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    Case Western Case Western Document Transcript

    • CASE WESTERN RESERVE UNIVERSITY"TruTranscripts, The Transcription Experts" (212-686-0088) 3-1 Case Western Reserve University Healthy Minds Across America April 10, 2010/Tape 3 NARSAD ROBERT J. RONIS, M.D., MPH: The importance of thework that Dr. Gao is doing, as he explained to you, the studies thatwe have of most of our treatments are in a rarefied population offolks. The people walking in our offices seldom have one diagnosis,no medical complications, no substance use, no other issues goingon at the same time. And yet the medicines and the other treatmentswe have are usually based on looking at those very few people thatmay have a single problem thats not otherwise addressed. Anybodyhere a gardener? Does anybody plant plants in the summertime?So if you went out and you bought a seed that was developed to be astrong and healthy plant, and all the studies done were on growingthat seed in a perfectly fertilized amount of soil, thats in a well-aerated pot, and well lighted, inside of a hothouse, and you took thatseed and you put it in your garden, chances are its not going to growas well as it did in the hothouse. These are the same kinds of thingsthat were dealing with. Well, lets move on to Dr. Pehek, whos going to give us alittle bit more of a basic science presentation, and maybe explain alittle bit about some of those pictures that Dr. Gao showed us. Dr.Pehek received her Ph.D. in psychology in 1988, from SUNY, atBuffalo, New York. She then completed post-doctoral work inpharmacology and psychiatry at Northeastern Universitys College ofMedicine, and Case Western Reserve University, respectively.
    • CASE WESTERN RESERVE UNIVERSITY"TruTranscripts, The Transcription Experts" (212-686-0088) 3-2 In 1992, she received a Young Investigators award fromNARSAD that enabled her to start an independent research career,investigating neurotransmitter interactions in brain areas implicated inschizophrenia. Since 1995, she has held a joint appointment withCase Western University School of Medicine and the Cleveland VAMedical Center. She is currently a tenured associate professor ofpsychiatry. Her research aims to increase our understand of theneurobiology of mental illness and to aid in the design of treatments.Dr. Pehek? (Applause) ELIZABETH PEHEK, PH.D.: Well, thank you, everybody,for coming. Im happy to be here. And as Dr. Ronis said, it wasfunding from NARSAD that, about 20 years ago, helped me launchmy independent research laboratory, and I was able to collect datawhich enabled me to get federal funding, more substantial funding,from the National Institute of Mental Health, and then later from theDepartment of Veterans Affairs, where I maintain my researchlaboratory. Thats just basically across the street, about a mile away. And just to give a very brief introduction ... were changinggears, now, talking about schizophrenia instead of mood disorder ...schizophrenia, we know, is a brain disorder. About one percent ofthe population has schizophrenia. Theres a great deal of evidencethat much of the risk is inherited. And when we look at schizophrenicsymptoms, they traditionally have been divided into positive andnegative symptoms, but more so in the later years weve alsoidentified another category that we really feel is separate, and that iscognitive symptoms.
    • CASE WESTERN RESERVE UNIVERSITY"TruTranscripts, The Transcription Experts" (212-686-0088) 3-3 Now, the positive symptoms refer to increases in behavior,hence the term positive. So these are extra behavior. Sohallucinations, delusions, and thought disorders, like disorganizedthinking. The negative symptoms, on the other hand, refer to lessbefore. So theres lack of emotion, lack of pleasure, lack of wantingto do things. Lack of volition. The cognitive symptoms refer totroubles in higher-order mental processing. This is not an all-inclusive list but, for example, trouble focusing. We call that,technically, troubles in selective attention. And what Im going to focus on, in this talk, are studies thatexamine working memory. This is the ability to hold something inmind to guide further action. Its not just simple memory; its higher-order executive function, like using a rule to make decisions;something that youve learned about thats in your memory. And inhumans, one way to test this working memory is a task called(Inaudible) task. And you can see here the cards. What happenswhen the person engages in the task, what they have to do is ...theyre presented with a single card that they have to use a rule tomatch to one of the other cards. And theyre not told what this rule is;they have to figure it out by trial and error. So, for example, it could be matched on the basis of red,matched on the basis of two, matched on the basis of causes. Sothey have to hold what this card was in memory, and then they haveto remember the rule that they have to classify it. And then to makethe task even harder, they keep switching the rule. And this is a hardtask, but for people with schizophrenia its really hard. You canempirically, in the laboratory, show they have deficits in this task.
