We do not have a biological test or a brain test or a MRI scan that we can run
on someone and say, hey, this person has schizophrenia. We don't have that.
And it wasn't until really the the 1990s, early 2000s that MR machines got
sensitive enough that we could actually start to detect in living humans some of
the subtle brain abnormalities that were present in schizophrenia early in the
disease course. The human brain is the most complex structure in the known
universe and we are in the middle of a scientific revolution to understand its
inner workings. Join us for a conversation with world-renowned
neuroscientists as they visit Rochester. I am Dr. John Foxe, Director of the
Del Monte Institute for Neuroscience at the University of Rochester and you are
listening to neuroscience prospectus. Thank you for joining us for this episode
of neuroscience prospectus. I'm thrilled to be joined by Dean Salisbury, professor
of psychiatry at the University of Pittsburgh. Dean is the principal
investigator of the clinical neurophysiology research laboratory and
that lab focuses on understanding the pathology and pathophysiology of first
episode psychosis and the progressive course of structural and functional
impairments in early disease. And Dean, thank you for taking the time to join us
to chat about your research while you're here and just life in general and what
brought you to science. Thanks for having me, it's such a pleasure to be here. So
let's dive right in. You know when I think about schizophrenia, you and I
share a passion for trying to do something about schizophrenia. I think
about what people often call like a wicked problem. It's a wicked
problem. Nearly 1% of the world's population there or thereabouts suffers
from this chronic disease. Our frontline treatment for schizophrenia is
something that was discovered in the late 1940s, early 1950s. That's what
we're doing today. Why in the intervening 75 years have we not been able to you
know move the ball down the field? You're right, it is a wicked problem. Very
debilitating disorder and over half of the people won't even be able to work
part-time for the rest of their lives. Drugs, the medications we use were
discovered accidentally years ago and they really haven't changed. When we look
at new medications that were developed, most of them haven't been effective.
We don't understand the mechanisms. However, I think there's an
exciting new trend which is non-invasive brain stimuli. So the
non-invasive brain stimulation studies show some promise in having long-lasting
effects. Right, right. Yeah and it's one of those things right, the
original drugs, D2 antagonists, these dopaminergic drugs are good at treating
these psychotic symptoms which is what everybody associates schizophrenia with.
But the truth is what really makes somebody ill with schizophrenia and turns
it into a chronic disease is not the psychotic symptoms. It's, well, do you
want to hold forth on that, right? Yeah, so we can think about three things. One
is sort of the psychotic symptoms that you were talking about like hearing
voices or having delusions and the medications we have treat those really
well. What they don't treat are the so-called negative symptoms which is
sort of abolition or sort of a lack of, you know, being able to do things or
apathy, not caring, or cognitive abnormalities, you know, sort of an
inability to think well really, right? So and we don't have good medications for
that right now. They're really untreated. There are other ways that people are
trying to get at those. There are some medications that are under investigation
that are trying to target, you had mentioned the D2 receptors, they're
trying to target either muscarinic or glutamatergic receptors. They haven't had
great success in clinical trials. So now you've been up to your elbows in this
schizophrenia work but not so much on the drug development side, right? I mean
obviously you know an awful lot about that but you spent a career first
at Harvard, now at Pittsburgh, trying to understand the basic brain physiology,
brain mechanisms, structural changes in the brain in schizophrenia. Do you want to
tell us a little bit about that and then I'm gonna I'm gonna ask you a couple of
tough questions about where that's going. We do not have a biological test or a
brain test or a MRI scan that we can run on someone and say hey this person has
schizophrenia. We don't have that and it wasn't until really the the 1990s,
early 2000s that MR machines got sensitive enough that we could actually
start to detect in living humans some of the subtle brain abnormalities that were
present in schizophrenia early in the disease course. And so if we think about
what areas might be impacted in the disorder, first of all when we think
about you know sort of the will to act and behave and motor systems and even to
some extent language systems, hearing voices about 70% of our individuals even
the first time they get sick hear voices. We think about the frontal lobes and we
think about the temporal lobes which are intimately involved in language and
behavior and planning and memory and so when we look early in the disease course
we see that the temporal lobes particularly in the left side where sort
of the expressive language is those areas show very subtle changes early in
the disease course. When you say subtle changes, tell us what those look like.
