Child Study Center Grand Rounds 02.02.2020

March 23, 2021

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Never too early to Intervene Neurodevelopmental Perspective of Schizophrenia

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00:00Hello and welcome to grand rounds.
00:03Today is the second of three lectures
00:07honoring our late director and friend,
00:10Doctor Donald J Cohen.
00:11Before we go to the main event
00:14with Kartik's presentation,
00:16I want to share some images and
00:20thoughts about Doctor Cohen,
00:22recognizing that many of us here today,
00:25especially our younger trainees,
00:27may not have known Donald Donald Cohen.
00:31To remind you who lived between 1940 and
00:332001 was a Sterling professor of child
00:36psychiatry psychology in Pediatrics,
00:38and he was the director of the Deal
00:41Child Study Center from 1983 to 2001.
00:44He was one of the most renowned
00:47child psychiatrists in the world
00:49and those of us who came under his
00:52influence remember him not only fondly,
00:55but our lives were really changed by him.
00:59As I talked the first time during
01:01Emily Olsen's presentation,
01:03I commented on Donald the builder.
01:05And when we talk when we have
01:07the third talk by Tom Fernandez,
01:09I will focus on Donald Cohen, the mentor.
01:12But today with Kartik's presentation,
01:15I think it's very fitting that
01:17I'll talk about Donald Cohen,
01:19the scientist,
01:19and one thing that Donald and
01:21Kartik had in common is that they
01:24both got science early on.
01:26They got the bug of science very early on.
01:29Karthik is the son of scientists.
01:32His early years were marinated
01:33in science and he is really the
01:36consummate scientist and like Donald,
01:38as I say he got the bug early on.
01:43Let me share with you how early
01:45Donald got this bug.
01:47This is an image from Donald in the
01:504th grade, 3rd grade, 2nd grade.
01:52I'm sorry and these are words
01:54that he wrote maybe a year later
01:57after this photograph was taken.
01:59So let me quote.
02:02Even at age 8,
02:03I was curious about relationships
02:04and thought about thinking,
02:06especially how we think about each other.
02:08This was the context of my
02:11first formal interview.
02:12Michael and I often went to
02:14the Garfield Park Conservatory,
02:16a wonderful institution available
02:17to youngsters in Chicago.
02:19We would wander through the rooms
02:21filled with the tall tropical
02:23trees and exotic Flowers,
02:25taking in the beauty and Misty musty smells.
02:28I became especially aware of one
02:30man who would always be standing
02:32quietly and watering the plants.
02:34He patiently did his job with a sense of
02:37calm and a gentle smile for the newspaper.
02:40I thought he would be the ideal
02:42person to interview and he consented.
02:44The interview was then published in
02:46our school newspaper and constitutes
02:48one of the earlier reports,
02:50though less widely.
02:51Circulated than that of Kanner and Asperger,
02:54of the central phenomena that
02:56still intrigue our field.
02:58Let me quote the full
03:00article published in 1948,
03:02at this time as a historic.
03:06And the documentation of the launching
03:08of a lifetime career in autism research.
03:11This is a verbatim interview.
03:13I was a shy and frail child.
03:17Therefore,
03:18I decided to become a gardener.
03:22This early reporting is socially
03:24dysfunctional.
03:25Adult identifies constitutional factors,
03:27shines,
03:27and possible biological coral.
03:30Its frailty with long term prognosis
03:33in a career that was socially isolated,
03:36the Gardner represents an optimistic
03:39adaptation to an underlying
03:41disability in social orientation.
03:44So that's not. Donald, of course.
03:46Went on to build a career focus on
03:49autism work that has continued with
03:52the likes of Red Oak Mark of Ami,
03:54Klin of Jane McParland and so
03:57many other of our colleagues.
04:00Donna was also a psychoanalyst.
04:02We're delighted that Phyllis Cohen
04:04is joining us today and here you see,
04:07Phyllis and Donald hanging out
04:10with Anna Freud.
04:11And this work in psychoanalysis and
04:13bringing analysis and science together,
04:16continues thinking of the
04:17individual and the science,
04:19not as two separate things,
04:21but together the importance of
04:24the lived experience.
04:26And this is work that also continues
04:28with Linda and the work at the
04:31unemployed Center in London today.
04:33Donald also was a pioneer
04:35in the use of medication.
04:37This is the persons of quantity
04:401979 for Tourette syndrome.
04:42And the rest, as we say, is history.
04:45This is a work that has continued with,
04:47I mean Amy Arnsten here at Yale with
04:50Larry Scale now at Emory and medications
04:53that have really revolutionized the
04:56way that we treat ADHD Tourettes.
04:58Here you have Donald in the 1970s
05:02working on the molecule of quantity.
05:05And that works.
05:06That focus on threats continues most
05:09notably with the work of Jim Lechman
05:12and the incredible influence that
05:14Donald had on Jim and the incredible
05:16influence the gym in turn has had on.
05:20Like a block on me personally,
05:23and certainly on our hero of
05:26the day on Karthik.
05:28So without further ado,
05:30let's see what the legacy of Donald
05:33and the funds from his chair have
05:35gone to do in the work of wonderful
05:38young scientists like Emily Olson and
05:40today Kartick Kartick take it away.
05:42The grades were dropping and then
05:44they started to notice that the child
05:47was spending more time in their
05:49room and eventually the mother was
05:51trying to concern and brought him
05:53into the emergency room because she
05:55noted that this child was talking to.
05:58Someone that wasn't there.
06:00Eventually the child is diagnosed with
06:02schizophrenia and from there schizophrenia
06:03is a progressive disorder where there
06:06is worsening psychotic symptoms.
06:07There's worse than negative
06:09and cognitive symptoms.
06:13And so I think this is an important
06:15point that schizophrenia is not just the
06:17psychotic symptoms or the madness, which is,
06:20I think is really focused on in a lot
06:22of different menu, specifically media.
06:24So there are positive symptoms
06:26which are hallucinations,
06:27delusions, or disorganized thought.
06:28But there's also negative symptoms.
06:30Which are Anna Donia, a motivation?
06:32Social withdrawal?
06:32I think that one of the initial
06:34terms autoset almost looks like
06:36autism as well as a flat affect.
06:38And finally,
06:39their cognitive symptoms can be
06:41quite debilitating for the patients.
06:42It's poor short term in working
06:44memory as well as difficult and
06:47difficulty in communication.
06:48And so once this child was
06:50admitted to our unit,
06:52we decided to start a medication
06:54for this child, an antipsychotic.
06:55You know everyone has their
06:57their choice and despite having
06:58medications to treat schizophrenia,
07:00the outcomes are still not great.
07:02In this.
07:03Once they show that 10% of patients
07:05with schizophrenia die by sight,
07:07suicide,
07:07which is greatly elevated from
07:09the rest of the population.
07:1125% have chronic severe symptoms,
07:12while most patients have some
07:14level of symptoms and they're
07:16just looking at symptoms,
07:17functional outcomes are actually much worse.
07:19I think part of the issue is that it
07:22was kind of highlighted in the Katy
07:25trial that was done early in the 2000s,
07:27where they showed in two at least.
07:30They followed patients with
07:31schizophrenia over two years and only
07:3326% of them actually stayed on their
07:35medication through this whole trial.
