Irritability: A Hidden Driver of Youth Mental Health Problems

Transcript

• 00:00Good afternoon, everyone. Hi,
• 00:03and welcome to Grand Rounds.
• 00:06Just gonna mute you there.
• 00:08I think
• 00:09it's a pleasure to welcome
• 00:10you all to Grand Rounds.
• 00:12I hope you're enjoying this
• 00:13nice, sunny, warm weather,
• 00:16and, I hope you'll all
• 00:18enjoy this this shorter week
• 00:19that we have coming up.
• 00:21Next week, we will have
• 00:22Shavana Khan coming from NYU
• 00:24to talk to us about
• 00:25telepsychiatry,
• 00:26particularly legal and regulatory considerations
• 00:29in telepsychiatry.
• 00:30So please do join us
• 00:31in person for that. That
• 00:32will be hosted by Pam
• 00:33Hoffman. As ever, if you
• 00:35would like to,
• 00:36meet with our speaker, do
• 00:37reach out to, Alex.
• 00:40Alex is waving from the
• 00:41back. Thank you, Alex.
• 00:43To try and set up
• 00:44a time to meet with
• 00:45our speaker.
• 00:46And today, we have one
• 00:47of our own, and we're
• 00:48delighted that Wanling Zhang will
• 00:50be giving us grand rounds,
• 00:52today.
• 00:53You'll all know Wanling and
• 00:54the incredibly innovative research program
• 00:56that she's developed around irritability
• 00:58that we will hear about
• 01:00today.
• 01:01Wanling completed her PhD in
• 01:03the Institute of Child Development
• 01:04at the University of Minnesota,
• 01:06followed by postdoctoral training,
• 01:08at the NIMH,
• 01:10and then joined the faculty
• 01:11here in twenty nineteen.
• 01:14Walling has published extensively,
• 01:15has been honored with numerous
• 01:17recognitions and awards from various,
• 01:20organizations.
• 01:21And I think one to
• 01:22highlight is from NIH itself,
• 01:24as a recipient of a
• 01:25DP two. So a director's
• 01:27award for early career investigators,
• 01:29really engaging and truly innovative
• 01:31and,
• 01:32advancing the science of, mental
• 01:34health research. So we're looking
• 01:36forward and wel to welcoming
• 01:37Wanling for Grand Rounds today.
• 01:38Thank you. Thank you, Kieran.
• 01:43Yeah. I wanna thank, Kieran
• 01:44for the wonderful introduction and
• 01:46the Grand Rounds committee for
• 01:48inviting me to, give the
• 01:49Grand Rounds talk. And I
• 01:51realized that I was looking
• 01:53at preparing my slide and
• 01:54looking back to the last
• 01:55time that I gave
• 01:56Rembrandt,
• 01:58and it was right before
• 01:59COVID hit. So March twenty
• 02:01twenty. So it's been a
• 02:02while. And the last time
• 02:04I did it, it was
• 02:05a year after
• 02:06I started my faculty position
• 02:08here.
• 02:09And so can't believe that
• 02:11I've been here for seven
• 02:12years. And so there's a
• 02:13lot to share with you
• 02:15about the work that we
• 02:16have been doing in my
• 02:17lab, since then. Yeah. So
• 02:19thank you for the invitation.
• 02:21And the title of my
• 02:22talk today is, irritability,
• 02:24a hidden driver of youth
• 02:26mental health problem.
• 02:28And why hidden driver? It's
• 02:30because irritability is an early
• 02:33indicator,
• 02:35of later psychopathology,
• 02:36but it's not often recognized,
• 02:38especially
• 02:39not by research attention
• 02:42until very recently.
• 02:44Yeah. And so,
• 02:46I wanted to share with
• 02:47you some of the work
• 02:48that we have been doing
• 02:50on trying to uncover and
• 02:51better understand
• 02:53the mechanism, the symptomatology,
• 02:55and the ideology
• 02:57of irritability.
• 03:03Okay.
• 03:04So if you need the,
• 03:06continuing education credit, and here
• 03:08is the
• 03:09sign in sheet.
• 03:14And here is, what I'm
• 03:15going to cover today. So
• 03:17first, I will tell you
• 03:19about what I mean by
• 03:20irritability
• 03:21in kids
• 03:22and irritability and its public
• 03:24health impact and the developmental
• 03:26trajectory, how it develops over
• 03:28time.
• 03:29And then I'll tell you
• 03:31introduce in this construct of
• 03:32frustrated nonreward,
• 03:34which is just a research
• 03:35term to study frustration.
• 03:38And oftentimes, when we use
• 03:40frustration,
• 03:41to design our experiment in
• 03:43our study to probe the
• 03:45underlying mechanisms of irritability.
• 03:48And
• 03:49I'll tell you why and
• 03:50some of the work that
• 03:51we have been doing in
• 03:52that area.
• 03:54And then towards the end,
• 03:56I'll tell you how we
• 03:57translate some of the research
• 03:59finding,
• 04:00in our previous study
• 04:02and use that new, knowledge,
• 04:04especially the neuro mechanism potential
• 04:06neuro mechanism that we identify
• 04:09and, to use a brain
• 04:11stimulation targeting that neuro mechanism
• 04:14to try to reduce irritability.
• 04:15And this is a pilot
• 04:17work that is in collaborations
• 04:19with, doctor Vaughn Steele,
• 04:22in psychiatry and is funded
• 04:23by the,
• 04:24Yale CBMH Center for Brain
• 04:27and Mind Health.
• 04:30K?
• 04:31So what do I mean
• 04:32by irritability in youth? So
• 04:34we see irritability
• 04:36oh, sorry.
• 04:37We see irritability as having
• 04:39two components.
• 04:40So one is temper outburst,
• 04:42and this could range from
• 04:43mild outburst such as huffing
• 04:46and puffing, snapping, arguing,
• 04:48name calling,
• 04:50to moderate outbursts such as
• 04:52yelling, screaming,
• 04:53physical displays of anger such
• 04:55as clenching fist,
• 04:57improper misuse or destruction,
• 05:00kicking
• 05:01kicking the wall or,
• 05:03breaking things, throwing things,
• 05:05to verbal and physical threats,
• 05:08and all the way to
• 05:09severe outbursts. So including things
• 05:12like hitting, shopping, getting into
• 05:14fights, pushing,
• 05:15physical aggression to self and
• 05:17to others.
• 05:19And some parents,
• 05:20tell us that their kids
• 05:21try to jump out of
• 05:22a moving vehicle,
• 05:24yeah, on the road,
• 05:25or repeated
• 05:27property destruction,
• 05:28kicking the wall continuously,
• 05:30to try to break it,
• 05:32or smashing objects,
• 05:34to try to break them.
• 05:37And the other component of
• 05:39irritability
• 05:39is this underlying
• 05:41negative and irritable mood that
• 05:43is sustained over a long
• 05:44period of time.
• 05:46So parents often tell us
• 05:47that their irritable kids have
• 05:49an underlying mood that is
• 05:51easily annoyed, grouchy, grumpy,
• 05:54unhappy, and moody.
• 05:56And so these are the
• 05:57kids that tend to have
• 05:58struggle with frustration tolerance.
• 06:00So any little things can
• 06:02easily set them off,
• 06:03and parents and family members
• 06:06often describe that they have
• 06:07to walk on eggshells at
• 06:09home in order to prevent
• 06:10temper outburst.
• 06:14And in research, we can
• 06:16conceptualize
• 06:17these two components as basic
• 06:19irritability and tonic irritability.
• 06:21So basic irritability,
• 06:24the peaks
• 06:25up here
• 06:26represents the periodic temper outburst
• 06:29that you that I just
• 06:30described,
• 06:31and the tonic irritability
• 06:33refers to the elevated,
• 06:35irritable mood and negative mood
• 06:37over a sustained period of
• 06:39time.
• 06:40And, it could be over
• 06:42weeks, over months, or over
• 06:44years.
• 06:45And even though these two
• 06:47component are highly correlated
• 06:49and research has shown that
• 06:51they are distinguishable,
• 06:52and they have a distinct
• 06:54correlates
• 06:56behavior and and neuro correlates.
• 06:59And,
• 07:00what has been found is
• 07:01that basic irritability
• 07:03tend to predict or is
• 07:05associated with ADHD
• 07:06symptoms, aggression, conduct problems, and
• 07:09substance use.
• 07:11While tonic irritability
• 07:13tends to predict and is
• 07:14associated with anxiety and depression.
• 07:20And you might be wondering
• 07:22what are some of the
• 07:23common triggers of
• 07:24irritability in kids nowadays.
• 07:27So we ask of these
• 07:29questions in over the family
• 07:31that came through our studies.
• 07:32So right now, we have
• 07:33screened more than hundred and
• 07:35sixty families
• 07:36and with the kids of
• 07:37a to,
• 07:38ages, a to thirteen.
