very pleased to have nll governess joining us to talk about her research on impact of epilepsy and memory performance and non-human non-human primate models of temporal lobe epilepsy and did her PhD in France with the very famous professor been a bit has been emory versus a is a research scientist or postdoc undertook an and is now assistant professor in neurology located at the research center where she directs the neuromodulation and epilepsy lab so very pleased to have her here as she's starting her lab and telling us what she's going to be doing over the next few years yeah thank you thank you for the invitation place so like Chris was saying I just started my lab maybe two years ago so it's a work in progress so what I'm going to present today it's what we are currently doing in my lab and what we plan to do do can you hear me well that's good okay so first I find I didn't know what kind of audience I was going to face so if I will give good idea to have if you're watching remotely will you please mute your microphone thank you okay operate disturbance in the brain with a deeper activity of the brain and epilepsy is the disease and it's characterized by recurrent seizure so the seizure is the same term of epilepsy you can have only one seizure but you're not going to be epileptic there is three million of America that has epilepsy so it's around one percent of the population 200,000 Nuuk each year still and it's not really age related so it's not like for packing tsundere people for heavy lips it can be it can touch very young child or very whole people so there is absolutely no age related and in most of the case the cause is unknown so we don't know the utility or the reason why you're going to have a seizure and why you're going to have recurrent seizure it can happen once but for some people it's going to happen more so every single brain and it in all animals you can introduce the seizure so that's something that is very interesting and that's something that we are going to discuss that as long as you have neurons that are connected between each other you can have a seizure and the way you are going to be able to induce the seizure there is many different way to do it so there is not one one model of epilepsy there is many modern of seizure so we have different type of seizure so just you again go back to the generalization so we have we call them partial fuckin but they are the same generalized and status epilepticus not the right computer the seizure is only going to affect one part of the brain to the place where the seizure is going to start is called the focus and the focus can do anywhere in the brain you can have a so it can be with or without lost of consciousness and but it's still the main characteristic of the focal is that it's going to stay in very small area of the brain at the beginning at least so if we also look at the different type of Pokemon we have the simple version so where the seizure is going to stay at the focus it's not going to spread and you're not going to have a lot of consciousness the complex portion it's when your decision is going to spread a little bit and you're going to have a loss of consciousness and the second secondarily generalized seizure it's when that evolved and barfed missed where are going to be involved and in this case you're going to have convulsive seizure so it's starting as a focal seizure it's spreading to called the brain and that's where you're going to have a generalized seizure so going back to the generalized seizure so the focus will there is not one focus it's like it's more spreading and you're going to have an implication of both hemispheres of the brain seizure generalized seizures of the tonic in this case you have a loss of consciousness and it can last in between so it's a very long you have the most of this is found in children then they're going to stop what they are doing stare at nothing and resume okay yeah I know you're good good good okay so for the absence sorry going back to that so you have the children that behave completely normally then they're going to stop what they are doing so if for example they are playing they are they are just going to stop and stare at the thing for a few minutes then resume their activity very normally though for them nothing happened but if you look at them indeed they were like blinking and nothing happened during this time most of the time this so it's not all of the children that they've loved absence that are going to have recurrent seizure later but most of them are very young so it's very freaking that the children that have absence are going to develop more clonic and tonic clonic seizure in the future the atonic seizure is another case when you have like a sudden loss of muscle tension so it's basically all of your muscle that just let go and you form so that's very dangerous because as you can imagine you don't know when a seizure is going to happen and in most of the case with the generalized seizure you're going to form ok the status epilepticus are the last one so in this case it's any type of seizure that can develop and become a status epilepticus so in the status epilepticus case it's when you have one seizure that is following another one without giving the brain the time to recover though there is no there is lost of consciousness and you don't recover consciousness in between this seizure so it's very dramatic and it's very dangerous for the patient so in most of the case it's a medical emergency so it's very very difficult to and that's from poor patient it's very dangerous but for the animals so when you induce a model of seizure and you have status epilepticus it's very difficult to recover at least poor monkey when we have a monkey under status epilepticus 90% of the time I know that I'm going to love the animal so that's why I don't te this type of seizure or I don't see the generalized seizure in my lab we focused on simple partial seizure the very token and and it's very already very difficult to manage on monkey because we as you can imagine we have a tons of regulation that we have to follow do that's why we want to have a model of seizure that we can control and that we