    • CASE WESTERN RESERVE UNIVERSITY"TruTranscripts, The Transcription Experts" (212-686-0088) 3-4 And researchers have shown that when theyre doing thistask that theyre not very good at, one region of the brain inparticular, the prefrontal cortex, shows reduced blood flow. This iswork that in part was done by Danny Weinberger at NIMH. He wasone of the people in the first video we saw. We call thishyperfrontality. So normally, in normal people, this brain area lightsup when youre doing this task; it does so less so in people withschizophrenia. So what is the prefrontal cortex? Well, Dr. Gao showed youa picture of it. Heres another picture, showing you the frontal area ofthe brain. On the human, its quite large. It has both lateral andmedial aspects. And again this is not an all-inclusive list, but some ofits normal functions are attention, working memory, planning,judgment. And really (Inaudible) this brain area have been linked toevery major mental disorder. Dr. Gao talked about depression. AlsoADHD, attention deficit disorder, drug addiction, and what Imfocusing on, in this talk, is schizophrenia, where theres a lot ofcompelling evidence for (Inaudible) within this area. But I want toemphasize in just this area. Its interactions with other brain areas.In that situation were going for an understanding of the neurocircuitryof mental illness, which necessarily were going to talk about onebrain area, but also going to talk about interactions with other brainareas. So the evidence that the prefrontal cortex is awry inschizophrenia ... the first speaker already told you about thehypofrontality. But weve also been gaining a lot of insight from workwith animals. And thats one of the take-home messages of my talk.We can do more invasive studies in animals than we can in humans.
    • CASE WESTERN RESERVE UNIVERSITY"TruTranscripts, The Transcription Experts" (212-686-0088) 3-5And it turns out, if you lesion this area, you purposely destroy it whilethe animals are anesthetized, in either monkeys or rats, they showdeficits in working memory. And this is to show you that the rat has a prefrontal cortex.In the rat, its totally along the medial wall. In the human, its shownhere both medially, but theres also lateral areas. But all thefunctions of both the lateral, the medial human prefrontal cortex aresubsumed in this medial wall in the rat brain. Obviously, they cantmake as complex decisions, and their executive function is not ascomplex as ours, but they do have working memory; its just muchmore limited. So if you put a lesion in this brain area, in the rat, andyou tell it to do a working memory test which involves holdingsomething in mind to guide action, they will do poorly on it. And here its just a very simple maze thats used. And therat has to learn a rule. You place food in one of the arms of themaze, it gets that food, it has to learn that now, next trial, it has to goto the opposite arm of the maze to get the food. And you prevent him... its usually males that are used ... you prevent him from seeingwhere the food is, simply. It is a memory test. They have toremember where it was the last time, and they have to remember therule: Ive got to go to the other arm, the next time. And this is nottrivial. This takes some days and weeks for them to get good at this.And this is just showing a mouse ... I got this from the NIH web site ...at a decision point in that maze. So since we know if we destroy thisarea, we get similar deficits in working memory to that shown inhumans that further implicates this brain area in schizophrenia. Weve also, more recently, with better anatomicaltechniques, been able to analyze the brains of people who have died
    • CASE WESTERN RESERVE UNIVERSITY"TruTranscripts, The Transcription Experts" (212-686-0088) 3-6who had schizophrenia, and discover some brain abnormalities.Now, theyre subtle. It is not like neurodegenerative disorder, butAlzheimers and Parkinsons disease, where you can see things likelewibodies, or dorsal-biliary tangles. This has been a problem withschizophrenia. You havent seen any gross, gross lesions. So itsweighted, really sophisticated neuroanatomical techniques. And a lot of this work has come out of David Lewiss lab.Hes at University of Pittsburgh. And this is showing dendrites, thereceiving end of neurons, in the prefrontal cortex. And they havespines on them. And in general its thought the more spines, thebetter. This is where synaptic contacts are made. And you can seehere ... and these are very well done studies ... that in people withschizophrenia ... and this is just one example ... there are leftdendritic spines. Now, theres a lot of details in this, and Im notexpecting you to remember the details, but I want to show you thereare other neuroanatomical findings. This pyramidal-shaped (Inaudible) cell, the big black oneand the smaller greenish one, this is the major output cell of theprefrontal cortex. And studies have shown that those cells aresmaller. Inhibitory ... and it uses (Inaudible) glutamate, which is anexcitatory neurotransmitter, and projects to other brain areas; likeother cortical areas, the thalamus, and other subcortical areas. It isenervated by inhibitory interneurons. These are GABA neurons.These are the small cells that (Inaudible) in the cortex. Theyre notprojecting outside the cortex. They release GABA onto these cellsand modulate these cells. And evidence for less inhibitory regulationof these pyramidal cells has been found. Good evidence.