Are we looking at a little bit of brain shrinkage, loss of tissue? That's
exactly right. What we're seeing is a reduction in gray matter, the gray matter
of the brain, and it's probably on the order of about 5% compared to a
healthy person of the same age. And you'll see that in the frontal lobes as
well and so early in the disease course so right around when psychosis emerges
you will have a large number of people where you can't detect any brain
difference and there's a small number of people that do have some brain
difference. So at the group level we could see a change between a group of
healthy people and a group of people at first psychosis but at the individual
level it's not big enough to use for any diagnostic testing. And what happens
during the disease course is the loss that we see, the volume loss or the gray
matter volume loss, the sort of shrinking of the gray matter in the brain spreads
across the entire brain over a period of 20-30 years. So it's a very subtle and
very slow change in the volume or loss of volume in the brain. So it's interesting
right because you're making a very important point right you can see these
these differences at the group level and the problem is you can't say very much
about the individual because there's a lot of noise or a lot of variability. But
if in the morning there was a super cheap imaging technology we could go into
CVS something or whatever you know once a week and you get a quick scan for a
brain volume the change at the individual subject level might be
diagnostic. Would that be a possibility you think? No I think you're right
that's a good insightful comment because one thing that we see in
the field is that and this comes out of the first episode work and following
these people longitudinally at first is as we mentioned there is that
progression there is that change. And so what you can see is that there are
some brain wave measures that we can get with EEG or MEG other kinds of imaging
measures and some MRI measures that tell us about the structure and we can see
that those are getting worse during the early course and so the question is well
we want to see people before the psychosis emerges we want to see can we
detect them these sort of changes before they get really bad so that someone
starts acting psychotic and we halt that process can we detect those people and
do some sort of intervention. One thing that's happened as a consequence of the
first episode work is now in clinics across the US and across the world we're
seeing earlier and earlier intervention of people and we know from I think
there's I think there's enough evidence out there to show that early
intervention intensive early intervention in people leads to less
hospitalizations and a better prognosis so we know what does that early
intervention look like what are we throwing at them? Well the thing is we
don't have medications for everyone we don't have a new medication that we can
give someone but if you have you know you could sort of think that intensive
family therapy intensive psychotherapy building social supports you know all
these kinds of things it's good for everybody yeah and it really is. So
behavioral changes withdrawing you know this is a person who's vulnerable let's
get them out of this super stressful situation. That's right I think
that's a big part of it. And what about low dose antipsychotics? I think
that once that someone becomes psychotic yes absolutely. Right so you wouldn't
treat prophylactically you wouldn't treat before. Well the problem is and this gets
back to what we mentioned earlier we don't have a good biomarker or diagnostic
test for it so you had you know you mentioned earlier about you know can we
look at change and one thing that's happened is now that we know there are
progressive changes early in disease course once psychosis emerges people
have started studying clinical high-risk individuals and what that means is well
these people don't have psychosis but we think they might and these might be
teenagers or young you know adolescents that look like they're maybe a little
further along than the average teenager they might be having some subtle
symptoms they might be worried about the neighbors or they might say they are
hearing things they know they're not real so it's like well they seem to be
having these clinical symptoms that aren't very severe but they're subtle
and it's this might turn into something so that would be a clinical high risk for
psychosis and the thing is most of those individuals will not develop psychosis.
