Yale Psychiatry Grand Rounds: October 20, 2023

Transcript

• 00:00We just go to the next slide.
• 00:03Yeah. Wow. It is. I mean, it's.
• 00:07I'm speechless. It's really so,
• 00:09so wonderful to be here.
• 00:10I was a little worried that I
• 00:12might actually tear up a little
• 00:14bit coming home to Yale where,
• 00:17you know, I just, you know,
• 00:19it was like cutting off a limb
• 00:22to leave this institution.
• 00:23I spent 18 years here through
• 00:26residency training getting
• 00:28through to associate professor.
• 00:30I was about to go up for full professor
• 00:33and and I had many long conversations
• 00:35with John about whether I was doing
• 00:37the right thing to leave Yale.
• 00:39And and I think that there's something
• 00:42about the importance of being
• 00:44able to move because so much of my
• 00:47success as a researcher and academic,
• 00:50you know, you have to wonder how
• 00:52much of it is the institution,
• 00:55you know, how much of it is the
• 00:57holding environment that you're,
• 00:58quote UN quote,
• 01:00raised in as an academic.
• 01:01And how much is really you?
• 01:04And I have to say,
• 01:05having left and then being able
• 01:07to see that I could succeed at
• 01:10other institutions was also a
• 01:12a a really wonderful lesson.
• 01:14And so I have to say,
• 01:16John,
• 01:16you did a great job supporting me through
• 01:19that transition and I am really grateful.
• 01:21And it's been 15 years,
• 01:24and I have to say I still to this day
• 01:26have such fond feelings for this institution.
• 01:29I cherish so many of the
• 01:30friends that I've made.
• 01:31Many have come and seen me and to cheer
• 01:35me on today because there's nothing
• 01:37like coming home and actually giving a talk.
• 01:39You can start to go, Oh my God,
• 01:42is this going to go OK?
• 01:43And I can be so loquacious that
• 01:45it was a little.
• 01:46I had to cut out some slides,
• 01:48but also too,
• 01:49I have to say the colleagues I had here,
• 01:52so many of you really pushed
• 01:53me to be a better scientist.
• 01:56And for that I'm grateful for all
• 01:59the mentors and some of them I'm
• 02:01going to highlight today and people
• 02:03that supervise me over the years.
• 02:05I mean,
• 02:06people believed in me here when
• 02:08they had absolutely no evidence
• 02:10at all because I don't have a
• 02:13PHDI didn't do research, really,
• 02:14in medical school or you know,
• 02:16I came to research kind of late in my career.
• 02:19And I had many mentors who believed
• 02:22in me without any evidence that I was
• 02:24going to have a successful research career.
• 02:28And I have to say it's truly an
• 02:30honor and privilege to be able to be
• 02:33the Henninger lecturer today and to
• 02:36recognize one of those mentors who,
• 02:39I don't know what you saw in me,
• 02:40George, I really don't.
• 02:42But you were an amazing mentor in many ways,
• 02:46not just in what you would say,
• 02:49but and how you led your life as a physician,
• 02:52scientist, as many of you know.
• 02:54And John highlighted, Dr.
• 02:55Henniguro has been in this
• 02:58department for 50-6 years.
• 02:59And I have to say, you know,
• 03:01John highlighted some of the ways
• 03:03in which you're truly foundational
• 03:05to this department. You know,
• 03:07biological psychiatry was not a thing.
• 03:10I mean, I mean the idea that psychiatrists
• 03:13should be concerned about how the brain
• 03:16works outside of the manifestation
• 03:18of the workings of the brain.
• 03:21Obviously, we were concerned about
• 03:23behavior and and sort of how the brain,
• 03:25you know, manifests those behaviors.
• 03:27But the understanding of the molecular
• 03:30basis brain regions that are important
• 03:33and and producing the behaviors that
• 03:36we treat that was relatively new and
• 03:39it was just kind of transitioning.
• 03:41Even when I got here.
• 03:43And I always saw George as foundational
• 03:46to that concept of biological psychiatry
• 03:49and that we as physicians or if
• 03:52you're a PhD or you're a clinician
• 03:55that we are meant to think of the
• 03:58brain as our organ of interest.
• 04:00You know that we are meant
• 04:02to understand and be curious.
• 04:04Even if you don't study the mechanisms for
• 04:07the psychiatric disorders that we treat,
• 04:09you should have an understanding
• 04:11and appreciation for the central
• 04:13nervous system and how it leads to
• 04:16the manifestation of these illnesses.
• 04:18And you were an amazing example
• 04:20of a physician, scientist.
• 04:21And I have to say that that,
• 04:24to me meant the world.
• 04:26And so I'm going to talk about my
• 04:30career based upon some of the lessons
• 04:32that I learned from you, George.
• 04:34I hope you don't mind.
• 04:36And I think we need to give Doctor
• 04:39Henniger another round of applause.
• 04:47So again, today is my my goal is to use
• 04:50some examples from my own research over
• 04:52the years to highlight lessons that
• 04:56I've learned from George in particular.
• 04:58And I'm going to also mention some of my
• 05:00other mentors and colleagues along the way.
• 05:02And I apologize ahead of time if I miss
• 05:05anybody because there were so many
• 05:07people who greatly influenced on my work.
• 05:10But I do have to also show you
• 05:11my disclosure slide.
• 05:12So I figured this was a nice segue.
• 05:15So life lessons from Doctor H, basically.
• 05:21How do I. Yeah. Or do I do this down here?
• 05:26Ah, yes. There we go.
• 05:29Like I said, psychiatrists should
• 05:31seek to understand the brain,
• 05:35the mechanisms by which the brain
• 05:38produces the illnesses that we see,
• 05:41and then be curious about our interventions,
• 05:44not just, you know,
• 05:45do they make our patients better,
• 05:47but how do they make our patients better?
• 05:50And this practice in clinical
• 05:52research has been fundamentally
• 05:53informing my research over the years,
• 05:55as well as my decision to become
• 05:58chair of a department of Psychiatry.
• 06:00Hopefully you'll see how those are connected.
• 06:02I also say that George took me out
• 06:04to lunch one day when I was making
• 06:07this decision to leave and it was
• 06:10about don't get too comfortable.
• 06:12Sometimes you need to try new scientific,
• 06:15scientific techniques,
• 06:16go to new places,
• 06:18try new things in order to have a
• 06:21greater impact.
• 06:22And I took that advice very seriously.
• 06:25And then one other thing that George
• 06:27H and I would say,
• 06:28George A also really spoke to me about.
• 06:32I remember when I would see them
• 06:34at the elevator and I was very
• 06:36pregnant with my children because
• 06:37I had two kids while I was here.
• 06:39And you all would say very you've
• 06:42always expressed concern and support.
• 06:44But also do you have supports in your life?
• 06:46Because to be a successful academic,
• 06:49you really do need not to have only
• 06:51mentors in your professional life,
• 06:53but you need to have people in
• 06:55your personal life that can really
• 06:57support you and help you.
• 06:58Because it is,
• 07:00it is no small thing to give birth to
• 07:03another human being and then have to
• 07:05raise those human beings into adulthood.
• 07:08So I always appreciated your
• 07:10thoughts about those things.
• 07:12So I came to Yale in 1992 after
• 07:15having done of a pediatric
• 07:17internship at Bridgeport Hospital.
