Child Study Center Grand Rounds 09.15.2020

March 23, 2021

CBT for Pediatric Irritability From Efficacy and Biomarkers to Personalized Interventions

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00:00So welcome everyone in case you're
00:03not familiar with this new way of
00:05doing business, it's called Zoom.
00:07I'm going to spell it for you at Zo Om.
00:11In case you haven't heard of it.
00:14And it's I think the first time
00:17that we're doing our actual
00:18grand rounds in zoom we've had.
00:20We had Linda's introduction.
00:22Last week, and we certainly had a
00:25series of presentations and some very
00:28moving presentations on race and race
00:31related issues over the late summer,
00:33but this is really the formal
00:36kickoff of our grand rounds series.
00:38For those of you who are new
00:41to the Child study Center,
00:44just a reminder that grand rounds
00:47happens every Tuesday from one to
00:50two and we try very hard to be.
00:53Very broad and what we aim to do.
00:57We go from science to policy,
00:59from neurons to neighborhoods,
01:01from interneuronal to extragalactic,
01:03and every point in between.
01:06Because we really want to reflect
01:08the the deep bench and the broad
01:11richness of the child study center
01:13and not just the child study center,
01:16we're also going to have occasionally
01:19visitors from near and far.
01:21But it's only appropriate that we
01:24start with our very own prodigal Son.
01:27Who I knew as a young child when she
01:31arrived here and now look at him.
01:34So Dennis and I arrive more or
01:36less at the same time,
01:39and it has been just wonderful to
01:41see Dennis who dulski's career
01:43blossom in an incredible way.
01:46We're very fortunate that Dennis.
01:49It's not fortunate for Saint Petersburg,
01:51but it's very fortunate for us that
01:53he left his native St Petersberg.
01:56He's been here enough for many
01:59years and Dennis says.
02:00Really the go to person for so
02:03many of us when we get stuck on
02:06anything having to do with CBT.
02:08We all claim to do CBT or all wannabe
02:11CBT sites. But the high priest.
02:14Is Dennis, you know?
02:16Dennis really sets the bar for
02:19how CBT is done,
02:20what the best practices are with the
02:23most innovative angles of CPR and
02:25and Dennis is incredibly generous
02:27with his time with his knowledge.
02:30Just looking at the faces around the screen,
02:33I know that so many of us
02:36myself certainly included,
02:37have been educated and moved
02:39and touched by Dennis,
02:41who is not only an incredible researcher.
02:44As you will see,
02:46but a wonderful communicator,
02:47he's able to breakdown very complex concepts
02:50into something that looks so simple.
02:53It looks cartoon like simple,
02:55because when he does it, it's very simple,
02:58but it it ain't so simple.
03:01But he's going to break it for us
03:03and Dennis were absolutely delighted
03:05that you're the Child study center.
03:08You have changed your citizenship
03:10from Saint Petersburg to Woodbridge.
03:12We are very happy about that.
03:15And it's a pleasure to have you here,
03:17so take it away, my dear friend Dennis.
03:20Go for it.
03:21Thank
03:22you, thank you for the introduction and
03:25rest and thank you so much for inviting me.
03:28It's an honor to start this
03:31year's ground round serious,
03:32and this is a topic that's
03:35very dear to my heart CBT.
03:37So I I think I like being
03:40called a high priest.
03:46And certainly will will use this designation.
03:50The topic. Of pediatric irritability and
03:53kind of predates our current political
03:56situation and all this social issues that
04:00we're going through, so my research.
04:08My research on pediatric irritability
04:10started some time ago when I arrived as a
04:14postdoc here at the Child Study Center,
04:17and today I will summarize some
04:19of this work in 45 minutes or so,
04:22hoping to save some time for questions.
04:26I won't be able to see comma
04:28and so somebody has questions.
04:29Please save them to the end or send them to
04:33the group and we'll circle back to them.
04:36So the goals for me today is to talk
04:40about clinical characterization
04:42and diagnostic issues,
04:44and pediatric irritability.
04:46Discuss CBT,
04:47which stands for Cognitive behavioral
04:49therapy and in children with irritability
04:52across diagnostic categories and
04:54with specific focus on autism.
04:57I will also say a few words about
05:00neuroimaging research that we have been
05:04conducted to understand brain mechanisms of.
05:07Irritability and biomarkers
05:08of treatment response.
05:10And Lastly I will tell you about
05:13our research studies.
05:14Some of those studies have been
05:17completed recently and others have
05:20been conducted through the COVID-19
05:22pandemic and we have really learned
05:25a great deal during the past six
05:28months about how to run clinical
05:32trials in our circumstances.
05:34So we're fortunate to be funded by NIH
05:37Simons Foundation and most recently
05:39by the DoD congressional director
05:41at the Medical Research Program,
05:43and this is a newer study that
05:46we will be starting any day now.
05:54I like to start with definitions
05:56because English is my second
05:58language and I am sometimes
06:00confused by what are those terms.
06:03What did this terms mean?
06:05Irritability was referred to.
06:08As the moon as.
06:11Behavior and personality
06:13characteristic the most latest.
06:16Definition is from Ellen Liban,
06:19left an I think it has been accepted
06:21by the majority of research is
06:24that irritability refers to as
06:27increased tendency to experience
06:29and express anger relative to peers.
06:33And now what is anger?
06:35In fact,
06:36my research started in general
06:39psychological research of anger
06:41is a human emotion and anger can
06:44be defined as emotional state.
06:46Something that will feel and this
06:48emotional state varies in intensity,
06:50from mild annoyance to rage.
06:53And one of the reasons we study
06:55anger in clinical populations
06:57because anger is presumed to
06:59have this tendency to increase
07:01our propensity for aggression.
07:03And So what is aggression?
07:05So aggression is a behavior and
07:08behavior is something you can see,
07:10so this is observable behavior which
07:13can result in harm to self or others.
07:16And reactive aggression is often viewed
07:18as an extreme form of irritability,
07:21so this is how irritability
07:23connects with anger and aggression.
07:25At least in my mind.
