Yale Psychiatry Grand Rounds: September 30, 2022

Transcript

• 00:00Honor the life.
• 00:04To honor the life and work
• 00:05of Doctor Steven Southwick,
• 00:07my name is Robert Peter Zack.
• 00:08I'm one of Steves mentees,
• 00:10a professor in the department,
• 00:11and I've had the privilege of knowing and
• 00:14working with Steve for 15 wonderful years.
• 00:16Steve was more than a mentor to me.
• 00:18He was the 2nd father,
• 00:19one of my biggest supporters,
• 00:21and dearest friend and colleague.
• 00:23We are joined today by several
• 00:25of Steve's family members,
• 00:26including his wife Bernadette,
• 00:27as well as many of his friends,
• 00:29colleagues, and mentees.
• 00:30I'm going to begin today with a
• 00:32brief review of Steve's life and.
• 00:34Academic work and we will then
• 00:36have three separate presentations
• 00:38from doctors Crystal Charney,
• 00:39Montalbo, Ortiz, and me.
• 00:45Steve was born on April 24th,
• 00:481948 in Boston, MA.
• 00:49Here's a picture of Steve
• 00:51as a child sitting on his
• 00:52father's lap with his family.
• 00:56Steve's family showed a clear
• 00:58commitment to service and education.
• 00:59His father, doctor Wayne Southwick,
• 01:01was the founding chair of orthopedic
• 01:04surgery at Yale and a gifted sculptor.
• 01:06His mother, Jesse Ann Southwick,
• 01:08helped organize the Fellowship,
• 01:10Place a supportive community to help
• 01:12promote mental health in New Haven,
• 01:14and actively supported the Connecticut
• 01:16Hospice and Old Lyme Art Academy.
• 01:19Steve, Sister Marsha was a creative
• 01:21writing professor, now retired,
• 01:22and his brother Frederick is a highly
• 01:25accomplished infectious disease.
• 01:26Position and professor at
• 01:28the University of Florida.
• 01:31During the Vietnam War,
• 01:32Steve served in the US Army
• 01:34and was stationed in Germany.
• 01:35After his service,
• 01:36he attended Yale,
• 01:37graduating in 1974 with a
• 01:40degree in psychology.
• 01:41Here's a picture of him playing football.
• 01:43He liked to joke that this was one of his
• 01:46earliest experiments and stress inoculation.
• 01:49He then attended medical school at
• 01:51George Washington University and
• 01:53completed his psychiatry residency at Yale.
• 01:56Steve then remained at
• 01:58Yale throughout his career,
• 01:59where he forged rich collaborations
• 02:01and decades long friendships.
• 02:03He was beloved by his friends and
• 02:05colleagues and mentored hundreds
• 02:06of trainees at all levels.
• 02:08Here are some pictures from Steve's
• 02:10inauguration as the Greenberg endowed
• 02:12professor giving a keynote address,
• 02:14and with his longtime colleague Andy Morgan.
• 02:19Here's one of my favorite pictures of Steve.
• 02:21I remember how proud he was to
• 02:23have organized his desk thanks
• 02:25to this large green garbage bin.
• 02:28And here is Stephen Action,
• 02:29reading and revising papers four at a time.
• 02:33I think the one with the most
• 02:35extensive editing is mine.
• 02:38On a more personal note,
• 02:39Steve was a loving family man.
• 02:41Here are some pictures
• 02:42of him with Bernadette,
• 02:43his daughter and son-in-law,
• 02:45with his grandchildren,
• 02:47and from his wedding day.
• 02:51Our dear colleague and friend
• 02:53Steve passed away on April 20th,
• 02:552022 at the age of 73,
• 02:58just four days shy of his 74th birthday,
• 03:01after a courageous 5 year battle
• 03:03with metastatic prostate cancer.
• 03:05At the time of his death,
• 03:07Steve was the Glen H Greenberg
• 03:09professor emeritus of psychiatry,
• 03:10PTSD and resilience at Yale and
• 03:13Medical Director emeritus of the
• 03:15Clinical Neuroscience division of
• 03:17the VA National Center for PTSD.
• 03:19There is no question as to Steve's impact.
• 03:22On the field of psychiatry,
• 03:24with over 400 published papers,
• 03:26books and chapters focused on
• 03:28understanding PTSD and resilience,
• 03:30he has received numerous awards
• 03:32for his research, teaching,
• 03:34mentorship and clinical work.
• 03:36His published work has been
• 03:38cited more than 62,000 times,
• 03:39and he has been recognized as among the
• 03:42most highly cited researchers by Thompson,
• 03:45ISIL.
• 03:45But more than that,
• 03:47Steve practiced what he preached
• 03:49and embodied and lived the
• 03:51resilience factors that he studied
• 03:53and that we will hear about today.
• 03:55Steve came into this world and
• 03:57changed our lives for the better.
• 04:00His kindness, compassion,
• 04:01love,
• 04:01and sense of humor touched all
• 04:03of us who knew him.
• 04:05In her eulogy and prayer of Thanksgiving
• 04:07at Steve's memorial service,
• 04:09the Reverend Shelley Emery
• 04:10Holness described him as a man
• 04:12of great faith and integrity who
• 04:14felt compelled to help veterans,
• 04:16especially Vietnam Veterans who
• 04:18did not return home to accolades
• 04:21of thanks for their service.
• 04:23She further noted that Steve brought
• 04:25light to the cracks in those he served.
• 04:30The presentations you will hear today,
• 04:32we will review the incredible
• 04:34breadth and depth of Steve's work.
• 04:35I would like to now introduce our
• 04:37first presenter, Doctor John Crystal.
• 04:39John, of course,
• 04:40does not need an introduction to this group,
• 04:43but I'll say that he has known,
• 04:44trained with and worked with
• 04:46Steve for nearly 40 years,
• 04:47beginning from being a resident under
• 04:50Steve to eventually becoming his boss.
• 04:52Together they have done some of
• 04:54the earliest and most pioneering
• 04:56studies on the neurobiology and
• 04:58pharmacological treatment of PTSD,
• 05:00which we will hear about today.
• 05:02John?
• 05:04Thank you, rob. And and it's wonderful
• 05:07to be with all of you to celebrate the
• 05:10life and career of Steve Southwick.
• 05:13I think we can all say that.
• 05:16That, Steve, was one of the most
• 05:19unique people that we ever met
• 05:22and someone who we anyone who
• 05:24who came into contact with them.
• 05:27Was better off for that contact,
• 05:29I I also wanted to acknowledge.
• 05:32That special to have Bernadette here
• 05:35with us and and to be presenting
• 05:38with Rob and Dennis is, is great.
• 05:40It's great to have the the
• 05:43old team back together.
• 05:45So I'm going to be talking about
• 05:47about the start of Steve's kind
• 05:50of neurobiology work and how his.
• 05:54Um, contributions to PTSD research really
• 05:59helped to begin the modern neuroscience
• 06:01of post traumatic stress disorder.
• 06:04You saw pictures already
• 06:06of Steve's early life.
• 06:07This is a picture that Bernadette
• 06:10shared from Steve's days at at Hopkins,
• 06:13the local high school.
• 06:15Here's a picture from the 1980s.
• 06:18Where, uh, where, uh,
• 06:20the very beginning of the work
• 06:23on PTSD was taking place.
• 06:25And here is Rachel Yehuda,
• 06:28who was with us at the VA Earl Giller,
• 06:30a former chief of psychiatry at the
• 06:33VA and and and Steve in the 1980s.
• 06:36Here we are, Steve, Dennis and I in Moscow.
• 06:41And this was late, Gorbachev.
• 06:46The uh,
• 06:47uh.
• 06:47This was after the terrible
• 06:50crisis in Chernobyl and also the
• 06:53Soviet invasion of Afghanistan.
• 06:56And this was one of the more
• 07:00extraordinary adventures that the
• 07:02three of us had the good fortune
• 07:04to share to to to be talking about
• 07:08PTSD with people in that context.
• 07:11So.
• 07:12What was PTSD like before Steve Southwick?
• 07:17Here's a review paper from the
• 07:20early 1980s which summarized the
• 07:23state-of-the-art at the time.