If you follow them over two or three years probably only two and ten maybe if
they're followed over ten years maybe three or four and ten so you can't put
everybody on necessarily treating people yeah that's not right. You can't put the other people on a
lifetime of tranquilizing medication. No. You just can't do it. So what we what we
need to do is we need to know what kind of tests can we develop that will
tell us who's at greatest risk and you're absolutely right people who are
showing change in brain volumes or behavioral measures or some of the
neurophysiological measures that we can record those are the ones that are at
greatest risk but we don't have a solid biomarker of risk yet. Yeah. So there's a
lot of research going on right now and that's the cornerstone of what you're
you're about right that's what your lab is about trying to develop those
biomarkers, neuromarkers. That's exactly right. Yeah so so we work in people that
have a first episode and we're trying to find biomarkers of the presence of their
psychosis that have a what we call a very large effect size and what that
means is that there's very little overlap with a neurotypical healthy
population so you could really see at the individual level that an individual
who's scoring poorly on this particular test doesn't really overlap with the
usual distribution of scores and then the hope is to say we can now take that
measure and put that in people that are at clinical high risk and maybe they'll
be two out of ten or whatever the number is that score very poorly on that test
or have an abnormality on that test and then those people we could maybe have a
more aggressive treatment that might include anti-psychotic medication. Yeah I
would say I always liken this to it's like neuroscientists in the hunt for our
version of serum cholesterol like a test that you would that would be a really
good predictor and everybody listening in will know oh yeah if I get my
cholesterol test and I score above 200 I probably need to be doing something
better I'm going to develop heart disease and that's really the same basic
logic that we go after in our field. Yeah that's precisely right. Dean I want to go
back to to you how did a lad from Long Island end up at the University of
Pittsburgh via Harvard and Whittier College and give us give us give us the
background because you're not from it no more than myself you're not from a
traditional academic family right this is so what's what's the story? Thank you
John yeah I know you well we've known each other for a long time so you know
my sort of backstory so yeah I come from a very blue-collar background on Long
Island and my mom was you know pretty much a single mom for a long time and
put herself through college with five children and became a nurse and then my
stepdad when she got remarried was a printer and you know so I I was always
you know just good at school and I enjoyed school and I knew I wanted to go
to college no one in my family had gone to college right out of high school
before me and I just somewhat accidentally ended up going to Whittier
College in California I got something in the mail and they offered me a
scholarship and went there and I knew we want to do psychology but that's all I
knew I didn't know I didn't know anything really about psychology or
about science or so I went there and I I graduated in what they called the
scholars program and it was sort of a design your own major and I said well you
know I really want to go into biological psychology because I got very much
interested in the brain and in how that worked and cognition in humans and they
did not have cognitive neuroscience which is what we would say we do clinical
cognitive neuroscience they didn't have that back in the early 80s you know so I
went to a biological psychology program at Stony Brook where I was lucky enough
to get into the graduate program there and started learning about human EEG and
I also did some work in animal recordings and surgeries and was doing
that but I thought I wanted to be a neuropsychologist and that's someone
who would do a lot of paper and pencil tests and test children or different
kinds of brain injuries and so I was I did a neuropsychology intern but it
happened to be at Stony Brook University Hospital on a psychiatric ward and that
was where I started to get exposure to people with psychiatric illnesses but my
dissertation was actually in sleep and sleep research and doing EEGs on sleep
and and how the brain responds to sounds when you're asleep and I guess you could
say it was essentially how do alarm clocks work right because you're
sleeping but the alarm clock still wakes you up right so but as it turns out then
I as I was getting ready to graduate my mentor at the time in graduate school
Nancy Squires one of the greats in the business she was one of the pioneers in
EEG work yeah and she she got a call from from Bob McCarley's group at Harvard
they were looking for a postdoc and so I went up and interviewed and I was gonna
do a two-year postdoc and I stayed there for 22 years before I moved to Pittsburgh
about 11 years ago fantastic fantastic it's a great story and and I think you
know we're about to run out of time you know but just just thanks for sharing
the stuff about schizophrenia and I think people will really appreciate what
what you're doing and I know I appreciate the passion that you bring to
this I know that it's like you care deeply about this particular issue and
and it's it's been really fantastic for me you know I count you of course as a
as a longtime friend at this point and we met through science but it's been
really fantastic for me to to follow the science and to have great conversations
with you over the years and so I'm really pleased that we get to share one
of those conversations with with our public thank you so much John and you've
been a great supporter over the years and a good friend and really and I hope
everyone enjoys it so cheers Dean thanks very much