07:32So when we think about anger
07:34and typical development,
07:35so this is a common human emotion.
07:38In fact, some people were saying
07:40that it is the most human,
07:42the most common human emotion.
07:44So if you think about when the last time
07:47you were genuinely happy and when was the
07:50last time you were mildly annoyed, right?
07:53So anger happens quite often.
07:55It signals to us that something
07:57is not right in our environment.
08:00In an average,
08:01people feel angry anywhere or report
08:04feeling angry anywhere from one
08:06time per day to one time per week,
08:08it ranges in intensity from
08:10barely noticeable to all consuming
08:12duration of anger episodes again,
08:14on average, lasts from anywhere,
08:16anywhere from 5 to 30 minutes,
08:18and it is associated with
08:20physiological responses,
08:21such as arousal of feeling hot
08:23and thoughts of retribution.
08:25Oftentimes,
08:25we might compose an angry email in our head,
08:29but then don't really have the.
08:31Energy of time.
08:33Motivation to write it.
08:35And anger is not a new topic.
08:38In fact,
08:40this diagram shows.
08:42The figure that I like from Florence
08:45Goodenough in 1931 Florence Goodenough
08:48published a book about anger in children
08:52and use another racial message.
08:55She demonstrated that.
08:57Anger spikes in its frequency in two
09:00year olds and after that it tends to
09:04decrease in frequency and duration.
09:07So how about child psychiatrist?
09:10He worked ability is a
09:12symptom of several disorders.
09:14Oppositional defiant disorder is diagnosed
09:17based on symptoms of irritability,
09:19such as temper tantrums,
09:21being angry and resentful,
09:23and becoming easily annoyed.
09:25Conduct disorder includes symptoms
09:27of aggressive behavior amongst other
09:29symptoms of rule, violation to syphilis,
09:32theft and property destruction.
09:34DSM Five has a new disorder called
09:38Disruptive Mood dysregulation disorder.
09:40It is diagnosed based on severe
09:42and frequent temper tantrums.
09:44So what's frequent three times
09:46per week or more?
09:48What severe?
09:49So those are temper tantrums that are much,
09:52much,
09:53much,
09:53much more intense and protracted
09:56than on in a child of the same age.
10:01Irritability is also an associated
10:03feature of modern anxiety disorder and a
10:06frequent problem in children with autism.
10:09In fact,
10:10in children with autism,
10:12irritability was studied for
10:13good 30 or 40 years,
10:16and most clinical trials of
10:18medication management of irritability
10:21symptoms was conducted in children
10:23with or doesn't by including by
10:25people like my mentor Leresche
10:27here at Yale Child Study Center.
10:31So why bother with treating irritability
10:35and associated disruptive behaviors?
10:37Because those behaviors really
10:39caused tremendous problems
10:40for children and families.
10:42Those behaviors interfere with education,
10:45pose, risk of injury, and property damage.
10:49Do real development children
10:51get expelled from schools and
10:53really constitute the major
10:56reason for mental health?
10:58Referral to both outpatient and.
11:01Inpatient services.
11:04And of course, when we talk about
11:07treatments for irritability,
11:08we want to consider mechanisms and this
11:11is a field of considerable research.
11:14So here are just summarized them.
11:17Several categories that we have been
11:20thinking about and then you can sort of
11:24like blow up any one of those bullet
11:27points into huge number of nuanced details.
11:31But family and parenting factors
11:33have been studied and connected to
11:36treatment interventions and this
11:38include helping families manage
11:40stress and helping parents to be more
11:43consistent in their parenting practices.
11:45Social cognitive deficits such as hostile
11:48Attribution bias and poor decision-making.
11:50Emotion regulation deficits such as
11:52low frustration, tolerance, and anger.
11:55Emanation in your cognitive forces
11:57is so just response and condition
12:00and cognitive flexibility.
12:02And vulnerabilities in your system.
12:04Such a threat forces and reward system.
12:10So what are the treatment options?
12:13There is psychopharmacology
12:14and behavioral therapy.
12:16There are two major classes
12:18of psychiatric medications.
12:19Stimulant medications have been
12:21studied quite extensively for
12:23irritability and aggression in children.
12:25In context of ADHD, right?
12:27So the primary diagnosis is ADHD and this
12:31is associated with disruptive behaviors.
12:33So then stimulus medications
12:35have been shown to help.
12:38And novel anti psychotics such as
12:41risperidone and Abilify have been
12:43studied in children with autism,
12:46developmental disabilities and
12:48severe forms of aggressive behavior.
12:51Now be here.
12:52Will interventions include parent
12:53training and cognitive behavioral therapy?
12:55And this has been the area of my
12:59research and the research in my lab.
13:02So parent training has been
13:04awhile for a long time, 50 years,
13:06some more and some would say that this is
13:09the most studied behavioral intervention,
13:11right?
13:12So all the research in all
13:14forms of psychotherapy.
13:16Parent training have been started the most
13:19and parents are taught how to help their
13:22children would be here all difficulties.
13:25That includes teaching
13:26the ABC's of behaviors,
13:28antecedents,
13:29behaviors,
13:29consequences and then parents are
13:32given different strategies for
13:34changing antecedents and consequences
13:35so that they can also improve the
13:38behavior such as pain differential
13:40attention to positive behaviors
13:42given more affective commands
13:44praising children form improvement.
13:46My baby here is setting up
13:47appropriate routines and overall
13:49strengthening family relationships,
13:50so I like this cartoon because I'm
13:53a proud father of two boys and I
13:56might have shown this cartoon before,
13:58but it is so true that I will
14:01show it to you again.
14:03So here it says,
14:04listen up and listen good because I'm
14:07only going to say it a million times,
14:10right?
14:10So it's just a common scenario in
14:13parenting where it's hard for parents
14:15to change their children's behavior.
14:17So in other remarkable things
14:20about parenting interventions that,
14:22despite being most research
14:23treatments in the world,
14:25they are really hard to access in Community.
14:29So this is a paradox that has been
14:32hard to overcome and I want to give
14:36a shout out to Andrew Dear Stransky,
14:40a Solnit child psychiatry fellow
14:42who completed a remarkable study.