    • CASE WESTERN RESERVE UNIVERSITY"TruTranscripts, The Transcription Experts" (212-686-0088) 3-7 And then of interest to me, because I come from a history ofstudying dopamine, Lewis has found ... Ive circled it in red ... thatthere are less dopamine axon terminals in this brain area. And toshow you, in schematic form, the dopamine pathways in the humanbrain ... this is from Mark Lorell ... you can see that theres onpathway that both pathways ... well, theres really considered to bethree major pathways. The cell bodies of these neurons are in themid-brain, and they project upstream. The ones that project to thestriatum are the ones the degenerate in Parkinsons disease. Theones Im going to be talking about project up here to the cortex. Andthere are also others that project to the limbic system, to the nucleusacumbens and hippocampus; amygdala. And weve learned quite a bit about the role that dopaminemay be playing in schizophrenia and antipsychotic drug action fromneurochemical experiments in animals, together with non-invasiveimaging studies in humans. You cant measure dopamine in thebrain of humans. We have to look towards rats for that. But we canget indirect measures of dopamine function. And more and more, asthe imaging techniques are getting more and more sophisticated. Soif you take evidence from both lines of work together, the sum isgreater than just looking at the individual components alone. And this is showing a monkey prefrontal cortex. And againits showing you this pyramidal cell. And what I wanted to illustratehere is you see ... this is based on work done by the late PatriciaGoldman Ratish(?) ... that the dopamine neurons, which again aresub-bodies in the mid-brain, but they come up here and theyenervate these neurons and, in particular, they release the dopamineonto these spines that Id shown you before.
    • CASE WESTERN RESERVE UNIVERSITY"TruTranscripts, The Transcription Experts" (212-686-0088) 3-8 And a working modern dopamine hypothesis ofschizophrenia ... which actually there is a lot of evidence for ... the oldtheory was dopamine hyperactivity, and thats because the drugs thatwe used initially, like haloperidol, blocked dopamine receptors. Andthey are good in (Inaudible) and psychosis. But the more moderntheories say that thats not entirely untrue, its just that different thingsare going on with dopamine in different brain areas in schizophrenia.So that actually its subcortical system where there is evidence ... andtheres actually indirect human imaging in it that was done by MarkLorell, that its the hyperactivation of dopamine here. And we thinkthat may be linked to those positive symptoms, again in concert withother brain areas. What Im going to focus on is that theres evidence foractually a hypofunction of dopamine in the prefrontal cortex, and thatthis may be linked to the negative and cognitive symptoms, which arethe harder symptoms to treat, and the ones that reduce the quality oflife the most for people with schizophrenia, particularly the cognitivesymptoms, and where drug treatments are really pretty ineffective, todate. Thats where drug development is going. Now, even within the prefrontal cortex, to say that its justsimply linked to ... schizophrenia and negative and cognitivesymptoms ... to a dopamine deficit is overly simplistic. Really, thereseems to have to be an optimal balance for cognition. And thistheory was really espoused first by Patricia (Inaudible) So that basaldopamine levels may be chronically low in schizophrenia, but whenthe individual undergoes stress ... and we know dopamine isreleased in this brain area ... normal people, cognition goes down;but people with schizophrenia are particularly susceptible to the