07:37And due to this progressive illness
07:38as well as the difficulty of keeping
07:41patients on their medications,
07:42the focus has been on prevention and
07:45this has been work done starting in the
07:47late 80s by various groups instead of.
07:50Anything including a strong group
07:51here in adult psychiatry with the
07:54focus has been as is intervening
07:56during this prodromal stage.
07:57So when our honor student is slowly
07:59starting to academically decline,
08:01can we interview at that point intervene?
08:03Sorry at that point to change the
08:05trajectory of schizophrenia and maybe
08:07prevent the transition to psychosis.
08:09And there's been a lot of
08:11great work done in that area,
08:13especially the focus on psychoeducation
08:15teaching the family what to expect,
08:17as well as reducing the stress
08:19that the child experiences
08:20as it's thought that stress.
08:22Can worsen the trajectory of the disorder
08:25and despite all these great studies,
08:27kinda bleak meta analysis came out
08:29July of 2020 and then I'll just
08:32highlight that first sentence.
08:33No evidence was found that that favored
08:36any indicated intervention over another,
08:38including control conditions.
08:39So despite all this work,
08:41we're not really preventing the transition
08:43to psychosis and later on they talk.
08:45There's actually no real obvious improvement
08:47in a lot of these other functional measures,
08:51So what gives?
08:52How can we prevent schizophrenia?
08:54And I think part of the issue
08:56has been this psychosis driven
08:58formulation of the disorder that
09:00prior to this prodromal phase
09:02there's no symptoms or few symptoms,
09:04and so the focus has been on the prodrome.
09:08But actually data shows something different.
09:11This was one of the seminal
09:13works that came out in 1994,
09:14led by Doctor Elaine Walker and what she
09:17showed along with when it came out in 1994.
09:20I thought it was kind of funny.
09:22Was that this is correlated.
09:24But 20 years after like home video
09:26cameras became popular with this study,
09:28did was they looked at the life they
09:30recruited patients with schizophrenia
09:31and then looked at their home videos
09:33from their childhood and they looked for
09:36neuromotor abnormalities and what they
09:37found specifically in infants is that.
09:39And so this population that
09:41later developed schizophrenia.
09:42Has schizophrenia as a child they showed
09:44increased abnormal motor movements
09:46while their healthy siblings did not.
09:47Just things that did not have
09:49schizophrenia and patients with
09:50other affective disorders also
09:52didn't have a significant difference
09:53from the patients of schizophrenia.
09:58Later, Lin walked.
09:59Walker was part of this other study
10:02that was more thoughtful 'cause
10:04they had no more time to design
10:07this study and what they did was
10:09they videotaped 1311 through 13
10:11year olds in Scandinavia that have
10:12an increased risk of schizophrenia.
10:14Specifically a parent with
10:16schizophrenia and they found that
10:17when they went and then waited to
10:19see which one of these children
10:21would later develop schizophrenia,
10:23they found that the children that
10:25later developed schizophrenia show
10:26deficits and social behaviors.
10:28Around 11:13 there wasn't an obviously
10:30significant different in motor.
10:31Even though it trended in boys
10:33towards having some motor atypical,
10:35atypical motor behaviors,
10:36and this more recent paper was
10:39something that I was really drawn to,
10:41and this was part of the Avon
10:43Perspective study where they just
10:45tracked children that were born in two
10:48years in this city of Avon and England,
10:50and then just did a bunch of like just
10:53neuro psychological battery on them
10:55and they found that children that
10:57later developed psychotic disorders,
10:59that's that red line around the age of.
11:0218 months somewhere to 18 months
11:04in four years start to show a
11:07decline in cognitive function.
11:08This is seen in full scale IQ,
11:11verbal IQ and nonverbal IQ and
11:12so I think these findings along
11:14with various other studies suggest
11:16maybe we're missing something.
11:18Maybe schizophrenia actually
11:20starts earlier than we thought.
11:23And so this has been led to kind
11:25of a new version of schizophrenia,
11:28which I feel is much more child psychiatry.
11:31Child psychology focused where
11:32initially their cognitive motor
11:34and social impairments and these
11:36progressively moved towards psychosis,
11:37and I think this is a really
11:40interesting theory because it kind
11:42of gives us a longer runway, right?
11:45Can we intervene much earlier and to
11:47later prevent this transition to psychosis?
11:50However,
11:50in order to turn this model into real?
11:53Real clinical intervention.
11:54We have to kind of understand the
11:56neurobiological underpinnings of this data.
11:58So what are the neurobiological
11:59correlates of the neuro developmental
12:01theory of schizophrenia?
12:02Which is something that I'm very
12:04interested and so the first thing we
12:07can do is look to our colleagues in
12:10psychiatric genetics such as my good friend.
12:13Emily Olson,
12:13who's like,
12:14does a brilliant work and gave an
12:16amazing presentation two weeks ago.
12:18As Doctor Martin mentioned and what
12:20she kind of talked about was the
12:23current state of psychiatric genetics,
12:24and in the last 10 years there's
12:27been amazing progress in the field,
12:29and schizophrenia is also seen
12:31great progress in schizophrenia,
12:32genetics,
12:32where they have identified several
12:34genes associated or enriched
12:36in mutations in several genes
12:37associated with schizophrenia,
12:38and what a recent study has done.
12:41And this is kind of.
12:43Where several labs are doing this
12:44where you have so many genes,
12:46how can we turn these jeans into
12:48specific targets or regions or time
12:50periods of development to study?
12:52And what this study did was they
12:54looked for regions in the brain
12:56in specific periods.
12:57They looked at fetal infancy,
12:58an adult adolescent stages and they
13:01looked at different regions of the
13:02brain and they looked for a place and a
13:05time where there was an enrichment of
13:07genes associated with schizophrenia.
13:08Almost like you have people
13:10involved in a crime.
13:11Are they in the same place together?
13:13As a way of maybe giving you a time
13:16point in an area to specifically
13:18dig deeper into to understand what
13:21they found was an enrichment.
13:22These alleles in the fetal cortex,
13:25specifically in the frontal lobe,
13:26and this is very similar findings to
13:28work done by Matt States Group and
13:31he was here at Yale in autism and
13:33this also coincides really well with
13:36earlier epidemiological data that
13:38shows that stress during pregnancy,
13:39specifically during the 2nd trimester
13:41increase the chance of having a child.
13:44That develops schizophrenia.
13:47So this led to our more focused
13:49question how does disruption of
13:51neurodevelopmental events in the mid
13:52fetal frontal cortex lead to the
13:55complex symptoms of schizophrenia?
13:56And so this is where the story starts.
14:00And So what we did is we use that
14:02same data set that these previous
14:04groups use is called psych encoder.
14:06Brain sandwiches generated in this
14:08test in lab to look for genes that
14:10were uniquely enriched in the frontal
14:12lobe during mid field development.
14:14We're looking for something specific
14:15to the mid function.
14:17The midfielder frontal lobe and that's
14:19why we looked for genes are enriched there.
14:21And so we identified 125 genes enriched
14:23specifically in the frontal lobe.
14:25During this period,
14:26Anna's Emily showed in her previous talk.
14:28We looked at what do these jeans?
14:30Share this click gene ontogeny analysis and
14:33what we found was that these genes are in.