14:45On improving access to parent
14:47training and this people is just
14:50accept it will be published in a
14:53day now to the Journal of Child
14:57and Adolescent Psychopharmacology.
14:59So Andy work with myself and David
15:02Grotberg to develop an intervention
15:05that combines online modules
15:07delivered via the Mind Nest,
15:10an online platform with three Tele
15:13health consultations provided by
15:15experienced child psychiatrists.
15:17And I should look for young children
15:20and included 15 children between
15:22the ages of three and nine years.
15:2512 Completed this study and despite
15:28their young age children met
15:30criteria for serious diagnosis,
15:32disruptive mood dysregulation,
15:34disorder, oppositional defiant disorder,
15:36ADHD, anxiety and PTSD.
15:38And there were two parents.
15:40Rated outcome measure.
15:42Disruptive Behavior rating scale
15:45that captures symptoms of.
15:47Oppositional defiant disorder.
15:49An affective reactivity index
15:51that captures irritability.
15:53So online treatment looks like that.
15:58So our parents are watching a
16:00number of animations that illustrate
16:02parenting principles and their job
16:05is to recognize specific behavioral
16:07challenges and to come up with
16:10solutions that then they did discuss
16:12with a clinician who helped them find,
16:15tune the solutions for their specific kits.
16:37So that those animated vignettes
16:39viewed by parents parents will
16:42receive their focus instructions
16:44and then this is discussed with a
16:47child psychiatrist by Tele Health and
16:50after six weeks of treatment there
16:52was a dramatic reduction in both
16:55disruptive behavior and irritability,
16:57which we are particularly delighted to
17:00have this program because I think it
17:04will make it much easier to deliver.
17:07Parent training for children.
17:08For parents of children with
17:11disruptive behavior.
17:12So now cognitive behavioral therapy
17:14is a treatment that involved
17:17both parents and children in.
17:19The aim is to give children strategies
17:23for managing their sort of emotions,
17:26including frustration,
17:27anger and irritability,
17:28and to give children strategy
17:31strategies for solving problems because
17:34usually frustration sort of arises in
17:37context of interpersonal situations.
17:39And then in our lab,
17:41we've been trying to understand if
17:44teaching children how to regulate
17:46their frustration can also engage
17:49brain mechanisms of frustration so
17:51that I will tell you about a study
17:54that we called our docs study because
17:56it was funded in response to an eye
18:00image research domain criteria approach,
18:02right?
18:02So that we conducted the study,
18:05it was a randomized control
18:07trial that involved 101 children
18:09with aggressive behavior.
18:11And they were randomly assigned to
18:1312 sessions of CBT or 12 sessions
18:16of weekly supportive therapy,
18:17which were the control condition.
18:19Outcomes were rated by the blinded clinician,
18:22which means that the person didn't
18:25know which treatment children were
18:27receiving and children also completed
18:29F MRI before and after treatment.
18:31So we're curious to see if treatment can
18:35engage brain mechanisms of irritability,
18:38and our hypothesis was straightforward.
18:40We saw that because children are
18:43taught to regulate their frustration
18:45that we thought that brain circuitry
18:49of emotion regulation is a good
18:52candidate for those neural targets,
18:54so that we thought that both
18:57cognitive control and implicit emotion
18:59regulation regions that include.
19:02Ventrolateral and dorsolateral
19:03prefrontal cortex and anterior
19:06singulate can be affected by
19:09children who show response to treat.
19:12And we use two tasks.
19:14One task we call it will lovingly
19:16call it frustration.
19:17Induction girl,
19:18no girl and this is a 16 minute task
19:21where children are playing on a go.
19:24No go game and their job is to
19:26push the button in response to
19:28objects and green frames and which
19:30hold the button press in response
19:33to object and red frames and task
19:35goes to stages where it speeds up
19:37so that it becomes impossible and
19:40then it goes through stages where.
19:42It slows down and it becomes possible to
19:44kind of answer the questions and children.
19:47I want to believe that they're winning
19:49and losing prizes during this task.
19:51At the end everybody went so,
19:53but don't tell the children, right?
19:55So if you're planning to refer
19:57children to our study,
19:58don't tell them about this task.
20:00Right,
20:01so that they come in and they don't
20:03know if they're going to win or lose.
20:06And then we're also have a
20:08face matching task,
20:10which is a very kind of
20:12common standard task of
20:13emotional face processing.
20:15So we conducted some piloten of
20:18this measures and with frustration
20:21induction go nogo task with sewer.
20:24Pretty drastic differences in children with
20:28aggressive behavior compared to community
20:31controls in terms of activation in.
20:34Prefrontal regions include an orbital
20:37frontal cortex and anterior singulate,
20:39so lack of activation during regulation
20:43of frustration on the go nogo task was
20:48associated with aggressive behavior.
20:50And then we preceded to
20:52look for study participants.
20:54So inclusion criteria really
20:55important to appreciate,
20:56so will look for children and the white
20:59age range with aggressive behavior can
21:02engaged by the T score of 65 or higher
21:05on the CBC L aggressive behavior scale.
21:08I think the average score at baseline
21:11with about 75 in our children,
21:13which means that there were two and a
21:16half standard deviations above the mean.
21:18So those kids had.
21:20Real difficulties was their
21:22behavior were also included.
21:24Children with all diagnosis,
21:26unless they had more pressing clinical needs.
21:29So for example,
21:31children with untreated PTSD were referred
21:35elsewhere because we thought that.
21:37Their effective frequency exist
21:39and there is no need to delay
21:42those effective treatments.
21:44Obviously severe depression or active
21:47suicidal ideations were exclusion criteria,
21:49but other than that we invited just
21:52about any Co occurring disorder,
21:55including children with the wettest.
21:59The only requirement was that
22:00children needed to be able to
22:02complete F MRI and that there was
22:04no plans for change in behavioral
22:06treatments or medication for the
22:08three month duration of the study.
22:12And we conducted a pretty extensive
22:14assessment about 8 hours or so that
22:17included structured interviews,
22:18cognitive tasks in neurocognitive testing.
