Carol Tamminga, MD: "Is it Psychosis or Schizophrenia?"

okay we have it's noon and early in January so it's still proper to wish everybody happy new year happy 2019 this is our first in the series of the Lin Kay Warren foundation of neuroscience talks and I'm very excited to have dr. Carlton inga join us today dr. dominga received a medical degree from the from Vanderbilt University and then she completed a residency training program at the University of Chicago she then went on to go to the National Institute of Neurological Disorders and Stroke stayed there for quite some time and then since 2003 has been in Texas at UT Southwestern really she current is the chair at UT Southwestern and has really had remarkable influence in the field of psychosis research from my perspective the most notable which he has many many accolades and has really had impact and all levels the things that has struck me the most is she's been one of the founding members of the International Congress of schizophrenia research which has really become one of the premier meeting for schizophrenia research across the world and has brought very really a broad range of researchers together for a number of years I used to go regular to was the scientific quality was just tremendous but beyond that I think that what really strikes me with dr. Mingus she's been trying to understand what is really at the heart of what we call schizophrenia and how can we use that knowledge to develop better and more efficient treatments in over the last few years and we've heard other speakers talk about this too there's been sort of the revolution of how we think about psychiatric disorders in terms of not just a specific diagnosis but in terms of range of dysfunctions and again dr. dominga has been at the forefront in trying to create an empirical basis for for the improved understanding of psychosis she's one of the principal investigators of the B snip study which is a large-scale study of bipolar and schizophrenia patients with a very detailed assessment of these patients in order to really try to tease apart the biology that underlies these disorders so I think it's very fitting that we have somebody who is so let's contribute so profound into psychosis and schizophrenia research opening up for 2019 wkw foundation lectures thank you very much for coming Thank You Martin I'm absolutely delighted to be here and Martin has given me an opportunity to not only say happy new year but also to acknowledge the role the William K Warren Foundation and the International Congress of schizophrenia research because the William K Warren Foundation was one of the founding sponsors of that meeting and it's morphed a little bit over time but we certainly appreciated it what I'd like to talk about today is and so I titled this lightly as it schizophrenia or is it psychosis and perhaps none of you really care about that but the the dimension of schizophrenia has been divided in these the different different and named the diagnosis by the DSM and in some people's mind these individual categories of diagnosis have really impeded research so we want to really see if we took all of these different dimensions all these different diseases that we sometimes think of as diseases and if you put them side by side and examine these people biologically what would we see would we see that there were well I'll tell you how the story developed over time whoops I have some disclosures I am on I'm a consultant for these companies here all of which are making new and very interesting medications for the treatment of psychosis all these medications are actually antipsychotic medicines they're not anti schizophrenic medicate medications I've been very I've been very much lucky to be part of a big group of psychosis investigators around the country that you see here the ones on the top are the five pis of the bee snip study and we're raising a middle level of people that have to have a big group of young people that were bringing along in the area of psychosis and it's all gotten very interesting and this is the story that I'll start with today and then I'll get you into a little bit more of my own research clearly there are people there are people who work in the field who are clinicians and think about clinical diseases and notice that psychosis is really a dimension of psychopathology that you can see in many different diseases it's not only it's not that psychosis is limited to psychotic bipolar disorder or limited to schizophrenia you get psychosis in many different brain disorders neurologic and psychiatric together it was Nancy Andreas and some number of years ago who first called called different who first used the term biotype and you'll see the significance of this terms assumed and drew attention to the idea that what we had to measure things about the brain like when you think about the heart you measure heart rate you measure the strength of the Cardiac I'm not a cardiologist gives me the strength with which the heart pumps blood you were the peripheral resistance and things like that we had we just don't have you have that much in psychiatry and this is how the idea have evolved for the for this particular study that I'll show I'll show you so schizophrenia is a diagnosis get so affective disorders that diagnosis psychotic bipolar and diagnosis we understood that there were areas there were areas of overlap in the middle spaces we did not start out to really show that there were these were not diseases we started out with the idea that we started out with the idea that when somebody comes in a doctor's office with psychosis what we wanted to generate was some intermediate phenotypes some measures we could do of the brain EEG brain imaging that that we could use to make the diagnosis we knew there would be some that would fall in between diagnoses but we were counting on having one or two of these follow-up schizophrenia one or two of these call fall on schizoaffective one or two of these default