    • CASE WESTERN RESERVE UNIVERSITY"TruTranscripts, The Transcription Experts" (212-686-0088) 3-9disrupting effects of stress on cognition. So a working hypothesis isthat the best antipsychotic drugs would be able to increase basaldopamine release while also, somehow, attenuating blocking ofstimulated dopamine release. And there are drugs out there thatseem to do that. Its not an absurd notion, and it would be based oncomplex interplay of receptor binding properties. So what have we found out about antipsychotic drugs inexperimental animals? Well, this is work I did a long time ago, whenI was first starting out. And this is showing that when you administerthe newer generation, so-called atypical antipsychotic drugs ...because they dont produce extrapyramidal side effects, those motorside effects ... to animals, and you measure dopamine in theprefrontal cortex, it goes up. This is clozapine. This is a drugimperazide(?), which was under investigational use at the time, andstill is being investigated; its not marketed. But both of these drugsincrease dopamine; whereas, the more traditional antipsychotic drug,Haldol, does not. And this has since been found when people havelooked at risperidone, olanzapine, Zyprexa. They all increasedopamine in the prefrontal cortex. The drugs that commonly blockD2 receptors, like haloperidol, do not. The question is why. And theanswer is we dont know. But a bunch of people are trying to figurethis out. This is a schematic of these pyramidal neurons. This is sosimplistic, but just to show you some of the receptor subtypes thatare modulating these neurons. These are serotonin receptorsubtypes. Theres multiple neurotransmitters modulating theseneurons.
    • CASE WESTERN RESERVE UNIVERSITY"TruTranscripts, The Transcription Experts" (212-686-0088) 3-10 And if you look at the receptor binding properties ofantipsychotic drugs ... all of these are the newer generation, excepthere is haloperidol ... you see haloperidol, this color, is a dopamineblocker. Predominantly a dopamine blocker. Whereas all of thesenewer generation drugs are not as good dopamine blockers. yet ifanything, something like clozapine is actually better clinically. It doesblock dopamine receptors, but not as well as haloperidol. What became striking to a lot of people, including myself,were some of these serotonergic blocking properties that you seevery prominent in risperidone. And could this be linked to clinicalefficacy? In my case, lets look at rats, is this linked to the regulationof dopamine? Because theres a longstanding modified dopaminehypothesis in schizophrenia. So I showed you some data before. This is to show youhow we do these experiments. This is state of the art experimentscalled (Inaudible) microdialysis. You put a microdialysis probe in thebrain of a rat or a mouse. Its the same principle as kidney dialysis.You can see the surgery has been done when these animals areasleep. Now somebody is inserting the microdialysis probe. Itenables you to measure chemicals in the extracellular fluid. As theseanimals recover from anesthesia, theyre awake. So youremeasuring chemicals that have been released and are now spillingover into the extracellular fluid. And this is showing you a schematicof how it works, that it mimics a blood capillary, and so (Inaudible)fluid, there are pores in this membrane, and they only let smallmolecules through. Like dopamine, serotonin, glutamate. It doesntlet big proteins through that would degrade them. So you collectthem.
