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We do not have a biological test or a brain test or a MRI scan that we can run

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on someone and say, hey, this person has schizophrenia. We don't have that.

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And it wasn't until really the the 1990s, early 2000s that MR machines got

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sensitive enough that we could actually start to detect in living humans some of

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the subtle brain abnormalities that were present in schizophrenia early in the

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disease course. The human brain is the most complex structure in the known

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universe and we are in the middle of a scientific revolution to understand its

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inner workings. Join us for a conversation with world-renowned

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neuroscientists as they visit Rochester. I am Dr. John Foxe, Director of the

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Del Monte Institute for Neuroscience at the University of Rochester and you are

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listening to neuroscience prospectus. Thank you for joining us for this episode

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of neuroscience prospectus. I'm thrilled to be joined by Dean Salisbury, professor

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of psychiatry at the University of Pittsburgh. Dean is the principal

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investigator of the clinical neurophysiology research laboratory and

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that lab focuses on understanding the pathology and pathophysiology of first

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episode psychosis and the progressive course of structural and functional

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impairments in early disease. And Dean, thank you for taking the time to join us

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to chat about your research while you're here and just life in general and what

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brought you to science. Thanks for having me, it's such a pleasure to be here. So

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let's dive right in. You know when I think about schizophrenia, you and I

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share a passion for trying to do something about schizophrenia. I think

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about what people often call like a wicked problem. It's a wicked

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problem. Nearly 1% of the world's population there or thereabouts suffers

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from this chronic disease. Our frontline treatment for schizophrenia is

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something that was discovered in the late 1940s, early 1950s. That's what

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we're doing today. Why in the intervening 75 years have we not been able to you

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know move the ball down the field? You're right, it is a wicked problem. Very

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debilitating disorder and over half of the people won't even be able to work

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part-time for the rest of their lives. Drugs, the medications we use were

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discovered accidentally years ago and they really haven't changed. When we look

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at new medications that were developed, most of them haven't been effective.

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We don't understand the mechanisms. However, I think there's an

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exciting new trend which is non-invasive brain stimuli. So the

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non-invasive brain stimulation studies show some promise in having long-lasting

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effects. Right, right. Yeah and it's one of those things right, the

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original drugs, D2 antagonists, these dopaminergic drugs are good at treating

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these psychotic symptoms which is what everybody associates schizophrenia with.

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But the truth is what really makes somebody ill with schizophrenia and turns

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it into a chronic disease is not the psychotic symptoms. It's, well, do you

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want to hold forth on that, right? Yeah, so we can think about three things. One

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is sort of the psychotic symptoms that you were talking about like hearing

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voices or having delusions and the medications we have treat those really

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well. What they don't treat are the so-called negative symptoms which is

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sort of abolition or sort of a lack of, you know, being able to do things or

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apathy, not caring, or cognitive abnormalities, you know, sort of an

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inability to think well really, right? So and we don't have good medications for

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that right now. They're really untreated. There are other ways that people are

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trying to get at those. There are some medications that are under investigation

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that are trying to target, you had mentioned the D2 receptors, they're

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trying to target either muscarinic or glutamatergic receptors. They haven't had

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great success in clinical trials. So now you've been up to your elbows in this

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schizophrenia work but not so much on the drug development side, right? I mean

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obviously you know an awful lot about that but you spent a career first

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at Harvard, now at Pittsburgh, trying to understand the basic brain physiology,

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brain mechanisms, structural changes in the brain in schizophrenia. Do you want to

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tell us a little bit about that and then I'm gonna I'm gonna ask you a couple of

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tough questions about where that's going. We do not have a biological test or a

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brain test or a MRI scan that we can run on someone and say hey this person has

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schizophrenia. We don't have that and it wasn't until really the the 1990s,

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early 2000s that MR machines got sensitive enough that we could actually

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start to detect in living humans some of the subtle brain abnormalities that were

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present in schizophrenia early in the disease course. And so if we think about

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what areas might be impacted in the disorder, first of all when we think

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about you know sort of the will to act and behave and motor systems and even to

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some extent language systems, hearing voices about 70% of our individuals even

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the first time they get sick hear voices. We think about the frontal lobes and we

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think about the temporal lobes which are intimately involved in language and

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behavior and planning and memory and so when we look early in the disease course

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we see that the temporal lobes particularly in the left side where sort

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of the expressive language is those areas show very subtle changes early in

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the disease course. When you say subtle changes, tell us what those look like.