on bipolar disorder so that when a patient walked into your office psychiatrists sit down I talked to the patient for an hour when I when somebody with the with a neurological disorder walks into a neurologists office they sit down and talk for 10 minutes and then the neurologist sends them out for two weeks of testing and then they come back and they get a diagnosis that's what we were looking for we were looking for this two weeks of testing the the idea also was that these intermediate phenotypes would fall differentially onto schizophrenia and that genes then would be attached to these intermediate phenotypes I show this hypothetical picture here because this is how we started out with the study I'm going to report you but I'll just say in anticipation that what we found was something entirely different than this but I just wanted to show you how you could how wrong you can be at the beginning but work at it carefully and collect good data and then correct yourself by the young so this is a page of data and I'm just gonna direct you only to this line right up here so this study this beast if this first beast of study included three different groups of psychotic pro bands and they were but this is adds up to about a thousand Pro bands and there's about one-third one-third one-third of each of the diagnosis a thousand of their relatives one relative per bipolar disorder four people and about 450 normal controls so it used to be before I did this study it used to be that I did studies with well I was pretty happy when I broke into double digits in the study so that twenty or thirty or forty seemed like a huge number now in fact were on be snipped to not even be snip one anymore and we're headed up to three thousand pro bands not just one thousand programs and it really goes to show what you can do with more power with more power in your study so what do we actually measure these thousand Pro bands these thousand family members and the normal controls we collected these clinical measures a skid medication lifetime history symptom scales we didn't do this we did not do the symptoms skills and normals it's a psychosocial scale personal and family history personality inventory so these were collected on each of the people and then we collected some of these biomarker measures or whatever you want to call them FINA phenotypic measures we looked at cognition we did a backs and then we we did others other computerized tests in addition to the backs we looked at i'm movements we looked at EEG both resting state animal potential we looked at MRI mostly in this in this study mostly structural MRI we looked at resting state fMRI and its connectivity DTI then we drew blood for DNA and i'll show you a little bit about that in a minute we had we've begun some plasma immune measures and we've taken in many of these but not all of them we've taken little dermal biopsies and we take those dermal biopsies and grow them into fibroblasts and then you can take these fibroblasts if you've read in the new paper lately these the the results of these these kinds of neural progenitor cell studies they're they're quite interesting and we have started to grow them ourselves I haven't found any it'll take a long time now I couldn't so all of these the these are the these are the measures that we had been hoping would diagnose schizophrenia would diagnose bipolar would diagnose schizoaffective disorder I could we've worked up all of these data for our very first V snip one database s has has has Martin who's gotten the V snip one database and helped us with the analysis also I won't um I won't bother you with the details of this but I'll just let you know overall that we did not find any of these biomarkers that fell on our conventional diagnosis so the diagnosis of schizophrenia of psychosis of bipolar disorder schizoaffective disorder were developed from clinical presentation they were they were never intended to be diagnoses that would represent brain activity it was everybody's hope that the clinical diagnosis would pair up pretty well with the phenotypic diagnosis and as it happened that didn't happen at all and we got a lot of data we published many many papers but still we didn't get a consistent story about a diagnosis being represented by an EEG for instance if you if you're thinking you have dementia you can go in and you can get an EEG pattern that specific to the dementia you can get a level of cognitive cognition and cognitive decline that would represent dementia you can go and get a an amyloid scan you could go and get a tau scan and you can see changes in the brain that's what we're looking for and that's what we did not find with our with our with any of our measures so in summary we found many interesting associations between psychosis and neurobiological measures that was really very fun so in this study we really we really were able to see some neuro by Mogi of these psychotic conditions schizophrenia was usually the most severe people with a diagnosis of schizophrenia were usually most severely affected but they were not different in kind than schizoaffective disorder or psychotic bipolar disorder I should just mention here that we've subsequently done a short little study by little I mean now eight year ninety people between psychotic bipolar and non psychotic bipolar just to see if we could cleanly see a psychosis interface and what we really showed was that psychotic bipolar bipolar disorder looks most almost exactly like schizophrenia and non psychotic bipolar disorder looks entirely like something else it's it wasn't our business to find that out but psychotic and non psychotic bipolar are very very different in terms of their presentation schizoaffective in schizophrenia were most often times exactly the same there was an unusual finding that we a structural finding that I'll show you later on that show that that suggested that bipolar psychosis was slightly different in its volume then schizophrenia like phenotype so I'll