• 07:41And what they mentioned as
• 07:42the most common trigger of
• 07:44irritability
• 07:45is social conflict.
• 07:46So this could be interactions
• 07:48with,
• 07:49their siblings.
• 07:51And so parents often describe
• 07:52that their siblings,
• 07:54annoy the irritable kids to
• 07:56no
• 07:56end,
• 07:57or it could be a
• 07:59problem with peers being made
• 08:00fun of, being teased at
• 08:02school,
• 08:04or adults trying to set
• 08:06limits
• 08:07or placing demand on the
• 08:09kid. So asking them to
• 08:10do chores and asking them
• 08:12to do, to clean clean
• 08:15up at a room, for
• 08:16example.
• 08:18Or frustrated and unreward,
• 08:20when they feel like things
• 08:21don't go their way or
• 08:23things is not going as
• 08:25they planned.
• 08:27Or school stress. So homework
• 08:29is too much, homework is
• 08:31too hard, or when parents
• 08:33ask them to stop playing
• 08:34video games and go do
• 08:36things that they don't like
• 08:37such as homework.
• 08:39Or routine change also commonly
• 08:41trigger irritability.
• 08:43But surprisingly,
• 08:44electronic or video game playing
• 08:46didn't, come up as one
• 08:48of the top reasons even
• 08:49though it's still commonly mentioned.
• 08:52Yeah. So, especially, it's a
• 08:54struggle when parents ask their
• 08:55kids to put away their,
• 08:58devices, put away their video
• 09:00games, and,
• 09:01their kids often throw a
• 09:02bit.
• 09:04And, some other reasons that's,
• 09:06a little less common include,
• 09:08feeling that things are unfair
• 09:10or unjust, sensory overload,
• 09:13or being tired and and
• 09:14hungry, etcetera.
• 09:19And so clinically,
• 09:20we can conceptualize
• 09:21irritability
• 09:22as this increased propensity to
• 09:24experience
• 09:25anger and frustration.
• 09:28And,
• 09:29it is often characterized
• 09:30by severe, frequent, and dysregulated
• 09:34developmentally inappropriate
• 09:35temper outburst,
• 09:37and this is often out
• 09:38of proportion
• 09:39to the situation.
• 09:42And as I mentioned earlier,
• 09:43the mood in between outburst
• 09:45is often irritable and negative.
• 09:49And,
• 09:50chronic irritability or severe irritability
• 09:53is a hallmark
• 09:55feature
• 09:56of this new DSM five
• 09:58on diagnostic category called disrupted
• 10:00mood dysregulation
• 10:01disorder, DMDD.
• 10:03And so it is meant
• 10:05to give this chronically
• 10:06irritable kids a diagnostic home.
• 10:10But irritability and anger is
• 10:12also present in many,
• 10:14pediatric conditions in at least
• 10:15twenty,
• 10:16or more conditions in the
• 10:18DSM five.
• 10:22So why do we care
• 10:23about irritability
• 10:24and related constructs such as
• 10:26anger and aggression?
• 10:29So we care about it
• 10:30because it is very common.
• 10:32It affects about three to
• 10:33five percent of youth, and
• 10:35it accounts for up to
• 10:36seventy five percent inpatient admission.
• 10:39And and
• 10:41about sixty percent of outpatient
• 10:43treatment seeking cases,
• 10:45irritability is mentioned as the,
• 10:47top problem.
• 10:50And as I mentioned, irritability
• 10:52is transdiagnostic.
• 10:53It's present in many pediatric
• 10:55disorder, including DMDD,
• 10:57oppositional defiant disorder,
• 11:00ODD, autism, and anxiety, ADHD,
• 11:03and depression.
• 11:06And your high,
• 11:09levels of irritability has been
• 11:10found to be highly impairing.
• 11:12It's associated with high rates
• 11:14of hospitalization,
• 11:16school suspension, service use, as
• 11:18well as psychotropic
• 11:20pick, medications to manage irritability.
• 11:26And research has also shown
• 11:28that early irritability,
• 11:31as early as could be
• 11:32identified in preschool age
• 11:35is a robust predictor of
• 11:36later anxiety and depression,
• 11:39as well as suicidality.
• 11:41And this is even after
• 11:43controlling for overall depressive symptoms
• 11:46and irritability
• 11:47remain a robust predictor of
• 11:49suicidality,
• 11:50and it often leads to
• 11:52lower income and educational attainment
• 11:54in adulthood.
• 11:59And so,
• 12:00I wanted to tell you
• 12:01some of the developmental research
• 12:03that has been published and
• 12:04also the approach that we
• 12:06are taking in our lab,
• 12:07which is, to
• 12:09follow
• 12:10your ability over a long
• 12:12period of time in order
• 12:14to gain a full picture
• 12:15of the the develop developmental
• 12:18trajectory because a single snapshot
• 12:21of assessment at one single
• 12:22time point is not adequate
• 12:24to capture the full,
• 12:26picture.
• 12:28And so in this study
• 12:30that's published,
• 12:31using a sample of over
• 12:33four thousand kids in the
• 12:34US,
• 12:35of kids that follow from
• 12:37age three to age fifteen,
• 12:40so they identified that kids
• 12:42follow different irritability trajectory.
• 12:45And so about fourteen percent
• 12:46show this,
• 12:48high and relatively stable irritability
• 12:51over time
• 12:52and from early childhood all
• 12:54the way to adolescence.
• 12:56And, of course, the majority
• 12:58of the kids follow this
• 12:59low low trajectory over time.
• 13:01So this is about sixty
• 13:02percent of the sample, and
• 13:04this is a relatively high
• 13:05risk group.
• 13:07And similar trajectory has been
• 13:09identified in another sample in
• 13:12Canada
• 13:13of over a thousand kids,
• 13:15follow from the age of
• 13:16six to age twelve.
• 13:18And, again, there is this
• 13:20group that show persistently
• 13:22high irritability
• 13:23over time, and that makes
• 13:25up about five percent of
• 13:26the sample.
• 13:28But the
• 13:29majority, has low irritability,
• 13:31about seventy four percent. But
• 13:33there are some kids that
• 13:34started out having high irritability
• 13:37that gradually decline,
• 13:39as well as other kids
• 13:40that started out having low
• 13:42irritability that gradually increase.
• 13:44And so this is a
• 13:46common pattern that has been,
• 13:48replicated in an even larger
• 13:50sample. So you can see
• 13:51that it's across multiple sample
• 13:54and across different countries and
• 13:56potentially culture.
• 13:58And so what is seen
• 13:59here in this u UK
• 14:01sample of close to eight
• 14:03thousand kids,
• 14:04about two point four percent
• 14:06has a high,
• 14:08stable irritability over time.
• 14:10And this tend to be
• 14:12boys,
• 14:13and, they also tend to
• 14:14have an ADHD diagnosis.
• 14:17And what's interesting in this
• 14:19study is this group
• 14:22that started out having low
• 14:23irritability in early,
• 14:26childhood,
• 14:27but starts to increase up
• 14:29to the level of the
• 14:30chronically
• 14:31irritable kids,
• 14:33by age fifteen.
• 14:35And so this is a
• 14:36group that tend to be
• 14:37girls
• 14:38and,
• 14:39tend to have an early
• 14:40onset of depressive symptoms.
• 14:42Yeah. And so there are
• 14:44different characteristics
• 14:46and correlates associated
• 14:48with different, developmental trajectories of
• 14:48kids. So this goes to
• 14:48show that it is important
• 14:51trajectories of kids. So this
• 14:52goes to show that it
• 14:53is important
• 14:54to try to,
• 14:56follow kids up longitudinally
• 14:58to see how they fare
• 14:59and how the symptom changes
• 15:01because the different trajectories may
• 15:03have,
• 15:05different underlying mechanism that may
• 15:07need on different sort of
• 15:09intervention and prevention strategy
• 15:11to promote better outcome.
• 15:14K? And so that is
• 15:16indeed the approach that we're
• 15:18taking in my lab on
• 15:19where we are conducting a
• 15:21longitudinal study to try to
• 15:23map out the irritability
• 15:24trajectory over time.
• 15:26And what we also wanted
• 15:28to do is to collect
• 15:29data data from multiple levels
• 15:32of analysis,
• 15:33including the brain, to study
• 15:35the neuro mechanisms of irritability.
• 15:38And we also are collecting
• 15:40physiological
• 15:41data, and I'll tell you
• 15:42more about the design and
• 15:43specific assessment later.
• 15:45Yeah. So we are combining
• 15:47brain,
• 15:48physio data,
• 15:50and behavior
• 15:51as well as looking into
• 15:52their social functioning
• 15:54and,
• 15:55put this all together in
• 15:57a machine learning,
• 15:58sort of predictive model
• 16:00to hopefully identify some of
• 16:02the most predictive features of
• 16:04the kids,
• 16:05who are on the chronic
• 16:07irritability trajectory.