• 07:20And this was before I actually fell
• 07:22under the influence of Doctor H But
• 07:25basically I came to yell into psychiatry
• 07:28thinking I was going to be a child
• 07:31and adolescent psychiatrist and I was
• 07:34going to go into private practice.
• 07:37Well,
• 07:37those of you who know me and
• 07:39you've heard from John that I
• 07:40didn't either of those things.
• 07:41So what the heck happened?
• 07:44And this is where I don't know how
• 07:47many trainees are on the on the zoom
• 07:49or or your trainees in this room.
• 07:51But I think most people ever who are
• 07:54clinician researchers,
• 07:55they wind up really experiencing their
• 07:59patients and their interactions with
• 08:02their patients with a level of curiosity
• 08:05that often stimulates their research.
• 08:07So it was my third year of my
• 08:10psychiatry training and I was at
• 08:11Duh with Alice Papsen and Anjali.
• 08:13You weren't at Duh where the No.
• 08:16CNRU. Yes, that's right.
• 08:17That's where we were, Pgy twos.
• 08:19But in that third year residency,
• 08:22I was one of the only women
• 08:25residents who was at Duh at the
• 08:26time or the Mental hygiene clinic.
• 08:29What do we call it now?
• 08:30What do we call Duh now at Yale Health?
• 08:33OK, there you go.
• 08:34Well, I'm using old terminology,
• 08:37but the bottom line is that I,
• 08:40my head referred to me,
• 08:41a Yale faculty member who was only
• 08:43a couple of months postpartum,
• 08:45And I was told she had postpartum depression.
• 08:48And I was like, OK, well,
• 08:50I've never seen a case of
• 08:51postpartum depression.
• 08:52So, all right, I'll, I'll see this lady.
• 08:55And they thought, well,
• 08:55you know, you're a woman,
• 08:57she's a woman.
• 08:57Maybe you guys are bond or something.
• 08:59It'll be a good clinical little.
• 09:02Did I know that this woman was going
• 09:05to set me on a career of investigation
• 09:08about how hormones affect the brain?
• 09:10So she came, sat down in my office,
• 09:12and she was indeed very distressed.
• 09:15But I realized pretty quickly
• 09:17into the interview that what the
• 09:19true problem was is that she was
• 09:22having infanticidal ideation.
• 09:23She was avoiding her children because
• 09:25she had thoughts of killing them or
• 09:28maiming them in some way, shape or form,
• 09:30and she was horrified by these thoughts.
• 09:33And they were like these intrusive images.
• 09:35And John mentioned that I had
• 09:37an interest in OCD.
• 09:38And I was just struck.
• 09:41I was like, wow,
• 09:42this is really different.
• 09:44This woman's not psychotic because
• 09:46these are egotystonic thoughts
• 09:48and what is going on here.
• 09:50And so I started reading and
• 09:52little did everybody know,
• 09:53I was actually pregnant at the time myself.
• 09:55And so I started reading about
• 09:58what causes infanticidal ideation,
• 10:00like how common is this, you know,
• 10:02and back in the 1990s there
• 10:04was some literature on this,
• 10:06but I fell across this one hormone,
• 10:08oxytocin.
• 10:09And I was like oxytocin is important for
• 10:14milk let down and uterine contractions.
• 10:16Well,
• 10:17little did I know that it was
• 10:19actually being studied in the
• 10:21initiation of maternal behavior.
• 10:23And I thought, wow,
• 10:24this is really fascinating.
• 10:26And so basically I took the first
• 10:29truism from George that as a
• 10:32psychiatrist I started reading about
• 10:34the mechanism behind what I was seeing.
• 10:38Now again,
• 10:38I don't think we know the true
• 10:40mechanism of infanticidal ideation.
• 10:42We think that maybe oxytocin is important,
• 10:45but in any case,
• 10:46it was something that was very
• 10:48got me interested in hormones.
• 10:50It also got me interested in
• 10:52hormones because people don't
• 10:53mind talking about hormones.
• 10:54They don't like to talk about mental illness.
• 10:56But you can talk about hormones.
• 10:58And when you tell a patient that,
• 11:00hey, it's not that you're a bad
• 11:01mother or that you're going to have,
• 11:04you know, be, you know,
• 11:05horrible to your children,
• 11:07you've undergone a huge hormonal shift.
• 11:09We can't tell you the exact mechanism,
• 11:12but we can say that it is related.
• 11:14You can just see the relief
• 11:16that falls over them,
• 11:17that they don't feel like all of a sudden it
• 11:20is my fault that I'm having these feelings.
• 11:22Luckily, Jim Lachman,
• 11:23who as many of you know at Yale Child
• 11:27Studies Center was also interested
• 11:29in oxytocin and obsessionality,
• 11:31and he's an ex world expert
• 11:33in tick disorders,
• 11:34which are often comorbid with OCD symptoms.
• 11:37And he gave me a book that was
• 11:40full of papers about oxytocin and
• 11:43maternal behavior and how estradiol
• 11:46during pregnancy is important for
• 11:48expression of oxytocin receptors.
• 11:50And I just got fascinated,
• 11:52but it was way over my head because I had
• 11:54never read any kind of rodent studies,
• 11:57molecular studies,
• 11:58Prairie bowl studies, sheep studies.
• 12:00I mean it was all in these non human mammals.
• 12:04And I remember saying to Jim,
• 12:06this is really hard.
• 12:08I don't understand these techniques.
• 12:09I don't know anything about these brain
• 12:11regions that they're talking about.
• 12:13And he just said keep with it,
• 12:14Neil.
• 12:15He said reading this work will
• 12:17get easier and that was the first
• 12:19advice I had to stick with as a
• 12:22clinician without a Bhd to stick
• 12:24with reading basic science research.
• 12:26And so that was incredibly helpful.
• 12:30So basically, I did have two children.
• 12:33And George was right.
• 12:34I needed lots of support and I was
• 12:37lucky to have that support with my
• 12:39spouse as well as our families.
• 12:41And then in 2009,
• 12:42I did go to where I would have better,
• 12:45more impact. And that was something.
• 12:48George took me out to lunch and he said,
• 12:50you know, I know this is a hard decision,
• 12:52he said,
• 12:52but I think that you will do well
• 12:54at the University of Pennsylvania.
• 12:56And so I went.
• 12:57And then again,
• 12:58I took his advice and chose to become
• 13:01a chair of a department in 2018.
• 13:05And a lot of this has been because
• 13:07of my mission and vision.
• 13:09I don't know how many people
• 13:10think they have a career mission.
• 13:14I actually think it's good
• 13:15to actually lay it out.
• 13:16Yeah, lay it out, write it out.
• 13:18So my career mission has been to
• 13:21promote the centrality of the brain
• 13:23with respect to all areas of health.
• 13:26And I did that through the field
• 13:28of psycho neuron terminology,
• 13:29which is the study of hormone
• 13:31effects on the brain.
• 13:32Because, again, when you are
• 13:34talking with people about something,
• 13:36hormones have such profound effects in
• 13:39so many different fields of medicine
• 13:41that it's easy for our colleagues
• 13:43in other fields of medicine to
• 13:44relate to what we're trying to say,
• 13:46It's easier for our patients to relate to us.
• 13:49And again, I never understood why
• 13:51the brain was a stigmatized organ.
• 13:55I mean, it just the brain is the
• 13:56most fascinating organ in the body.
• 13:57I mean, why do we stigmatize it?