    • CASE WESTERN RESERVE UNIVERSITY"TruTranscripts, The Transcription Experts" (212-686-0088) 3-11 And this is showing a coronal section of the brain. So if youcut the brain this way and its showing you ... this is a rat brain ... anactual schematic of a probe, pumping in fluid, but its plugged up, thefluid is forced through this glass tubing and out. And then dopamine,because we dont have any dopamine in this fluid, will flow along thisconcentration gradient, into the lumen of this probe. We can collect itand measure it. And this is data of the work we did with another atypicalantipsychotic drug, risperidone, showing that using this technique ...like I showed you before with clozapine ... you get an increase indopamine release. This drug has been injected systemically into therat. We probably did this with subcutaneous administration. So itsgoing to go everywhere in the brain. We cant localize the effects thisway. However, as a neuroscientist, I am interested in localizingthe effects. Im interested in uncovering the neural circuits. So whatwe do, to do this, is you can also administer a drug through thatmicrodialysis probe, and it will go along through those pores, into thebrain area that you implant it into. So this way you can tease outneural circuitry of these effects. So this is a schematic of that. Thisis prefrontal cortex. And when we did this with risperidone, and weput it right into the brain ... remember, before, when we gave itsystemically, it increased dopamine ... we put it right into theprefrontal cortex, it didnt. Which tells us that however it increasesprefrontal dopamine, it doesnt do so by acting in the cortex. And again the details of this are not whats important. Iwant to highlight that when we do some work with actual drugs thatare used clinically, we do a lot of our work with preclinical compounds
    • CASE WESTERN RESERVE UNIVERSITY"TruTranscripts, The Transcription Experts" (212-686-0088) 3-12that may be in drug development, but for our purposes are nice,because theyre more selective. I showed you those pie charts.Those drugs are messy. How can you draw (Inaudible) conclusions?So what we do, there are some drugs that are selective ... if I wasinterested in the 5HT2 receptor ... OSE is not selective; its not a drugwe use, but I have I here to highlight that agonists, drugs thatstimulate this receptor, are believed to produce hallucinations byacting here. These are visual hallucinations so (Inaudible) is a goodmodel for schizophrenia, where most hallucinations are not visual.But this is a drug that we have used a lot that blocks the serotonin 2Areceptor, very selectively, unlike risperidone. It doesnt have D2blocking properties. It was in development, it made it to the phase two trials inschizophrenia, but then in phase three it didnt pan out, but its stillbeing held onto. You know, if one drug company buys another ... itwas first Drusseau(?), and now its been bought by another, so I dontknow who has it. But there still is some interest. I think, nowadays,theres interest in developing add-on treatments that might help treatcognitive functions. They may not, by themselves, be good enoughto treat schizophrenia. So the next slide is showing you that if we put this drug,which is just blocking 2A receptors, into the cortex, it also doesntincrease dopamine. So, like risperidone, it doesnt seem that if youselectively block serotonin receptors there, you increase dopamine.So were talking about basal dopamine release here. But remember Ishowed you this graph, and I talked about stress-induced dopaminerelease versus basal.
    • CASE WESTERN RESERVE UNIVERSITY"TruTranscripts, The Transcription Experts" (212-686-0088) 3-13 What about these 2A antagonists? Would they alter stress-induced dopamine release? I said dopamine goes up, during stress,in the prefrontal cortex. And actually more so than other brain areas,which is interesting in and of itself. And we could test this inexperimental animals. Here how we stress these rats ... these ratsare not pets. Normally, we dont handle them. But we came in here,we petted them for 20 minutes. And they are scared of us, so it is astressor. And this is showing you how dopamine goes up. It aboutdoubles. And also serotonin does, too. And then, when we infused that selective 2A antagonistthrough the probe, into the cortex, it actually did block the increase.So the 2A antagonist is blocking stimulated dopamine release.Stress induced. And then when we tried this with risperidone, we gotthe same thing. So these drugs are affecting phasic dopaminerelease, we think, through acting at that serotonin receptor subtype.And then, very recently, weve looked at paloperidone ... the brandname is Invega ... we get the similar effect to risperidone, which isnot surprising, because this drug is a metabolite of risperidone that isalso efficacious clinically. So then conclusions and future directions. Conclusions isthat we need to do a lot of other work. Again, a take-home messageis that using no chemical data from animals, where we can doinvasive studies, we can map our neurocircuitry ... but we have totake that target with non-invasive imaging studies in humans. And ifwe do that, we can start to look at some of the neurocircuitry of thenormal brain, and that might be problematic in schizophrenia. This is just to show the complexity of the neurocircuitry thatwere dealing with. Because I had shown you some very simple