• 16:08But, of course, we're also
• 16:10interested in,
• 16:11other trajectories. So for example,
• 16:14the, rising trajectory as well
• 16:16as the declining
• 16:17trajectory.
• 16:18Declining trajectory
• 16:20is you can consider it
• 16:21as a resilient group. So
• 16:23we wanted to see whether
• 16:24there are different,
• 16:26sort of predictive feature associated
• 16:28with each, distinct trajectory.
• 16:31And then we can take
• 16:32those knowledge, then we learn
• 16:34from those features to tailor
• 16:36intervention and prevention.
• 16:40And as many of you
• 16:42know, it's very expensive to
• 16:43conduct our neuroimaging
• 16:45study. So each scan, at
• 16:47least at Yale here,
• 16:50cost over,
• 16:51six hundred bucks and for
• 16:53an hour scan. And it
• 16:55is if we can identify
• 16:57other,
• 16:59features from other the levels
• 17:00of analysis outside of the
• 17:02brain that is more predictive
• 17:04than the brain itself,
• 17:05then that would
• 17:08make,
• 17:09our research more
• 17:10economic,
• 17:11to conduct. Right? As well
• 17:13as the, more feasible to
• 17:15sit scale up the intervention.
• 17:22And so I alluded to
• 17:24earlier
• 17:25that we focus on the
• 17:26construct of frustration
• 17:27in many of the studies
• 17:29that we do,
• 17:30and we define frustration as
• 17:32this normative
• 17:33emotional and behavioral response to
• 17:36to block goal attainment.
• 17:38So it is a common
• 17:39emotion that we all feel
• 17:41at at some point in
• 17:42our life.
• 17:43Yeah. But why is it
• 17:44important for irritability?
• 17:46It's because they often struggle.
• 17:48Kids with irritability often struggle,
• 17:51with frustration tolerance.
• 17:53And, we also illustrated
• 17:55in our recent studies
• 17:57that
• 17:58frustration
• 17:59emerge as one of the
• 18:01central construct, in the symptomatology
• 18:04of irritability.
• 18:06And, we do so by
• 18:08using EMA data, ecological momentary
• 18:11assessment.
• 18:12So it's like a smartphone
• 18:14based, survey.
• 18:15We have, children and parents
• 18:18install an app on their
• 18:19phone,
• 18:20and,
• 18:21we send them notifications and
• 18:23beeps three times a day
• 18:25for seven days
• 18:26straight to fill out a
• 18:28questionnaire to,
• 18:29so ask ask about the
• 18:31children's,
• 18:32irritability and related symptoms.
• 18:35And we take the data
• 18:37and then put it into
• 18:38a network analysis.
• 18:40And what you see here
• 18:42are the symptom,
• 18:44nodes.
• 18:45So feeling frustrated, feeling that
• 18:47things are unfair, and feeling
• 18:49grouchy and had mood changes
• 18:52or feeling worried.
• 18:54And what emerged as the
• 18:56most central node is this
• 18:58frustration node.
• 18:59And what do I mean
• 19:01by central is that it's
• 19:02the most
• 19:03connected,
• 19:05it's the nodes not most
• 19:06connected to all other symptoms
• 19:09in this network.
• 19:10And so the
• 19:11thicker the line is, the
• 19:13stronger the connection,
• 19:16between the two nodes.
• 19:18And so frustration is the
• 19:20most central node followed by,
• 19:22feeling that things are unfair.
• 19:26And according to network research,
• 19:29the most central node in
• 19:31the system is considered to
• 19:33be the most influential,
• 19:35sort of construct,
• 19:37that's related to other nodes.
• 19:40And it's also a potential
• 19:42promising target for intervention.
• 19:44So imagine
• 19:46if we have an intervention
• 19:47that target
• 19:49frustration improving frustration tolerance,
• 19:51perhaps
• 19:52we can potentially cut off
• 19:54its connection to all the
• 19:56other symptoms
• 19:57and over reduce the overall
• 19:59severe severity of the symptom.
• 20:05K?
• 20:06And we also often refer,
• 20:09frustration to us, frustrated nonreward.
• 20:12So this is a research
• 20:13construct,
• 20:14and it is a study
• 20:16construct in the negative valence
• 20:18system in the research domain
• 20:19criteria
• 20:20put forth by National Institute
• 20:22of Mental Health. And we
• 20:24define frustrated nonreward
• 20:26as an emotional and behavioral
• 20:28response to omission,
• 20:30decrease, or delay of an
• 20:32expected reward.
• 20:34And this is a cross
• 20:35species
• 20:36translational
• 20:37construct that is first defined
• 20:39in rodents,
• 20:41back in nineteen fifty eight
• 20:42by doctor Emsel.
• 20:44And so,
• 20:47he and the lab put
• 20:49the animal,
• 20:50through some conditioning paradigm, instrumental
• 20:52learning paradigm. And so animals
• 20:54have to perform some action
• 20:56in order to obtain reward,
• 20:59And then they would change
• 21:01the reward schedule,
• 21:03such that,
• 21:04once animal have been conviction,
• 21:07to expect reward, they start
• 21:09withholding reward and omitting reward
• 21:12and to frustrate the animals.
• 21:16And what has been found
• 21:18in animal research is that
• 21:19following frustration or frustrated nonreward,
• 21:22animals tend to show increased
• 21:24motor activities and increased aggression,
• 21:27and this has been
• 21:28replicated in humans as well.
• 21:31And it sort of parallels
• 21:32the temper outburst that we
• 21:34see in irritable kids. Right?
• 21:39And so, historically,
• 21:41FNR research,
• 21:43frustrated non reward research
• 21:45has been conducted in animals.
• 21:47And it is not until
• 21:48recently,
• 21:49there is an upsurge,
• 21:51of frustrated non reward research
• 21:54in humans,
• 21:55but it has not been
• 21:56matched with a similar increase
• 21:58in animal studies.
• 22:01And so,
• 22:02I wanted to,
• 22:04sort of,
• 22:05tell you a study that's
• 22:07conducted by a collaborator,
• 22:09doctor Zheng Li, who's an
• 22:11animal researcher,
• 22:12to try to revive
• 22:14this line of animal work
• 22:16and to collaborate
• 22:18on across species of work,
• 22:20using parallel paradigms
• 22:22to study the neuromechanism
• 22:24of an r FNR.
• 22:28So she and her student,
• 22:31develop a very interesting paradigm,
• 22:34called APRO,
• 22:36alternate poking reward omission.
• 22:39So they first, restrict water
• 22:41restrict the mice, and these
• 22:43are mice that's,
• 22:47of human age of ten
• 22:48to fifteen.
• 22:49And,
• 22:50frustrated and unreward
• 22:52animal research in juvenile
• 22:55animals is pretty rare in
• 22:57the past studies. So her
• 22:59study is one of, the
• 23:01few that looked at focus
• 23:02on the juvenile,
• 23:04animals.
• 23:05And
• 23:06so she first trained the
• 23:07animals
• 23:08to perform,
• 23:11behavior
• 23:12to poke in the water
• 23:13spout at the end of
• 23:15a runway.
• 23:16And so, of course, animals
• 23:18were water restricted, so they
• 23:20were motivated
• 23:21to perform the task.
• 23:23And,
• 23:24after three days of training,
• 23:26animals and the row the
• 23:27mice can perform the task
• 23:29at hundred percent success rate.
• 23:32And after that, she start
• 23:34on putting the animals
• 23:35through the APRO paradigm. So
• 23:38on day four,
• 23:39when animal,
• 23:40mice perform the task correctly
• 23:43and, they withhold fifty percent
• 23:46of the reward.
• 23:47So fifty percent of the
• 23:48time, they withhold reward.
• 23:50And then on day five,
• 23:52the nonreward rate is increased
• 23:54to eighty percent.
• 23:56Yeah. And what they found
• 23:58is that
• 23:59on day four,
• 24:01animals,
• 24:03that the animals that went
• 24:04through the frustration paradigms,
• 24:06which is the,
• 24:08sort of the
• 24:09pink bar here or pink
• 24:11dots here compared to the
• 24:13control mice who has never
• 24:14went through the frustration paradigm.
• 24:17So the frustrated
• 24:18mice, tend to show increased
• 24:20motor activity in terms of
• 24:23visiting the port,
• 24:24more frequently
• 24:26and more times.
• 24:27And they also show increased
• 24:28running speed when they are
• 24:30going between the two different
• 24:32port water,
• 24:34spouts.