14:35This list is enriched for genes that
14:37are involved in circuit formation so
14:39synapse assembly Axon development in
14:41circuits are kind of the functional unit.
14:43I think I, uh,
14:45I guess eventually unit.
14:46That's like high truly focuses on the brain,
14:49but we also saw something that
14:50was unexpected which was jeans
14:52that are responsive to rent.
14:54No gas or jeans that are regulated
14:56by retinoic acid and this was very
14:58exciting for us. For several reasons.
15:00There was a basic science.
15:02Perspective which I want talking
15:04or evolutionary perspective that
15:05I want to talk about.
15:07But there was a very interesting
15:09clinical perspective.
15:10So disruption of retinoic acid signaling
15:11has been implicated in schizophrenia.
15:14And it seems that the your polygenic
15:16risk score or how many genes associated
15:18with retinoic acid's are affected seem
15:20to be elevated in patients schizophrenia
15:23with severe cognitive symptoms.
15:24So this was something very
15:26interesting and very exciting to us,
15:28so we postulated that disruption
15:30of RA regulated or related genes.
15:32Causes some change in brain development.
15:34Likely circuit formation as
15:36those are what those genes are.
15:38Also enriched and and that can lead
15:40to the early cognitive symptoms
15:42of schizophrenia.
15:44So to study this,
15:45we turn to a mouse model and
15:47we asked what is retinoic acid
15:49doing specifically in
15:50the frontal cortex.
15:52So we generated a mutant mouse line
15:54where we're able to specifically
15:55reduce retinoic acid signaling Justin,
15:57the mouse equivalent of
15:59the prefrontal cortex,
16:00and So what you see here is a PO
16:02mouse brain which is equivalent to
16:05mid fetal about post Conception Week
16:0724 in the human and these purple
16:09dots are cells where there's active
16:11retinoic acid signaling going on,
16:13and so this is the control.
16:15And this is the mutant where we've
16:17modified retinoic acid signaling,
16:18and you can see a dramatic
16:20reduction in purple cells which
16:22is quantified here on the right.
16:23And so now that we've reduced
16:25retinoic acid saying we looked at
16:27what happens to circuit formation in
16:28the frontal cortex or specific middle
16:30prefrontal cortex in the mouse and
16:32what we found was a couple things.
16:34But I'll highlight just a few phenotypes.
16:36First,
16:36we found a reduction in dendritic spines
16:38which are kind of excitatory connections
16:40in the brain which is quantified here.
16:42This is done in the adult,
16:44and so you can see a
16:46reduction in total spines.
16:47But also,
16:47reduction in mushroom bodies,
16:49which are mature spines and we replicate
16:51this finding both during the equivalent of
16:53midfield development in the human at PO.
16:56So this occurs very early.
16:57But we also saw this
16:59finding in adults as well,
17:01so this seems like this deficit in
17:03excitatory connections starts very early,
17:05but the finding that I want to focus
17:07on is this very interesting deficit
17:09that we found that got us all excited.
17:12We first found this data,
17:14so this is a study using this mutant
17:16mouse line using diffusion tensor.
17:18Which looks at connectivity in the brain,
17:21and so this is a five day old
17:23mouse brain which you can see
17:25kind of as a Gray fuzzy outline,
17:28and so about five days equivalent to
17:30birth in the human and what we found
17:32was a dramatic reduction between
17:34connections which are shown by these.
17:36These red lines between the
17:38prefrontal cortex and the thalamus
17:40on the right is the control,
17:41so you can see this thick bundle
17:43and on the left is the mutant where
17:46you see a dramatic reduction in
17:48connectivity which is quantified.
17:50Here on the left,
17:51and so we found this deficit very early,
17:54but it seems like this may.
17:55This deficit is maintained during
17:57adolescence, so we checked it P.
17:5921 but we also checked it P.
18:0116 The adult.
18:02So this isn't, you know,
18:03a delay in development.
18:05This is a complete disruption of
18:06the circuit in our mouse model.
18:11And this was kind of fits what
18:13we've been thinking about with
18:14schizophrenia, so this connection,
18:16the connection between the medial
18:18prefrontal cortex and the thalamus
18:19is essential for cognition,
18:20specifically working memory.
18:21This is a study.
18:23This is a reviewed written by
18:25Doctor Gordon Josh Gordon,
18:26who is now the head of the MH,
18:29who showed that the connection
18:30between the mediodorsal thalamus
18:32and the prefrontal cortex,
18:33and there's typical connection
18:34between the prefrontal cortex
18:36and the mediodorsal thalamus is
18:38essential for the delay in the
18:40retrieval steps of working memory.
18:41The circuits also been
18:43implicated in social behavior,
18:45so it's a circuit that's very it's
18:48highly studied in psychiatric biology.
18:54And so our proposed model is that
18:56disruption of retinoic acid,
18:58associated and regulated genes lead
19:00to reduce connectivity between the
19:02prefrontal cortex in the thalamus
19:03and that leads to the early
19:05cognitive symptoms of schizophrenia.
19:07This deficit occurs during the 2nd
19:10trimester of development in scene
19:13right at birth in our mouse model.
19:16So this led to a lot of important
19:18questions of future directions,
19:19which I'll talk about.
19:21So first this is the mouse model.
19:23This is have any relevance to
19:25patients with schizophrenia?
19:25And so this in this case we turn
19:28to another set of colleagues,
19:29colleagues that are involved
19:31in functional imaging,
19:32functional neural humanit,
19:33functional imaging.
19:34And this is a study done in 2015 and
19:36what they found they were specifically
19:38looking at the lambic cortical
19:40networks in healthy subjects that
19:42compare them to patients within four
19:44weeks of their diagnosis of schizophrenia.
19:46And then patients with chronic
19:48schizophrenia chronic psychosis.
19:49So this has been over a couple years.
19:53Of being diagnosed with schizophrenia
19:54and we can see in the blue bar,
19:56so this is functional connectivity so
19:58it's looking at just connection between.
20:00Different regions,
20:01specifically the almacen regions
20:02of the cortex,
20:03and they showed that compared to
20:05the control which is the blue bar,
20:07there is reduced connectivity
20:08both at diagnosis,
20:09which is shown at the yellow bar
20:11and both in the chronic stage.
20:13So that seems like this disruption
20:15is present,
20:16and at least this population
20:17of patients with schizophrenia,
20:19something else that was really interesting
20:21was a study done by Alan and Tisha Vich,
20:23who is in I guess now apiai in
20:26adult psychiatry.
20:27But this is when he was working
20:29in Doctor Tyrone Cannons Lab.
20:31And they looked at patients with high
20:33risk of developing schizophrenia.
20:34They had a certain set of criteria
20:36to kind of identify these patients
20:38and what they showed was this
20:41disconnection between Hypo connection
20:42with they called it between the medial
20:45frontal cortex or the frontal cortex,
20:47and the thalamus was present even
20:49prior to conversion in two psychosis.
20:51Specifically,
20:52that then I guess in addition
20:54to what they showed,
20:55was that the worst the psychotic symptoms,
20:58the more the reduced connectivity
21:00there was between.
21:01These two regions,
21:01so it seems like even prior to conversion,
21:04there seems to be this disconnection
21:06between the thalamus in the cortex,
21:07and so I think this is an interesting
21:10circuit to study in and further work from.