• 07:25Which was that there was evidence
• 07:29of hyperactivity of the autonomic,
• 07:32or sympathetic nervous system that was
• 07:35increased by exposure to trauma reminders.
• 07:39And that there were elevated 24
• 07:43hour urine levels of norepinephrine.
• 07:47In people with PTSD,
• 07:49and that this relative increase in our
• 07:52predefine was greater than the levels of
• 07:56cortisol that one might have expected,
• 07:59and that animal models suggested this
• 08:02regulation and conditioned activation
• 08:04of the noradrenergic system based
• 08:06in the locusts release in the brain
• 08:09and providing noradrenergic input
• 08:12to the higher centers of the brain.
• 08:16So there had been some general ideas.
• 08:20About that PTSD had a neurobiology,
• 08:26but actually at that time the idea
• 08:29that there was a biological component
• 08:32to PTSD was still hotly debated,
• 08:35and in fact some people felt that
• 08:38PTSD shouldn't even be studied
• 08:40from a biological perspective,
• 08:42given the the interpersonal nature of a
• 08:47lot of the trauma that people experience.
• 08:51But how could we study the
• 08:54neurobiology of PTSD?
• 08:56The the tool that we initially stumbled
• 08:59on came from the work of of Dennis and
• 09:03his collaborators in the early 1980s,
• 09:06Alan Breyer,
• 09:08George Henninger.
• 09:09Which was the idea to probe.
• 09:13To probe the integrity of a particular
• 09:17neural signaling mechanism by giving a drug
• 09:20that would stimulate a specific target
• 09:22in the brain and then measuring outcomes,
• 09:25behavioral and biological,
• 09:27that could end index or provide a measure
• 09:30of the sensitivity of that signaling
• 09:33mechanism in the brain and body.
• 09:36So for the case of trying to
• 09:38understand noradrenergic systems that
• 09:41had been implicated by the animal
• 09:44models and sympathetic arousal.
• 09:46Doctor Charney developed a technique
• 09:48of giving a drug that blocked feedback
• 09:51inhibition via blocking the Alfred
• 09:54to noradrenergic receptor and then
• 09:57measuring the behavioral responses.
• 09:59And you can see that this approach
• 10:02produces very little response in terms
• 10:05of changes in anxiety and healthy
• 10:08subjects and of limited span of.
• 10:11Increases in a metabolite of
• 10:13neuropil nepheline called MHB G,
• 10:16which can be measured in the blood.
• 10:19But when he gave the same drug
• 10:21to patients with panic disorder,
• 10:22he got much bigger increases in anxiety
• 10:26and much bigger increases in MHG,
• 10:29in other words,
• 10:31indicative of a greater norepinephrine
• 10:34response associated with the
• 10:37symptoms of of panic disorder.
• 10:39This was a sign that the
• 10:41feedback inhibition mechanism,
• 10:42the A2 adrenergic receptor,
• 10:46was.
• 10:47Functioning in a deficient way
• 10:49in panic disorder,
• 10:50and this was in some ways one of the
• 10:53first specific mechanism a signaling
• 10:56mechanisms identified as contributing
• 10:58to the biology of panic disorder.
• 11:01When Steve and I just to
• 11:04illustrate this idea graphically,
• 11:07normally when the norepinephrine
• 11:08neurons are activated,
• 11:10you get a little bit of norepinephrine
• 11:12release and and that's because
• 11:15when norepinephrine is released
• 11:16by neighboring neurons,
• 11:18it shuts shuts down the norepinephrine
• 11:21neurons via the A2 adrenergic receptor.
• 11:24In panic disorder,
• 11:26when you get the same degree of
• 11:29neural activation because the A2
• 11:31receptors are less functional,
• 11:33you get much bigger norepinephrine releases.
• 11:37And one consequence which I'm going
• 11:40to come back to in a little bit is a
• 11:43down regulation of the postsynaptic
• 11:46response to norepinephrine overtime
• 11:48via the beta adrenergic receptor.
• 11:52So.
• 11:52Steve and Dennis and I conducted
• 11:56this first study trying to identify
• 11:59a neural signaling mechanism in
• 12:02post traumatic stress disorder.
• 12:05And we did this by giving yohimbine.
• 12:08And showing that there was,
• 12:10for the first time,
• 12:12an increase in PTSD symptoms severity
• 12:16that could be attributed to a
• 12:19manipulation of a specific neural mechanism.
• 12:22Also,
• 12:22that this increase in PTSD symptoms was
• 12:27associated with a greater increase in in MHG,
• 12:31meaning a greater activation
• 12:34of norepinephrine,
• 12:35meaning that this mechanism,
• 12:37the A2 noradrenergic inhibition
• 12:40of norepinephrine neurons,
• 12:42was deficient in PTSD.
• 12:46This work was followed by a study led
• 12:48by Doug Bremner, who was with the
• 12:51National Center for PTSD at the time.
• 12:54And he gave he did the same study,
• 12:57giving yohimbine to healthy
• 12:59people and people with PTSD.
• 13:03And measuring brain activity,
• 13:05this time using positron emission
• 13:08tomography to measure cortical metabolism.
• 13:12And what Doug showed was that when
• 13:14you give yohimbine to people,
• 13:16you activate prefrontal cortical metabolism.
• 13:20However, when you give.
• 13:23Yohimbine to people with PTSD,
• 13:26you don't produce the same degree
• 13:29of prefrontal cortical metabolism,
• 13:30and this was a sign that
• 13:33the postsynaptic response.
• 13:35In other words,
• 13:36the response to norepinephrine
• 13:37by neurons by cells in the
• 13:40prefrontal cortex was also blunted.
• 13:42So both the presynaptic inhibition
• 13:44feedback inhibition of the
• 13:47norepinephrine neurons was deficient,
• 13:49as well as the postsynaptic
• 13:51reactivity to norepinephrine.
• 13:55One of the most striking things
• 13:58about this study that Steve LED.
• 14:01Was the experience that people
• 14:04participating in this study.
• 14:06Had when they received yohimbine.
• 14:09And so Steve and I would would
• 14:13sit with the patients and record
• 14:16aspects of of the sessions and
• 14:19and and and what we saw was that.
• 14:23For the first time that we could bring on
• 14:29symptoms of dissociation and flashbacks
• 14:32and intrusive memories in people
• 14:34with post traumatic stress disorder.
• 14:37In this case,
• 14:38a veteran with PTSD who is getting yohimbine,
• 14:41who then has a flashback to a scene
• 14:44from his combat exposure where he not
• 14:46only sees a helicopter going down,
• 14:49he can hear it and he can smell it.
• 14:52And this was really a powerful message
• 14:56about the link between the biology
• 14:59of PTSD and the symptoms of PTSD and
• 15:04help to stimulate further research.
• 15:06Trying to understand the the neural
• 15:10contributions to the symptoms of PTSD.
• 15:12This work also led to the testing
• 15:14of a number of treatments for PTSD,
• 15:17including PRAZOSIN.
• 15:20And desipramine,
• 15:21which is a study here led by Esmini Petrakis,
• 15:25which was one of the first to show
• 15:27evidence of efficacy of desipramine as a
• 15:30treatment for post traumatic stress disorder.
• 15:33So.
• 15:35That is really the the,
• 15:37the kind of the first generation
• 15:40of research that was done
• 15:42here and and as you can see.
• 15:47There was a we were.
• 15:49Really striking new ground.
• 15:53Steve was leading studies that that
• 15:57really put PTSD on the map from the
• 16:01perspective of neurobiological research.
• 16:03Um, and So what I thought I
• 16:06would do in the in the next two
• 16:09minutes or so is just highlight.
• 16:12How far some of this work has come in the
• 16:14effort to understand the biology of PTSD?
• 16:17First in the effort to map circuits
• 16:21involved in PTSD and and to link
• 16:24them potentially to deep brain or
• 16:27other innovative treatments for PTSD.
• 16:31So in this regard,
• 16:33I want to highlight the work of Al
• 16:36Qaeda in the Department of Psychiatry
• 16:37and Yemi Dami saw in the Department
• 16:40of Neurosurgery who are conducting
• 16:41a study involving Intracortical
• 16:44recording of brain activity in
• 16:47epilepsy patients prior to epilepsy
• 16:50surgery in order to map the circuitry
• 16:54of fear and fear regulation.