• 24:35And,
• 24:36the increased motor activity in
• 24:38terms of a port visit
• 24:40continue,
• 24:41to be suspended
• 24:43and to be high even
• 24:44on day six. So
• 24:47after the,
• 24:48the day
• 24:49after, the the mice had
• 24:50been frustrated.
• 24:52That's the Yeah.
• 24:55The behavior they have to
• 24:56sort of,
• 24:58follow a pattern in terms
• 25:00of left side or right
• 25:02side poking.
• 25:03Yeah. Yeah. There's a schedule
• 25:05pattern.
• 25:06Mhmm.
• 25:08Yeah. Yeah.
• 25:12And they also do, put
• 25:14the animal through a series
• 25:15of tests and to make
• 25:17sure this is not just
• 25:18a fluke. So they put
• 25:20the animal through an open
• 25:21field test,
• 25:23and they this time, they
• 25:24have all three different groups.
• 25:26So one is control, and
• 25:28then they also have a
• 25:29water restricted
• 25:31group,
• 25:32and then the, frustrated
• 25:34or non reward group to
• 25:35rule out on the effect
• 25:37due to a water restriction.
• 25:39Yeah. To show that it
• 25:41is specific to frustrated non
• 25:42reward and not, because of
• 25:44water restriction.
• 25:46So what they found is
• 25:47that when, animals,
• 25:49after being frustrated, when you
• 25:50put them in an open
• 25:52open field test,
• 25:53they tend to travel longer
• 25:55distance around the peripheral.
• 25:58Yeah.
• 25:58Demonstrating here.
• 26:00And this is male, and
• 26:01this is female, and they
• 26:03show very similar pattern. And
• 26:05same here. This is the
• 26:06mice that's,
• 26:08been frustrated.
• 26:09And,
• 26:10and this is
• 26:12also this is this is
• 26:14male, and that's female. And,
• 26:15again,
• 26:16they have, no differences in
• 26:18terms of, their
• 26:20increased motor activity. So both
• 26:22show increase on motor activity
• 26:24in terms of, travel distance.
• 26:31And another test that they
• 26:32put animals
• 26:34through is this residence
• 26:36intruder test where an unfamiliar
• 26:38mice, were put into the
• 26:40same cage as the frustrated
• 26:43mice. And they found that
• 26:44the,
• 26:45frustrated mice tend to,
• 26:48are quicker to attack the
• 26:50intruders
• 26:51and also attack for
• 26:53a longer duration,
• 26:55and they also attack more
• 26:57often.
• 26:57And this is not simply
• 26:59due to an increased
• 27:01nonaggressive
• 27:02social interaction time. Yeah. So
• 27:04it is specific to aggression
• 27:06behavior.
• 27:07And, again, there's no,
• 27:09sex differences.
• 27:15And there's no effect on
• 27:17anxiety. Frustration has no effect
• 27:19on anxiety or depression like
• 27:21symptoms as well.
• 27:23So this seem to be
• 27:24a pretty robust evidence showing
• 27:27that, frustration,
• 27:28may lead to increased motor
• 27:30activity and aggression.
• 27:32And in my later work
• 27:34in in humans, I'll tell
• 27:36you some of the ways
• 27:37that we try to use
• 27:39motor activities as a sort
• 27:41of translational
• 27:42indicators
• 27:43of frustration
• 27:44in our human work.
• 27:48So you can imagine
• 27:49we could design a similar
• 27:52paradigm, right, by first conditioning,
• 27:55humans to expect reward
• 27:58and then start frustrating that
• 28:01frustrating them by taking away,
• 28:03the reward that they expect
• 28:04to receive.
• 28:06And indeed, and that has
• 28:07been what we have been
• 28:08doing in the lab.
• 28:10Yeah. And so we have
• 28:12done this, to induce frustration
• 28:14in the lab, in the
• 28:15clinic, and inside the scanner
• 28:17so that we can study
• 28:18the
• 28:19physiology
• 28:20behavior and, the neuro mechanism
• 28:23before, during, and after frustration.
• 28:27So one of the common
• 28:29paradigms that we use extensively
• 28:31in the past is this
• 28:33paradigm called effective postner,
• 28:35task.
• 28:37And this is a very
• 28:38easy paradigm where participant just
• 28:40have to press a button
• 28:42left or right to identify
• 28:44the target,
• 28:45on here.
• 28:47So the target could be,
• 28:49and then before the target
• 28:51shows up, they would see
• 28:52a blue cue either showing
• 28:54up, on the same side
• 28:55as the target or on
• 28:57the different side of the
• 28:58target
• 28:59to assess attention shifting.
• 29:01And so they have to
• 29:03respond to where the target
• 29:04is. And after they respond,
• 29:06they were given some feedback.
• 29:08And for each trial, they
• 29:10perform correctly. They win fifty
• 29:12cents.
• 29:13And so the task is
• 29:14structured such that the first
• 29:16half of the task is
• 29:17very easy and everybody quickly,
• 29:20earn up to close to
• 29:22fifty dollars And we tell
• 29:23them beforehand that whatever amount
• 29:25that you win during the
• 29:26task, you get to take
• 29:27home with you. And you
• 29:29imagine you're a little kid
• 29:30and you get very excited
• 29:31about fifty dollars. Right? Yeah.
• 29:33So once they earned,
• 29:36a big pile of money,
• 29:37it this is when we
• 29:38start frustrating them
• 29:40by giving them break feedback.
• 29:42So, sixty percent of the
• 29:44times and when they were
• 29:45correct,
• 29:46we told them that, oh,
• 29:48too bad you're too slow.
• 29:49And then we take away
• 29:51their money. And so we
• 29:52gave them this,
• 29:54cover story telling them that
• 29:56there's a complex algorithm
• 29:58that goes into calculation of
• 30:00how fast you are and
• 30:01whether you're fast enough. Yeah.
• 30:03So most of the participants
• 30:05believe that's true and why
• 30:07they were deducted money.
• 30:09But a lot of the
• 30:09times, they feel like they
• 30:10were fast enough, but they
• 30:12were still wrong or too
• 30:13slow.
• 30:14And,
• 30:15that caused quite a bit
• 30:16of frustration as well.
• 30:18Yeah.
• 30:19So that's,
• 30:20one paradigm that we use
• 30:22commonly to induce frustration,
• 30:24and I'll tell you some
• 30:25of the work,
• 30:26funny findings from that.
• 30:28And
• 30:29so,
• 30:31we have started,
• 30:33cross species collaborations
• 30:35with doctor Li,
• 30:37along with my previous,
• 30:39postdoc mentor, doctor Lee van
• 30:40Luft to, conduct cross species
• 30:43work.
• 30:44And we submitted a grant,
• 30:46still waiting to, find out.
• 30:48But hopefully, next time when
• 30:50I presented it in Grand
• 30:51Rounds, maybe six years down
• 30:53the road, I can tell
• 30:54you.
• 30:55No work from there.
• 30:57Okay.
• 30:58And so,
• 31:00as I mentioned,
• 31:01we are currently conducting this
• 31:03DP two study funded by,
• 31:05NIH's director's new innovator award.
• 31:09And I'm going to tell
• 31:10you,
• 31:11some of our attempt to
• 31:13try to come up with
• 31:14a parallel,
• 31:15across species of in our
• 31:16paradigms and how we do
• 31:18that in humans.
• 31:21K.
• 31:22And we started data collection
• 31:25about a little over a
• 31:26year ago, and we just
• 31:27wrap up our, first year
• 31:29data collection. And but our
• 31:32goal is to recruit hundred
• 31:33and eighty kids. And so
• 31:35far, and thanks to my
• 31:36amazing,
• 31:38lab,
• 31:38and we have, enrolled more
• 31:40than ninety kids. Yeah. So
• 31:43almost half of our about
• 31:45half of our goal, but
• 31:46we still need to follow
• 31:47them up. But the goal
• 31:48is hundred and eighty kids,
• 31:50age, eight to thirteen and
• 31:53half male, half female.
• 31:55And we want to oversample
• 31:57for high irritability.
• 31:58So about two thirds of
• 31:59them will have high irritability.
• 32:02And it's a longitudinal
• 32:04imaging study, and so each
• 32:06kid and family will be
• 32:07in our study for,
• 32:09over the course of two
• 32:10years. So they come in
• 32:12for baseline assessment, time one.
• 32:14And then a year later,
• 32:15we invite them back for
• 32:17time two assessment, and then
• 32:18another year later, time three
• 32:20assessment.
• 32:21And we give out this,
• 32:23really cute, three d printed,
• 32:26brain mod. I should have
• 32:27brought it.
• 32:30Yeah. Amanda was,
• 32:31Amanda's kids, and we're in,
• 32:33one of our previous studies,
• 32:35so has a two d
• 32:36brain model.