show you that in the future but what we but what we concluded was that there were no biomarkers none of these measures we made which reliably distinguished dsm psychosis diagnosis well that was awfully difficult for us because we've gotten together and we'd analyzed the data this was an NIH grant five years we're at 3 and 7/8 almost four years we have to we have to submit our preliminary data and make our plan for the next study or otherwise we would just have to disband so we're sitting there and it became quite clear that our original hypothesis which I showed you in that first very pretty picture was not right at all it was not even simply a little bit altered it was completely wrong so then we had to come up with another way of saying these data are still very significant so we could you can't go into grant and say we we have all these interesting data and we have five sites around the country we have very good site rep ability and between site reliability and all of that but we got some date and we don't know what it means yet but we'd like to collect more this is not the way to get more money from NIH so we had to sit down over a day or two and make make a story I don't mean make us an unimportant story but we had to figure out what we were going to do so the first thing that we did is that we pooled all upses men we put I have to get the right button here we pulled all of the B snip data from the programs so he took all of these 1000 programs and simply stripped their diagnosis from the we sit we stripped the diagnosis from the programs we had already we had already differentiated them from healthy controls we had looked to see if we could find biomarkers that were unique to their conventional diagnosis and then we carried out some multivariate integration we had about 70 or 80 different biomarkers now some of these biomarkers were not all independent there were really clusters of biomarkers that if that represented one or another that that were that were that were that were organized together so we did a multivariate integration analysis and we found those factors that were independent for each other then we went on to another kind of analysis where we asked the question are there subgroups here that are defined by biology that are not defined by by that are not defined by diagnosis and the answer was yes these were the categories these are the seven categories and six nine categories that we use which were independent categories these are all complex categories from those different biomarkers I showed you and we asked the question that amongst the our thousand programs are there clusters that look alike and the answer was yes and so we we developed that we just made up that word biotypes and we call these bio types one two and three which isn't very inventive but it was better than Tam and gun disease and any anything else we could figure out now this is what the numbers are that we that the biotype characteristics but let me show this to you in a in a cartoon this is essentially was it was essentially our study and this essentially is a kind of a summary in very gross pictorial illustrative terms of what we found so we looked at schizophrenia schizoaffective disorder psychotic bipolar disorder and when we looked at biomarkers we we saw these groups look almost the same so we just combined them into a single group that we called psychosis then we put these the characteristics of these people through a kind of a prism and that prism differentiated these people by cognitive control and sensory motor reactivity so this cognitive control is essentially all the markers we had for cognition and the sensory motor reactivity was like different kinds of EEG biomarkers we had and we found three different subgroups 1 2 & 3 now bio type 1 was clearly the people with the worst illness they had the worst they had the lowest ratings of anything they had the lowest ratings of cognition low but not very low ratings of cognition and bio type 3 was almost normal cognition which was interesting this is when we looked at EEG this is a bio type 3 had almost exactly normal EEG as well as cognition normal EEG evoked potential and resting state if you look then at bio type 1 and compare these two graphs you can see how low both resting state and evoked potential bio type 1 had instead of low biotype 2 had high higher than bio type 3 abnormally high resting state EEG and evoked potential so we had a kind of linear in terms of cognition we had a kind of a linear but without type 1 being the worst bio type two in the middle and bio type 3 being normal but the best that kind of continuum but in the EEG s we had very low EEG for bio type 1 very high eg for bio type 2 and very and normal EEG for biotech 3 now the people the relatives in biotech one had about the usual incidents of family skits a typical personality disorder that we're used to seeing and schizophrenia 2020 22% dish the that same percentage a little lower was present in bio type to bio type 3 had essentially no family no family and no additional family interested in it propensity towards a psychotic or a minor psychotic disorders so we figured that biotech one might be the most the most genetic bio type 3 was really one of the biggest puzzlers because biotype all these people all these different groups had almost the same psychosis so that they had the same level of psychosis they were psychotic like doctors are just used to seeing everybody and you could not clinically distinguish between these two groups so what was this group this group had almost normal cognition normal EEG normal almost everything compared to this group that that was very very impaired on their biologic measures what what was up with this group well we were sitting around talking on this day we were trying to think of something clever to write in our next grant and one of the guys around the table said oh I bet these are the pockets so we look to see whether there was a differential use or early cannabis and then