• 13:59So my vision has been that we would,
• 14:03through all of this work,
• 14:04that we would be able to get
• 14:06brain health for all,
• 14:07for life because people would be,
• 14:09we wouldn't be stigmatizing
• 14:11this organ system.
• 14:13And the top is the weighting of the scales.
• 14:16Are we ever going to have true parity?
• 14:18And I always feel like if we can really
• 14:21emphasize the importance of psychiatry,
• 14:23psychology,
• 14:24mental health to all health,
• 14:26that we ideally,
• 14:27and this is aspirational,
• 14:29that we will have parity before
• 14:31hopefully or for I'm George's age,
• 14:34I hope that we will have parity.
• 14:35I don't know and I hope that
• 14:38we will have reduced stigma.
• 14:39But I've done this through really
• 14:42focusing on the endocrine system
• 14:44and psycho neuron chronology.
• 14:46So John mentioned reproductive psychiatry,
• 14:48and this is what we refer to when we
• 14:51sort of a area of psychiatry where you
• 14:54are thinking about and you're applying
• 14:57the psychoneurin endocrine sort of
• 15:00knowledge that knowledge base to
• 15:03the assessment and treatment of women,
• 15:05particularly reproductive time points.
• 15:08Now, what percentage of a woman's
• 15:10life do does she spend pregnant?
• 15:13Very small, yes.
• 15:14It's about 4% if you have
• 15:16on average two children.
• 15:17And some people don't choose
• 15:18to have children at all.
• 15:19Some people have one.
• 15:21Obviously people have more,
• 15:22but it's on average about 4% of
• 15:25the entire life of the female.
• 15:27So why is,
• 15:29and I refuse to call reproductive
• 15:31psychiatry perinatal mental health?
• 15:34Because it really is about sort of
• 15:36the broad aspects of hormonal effects
• 15:39on the brain and behavior in women.
• 15:42And so I'm fascinated with
• 15:44this particular area.
• 15:46And I started out in perinatal.
• 15:48And this is Fred Naphtalon.
• 15:49Fred Naphtalon was chair of the
• 15:52department of OBGYN when I first got
• 15:55interested in perinatal depression.
• 15:57And George,
• 15:58I'm sorry,
• 15:59Fred was very interested in estrogen
• 16:02effects and the hypothalamus
• 16:04and neuronal spine and dendritic
• 16:07connections and things like that.
• 16:09And so he was fascinated that
• 16:11I was interested in estrogen
• 16:12effects on other areas of the
• 16:14brain and was very supportive.
• 16:17It is incredibly helpful when
• 16:19you're a young whippersnapper
• 16:20coming up to have not only
• 16:22your own chair be supportive
• 16:23of you, but a chair of
• 16:25another field of medicine.
• 16:26And again, I was trying to make the brain
• 16:29relevant to all areas of healthcare.
• 16:31And then David Rubenow and Peter Schmidt,
• 16:33who are at the NIMH, Peter still there.
• 16:35David went on to be chair at UNC Chapel Hill,
• 16:38my alma mater and is now
• 16:40kind of semi retired.
• 16:42But I see him quite frequently in meetings.
• 16:45And again, they were incredibly
• 16:47helpful at the time because they were
• 16:50showing that it's not about hormone
• 16:52levels when it comes to these issues,
• 16:55depression and perinatal period or menopause,
• 16:58that it has to do with how the
• 17:00brain is responding to normal
• 17:02fluctuations and gonadal steroids.
• 17:05And you can say, well,
• 17:06we know that now.
• 17:07Well, this was the 1990s,
• 17:08and people didn't know that.
• 17:10And Peter and David's work were
• 17:13incredibly influential.
• 17:14They also showed us how to manipulate
• 17:17hormone levels safely and then be able to
• 17:20study the behavior and biological effects.
• 17:22And so, again, very important.
• 17:25Kathy Wisner, Barb Perry and Lee Cohen
• 17:28were also subject matter experts.
• 17:31I actually just was on a call with
• 17:33Kathy because we're going to be on a
• 17:35panel together at ACMP and she mentioned
• 17:37that George Anderson and she are
• 17:39collaborating on research together.
• 17:40And so it's always kind of interesting
• 17:43how full circle Linda Mays who as
• 17:45you know is the head of the Child
• 17:48Study Center now was also very
• 17:50helpful in getting me thinking
• 17:52about the of women who are going
• 17:54through pregnancy and maybe having
• 17:56depression or other kinds of stress.
• 17:58And then trace of John Crystal.
• 18:01I have to say,
• 18:02the one thing I always say about
• 18:04John I always say about you is that,
• 18:07you know, those people who know
• 18:08something about everything.
• 18:10Sean knows a lot about everything.
• 18:12I mean it it would just like
• 18:14blow my mind that,
• 18:16you know,
• 18:17he's not a reproductive psychiatrist.
• 18:19He doesn't study psycho neuro endocrinology.
• 18:21And I would come out of a meeting with
• 18:23him and he would be telling me something
• 18:25about estrogen and ampereceptors or,
• 18:26you know,
• 18:27and I'd be just like,
• 18:28how in the world do you even know about this?
• 18:31You know,
• 18:32I'm supposed to be the hormone expert and
• 18:34instead people always taught me something.
• 18:36So it was really remarkable.
• 18:38Very humbling I would say.
• 18:40And then Angela Capiello,
• 18:42yes,
• 18:43I mentioned you because you started
• 18:45the menopause research when you
• 18:47were at the VA and how you were
• 18:48doing menopause at the VA is
• 18:50like was especially in the 1990s,
• 18:52was beyond me.
• 18:53But I always wanted to do the
• 18:55whole reproductive lifespan
• 18:57because the things that you can,
• 18:58if you're really interested in
• 18:59how hormones affect the brain,
• 19:01you don't need to study just one
• 19:03area of the reproductive lifespan.
• 19:05You need to be able to interrogate
• 19:08questions across the reproductive lifespan.
• 19:10And Angela is the one that got her
• 19:12menopause research up and running.
• 19:14I think you got a grant from Eli Lilly that,
• 19:17you know, really helped it to get going.
• 19:19And then Tracy Bale,
• 19:20was John mentioned again,
• 19:22really such an amazing collaborator.
• 19:25I think part of my bucket list
• 19:26is I always wanted to collaborate
• 19:28with the basic scientists
• 19:29because as a clinical researcher,
• 19:31you can only get so far when it
• 19:33comes to mechanism and it would
• 19:35drive me bananas that everything was
• 19:37associative or correlative, you know.
• 19:39And the idea that you could actually
• 19:42get in and do more basic science
• 19:44research was in this area was terrific.
• 19:47So Tracy and I have been focusing on
• 19:50preconception and intergenerational
• 19:52transmission of stress and how
• 19:54stress hormones as well as gonadal
• 19:57steroids are involved.
• 19:58So you can see I've had a lot of
• 20:01support and George was right,
• 20:03it's really important to have.
• 20:05These professional colleagues that
• 20:06kind of help you get your start and
• 20:10support you all along the way and
• 20:13basically premenstrual dysphoric
• 20:15disorder effects about 5% of misrating women,
• 20:18although more than 50% will have some
• 20:21kinds of what we call premenstrual
• 20:23symptoms or premenstrual distress.
• 20:25About 20% of women will have some
• 20:28level of perinatal depression,
• 20:30and menopause is a very
• 20:32interesting transition.
• 20:33And if all of us are who identify as female
• 20:36and have our ovaries live long enough,
• 20:39we will go through this transition.