21:12Functional neurology is important
21:13to kind of see if this is a much
21:16more generalizable etiology.
21:17We also plan to study this in
21:20various mouse models as well.
21:22So the second question,
21:23which I think is something that
21:25I'm very excited about and I think
21:27is an essential question to really
21:29understand how to understand the
21:31complex symptoms of schizophrenia,
21:33is how can a specific deficit in
21:34one circuit that's involved in
21:36cognition lead to the complex
21:38symptoms of schizophrenia?
21:39Just as a quick refresher we talk
21:41about we're talking about a circuit
21:43that's important for cognition
21:44and maybe some
21:45social behavior,
21:46but there's also the hallucinations,
21:48delusions, the various other
21:49symptoms of schizophrenia,
21:50so we turn back to those studies that
21:52I just mentioned from functional.
21:54Human neuroimaging and what we see is in,
21:58so I showed you this panel here,
22:01which is the connectivity between
22:03the prefrontal cortex and the family
22:05showed reduced connectivity during
22:07chronic psychosis and early stages,
22:09but we actually see a commensurate
22:12hyper connectivity between the
22:14thalamus in the motor cortex and the
22:16thalamus in the somato sensory cortex.
22:19What's interesting is that that the
22:21study done by Allen Tiffin Teacher
22:24***** so that same hyperconnectivity
22:26as well in these prodromal patients.
22:31And so that in this kind of I turned
22:34back to kind of some of our mouse works.
22:37So we not only looked at connections
22:39between the thalamus and the frontal
22:41cortex in our mutant mouse time,
22:42we looked at various other
22:44connectivity at specifically at P4,
22:46which is equivalent to birth,
22:47and at this stage the only deficit that
22:49we found was a connection between the
22:52thalamus and the medial prefrontal cortex,
22:54and we did not see reduced connectivity
22:56between the thalamus in the motor cortex or
22:59the thalamus in the somatosensory cortex.
23:01So what we're interested in doing is
23:03seeing whether there's a change in
23:05this kind of diagram in connectivity.
23:06As the mouse gets older,
23:08do we see a change in adolescence,
23:10and do we see a change in adulthood?
23:12We know that the connection between
23:14the medial prefrontal cortex,
23:15the prefrontal cortex in the thalamus,
23:17is lossed all the way through.
23:19But what happens to other circuits?
23:21Are there progressive change and
23:22so kind of fleshing out this model,
23:24which is something that we need
23:26to continue to test and study?
23:28Is that retinoic acid associated
23:30genes disruption in these genes
23:31lead to reduced medial?
23:32The frontal cortex,
23:33medial dorsal thalamus and medial prefrontal
23:36cortex connectivity and that leads
23:38specifically to early cognitive symptoms.
23:40However,
23:40the brain now has to compensate so this this
23:43disruption of a circuit occurs very early.
23:46So during childhood the brain is
23:48trying to compensate for this deficit.
23:51As we know,
23:52the brain can do through neuroplasticity,
23:54and maybe these secondary changes
23:56may underlie the positive and
23:57negative symptoms of schizophrenia.
23:59Abig critique of the
24:01neurodevelopmental theory is what?
24:02Explains that big gap between what's
24:04supposed to be the deficit during
24:06development and the positive symptoms later,
24:08and what what it could be is
24:11that the brain is compensating
24:12it's compensating it's working.
24:14It's kind of figuring out different ways to
24:16try to make up for this cognitive deficit,
24:19and eventually as expectations get higher,
24:21there's a breakdown in the system,
24:23and that leads to the psychotic symptoms.
24:25This can also kind of dovetail well with
24:27kind of the current driving force kind
24:29of driving neurodevelopmental theory that
24:31it's a specific synaptic pruning deficit.
24:34During adolescence,
24:34and that's where you see the break then.
24:37So maybe as you prune more,
24:38you've lost some of these
24:40compens atory mechanisms,
24:41leading to a psychotic break.
24:42And this is something that I'm really
24:44interested in testing in a mouse model.
24:46What happens to our mouse when we have
24:48a specific deficit in this mediodorsal
24:50prefrontal cortex connection,
24:51and how does it change the rest of the brain?
24:54And how does it change behavior
24:56progressively through time?
24:58And I think this also gives us
25:00an opportunity to think about
25:02interventions or future interventions.
25:04If this is the primary insult,
25:06a connection between the mediodorsal
25:07down in the prefrontal cortex,
25:09can we try to strengthen this
25:11connection using in the few?
25:13It's very futuristic at this point,
25:15but maybe deep brain stimulation
25:17or TMS or other processes.
25:19Or we could just work on cognitive skills.
25:22Could we do brain training apps
25:24almost like a burst to three?
25:26However, for patients that are at high risk?
25:29Of schizophrenia and the thought is
25:31by not only by treating this trying
25:34to strengthen this circuit can we
25:36improve these early cognitive symptoms?
25:39We can altogether prevent the secondary
25:41circuit changes and maybe prevent
25:43positive and negatives symptoms.
25:45And this is something I'm just
25:47generally interested in studying.
25:49Currently circuits neuroscience,
25:50which is, I think,
25:52a big crux of adult psychiatry has
25:54an adult focus of what they do.
25:57Is they disrupt relevant circuits?
25:59Like the study I showed that
26:01was done by Josh Gordon's lab.
26:03They just daily disrupt these
26:04circuits during adult in adults or
26:06they disrupted during adolescence.
26:08And then they look, went to disrupt it.
26:10How does that affect behavior?
26:12But what I'm interested in is I think
26:14more relevant to disorders like autism,
26:16schizophrenia,
26:16where we see this disruption occurs
26:18very early and so we can then study
26:20if we disrupt in the development
26:22of specific circuits early.
26:24How does that affect the rest
26:25of brain dump development?
26:27I think this could generate a more.
26:30A better version or better model of
26:34neuro psychiatric disease in our
26:37model systems to further study.
26:39So this is a summary of the talk.
26:42I think the main points I want
26:44everyone to take away within some
26:46that we can further discuss is that
26:49the cognitive and motor symptoms
26:51of schizophrenia may precede the
26:53positive symptoms in schizophrenia.
26:54This is underlying the neuro
26:56developmental theory of schizophrenia
26:57and disruption of frontal cortex
26:59development during the 2nd trimester
27:01has been associated with schizophrenia,
27:02both genetically as well as from
27:04epidemiological data and then
27:06finally prefrontal cortex,
27:07Islamic connectivity.
27:08Maybe the underlying developmental
27:09etiology of schizophrenia and a target.
27:11For early intervention.
27:14So this was the data that I showed
27:16was part of a as netted,
27:18mentioned a large collaborative
27:19effort at specifically like to thank
27:22men and who's been an excellent
27:24mentoring is really giving me a
27:25great opportunity in the lab and
27:27as well as a Mickey to Shibata,
27:29who we worked very closely in
27:31leading this project.
27:31But as I said,
27:33there were so many different people in
27:35the lab that were involved in this project.
27:37Doing experiments giving feedback.
27:38It's just been really amazing process,
27:40but I also like to thank all
27:43of our collaborators.
27:44They helped us with both the generating
27:46the mice as well as the neuroimaging.