22:23Very focused measures of aggressive behavior.
22:25We used sharp report that really helped
22:27us with dissociate an oppositional defiant
22:30disorder from disruptive mood dysregulation.
22:32Because when you have a mood problem, right?
22:35So you feel it and children with
22:38oppositional defiant disorder that
22:39usually dump sort of like self report.
22:42A lot of negative affect
22:45children with DMD Dia do.
22:47And we ended up having 101 children.
22:5193 Completed this study,
22:53which is really good for this particular.
22:56I'm sort of demographic.
22:588% dropout rate was great and kids needed
23:02to do a lot of assessment fMRI an so on.
23:0711.7 years on average, 73 boys, 28 girls.
23:11So we had a lot of girls and
23:14sample was representative of.
23:17Race and ethnicity
23:20distribution in Connecticut.
23:2247% were receiving medications
23:24and this is a list of diagnosis.
23:27So most met criteria for
23:29oppositional defiant disorder, ADHD.
23:31We were probably conservative
23:33with assigning DMD diagnosis,
23:35but we did.
23:36I have about 18 kids with DMD and
23:39were also included.
23:4117 children with the wedding song.
23:45And we provided treatment
23:47using our favorite approach,
23:49cognitive behavioral therapy,
23:51in 12 sessions that were
23:53delivered by trained clinicians.
23:56So the treatment really helps on children.
23:58Think about what happens when they
24:00get angry or what happens when they
24:03don't get what they want or what
24:05happens when they are told to turn
24:07off their video games and go do their
24:10homework or go brush their teeth.
24:12And we think about this as triggers
24:14and that can lead to certain emotions
24:17and emotions can lead to actions.
24:19And then there is an outcome.
24:22So the children invited to discuss
24:24various episodes that happened
24:26to them when they don't get what
24:28they want and we discuss with
24:30them how they feel about this,
24:32what they did about this and is
24:34there anything that they could have
24:36done differently and then we're
24:38role played better behaviors, right?
24:40Let's practice practice and practice,
24:42and we're also encourage children to
24:44think about this social circumstances.
24:46Where this. Situation was happening.
24:48It's not a school bus in a classroom is it?
24:52Was you and your friends on the
24:54playground and then we were encouraging
24:56children to think differently about
24:58their behavior in different situations.
25:01Or also.
25:03Asking kids to kind of consider
25:06various social cognitive processes,
25:07such as hostile Attribution bias, right?
25:09So what's that?
25:10So imagine that you're working on your
25:13homework and have about half an hour.
25:15If you report typed up when
25:17you monical you for dinner,
25:19you go right away because you're
25:21very hungry and you forget to
25:23save your file after dinner.
25:25It's over.
25:26You have to call a friend to ask
25:29her something.
25:30At that time your brother goes
25:32on computer to play his game.
25:34And he closes your homework file
25:36without saving.
25:37Why did your brother do that right?
25:39Try to think about it.
25:40If you do it on purpose
25:42where there's an accident,
25:44was he trying to ruin your life
25:45so that kind of question that we
25:47discussed with the kids to help
25:49them consider alternative right?
25:51So when you get angry about something,
25:53think about it before acting.
25:57And we had various sort of like
25:59tricks to get kids do this right,
26:02so nobody wants to sit and talk
26:04about their anger when they're 12.
26:06So we had various kind of
26:08like therapeutic tools,
26:09right side just consequense tic tac toe,
26:11right?
26:12So when you come up with a with an
26:14answer to a social situation, right?
26:17So you can take a turn and
26:19whoever wins gets a price, right?
26:21So that will try to engage kids.
26:23Best way we can.
26:26And parents were also given
26:28strategies for helping their kids
26:30where their challenging behaviors.
26:32And we were focusing on prevention,
26:34prevention, prevention.
26:35And we're also called antecedent management.
26:37So with kids,
26:38you really need to control the environment,
26:41particularly with kids with
26:43challenging behaviors.
26:43Just like in this picture,
26:45we need to kind of childproof our house
26:48when we have little kids in the house.
26:51When you have kids with severe
26:54irritability in the house, you need to.
26:57Put away those steak knives and baseball
27:00bats and any objects that can be broken
27:04in the moment in the heat of the moment.
27:08And we're also focusing
27:09on positive consequences.
27:11So when parents think about consequences,
27:13something sometimes they think about
27:15timeout or ground and their kids,
27:17and we're really trying to focus
27:19on positive consequences such
27:21as catching kids when they're
27:23just sitting and written a book,
27:25having enjoyable interactions
27:26with their kids,
27:27and we tried to peer those
27:30enjoyable interactions with those
27:32times when kids are not misbehave.
27:35And we're also give parents various sort
27:37of like strategist will manage in the
27:39tantrum and so it's like when people ask.
27:42Like how about this out of control
27:44behaviors so out of control I
27:46usually think about it when parents
27:48don't know what will happen right?
27:50So that really parents can help
27:52their kids to get through those
27:54challenging moments.
27:56The key is to praise the child for
27:58calming down right and the brief
28:01after the moment is behind you.
28:03And of course,
28:04after every session we will come up
28:07with a plan for what to do next week
28:10and we will ask the children got
28:12to write down a little diary about
28:15their most successful moment of
28:17handling frustration and when they
28:19come back we will give them a price.
28:21So treatment is individualized as
28:23we will try to come up with prizes
28:26that kids really enjoy.
28:27So I like this yugioh card because by
28:30the time when we were working with this kid.
28:33He asked for you go karts.
28:35I didn't know what they were and
28:37we went out and got some for him.
28:40Little later my kids grew into
28:42the age of Yugioh cards and like
28:44after a few months I had thousands
28:47of those cards in in my house.
28:49So kind of like those things.
28:50They come and go in waves like
28:53different items become popular
28:55for different age groups.
28:57Now I I I wanted to kind of
28:59like show this case example.
29:02I'm pretty sure this is the boy who
29:05referred to us from Winnie one and
29:07we kind of for the purpose of this
29:10presentation will refer to him as Antonio.