• 20:42And I don't know if you know,
• 20:43but basically if you've never had a
• 20:48depressive episode in your entire life,
• 20:50as you go through the perimenopause,
• 20:52you're at threefold increased risk
• 20:54of having your very first episode
• 20:57in the perimenopause.
• 20:58It was a very powerful time in people's
• 21:01lives with respect to hormones,
• 21:02and that is if you go through
• 21:04a natural process.
• 21:05So I studied the whole reproductive lifespan.
• 21:08So clearly I took George's advice,
• 21:10and I never allowed myself to get too
• 21:13comfortable in any one particular area.
• 21:15I also never allowed myself to get
• 21:18too comfortable when it came to the
• 21:20techniques I used to interrogate the
• 21:22questions that I had about how these
• 21:25hormones were affecting the brain.
• 21:27I would do pharmacologic manipulations of
• 21:30proton magnetic resonance spectroscopy,
• 21:33functional imaging network analysis early on,
• 21:37and I'll talk a little bit about
• 21:39the serotonin work.
• 21:40But, you know,
• 21:41going and attending a grand rounds
• 21:42as a junior faculty member here at
• 21:45Yale and hearing somebody talk about
• 21:47the platelet serotonin transporter,
• 21:49I knew nothing about the platelet
• 21:51serotonin transporter.
• 21:52I mean,
• 21:52I had no idea that your platelets
• 21:54had a serotonin transporter.
• 21:56And then to hear in that talk that
• 21:59that transporter is identical
• 22:01to the transporter on neurons.
• 22:04And at that point,
• 22:05I was about to start a postpartum
• 22:06depression treatment study with an SSRI,
• 22:08and I wanted to allow people to breastfeed.
• 22:11And I thought,
• 22:12I can use that system to test
• 22:15whether this is going to have an
• 22:17impact on the infants.
• 22:18And I'll show you those data.
• 22:20I've done a number of
• 22:22stress Physiology tests,
• 22:23everything from threatening
• 22:24people with shock and measuring
• 22:26their psychophysiologic
• 22:27response to a threat of shock
• 22:29to the trirosocial stress test.
• 22:31And now we've moved the trirosocial
• 22:33stress test during the pandemic
• 22:35to a virtual model for the TSST.
• 22:38I've done a number of hormonal
• 22:41manipulations and again psychophysiology.
• 22:43And then came my interest in this
• 22:47concept of why do some people
• 22:49experience their very first episode of
• 22:53depression or psychosis or cognitive
• 22:55change or obsessionality in the
• 22:58context of these hormonal changes?
• 23:00And it's not just about the biology of the
• 23:03hormones and how they affect the brain,
• 23:05but we know that early life adversity,
• 23:07childhood adversity,
• 23:08changes the brain.
• 23:10And so I started wondering about
• 23:13whether the patients I was seeing
• 23:15if adverse childhood experiences set
• 23:17them up for having this risk that when
• 23:21the hormones change later in life
• 23:23that that would unmask some of the
• 23:26impact of these adverse experiences.
• 23:28So that it was like a when a perfect storm,
• 23:32if you will.
• 23:33And perhaps because I'm married to a
• 23:36child and adolescent psychiatrist who
• 23:38does trauma work with youth and adults,
• 23:40I started measuring the adverse
• 23:43childhood experiences in all of my
• 23:45patients and all of my research.
• 23:47And for those of, you know,
• 23:48the ACE questionnaire,
• 23:49it's a 10 item scale that's still being,
• 23:51you know, used in multiple states.
• 23:54It has a very strong epidemiologic sort
• 23:58of reliability and it's used in mint,
• 24:00like I said in many states as part of
• 24:03their risk assessments for individuals
• 24:05measures three types of abuse,
• 24:07neglect and house five times
• 24:10of household dysfunction.
• 24:11Again,
• 24:12this concept that you want to make
• 24:15brain health relevant to all health
• 24:18people have shown that average shotted
• 24:20experience has not only increased
• 24:22the risk of psychiatric illnesses,
• 24:24but a number of medical conditions,
• 24:26even loss of your first pregnancy.
• 24:29If you have four more Aces on your
• 24:32childhood before the age of 18,
• 24:33you're at greater risk of that
• 24:34loss of that first pregnancy.
• 24:36So there's migraines, endocrine disorders,
• 24:39obviously metabolic disorders.
• 24:41So again,
• 24:42it was a way to think about can we
• 24:44use instruments that will help other
• 24:46clinicians from other fields of
• 24:48medicine understand what we're talking about.
• 24:51And I'm sorry but the CTQ is a little
• 24:53bit too sophisticated for the internist,
• 24:56but an ACE questionnaire is very
• 24:59easy to administer.
• 25:01So I'm just going to highlight some
• 25:03of the areas of research that my my
• 25:05that I have touched over my career,
• 25:07focusing first on the perinatal.
• 25:09So I promised that I would talk about
• 25:11work all over the my career and some
• 25:14that I did here and in other institutions.
• 25:17But because I was interested
• 25:19in perinatal mental health,
• 25:20people weren't sure whether postpartum
• 25:22depression was the same as major
• 25:24depressive disorder occurring at other times.
• 25:26And so I was really interested again
• 25:29in that question of obsessionality
• 25:31and I wanted to use antidepressants
• 25:34as a way to tease apart whether
• 25:38obsessionality is more serotonergic based
• 25:41like we were seeing with OCD at the time,
• 25:44at least with respect to treatment.
• 25:47But and so I had designed this
• 25:49NARSAD grant that was really
• 25:51kind of probably not feasible.
• 25:54And and Larry Price said,
• 25:56Neil, I'm sorry if there's no
• 25:59placebo-controlled study in the
• 26:00treatment of postpartum depression.
• 26:02That's the study that you have to
• 26:04do is the antidepressant study.
• 26:06I said, but that's so boring.
• 26:08I said, you know, you know,
• 26:10can't I do the other one he gives me?
• 26:11How are you going to recruit women?
• 26:13You're going to put out advertisement
• 26:14in in the newspaper that says if you
• 26:16have thoughts of killing your child,
• 26:17come see me, you know,
• 26:19He said you're you're,
• 26:20you can measure that,
• 26:22but you're going to have to
• 26:23do the SSRI study first.
• 26:25And so we showed that Sir Trilling
• 26:27was more effective than placebo
• 26:29and the treatment of depression
• 26:31with onset according to DSM 4
• 26:34criteria for postpartum onset.
• 26:35So that's onset within
• 26:37four weeks of delivery.
• 26:38And I have had,
• 26:39I had a number of people who were
• 26:42really involved in that work and I
• 26:43have to thank Larry Price for sort of
• 26:45guiding me in the right direction.
• 26:47And that's the thing about I've,
• 26:48I've noticed with some of my mentees,
• 26:50you know,
• 26:51people have that pie in the sky
• 26:52idea for what they want to do
• 26:54as their first research study.
• 26:56Dear God, listen to your mentor.
• 26:59They know what they're talking
• 27:00about when they say no,
• 27:02you should do this study first.
• 27:04So I used to lie in bed at night and go,
• 27:07Oh my God,
• 27:08I'm letting mom's breastfeed and take SSRIs.
• 27:11And at that point we had no
• 27:13idea for sure whether SSRIs.
• 27:15We knew that they got into
• 27:17the baby at low levels.
• 27:19There were low levels in the breast
• 27:20milk and low levels in the baby,
• 27:22but I didn't know whether
• 27:24they had a biological effect.