27:48The diffusion tensor imaging
27:49in the mouse model,
27:51as well as our funding sources
27:53there retinoic acid choice,
27:54specifically was funded by Safari
27:55Assignments Foundation for Autism Research,
27:57and then it is funded by the NIH,
27:59and I received some money from
28:01the Riva Ariella Ritvo endowment,
28:03which I'm using towards kind of
28:05answering that last question that I'm
28:07really interested to and then finally
28:09like to thank the Solar Program.
28:11The Child Study Center this other
28:12program has been really amazing
28:14opportunity to really kind of get
28:16into lab and really kind of bridge.
28:18The clinic as well as my
28:20basic science interests,
28:21so I'm really thankful to doctor Block,
28:24Doctor Stube and Tiny Cologne
28:25who really do the heavy lifting.
28:27The program as well as the T 32 fellowship,
28:30which funds my last two years in the program.
28:35And that's the talk.
28:46I have a question if I can
28:48jump in and it's amazing data,
28:51I just think it's so important.
28:55I had a question about connectivity.
28:57Were you able to see reduced
28:59connectivity and other pathways,
29:01either longranger or local?
29:02I know it's very challenging
29:04in the mouse where there isn't
29:07that much cortical cortical,
29:08but I'm guessing that this is and
29:11the the thalamic mouse prefrontal
29:13connection is extra important in
29:15a mouse compared to a primate.
29:17I think 'cause of that were
29:19you able to see others here,
29:22so we definitely looked
29:23at that. We wanted to make sure.
29:26Whether this was a specific
29:27lesion and before we started,
29:29we were kind of agnostic about the
29:31circuit that we were expecting,
29:32so we did a couple things.
29:34First, I kind of went quickly to this side,
29:37so this is very diffusion
29:38tensor imaging data from P5.
29:40So we kind of basically
29:41parcel atede using an Atlas.
29:43Different regions of the brain,
29:44and so we didn't see any deficits
29:46in inflamma cortical connections
29:47besides the connection to the
29:49medial prefrontal cortex.
29:50We did see a little bit of a
29:52deficit in the orbitofrontal cortex,
29:54which isn't shown here.
29:56What was really interesting
29:57is that it seems like both of
29:58these tracks ride together,
29:59and so we were one day.
30:00Weather DTI was aimed really had
30:02some issues separating them,
30:03but we didn't see any and I'll show
30:05some later date a couple slides
30:07down but we shot so no deficits
30:08in cortical cortical connectivity
30:10between the somatosensory cortex
30:12with the motor cortex as well
30:14as the prefrontal cortex,
30:15and we didn't see any changes
30:17in cortical amic tracks.
30:18We also looked at dopaminergic input.
30:20We actually initially thought we would
30:21see a deficit in dopaminergic input
30:23and made that underlies the positive
30:25symptoms of schizophrenia and at
30:27least at the ages that we looked at,
30:29we didn't see any.
30:30Gross abnormalities in dopaminergic input,
30:32and I know times aren't senior
30:34interest in the prefrontal cortex,
30:36so we also did.
30:40Yeah, so we also didn't show this slide,
30:43but we also did viral tracing
30:45from the prefrontal cortex and
30:47so this was in the so we did.
30:49This was in the adult where
30:51we and this was nabbed car.
30:53Doctor Carr was a postdoc in the
30:55lab who did an injection in the
30:57prefrontal cortex and then we
30:59looked at just inputs into the
31:01prefrontal cortex and whether
31:03there are any specific deficits.
31:04We saw a little bit of reduction
31:06connectivity between in the insula,
31:09but still once again the primary deficit was.
31:11The mediodorsal doubtful amic
31:13input into the prefrontal cortex.
31:18And I'm copying
31:20that slide so I can look at it is.
31:23Is that also a reduced connectivity
31:25with is that medial orbital?
31:30We didn't see
31:31that much, so I called that date.
31:33We call that the insula.
31:36There wasn't much connectivity that we
31:37could see in our tracing experiment,
31:39but I can look more closely over the data.
31:42I can definitely email you some
31:43of the slides so we can look
31:45at it more closely together.
31:46Great if I may interject.
31:48Amy, I think you are right.
31:49Actually, we do suspended that,
31:51but you know, the problem is that we just.
31:54Our goal for us not to claim too much.
31:58I totally understand
31:59that for publication in particular, but.
32:04Especially, you know, given the cortical
32:08cortical connections and and the.
32:11Between hemispheres was that one
32:13also not affected that was
32:16not affected as well. The closel.
32:18I just imagine that if it's
32:21more general than the thalamic,
32:24we really see that in the human, and
32:27that it would be tremendously important.
32:32Ask your question.
32:34Kept up or you know about 30 years ago,
32:38Danny Weinberger at NIMH had
32:41a developmental theory about
32:43schizophrenia and that the
32:45reason that it sort of showed
32:48up at around age 20 or so.
32:51Why is that? The
32:53kind of prefrontal inhibitory
32:55functions that usually
32:57began to come online it around that time?
33:01Somehow words and I was just curious.
33:05This is a naive question in terms of
33:09my understanding of DTI and maybe this
33:12retrograde study shows something.
33:14But what is the directionality?
33:16You talk about defects in
33:18connectivity between the
33:20prefrontal cortex and the thalamus?
33:22Are those simply reciprocal,
33:24or are they mostly kind of top down? And
33:30then the other question is
33:32that you know going way back
33:35to the 70s and 80s with work by
33:39Barbara Fish and Kornblatt and
33:41other people who are studying
33:43children of skits, high risk
33:46offspring of schizophrenic patients.
33:47I mean they showed a lot of
33:51early kind of minor ADHD
33:53inhibitory difficulties,
33:54subtle neuropsychological deficits,
33:55and I was wondering if
33:58you had thoughts about what
34:00the? Underlying neural correlate's
34:02of those are. Definitely yeah,
34:06and I think that Danny Weinberger's work.
34:08I have a Erica. That's a slide from his.
34:11So he really was the creator of this
34:13theory of the neuro developmental theory.
34:15And this is actually from one of
34:17his more recent reviews and I
34:19think that's really interesting.
34:20And so I think the focus has
34:22been really in that adolescence,
34:24and it makes sense, right?
34:25Maybe there.
34:26I think it combines two theories together.
34:28I tried to touch on that and that what
34:31we see is that the brain is trying to
34:33compensate the brains trying to compensate.
34:36As I mentioned.
34:37And then, once the.
34:38The normal processes of development
34:40that occur during adolescence,
34:41which strips away these
34:43connections at reduced plasticity.
34:44With the closure of these neural Nets,
34:47you lose that compens atory mechanisms,
34:49and then that kind of breaks
34:52through and leads to the symptoms.
34:56Maybe that's something that needs
34:57to be really studied, right?
34:59I mean, I think this is still something
35:01that we're looking at in a mouse model.
35:03I kind of pull on a little adult
35:05data to try to give it some support.
35:07You're actually,
35:08I'm not familiar with the papers like ADHD,
35:10so definitely to look those up,
35:11but they kind of make sense.
35:13ADHD is also distorted.
35:14The frontal cortex,
35:15something that I have been interested in is,
35:17you know,
35:18it's thought to be like a dopaminergic
35:20deficit that occurs in ADHD.
