of the lab again Who are some of which are in the audience thank you for coming not just for the free lunch hopefully and I want to thank you all for attention I'll take any questions on our last bit of time.

[00:52:48]
Yes. Yes So the question is when you when you stimulate you induce a huge electrical artifact for one in the simulation and so one way we deal with that is hardware actually that we can now get returned to baseline activity within about 5 milliseconds after the stimulation is delivered so we can get what we consider physiologic signal within 5 milliseconds after that but we also look at pre post simulation to see if there are actually underlying changes in the the Igi signal that may or may not be related to the.

[00:53:49]
Right. So yes so the so the actual induced activity so that's actually what we're really interested in is right at the induced sort of this phase locked activity that solicited by the team asked to see this reactivity change and so we know from animal work and from some other very nice work that the responses last about 200 milliseconds and so we look in that time window to really see this focal least in the area that's focally stimulated right the other propagation can last longer and other cortical regions but within the reason so local to the side of stimulation we look at the 1st $200.00 milliseconds to evaluate the vote reactivity So looking at this phase but there are ways that you can use a look at it outside of that to see if there's a persistent effect or compare that period of time to sort of pre-stimulus activity but that's really what we're sort of interested in yeah we do yes so in some ways it might be considered sort of an exotic ness activation of the but it's really what we're what we're focused on.

[00:54:54]
Yeah. Yeah so and in terms of this I assume you mean sort of perturbation the multi-modal things yeah so especially one of the ways and some colleagues in medical university itself Caroline are using this approach to use what we call e.g. inform to Mass for drug resistant depression so indorse a lot of prefrontal cortex looking at different rhythms and only stimulating when you see sort of what we might consider the average rhythm to try and do this phase resetting for example so that's just one I think really sort of obvious example but you can imagine sort of translating that into any number of neurological disorders where you at least have a quarter call substrate although we know that stimulation is going to indirectly affect some cortical tissue really when we're talking about sort of using e.g. for example to guide stimulation to the very really interested in the cortical sort of activity and so any you know the other one that is been talked about I don't know if anyone's really doing the looking at even an $88.00 c. or in other reasons that are considered disorders of conic to be.

[00:56:03]
Looking at trying to identify sort of the prime node of the comic to Vittie and trying to essentially disrupt it to reset the system in a sense so those are some just a few of the ways that I think this approach is being investigated or kind of developed in the field.

[00:56:28]
Well there are yeah there there are and that's that's sort of the I said that I should have added the cabbie with. The other thing is that I say yes we do all this and but the magnitude of fact actually of just stimulation alone is quite transience quite small so if we just do for example we've never had a trial that we've done if we just do stimulation alone that we see a persistent change in behavior so it requires that pairing or that synergistic application with an actual experience of the stimulation alone doesn't seem to do much for that there are some there is some reasonable evidence showing like for example using Transcranial direct current stimulation while someone is doing a cognitive task if you hit the right area that you can see sort of in the moment improvements in performance but then so that's what's gotten the sort of our mentation the stimulation and you know you can wear it during your test and you're going to do better and of course it brings up all the other issues is where do you stimulate how much you stimulate and so at this point it's totally unadvisable for anyone to try and use any kind of stimulation on their own to try and augmented performance you might augmented but it's not at all certain that it will be for the good.

[00:57:47]
You.