• 27:25So our first study was with sertraline.
• 27:27You can see here that the moms had
• 27:30a dramatic drop in their platelets,
• 27:33serotonin levels because the drug
• 27:35blocked the serotonin transporter.
• 27:37And you can see that in this very
• 27:39small sample of babies that we
• 27:41had very little effect at all.
• 27:42And so then we went and did this
• 27:44in a larger sample.
• 27:45Again,
• 27:46moms have a dramatic drop in platelets,
• 27:49serotonin levels because they
• 27:51blocked the drug.
• 27:52They're getting enough of the
• 27:53drug to block the transporter.
• 27:54But our babies on average did not
• 27:57have a sufficient amount of the
• 27:59medication in their bloodstream to
• 28:01block the serotonin transporter on platelets.
• 28:03And again,
• 28:04that's a proxy for what we,
• 28:06or at least we were saying is proxy
• 28:08for what might be happening at
• 28:09the central nervous system level.
• 28:11And it turns out that Kathy Wisner
• 28:12and George are going to be doing
• 28:14this now with pregnant women
• 28:15because obviously during pregnancy,
• 28:17women get exposed the baby and the
• 28:19fetus gets exposed to more medication.
• 28:21And so there are a number of people.
• 28:23Chris McDougal, who's long left Yale,
• 28:27was very supportive to me early in
• 28:29my career as well. And and George
• 28:31and Peter Jatlow were terrific.
• 28:33And that most of you might
• 28:35remember Catherine Zarkowski,
• 28:36who basically was, I have to tell you,
• 28:39the people who work for you and and
• 28:41and partner with you on this journey,
• 28:44they're really incredibly important.
• 28:46So then I went to Yale.
• 28:48I mean, sorry,
• 28:49I went to Penn and I wanted to study sort
• 28:53of maternal early childhood adversity
• 28:55and how it might be transmitted.
• 28:57That information might be
• 28:58transmitted to the next generation.
• 29:00There's been plenty of evidence
• 29:01from like the Dutch hunger,
• 29:03winter and other sort of
• 29:05large epidemiologic studies.
• 29:06We know that maternal stress during
• 29:09pregnancy can have a negative
• 29:12impact on infant neurodevelopment,
• 29:14even sort of their stress
• 29:16response later in life.
• 29:18But our hypothesis was that women
• 29:21who've been adversely affected in
• 29:23childhood come into the pregnancy with
• 29:26a way of responding to environmental
• 29:29stressors that is likely to be unique.
• 29:33And so we wanted to study how this
• 29:35might impact fetal development and we
• 29:37wanted to do so in a sex specific fashion.
• 29:40So we basically measured on,
• 29:42borrowed from the OBGYN and maternal
• 29:46fetal medicine literature and
• 29:48research using 3D ultrasound to
• 29:50measure the fetal adrenal volume.
• 29:53We measured it over two time points.
• 29:55Eileen Wong was at OBGYN.
• 29:57Debbie Kim was a psychiatrist
• 29:59researcher at the time and Lisa Hanso
• 30:01is assistant professor at Hopkins.
• 30:03So this was a team effort,
• 30:06and again, to George's point,
• 30:08beware of getting too comfortable,
• 30:10try new techniques,
• 30:11and really think about how you
• 30:13can use technology from other
• 30:15fields of medicine to potentially
• 30:17interrogate the questions you have.
• 30:19So because I'm showing you these data,
• 30:21they must have come out positive.
• 30:23You need a really good biased
• 30:25statistician to do a lot of this work.
• 30:27Mary Sammel and her mentee,
• 30:29Rachel Johnson,
• 30:30and then Karina Duffy is a science writer.
• 30:34Now that I'm a chair of a department,
• 30:35I just don't have as much time to write.
• 30:37I have to tell you,
• 30:37I hired 2 science writers and they
• 30:40have been amazing at helping us to
• 30:42stay as productive as possible.
• 30:44So I'll walk you through this.
• 30:45This is weight adjusted fetal adrenal volume.
• 30:47You have to weight adjust because baby
• 30:50boys have larger adrenals and they're bigger.
• 30:52By and large,
• 30:53this is the female group and these
• 30:56moms either had high amount of adverse
• 30:58childhood experiences or low amounts.
• 31:01And we looked at whether that was
• 31:03there a fetal sex by maternal ace
• 31:06interaction and the answer is yes.
• 31:08And if you look at who's mostly affected,
• 31:11not the females,
• 31:12the low and highest females
• 31:13look pretty similar.
• 31:15The low and highest males
• 31:16look very different.
• 31:17The highest males have a much
• 31:19smaller weight adjusted fetal
• 31:21adrenal volume to the point that
• 31:23they look more feminized.
• 31:24And actually that's their data in
• 31:27animal studies that do talk about
• 31:29feminization of the male phenotype,
• 31:31Often they're looking at their sex behavior,
• 31:36but there are data to suggest that maternal
• 31:39stress can have this kind of impact.
• 31:42And so our question is, is OK,
• 31:44does that play out later in life?
• 31:46And we looked at six months of age,
• 31:49we took babies away from their moms
• 31:51and did a stress test where basically
• 31:53it was hold the baby's arms down,
• 31:56don't look at the baby,
• 31:58have built a bullhorn,
• 32:00make three loud noise bursts.
• 32:02So it is pretty stressful.
• 32:04And the moms would have to sit in
• 32:06another room while their babies
• 32:08were undergoing distressor.
• 32:09And with 95 infants,
• 32:11we basically showed that overall,
• 32:15there's no significant maternal
• 32:17ace bifetal baby sex interaction.
• 32:20But if you take it apart and
• 32:22you actually look at the high,
• 32:24the girls of high ace moms
• 32:25and the boys of high ace moms,
• 32:27you see this kind of dampened
• 32:30response in those boys who had
• 32:32the more small fetal adrenals.
• 32:35And so again,
• 32:37suggesting that you know what was
• 32:39going on and what you could say,
• 32:41well, wait a minute, wait a minute.
• 32:42These women had adversity.
• 32:44Were they more stressed during pregnancy?
• 32:47Luckily,
• 32:47we found that their perceived
• 32:49stress was not different between
• 32:52the high and lowest moms.
• 32:53And so we're really thinking that
• 32:56this has some relationship to what
• 32:58happened to moms earlier in life.
• 33:00And one of the ways in which
• 33:02we might have intergenerational
• 33:03transmission of stress.
• 33:05Now, you could say,
• 33:05well,
• 33:05what's the clinical significance of this?
• 33:07Well,
• 33:07the one thing about moving around
• 33:09a lot is we weren't able to
• 33:11follow those children until like
• 33:13four and five years of age.
• 33:14But there are data in the
• 33:17literature that when children
• 33:18have attention attention deficit
• 33:20disorder kinds of symptoms that they
• 33:23have a dampened stress response.
• 33:25There's also data from college students,
• 33:28whether you're male or female,
• 33:30that even in normal populations,
• 33:32that psychopathy symptoms are
• 33:34greater in those that have a
• 33:36dampened response to a stressor.
• 33:39So again,
• 33:39we need to follow this up to determine
• 33:42the sort of clinical significance.
• 33:44But again,
• 33:45as George says,
• 33:46you need to be thinking about
• 33:48mechanisms that could lead to
• 33:51risk for psychopathology and
• 33:52offspring due to these events.