35:21That's why stimulant works so well.
35:23And so I wonder what would
35:24be the secondary changes in
35:25dopaminergic innervation?
35:26We looked kinda early,
35:27but.
35:28Is there some subtle change and
35:29that's why antipsychotics work in
35:31schizophrenia despite focusing?
35:32I'm focusing on a non dopaminergic circuit,
35:34so that's something that I probably
35:36have to read into a lot more,
35:38but it's really interesting
35:40of like 80s ADHD symptoms.
35:43There's a lot of evidence
35:45out of Judie Rapoport's group,
35:47that ADHD involves impaired development
35:50of the right inferior frontal,
35:52and one wonders if somehow that's
35:55associated with reduced retinoic
35:57acid in a mosaic sort of way.
36:00I also wonder if is there any
36:03evidence that inflammation reduces
36:05retinoic acid since there's so
36:08many ties between inflammatory
36:10insults in utero and schizophrenia.
36:13Definitely. I mean,
36:13I think the inflammation thing
36:14is is quite interesting, right?
36:16How can we coincide both?
36:17I mean, I just read a recent paper by
36:19archive of more about the compliment pathway,
36:21so that's something that could
36:22be quite interesting.
36:23And what I didn't touch it.
36:25I think we talked a little
36:26bit before awhile ago.
36:27We were talking about the RA paper
36:29is what we show in the human,
36:31at least compared to the mouse.
36:32And there's a great expansion of retinoic
36:34acid signaling in the frontal cortex,
36:35so you could see similar deficits may
36:37be in the human that you don't see
36:39in the mouse of these connectivity
36:40changes in other regions of the
36:42Association aspects of the frontal lobe.
36:46Arctic, this was real.
36:47Thank you.
36:47This was really great and one
36:49of the things I love when you
36:51talk is that you always get us
36:53to think about things in a
36:55very different way. So I just had a
36:57question about your idea about
36:59stress and if you think of you know,
37:01as you suggested, that you know
37:03later around the skits of the brain.
37:06Of the schizophrenic,
37:07you know just can't manage all
37:09the all the stress and all the the
37:12the bombardment of demands on it.
37:14Could you think
37:15of those you know? Individuals early
37:19on in childhood who are doing better
37:21not being exposed to as much stress
37:23and having much more early supports.
37:25You know the the work of us in the
37:28field of child psychiatry that would
37:30somehow prepare them in a way to have
37:33kind of a more resilient brain for
37:35later on and hopes of doing better.
37:37Does that make any
37:39sense to you? I
37:40really like that approach.
37:41I think you know, it's really easy
37:44to get very sized by in science.
37:46You know, like we're going to virally
37:48infect the brain changes gene
37:50expression on this other thing, but.
37:52I think we're quite far from that,
37:54so building these skills very
37:55early in these high risk children,
37:57especially something like you know
37:59resilience, skills or cognitive skills.
38:00Now what I like about these types
38:02of interventions is that the risk
38:04profile is really low, right?
38:06If we're stimming a circuit,
38:07or we're giving retinoic acid or work
38:09virally infecting the brain, right?
38:11You have to be pretty confident
38:13that this child is going to develop
38:15a disorder that will be, you know,
38:17quite dramatically, life altering.
38:18And so I like building on these skills
38:20because if this child doesn't convert
38:22to psychosis even in the prodromal stage.
38:24Data about a third of these high risk
38:27patients actually develop schizophrenia,
38:28and so building skills that I think
38:31could help this child leaders and
38:33help manage the stress which is
38:35clearly been shown to affect kind
38:37of severity of symptoms.
38:38I think it just makes a ton of sense.
38:42It just fits
38:43so nicely with her model of lowering.
38:45You know inflammatory insult
38:46from stress and things.
38:47So thank you very much.
38:49I really enjoyed this very much.
38:52Hi Christine.
38:53Hi, this is Flora vaccarino.
38:54I have a question very interesting so can
38:57you go a little bit into the mechanism?
39:00What do you think is happening here?
39:02Do you think that there is a relative
39:06deficit over 18 OIC acid that?
39:08Somehow, directly or indirectly
39:10stunts the growth of this connection
39:12downstream connection to that Alamos.
39:14Do you think there is a chemoattractant
39:17role for 18 OIC acid in attracting
39:20those connections in that alamaze or?
39:22Or what do you think is going on?
39:25Because retinoic acid is thought to
39:27be a very important more for John
39:30earlier on to write much earlier,
39:31but it seems to be more in
39:34posterior regions of the brain,
39:36where here you're talking about something
39:38specific for prefrontal cortex,
39:39yeah, is that right? I mean can you?
39:43Something that netted an in the lab is
39:46talked about, kind of retinoic acid.
39:47Historically we have been thought
39:49of as a post theorizing factor,
39:51especially in the hindbrain,
39:52but I think then it has a more
39:55complex theory of how it goes,
39:56but I think your point is well taken overall,
39:59that retinoic acid.
40:00Is pleiotropic.
40:01It's involved in almost every
40:03process of brain development and
40:04development overall and so I guess
40:06to answer the couple questions and
40:08remind me if I missed some of this.
40:10First, what we show in the paper is
40:12that retinoic acid during mid field
40:14development is tightly regulated
40:16to just the prefrontal cortex.
40:18So there's actually the sink,
40:19so there's 626B1 which is a retinoic
40:21acid degrading enzyme which is
40:23great enriched in the medial pre
40:25installed in the motor cortex.
40:26So that kind of restricts it to
40:28and then we also showed various
40:30different sources of synthesizing.
40:32AXA of genes of both intrinsic
40:34to the parenchyma itself as well
40:36as inputs that are coming in from
40:38other regions of the cortex that
40:40seem to be expressing a retinoic
40:42acid synthesizing enzyme.
40:43So it seems to tightly restrict
40:45it that mechanism that first
40:46question you asked is something
40:48that I'm very interested in.
40:49So what is retinoic acid actually
40:51doing in making this circuit?
40:53And So what we looked at is so we have
40:55we did RNA seek in our mouse model where
40:58we reduced retinoic acid signaling a
41:00specific the medial prefrontal cortex.
41:02So we microdissected the
41:04medial prefrontal cortex.
41:05Orbital frontal cortex in the motor
41:07cortex and looked at what's different
41:08between the control and the wild type.
41:10And we found a lot of target genes,
41:13specifically adhesion molecules
41:14instead of chemo attractants that
41:16are seem to be at the synapse.
41:17And so we're thinking that my kind of
41:19general interest is in cortical connectivity,
41:21especially long range connectivity,
41:23and so we're I'm thinking is that
41:25these axons are able to navigate the
41:27striatum and all these cues there to
41:29get to the doorstep of the cortex,
41:31but they're not getting that final
41:33chemoattractant that retinoic
41:33acid is specifically regulating,
41:35and so it's getting there and not.
41:37To form the connection and then
41:39actually kind of loses it and I forgot
41:42something that Doctor King as it we see.
41:45Reciprocal loss of glamo,
41:46cortical prefrontal connections,
41:47both Pfc to Mia dorsal thalamus
41:49about Mr prefrontal cortex.
41:51Yeah doctrina, that's a vacuum.