can make sure of the safety of the animal that's our highest priority to do in my lab we focus on two type of seizure the temporal lobe seizure and the frontal lobe seizure do we have to see I'm going to focus after and on the temporal lobe seizure but I just wanted to give you an idea of what's going on and what we are doing but in the temporal lobe so the the seizure so the focus is going to come from the hippocampus so and it's going to spread but stay into you this network so if you start the seizure for example in depo campus it's going to spread to new nuclear second vents and all of this network but it's not going to generalize at least not on the model though the temporal lobe epilepsy are the most frequent type of epilepsy the onset is often in childhood or early child adulthood though the symptoms are very variable you can have like aura or like him it's like feeling most of the patients sometimes tells you that they didn't realize that they were having seizures they were like smelling like smoke for example and after when you do the heat you realize that they were having seizure for years without knowing it though it can be a strange smell it can be like a feeling in your stomach for example one of my monkey when we induced seizure it was vomiting every time not every time that he had was having a seizure but that was his symptoms he was like feeling nose ears and he was literally booming so we had to give him and she would and she vomiting even medication some of the patients are going to hear voice or like having like sensation different sensation also in their limp some of them in some cases you can have motor manifestation with like some chewing for example or lip smacking or people that are doing that and rubbing and some but it's very very I'm going to shout out to laugh hysterically the VCG are pretty short they can last one or two minutes and after the seizure you have like a kind of a confusion from the patient so he didn't really lost consciousness but it is not you know you need sometimes to go back to its normal state the second type of Eclipse unit we are studying in the lab is the frontal lobe epilepsy so in this case we induce seizure here in the frontal lobe and we can induce as you can imagine the frontal lobe is implicated in a lot of different things if you induce a seizure here or if you induce a seizure here you're going to have different type of manifestation the frontal lobe are the recurrent seizure rising from this area the possible cause at least in human it's most of the time a tumor head trauma or it can be genetic in this case it can be with or without a clusterf consciousness - again what we are targeting in my lab is not lost of consciousness we don't want the animal to lost consciousness and as you can imagine the symptoms are going to vary in function of the focus so here you are if you induce a seizure here you're going to have a motor symptoms if you induce a seizure here in the prefrontal area you're not going to have much motor symptoms except if the seizure is going to spread but in this case what we notice well yeah very not nothing much so if you just look at the animal you will not know that he is having a seizure and I'm going to show you some videos of animal under seizure so while studying this to specific type of seizures so first it's because this to specific seizure are pharmaco resistant does that mean that they don't respond very well to medication so pharmaco resistance is defined by if you tried at least to antiepileptic drug in a patient and they were not responding there consider as pharmaco resistant and also because as you can imagine one of the treatment for epilepsy is to remove the focus and if we serve if we do the surgery and we'll remove the focus so imagining that turning to imagine that you remove this part of the brain and you're going to have some memory loss for example and so that's very indicating for the patient and here if your focus is here in the motor area if you remove the motor from here area obviously it's not good for the patient so that's something that is very difficult to treat and one of the option is the neuromodulation in this case but to be able to apply our modulation and to try to treat the patient you need to know the network you need to know how it works you need to know what's going on during the seizure what's going on at the focus but also how it's going to spread because if you induce a seizure right if you induce a seizure if the focus of the seizure is here or here the network that is implicated in the propagation and the in the control of the seizure is going to be different so the other question that I you know I need to you address is why are we doing that in monkey we can do that in the house we can do that in rat but I choose to do it in monkey though first if we looked at the hippocampus on rats human and monkey as you can see here I'm not going to go into much detail for that but it's quite obvious that there is a lot of stimulated between the human and the monkey and a lot of discrete discrepancy with the with the mouse the directory yeah and so that's for the temporal lobe epilepsy project the other project that I told you it's studying the implication of the basal ganglia during frontality let's see and so that's the secret of the basal ganglia and what I really want you to study needs to look at the telomere cortical loop in this case in during the propagation and during we during the focal cortical seizure so in this case I am very interested in the vessel can be a receiving area of the thalamus and one major difference between rodent and moon and primate that drink in the thalamus for at least hinder basal ganglia a receiving area of the thalamus you have interneurons in primate that you don't have in rodent and so I really think that this interneuron I'm going to play a very major role in the control of seizure so I think that's why I decided to go with non-human cremate okay so very briefly I just wanted to talk about the type of model that we could use and the difficulty we have you have a right and a good model for seizure in monkey though as I told you there you can induce a seizure by modulating