• 33:55And mom also thinking about
• 33:58working with a basic scientist.
• 34:00I'm going to walk you through this.
• 34:01This is a project that I did with
• 34:04Tracy early in our career work
• 34:07together and Katie Morrison is
• 34:10now an assistant professor at
• 34:13How much more time do I have?
• 34:14I'm just trying to figure this out.
• 34:16OK, OK, OK, good. OK, great.
• 34:20So basically these moms we're
• 34:22having their babies taken away
• 34:24from them to go do that stress
• 34:26test that was just talking about
• 34:28and our research coordinator,
• 34:30we were having a whole lab meeting
• 34:32sort of basic science and our
• 34:34clinical lab was meeting and
• 34:36the the our research coordinator
• 34:39said you know we can tell which
• 34:42mothers are high A's moms versus
• 34:44low A's moms based upon
• 34:46how they act when we take their child.
• 34:50And we were like, oh,
• 34:51will tell us more about that.
• 34:52They were like, well, you know,
• 34:54the moms that are lowest did
• 34:56not have childhood diversity,
• 34:57asked a lot of questions.
• 34:59They make us promise that if the baby
• 35:01cries for a minute straight that they
• 35:03we will bring the baby back right away.
• 35:05They're much more concerned and kind
• 35:08of agitated about this separation.
• 35:11And then the other moms,
• 35:12the moms that underwent a lot of adversity,
• 35:16we're not as concerned.
• 35:17They were sort of yes,
• 35:19fine here, here's the baby.
• 35:23So, so basically we said wow,
• 35:25maybe we should start looking at the moms.
• 35:27So we basically started testing
• 35:30the mom salivary cortisol response
• 35:32to having the infant separation.
• 35:34And you know,
• 35:35so we had them come in and rest
• 35:37and relax just like what they
• 35:39were doing with the baby.
• 35:40And you can see the sort of the paradigm
• 35:43as we measure salivary cortisol.
• 35:45And what you can see here is what you
• 35:47would expect based upon the phenotype
• 35:49and the behavior is that the women
• 35:52in the lowest group had a higher
• 35:55cortisol response to the stressor of
• 35:57infant separation than the moms in
• 36:00the more adversely experienced group.
• 36:03And Katie said,
• 36:05well,
• 36:06I can model that and I wrote it.
• 36:08So she created this little box here
• 36:11where these moms are either controlled
• 36:13rat moms or they were stressed in
• 36:17the peripubertal window with a 14
• 36:20day chronic variable stress model.
• 36:23And then they separated the moms.
• 36:25After they let the moms grow
• 36:27up and have babies,
• 36:27they separated the moms from their pups.
• 36:30The moms could smell the pups.
• 36:32The moms could hear the pups,
• 36:34and I can tell you normal maternal
• 36:37mouse mom behavior is to go and scurry
• 36:39and get that pup and bring it back,
• 36:42sniff it, lick it, put it in the nest,
• 36:44make sure it's warm.
• 36:46That's normal maternal behavior.
• 36:48So we hypothesize that the moms
• 36:50with early life or peripheral
• 36:53stress wouldn't would just kind
• 36:55of give up or maybe not try as
• 36:58hard and that they would have,
• 36:59they would have this kind of
• 37:01behavior that it just showed that
• 37:02they they kind of like you said,
• 37:04they kind of gave up in that situation.
• 37:06And what we found is very similar.
• 37:09They basically travelled,
• 37:10they made the control.
• 37:12Moms kept going around and round
• 37:14and the more they kept going
• 37:16around and around the more
• 37:17they produced corticosterone.
• 37:18And then the moms that have
• 37:21peripedal stress did start to have
• 37:24they produced less corticosterone
• 37:26and did not travel around as much
• 37:29to get the pups and their overall
• 37:32corticosterone levels look very
• 37:34similar to what we saw in humans.
• 37:36Now I last time I checked moms,
• 37:40human moms don't like you to take a
• 37:42piece of their brain so that you can
• 37:45measure any kind of protein expression
• 37:48or gene changes or things like that.
• 37:51And so Tracy and them were able to do that
• 37:54in the mice and they definitely saw
• 37:56in the peripuperally stressed rat
• 37:58mothers or mice mothers that there
• 38:00were changes in up regulation and a
• 38:03number of genes and many of these
• 38:05genes were immediate early genes
• 38:07that are going to be responsible for
• 38:09various protein expression particularly
• 38:11related to the stress response and so.
• 38:14So again, it's a model that we created
• 38:17that we can now use again to continue
• 38:19to study what might be happening with
• 38:24peripuperal stress and how it impacts
• 38:27actual changes in the brain of the mom.
• 38:31All right, so moving on,
• 38:33menstrual cycle studies,
• 38:33I know it's a Tour de force when
• 38:35you when you do the whole lifespan.
• 38:40So this is early premenstrual dysphoric
• 38:43disorder research that I did hear at Yale.
• 38:47And I have to say,
• 38:48this was me actually going against
• 38:51what a mentor suggested at that time.
• 38:53Dennis Charney was still here, I know.
• 38:55So it feels like a long time ago.
• 38:57And he really thought that I should
• 39:00study estrogen effects on the brain.
• 39:02And I'm like, you know,
• 39:03well dude, that's really helpful.
• 39:04But did you read the Women's Health
• 39:06Initiative study that just came out?
• 39:08I don't think the NIH is going to be
• 39:11funding any grants to study estradiol
• 39:14and the brain for a number of years
• 39:17because we're all reeling from what
• 39:19happened with Women's Health Initiative.
• 39:21So I was very interested in the fact
• 39:23that progesterone gets converted to
• 39:25allopregnanolone and allopregnanolone
• 39:26is a very potent gastric,
• 39:28a receptor agonist.
• 39:30And at that time,
• 39:32Jerry Sanacora and a number of other people,
• 39:35Graham Mason and Doug Rothman and
• 39:38John Crystal were all involved
• 39:39in building out the Mrs.
• 39:41program here.
• 39:41And what we were able to show is that in
• 39:44women with premenstrual dysphoric disorder,
• 39:46GABA,
• 39:47concentrations varied across the
• 39:49menstrual cycle in a menstrual cycle
• 39:52dependent and diagnosis dependent manner.
• 39:54So that we saw these differences in
• 39:58how the brain of a woman with PNDD
• 40:01responds to this neurosteroid and again
• 40:06understanding mechanisms of what we do.
• 40:09So this work also supported
• 40:12research done internationally
• 40:13with Toby Backstrom's group.
• 40:15Looking at sopranolone which actually
• 40:18blocks the effects of allopregnanolone
• 40:20at the GABA A receptor and we showed
• 40:24that that it decreased the premenstrual
• 40:27sport disorder symptoms and then
• 40:30SAGE therapeutics basically started
• 40:31studying a GABA A receptor agonist,
• 40:35allopregnanolone,
• 40:35brexanolone in the treatment of
• 40:39postpartum depression and anxiety.
• 40:41We also looked at sleep and you can
• 40:44see that with a basically a 60 hour
• 40:47infusion that there's a separation from
• 40:50placebo with this GABA A receptor agonist.
• 40:53The IV version is really almost
• 40:56identical to allopregnanolone
• 40:58that's naturally occurring.
• 41:00The oral Zuranolone that is now FDA
• 41:02approved for the treatment of postpartum
• 41:04depression and is an oral preparation.
• 41:07It just has a little modification
• 41:09so that it's bioavailable.