41:52That's a great question,
41:54and that's something that we're
41:56really careful to show in the paper
41:58that we're not altering cell number
42:00or brain size or all these other
42:02kind of factors that retinoic acid
42:04is involved in seems to be very
42:06selectively involved in kind of circuit.
42:09Formation if you reduce it just to that
42:11period, I'm just asking how you doing
42:13there asking the obvious question.
42:15Organize stuff.
42:17You can easily test this in organoids
42:18from Cortex entoloma schizophrenic,
42:20personally definitely.
42:20So this is something that
42:22we're really interested in.
42:23I I know that you're so far ahead in
42:25the field and we've been reading a
42:27lot of assembly papers in the paper.
42:29I was really like the Pasco paper
42:31that showed kind of like this
42:33cortical striatal connection.
42:34It's really interesting that
42:35that connectivity can then maybe
42:36alter the properties,
42:37so I think that's a great mechanism
42:39to study specifically human if
42:41this is relevant in a human.
42:42So I agree, yeah,
42:43I should have actually figured it out.
42:47Find the results and the way we're
42:50developing a system where you can develop,
42:53organize from different brain regions
42:55using gradients of morphogens,
42:57so that could be also used to actually
43:00specifically do at Alamo Alamo
43:02particles system that you could use.
43:05That sounds great.
43:06Yeah, 'cause it is. Great
43:09idea. Yeah thank
43:10can I can I? I'm delighted to see how
43:14much interest your talk has taken and
43:17I want to go in another direction.
43:19I want to go from organoid to humanoid
43:21because one of the things then Karthik.
43:24We've had the pleasure of working
43:26together and I've seen you as a
43:28clinician and your clinician as well.
43:30And you know the the experience of
43:32individuals with schizophrenia,
43:33which is something that we see
43:35and I just want to in the chat,
43:37which has been very active. Angie,
43:39thank you for mentioning gating systems.
43:41You know there's a question about gating.
43:44I want to call your attention and to
43:46everyone and there's this wonderful
43:48book called Hidden Valley Rd that
43:51came out last year about a family that
43:53had 7 / 12 siblings had schizophrenia
43:55and what's interesting is both
43:57the experience of schizophrenia.
43:58But this is a family that was followed very,
44:02very closely by Robert Friedman.
44:03You know,
44:04the great psychiatrist in Colorado
44:06who was the pioneer of gating
44:08so highly recommended.
44:09But if you could comment something
44:11about gating and then moving
44:13in the humanoid direction.
44:14I wanna after you answer that I want to
44:16call our attention to Doctor Yankee Yazgan,
44:18who is our colleague from Turkey
44:20who is joining us here and he
44:21will have a comment after you met.
44:23Maybe you mentioned that thank
44:24you for great great talk Arctic.
44:26Yeah,
44:26I think getting
44:27it first before I actually reflect on
44:28some of my time back on when he wanted
44:31something that did strike me when I
44:33was there 'cause we were actually doing
44:34the work while I was on when he won.
44:36My last run. Was that some of the kids
44:39that come in with early onset psychosis
44:40or a couple of stick in my head.
44:42I won't give the names obviously.
44:44But they showed distinct low IQ's.
44:46I think they were running in the
44:4860s and 70s and so that kind of was
44:51something that I always kind of brewing
44:53that idea as as I was going there.
44:55Yet gaining is a really interesting
44:56question right?
44:57Especially for positive symptoms, right?
44:58Can you gate sensory information?
45:00That's going into the cortex right?
45:02And and there's great work by Al Powers.
45:04Who's in the adult Department?
45:05He's a young faculty of the question.
45:07It is actually the information that's going
45:09in from the founders of the cortex incorrect?
45:12Or is the cortex processing
45:13that information incorrectly?
45:14And I think that kind of.
45:16Really eludes to kind of what I was
45:18saying without trying to put my foot
45:20down that as the you're getting abnormal
45:22extra connectivity with these sensory
45:24areas between the thalamus in the cortex,
45:27so maybe you're getting too much
45:29information going in and you're not able
45:31to really parse what's truly occurring
45:33as well as a kind of background noise,
45:35and that could be a nice kind of circuit.
45:38Kind of psychobiology kind of thought
45:40about how you create a hallucination or a
45:43delusion or disorganized thought as well.
45:45Any of the positive symptoms.
45:46To be honest,
45:47so on an international angle,
45:49we're going first to Turkey and
45:51then to France. So Yankee asking,
45:53and then Lilia Benoit Yankee, please.
45:57Just hi there everybody.
45:59So glad to be back in New
46:01Haven, at least for a couple
46:04of weeks after 25 years.
46:06So I've been following what's
46:08going on at child study closely,
46:10but haven't had the chance to be in
46:13grand rounds for awhile. Thanks for.
46:17Including me and great to see
46:20friend friendly faces and friends.
46:22I'm really impressed by the
46:24quality of the work that says that
46:28seemed to that will be changing
46:31the way we deal with these cases,
46:34but so if you questions or
46:37minor questions probably.
46:38I'm also I have been interested
46:41in the neuromotor signs as an
46:44indicator of future psychopathology
46:46an my my question would be.
46:49How would how is the the diagnostic
46:53specifity established either
46:55schizophrenia or aspergers or
46:58whatever based on these findings?
47:01I mean can we replace schizophrenia
47:04with ASD or with another
47:07new developmental disorder
47:09on neurological terms? Thank you party, nice
47:13nice meeting you by the way.
47:18That's a great question.
47:19Even the initial paper by Elaine
47:21Walker specifically said that
47:22this is not specific, right?
47:24Like there, other disorders ASD that
47:26showed these same type of things.
47:28So I think the diagnostic.
47:31Capacity of these things
47:33is probably quite for,
47:34I think, over all right.
47:35I think there might be
47:37something subtle I mean,
47:38and so if you look at the kind of the listed,
47:41all the criteria they looked
47:43at through motor right?
47:44So it was like increased tone
47:46like abnormal hand movements.
47:47All these things that we could see in a
47:50lot of developmental disorders because
47:51they if we think of cerebral palsy,
47:53is like the classic developmental disorder.
47:55Some sort of deficit in
47:57circuit formation early.
47:58They show these signs very distinctly,
48:00so I think the.
48:01Specificity is probably extremely
48:02low for these types of things,
48:04but I think that as we start turning
48:07our focus to early in earlier stages,
48:09which is what these perspective
48:11studies are so exciting to me,
48:13I think maybe we can narrow it
48:15down to something specific.
48:17One thing I didn't know in these
48:19studies is that patients that later
48:21developed bipolar disorder which
48:22have you know a similar psychotic
48:25E type presentation untreated,
48:26those time control don't show
48:28these motor signs,
48:29and so that's I thought quite interesting.
48:31But I think ASD and Sara
48:33Palsy and schizophrenic.
48:34There's a lot of overlap and
48:36I think disease pathology.
48:37You know,
48:38both in the time period that specifically
48:40sensitive the cells that are affected,
48:42the jeans that are effective.
48:44There seems to be similar processes
48:45that are affected or altered and why
48:48they manifest is different disorders.
48:49I think that's still a long way away,
48:52and it needs a lot of research to
48:54make sense that thanks very much.
48:58Paid Lilia and
48:59then Ellen Hoffman. High thank
49:01you very much. Much chaotic.
49:03So just a comment.