the GABAergic system the cholinergic system and and you can also induce seizures by doing a lesion so everything has been tried in rat monkey and it's very difficult to have a sustainable model in monkey so for example just your list you this one so IP injection of pillow caffeine that you can use for example for rat in monkey you're going to in to last a lot of monkey so in this study in the incheon marmosets I think they they lost a deal around 80% of the monkey died after the injection of pilocarpine so that's absolutely not something that I will be agreed to do on my animals so there is other models so for example one thing that will be interesting it's to study the genetic models so some of the papua popu so it's the type of baboon have developed a genetic seizure so if you flash a light in front of them they are going to have an absence seizure though the kid Ling has also been tried in in monkey but without really good success so the kindling can be an electrical killing or chemical clean kindling and so the way it works is that you inject a drug like many times and after a certain amount of time so for example if you stimulate the first stimulation is going to induce one seizure the let's say one week after you stimulate again and it's going to induce two seizure and the third week and so and so on and at some point the animal is going to develop spontaneous recurrent seizure so that's something that is it's a very interesting model it's just that in terms of regulation it's very difficult to manage so it's it's something that we are working on but we are not there yet the model that we choose to use is the penicillin model do penicillin is a gaba antagonist and it's very it has been where I used that for years to be honest and it works pretty well you just inject the pennies in where you want to have your focus and you're going to have seizure for like up to six hour I would say even sometimes eight and after that the day after the use the penicillin injection the monkey is only going to have intellectual activity the intellectual activity is just an abnormal activity it's like a spike of abnormal activity but no seizure were detected 24 how were the injection so you can inject the penicillin directly into the brain so if you want to target for example the temporal lobe you just lower your injection system into the temporal lobe do an injection of penicillin and you know that your animal is going to have cereal for six hour so it's a very good model if you want to study if it's because when you do electrophysiology specially on the monkey have to bring the animal upstairs you have to put him on the chair you prepare everything and if you don't know when the seizure is going to happen it's a real nightmare though with this model at least we know that we are going to have a good amount of seizure for up to six hour okay so I guess I can just spoke a little bit about this project then we will move on to the next one though like I said I'm in this project that's the motor cortex that's where we are going to induce the seizure then what we will do is to record the activity into the thalamus and see if we can modulate the activity of the thalamus and if we if we are able to modulate this activity by doing either electrical stimulation have they add the outputs level of the basal ganglia or later directly into the thalamus the other option that we have it will depend of the type of activity that we are going to record into the thalamus but if we can see that there is an increase of bursting activity in this thalamus during the seizure so for example I imagine that every time that you have an anecdote spike in the motor cortex you're going to have a burst in the telomeres and is if this bursts a certain characteristic we could eventually try a t-table calcium blockers to try to stop this bursting activity into the thalamus and if we're able to stop this bursting activity I hope to be able to disrupt this loop that generate and propagate the seizure though just to give you an idea just going to show you very briefly the type of seizure that we can have on a monkey so it's a monkey that I recorded long time ago and he's a half so how she will see is going to have Tony clonic seizure so just something like that but it's very focal you're going to see that it doesn't affect the other area of the brain if it works so just focus on is harm here and you're going to see that during this activity you just have like small tonic-clonic movement of the arm it doesn't spread to any to his face or to his lab and you can see on ECG it's very focal though that's the type of activity that we call in Toretto and so you're going to see that draining character he has a small turn more movement over you so that's exactly what we are going to do in in my lab so we are going to induce this activity this type of seizure on the monkey and record the dynamic activity at the same time the VA project is about I think her new super compost emulation so it's one new type of stimulation to treat temporal lobe epilepsy so it has been tested in a rat and it seems to be working pretty well on right so he had decided to test that in monkey so for that we induced temporal lobe epilepsy by injecting penicillin into the hippocampus and sorry the we are testing like I said the new type of stimulation that is called a synchronous distributed multi electrode stimulation though I'm not going to talk too much about that today and I'm going to focus about the other stuff that we are doing in parallel in this monkey because there we don't have the results yet of this study so we had this monkey and we know that patients are suffering from epilepsy if suffering from this specific type of epilepsy also suffer from memory impairment and so I was curious to see if we were going to be able to find the same type of memory lost and how a synchronous distributed multi electrode stimulation was going to affect this memory in because we were going to we are going to more the activity of the hippocampus we know that the hippocampus is very implicated in memory though there is a chance that if we reduce seizure it's good but if the patient don't remember anything