chronic cannabis in this in bio type 3 compared to the other two and in fact and the first study we did and we we have more data now to re-evaluate it but in the first study we did these were the early cannabis users and these were the heavy pot users and not to say that there weren't other differences in addition to that but that was sort of interesting here is let me just show you this is bio type 1 this is bio type 2 and this is bio type 3 the orange dots are psychoactive schizophrenia the purple dots are psychotic bipolar and these dots in between our schizoaffective disorder so you can see you know the bio type 3 has a significantly increase a significant increase in psychotic bipolar disorder compared to bio type 1 but you can still see that in all of these bio types there's a good representation of all of the diagnosis one of the interesting things is that the biology of the family members reflected the biology the pro bands here's the probe and this is cognitive control this is sensory motor reactivity that I explained to you from the other slide all I'm going to show you is the pattern of these this the gray bars the healthy controls healthy controls have a cognitive control right here these are the bio types and these are the family members of the bio types and you can see that the pattern in the bio type pro bands very low cognition medium low cognition almost normal cognition is really reflected in the biota and the relatives in the performance of the relatives in cognition and then in sensory motor reactivity here we have the healthy people in the middle I told you that the bio type programs had very low activity very high sensory motor activity and almost normal activity and the the the family members really reflected that so this gave us some confidence that we were working with a biology that stimulated this in relatives that might that might be important i'mjust we there were various so this is the study that I showed you about I told you about before the volume brain volume it's known that psychosis has reduced gray matter volume in the brain when we looked at the DSM groups and we looked at total gray matter volume the bipolar disorder and the normals ran exactly together schizophrenia and schizoaffective disorder ran together this was when we divided them by DSM diagnosis when we divided them by the biotite groups that had already been defined by the by the cognition and by the sensorimotor reactivity we found a stepwise decrease in psychosis from normal to for to schizophrenia on the excuse me from new from normal through to biotype one which is the worst but if you look at you can't probably see this very well in bio types but there's a different part of the brain that's involved in the reduced gray matter volume and bio type Juan biotype - in biotech 3 and that's almost more important than the sum this summary slide in bio type 100 all the gray matter and the whole brain is reduced throughout the cold cortical mantle you see here the yellow areas are the areas of reduced gray matter volume and that reduced gray matter volume is really throughout the whole neocortical area in biotech - which has a slightly better course the gray matter volume is really localized to frontal frontal and parietal areas in bio type 3 which is the healthiest and all these people are almost like normals it's really the the limbic system a little bit in the in the frontal limbic system and then in the hippocampus and in the insula where the reduction in gray matter volume is so I'll show you a few pictures about this resting state EEG connectivity now this is a this is a this shows you the figure from normal controls and this is connectivity simply between the hundred and twenty EEG electrodes but you can see the pattern of electrical connectivity at the surface of the brain and this is what it looks like in healthy people if you look at the DSN DSM syndromes schizophrenia schizoaffective psychotic bipolar they look almost the same with some increased connectivity here posteriorly a little bit of increased connectivity and anteriorly but there's no distinction between these groups if you look at the psychosis biotypes biotech juan bauer type to biotech 3 you can see that just like the level of EEG resting state an Evoque potential in b1 there's a decrease in connectivity in b1 there's a tremendous increase in connectivity in b2 and b3 actually looks more like the the other diagnoses with some areas of increased activity now we don't know what this means yet but we're we're we're looking to find out what this means and we have groups that are distinct from each other in biology as well as clinical presentation we asked ourselves the question what's the best in the phenotype if we wanted to do say we were going to do a drug study and we had we were going to do a drug study but using clozapine in biotech one and I'll show you some data in a minute that suggests that what should we really measure so this is a bio type 1 this is bluest biotech 2 and green is bio country and you can just ignore the dotted lines because those are those are the relatives it turns out that of course I just told you that bio type 1 is worst in in antipsychotic error and in the backs and in some of the n100 p300 intrinsic EEG activity bio type 2 is has some decreases in cognition but mostly increases mostly what they have are increases in these three EEG measures with normal people with biotech 3 being almost normal so we're where we are now when we started when we were ready to start a be step 2 we actually made an intriguing enough story about this to get our next grant funded be snip 2 and so we we didn't just say there's something interesting happening here we said if you look at the if you look at psycho psycho people with psychosis and if you make a clinical diagnosis it doesn't give you a biologically consistent sample if you if you take their biology and divide them up you'll find that they have very characteristics here that are interesting