• 41:10But again potent GABA A receptor agonist.
• 41:14And it appears that again that the
• 41:16GABA A receptor as obviously seems to
• 41:19be really important in some of these
• 41:22reproductive mood disorders having the.
• 41:24So when I first started research,
• 41:27PMTD was actually not in the DSM 5 or
• 41:29of the DSM 5 wasn't even developed,
• 41:32but it wasn't in the DSM.
• 41:33It was a mood disorder,
• 41:35not otherwise specified.
• 41:36But because of some of this research,
• 41:39mine and that of others,
• 41:41we were able to really get together
• 41:43as a team and encourage the DSM 5
• 41:47version to include PMDD as a diagnosis.
• 41:51OK,
• 41:51that was a quick run through menstrual cycle.
• 41:54Let's go to menopause. All right.
• 41:57I want to make it very clear that the
• 42:00experience in menopause is not a,
• 42:02you know, one-size-fits-all.
• 42:04It's really depends a lot on
• 42:06whether you go
• 42:08through a natural menopause.
• 42:09It depends on whether you
• 42:11go through it prematurely.
• 42:12I've, you know, worked with women who
• 42:14were on oral contraceptives, age of 28.
• 42:17I'm going to go off my oral contraceptives
• 42:19because I want to have a baby.
• 42:21And guess what?
• 42:22They have hot flashes and
• 42:23night sweats and they're post
• 42:25menopausal and they didn't know it.
• 42:27That's obviously not what
• 42:28people expect at the age of 28.
• 42:31I also work with a lot of women
• 42:33who undergo inferectomy for cancer
• 42:36risk reduction and it's it's really
• 42:39remarkable the differences between
• 42:40what they go through and somebody's
• 42:43going through a natural menopause.
• 42:44So I tend to think impairing
• 42:46menopause is the perfect storm.
• 42:47You have this fluctuating mass of
• 42:50fluctuations in estradiol, progesterone,
• 42:52forget about it, alopregnanolone,
• 42:54who knows what's going on,
• 42:56But eventually you have a dearth of
• 42:59any kind of this hormonal production.
• 43:02I've often seen childhood adversity and
• 43:05some of my research put women at risk
• 43:08for mood disorders during this time.
• 43:11We've also seen that it puts women
• 43:12at risk for cognitive issues and
• 43:14that I don't have time to get into
• 43:17current life stress and inflammation.
• 43:18But we these are some other areas that
• 43:21we're investigating and have seen some
• 43:23relevance to what we're looking at.
• 43:25So this is just like sort of where
• 43:28primary places that estradiol exerts
• 43:30its effects in the human brain.
• 43:33We know that cognition,
• 43:35mood regulation,
• 43:36stress perception and reward processing,
• 43:39estradiol impacts all of those brain regions.
• 43:42I was particularly interested in the area
• 43:45of the brain for working memory because,
• 43:48again, patients are our muses.
• 43:50And when you sit down with women
• 43:52who come to you with complaints
• 43:53that my memory is not very good,
• 43:55am I going to have dementia?
• 43:57Because we know that women are
• 43:59at increased risk of Alzheimer's
• 44:01disease compared to men or males,
• 44:03and they're worried about that.
• 44:05And you're like,
• 44:06this doesn't sound like dementia.
• 44:08This sounds like ADHD to me.
• 44:10And so while I was still at Yale,
• 44:12I started working with Tom Brown who had
• 44:14the Brown Attention Deficit Disorder scale.
• 44:17He saw a lot of patients and he goes,
• 44:18yeah, I do keep getting these
• 44:20middle-aged women coming in and telling
• 44:22me that these things are going on.
• 44:25And he created the subscale,
• 44:27and I really love it because it addresses
• 44:29organization and activating for work.
• 44:31So that that momentum that it takes
• 44:33to do the things that you need to do,
• 44:36sustaining the tension and concentration,
• 44:39alertness,
• 44:40effort and processing speed,
• 44:42managing affective interference
• 44:44and working memory.
• 44:46So my doctoral student,
• 44:47who then became a postdoc
• 44:49of Ted sutterweight,
• 44:51Sheila Chen Moogan and I worked with
• 44:54Susan Domchek to recruit a group
• 44:56of women from the bachelor center
• 44:58bras clinical care and research.
• 45:00And they completed the not only the
• 45:03Adverse Childhood Experiences Questionnaire,
• 45:05but we got assessment of their mood.
• 45:08They could have major depressive illness.
• 45:10They could be on medications.
• 45:11It was a large sample.
• 45:12So we kind of allowed all comers
• 45:15to come in and in that sample 202,
• 45:18we're in our highest group.
• 45:19And we measure not only their self
• 45:21report of executive functioning,
• 45:23but we also measured 2 aspects of
• 45:26executive functioning in an objective way,
• 45:29working memory using the N back and
• 45:32then a continuous performance task,
• 45:34which is really boring, you know.
• 45:36So you want to test people under
• 45:38conditions that are really hard,
• 45:40and you want to test people under
• 45:42conditions where there's not going to be
• 45:43a lot of salience to what they're doing.
• 45:45And it can be kind of boring because
• 45:47that's when our attention wants to go off.
• 45:50And we looked at the ACE effect.
• 45:52And if you look over here for
• 45:53the total score,
• 45:54the green bars are the highest group.
• 45:56And you can see that across
• 45:58not only the whole measure,
• 45:59but across every domain except for
• 46:02managing affective interference,
• 46:04that the highest group reported
• 46:06more symptoms,
• 46:07more problems and those particular
• 46:10areas of executive functioning.
• 46:12And then when we looked at objectively,
• 46:14we saw that they performed worse
• 46:17if they were in the highest group.
• 46:19So they had.
• 46:19And again, we control for everything BMI,
• 46:21you know, education,
• 46:22all of the kind of things that you
• 46:25should control for in a study like this,
• 46:27race, ethnicity.
• 46:29And so again,
• 46:30we can see not only subjectively
• 46:32they were having more complaints,
• 46:34but we also saw that on these two
• 46:37tests that they perform worse.
• 46:39Now you can say, well that doesn't.
• 46:41So what?
• 46:42I mean, you measure depression and anxiety.
• 46:45So maybe Aces are contributing to
• 46:48depression and anxiety and that depression,
• 46:51anxiety is having a negative effect
• 46:53on these cognitive measures.
• 46:55And so we did a mediation analysis.
• 46:57And yes,
• 46:58it is true that depression and
• 47:01anxiety mediated A portion of the
• 47:03ACE effect on self report as well
• 47:06as the continuous performance test,
• 47:08but it did not mediate relationship
• 47:11with the working memory.
• 47:14So we also had funding for the
• 47:17National Cancer Institute to study.
• 47:19Well, this was during the pandemic.
• 47:22So during the pandemic,
• 47:24we focused on doing an online
• 47:26study because we wanted to see how
• 47:28many women that are not treatment
• 47:31seeking are developing these kinds
• 47:33of executive functioning issues
• 47:34and how much does mood play a role.
• 47:36And you can see here this
• 47:39premenopause baseline.
• 47:40You can see the perimenopause has worse
• 47:42complaints of executive functioning.
• 47:44These are attenuated a little bit once
• 47:46people are in the natural menopause.
• 47:48But you can see here again,
• 47:50the surgical menopausal group
• 47:52is having the greatest problems
• 47:54with executive functioning.