29:1412 year old boy.
29:15Average IQ who was living with his mother,
29:18maternal grandmother and maternal on
29:20had occasional visits with his father
29:23had seven hospitalization due to
29:25aggression over the past two years,
29:27including extended stay.
29:28And all aggression was directed toward
29:31his mother I, including punching her,
29:33choking her, being anchored down,
29:35and like really dramatic.
29:36Sort of like behaviors,
29:38and he was a big boy for his age,
29:41and his mother was a 5 foot 130 pound woman.
29:44So it was like really kind
29:47of like dangerous situation.
29:49So what was striking is that
29:51over the past two years,
29:53Antonio tried or was tried on
29:54a long list of medication,
29:57and when he arrived to the
29:59study he was received.
30:01Weekly psychotherapy in a Community
30:03Center and 30 hours of ABA at home,
30:06right so it would look pretty like.
30:09Recognize that he was an impaired
30:11kit and at school he was attending
30:13special school for Children where their
30:16emotional and behavioral problems right.
30:18He was classified as having
30:21emotional disturbance.
30:22And in school, most of his
30:24stuff like programming was.
30:26Geared toward consequences based strategies.
30:31Now we thought long and hard whether
30:33or not we're going to help him and
30:35wonderful inclusion criteria was that
30:37children do not need other services
30:39and he was already receiving all other
30:42services that were humanly possible.
30:43So we thought that will put him in a study.
30:47And so we can put him in a study and he was
30:51treated by experienced clinician in the lab,
30:54turned down that he also had a lot of
30:56kind of like highly valued interest
30:58such as he was interested in Pokémon.
31:01So we rewrote all our kind of
31:03treatment materials with a Pokémon
31:05as the main character,
31:06and it also turned down,
31:07though some of his behaviors such as
31:10hugging with the repetitive behavior and he
31:12kind of like insisted on hugging his mother.
31:15And if it didn't feel right,
31:17so that.
31:17When aggressive behavior
31:19was very likely to happen,
31:20so it kind of like put in place a focused
31:24program on helping him to sort of reduce
31:27this restricted repetitive behavior.
31:30And we're also work hard with the
31:32school wrote a number of lettuce to
31:34change his classification to August,
31:35so we kept him in the study and
31:38he graduated from the study and
31:40we were extremely proud of him.
31:42Now this is the results, right?
31:45So 101 children were randomized,
31:4893 completed this study and at
31:52baseline there were about the same
31:55in terms of modified aggressive
31:58behavior scores at endpoint,
32:00where sore much stronger reduction in CBT
32:05compared to supportive therapy and on
32:09the CGI global Impression Scale was also 75%.
32:14Improvement in children who received
32:16CBT compared to 26% in children who
32:19receive supportive psychotherapy.
32:20So we called it good right?
32:23So we were pleased with that,
32:25that that was a strong clinical
32:28effect in Chrome.
32:29So production of aggressive behavior
32:31were also sort of changes in brain
32:34function and some of the regions that
32:37we were interested in specifically
32:39on the frustration induction
32:41gonna go we saw increased.
32:43Activity in rostral answer,
32:45general anterior Cingular Portis is
32:48an also changes in activity in medial
32:51and dorsal medial prefrontal cortex
32:53is so this is a 3 way interaction,
32:56right?
32:57So we kind of randomized studies,
33:00so two treatments two times before and
33:03after treatments and two condition of
33:05the task so that we interpret those
33:08results as increases in activity in
33:11those regions in children who were in CBT.
33:15After treatment control and for pre
33:17treatment and changes in supportive
33:21psychotherapy control condition.
33:23There were also changes in brain
33:26response to the phase processing
33:29task in dorsal anterior singulate
33:32and were also able
33:34to detect an A correlation of the magnitude
33:38of reduction in aggressive behavior and
33:42magnitude of change in an dorsal anterior
33:46singulate cortex response to faces in
33:49CBT compared to PST right so that.
33:53Those were very encouraging results
33:55and we're pleased with that.
33:57Now back to this 17 children
33:59who had autism right?
34:01So because that was a trans diagnostic study.
34:04Wanted to make sure that we include
34:07everybody and given the rest of
34:10our work and kids with autism,
34:12but didn't feel like excluding them.
34:15But if you think about clinical
34:17trials children,
34:18which is my usually excluded from trials in
34:21children with other disorders and vice versa.
34:24So we thought long and hard
34:27about the 17 children.
34:29They did your response not as robust as
34:32children without autism and behavioral
34:34problems in kids on the spectrum.
34:36I really sort of like different
34:38because of social deficits restricted,
34:40repetitive behaviors,
34:41sensory issues,
34:42another kind of striking example
34:45that comes to my mind is a girl
34:47who refused to go to school and if
34:50she did go to school she was very,
34:52very unhappy and refused to go
34:55from one room to the next.
34:57So it turned down she didn't like your shoes.
35:00Right,
35:01so his shoes were uncovered
35:02were uncomfortable,
35:03but she didn't have the words to
35:05kind of like explain this to to
35:08the parents into the teachers,
35:09so they're kind of like sensory
35:11issues translated themselves
35:12into behavioral problems,
35:14but it was not easy to get to the bottom
35:17of the sensory issues with the skin.
35:21So we really wanted to see if it
35:23gives him the spectrum are different
35:26not only in their behaviors,
35:28but also in their brain response
35:31to frustration.
35:32And we did what no one has done before,
35:35right?
35:36So we compared children with
35:38autism plus aggressive behavior.
35:40We would call it disruptive
35:42behavior in this paper.
35:44For children with autism who have no
35:47disruptive behavior at all and no anxiety,
35:50right?
35:50So we found children with autism
35:52who come who don't misbehave,
35:54corner, anxious rank,
35:56who just kind of like,
35:58have core symptoms and basically
36:00nothing else except a little ADHD.
36:02We will look for them high and low,
36:05and we found them will match them
36:08with our sample of children with autism.
36:11And we put them through fMRI experiments.
