Yale Psychiatry Grand Rounds: October 20, 2023

October 20, 2023

Information

George Heninger, MD Annual Lecture: "Translational Neuroscience in Reproductive Psychiatry: Lessons Learned from George Heninger, MD"

Speaker: Neill Epperson, MD, Robert Freedman Endowed Professor and Chair, Department of Psychiatry, University of Colorado School of Medicine-Anschutz Medical Campus

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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.