• 16:56And so in this work,
• 16:59people are playing a video game that
• 17:02little bit like the game asteroids,
• 17:05where they're sometimes evading.
• 17:08Crashing into the asteroid and
• 17:11sometimes they crash and so we can look
• 17:14at the neural activity as they are
• 17:17actively avoiding crashing but also
• 17:19anticipating a crash and and where
• 17:22we can look at that fear response.
• 17:28One of the elegant parts of this
• 17:30work is that AL is an expert in
• 17:34computational modeling, and so we can.
• 17:38Very elegantly mapped the pattern of
• 17:41behavior across trials as we study
• 17:44the acquisition of the anticipatory
• 17:47fear of crashing during these trials.
• 17:53And because we're recording from
• 17:55electrodes that are placed in the brain
• 17:58as part of the neurosurgical evaluation,
• 18:01we can get a unique window into
• 18:04the neural circuitry and neural
• 18:06mechanisms of fear and fear regulation,
• 18:09which we can then use to inform the
• 18:12development of brain stimulation treatments
• 18:15aimed at helping people to regulate
• 18:19these circuits in a more adaptive way.
• 18:22A second new area of exploration
• 18:25has to do with molecular biology.
• 18:28We've long known,
• 18:29and this is a quote from Linus Pauling,
• 18:31the Nobel laureate from 1952.
• 18:35That someday we'll have a a understand
• 18:38the molecular basis of our diseases,
• 18:41and then in the process discover why certain
• 18:45molecules are effective as treatments.
• 18:48And the identification of molecular
• 18:50targets in PTSD research in some ways
• 18:54begins with a pet study conducted or
• 18:57spec study conducted here at Yale,
• 19:00also led by Doug Bremner,
• 19:02in which Steve and Dennis were collaborators,
• 19:06which identified a change in in
• 19:08the binding of a particular ligand
• 19:12in Vivo 2 receptors in the brain.
• 19:14This is a GABA a receptor.
• 19:18Now for the first time we have the
• 19:21ability of studying in a deep way in
• 19:24postmortem tissue the actual molecular
• 19:27signatures of post traumatic stress disorder,
• 19:30the actual molecular pathology of the
• 19:33disorder and the first well powered
• 19:37study led by the late Ron Duman and
• 19:40and and conducted by Matt Girgenti,
• 19:43a faculty member now in our
• 19:46department provided some of the 1st.
• 19:48And profoundly interesting molecular
• 19:50insights into the biology of PTSD.
• 19:54Where we can look across the entire genome
• 19:57and look at the levels of expression
• 20:00of the individual genes and identify
• 20:03many changes associated with PTSD.
• 20:06I'm just going to mention 21A change in a
• 20:12molecules expressed by Gabba nerve cells.
• 20:15In other words,
• 20:16a signature related to the earlier
• 20:19pet study whose biology we couldn't
• 20:22possibly understand in detail.
• 20:24At that time,
• 20:25and another interesting and exciting
• 20:28area was pathology in a group
• 20:31of cells called microglia that
• 20:33regulate inflammation in the brain.
• 20:36Unlike depression,
• 20:37which is associated with immunologic
• 20:40activation,
• 20:41PTSD seems to be associated
• 20:44with suppression of the of the
• 20:47genes associated with microglia.
• 20:50Another profound insight to
• 20:52emerge from this work,
• 20:53and this is the last neurobiological
• 20:56finding that I'll share,
• 20:58is that PTSD and major depression?
• 21:01Do have limited,
• 21:03very limited areas of
• 21:05overlap in their biology.
• 21:08But.
• 21:08They are profoundly different or
• 21:11disorders from the perspective
• 21:14of their molecular fingerprints.
• 21:17This is really a profound idea for
• 21:19us as all of the treatments that
• 21:22we have for PTSD were developed
• 21:24initially as treatments for major
• 21:27depression and then adapted for PTSD,
• 21:30and it highlights how important
• 21:32it is to characterize.
• 21:34You need the unique pathology
• 21:36of PTSD if we hope to develop
• 21:38treatments that are more effective.
• 21:41For helping people be resilient
• 21:43and recover from the impact
• 21:45of their life traumas.
• 21:47All of this legacy builds from the first
• 21:51profound insight from Steve Studies,
• 21:54which is that there are
• 21:56is a knowable biology of
• 21:58PTSD and that the symptoms of PTSD
• 22:02are related to this biology. So.
• 22:05In some ways, today we both celebrate
• 22:09and mourn the end of the beginning of the
• 22:13field of PTSD neurobiological research.
• 22:16Steve Southwick, a beloved and
• 22:19respected pioneer, is sorely missed.
• 22:22He identified the first signalling
• 22:25mechanism altered in PTSD and influenced
• 22:27the development of treatments for PTSD.
• 22:31He helped foster a more mature
• 22:34understanding of the biology of PTSD,
• 22:36which is emerging from this bleeding
• 22:40edge of neuroscience research.
• 22:42Their PTSD is not simply depression.
• 22:46And it's enormously it's biology
• 22:48is enormously more complex than
• 22:51we ever could have predicted.
• 22:53We acknowledge our loss.
• 22:55And thank Steve as he cared
• 22:58for countless patients,
• 23:00mentored the next generations
• 23:02of clinician researchers.
• 23:03And his the legacy of his research
• 23:06lives on with us. And those.
• 23:10Stimulated by his research contribution.
• 23:13So I'll stop there. And and.
• 23:17We can move on.
• 23:18Thanks.
• 23:19Thank you, John, for such a wonderful
• 23:21overview of Steve's early work.
• 23:22Truly groundbreaking and setting the
• 23:25foundation for where the field is today.
• 23:27It's my honor to now introduce our
• 23:30second presenter, Dr Dennis Charney.
• 23:32Dr Charney is a world renowned expert
• 23:34in the neurobiology and treatment
• 23:36of mood and anxiety disorders.
• 23:38Dr Charney began his career at Yale
• 23:41in 1981 or within nine years he rose
• 23:43to tenured professor of Psychiatry.
• 23:45He then remained.
• 23:47Deal for a decade before being recruited
• 23:49to lead the NIMH mood and anxiety
• 23:52disorder research program in 2004,
• 23:54Doctor Charney was recruited to Mount
• 23:56Sinai as Dean of research and is
• 23:58currently the Anne and Joel Aaron Krantz,
• 24:00Dean of the Icon School of Medicine at
• 24:02Mount Sinai and president for academic
• 24:05affairs for the Mount Sinai Health System.
• 24:07Doctor Charney has known Steve
• 24:09for more than 40 years,
• 24:10and together they have co-authored
• 24:12more than 100 papers as well as two
• 24:15of the leading books on resilience.
• 24:17Today,
• 24:18we will hear about their groundbreaking
• 24:19work on the science of resilience.
• 24:21Dennis,
• 24:21we're delighted to have you here today,
• 24:23and thank you for joining us to honor Steve.
• 24:27Thank you, Rob,
• 24:28and it's it's a pleasure to be here.
• 24:31Maybe that's not the right word.
• 24:33Steve and I, as you mentioned,
• 24:36Rob, you know, we were friends
• 24:38and colleagues for 40 years.
• 24:42We kept in contact, constant contact.
• 24:47Every week talked every week
• 24:50as friends and and colleagues.
• 24:52So I want to talk a little bit about
• 24:55Steve the scientist and I will touch
• 24:57on our work it and resilience and also
• 25:00Steve as a as a friend and a person,
• 25:04so as colleagues.
• 25:07John and I, little history here for
• 25:09those of you who may not know the
• 25:11history but you know John and I were
• 25:14at the clinical neuroscience unit.
• 25:16At CMHC.
• 25:17And then, you know,
• 25:18we decided to move over to the VA.
• 25:21And that that happened around
• 25:25198087 or so and we changed what the VA
• 25:29was like at that time to make it more
• 25:33scientifically based to affect I would say
• 25:36more evident evidence based treatments.