that's not so good that we also want to make sure that the patient remembers and so that's why we decided to do it also in army so here I'm going to show you a completely different type of seizure so that's a monkey that has any temporal lobe seizure it flips some pile of seizures do you have the eg trace on the bottom here and you're going to see is just started to have a seizure here too because if we don't do any unit activity recording on this monkey it is completely free to move who is just one cable that is attached to his head but over then that he can move freely the decision is still going on it's a long one and as you can see nothing happened do if you had not seen the electrophysiological activity you will not have guessed than be sanding animal was under seizure and that's what happened to patient also that's why they consult only when there is a generalization but a lot there is potentially more patient that have this type of seizure because they don't know and investigate so for him the clinical manifestation was vomiting okay so we already induced this type of seizure into monkey so we have monkey a that has received 16 injection of penicillin and monkey B that I received 17 - what we do it's always give them a week in between each injection to fully recover so we induce seizures they have seizure for six hour and after that we give them the full week to recover completely though and that's what you're going to see so that's for example if we just record the number of seizure and after the penicillin injection so as you can see not much after 20 minutes but after 40 minutes you already have five seizures per 20 minute or e yeah so three to five seizure well bye-bye sorry right a lot of 20 minutes so it's a very good amount of seizure and each stage will last in between 30 to 60 s a second so when you really do with your - so if you want to true that's the new treatment it's very useful to have a high frequency of seizure though we just started that do you look at the anatomy and the effect of penicillin injection because we were very curious to see if the monkey we're going to develop a pokémon's sclerosis as a lot of patient have though I'm not going to go into too much too much detail because it's not my part but as we have seen here and there is a loss of neuron in C a1 and c4 but also in the tunnel cherries and an increase of ghee activation so we are currently looking at the Cephas so to see the spreading of activity after after the seizure into the temporal lobe so the good thing is that like I said this model can be used for Tara particular to develop and also to test her petting method but it also gives us the opportunity to get to study cognitive impairments that are associated with major temporal lobe epilepsy so in this case what we did was to use a visual pair comparison test so the monkey is facing a screen and you present a new object in front of the screen you make sure that he is going to look at it for 15 seconds though I don't know for right but monkey are very smart and they are looking at the screen and you present something at the screen and they have the hard fix but they don't look at the screen so that's something that is very if we were not expecting that but they don't they don't really want to do the task and you cannot really force them to do the task because that's not a task that implies any reward so it's it's a task that takes a lot of time and I'm going to show you here that we can start with let's see 100 picture and at the end to put the bass line you can only use 40 of them and after penicillin only 25 of them do it yeah we need to repeat that and it's very intense so the first thing to do is to make sure that the monkey is going to look at the screen so we have a stopwatch and I'm going to show you a video - the monkey is facing the screen and we have a that is looking at the monkey's eyes so we can see exactly what is looking at and after a certain delay we present again the new object and sorry we present again the old and the new object and we compare which one is going to look at most so if you remember this object is going to spend more time on this one so let me show you an example and I'm sorry there is a an issue with the encoding of the video so there is a flash and it's not supposed to be there it's not to injure Caesar but it's just an encoding issue so we present a new object so we make sure that is going to look at that and each red dot here it's where the monkey is looking at so we know exactly in real time what is looking at and where and we just have with the stopwatch we count 15 seconds and when the monkey reached this 15 seconds sorry it goes back to the delay so a white screen and as you can see it's looking all around during the white screen so that's the flash that I was making reference to then we present a new and the hold object and as you can see is going to spend more time on the new one then a delay then we reverse so the new is going to be on this side and the haunt one will be on this side so the side is randomized so one time it's going to be and the first time on the right or first time on the left just to make sure that they don't have any side preference okay so what did we found on our monkey is so patient as you know you and use a lot of Caesar into deeper compass the compass is implicated in memory we expected that the monkey we're not going to be able to remember the picture well that's not what we found in both monkey so at baseline they remember very well the picture but after penicillin they remembered the picture too and that's for the first monkey and that's for the second though the factory induce repetitive seizure we're not affecting at least this short-term memory though this one has you have seen was tested really like a short interval so it was between thirty to sixty second and what we also we were interested to see if it was any linked with the cumulative volume of penicillin that they receive because I told you we injected penicillin and I record the seizure tested the monkey then the week after we did the same thing so maybe it's just because after the first seizure they were very good and after you know the fifteenth