49:05We had just seeing that the 30 years
49:08of research carried on clinical
49:10transition by our Australian colleagues,
49:13for instance, Patrick Mcgorry trying to
49:16to build clinical tools like the cars
49:19and following clinical subjects like
49:21we see with the drama that it's not
49:24really working as as we would have reached 2.
49:28Because it was a great hope to
49:30to have those clinical tools and
49:32psychoeducation and omega-3 etc.
49:35So I mean, it's really important to see
49:37that we still need the fundamental research,
49:40so that's still very much needed,
49:43so it's interesting.
49:46But I think that's something that was
49:50also interesting in this clinical
49:52assessment was to build strong cohorts an,
49:55so that's something that they
49:57they really managed to do,
49:59and I'm wondering because.
50:00Cohorts that you cited include
50:03very few children.
50:04So do you know of ongoing
50:08cohort that would maybe?
50:10Gather better data on neuromuscular skills,
50:12etc.
50:13Yeah yeah,
50:13yeah yeah,
50:14I'm new to
50:15them or the clinical world as I
50:18actually recently talked to one
50:20of our graduates from our program,
50:22Jerome Doctor Taylor,
50:23who's now faculty at Penn,
50:25and he's working as part of the
50:28lifespan lifespan group with the girls,
50:30and so they have this larger study.
50:33I don't know the exact things
50:35like Philadelphia, children,
50:36something where they're really
50:38deeply profiling children,
50:39just agnostically kids that.
50:41Initially, like a lot of the
50:42work was focused on stress and
50:44like kind of exposure to trauma.
50:46We heard like a presentation from we
50:48went there for a treat a couple years ago,
50:51but they are actually interested
50:52in psychosis and so they are
50:54looking more closely at that group.
50:56That same group actually does
50:57looks at patients of 22 Q 11,
50:59which is a genetic deletion that
51:01has a 30% increase chance of
51:03developing schizophrenia is way
51:04higher than the normal population.
51:05So there are also carefully built a
51:07large cohort of these patients because
51:09the issue is schizophrenia as it's rare.
51:11Right?
51:12Like even in highly focused
51:13clinical populations of high risk,
51:1530% convert.
51:15And so if you're taking all takers,
51:18you're going to get the population
51:19rate and so something like 22 Q 11
51:22are some of these genetic disorders
51:24that you can pick out immediately.
51:25Who has these, and you can really trace them.
51:28Could be, I think,
51:29a fruitful way of making sense of this.
51:32But yeah, numbers,
51:33you just gotta get higher and higher numbers.
51:35But I think the Philadelphia
51:37size actually is really cool work
51:39in the garage slab there.
51:41Can I just say before LL and will
51:43have one last question and then
51:45we can hang out with with Kartik?
51:47We won't close a room but if people
51:49need to leave but I just want to
51:52call your attention to next week's
51:54grand rounds which is going to be
51:56a little bit continuing and some
51:57related way so Kieran O'Donnell,
51:59one of our newest faculty members is going
52:01to be talking to us about early early,
52:03early, early early years and the
52:05impact on the developing brain.
52:07So I think it's going to be very
52:09in keeping with today's talk.
52:10So Ellen last question for Karthik.
52:13Carter
52:13great great talk, I really enjoyed it.
52:16You know, I guess as we think about a lot
52:19of different questions that one question
52:22which I wrote in the chat with you.
52:25Sorry you arrived at the
52:27retinoic acid pathway.
52:28Sort of thinking about risk genes
52:30or following the genes there.
52:32So to what extent do you think that
52:35this pathway and the thalamus to
52:37prefrontal cortex connection might
52:39represent a common pathway across?
52:42Schizophrenia risk genes versus one
52:44of several routes there and the sort
52:46of related to the other question.
52:48Previous question,
52:49to what extent might this represent
52:51a common pathway across other
52:53neurodevelopmental disorders?
52:54And that's such an important
52:56question for us to
52:57really be able to transition
52:59this intervention right?
53:00Because as this was a mouse model, right?
53:03And we actually weren't
53:05looking at schizophrenia,
53:06we were really interesting.
53:08Just prefrontal cortex evolution
53:09and development when we initially
53:11started this study and so retinoic
53:13acid actually agnostically popped up.
53:15There was some data before from
53:17an earlier study in this testing
53:18lab that pointed at retinoic acid,
53:20and then we kind of reconfirmed
53:23it and then analyzed it.
53:25Retinoic acid specific.
53:26There's a couple of papers that
53:28have really kind of focused on
53:30retinoic acid as as possible as
53:31a possible signaling pathway.
53:33I still I'm kind of wary about
53:35specifically retinoic acid.
53:36I think as Doctor Vaccarino mentioned
53:38is I think something downstream
53:40and also kind of putting together
53:42with our current knowledge that
53:44seems to be like a lot of the
53:46schizophrenia associations an
53:47autism will soon be at the synapse.
53:49Maybe it's something specifically
53:51about Synapse connectivity and we
53:53just happened to stumble upon it by.
53:55Going the retinoic acid path,
53:56I do though to you later point.
53:59I do think plama cortical dysfunction may
54:01be some core pathology in the disorder,
54:03and that I like that circuit based
54:06focus versus like a signaling pathway,
54:08because I feel like,
54:09as I mentioned before,
54:11like retinoic acid involved in everything.
54:13So it would be really hard to target it,
54:16and so I think there is some data that's
54:18coming together that Flamel cortical
54:20dysfunction is specifically an issue,
54:22whether it's specifically
54:23thalamic to prefrontal cortex.
54:24I think that might be at
54:27least a subpopulation.
54:28Of it will be interesting,
54:29kind of the gating question.
54:31Maybe other Islamic deficits,
54:32Lima cortical connectivity deficits
54:33could explain other things.
54:34And if you kind of read I I spent
54:36a lot of time before this talk,
54:39like kind of reading through all
54:41this schizophrenia literature
54:42because I spend more time reading
54:43like gene regulation stuff and one
54:45of the theories has put forward.
54:47There's almost two types of schizophrenia.
54:48There's like a classic honor
54:50student type of schizophrenia,
54:51word, psychotic symptoms,
54:521st and then you kind of progressives
54:54are very responsive to antipsychotic's.
54:55But there's also the second
54:57type which is very driven.
54:58This cognitive negative symptoms,
55:00so I wonder if, like you know,
55:02one population is specifically shows
55:04this Pfc Flamel cortical deficit,
55:06and while his other population doesn't.
55:08You know,
55:08kind of phenotyping versus maybe
55:10thalamic cortical connectivity.
55:11Maybe something that spans across
55:13these different endo phenotypes,
55:14but I think we just need more close,
55:17thoughtful thinking.
55:18Like I guess,
55:19characterization of these patients
55:20of patients schizophrenia to
55:22really kind of link a disorder.
55:23But yeah,
55:24I do think there's something with
55:26the llama cortical connectivity.
55:28It's always in some.
55:29I've been interested in that may
55:30underlie schizophrenia across the board.
55:34Well Kartik, thank you for a
55:36really magnificent grand rounds.
55:37We're going to leave the room
55:39open if anyone wants to join,
55:41but I want to thank you.
55:42And you've taught us a lot of
55:44science science with a heart,
55:46so that's that's really good.