where what what else do we have we have to do we have to be able to replicate this data we have to show stability of these measures over time um what do these do these different groups have a distinct genetic fingerprint are their treatment implications and then the path to neural biology I won't touch on each of those areas just a couple of I have to want a clock Martin so the replication so what I can say is that with the second study that we're doing now we have essentially replicated these three different groups using the same measures here is a B snip one study and then it shows you the relationship of the individuals each of whom is a dot to cognitive the relationship between cognitive control and sensory or motor reactivity and B step two this picture looks almost exactly the same perhaps a little bit better but it's certainly the same let me show you here this is all the data from B snip one and half of the data where we are enough for me step two and it shows you again for biotype one two three and normals it shows you the cognitive control data and the reactivity data which really biotech water might have to fell right on top of each other in these studies we're doing a stability study so though one of the criticisms could be well you just collected all these data at one point in time and if you collected them at two points or three points they could be very different from each other so we did a baseline Lisa the battery on where this number will be up to 200 by hopefully 180 maybe by the time we get to do the analysis and then we analyze them that's at six months and reanalyze them at 12 months we've taken a we haven't done a real analysis of this but we've taken a sneak peak and that would suggest that sneak peak would suggest that there really is a great deal of stability even in the EEG measures over time and we've done just a G we've done just a G wass usually the psych chip we haven't found a distinctive distinctive fingerprint yet for our bio types but we will are real interested in doing that well was to our real interest in doing B step 2 with 3,000 programs this probe answers to try to get a try to get an answer to that we did find three genes that were of interest and they associated with different parts of the brain the ante your ventral volume these three all did in particular this is it isn't such a strong finding because it only came from a 450 of the of the pro bands but we'll look at it next time you need really a lot of different a lot of different a lot a lot a lot of cases in order to make genetics work we thought a little bit about distinctive treatments for pro bands it would be nice if we could if we could show that there was a treatment that really advantaged that was really good for biotech 1a treatment that was really good for bio type 2 and then something for bio type 3 we looked at both if for bio type 1 you might remember that I said that the problem the EG problem is a reduction in a reduction in the intrinsic activity and we had some of the people who were on clozapine and some of the people who are not on close to being the this the this group of people was a pro bands was on clozapine these were not on clothes of people and there's we I can't say that there's a causal relationship here because this is just comparing two groups each of whom are each of whom are sampled at one time but clearly the the the group on clozapine is is the the group on clozapine has a higher EEG than the group off clozapine and that's true actually for bio type tool except that it's in the wrong direction this is the this is the increased EEG level the intrinsic activity level of bio type 2 and clozapine on top of this and bio type 2 makes these people increases their intrinsic activity we would have the idea and we would have to develop preliminary data for this that clozapine would be uniquely therapeutic in bio type 1 and bio type to it might generate additional side effects and the same thing is true really of depakote in individuals depakote is and is a drug that would be known to decrease EEG in brain and hearing by in bio type 2 you see an increase biotype - and EEG and then on depakote you see a decrease in intrinsic activity and you see that same thing in in bio type 1 except this is the wrong direction that we would hypothesize to go and we haven't done we haven't done these kind of treatment studies but at least these data would indicate that we should go in this direction so one of the things that we really wanted to do is to look is to use these kind of data to look for a mechanism for psychosis so we did a study with Robert Gibbons at the University of Chicago a mathematician and he he used one of his statistical approaches Mir T to look for psychotic symptoms that hung together that that that associated with each other and then he looked at which regions the that correlated with these psychotic symptoms and one might think say that this could be the psychosis fingerprint the fingerprint of these psychotic symptoms right here you'll see in a minute why I'm very very pleased that these all fell on the temporal lobe and then regions both in the frontal cortex and the posterior cortex that were around them but at least this is one way to move forward I want to tell you about a little bit of research that's in my own laboratory and we in thinking about what is a mechanism for psychosis one is a brain mechanism for psychosis is that a mechanism that's around the whole brain is it a service-based mechanism or molecular basis and the answer is probably all three but let me tell you what we found anyway this is my laboratory team that does the research that I'll show you now this is a hippocampus we we developed a focus on the hippocampus this is what this is the head of the hippocampus this is the tail of the hippocampus and we we recruit cases with post-mortem cases from the medical examiner's office in Dallas and we we use the whole grain to do studies of the whole brain but in particular we we have