• 32:37Yeah. So we, after they
• 32:39complete their scan,
• 32:41we process the brain data
• 32:42and then put it through
• 32:43three d printer. And so
• 32:44every kid get a souvenir
• 32:46that they take can take
• 32:47home with them. And we
• 32:49plan to do this,
• 32:51over,
• 32:53the over time and then
• 32:55print out each model a
• 32:56little bigger at each time
• 32:58point so that they can
• 32:59have it on their desk
• 33:00and signal their brain growth
• 33:02over time.
• 33:05K? And so at each
• 33:07time point,
• 33:09we have them do the
• 33:10same assessment,
• 33:11and so then we can
• 33:12see how
• 33:14the behavior,
• 33:15symptoms, and,
• 33:16neuroresponses
• 33:17changes over time.
• 33:19So one of the main
• 33:20thing that we have them
• 33:21do is, parent child interaction
• 33:24tasks. So both parent and
• 33:26child come into the lab
• 33:27and they have to engage
• 33:29in conflict discussion.
• 33:30And so they have to
• 33:31pick out two topics and
• 33:33that elicit most complex between
• 33:35parent and child. So it
• 33:38could be homework, it could
• 33:39be screen time, could be
• 33:40hanging out with friends.
• 33:41Yeah. And they also have
• 33:43to work together to solve
• 33:45some puzzle.
• 33:46And even though, some of
• 33:48the puzzles are unsolvable,
• 33:50unbeknownst to them. Yeah. This
• 33:52is our attempt to try
• 33:53to elicit frustration
• 33:55in the kids. But oftentimes,
• 33:57even though the tasks are
• 33:59designed to frustrate kids,
• 34:01we often end up frustrating
• 34:03parents.
• 34:03So it is interesting to
• 34:05see
• 34:06how,
• 34:07we how the effect go
• 34:09from child to parent and
• 34:11parent to child, and then
• 34:13we can hopefully use some
• 34:14data to,
• 34:16better probe those dynamic interact
• 34:20interaction. And so while they
• 34:21are engaged in those interactive
• 34:23tasks, they have to wear
• 34:25a smartwatch,
• 34:27Empedica
• 34:27smartwatch,
• 34:28that record their physiology.
• 34:30So this, could be heart
• 34:32rate, skin conductance,
• 34:34heart rate variability, as well
• 34:35as motor activity.
• 34:37So we can see how
• 34:38their physiology
• 34:39unfold,
• 34:41as
• 34:42the task goes on through
• 34:43the different frustration manipulation.
• 34:47And not only
• 34:48we can,
• 34:50see how individuals'
• 34:51physiology
• 34:52unfold,
• 34:53we can also study how
• 34:55parents'
• 34:56physiology
• 34:57are in sync or out
• 34:58of sync with the child's
• 35:00physiology.
• 35:01And this parent child synchrony
• 35:03could be a biomarker
• 35:05to indicate a parent child
• 35:06coregulation.
• 35:07And this is particularly
• 35:09important,
• 35:10especially when the kids are
• 35:12still young. They still rely
• 35:13on parents a lot for
• 35:15emotion regulation.
• 35:17Yeah. So
• 35:18we will be able to
• 35:19look at that.
• 35:20And then they would comp
• 35:23they also have to complete
• 35:24comprehensive clinical interviews and,
• 35:27assessments
• 35:28and do the smartphone survey.
• 35:30So three times a day
• 35:32before school, after school, right
• 35:34before bedtime,
• 35:35and over the course of
• 35:36seven days.
• 35:38And importantly,
• 35:39the child have to go
• 35:40through fMRI,
• 35:42doing a frustration paradigm.
• 35:44And so I'm gonna tell
• 35:45you more about the frustration
• 35:47paradigm and which we,
• 35:51newly developed
• 35:52to try to model the
• 35:54paradigm that I just show
• 35:55you in animals.
• 35:57So this, APRO paradigm.
• 36:00So we thought that we
• 36:01can,
• 36:02design something that's similar,
• 36:05removing the cognitive component because
• 36:08animals don't use
• 36:10higher cognitive functions
• 36:11when they're performed
• 36:13on those reward tasks. Right?
• 36:15But a lot of the
• 36:16existing,
• 36:17FNR
• 36:18paradigms in humans do have
• 36:20a cognitive component.
• 36:22So we wanted to remove
• 36:23that cognition.
• 36:24And so what we come
• 36:25up with is to take
• 36:28the doors task, which is
• 36:30a traditional
• 36:31reward sensitivity
• 36:32task
• 36:33where,
• 36:34participants are presented with two
• 36:36doors, and they just had
• 36:38to select one of the
• 36:39door to find out whether
• 36:40they get reward or not.
• 36:42And so this would, be
• 36:44similar to animal having to
• 36:46run to the left or
• 36:47run to the right to
• 36:49obtain the reward. So control
• 36:50for that motor component.
• 36:53And,
• 36:55but our reward schedule is
• 36:58slightly different than the animal's
• 37:00reward schedule, and this
• 37:03is, after a lot of
• 37:05piloting. And this is the
• 37:07reward schedule that we settle
• 37:08on because one of the
• 37:10challenges
• 37:11of,
• 37:12doing frustration work is that
• 37:14you have to strike a
• 37:15fine balance between,
• 37:18not frustrating kids too much
• 37:20and too fast right away
• 37:21that they decided to quit
• 37:24and not complete your task.
• 37:25But you also want it
• 37:27to be potent enough that,
• 37:29would elicit enough negative effect
• 37:31that allows you to probe
• 37:33the underlying mechanism.
• 37:35Right? And so we settle
• 37:36on,
• 37:39eighty percent reward,
• 37:41when we first condition them
• 37:42to expect reward.
• 37:44Hundred percent would just be
• 37:45very unbelievable.
• 37:47Not not not believable.
• 37:50Right? Yeah. So we settle
• 37:51on eighty percent reward,
• 37:53during conditioning,
• 37:54which is the nonfrustration part,
• 37:57and then we start frustrating
• 37:59them, by taking away,
• 38:01their reward that they expect
• 38:03to get,
• 38:04so sixty percent of the
• 38:06trial.
• 38:07And then, we revert back
• 38:10to the original,
• 38:12reward schedule, eighty percent, so
• 38:14that they don't
• 38:15end
• 38:16a negative no or negative
• 38:18move before going home. Yeah.
• 38:20Otherwise, parents will not
• 38:22be very happy with this.
• 38:24Yes.
• 38:25Okay. So that is what
• 38:27we do. So they have
• 38:28to go through the doors
• 38:30task and then find out
• 38:31they get reward or not.
• 38:35K?
• 38:36And another thing that we
• 38:38try to address
• 38:39in our paradigm
• 38:41is to is the is,
• 38:43because of the gap in
• 38:45the existing,
• 38:46fMRI
• 38:47research,
• 38:49which is that most of
• 38:51the paradigm use nonsocial
• 38:53reward,
• 38:54especially monetary reward,
• 38:57and not a lot of
• 38:58studies. I think so far,
• 38:59there's only one study
• 39:01that use social feedback, sort
• 39:03of, social stimulus
• 39:06as a rewarding stimulus,
• 39:08to frustrate as the source
• 39:10of frustration.
• 39:11And as I show you
• 39:12earlier, remember the trigger,
• 39:15common triggers, and one of
• 39:16the top trigger is social
• 39:18conflict.
• 39:19So it seems to be
• 39:20an important gap before not
• 39:22tapping into this social domain
• 39:24while designing a frustration paradigm.
• 39:27And especially,
• 39:28so social frustration
• 39:30could come from, like, with
• 39:31parents, with peers,
• 39:34or with siblings. Right? But,
• 39:36in our study, we wanted
• 39:37to
• 39:38sort of focus on peers
• 39:40as,
• 39:41the
• 39:42source of social frustration because
• 39:44we already have the parent
• 39:45child interaction.
• 39:47Yeah. So
• 39:48looking at parent child interaction
• 39:50and the peer,
• 39:51component,
• 39:52will provide us more,
• 39:55more information.
• 39:58And I think I don't
• 40:00need to tell,
• 40:02the audience in this room
• 40:03how important,
• 40:05peer
• 40:06influence is,
• 40:07especially to school age kids.
• 40:10And even though parental influence
• 40:12remained, and parental support remained
• 40:15important
• 40:15as kids grow older,
• 40:17but as they get into,
• 40:19preteens
• 40:20and teens,
• 40:22peer influence
• 40:23start gaining its traction in
• 40:25salience.
• 40:27And this I was made
• 40:29keenly aware of this,
• 40:31recently
• 40:32when my son and I,
• 40:34a nine year old at
• 40:34the time, went to a
• 40:36water park, and they have
• 40:38this giant water slide that
• 40:40has a sixty feet drop
• 40:41off, and that will take
• 40:43you right down
• 40:44onto the water.