36:14And here I want to give a shout
36:17out to Corinne Abraham,
36:19a great guy computer pose down became
36:22junior faculty this year waiting for his
36:25career work to be reviewed next month.
36:28And so he published this amazing paper.
36:31First people that compared children
36:34with autism with disruptive behavior to
36:37children with autism without disruptive
36:39behavior and the results were clear.
36:42Amygdala to ventrolateral preferrable
36:45cortex connectivity is a brain signal
36:50that separated those two groups,
36:54and.
36:56The weaker of the connectivity at the
36:58Great Giant was aggressive behavior
37:00so that that was quite amazing
37:03and sort of like for what's it?
37:05Worse,
37:06I,
37:06I feel that we're sitting on a biomarker
37:09of aggression and autism so that
37:12this is really remarkable result.
37:14Now Karim is doing even more exciting
37:17things where he is looking at the
37:20connector on prediction of aggression in
37:23a sample of all children with aggressive
37:26behavior with and without autism,
37:28where he is using a brain
37:32parcellation Atlas that consists of.
37:34268 and not, and the correlation amongst
37:37this nods is then used to predict behavior
37:41aggressive behavior in this case.
37:44So dorsal lateral ventral lateral
37:47prefrontal cortex is come up as
37:50central nodes in this models.
37:52And what's exciting when you breakdown the
37:55subgroups by Corcoran disorders, right?
37:58So the networks change,
38:00but the keynotes in ventral
38:02lateral and ventral medial cortex.
38:05Remained the same,
38:06so we're hopeful that Network
38:08Connect to modeling can be a tool
38:11that would enable more precise,
38:13newer prediction of who will respond
38:16and who will not respond to CBT.
38:20So now moving on.
38:21I want to change gears a little
38:24bit and tell you about the study
38:26that we have been conducting for
38:29the past three years or so and
38:32continued to conduct it during kovit.
38:34So I I thought that I will share our
38:37experiences with you and kind of tell us
38:40to tell you about what lessons learn.
38:43So this trial is similar in design
38:45but different in treatment and
38:47in treatment targets, right so?
38:49This is a study of CBT in children
38:52with autism,
38:53and we're specifically treating anxiety
38:54in children with autism, right?
38:56So why is that so?
38:58Why am I switching from irritability
39:00to anxiety so sharply and we got
39:02funded to do this study right?
39:04And we really wanted to do this
39:06study and we have been doing it.
39:09And anxiety and irritability
39:10at different things.
39:11Even though people often confuse them so.
39:15Don't be surprised if by the end
39:17of this talk I I will fail to
39:20explain the difference between the
39:22two and I'll try my best.
39:24So this is a study of CBT
39:26for anxiety in autism.
39:28We've been running it for him severally for
39:31three years with projected sample of 100,
39:33so were recruited 62 children to date.
39:36This is for children with which is my
39:39anxiety in the age range of eight to
39:4214 and kids are treated with CBT for anxiety.
39:45Which has cognitive behavioral
39:47principles but very different from CBT.
39:49For her to be able to essentially
39:52is based on exposure and response
39:55prevention and sort of like various
39:58forms of social support hand.
40:01Like help with social deficits
40:02confirmed by autism.
40:03Now we've been conducting this study
40:06remotely and now we are back in business.
40:09In fact,
40:09our first reactivation subject is scheduled
40:12for next week and this is our flyer.
40:14So kind of like at a loss of
40:17where do we hang our flights now?
40:20So I thought that I will show
40:22it here so please refer right.
40:25So we're looking for participants
40:27and I would greatly appreciate it.
40:29If you would spread the word.
40:32Now, how is anxiety and
40:34irritability are connected, right?
40:36So obviously many kids would have both.
40:39Now for this study of CBD for anxiety.
40:43For autism we actually excluded children
40:46with aggressive behavior that was
40:49severe enough to warrant a diagnosis,
40:51but a bunch of kids still
40:54had disruptive behaviors,
40:55and when we had 50 subjects in this study,
40:59we decided to take a look.
41:02At what is sort of irritability
41:05and aggressive behavior.
41:07Doing to this kids and their
41:10lifes and a striking result came
41:14out so it turned out that in this
41:18study or 52 children with the.
41:21What is an anxiety?
41:23Those who had right addressed
41:26him behavior measured by CDCD
41:29aggressive behavior subscale?
41:31Above the card off of T score of 65, right?
41:36So when we compare this to subgroups
41:39so aggressive behavior had a dramatic
41:41impact on violence socialization,
41:43right?
41:44So aggressive behavior pushed down
41:46the scores on violence socialization
41:48by 1 standard deviation, right?
41:50And if you think about sort of
41:53autism kids already super impaired
41:55and kind of like our group of
41:59organisms without aggression.
42:01Violent scores of 70,
42:03but when you add aggressive behavior,
42:06violence cords go down to 60,
42:08so this really is striking to me
42:11and it goes to show that even when
42:15kids are invited and evaluated,
42:17super careful therefore kind of
42:20Corcoran disorders and psychopathology.
42:22You really need to pay attention
42:24for aggressive behavior because
42:26even if they are not reaching the
42:29level of diagnostic significance.
42:31They can still impact shells
42:34function in profound ways.
42:37And this work was done by Carla Calvin.
42:40I postdoc in my lab who has
42:43done remarkable work with that,
42:45treating a lot of children,
42:47an unpacking their phenomenon,
42:49the kind of phenomenology or Corcoran
42:52problems in a serious of terrific
42:54presentations. In publications.
42:57So now.
43:04Where, where are things now, right?
43:06So what did we do during covert?
43:09So the University moved to remote
43:11working on March 16th an we had 12
43:15subjects in the active phase of the
43:17study and we felt that we needed to
43:20treat them and we preceded to treat them.
43:23So we move all our words.
43:26Sort of like treatment to zoom and we
43:29moved our data collection to Qualtrics.
43:32Anne working with kids.
43:33We've learned a great deal from
43:36them and their families.
43:38How to sort of support families
43:40of children on the spectrum
43:42through those unprecedented times.
43:44The family stress and kind of
43:47anxiety about getting covid.