• 25:40And and Steve was there and personally
• 25:43when we went, John and I and some
• 25:45others when we went to the VA,
• 25:47Steve had been there for a couple of years.
• 25:50And I must admit,
• 25:52I didn't know hardly anything about PTSD.
• 25:55Steve was in the military.
• 25:57I knew a lot about veterans,
• 25:59knew a lot about war.
• 26:00I was Vietnam era, you know,
• 26:03which means I did not go to Vietnam.
• 26:06I I got deferments from going into the
• 26:09military because at that time I was in
• 26:12college and then I was in Med school.
• 26:14That's another story why people who
• 26:16are in college don't go to war as
• 26:18opposed to if you're if you're not,
• 26:20you get drafted.
• 26:21But actually,
• 26:22I didn't know much about PTSD or veterans.
• 26:25And so we we go to the VA.
• 26:28And Steve taught me.
• 26:29He taught me a lot about PTSD
• 26:32as a as a clinical phenomenon.
• 26:35You know what what it meant to come
• 26:37back from Vietnam and not be welcomed,
• 26:39and how serious PTSD was as a as an illness.
• 26:44So I really was a student of Steve's
• 26:47in terms of understanding PTSD.
• 26:51And I and I became fascinated by PTSD.
• 26:54I've been doing mainly work,
• 26:56as John mentioned in depression
• 26:57and and panic disorder.
• 26:59And I saw understanding PTSD biologically
• 27:03could really help understanding the
• 27:05disease and developing new treatments.
• 27:08So Steve and I and John you know,
• 27:10we we became partners in that adventure
• 27:13and Andy Morgan and and Rasmussen and
• 27:16others got you know, got involved and.
• 27:20I hope a lot of you experience this.
• 27:22It was fun, you know, to do the work.
• 27:25You know we would.
• 27:27At 5:00 or 6:00 o'clock at night,
• 27:28we would all get together and and
• 27:31talk about what we're learning a new
• 27:34studies that we we crafted it was.
• 27:38It was just great.
• 27:41And working with Steve and John and others,
• 27:43it was, yeah, it was just so much fun.
• 27:45And and so we started conducting the
• 27:47studies that John reviewed with you.
• 27:49That gave us a lot of insight into
• 27:52what might be what stress does
• 27:53to the brain and and the body.
• 27:56It it was really a new field that,
• 27:59you know, almost every couple of
• 28:00weeks we learned something new.
• 28:01It was just,
• 28:02you know, fantastic.
• 28:03And also, you know,
• 28:05other things started to happen.
• 28:06Andy Morgan you know,
• 28:08got involved and he he had
• 28:10connections you know,
• 28:12with the military and and we did a study,
• 28:14Steve I and Andy John was involved
• 28:18where we we studied veterans
• 28:20actually active duty military who
• 28:23were involved in active training and
• 28:26these were mainly special forces.
• 28:29They were in their seer course
• 28:32called Survival, Evasion, resistance.
• 28:34Escape a very serious training exercise.
• 28:38Andy connected us and what we
• 28:41found under the very
• 28:43significant stress of a training exercise
• 28:47that we characterize the biologic
• 28:50neuroendocrine responses to stress.
• 28:53And how it might even relate
• 28:56to resilience to stress.
• 28:57And one of the things we we found,
• 28:59norepinephrine,
• 29:00obviously was involved cortisol ACTH,
• 29:04and also neuropeptide Y,
• 29:06which is a naturally occurring neuropeptide
• 29:10that has anxiolytic properties.
• 29:14And so you know that was you know a
• 29:17real eye opener to study in a sense
• 29:20normal stress and related to resilience.
• 29:23Ultimately down years later with with
• 29:26Steve was very involved in this too.
• 29:29We made neuropeptide Y and we began to
• 29:32study it as a treatment for PTSD and
• 29:35we're still involved in that work and
• 29:38it started with the work with Andy and
• 29:41Steve and John with that CPR course.
• 29:45At some point in the 1990s.
• 29:50Stephen, I thought, you know,
• 29:51maybe we could learn.
• 29:53A lot more about PTSD and maybe
• 29:56come up with new treatments if
• 29:59we learned about resilience.
• 30:01And so we started studies
• 30:04and resilience that lasted.
• 30:06Up till the day Steve died that we
• 30:10ended up studying hundreds of people,
• 30:13interviewed them.
• 30:16To learn about resilience and as Steve
• 30:18and I would say and Steve would say,
• 30:20we started with a blank slate.
• 30:22We,
• 30:22we did not know what characterized
• 30:26resilient people who who faced very
• 30:29significant stress and in some cases
• 30:33experience post traumatic growth.
• 30:35Didn't develop depression or PTSD,
• 30:38or if they did,
• 30:39they were able to deal with it and recover.
• 30:43And so we studied POW's from Vietnam.
• 30:47People who had to face natural disasters,
• 30:52congenital disease,
• 30:54studied every socioeconomic group
• 30:58you could think of, and so it was a.
• 31:01It it was an amazing experience,
• 31:03you know,
• 31:04Steve and I and others doing that together.
• 31:07We studied the POW's when I was
• 31:09at NIH and Steve would fly down,
• 31:13stay with me,
• 31:14and we would interview the the
• 31:16POW from Vietnam.
• 31:18We interviewed about 40 of them.
• 31:20John McCain is the most famous,
• 31:21but there are many others who
• 31:23did very well in life,
• 31:25despite being held in prison
• 31:27for six 7-8 years,
• 31:29heavily tortured solitary confinement.
• 31:32It was an amazing personal experience
• 31:35for Steve and I and the way we did it.
• 31:38Steve was an amazing clinician,
• 31:40you know, one of the best clinicians
• 31:43I've ever come in contact with.
• 31:44You know,
• 31:45when you were interviewed by Steve,
• 31:47you just felt you had to tell
• 31:50things about yourself.
• 31:51And and in an environment that felt
• 31:53safe and and Steve was so insightful.
• 31:55So when we interviewed the POW,
• 31:59Steve mainly interviewed and I
• 32:01would pop in now and then ask me
• 32:03a question and we learned so much
• 32:05from the POW's about resilience.
• 32:07We we go home at night to my house
• 32:11and recount what we just learned to
• 32:13my wife and it changed our lives.
• 32:17Those POW's and others became role models.
• 32:21To us.
• 32:22And so when we faced the stress in our lives,
• 32:26we would think back about all
• 32:28the resilient people we
• 32:30met and. Trying to learn
• 32:32from that experience.
• 32:33So, you know, I want to leave everybody,
• 32:36you know, with a couple of things.
• 32:38One, Steve was an amazing clinician.
• 32:41In addition to being an amazing
• 32:44person but unbelievable clinician,
• 32:45he had unbelievable insight into the nature
• 32:49of disease from a psychological perspective.
• 32:54And from a biologic point of view,
• 32:55we became partners.
• 32:57John and I kind of brought the biology.
• 33:00Steve, you know, became an expert,
• 33:03learned from it and the combination
• 33:06of psychological insight.
• 33:08And biologic insight was so very powerful.
• 33:13So in terms of resilience and foul stuff,
• 33:17we can show the first slide.
• 33:19The. So Steve and I.
• 33:23Went in with a blank slate.
• 33:26And as I you know mentioned,
• 33:28we learned from these hundreds and
• 33:30hundreds of of people of all different.
• 33:33So different groups of people,
• 33:35every ethnic group, every type of trauma and.
• 33:39Eventually we found that there were these.
• 33:42These factors that characterized
• 33:46resilience and and these are listed.
• 33:49We started calling it the resilience
• 33:51prescription and these are listed on this.
• 33:54Slide and they they became
• 33:56the basis of a book we wrote,
• 33:58but that's now in the 3rd edition.
• 34:02It it also became you know
• 34:04the basis for developing.
• 34:07Clinical approaches.
• 34:09To enhancing resilience.
• 34:12We we used this at at Sinai during
• 34:15the pandemic where you know when we
• 34:18were the epicenter of the epicenter.
• 34:21At one point we had over 2000
• 34:23patients with COVID in our hospitals.