• 40:46And so we were very
• 40:47excited to try it, and
• 40:48both of us got up
• 40:49there
• 40:50and he started, getting cold
• 40:52feet and was a little
• 40:54scared to go down. So
• 40:56I was like, why don't
• 40:57I go down? And then
• 40:58you can see whether you
• 40:59want to come down or
• 41:01with me or you wanna
• 41:02take the stairs back down.
• 41:04Yeah. And so I went
• 41:05down and immediately as I
• 41:07let go, I regretted it.
• 41:10I'm too old for this.
• 41:12Yeah. So I did. And
• 41:13then I went down and
• 41:14thinking that,
• 41:16he would just take the
• 41:17stairs down because,
• 41:19he tend to be a
• 41:20little tentative and cautious when
• 41:21it comes to height.
• 41:23But surprisingly,
• 41:24he came down.
• 41:25And I asked him,
• 41:27yeah. I didn't think that
• 41:28you were gonna do it.
• 41:29So what made you change
• 41:30your mind?
• 41:31And he was like, there's
• 41:33a group of teenagers right
• 41:35behind me, and they keep
• 41:36telling me, it's not as
• 41:38scary. Do it. Do it.
• 41:40Yeah. And that's when I
• 41:41realized, wow. And age nine,
• 41:44I thought I had more
• 41:45time.
• 41:46You start caring about what
• 41:48other kids would think and
• 41:49what other peers would think.
• 41:51Yeah.
• 41:52And so age nine,
• 41:54is sort of in the,
• 41:56age range that we target
• 41:58in our,
• 41:59study
• 42:00sample.
• 42:01So this give us confidence
• 42:03in that at least give
• 42:04me confidence
• 42:06that we are tapping into
• 42:07an important,
• 42:09phenomena.
• 42:10Yeah. So we wanted to
• 42:11use peer feedback
• 42:13as
• 42:14a stimulus in our paradigm.
• 42:18And this and I don't
• 42:19need to tell you the
• 42:20importance of social media
• 42:22and teens. So not only
• 42:24their real world peers has
• 42:26an influence
• 42:28on them, the peer feedback
• 42:29and the,
• 42:31like or dislike feedback,
• 42:33in the virtual world
• 42:35also has a large impact
• 42:37on the,
• 42:38kids' life.
• 42:41So
• 42:41in our study,
• 42:43we wanted to use peers
• 42:46as the source of social
• 42:47frustration.
• 42:48And but we have to
• 42:50make the social and nonsocial
• 42:52conditions as similar as possible.
• 42:55So we had this idea
• 42:56of showing two peer, pictures
• 42:59side by side,
• 43:00And we have,
• 43:02we told them this cover
• 43:03story that,
• 43:05oh,
• 43:06when you come into our
• 43:07lab, we have to take
• 43:08a photo of you, and
• 43:09then we are gonna upload
• 43:11your photo onto
• 43:13a nationwide
• 43:14database,
• 43:16of kids that participate in
• 43:18this nationwide peer evaluation study.
• 43:21And so they'll get to
• 43:22see your photos and rate
• 43:24whether they wanna be friends
• 43:25with you or not, whether
• 43:26they like you or not.
• 43:27I know it's a little
• 43:28cruel. We had a hard
• 43:29time with IRB.
• 43:32Took us five months,
• 43:34to get through IRB. Yeah.
• 43:36And,
• 43:37but then we didn't, and
• 43:38we made them believe that
• 43:40they are participating
• 43:41in this peer evaluation study.
• 43:44And in the scanner is
• 43:46when they will find out,
• 43:48which peers like them or
• 43:49dislike them.
• 43:51So when they come into
• 43:52the scan,
• 43:53they have to pick one
• 43:54of the peers,
• 43:56side by side.
• 43:57And once they make their
• 43:59choice, they will find out
• 44:01whether the peer like them
• 44:02or dislike them.
• 44:04Yeah. And similarly
• 44:06to the nonsocial, the doors
• 44:08condition,
• 44:10We condition them to expect,
• 44:12more positive reward in the
• 44:14beginning.
• 44:15So eighty percent positive,
• 44:18feedback.
• 44:19And then we start frustrating
• 44:21them by giving them more
• 44:23negative feedback.
• 44:24Yeah. Now in during the
• 44:25frustration block, can they receive,
• 44:28mostly
• 44:29dislike
• 44:30feedback? And then,
• 44:31in the recovery block, reverted
• 44:33back to the original block
• 44:35with more yes, Amanda? How
• 44:37long is each
• 44:39block? How long? About,
• 44:41each run is about six
• 44:43minutes, so twelve minutes each
• 44:45block. Yeah. Mhmm.
• 44:47Yeah.
• 44:48And throughout the task,
• 44:50they have to rate, how
• 44:52frustrated they feel and how
• 44:53sad or unhappy they feel
• 44:55using
• 44:56a scale from one to
• 44:57nine. So one is not
• 44:59frustrated at all to nine
• 45:01feeling, completely frustrated
• 45:03extremely frustrated.
• 45:07So here is some of
• 45:08our preliminary
• 45:09results from fifty four kids,
• 45:11that we have,
• 45:13analyzed the data for.
• 45:15And so on the left
• 45:16side here
• 45:17is the nonsocial
• 45:19frustration, frustration that they feel
• 45:21during nonsocial condition.
• 45:23And on the right here
• 45:24is the social conditions.
• 45:26And these are individual subjects,
• 45:28ratings over the course of
• 45:30the three blocks.
• 45:32And if you average all
• 45:33of the lines together,
• 45:35this is what the group
• 45:36rating look like.
• 45:37So you can see that
• 45:39the two curves are very
• 45:40similar. Right?
• 45:42But,
• 45:43they they both show,
• 45:46elevated frustration level
• 45:48during the frustration block
• 45:50compared to the baseline or
• 45:52recovery block.
• 45:53And so even though the
• 45:54recovery block,
• 45:56the frustration level dropped, but
• 45:58it remains slightly elevated,
• 46:01and not returned to baseline.
• 46:03Right? And so this is
• 46:04still significant.
• 46:08And this goes to illustrate
• 46:10that indeed our task manipulation
• 46:12works. Yeah. And
• 46:14peers could be used as
• 46:16a source of, frustration.
• 46:18Yeah. And socially
• 46:20social and nonsocial frustrations are
• 46:22equally frustrating. There's no differences
• 46:25in in terms of their,
• 46:27effective ratings.
• 46:30And so,
• 46:32and we found that the
• 46:33levels of frustration that they
• 46:35feel is significantly
• 46:37related,
• 46:38to
• 46:39their irritability in the real
• 46:41world.
• 46:42So the more irritable the
• 46:43child is in general,
• 46:46the more frustrated they get,
• 46:48especially during the frustration block
• 46:51and during the baseline block.
• 46:56So we wanted to see
• 46:57whether,
• 46:57the social and nonsocial frustration
• 47:00differ in terms of the
• 47:01neural
• 47:02responses.
• 47:03And,
• 47:05this is a little,
• 47:07out of sorts, but, k.
• 47:09Please
• 47:10ignore. So the bottom line
• 47:11is that we didn't find
• 47:13any differences in between,
• 47:15neural responses in social versus
• 47:17nonsocial frustration.
• 47:19But,
• 47:20the degree
• 47:22of the differences,
• 47:24when viewing social versus nonsocial
• 47:26frustration
• 47:28is associated
• 47:29with participants' irritability
• 47:31irritability
• 47:32level,
• 47:33especially in regions such as
• 47:36insula,
• 47:36thalamus,
• 47:38parietal lobule,
• 47:39which are regions important for
• 47:41sensory information
• 47:43processing
• 47:43and integration.
• 47:45And so what we found
• 47:47is that the more irritable
• 47:48the child is in the
• 47:49real world,
• 47:51the more activation they have
• 47:53in those regions
• 47:55in response to nonsocial
• 47:57compared to social feedback.
• 47:59Yeah. So they tend to
• 48:01show a little more, neuroactivation,
• 48:04to the nonsocial
• 48:06frustration.
• 48:09K.
• 48:11So I wanna are we
• 48:12good on time?
• 48:14Five minutes? Okay. I wanna
• 48:16switch gear a little bit
• 48:18and quickly tell you a
• 48:20pilot on TMS that we
• 48:22can we are conducting in
• 48:23adults,
• 48:25to try to use our
• 48:26neuromodulations
• 48:28as a potential approach to
• 48:30reduce irritability.
• 48:32And so,
• 48:34I probably don't need to
• 48:35tell you,
• 48:36that,
• 48:38many adults feel frustrated or
• 48:40irritable at some point during
• 48:42their life,
• 48:43and especially when you're stuck
• 48:44in bumper to bumper traffic
• 48:47or waiting a long time
• 48:49and finally got somebody on
• 48:50the
• 48:51on the phone,
• 48:53but they're not being very
• 48:54helpful.