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Are we looking at a little bit of brain shrinkage, loss of tissue? That's

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exactly right. What we're seeing is a reduction in gray matter, the gray matter

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of the brain, and it's probably on the order of about 5% compared to a

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healthy person of the same age. And you'll see that in the frontal lobes as

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well and so early in the disease course so right around when psychosis emerges

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you will have a large number of people where you can't detect any brain

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difference and there's a small number of people that do have some brain

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difference. So at the group level we could see a change between a group of

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healthy people and a group of people at first psychosis but at the individual

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level it's not big enough to use for any diagnostic testing. And what happens

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during the disease course is the loss that we see, the volume loss or the gray

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matter volume loss, the sort of shrinking of the gray matter in the brain spreads

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across the entire brain over a period of 20-30 years. So it's a very subtle and

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very slow change in the volume or loss of volume in the brain. So it's interesting

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right because you're making a very important point right you can see these

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these differences at the group level and the problem is you can't say very much

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about the individual because there's a lot of noise or a lot of variability. But

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if in the morning there was a super cheap imaging technology we could go into

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CVS something or whatever you know once a week and you get a quick scan for a

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brain volume the change at the individual subject level might be

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diagnostic. Would that be a possibility you think? No I think you're right

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that's a good insightful comment because one thing that we see in

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the field is that and this comes out of the first episode work and following

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these people longitudinally at first is as we mentioned there is that

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progression there is that change. And so what you can see is that there are

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some brain wave measures that we can get with EEG or MEG other kinds of imaging

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measures and some MRI measures that tell us about the structure and we can see

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that those are getting worse during the early course and so the question is well

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we want to see people before the psychosis emerges we want to see can we

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detect them these sort of changes before they get really bad so that someone

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starts acting psychotic and we halt that process can we detect those people and

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do some sort of intervention. One thing that's happened as a consequence of the

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first episode work is now in clinics across the US and across the world we're

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seeing earlier and earlier intervention of people and we know from I think

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there's I think there's enough evidence out there to show that early

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intervention intensive early intervention in people leads to less

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hospitalizations and a better prognosis so we know what does that early

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intervention look like what are we throwing at them? Well the thing is we

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don't have medications for everyone we don't have a new medication that we can

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give someone but if you have you know you could sort of think that intensive

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family therapy intensive psychotherapy building social supports you know all

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these kinds of things it's good for everybody yeah and it really is. So

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behavioral changes withdrawing you know this is a person who's vulnerable let's

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get them out of this super stressful situation. That's right I think

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that's a big part of it. And what about low dose antipsychotics? I think

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that once that someone becomes psychotic yes absolutely. Right so you wouldn't

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treat prophylactically you wouldn't treat before. Well the problem is and this gets

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back to what we mentioned earlier we don't have a good biomarker or diagnostic

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test for it so you had you know you mentioned earlier about you know can we

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look at change and one thing that's happened is now that we know there are

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progressive changes early in disease course once psychosis emerges people

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have started studying clinical high-risk individuals and what that means is well

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these people don't have psychosis but we think they might and these might be

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teenagers or young you know adolescents that look like they're maybe a little

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further along than the average teenager they might be having some subtle

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symptoms they might be worried about the neighbors or they might say they are

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hearing things they know they're not real so it's like well they seem to be

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having these clinical symptoms that aren't very severe but they're subtle

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and it's this might turn into something so that would be a clinical high risk for

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psychosis and the thing is most of those individuals will not develop psychosis.