developed a hypothesis and developed some interesting pathophysiology looking at the hip and psychosis I should apologize for this brain picture being so bloody but I have to say that when I give lectures to my medical students they may hardly look at pretty slides they only look at really bloody slides so this is this is really meant to get medical students to pay attention to pay attention to this in schizophrenia out there I'm gonna show you this next picture first this is these are data from the recent study actually looking at resting looking at regional resting state as it's plotted out throughout the brain everything you see in blue is a reduction in resting state most and in throughout cortex both it's both the neuronal volume the resting state are all reduced there's only one place in brain where resting state EEG is increased and that's in the it's in the parahippocampal cortex the medial temporal lobe cortex and these are data from our own beast of study but these are there also other data that I've generated in other different studies this is the way the hippocampus looks in the brain and it's usually in the anterior hippocampus not the posterior but the anterior become this where you see increases in in inactivity in most of the brains and skits that most of the regions of the brain and schizophrenia the activity is decreased in the prefrontal cortex and most people study prefrontal cortex there was plenty of people when I started out this work studying prefrontal cortex and and the prefrontal cortex and findings are very well defined so I decided to move ahead in the hippocampus using some of the post-mortem tissue this is what a hippocampus looks like it's a very pretty organ in the brain it's wound in on itself and this is the dentate gyrus right here this is the ca3 activity right here this is a CA one and the cibecue ler so knowing that the hippocampus is hyperactive in people with psychosis we either that could be either that the psyche that the excitatory mechanisms were elevated or that the inhibitory mechanisms were unregulated and that what we had to do it and then and there was a disinhibition so I set out using a human postmortem tissue like you see here on the left looking at markers for excitatory activity and markers for inhibitory activity so what I could just say first and I don't have a slide about this but I'll just say it all the markers that we looked at for inhibitory activity were the same in in the controls and in people with schizophrenia so we found no differences in the hippocampus between inhibitory activity between yeah in it and inhibitory activity the first thing with that we measured was the this shows you the level of the essential excitatory subunit of the NMDA receptor glue and one so this these data would indicate what the activity in these regions is for the NMDA receptor the NMDA receptors one of the most powerful of the excitatory receptors Green is normal red is schizophrenia and what you can see is that in the dentate gyrus in this area right here and not in any of the other areas in hippocampus the level of this excitatory protein is decreased it was the first one that I had measured and it went in the wrong direction I said like many experiments of science this was really the wrong answer of course I teach my students data our data and you'll it'll be most interesting if you just pay attention to those data and that's how it turned out here then we took a look in CA 3 and we took a look in CA 1 downstream downstream regions in CA 3 but not in CA 1 we found an increase and for post-mortem data this is actually a big increase in the gluon to be in gluant to be containing NMDA receptors and this is increased so that this blue and to be containing NMDA receptors a particularly sensitive a the glutamate receptor so we found in crease in the most sensitive glutamate receptor but in sea but but in ca3 but not in ca1 then when we look at PSD 95 this is another protein that sits inside of the glutamate synapse inside the excitatory synapse and it takes glutamate receptors and it sticks them to the postsynaptic membrane so it increases the number of excitatory receptors at the at the postsynaptic membrane so you see there's an increase also and again a substantial increase in PST 95 so what was most interesting actually this would suggest that in the dentate gyrus there's a reduction in excitatory signaling and then something happens in CA 3 so that reduction turns into an excitation and I just what I showed you before were just measures of proteins proteins that were associated with inhibitory and excitatory activity this is in CA 3 and this these data were really very interesting and I'll I'll tell I'll just walk you slowly through this like this is a Golgi stain this is a human pyramidal neuron in the in the CA 3 of hippocampus this is a cell body these are the axons that turn into the axons that go on to C a1 this is what's called the apical dendrite and right at the first bifurcation of the apical dendrite this is right where the the the the the affairs from dentate gyrus synapse right there and this is the same thing in a in the in tissue Golgi stain tissue from people with schizophrenia this tissue is just cleaned a little inadequately so those blotches you see are just unimportant but they're do they just they're just yes and but this is the a this is the bifurcation of the of the apical dendrite and this for schizophrenia is picture down here in E and this for normals this picture down here and C and I hardly have to tell you you could just see the difference what we found in funny it was a real increase in the number of the number of Bouton's the it in each one of these Bouton's are located increased numbers of receptors and this really is a reflection of LTP based reorganization in CA 3 so these kinds of differences between a normal CA 3 and a schizophrenia CA 3 really means that in CA 3 in people with schizophrenia there's a long-standing increase in excitatory signaling