• 34:28A lot of that was pre vaccine,
• 34:30pre understanding how to treat the disease
• 34:33and and so we had to develop means to.
• 34:36Help our frontline healthcare
• 34:38workers get through the stress.
• 34:40I know you did that.
• 34:41You've been doing this at Yale.
• 34:43And Steve and I and others at Sinai
• 34:45used what we had learned from our
• 34:47studies and resilience to develop
• 34:50a Center for stress resilience and
• 34:52personal growth and use what we learned
• 34:56from our resilient studies to help
• 34:58our frontline healthcare workers.
• 35:00So these are the factors that we.
• 35:04We identified and and personally
• 35:06Steve and I both. That help.
• 35:09It helped us personally.
• 35:12As some of you may know,
• 35:13I was the victim of a violent crime.
• 35:16Six years ago I was shot with a shotgun
• 35:21by a disgruntled former faculty member.
• 35:23And I didn't know if I was
• 35:26resilient or whether how valid the
• 35:28factors we came up with,
• 35:30and I found that they were very
• 35:33valid because it helped me.
• 35:35Recover a fully recover from that trauma
• 35:39in my life and Steve was unbelievable
• 35:43in how he dealt with. Cancer.
• 35:46You know, he died from prostate cancer.
• 35:49He was incredibly courageous and,
• 35:53you know, with Bernadette.
• 35:55Yeah, right by his side.
• 35:57The whole time.
• 35:57He got most of his treatment at Mount Sinai,
• 36:01and he.
• 36:03He became a role model for the doctors that
• 36:07treated him in the 3rd edition of the book.
• 36:12You know which is.
• 36:13And I'll show you in a
• 36:15moment which is coming out.
• 36:17Next next fall, but it's already written.
• 36:21In the epilogue, which we devoted to Steve.
• 36:25It it puts all the doctors that treated him.
• 36:28It also quotes how Steve.
• 36:31Was so resilient in fighting this disease,
• 36:34it was.
• 36:36It was amazing and for me as.
• 36:39His closest friend,
• 36:41it was.
• 36:45It was something I'll never forget.
• 36:47So I want you to all remember Steve as.
• 36:51In a very full way, you know,
• 36:53not not just as a fantastic clinician,
• 36:57a wonderful science that has impacted
• 37:00the field, as John mentioned,
• 37:02but as an amazing person that
• 37:04can be a role model for you.
• 37:07Even though he's gone.
• 37:10We can go to the next slide.
• 37:15So you know, as I mentioned,
• 37:16Steve and I were buddies.
• 37:18That's that's the 1st edition of our
• 37:22book and this was at a book signing.
• 37:26Yeah, amazing. Next slide.
• 37:30Now, we did a lot of things together,
• 37:32you know, outside of work.
• 37:34We actually another thing
• 37:35that Steve taught me. I I.
• 37:39I was a rower, you know,
• 37:41a scholar, and Steve said to me,
• 37:43you know, you would have a lot
• 37:45of fun learning how to kayak.
• 37:47And for the next 30 years,
• 37:49Steve and I kayak together and.
• 37:52We we did many races, you know,
• 37:56around the Northeast and
• 37:57this was a race that we did.
• 37:59In night in 2005 and just, you know.
• 38:04For a crazy reason,
• 38:05we got on the cover of the Newton tab,
• 38:08which is a a newspaper outside of Boston.
• 38:11This was the run of the Charles Race
• 38:14and this is Steve and I coming out of.
• 38:17Of the water doing what's called a Portage,
• 38:19you know, taking the boat from
• 38:21one part of the river to another.
• 38:23This is the Charles River.
• 38:27Never forget that.
• 38:28That race.
• 38:28Next slide.
• 38:32And. This is the last time we kayaked
• 38:36together and this was in the fall of 2021.
• 38:42And and Bernadette took this picture.
• 38:44We went kayaking with Bernadette.
• 38:46That's, that's my son on the right, Alex,
• 38:49who's now a faculty member at Mount Sinai.
• 38:53That's Steve in the front,
• 38:54and here he is, kayaking. You know,
• 38:57he's got metastatic prostate cancer.
• 39:00But that was Steve.
• 39:02And actually,
• 39:02he was great in the water.
• 39:03He was great athlete.
• 39:07And then the next slide.
• 39:10So Steve died and then?
• 39:13A few days after Alex.
• 39:21Went to the same spot.
• 39:24Just to remember, Steve.
• 39:27So that was a couple days after he died.
• 39:31And you can cut down the slides then.
• 39:37So. Steve is somebody that I'll never forget.
• 39:40He's inside me and he's inside so
• 39:43many of you that have got to know him.
• 39:46It was a privilege.
• 39:47A privilege to, you know,
• 39:49Bernadette, who we still are,
• 39:51still stay in contact with.
• 39:54I'm a Bruce Springsteen fan.
• 39:56As many of you know,
• 39:58he wrote a song called Terry Song about
• 40:02somebody he lost and aligning that.
• 40:05Song that is gives me.
• 40:10It makes me feel a little bit better
• 40:12and to remember Steve, and that is
• 40:14love is a power greater than death.
• 40:16And that's why we'll never forget Steve.
• 40:21So thank you for the privilege
• 40:23of talking about.
• 40:24Have mean, Steve.
• 40:25Thank you, rob.
• 40:27Thank you so much, Dennis.
• 40:36OK, so far our last presentation,
• 40:38I'm going to talk about some of
• 40:41the quantitative epidemiologic,
• 40:42genetic and epigenetic work that Steve,
• 40:45our colleagues and I have
• 40:47done specifically in U.S.
• 40:49military veterans and this will
• 40:51feature mostly my presenting on
• 40:53the work and then Janicza Montalvo
• 40:56Ortiz will present on some of
• 40:59the genetic epigenetic studies.
• 41:01So today Steve and I and our colleagues
• 41:03have published over 150 papers together.
• 41:05I went back and calculated this
• 41:07works out to about one per month.
• 41:09We were an incredible dynamic duo
• 41:12where Steve would often conjure up all
• 41:14kinds of ideas and I was the one who
• 41:15went to the data and and looked to see
• 41:17if we could resurrect some of those findings.
• 41:20Our work primarily centered on the
• 41:22psychosocial and genetic epidemiology
• 41:24of trauma related disorders,
• 41:26but also on resilience and and
• 41:28salutogenesis outcomes related
• 41:29to resilience like successful.
• 41:30Aging we intentionally,
• 41:32as Dennis mentioned with Steve's
• 41:34background in clinical psychiatry,
• 41:37took out translational approach in this work.
• 41:39So we were interested both
• 41:40in the backward translation,
• 41:41for example,
• 41:42looking at genetic and and neural
• 41:45biomarkers of PTSD symptom dimensions,
• 41:47but also forward translation.
• 41:48You know, we don't do epidemiology
• 41:50strictly for bean counting.
• 41:52You know,
• 41:52we want to identify modifiable risk and
• 41:55resilience factors that could be targeted
• 41:58in prevention and treatment efforts.
• 42:00As is often the case in trauma research,
• 42:01we've studied a number of different
• 42:04trauma affected populations of
• 42:05most notably military veterans,
• 42:07but also World Trade Center first
• 42:09responders and most recently,
• 42:11COVID-19 frontline healthcare workers.
• 42:13These are two mottos that are pervaded
• 42:15the work that Steve and I and our
• 42:18colleagues did over the years that,
• 42:20you know,
• 42:20we wanted to to focus not only on
• 42:22fixing what's wrong in trauma survivors,
• 42:24but also building what's strong and and as,
• 42:26as Dennis shared, you know,
• 42:27character traits and resilience
• 42:29factors and people affected by trauma.
• 42:31And then also on phasing,
• 42:33on growing through,
• 42:33what one goes through this
• 42:35idea of post traumatic growth,
• 42:36which I'll describe in a moment.
• 42:39So when one does a literature research,
• 42:42literature search,
• 42:42just even thinks about the words
• 42:44that come to mind when we think
• 42:46about post traumatic stress disorder,
• 42:47we're we're highly, highly negatively biased.
• 42:50You know,
• 42:50things like fear and numbing flashbacks,
• 42:53helplessness. It's quite overwhelming.