    • CASE WESTERN RESERVE UNIVERSITY"TruTranscripts, The Transcription Experts" (212-686-0088) 3-14schematic diagrams, and I dont want to minimize the complexity.This is work from Arvid Carlsson, a Nobel Prize winner. And other future directions are to correlate recent geneticsfindings. These are some proteins that the genes have been linkedto schizophrenia in human studies. And in fact in a very, very smallsubset of schizophrenics, this has been shown to causeschizophrenia. Probably, in most cases, its not a single-gene defect(Inaudible) schizophrenia. Its multiple genes, so its making it verydifficult to study. This protein is catechol-O-methyltransferase. It is aprotein that breaks down dopamine in a subset of people who have agenetic mutation where this enzyme is hyperactive. So this is workby Danny Weinberger. So that means more dopamine is beingdegraded, because it has less dopamine in the prefrontal cortex. And then I took off a recent ... from the NIMH web site ...this is a citation to a recent study, where they have ... all of theseproteins have been knocked out, so to speak, in mice. So theyvedone genetic mutations. So the gene is abnormal, and they dontmake these proteins. And so now you could say the neurochemistry,the neuroanatomy of these mice ... and you can see here, in this 22mutation, they have found impaired neurocircuitry in these mice. AndI showed you the working memory pack, and thats one thing thesemice ... their working memory is aberrant. And they actually have apicture of the mouse, it was taken from the NIMH web site. So I want to acknowledge NARSAD. And then our workhas been funded by NIMH, and also the Department of VeteransAffairs. Thank you. (Applause) ELIZABETH PEHEK, PH.D.: Yes?
    • CASE WESTERN RESERVE UNIVERSITY"TruTranscripts, The Transcription Experts" (212-686-0088) 3-15 WOMAN: (Inaudible) ELIZABETH PEHEK, PH.D.: I think boosting dopamine inthe prefrontal cortex is helpful. And for ADHD, a lot of thesenorepinephrine uptake blockers, in preclinical studies, they reallyincrease dopamine in the prefrontal cortex. WOMAN: (Inaudible) ELIZABETH PEHEK, PH.D.: But I think theres going to beadd-on medications. Add-on maybe help ... I mean, right now,theres agonists in another subtype of dopamine receptor, D1.Theres a lot of those receptors in the prefrontal cortex. And thatsbeing looked at. So I dont think by itself. You might also have tohave another dopamine blocker on board. But I think an add-on. WOMAN: (Inaudible) ELIZABETH PEHEK, PH.D.: You can ask the cliniciansmore, but I dont think its at the point, diagnostically. WOMAN: (Inaudible) ELIZABETH PEHEK, PH.D.: Yeah. WOMAN: (Inaudible) ELIZABETH PEHEK, PH.D.: Well, theyre bothneurotransmitters, so theyre released by neurons, and they havetheir own receptors in the brain. They have different receptors in thebrain. And they have different pathways in the brain. So thats whythey do different things. So serotonin is associated with sleep.Obviously with mood, SSRIs. Dopamine, Ive mentioned cognitivebut also reward is a big thing. So psychostimulants. Amphetamine.They all increase dopamine. In fact, amphetamine,in a subset ofindividuals, causes psychosis, which you walk into the ER, you cannot distinguish that from paranoid schizophrenia, based on
    • CASE WESTERN RESERVE UNIVERSITY"TruTranscripts, The Transcription Experts" (212-686-0088) 3-16symptoms. And so like amphetamine, which causes dopamine, isused in clinical animal models of schizophrenia. So these are allmodulating the activity of other neurons, and they have their separatereceptors, so they have ... WOMAN: (Inaudible) ELIZABETH PEHEK, PH.D.: Im saying that there may be aproximal relation to the effect being poor cognitive. But the ultimate,the initial insult that causes schizophrenia, the genetic insult probablyits the initial cause or problems in those pyramidal or those GABAcells that I showed you in the cortex. Maybe secondarily. We havedopaminergic abnormalities. To say thats like a primary cause ofschizophrenia, I dont think anyone would say that. Whether(Inaudible) of dopamine contribute to the symptoms, I think theresevidence for that. WOMAN: (Inaudible) (END OF TAPE)