so then we changed our whole our whole hypothesis and what we our model became if we take the dentate gyrus and we just D cui D afferent CA 3 and the D afferent ation and CA 3 increases measures of excitatory signaling and increases measures increases a neuron atomic reorganization for excitatory for excitatory signaling this looks these data would suggest that if we simply give a drug leve trosset am being one of them that would reduce excitatory signaling in the hippocampus that we might be able to at least correct this defect and potentially correct what's associated with psychosis we haven't done that yet but we're really starting to do that so then this is our overall model is is that there's a lesion some kind of excitatory lesion and the dentate gyrus there could be many different excited to our lesions there's a decrease in our agenda there's thought to be decreased neurogenesis and dentate gyrus there could be lesions of the gluon one excuse me of the glue and one receptor like I showed and this produces a particular kind of cognitive dysfunction the pattern a poor pattern separation and we actually tested this in people with schizophrenia and found poor pattern separation then when there's when this inadequate a ferrant goes on to see a three in this just in this usual try somatic pathway in hippocampus the the low a fat stimulation produces a new really large increase in LTP and regional cerebral blood flow and that is just passed on to ca1 passed on to Civic ulam and then working in other circuits with the brain we would suggest that psychosis occurs so this is our model it turns out that there's a there's a there's a mouse model produced in produced at UT Southwestern actually but worked up in the tonic Iowa memory lab in at Harvard and this mouse model has a single lesion and that is a decrease in glue and one in dentate gyrus the it's a it's a it's an anatomically selective region only in only in dentate gyrus so this would be really an exact match of what we were saying happens and schizophrenia so we got a hold of that mouse and let me show you just a little bit about what we found so what these are data these are data from a mouse okay you can really can't generate these kind of data from people but the this is a mouse that had this glue in one lesion in dentate gyrus and ce1 just like we found in schizophrenia when we first looked at this NMDA amber Asia we found it to be almost zero but that wasn't because something something wasn't happening but it was happening equally in the AMPA receptor and in the end of the a receptor these are two of the most powerful excitatory receptors and this is a measurement of epsp the excitatory postsynaptic potential and it's a measure of the exit if 'ti at this NMDA receptor in CA 3 all of these are measurements as they're made in CA 3 so the AMPA receptor is unusually is super sensitive that has masane stimulus it will give a bigger response than in the wild-type animals and the normal animals both for the amp receptor and for the NMDA receptor then when we look at the level of activity in CA 3 instead of doing brain imaging in this in a little mouse because that's they're actually pretty hard to do we just count CA 3 we just count C receptors we can't we can't see Foss activated neurons so seefox activated neurons are increased these cephas activated neurons are neurons that are that are the height that have a higher activity the cephas is a marker not exactly it's not the best marker but it's it's it's a workhorse marker of increased increased activity both in CA 3 and also in CA 1 this act this increase in activity both and ca3 and CA 1 is located in the anterior part of the mouse hippocampus just like in the human hippocampus that was a little bit of a surprise we've looked a little bit in other brain regions and find an increase perpetuated downstream to the amygdala and to the prefrontal cortex and we find these increased cells in the pyramidal neurons in CA 3 CA 1 and the neurons in amygdala they're not in the inter neurons oh wait I won't go through this slide but just to say that we did various markers of of mouse behaviors mice nobody is really determining if you can tell if mice are psychotic but they have some behaviors that are associated with psychosis and those behaviors are all evidenced by these gluten dentate gyrus specific glue in one mouse it right here so all of this about the we I've been telling you all along what our hypothesis and what our model is but we would really suggest that reduced dentate gyrus activity is associated with poor pattern recognition leading to reduced fidelity in memories and associated with potential memories with psychotic content if you take a look at people who are psychotic and if you notice the content of their psychosis the content of their psychosis is really like a psychotic memory and they don't have new psychotic memories every day I mean most people if you if you're talking to a patient and following a patient over time who has a delusion that delusion will be pretty much the same day of day after day some some patients would have might have a delusion that their brain is positioned accordion American border and it's giving signals to generals in Washington to keep track of what happens at the mexican-american border this is actually a true delusion now that delusion changed very modestly after day after day and it wasn't highly impacted by the news or any other real events about the mexican-american border some people have a delusion that they're being poisoned perhaps that their mother is poisoning them and that delusion is pretty much the same day after day hallucinations and people with schizophrenia are a little bit more fluid but they're really quite similar they day after day after day so that it's not unreasonable for my point of view to think that the memory organ in the brain which is the hippocampus is is important in psychotic illness and with that I'll end and take any questions if you have man