• 48:55And
• 48:56or after a long day
• 48:57at work, you come home
• 48:58to a mess.
• 49:00Or when you're dealing with
• 49:01a deadline, but a computer
• 49:03keep crashing on you. Yeah.
• 49:05Or your favorite sports team
• 49:07is losing a game that
• 49:08they're not supposed to lose.
• 49:11Yeah. So turns out your
• 49:12ability is very common, and
• 49:14this is backed by data,
• 49:17of a
• 49:18study recently published by doctor
• 49:20Perlis
• 49:21of over forty two thousand
• 49:23adults across fifty states in
• 49:25the US.
• 49:27And so the adults are
• 49:28eighteen to, sixty five years
• 49:30of age
• 49:32and, a little over half
• 49:33are female.
• 49:34So they have a survey
• 49:36asking about irritability
• 49:37using those five items.
• 49:39And what they found is
• 49:40that,
• 49:42the average irritability
• 49:44score is thirteen point six
• 49:47on a scale from one
• 49:48to
• 49:49from five to thirty.
• 49:51And this translate to endorsing
• 49:54sometimes,
• 49:55at least three plus,
• 49:58three or more of the
• 49:59irritability
• 50:00symptoms in here. Yeah. You
• 50:01can probably all relate to
• 50:03some of those symptoms. Right?
• 50:06And irritability is more,
• 50:09increased
• 50:10in female
• 50:11and in younger adults and
• 50:13in those with lower SES.
• 50:17And it is especially high
• 50:18in those with depressive
• 50:20and anxiety
• 50:21disorders.
• 50:23And even in those without
• 50:25depressive or anxiety symptoms,
• 50:28about two percent
• 50:29also endorse,
• 50:31if experiencing
• 50:32irritability.
• 50:34So it is a very
• 50:35common,
• 50:35problem.
• 50:37And it's also significantly linked
• 50:40to
• 50:41thoughts of suicide
• 50:42even among some of the,
• 50:44sort of robust predictors such
• 50:46as, urbanacity.
• 50:48Yeah. Irbidability
• 50:49emerged as a predictor
• 50:51of suicidality.
• 50:56K. So,
• 50:57here is our attempt to
• 50:59try to use TMS to
• 51:00reduce irritability,
• 51:02and this is a work,
• 51:03by,
• 51:04me and doctor Von Steele
• 51:06from psychiatry.
• 51:07And it's supported by a
• 51:09pilot grant that we obtained
• 51:10through Center for Brain and
• 51:12My Health.
• 51:13And so we initially,
• 51:15had the thought of translating
• 51:17one of the study that
• 51:18we've, study finding that I
• 51:20found
• 51:21in adolescents. So kids and
• 51:23adolescents.
• 51:24But we thought it will
• 51:25be premature,
• 51:26to do a TMS study
• 51:28in kids.
• 51:29Yeah. And it will not
• 51:30be very, feasible
• 51:32and or accepted by families.
• 51:34So we wanted to try
• 51:35in young adults and see
• 51:37if we it's effective
• 51:39before we down translate into
• 51:41adolescence.
• 51:42And so this is informed,
• 51:44by
• 51:45a a study that I
• 51:47found and that's published in,
• 51:50twenty nineteen
• 51:51and using the frustration paradigm
• 51:53that I talked about.
• 51:54And in this study, we
• 51:56found that higher irritability is
• 51:59related to increased,
• 52:01activations
• 52:02in,
• 52:03pre in frontal striatal regions.
• 52:06So especially,
• 52:07singular gyrus, dorsal singular dorsal
• 52:10anterior singular gyrus in particular.
• 52:13And we also found, increased
• 52:15activations
• 52:16in dorsal lateral prefrontal cortex
• 52:19and caudate.
• 52:20And so we wanted to,
• 52:22target this frontal striatal circuit.
• 52:25And so we look into
• 52:26the data that we have
• 52:28by focusing on the older
• 52:29kids, so the late adolescents,
• 52:32hoping that the data will
• 52:34be close enough to our
• 52:35the young adult population that
• 52:37we try to target.
• 52:39And so what we found
• 52:40when we focus on, the
• 52:42connectivity between the frontal striatal
• 52:45region
• 52:46is
• 52:47that when when lay adolescents
• 52:49were frustrated,
• 52:51they tend to show decreased
• 52:53frontal striatal,
• 52:54connectivity.
• 52:56And this is,
• 52:58even more pronounced when,
• 53:00for those with high irritability.
• 53:02So the one with high
• 53:03irritability
• 53:04show more higher degrees of
• 53:06decreased,
• 53:07connectivity.
• 53:10And we also needed to
• 53:12illustrate that we could use
• 53:14the same frustration paradigm
• 53:16to, frustrate adults. So indeed,
• 53:18we did. And in seventy
• 53:20two young adults,
• 53:22that
• 53:24we, have them do this
• 53:26frustration paradigms for, and this
• 53:28is supported by the child
• 53:29study center faculty
• 53:31development award.
• 53:33We can't,
• 53:35use the same paradigm that
• 53:36we frustrate kids to frustrate
• 53:38adults.
• 53:39And so,
• 53:40when
• 53:41during the frustration runs,
• 53:43young adults reported increased levels
• 53:46of frustration
• 53:47or unhappiness,
• 53:49and this tracks with on
• 53:51the levels of irritability
• 53:52symptoms that they experience in
• 53:54daily life.
• 53:57And I mentioned to you
• 53:59earlier that motor in motor
• 54:01activities
• 54:02is a robust across species,
• 54:05indicator of frustrate frustration responses.
• 54:08So we wanted to also
• 54:10use a motor activity
• 54:12as a
• 54:13sort of marker,
• 54:14for frustration.
• 54:16And so we did a
• 54:17pilot study in fourteen,
• 54:19young adults,
• 54:21and we use this device
• 54:22called dynamometer
• 54:24that will measure how hard
• 54:26they grip, how hard they
• 54:28exert,
• 54:29motor effort while they're responding
• 54:31to the task.
• 54:32And, indeed, we found that
• 54:34when participants were frustrated
• 54:37compared to before frustration and
• 54:39after frustration,
• 54:40They show this increased grip
• 54:42force,
• 54:43yeah, while they were frustrated.
• 54:47So seems like, we do
• 54:49have some studies,
• 54:51some data that suggests that
• 54:52frustration is related to
• 54:55decreased frontostriatal
• 54:56connectivity,
• 54:57increased motor activity,
• 54:59and increased negative effect.
• 55:02So our hypothesis
• 55:03is that, perhaps,
• 55:05TMS
• 55:07can be used to rescue
• 55:08those, responses
• 55:10by increasing,
• 55:12frontostriatal
• 55:13connectivity,
• 55:14decreasing motor activity, and decreasing
• 55:16their negative effect to normalize
• 55:19the frustration responses.
• 55:23And so this is our
• 55:24study design,
• 55:25and I'm gonna quickly skip
• 55:27this skip through the this
• 55:29in the interest of time.
• 55:31But,
• 55:33so very quickly is that
• 55:34they,
• 55:35have to complete a baseline
• 55:36assessment before coming to the
• 55:38lab
• 55:39for two TMS day. And
• 55:41before TMS, they complete the
• 55:43frustration paradigm during fMRI,
• 55:46and then,
• 55:47have,
• 55:48TMS receive TMS,
• 55:50and then complete the same
• 55:52frustration paradigms again.
• 55:54And on day one and
• 55:55day two,
• 55:57either they receive active,
• 55:59TMS on the first day
• 56:01and then,
• 56:02sham TMS on the second
• 56:04day or vice versa. So
• 56:05it's counterbalanced
• 56:07within,
• 56:07subjects.
• 56:09And so far, our target
• 56:10is twenty,
• 56:12participants, and
• 56:13we have had,
• 56:15nineteen participants.
• 56:16And we have one last
• 56:17participant
• 56:18scheduled to come in for
• 56:19day two
• 56:21in two weeks. So we
• 56:22will be soon, finished with
• 56:24a study, which is ahead
• 56:26of schedule. Unheard of. Yeah.
• 56:28But we're happy about it.
• 56:30Yeah.
• 56:31And,
• 56:32another happy news is that
• 56:34the fact that we can
• 56:35frustrate,
• 56:37adults
• 56:38four times
• 56:39using the same frustration paradigm
• 56:41and they keep coming back
• 56:43is good news. Yeah. So
• 56:45this means that we can
• 56:47try to pursue this work
• 56:48in a larger sample. And,
• 56:50indeed, that's what we're doing
• 56:52with a pending r o
• 56:53one
• 56:54that was reviewed
• 56:55last week. Unfortunately,
• 56:57it was not discussed, but
• 56:58we're going to persist and
• 57:00resubmit.