• 42:54And it's actually surprising in a way,
• 42:57given that most people who are
• 42:58affected by trauma are resilient.
• 43:00And this includes even people who are
• 43:02very highly exposed to traumatic events,
• 43:05as Dennis mentioned,
• 43:06and special forces communities.
• 43:08But also in natural disasters.
• 43:09I mean,
• 43:10we have this natural tendency to bounce back.
• 43:12And what Steve was very interested in
• 43:15learning are what are those ingredients
• 43:17that go into making people resilient?
• 43:20So one approach that we took to
• 43:22trying to understand this was
• 43:24to study this in large,
• 43:25nationally representative
• 43:27prospective cohort studies.
• 43:29So we we design now more than 10 years ago,
• 43:31the National Health and
• 43:33resilience and Veteran study,
• 43:34which to date now has recruited 3 separate
• 43:37prospective cohorts of US veterans.
• 43:39And as is often the case
• 43:40in epidemiologic studies,
• 43:41we wanted to look at the prevalence and
• 43:43correlates of major psychiatric disorders,
• 43:45but also trying to quantify
• 43:47and operationalize these more.
• 43:49Nebulous constructs like resilience and
• 43:51healthy aging and even post traumatic growth.
• 43:54And then we had a number of secondary aims.
• 43:56As as Janicza will describe in a moment,
• 43:58I'm looking at genetics and
• 44:01epigenetics of common disorders.
• 44:03This is a busy slide.
• 44:04The the only thing that's most
• 44:06relevant here I think is to to say
• 44:08that we've now recruited more than
• 44:098000 veterans into these studies.
• 44:11These are all prospective cohorts.
• 44:14Our most recent cohort was
• 44:16recruited before the COVID pandemic.
• 44:18So we had the rare opportunity
• 44:19to see how the pandemic affected
• 44:21mental health and we just recently
• 44:23completed a three-year follow-up
• 44:25of that cohort on 2 weeks ago.
• 44:27And so these samples are drawn
• 44:28from a very high quality survey
• 44:30research panel that's designed
• 44:31to be representative of the.
• 44:33The US Adult USA adult household population.
• 44:37And then we also apply post
• 44:40stratification weights to ensure that
• 44:42our results are generalizable to
• 44:44the US veteran population at large.
• 44:46So this is just a sample of some of the
• 44:49the studies that we've published over
• 44:51the years on the topic of resilience.
• 44:53And when one gets into this literature,
• 44:56it's surprising just how complicated
• 44:57it is to define what one means
• 45:00when we say resilience.
• 45:01So these are the two definitions
• 45:03that Steve embraced, and one,
• 45:05the first, is from the American
• 45:07Psychological Association,
• 45:08which defines resilience as a process of
• 45:11adapting well in the face of adversity,
• 45:13trauma, tragedy, threats or even
• 45:16significant sources of stress.
• 45:18Steve also liked the definition
• 45:19from George Vallant,
• 45:20a psychiatrist at Harvard,
• 45:22who described resilient individuals as those
• 45:25who resemble a fresh green living twig.
• 45:28When twisted out of shape,
• 45:29such a twig bends but does not break.
• 45:32Instead,
• 45:32it springs back and continues to grow.
• 45:37So we took,
• 45:37and this was largely on Steve's urging,
• 45:39a bottom up data-driven approach.
• 45:41So we allowed the data to tell us how
• 45:43it's organized when we consider the
• 45:45role that trauma has on mental health.
• 45:48And so we took a number of these
• 45:50data-driven analytic approaches.
• 45:51Our cluster analysis is the one I'll
• 45:54show today where we simply submitted
• 45:56a count of lifetime cumulative
• 45:58traumatic adversities really across the
• 46:00entire lifespan and then a composite
• 46:02measure of psychological distress
• 46:04given that trauma does not simply.
• 46:06Yield on a potential increase
• 46:08in PTSD symptoms,
• 46:09but may also lead to an uptick in in major
• 46:12depressive and generalized anxiety symptoms.
• 46:14More recently,
• 46:15we've been employing these
• 46:17discrepancy based resilience scores,
• 46:18which computes at a population level
• 46:20ones expected score given their trauma
• 46:23burden and their actual or observed score.
• 46:25And you could compute relative resilience
• 46:27scores at an individual level.
• 46:29And for longitudinal data,
• 46:30we published several studies now using
• 46:32latent trajectory modeling,
• 46:34which allows us to characterize predominant.
• 46:36Trajectories of how one might respond
• 46:39to trauma, and then, in particular,
• 46:41given the translational emphasis,
• 46:43we were interested in comparing the
• 46:45resultant groups on demographic,
• 46:47military, trauma,
• 46:48health and psychosocial variables.
• 46:51This is from a longitudinal
• 46:53study of veterans,
• 46:54the first nerves cohort study first in 2011,
• 46:57where we did a cluster analysis and
• 46:59we found that the majority of veterans
• 47:01are minimally trauma exposed and have
• 47:03minimal psychological distress symptoms.
• 47:06But then there were these other
• 47:08two groups that emerged at 27.5%
• 47:10were in this resilient group,
• 47:11and they were matched with regard to
• 47:13how much trauma they have endured
• 47:15over the course of their lives
• 47:17relative to a distressed group,
• 47:18about 12% of the sample.
• 47:20Importantly.
• 47:21Steve would always emphasize this is
• 47:23resilience is not a marker of low exposure.
• 47:26There has to be a prerequisite
• 47:28of high level of trauma burden
• 47:29in order to be resilient.
• 47:31So this clearly shows both of these
• 47:33groups being significantly tested by
• 47:35cumulative trauma burden by having
• 47:37very different psychological outcomes.
• 47:39And if you look at the the average
• 47:41score in the resilient group,
• 47:43it's on par with our minimally
• 47:45exposed control group when we look
• 47:47at screen positive rates for PTSD,
• 47:49MDD and GAD, both 3/4 of our.
• 47:52The stress group is screening positive
• 47:54and not a single person in the
• 47:56resilient group is screening positive.
• 47:58And not all traumas are created equal.
• 48:00So when we look at the trauma profiles,
• 48:02they're strikingly similar.
• 48:03In fact,
• 48:03our resilient group was actually
• 48:05more likely to have reported in
• 48:07during a natural disaster.
• 48:08But other than that,
• 48:10we see a striking similarity in terms
• 48:12of the degree of trauma exposure.
• 48:15And then when we looked at wave one
• 48:16predictors of resilience over time
• 48:18relative to the distressed group,
• 48:20not surprisingly the resilient
• 48:21veterans had a lower likelihood of
• 48:24early life psychiatric disorder.
• 48:25So this is, if you will,
• 48:26the inverse of stress sensitization.
• 48:29They were also physically healthier.
• 48:30And then what was of most interest to
• 48:32us is these modifiable characteristics.
• 48:35So they scored higher on measures
• 48:36of emotional stability.
• 48:37So a personality characteristic
• 48:39characterized by a high degree of
• 48:41emotion regulation and also these protective.
• 48:44Psychosocial traits,
• 48:45some of which are Dennis,
• 48:46showed in the resilience factors,
• 48:47in particular having a strong sense
• 48:49of purpose, dispositional gratitude,
• 48:51and a high sense of Community integration.
• 48:54And finally,
• 48:55and this was a resounding theme
• 48:56in the work that Steve and I did,
• 48:58and we actually have a perspective
• 49:00piece that we finished before he
• 49:02passed away that's currently under review,
• 49:04underscoring the importance of social
• 49:07connection and social integration,
• 49:09and in particular having a
• 49:11secure attachment style,
• 49:12having a strong social support network.
• 49:14And and deriving a high sense of
• 49:16emotional support from that network.
• 49:20And so now I'm going to
• 49:23introduce Janissa Montalvo Ortiz,
• 49:24who's been our collaborator with our
• 49:27colleagues on genetic and epigenetic,
• 49:30NHRS and nerve studies.
• 49:31Joga Lerner is the the lead on the
• 49:34the molecular studies that we've been
• 49:36doing and we've also been collaborating
• 49:39with Renado Pullmantur's group.