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If you follow them over two or three years probably only two and ten maybe if

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they're followed over ten years maybe three or four and ten so you can't put

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everybody on necessarily treating people yeah that's not right. You can't put the other people on a

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lifetime of tranquilizing medication. No. You just can't do it. So what we what we

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need to do is we need to know what kind of tests can we develop that will

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tell us who's at greatest risk and you're absolutely right people who are

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showing change in brain volumes or behavioral measures or some of the

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neurophysiological measures that we can record those are the ones that are at

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greatest risk but we don't have a solid biomarker of risk yet. Yeah. So there's a

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lot of research going on right now and that's the cornerstone of what you're

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you're about right that's what your lab is about trying to develop those

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biomarkers, neuromarkers. That's exactly right. Yeah so so we work in people that

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have a first episode and we're trying to find biomarkers of the presence of their

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psychosis that have a what we call a very large effect size and what that

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means is that there's very little overlap with a neurotypical healthy

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population so you could really see at the individual level that an individual

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who's scoring poorly on this particular test doesn't really overlap with the

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usual distribution of scores and then the hope is to say we can now take that

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measure and put that in people that are at clinical high risk and maybe they'll

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be two out of ten or whatever the number is that score very poorly on that test

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or have an abnormality on that test and then those people we could maybe have a

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more aggressive treatment that might include anti-psychotic medication. Yeah I

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would say I always liken this to it's like neuroscientists in the hunt for our

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version of serum cholesterol like a test that you would that would be a really

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good predictor and everybody listening in will know oh yeah if I get my

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cholesterol test and I score above 200 I probably need to be doing something

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better I'm going to develop heart disease and that's really the same basic

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logic that we go after in our field. Yeah that's precisely right. Dean I want to go

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back to to you how did a lad from Long Island end up at the University of

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Pittsburgh via Harvard and Whittier College and give us give us give us the

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background because you're not from it no more than myself you're not from a

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traditional academic family right this is so what's what's the story? Thank you

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John yeah I know you well we've known each other for a long time so you know

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my sort of backstory so yeah I come from a very blue-collar background on Long

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Island and my mom was you know pretty much a single mom for a long time and

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put herself through college with five children and became a nurse and then my

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stepdad when she got remarried was a printer and you know so I I was always

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you know just good at school and I enjoyed school and I knew I wanted to go

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to college no one in my family had gone to college right out of high school

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before me and I just somewhat accidentally ended up going to Whittier

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College in California I got something in the mail and they offered me a

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scholarship and went there and I knew we want to do psychology but that's all I

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knew I didn't know I didn't know anything really about psychology or

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about science or so I went there and I I graduated in what they called the

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scholars program and it was sort of a design your own major and I said well you

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know I really want to go into biological psychology because I got very much

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interested in the brain and in how that worked and cognition in humans and they

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did not have cognitive neuroscience which is what we would say we do clinical

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cognitive neuroscience they didn't have that back in the early 80s you know so I

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went to a biological psychology program at Stony Brook where I was lucky enough

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to get into the graduate program there and started learning about human EEG and

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I also did some work in animal recordings and surgeries and was doing

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that but I thought I wanted to be a neuropsychologist and that's someone

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who would do a lot of paper and pencil tests and test children or different

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kinds of brain injuries and so I was I did a neuropsychology intern but it

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happened to be at Stony Brook University Hospital on a psychiatric ward and that

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was where I started to get exposure to people with psychiatric illnesses but my

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dissertation was actually in sleep and sleep research and doing EEGs on sleep

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and and how the brain responds to sounds when you're asleep and I guess you could

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say it was essentially how do alarm clocks work right because you're

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sleeping but the alarm clock still wakes you up right so but as it turns out then

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I as I was getting ready to graduate my mentor at the time in graduate school

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Nancy Squires one of the greats in the business she was one of the pioneers in

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EEG work yeah and she she got a call from from Bob McCarley's group at Harvard

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they were looking for a postdoc and so I went up and interviewed and I was gonna

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do a two-year postdoc and I stayed there for 22 years before I moved to Pittsburgh

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about 11 years ago fantastic fantastic it's a great story and and I think you

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know we're about to run out of time you know but just just thanks for sharing

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the stuff about schizophrenia and I think people will really appreciate what

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what you're doing and I know I appreciate the passion that you bring to

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this I know that it's like you care deeply about this particular issue and

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and it's it's been really fantastic for me you know I count you of course as a

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as a longtime friend at this point and we met through science but it's been

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really fantastic for me to to follow the science and to have great conversations

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with you over the years and so I'm really pleased that we get to share one

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of those conversations with with our public thank you so much John and you've

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been a great supporter over the years and a good friend and really and I hope

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everyone enjoys it so cheers Dean thanks very much