you know fifteen times they were not that great but in fact it's not it's not related and the only thing that we found that was related was the cumulative dose of Penniston that they have received in the percentage of time that they are looking at the screen meaning that and I'm not it's just print very and we need to do more data analysis on that but it looks looks like they are losing their attention they just let us get bored they don't want to look at the screen and they look at it less and less with the time that will be the problem with that we need to do the same thing with the control monkey to see if it's really related to the penicillin if it's just because you know after a while the monkey just get bored and don't want to do the task anymore so that's what we are currently doing with some of our monkey that are right tamo for monkey that don't have any in seizure also we are going to do that with the monkey that have front-row seat have motor seizure so it should not have fact their memory because the hippocampus should not be implicated in that sorry so the other thing that we did was to test and their long-term memory effect and in this case we presented the new and so the whole sorry and a new picture 24 hours before the after the memorization and in this case the monkey was not remembering the the picture no difference between the new and the hold one after the penicillin and again and there was something the cumulative link cumulative amount of penicillin was negatively related to the percentage of time that the monkey was looking at the picture though that is only on one monkey and we didn't had a lot of that time behind - I am very less confident on this result to be honest so we are still trying to had more animals on this part so the other thing that I'm really interested in that we started was we know that mr. Pollard epilepsy is going to affect memory ok that's a fact we looked at it was affected okay the other thing that is very important in memory and that is going to affect memory is sleep so if you have about night you know that your memory is not going to be as good and the thing is that temporal lobe epilepsy is going to affect your sleep activity the sleep activity is going to affect your let's see the frequency of your seizure or near the the risk you have a seizure so if you have a very short night you're going to have more risk to have a temporal lobe seizure so as you can see it it's a bit of a mess right now so that's what we propose to do exactly the same thing but on the modern of motor seizure where there is no link in between motor seizure and memory so we should be able to see only the effect of a bad night and to do that right so what we did we have to create new system or like to adapt a system that was using in rat Oh monkey do we and decided to go with the system that is called encounter it's not showing up here but it's gone yeah and it's going the road and back that's something that if you're familiar with telemetry so what we wanted to do was to record the eg activity of the monkey at night so the telemetry system there is a lot of them but most of the time you need to implant the telemetry system on the back of the animal but this animal are going to have another implantable device then is called air surpluses it's for the stimulation of the hippocampus so I couldn't equipped my honeymoon with that so I needed to find another way to do telemetry system recording so what I did was to use this system which is a very good system for seizure detection that's the only one I found that is able to detect leisure online and to stand like a triger so you can send me a text message or an alarm or like a phone can make my phone ring something like that every time that the monkey has a seizure which is a great thing because right now in my regulation I have to wake up every hour at night to make sure that my monkeys ok so that means that we have a rotation system in the lab and we wake up after inducing seizure so the day where we induced issue we have to rotate so one is going to wake up at 3:00 the other one is going to wake up at 4:00 and stow and so on just to make sure that the animal is fine so if I'm involved you use this system and she proved that the system is working that would be great so that's also what I'm working on though because if not I'm going to study my sleep activity so for that we had you because as you may know if you work on rat you can put that on the rat head it's going to stay there the rat is not going to damages I put that on my monkey's head it doesn't last one second he's going to grab it and he's going to destroy it to a higher to build an enclosure system for the monkey and because it's a telemetry system we had to make sure that it was not in metal so we came up here with different design to be honest the first one didn't last a week it was destroyed the second last the second device lasted maybe a month and the third one has John the monkey's head and it's still working so we're making progress but it's it's difficult to be on something that is monkey proof it's really not something that is easy you just want to make sure that they cannot destroy it and they can destroy a lot of things though this system has many advantages so it's cost-effective because you can remove it and move it to another monkey's head the day after so it's not something that you can implant so you can really move it you can do your online analysis and and because it's not a fully implanted device and that's something that I really like you have your connector that is implanted into the monkey's head so that mean that I can use the same each electrode to record my telemetry system but I can also plug it to you my a phase system and I can record the EEG activity at the same time that I'm recording hippocampal activity or at the same time that they are doing their memory tasks so that's a very good advantages dueling and like I said we need to validate this system but it's in progress because well the two first monkey where with temporal lobe epilepsy so meaning that you don't record any abnormal activity at the cortical level so you cannot validate that because you were