43:48It was just striking and I'm
43:51extremely grateful to my lab to
43:54Carl and Kareem and otherwise.
43:56So we're kind of free clinicians
43:58who really hit the ground running,
44:01working with families and.
44:03Just being available to everybody
44:06to provide study treatments
44:09and whatever supportive.
44:11Communications we were able
44:13to offer during this time,
44:15so some of the most important issues were
44:18loss of structure and daily routines.
44:21Loss of school services
44:23for children with autism.
44:24As far as treating pre pre
44:27existing pre covid anxiety right?
44:29So if you had fear of Heights
44:32there was nowhere to go.
44:34If you have fear of crowds
44:36you have to stay home.
44:38So really it was really hard to kind of.
44:42Address issues that brought children
44:45in the study to begin with.
44:47But other problems just
44:49became extremely dramatic,
44:50such as learning to use zoom for kids on
44:54the spectrum and refusing to go to school,
44:58online separation anxiety.
45:00Kids were extremely worried about
45:03their parents getting kovit when
45:05parents are out of the house,
45:07so we're trying to advance to
45:10be helpful with this issues
45:12while conducting how it studies.
45:15So this is a research project, right?
45:18So that.
45:18Our job as researchers is to run
45:21clinical trials in accordance with
45:23standardized research protocols
45:25so that we videotape everything we
45:27documented everything and we're actually had,
45:30like a great manuscript that we
45:33are ready to submit about,
45:35then treating anxiety in children with
45:38ordering during COVID-19 pandemic.
45:41As far as what are we going to
45:43do with this 12 kits so there
45:46is tremendous variability in how
45:49we drive administered treatment,
45:52how we conducted data collection
45:54changes in the timelines,
45:56and so on and so forth.
45:59So these are some of the results
46:02on our primary outcome measure.
46:07Pediatric Anxiety rating scale and
46:10I should give Shannon out too.
46:13To hide the grants, who is our
46:16independent rater and to Rebecca Jordan,
46:18the study coordinator who really
46:20worked incredibly hard to make sure
46:23that we can get this data remotely
46:25from families and children, right?
46:27So this interview is conducted
46:29with family and child.
46:31So here if I can see it on my screen.
46:38So subjects in CBT condition are shown in
46:41blue and subject in supportive psychotherapy
46:44condition as shown in orange right?
46:47And as you can see and then the green dotted
46:51line is when University closed for covid.
46:55So these are kids who were in treatment.
47:00Or on the day of covert right?
47:02So that they were like a couple
47:05of kids who were evaluated pretty
47:07closely to the to the green line.
47:10And as you can see,
47:12blue subjects right subject in CBT there
47:16showing some reduction in anxiety but
47:18not by much right now when you look.
47:21Through April and May so kind of
47:24like anxiety is sustained pretty
47:26high and Paris has its limits.
47:28So what was interesting to me is
47:31that it didn't go through the roof,
47:33but certainly didn't improve by much.
47:36And then by July and August when
47:38subjects were getting to the end
47:41point assessments that we call them.
47:43So we saw reduction in blue lines.
47:46But we're also saw reduction in Orange line,
47:49so that if we were to compare.
47:52Focus CBT for anxiety.
47:54In order like highly specialized
47:55training to support.
47:57It's like a therapy during covid so
47:59I think we probably won't see the
48:02difference because it was hard to target.
48:05It was hard to address targeted symptoms,
48:07but the new problems came up and I
48:10think that supportive therapy was
48:12really critical during this period.
48:14So I think the bottom line is that
48:17we help the family as best we can.
48:20We collected the data best we can.
48:23And we think that that was really
48:25good for us to continue this study,
48:28and I hope that we help the families
48:31who were involved.
48:33Now,
48:33how does this connect to the topic
48:35of our lecture today? Irritability.
48:38So of course.
48:41You know we won't be the Super
48:43Dulski lab if we didn't measure
48:45irritability in every possible way.
48:48So here will measure irritability with
48:50a scale called disruptive behavior.
48:52Rating scale and remember.
48:53So this is a study for children
48:55who do not meet criteria for
48:58high disruptive behaviors,
48:59so everybody was kind of like below.
49:02This cutoff of 12,
49:03but one kid kind of like spiked up in
49:06the scores and disruptive behavior right
49:09around the time when we got closed.
49:12Down for Kogate we work with
49:14the family period close land.
49:16The boy really wanted to go
49:18to McDonald's and who didn't,
49:20but he really wanted to go and
49:22kind of for for a couple of weeks.
49:26That generated a lot of kind of problems
49:29at the family so Luckily they were able to.
49:33This issue no trips to the
49:35emergency Department with required,
49:36but now we have this new study.
49:38Let me see if I can do it again.
49:41Did you see that took me
49:43awhile to figure it out right?
49:45So we have this new study,
49:48PTI behavioral therapy for
49:49irritability and adolescents with
49:51****** so this will be the boy who
49:54is a candidate for our next study,
49:57and so this is the study that we just well,
50:01The funny thing is that we heard
50:03that were being funded for the
50:06study in January and like DoD,
50:08it takes time to process the paperwork.
50:11So I think the notice of award
50:14arrived recently and even.
50:16I'll be approvals have been completed by now,
50:18so. This is the stadium for which we
50:23developed a new intervention and we
50:25decided to come up with a new name for it.
50:28Behavioral therapy for irritability in
50:29autism. I thought it would be cash,
50:32right? BT I.
50:33And this is a longer treatment that
50:35standard CVT for your writability.
50:38And it has more flexibility.
50:41Close functional assessment for why is
50:44that the children have anger outbursts?
50:47Small parenting and dedicated modules
50:49to address social deficits and
50:50restricted repetitive behaviors,
50:52and this will be a form adolescence,
50:55and we hope to kind of like help those
50:59kids with their kind of transition to adult.
51:02Right, so we're looking for the
51:05age range from 12 to 18,
51:07but we're hoping to to get more kind of
51:10like older adolescents in this study.
51:13So this will be a four year
51:16project funded by DoD,
51:18Congressionally directed Medical Research,
51:19Foreface approved by LRB and Department of
51:23Defense Human Research Protection Office.