• 49:40Janita is an assistant professor
• 49:43in our department and also a
• 49:45research biologist with the Clinical
• 49:47Neuroscience division of the
• 49:49National Center for PTSD. Pizza.
• 49:51Thank you, Rob,
• 49:52and thank you for including me.
• 49:54It's an honor to be included in the grand
• 49:58rounds in honor of Doctor Southwick.
• 50:01So I'll be presenting data.
• 50:03All of this data is from the NIH RDS cohort,
• 50:06so it's tailored to understand
• 50:10better the veteran population.
• 50:12So we concentrated in looking at
• 50:15epigenetics to understand better the
• 50:17role of gene by environment interplay
• 50:19and for this we first conducted.
• 50:21And the pigeon?
• 50:23The pigeon of Wide Association
• 50:26study in 1135 made veterans of
• 50:29European ancestry and look at
• 50:32both current and lifetime PTSD.
• 50:35I'm showing their um Manhattan plots
• 50:38where you can see the different
• 50:40genes that were identified and from
• 50:43these we were able to replicate
• 50:45the gene SNP 7 in an independent
• 50:48cohort of 608 mile veterans from
• 50:51the backs biobank cohort.
• 50:54DNA methylation levels at this
• 50:56gene were found to be decreased
• 50:58in PTSD cases in both cohorts.
• 51:01To assess the functionality
• 51:03of these findings,
• 51:04we evaluated the patterns of gene
• 51:06expression of CE NP7 in human
• 51:09postmortem brain samples from
• 51:10the national PTSD Brain bank,
• 51:12and we found that this gene is
• 51:15differentially expressed in the
• 51:17medial orbital prefrontal cortex,
• 51:18showing a significant decrease in PTSD.
• 51:23This gene is known to be involved
• 51:25in transcription regulation,
• 51:26but more interestingly,
• 51:27genetic variants identified
• 51:29in Jewish studies have found
• 51:31associations with risk taking
• 51:33behavior and alcohol consumption.
• 51:38We also evaluated DNA methylation
• 51:40aging in this cohort.
• 51:42This work it's led was led by
• 51:44Amanda Teman and Peter now.
• 51:47Epigenetic clocks are known to be
• 51:49associated with disease and mortality risk,
• 51:52and in this cohort we found that
• 51:54nearly one in five male US veterans had
• 51:58accelerated DNA methylation age with
• 52:00an average of eight years older than
• 52:03chronological age by evaluating social,
• 52:06demographic, military, health,
• 52:08and psychosocial variables.
• 52:09We found diabetes and child sexual
• 52:12abuse as the strongest correlates,
• 52:14each explaining 1/3 of the variance.
• 52:17We also found associations with
• 52:19negative beliefs of aging,
• 52:21as well as hypertension and body mass index.
• 52:25By evaluating grim age,
• 52:26which is a recently developed
• 52:28epigenetic clocks that is known
• 52:30through outperforms other clocks in
• 52:32predicting mortality and disease risk,
• 52:35and evaluating PTSD symptoms
• 52:37and different types of trauma,
• 52:39we found that PTSD was associated
• 52:42with twofold greater odds of
• 52:44accelerated DNA methylation H,
• 52:46which aberration nearly a full decade.
• 52:49Associations were also observed with
• 52:52greater severity of trauma related
• 52:54detachment and sleep disturbances.
• 52:58And lastly, we also asked the
• 53:00question of whether genetic variation
• 53:02associated with PTSD risk may be
• 53:05influenced by environmental factors.
• 53:07This work was led by Amanda Tamon and in
• 53:10collaboration with Renato's Polianthes
• 53:12Group for these polygenic risk course,
• 53:15which is a summary of the genetic
• 53:18associations calculated based on
• 53:20recent large scale genome wide
• 53:22association studies and evaluating
• 53:24the effects of attachment style.
• 53:26We found that attachment style moderates.
• 53:28The polygenic risk for both
• 53:31lifetime and current PTSD.
• 53:33When evaluating polygenic risk
• 53:34of different PTSD symptoms,
• 53:36we found that higher reexperiencing
• 53:39PRS is associated with greater
• 53:41severity of PTSD symptoms,
• 53:44and this was an effect of served only in
• 53:47veterans with an insecure attachment style.
• 53:49We also evaluated this using a Jeep
• 53:52IE model and found that PRS by
• 53:55attachment style interaction was
• 53:57associated with greater severity.
• 53:59Of PTSD symptoms to disentangle the
• 54:03relationship between attachment
• 54:05style and PTSD and investigate
• 54:08potential causal effects.
• 54:09We conducted middler randomization
• 54:11analysis and found that these
• 54:14relationship was actually bidirectional.
• 54:17In summary,
• 54:17the work described showed the
• 54:19contributions in the understanding of
• 54:21the biological underpinnings underlying
• 54:23the gene by environment influences on PTSD,
• 54:26specifically in a US veteran population.
• 54:31Thank you so much, Janice.
• 54:32And I'll also just comment when I
• 54:34first showed Steve these figures,
• 54:36how excited he was given just
• 54:38how powerful the effect of social
• 54:40connection and in this case attachment
• 54:42style has been in our studies and
• 54:43to to here to show basically that
• 54:45it's even under conditions of
• 54:47very high polygenic risk for PTSD,
• 54:50you basically don't see an
• 54:52elevation and risk for the disorder.
• 54:54So he was absolutely ecstatic
• 54:56about this finding.
• 54:58So in the next section,
• 54:59I'm going to go back to this negative
• 55:01bias that we've had in the the trauma
• 55:04literature and is this question that
• 55:06PTSD is it always doom and gloom?
• 55:08So as you saw when I started with the
• 55:11slide on all the negative concepts
• 55:13associated with people with PTSD,
• 55:15there's a preponderance of evidence
• 55:17negatively valenced in this literature
• 55:19linking PTSD to negative outcomes.
• 55:21So this includes psychiatric
• 55:23comorbidities and suicide,
• 55:25physical health problems
• 55:26such as cardiovascular.
• 55:28Disease and functional difficulties
• 55:29in various life domains and
• 55:31as janita just mentioned,
• 55:33also has been linked to a twofold
• 55:35increase in accelerated epigenetic aging.
• 55:37And there's also evidence linking
• 55:40PTSD early mortality.
• 55:41But one of the questions that
• 55:42Steve and I are very interested
• 55:44in is could there potentially be
• 55:46a silver lining to PTSD?
• 55:48Is it possible that living with PTSD
• 55:51may help foster positive psychological
• 55:54changes and potentially also
• 55:57resilience to subsequent traumas?
• 55:59So this is not a new idea.
• 56:01This notion that suffering can be
• 56:03potentially transformative has
• 56:04been embraced by ancient spiritual
• 56:07religious traditions, literature,
• 56:08philosophy,
• 56:09and ideas and writings of ancient Hebrews,
• 56:11Greeks, early Christians,
• 56:13as well as teachings of Hinduism,
• 56:15Buddhism and Islam.
• 56:18For example,
• 56:19the Greek philosopher Aristotle
• 56:20said that it is during our darkest,
• 56:23darkest moments that we must focus
• 56:26to see the light.
• 56:28The philosopher Charlie Brown has
• 56:30also tried to convince Lucy that
• 56:32adversity is what makes us mature.
• 56:35The growing soul is watered best
• 56:38by tears of sadness.
• 56:41So we've published a number of
• 56:42articles in this area as well
• 56:44and including some of the first
• 56:46nationally representative studies to
• 56:48look at post traumatic growth in a
• 56:50population based sample of military veterans.
• 56:53And most recently and and Steve was
• 56:55very proud of this paper showing
• 56:58that the the pandemic was associated
• 57:00with positive psychological changes.
• 57:03So what is this idea of post
• 57:05traumatic growth?
• 57:06So these are positive,
• 57:08meaningful psychological changes
• 57:09that an individual can experience
• 57:12as a result of struggling with
• 57:14traumatic and stressful life events.
• 57:17These are the various domains
• 57:18that have been identified.
• 57:19The first five have been or considered the
• 57:22original dimensions of post traumatic growth,
• 57:24increased appreciation of life,
• 57:26greater sense of personal strength
• 57:28and coping,
• 57:29self efficacy,
• 57:29embracing a future paths for one's life.