we were not able to make sure we had to induce porticoed seizure to be able to validate the model to validate the system so that's something that we are going to be able to do with the Newman that we are using with the focal motor seizure but that we couldn't deal with the temporal lobe seizure right so what we have will be system it's to ecog one EOG and one accelerometer plus the video so we are currently working on an identification of the Vigilant stage so the different stage of sleep using a 22nd epoch we do that manually and we are going to compare with the automated scoring so we currently have two states wakefulness light sleep deep sleep and non REM do Ansari and Ram so it's going to be difficult to identify the RAM but we are trying one of the thing with Ram is that it really looks like wakefulness but what is very important is there we don't have young EMG unfortunately in our monkeys so that's going it's going to rely on the power spectra of the on the power spectra your video but I hope that we are going to be able to use the ug for that so we are working on it and you conclude and just to give you an idea of what we are hoping to do next do ya Penniston is not perfect but it's a good model at least and we know that we every time that we are going to you want to have seizure we can have this on demand stager in the monkey and it's also safe probably anymore so that's really my point is that I know that they are not going to have any generalization because that's really what I want to avoid it also allowed us to study over parameters so that are affected by seizure like memory or sleep or different type of things and so what we would like to do next in you know model of temporal lobe epilepsy so like I said we didn't see any effect on short-term memory - what we can do it's to continue or work on long-term memory effect and also try to we just created a new task do do to test the spatial memory during this task we are going to present objects to like five objects that are randomly positioned then we are going to select three of this object that are going to be moved and we'll see if if the monkey can identify the new versus the whole picture that's going to be interesting if we just started that like they the monkey should be currently doing it right now at bad line to see if it's working on us and if it's working we will test that after injection of theater and here's the team so we like to thank you all of my collaborators so I work a lot with dr. gross Don still with Clara and yet against that is in charge of the anatomy back my Mooji that is in charge of the data data analysis for the temporal lobe epilepsy in the asynchronous stimulation dr. Whitman who was my mentor and still working with me on the telomere cortical project and so that's our lab members and the different that we currently have in the lab and also we have a strong collaboration with a lab in France and we just obtained NIH grants together though you were I need to repeat so you were asking why we didn't use the reward-based pants for the task for the monkey and so it's because it takes a lot of time to train them just to train them to do that took a lot of time and this specific task was not something that was that was not the point the point of the study is to study a synchronous dispirited stimulation and so we just wanted to know if it was affecting memory but if we use a different type of task like you were suggested and that will be create it's just that it's going to take a lot of time but the monkey and we didn't have this luxury at the time yes yes yeah so the sorry the pennies you were asking your opinion and how the penicillin is going to work that there is a lot not a lot but most of the paper using Palestinian we're in the ad so when you were not born and it just fade away after a while so what happened in epilepsy and seizure model is in the ad a lot of people were using makkac we're using dogs we're using cat and after a while it's just I think it's because it's because of the gyres I'm pretty sure no but and they discover some genetic modern in rats and Rodan and so everything moved from that from the monkey to the rats then the monkey is starting to go back so we have new studies that are coming with the pillow caffeine with the penicillin and so the Peniston has been arisen recently also used in rat too so it's a very it's a very good model because so you're going to it's it's a very basic thing you just block the gaba intact it's a very simple way to induce this easier do you just block the inhibition so you have a massive excitation so it nothing like opto genetics or something like that it's basic mechanism yeah yes but it's not it's not very easy to study so what we there is some way to study it just you need the attention deficit and this in the monkey again that's something that we need to explore but that's something that we were not expecting so we really need to think about again I think in make change in our paradigm to see exactly what we are doing to the upper campus and how we can really evaluate the deficit that we are interesting to our monkey so it's also so it it's surprising to some extent because the seizure is going to spread it's not something that is very that stage today per campus but at the same time there is also some studies that have shown at least in monkey that if you do a lesion in the hippocampus the monkey recovered very well and so you have some plasticity in the hippocampus that are going to you to make sure that the monkey are going to remember so for example and just link - evaluated study where she was doing some small lesion into deeper campus and she almost didn't see any effect on the memory only small effect on special memory so I think that's really the direction that we have to go it's in to spatial memory but we are going to also look at the attention deficit by looking at for example the number of picture that they completed though as you have seen so we don't know if you noticed but one of the monkey had decreased but the other one was stable so right now we've only to honeymoon it's very difficult to conclude on something but we are going to continue to look for that