• 47:56And if you control for depression,
• 47:58ADHD diagnosis, sleep problems,
• 48:00you see the same pattern,
• 48:03although it's somewhat dampened.
• 48:05So what this tells me is that again,
• 48:08menopause has an impact and that
• 48:10surgically menopausal women are going
• 48:12to have a more sustained worsening
• 48:15of executive functioning on average,
• 48:17but that if we can manage depression,
• 48:19anxiety,
• 48:20sleep problems,
• 48:21we can dampen those effects.
• 48:24And in women who've undergone uferectomy
• 48:26that are complaining of new onset
• 48:29executive functioning difficulties,
• 48:31we've also used Lisdexamphetamine,
• 48:33which is a psychostimulant Vyvanse and
• 48:36shown that these women do have a better
• 48:40response than they do with placebo.
• 48:42And it basically this was a crossover
• 48:44study with a good sample size and we
• 48:46saw this effect within three weeks of
• 48:49treating them with a psychostimulant
• 48:50and they had very few adverse
• 48:53symptoms or dropouts in the study.
• 48:56So it's again psychostimulants can sometimes
• 48:59be a stigmatized medication so to speak,
• 49:02but we should be feeling free to use
• 49:05them in our folks if they need them.
• 49:08This I'm going to run through really
• 49:10quickly because I think that we're
• 49:12going to probably about 5 minutes.
• 49:15Again, we were very interested in the impact
• 49:18of of ACE history actually on the brain.
• 49:22So we recruited a group of
• 49:24naturally menopausal women.
• 49:25They were within 10 years of their
• 49:28final menstrual period and they
• 49:30underwent brain imaging as well as,
• 49:32yes, tryptophan depletion.
• 49:35For those of you that were here in the 1990s,
• 49:38you know that we tryptophan
• 49:40depleted many people.
• 49:41Well,
• 49:42this was a study that I did at
• 49:44Penn with tryptophan depletion.
• 49:45Again a number of colleagues that you
• 49:47can see here and this is the paradigm,
• 49:50women came in hypogonadal,
• 49:52meaning they were postmenopausal
• 49:54low estrogen.
• 49:55They either got an active tryptophan
• 49:57depletion or a sham depletion and
• 49:59then underwent brain imaging using
• 50:01the N back task and then they crossed
• 50:04over a week later and came back.
• 50:05So it was counterbalanced.
• 50:07So that's phase one.
• 50:08Everybody's hypogonadal,
• 50:09they go through a sham depletion
• 50:11and an active depletion.
• 50:13And again,
• 50:13the reason to do this is that we're very
• 50:16curious about if the estrogen effects,
• 50:20but also the estrogen serotonin interactions,
• 50:23they all got either estrogen or placebo.
• 50:25So they were randomized 8 weeks of estrogen,
• 50:278 weeks of placebo and came back for
• 50:30phase two where they again underwent
• 50:33the active and sham depletion.
• 50:35So this is the working memory task we used.
• 50:38So basically,
• 50:38this is the hardest version.
• 50:40You're lying in the magnet and you see this
• 50:42image and you have to press the button when
• 50:45the image you're seeing there is the same
• 50:47image that you saw three times before.
• 50:49So it's not easy and it comes
• 50:51at you quick and furious.
• 50:53People do better than they
• 50:54think they do by and large.
• 50:56But we know that this particular
• 50:57area of the brain,
• 50:58the DLPFC and middle frontal gyrus,
• 51:01are very important or robustly
• 51:03activated with this task.
• 51:05And So what we did is we took
• 51:07then a whole brain analysis and we
• 51:09looked at the effects of tryptophan
• 51:11depletion and how it might differ
• 51:13on the whole brain analysis,
• 51:15whether the woman has high levels
• 51:18aces in her childhood or low levels.
• 51:20And what we found is that this is a
• 51:23brain region where we saw the biggest
• 51:25contrast that held up to multiple compare,
• 51:28you know, comparisons and
• 51:29analysis that you have to do.
• 51:31So we took the BOLD signal from
• 51:34this particular brain region and
• 51:36I'm going to go through really
• 51:38quickly here and show you down here.
• 51:40So this is the lowest group
• 51:41and this is the highest group.
• 51:43I hope that you can look at
• 51:44those two even if you don't know
• 51:46which is the act of depletion,
• 51:47which is the sham depletion that
• 51:48they don't look the same, right?
• 51:50They don't.
• 51:52The depletion did something very
• 51:54different in the highest versus low,
• 51:56but there were baseline differences
• 51:58even during the sham condition,
• 52:00the women in the highest group had
• 52:03to activate the brain region more
• 52:05in order to get the to get the the
• 52:07the to do get correct number of
• 52:11choices and so they had to work
• 52:13harder if you want to say that.
• 52:14All right,
• 52:15so then they go through the randomization.
• 52:17This is phase two.
• 52:18So this is what I just showed you.
• 52:19Pre randomization, again low estrogen,
• 52:22the highest women had to activate
• 52:25far more at baseline.
• 52:27And then when they got tryptophan depleted,
• 52:28they did just the opposite to
• 52:30what the lowest women did.
• 52:32Placebo, There's not a significant
• 52:34difference between here and here.
• 52:37But then let's just focus on what
• 52:39happens when they got estradiol.
• 52:41Do they look the same now?
• 52:43It is remarkable.
• 52:44I mean, it's almost like the
• 52:46estradiol and the highest women.
• 52:48So the estradiol and the lowest
• 52:50women didn't do very much so,
• 52:52but in the highest women,
• 52:54they performed different,
• 52:55the brain acted different
• 52:57and they had to work harder,
• 52:58so to speak,
• 52:59you know,
• 52:59activate more area,
• 53:01more of the prefrontal cortex and
• 53:04then basically giving them estrogen,
• 53:06help them to look like they
• 53:08didn't have aces anymore.
• 53:09So to me,
• 53:10that's suggesting that if we want
• 53:11to say is there a brain reason,
• 53:13reason to give women estradiol,
• 53:17perhaps it's because they
• 53:18have childhood diversity.
• 53:19Again,
• 53:20I think it's going to be a long time before
• 53:22our OBGYN colleagues will agree to this,
• 53:24but that's OK All right,
• 53:27So in summary,
• 53:27I just took you through a very long lifespan.
• 53:31The lifespan of the female and
• 53:34doctor HS truisms have played a
• 53:36critical role in this research,
• 53:38encouraging us to focus on mechanism.
• 53:40Don't get too comfortable with
• 53:42one particular area of research.
• 53:44Psycho neuroendocrinology is pretty broad
• 53:46range of research topics and methods.
• 53:49And then collaborate with basic
• 53:50scientists that can help you become
• 53:53more molecular in your focus.
• 53:55And then you should go where
• 53:57you have the greatest impact.
• 53:58Move to Penn and then to the
• 54:00University of Colorado predominantly
• 54:02to pursue my career mission,
• 54:05promote the centrality of the brain
• 54:07with respect to all areas of health,
• 54:09understanding hormonal and
• 54:11not just gonadal steroid,
• 54:13but stress hormone impact
• 54:14on the brain and function.
• 54:16And I really believe that this
• 54:18helps us to bridge the brain and
• 54:20other organ systems and ideally
• 54:21I'd like to think that this
• 54:23helps to reduce stigma.
• 54:24So, and I want to thank you Doctor Henniger,
• 54:27for this wonderful career that
• 54:30and I'll let you did to sort of
• 54:33really support me along the way.
• 54:34Thank you very much and.