• 57:02Okay. So some of the
• 57:04preliminary finding here
• 57:06is that,
• 57:08we we indeed
• 57:09found that we are able
• 57:11to use TMS to increase
• 57:13frontal striatal connectivity
• 57:15and only,
• 57:17in the active
• 57:18condition, but not in the
• 57:20sham,
• 57:20TMS.
• 57:22And we are able to,
• 57:24decrease motor activities
• 57:26only in the active condition,
• 57:28but not in sham.
• 57:29And we found some
• 57:31partial evidence
• 57:32that we could decrease negative
• 57:34effect and to a greater
• 57:36degree compared to the sham,
• 57:38inactive compared to sham.
• 57:40But this difference is not
• 57:42significant,
• 57:43perhaps
• 57:44due to small symbol size
• 57:46or the problem with self
• 57:48report. We all know the
• 57:49limitations of self re self
• 57:51report.
• 57:52Yeah.
• 57:53So we are pleased to
• 57:54found evidence to support
• 57:57pretty much all of our
• 57:58hypothesis
• 57:59except for the self report,
• 58:01and this is probably one
• 58:02of the the most clean
• 58:04data that I've seen in
• 58:05my whole research career. So
• 58:07we were initially, we were
• 58:09shocked, but, hopefully, this is
• 58:11not just a fluke once
• 58:12we expand our sample size.
• 58:15Yeah.
• 58:17Okay.
• 58:18So I'll wrap up my
• 58:20talk there in the interest
• 58:21of time, but,
• 58:23I cannot end my talk
• 58:24without thanking
• 58:26thanking my fabulous
• 58:27lab that has done an
• 58:29amazing job.
• 58:31They are why I was
• 58:32able to present all the
• 58:34all of the work, that
• 58:35I did today.
• 58:37So and this include
• 58:39and special shout out to
• 58:40Alexa, who's my lab manager
• 58:43and who has done a
• 58:44tremendous job on recruiting participants
• 58:46and taking participants
• 58:48through the study procedures and,
• 58:50many students sitting in the
• 58:52audience.
• 58:53Right? And then a fabulous
• 58:56collaborators,
• 58:57and it has been fun
• 58:59on doing all of the
• 59:00work, with you guys.
• 59:01Yeah.
• 59:04Good.
• 59:08And final thing, we are
• 59:10still actively recruiting. So if
• 59:12you know somebody, please reach
• 59:14out.
• 59:15Oh, one thing that was
• 59:16amazing. I think the win
• 59:17the award for most innovative
• 59:19incentive for participants. I think
• 59:21a three d printed brain
• 59:22is something I would
• 59:23oh, there we go. Oh,
• 59:25thank you.
• 59:27And we can pick,
• 59:29print in the color of
• 59:30your choice.
• 59:33And So you know. Questions
• 59:34for for Wanling?
• 59:36Could
• 59:42could you just
• 59:43describe
• 59:44what,
• 59:46is TMS a voltage? What
• 59:48is of of the voltage
• 59:49you use? Yeah. Yeah. Yeah.
• 59:51Yeah. I I don't know.
• 59:52It stands for transcranial
• 59:54magnetic
• 59:55stimulation. It's basically sending,
• 59:58it's noninvasive.
• 59:59It's just a coil on
• 01:00:01the head or depending on
• 01:00:03which region that you target.
• 01:00:04It sends electrical,
• 01:00:06pulses and to try to,
• 01:00:09modulate the, neuro activities
• 01:00:11inside the skull. Yeah.
• 01:00:13I'm not an expert on
• 01:00:14TMS, and doctor Bon, still
• 01:00:17is. So,
• 01:00:18yeah, I'm sure he will
• 01:00:19be happy to answer any
• 01:00:21of your questions. So reach
• 01:00:22out to him.
• 01:00:23He's in psychiatry.
• 01:00:25Yeah.
• 01:00:26Great.
• 01:00:27If I may, just really
• 01:00:28quickly, I was, so it's
• 01:00:30interesting when you look at
• 01:00:31the mouse work that you
• 01:00:32see the increased locomotor activity
• 01:00:34in response to frustration.
• 01:00:36And I'm just wondering to
• 01:00:38what extent is that an
• 01:00:39adaptive response to the frustration
• 01:00:41that helps with coping. So
• 01:00:43I'm thinking about Robert Sapolsky's
• 01:00:44book, why zebras don't get
• 01:00:46ulcers, and the idea of
• 01:00:47that stress response and then
• 01:00:49kind of movement or response
• 01:00:50to that stress, kind of
• 01:00:52alleviating that stress. So
• 01:00:54if you then translate to
• 01:00:55the human condition,
• 01:00:57you've got the grip strength
• 01:00:58condition. If you block someone
• 01:01:00from using
• 01:01:01that device,
• 01:01:02does that actually take longer
• 01:01:03for the frustration
• 01:01:05to subside and that reconnectivity
• 01:01:07to be reestablished?
• 01:01:09Mhmm. That is a very
• 01:01:10good question
• 01:01:11and,
• 01:01:12something that we are grappling
• 01:01:14with as well. So indeed,
• 01:01:17in animal research,
• 01:01:18increased motor activities
• 01:01:20have been shown to
• 01:01:22be an adaptive
• 01:01:23strategy
• 01:01:25in that
• 01:01:26if what, they were doing
• 01:01:28no longer leads to reward,
• 01:01:30then they have to scramble
• 01:01:32or change a strategy in
• 01:01:33order to sort of forging
• 01:01:35strategy
• 01:01:36and in order to obtain
• 01:01:38resources somewhere else. So it
• 01:01:40is an adaptive strategy in
• 01:01:42that sense.
• 01:01:43And, what we are but
• 01:01:45the degree
• 01:01:46of the
• 01:01:48motor activity that is sustained
• 01:01:50and,
• 01:01:52continue to be there
• 01:01:54might be why that's, could
• 01:01:55be maladaptive
• 01:01:56assigned for maladaptive responses.
• 01:01:59And in terms of blocking
• 01:02:01the devices
• 01:02:02in order to obtain reward,
• 01:02:04that has also been used
• 01:02:06in some of the previous,
• 01:02:07human research.
• 01:02:09And what they shown is
• 01:02:10that that also induced frustration,
• 01:02:13and it might actually,
• 01:02:16elicit higher levels of frustration
• 01:02:18because
• 01:02:19it sort of impede your
• 01:02:21sense of agency
• 01:02:23when you are,
• 01:02:25doing something right, and then
• 01:02:26it's out of your control,
• 01:02:28and then you can seem
• 01:02:29to do anything about it
• 01:02:31and not being able to
• 01:02:32obtain reward.
• 01:02:33Yeah. So it's just some,
• 01:02:36sort of approach that other
• 01:02:37labs has take to induce
• 01:02:39prostration.
• 01:02:40But yeah. Well, now we're
• 01:02:42currently pursuing right now, but
• 01:02:43interesting.
• 01:02:45Okay. Pam, real quick.
• 01:02:48K. There we go. Of
• 01:02:49course.
• 01:02:51I'm I'm really curious about
• 01:02:53the, the question of
• 01:02:55attenuation.
• 01:02:56You know, I know that
• 01:02:57you were surprised at that
• 01:02:58you can bother and frustrate.
• 01:03:00Sorry. Not bother. Frustrate someone
• 01:03:02over and over again, and
• 01:03:03it still works. I do
• 01:03:04wonder if there's going to
• 01:03:05be some sort of signal
• 01:03:06loss or attenuation at the
• 01:03:08fourth or fifth time, especially
• 01:03:10because they know it's gonna
• 01:03:11get better. I don't know
• 01:03:12how you'd be able to,
• 01:03:13you know, gauge for that
• 01:03:14or study that or call
• 01:03:16it learning as opposed to
• 01:03:17an I'm I'm wondering how
• 01:03:18you're gonna handle that. Yeah.
• 01:03:20Yeah. Definitely. We do see
• 01:03:22some attenuation.
• 01:03:23So the second time when
• 01:03:24they perform the same structure
• 01:03:26in paradigm,
• 01:03:27they don't break themselves with
• 01:03:29scale as structured compared to
• 01:03:31the first time.
• 01:03:32Yeah. But,
• 01:03:34everybody dropped. Right? But the
• 01:03:35decrease of whether they,
• 01:03:37how how much they dropped,
• 01:03:39I could vary by individual.
• 01:03:41And we are hoping that,
• 01:03:43the degree of drop will
• 01:03:45be less in those who
• 01:03:46are elevated who has elevated
• 01:03:48the
• 01:03:49immune
• 01:03:55Wonderful. Just in the interest
• 01:03:57of time, maybe we'll wrap
• 01:03:58it up there, but please
• 01:03:59join me in thanking while
• 01:04:00I'm saying for a great
• 01:04:00friend, Rams.