51:25So I, I think we've had.
51:29About six months to give this
51:31through the Department of Defense
51:32University Protection Office.
51:34But we did it so it's a remarkable
51:37process and just wanted to mention this to
51:40those who are aiming to apply for this grant.
51:44Lots of paperwork.
51:46And so this will include full assessment I,
51:50including a DI dash self and violent
51:53everybody is randomized to either
51:5615 sessions or BT or 15 sessions
51:58of supportive therapy.
52:00If you randomize to supportive,
52:02therapy will offer BTI a free of
52:06charge at the end of this study,
52:09endpoint evaluation and we can conduct
52:12therapy in person or by Tele health.
52:16So now to conclude.
52:18So we spoke mostly about the
52:21transdiagnostic approach to irritability.
52:24Tent with.
52:25Think CBT for irritability is helpful,
52:29reduces aggressive behavior or
52:31ability in children across diagnostic
52:35diagnostic categories we saw
52:37increased activities of Daniel and
52:40dorsal anterior singulate after CBT
52:43compared to a control condition.
52:45One thing that we learned is that
52:48comprehensive diagnostic and your
52:50cognitive assessment to the must.
52:52So we're really need to understand
52:55Corcoran disorders even though
52:56we are claiming that this is a
52:59trans diagnostic treatment.
53:01Still hard to predict who will
53:02respond and who will not respond
53:04will still have this 26% kind of
53:06like non response rate and the
53:08kids who want to help too.
53:09So that's still lots to do.
53:12And we're also learning that biomarkers
53:14for what you were stability should
53:17consider Co occurring diagnosis very
53:19carefully and end of this process were
53:22able to fine tune our treatment for
53:25irritability for children with autism.
53:28Now this is the most important
53:31slide sort of the thank you to
53:34my lab and to collaborate us to
53:36want to acknowledge Rebecca Jordan.
53:40Swing around Lee and study
53:42coordinators Corinne Abraham and
53:44Carlo Calvin on postdocs T 32 pools.
53:47Doctors like myself on a 2002
53:50graduate and really delighted to
53:52have T32 fellows in my lap Korean
53:55with the faculty now otherwise.
53:58The psychology extra in the lamp
54:00Heidi Grants is an independent
54:02evaluator in all of our studies,
54:05and I think that we we owe the
54:08success of our studies to her.
54:10Jeff Albert is a data manager
54:13and data analyst extraordinaire.
54:14He cannot keeps all our fMRI
54:17data saved and organized.
54:18Jayden traffic and everything else
54:20owner I yell under grants in the lab.
54:24Anthony just graduated and Innocent fellow
54:26who is now a faculty at Duke University.
54:30Simon Lauren Blue is a postdoc
54:32from Canada and Merritt Henrickson
54:34is a PhD student from Norwegian
54:37Institute of Science and Technology.
54:39The Great Land have been really
54:41honored to work with everybody,
54:44particularly during this kovit when,
54:46so we've been zooming each other and
54:49this could have been really terrific.
54:52And a great team of collaborators
54:55at Yale and other universities.
54:59So thank you.
55:02Dennis, thank you so much
55:03and we have time for one
55:05or two questions from.
55:07From the admiring crowd,
55:08that was wonderful.
55:09So any any questions?
55:17And so thank you all for zooming
55:19in today, so please send email so
55:21questions so that we can but we
55:23don't have enough time to discuss.
55:27So Dennis, in the last
55:28two minutes one minute.
55:30I know that you are not only
55:32a wonderful researcher as we
55:33saw your wonderful mentor.
55:34So the last word doesn't go to you.
55:37It goes to Kareem Kareem tell us
55:39something about you about your career
55:40and how it all fits in with Dennis.
55:43Because you have great news and thank
55:45you for sharing those findings.
55:49You're happy to do so, I think.
55:53I think one of the valuable things
55:57out of many has been Dennis is
56:00dedication and I think through all
56:04the ups and downs his his mentoring
56:07has been very persistent and really
56:11instilled that determination.
56:13And men as well as in the other trainees so.
56:18They were all very thankful
56:20for his mentor ship.
56:23Thank you, thank you great.
56:28And Heidi, you're the unsung hero.
56:30While he sang a little bit.
56:32But do you want to say something?
56:34Heidi your your other CBT gruesse
56:36so anything you want to add.
56:40I am, I would just say that you
56:43have been wonderful working with
56:45Dennis over the years, so. You
56:48know this is we've got.
56:50We've got to do this through
56:52a couple of studies now with
56:55the CBT and irritability.
56:56The CBT with kids and anxiety.
56:58And yeah, it's it's.
57:00It's definitely these are.
57:02There's a great project I
57:03enjoy doing it evaluations.
57:06There are alright Dennis.
57:08Do you feel the love you feel
57:10a lover more studies I do feel the love
57:13and I really appreciate the comments
57:15so Kareem Heidi thank you guys.
57:18I was preparing for a question
57:20about network analysis. So no,
57:22no no, no no. You know what you were
57:26getting ready for before we depart.
57:28I just want to give you a heads
57:30up of the next two grand rounds.
57:32Next week we're going to have one
57:34of our soon to graduate fellows.
57:37Eunice Young is going to be talking
57:39about something very, very different.
57:41She has been doing some really
57:43exciting stuff with Asian American
57:45families looking at cohesion,
57:46looking at the coming out process
57:48in Asian American families,
57:50using theater, using all sorts of
57:52very different tools and tool kit.
57:54So I encourage you to come and
57:56support units next week and then in
57:58two weeks we're going to have the
58:01first compassionate care rounds,
58:03in which Lori Cardona will
58:05be taking the lead.
58:06But for now, the man of the hour is Dennis,
58:09who Dulski thank you very much and
58:11we will see you all next week.
58:13Thank you again,
58:13then undress.
58:14Hopefully we'll see everyone on
58:15tomorrow for our community
58:17meeting. Everyone invited
58:18at 10 to the community meeting so
58:21thank you. Alright. See you bye see you
58:26again bye bye.