sir Williams when you turn to a regular basis of psychosis you went back to sort of a traditional differentiation in schizophrenia but actually that's politics you can buy top-12 changes so if you would be Seward and some of the fines that you have on the brains of these people that's a very good question and we you know if you think about the hippocampus as a memory organ the hippocampus is only an organ that makes memories it doesn't store memories so if you would hypothesize that the hippocampus would make a psychotic delusion they wouldn't keep that psychotic delusion there they would send it out to the neocortex and then that the dynamics of the long-term storage and the the ree-ree remembering would depend on neocortical pathology as well as hippocampal pathology so you know the EEG is all Magee I struggle we we had some discussions this morning in the in the Imaging Center about how you you can't localize very things very well if I could localize an EEG signal to the hippocampus compared to an EEG signals from the neocortex that would be nice a lot of the the research on psychosis and it's because here's me on schizophrenia and the hippocampus started way before we got these results with the beast of study I can go back now and combine I can do psychotic bipolar people and I can do some people with a schizoaffective diagnosis and I will I have to do that yet with these people but I haven't been able to do a retrospective biotype diagnosis the rule the bio type diagnosis is so dependent on on neuronal activity and on cognition both of which are just an almost impossible to get in the in the post ward of tissue so I'm trying to figure out now if you have any good ideas I'd love to have them on how to look for post-mortem and it changes by biotype what we've done really is now we're making these stem cell lines so we'll have stem cell lines and from biotech one biotype two and biotype three that doesn't and stem cells don't don't substitute for brain tissue but at least they're I placed the start think that this entire nation is related to other areas of the three Association cortex cortex this isn't the independent iris a primary recipient of a lot of important input to the hippocampus right so do you think that sort of everything is generating from the dentate gyrus focus about verbal activity there or we think that there's sort of a broader disconnected circuitry that you're detecting Evan so in these studies you know the the microcircuitry of the hippocampus is quite well defined thanks to HM who and the mistake of neurosurgeons the the primary input to the dentate gyrus is from the in Toronto cortex and I have a colleague now who's interested in the in Toronto cortex so he's going to go back in all of this tissue the human tissue and in the animal tissue and study the in Toronto cortex but the all of them the sensory cortex and all information from all over the brain gets funneled into really the parahippocampal area and then gets kind of condensed and sent through the under rana cortex into the enter into the dentate jars the dentate gyrus is that is a part of the brain that's very sensitive to the oxygenation and so during birth during critical times in a normal life time you could injure your dentate gyrus pretty easily which is why i but i haven't focused on the sense the the other parts of that system at all oh boy that's a real question and essentially the answer is that we have not accounted for stage of illness most of the people in the in the bee snip studies have been mid mid disease people probably between the ages of 30 and 40 something like that I forget what our average age is but it could be 35 ish you know the focus on early psychosis now both in early psychosis for treatment efficacy and early psychosis because it's a particular disease stage is there's a lot of attention on that and in fact one of my colleagues is doing a doing a study where she's using imaging and using EEG using biomarkers to look at very early psychosis before the age before two years after diagnosis and she's comparing that to mid stage diagnosis 15 years later this is kind of a hard study to do because people with psychosis as you may know don't stick around you know you it's hard to follow them for 15 years it's hard to keep your hands on them for 15 years so she's doing a study in two different groups and that has lots of troubles to it but it's better than nothing but there is a that we do have to study early psychosis research that showed differential patterns of neuro psychological dysfunction about folks that manifested on the cross each of those emotions and with your micro markers and wondering I'm not familiar with certainly negative symptoms are over associated with biotype one so there's probably there's a significant and highly the sizes the magnitude is high of the increase in negative symptoms and people think they're symptoms about type one when we look at cognition other than negative symptoms and that isn't really cognition we don't find a differential cognitive pattern we don't and we were we thought that well maybe we've picked the wrong measures to do in biotech one so we picked slightly different measures of cognition in biotech too so we'll be able to ask that question over time you know there's a speaking of like in in trying to understand how you would you would you would study this in a doctor's office er if if we should we manage your social and some importance of this bio type distinction how would you do this in a in a in a doctor's office but there's all sorts of little EEG type devices that are popping up now I don't I guess I think that the techniques will catch up to the knowledge if we are able to define some knowledge my hope well you've been a very nice audience and thank you very much for your attention [Applause]

Channel: Laureate Institute for Brain Research

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Id: lvcfllWdQsw

Length: 58min 52sec (3532 seconds)

Published: Tue Feb 19 2019