Child Study Center Grand Rounds 02.02.2020

Transcript

• 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.