• 57:32We're seeing new possibilities after trauma,
• 57:35experiencing a renewed appreciation
• 57:37for interpersonal relationships,
• 57:39positive spiritual changes and the
• 57:41the two here were actually added more
• 57:43more recently in the past five years
• 57:45or so that one might experience.
• 57:47Increase in compassion and altruism and
• 57:49and and a tendency to want to give back
• 57:52to others and also creative growth.
• 57:54And this came up largely in the context
• 57:56of the pandemic where many individuals
• 57:59took on new hobbies and interests.
• 58:01And one of our earlier studies we
• 58:04found that 50% of veterans reported
• 58:06experiencing post traumatic growth and
• 58:08some of the independent correlates
• 58:10and drivers of post traumatic growth
• 58:13interestingly were re experiencing
• 58:15or intrusive symptoms of PTSD.
• 58:17Which suggests that there has to
• 58:19be this struggle with the trauma,
• 58:20which potentially can then lead to
• 58:22a reappraisal of it and potentially
• 58:24also a reintegration of that traumatic
• 58:27experience into one's life narrative.
• 58:29Importantly this has to happen in
• 58:31the context of support of others.
• 58:33Rich Tedeschi and others who have
• 58:35largely developed this concept have
• 58:37long argued for the importance of
• 58:39social connection and strong sense of
• 58:41purpose and these solution genic factors.
• 58:43And similarly we see these emerging as
• 58:46key correlates of post traumatic growth.
• 58:50When we look among veterans with PTSD,
• 58:53they're actually more likely to
• 58:54experience post traumatic growth.
• 58:56We see about 3/4 of veterans with
• 58:58PTSD who were poor,
• 59:00at least moderate or higher levels
• 59:01of post traumatic growth.
• 59:03And this was Steve's idea to say,
• 59:05even in the context of PTSD,
• 59:07if you have post traumatic growth,
• 59:08are you functioning better?
• 59:09And indeed, that does happen to be the case.
• 59:12Veterans who had PTSD and post traumatic
• 59:14growth actually scored better on
• 59:16measures of mental functioning than
• 59:18those with PTSD who did not have.
• 59:20Post traumatic growth and So what we observe,
• 59:23and these are empirical data where we
• 59:25try to fit the the the association
• 59:27between the level of PTSD symptom
• 59:29severity and post traumatic growth,
• 59:31we see this inverted U-shaped association.
• 59:34So growth is really maximized right
• 59:37around this moderate threshold of
• 59:39PTSD symptoms.
• 59:40And so if you have too few symptoms,
• 59:42there's really nothing to grow from and
• 59:44once you exceed a certain threshold,
• 59:46you've reached the point of
• 59:47diminishing return.
• 59:48So really this is the sweet
• 59:49spot of post traumatic growth.
• 59:51Just right around that moderate threshold.
• 59:53And interestingly,
• 59:53this happens to be right around the
• 59:56threshold that we typically impose
• 59:57for a positive screen for PTSD.
• 01:00:01Importantly, we've also found that post
• 01:00:04traumatic growth can fluctuate over time.
• 01:00:06About 60% report stable post traumatic
• 01:00:08growth over a two year period,
• 01:00:10and it's maintained by PTSD symptoms,
• 01:00:13most notably intrusive thoughts.
• 01:00:15But also these Saluda genic
• 01:00:17factors purpose in life,
• 01:00:18altruism, gratitude, religiosity,
• 01:00:20and active lifestyle,
• 01:00:22which is likely linked to active coping.
• 01:00:26And this is a question that that
• 01:00:28Steve posed and we ended up being
• 01:00:30very interested and he was very proud
• 01:00:32of this finding is that is post
• 01:00:35traumatic growth an end in and of
• 01:00:37itself or can it serve potentially as
• 01:00:39somewhat of a psychological shield,
• 01:00:41if you will,
• 01:00:42to promoting resilience to
• 01:00:44subsequent traumas?
• 01:00:45And so we looked at this empirically
• 01:00:47using the longitudinal nerves data set
• 01:00:49and we found that indeed veterans who
• 01:00:51reported a greater sense of personal
• 01:00:53strength in relation to a trauma that.
• 01:00:56Occurred more than 25 years earlier,
• 01:00:58we're actually substantially less likely
• 01:01:00to develop PTSD to a new traumatic event,
• 01:01:03and this is a pretty strong effect.
• 01:01:05For each standard deviation unit increase,
• 01:01:07we saw a 32% lower likelihood
• 01:01:10of developing PTSD.
• 01:01:12So it's underscores the importance
• 01:01:14I think of looking at these
• 01:01:16constructs interchangeably.
• 01:01:17So resilience, post traumatic growth,
• 01:01:19PTSD and what it suggests to us
• 01:01:21is that post traumatic growth even
• 01:01:23in the presence of Co occurring.
• 01:01:26PTSD symptoms may help an individual
• 01:01:28develop coping skills to better
• 01:01:30manage subsequent traumas.
• 01:01:32There's now a program that's been
• 01:01:34developed called Boulder Crest
• 01:01:35by Rich Tedeschi, Steve and I.
• 01:01:37Unfortunately, before he passed,
• 01:01:38we we, we hadn't.
• 01:01:39We had reached out to rich to to
• 01:01:41potentially go there and actually
• 01:01:42experience the training.
• 01:01:43And these are veterans who've tried all
• 01:01:45kinds of treatments and nothing's worked.
• 01:01:46But the BOULDERCREST program
• 01:01:48really centers around the themes
• 01:01:49of post traumatic growth.
• 01:01:50It's not pushing the trauma away,
• 01:01:52but growing from it,
• 01:01:53benefiting from it and moving
• 01:01:55on and incorporating it.
• 01:01:56Into one's life.
• 01:01:59I also want to comment on Steve.
• 01:02:01Just incredible contributions and
• 01:02:03productivity during the COVID pandemic.
• 01:02:07Steve was a member of the Yale
• 01:02:09COVID-19 Mental Health Task Force,
• 01:02:10the Mount Sinai COVID-19
• 01:02:12mental health research team,
• 01:02:13which he of course wrote me into and
• 01:02:16was heavily involved in in several of
• 01:02:18our national studies on US veterans.
• 01:02:21I looked and and she's published 18 papers,
• 01:02:24including three perspective pieces,
• 01:02:26including one incredibly well
• 01:02:28written and and, you know,
• 01:02:30forward Thinking Piece published in JAMA on
• 01:02:33the pandemic related post traumatic growth.
• 01:02:37Highly encourage folks to read that if
• 01:02:39they're interested in this concept.
• 01:02:41And of course he was doing this all
• 01:02:43while undergoing intensive treatment
• 01:02:44for metastatic prostate cancer.
• 01:02:46Absolutely amazing.
• 01:02:47I'm going to play a brief clip
• 01:02:50on video clip of Steve.
• 01:02:52I think we need his voice with us.
• 01:02:54This was from last year's grand
• 01:02:56rounds when John had asked for
• 01:02:58members of the faculty and and staff
• 01:03:00and Yale psychiatry to describe
• 01:03:02what the pandemic meant to to them.
• 01:03:05And what really strikes me about
• 01:03:06this is just.
• 01:03:07So grateful Steve was to be involved
• 01:03:09and to be part of the teams that were
• 01:03:12involved in doing research around the
• 01:03:14COVID pandemic and the response to it.
• 01:03:25Everyone. With you.
• 01:03:30I retired over two years ago.
• 01:03:34During my entire social movie revolved around
• 01:03:37the outside psychiatry department and the.
• 01:03:41He no longer had a novels.
• 01:03:44Good reasons to visit him.
• 01:03:47On regular basis.
• 01:03:49And with the start of COVID, it looked as
• 01:03:52if the situation would get even worse.
• 01:03:55I also started to feel guilty about not
• 01:03:58being in the hospital on the front line.
• 01:04:01I mean no way to contribute.
• 01:04:05I like being on the front line.
• 01:04:08And felt that my role as a physician
• 01:04:11who caretaker. He's slipping away.
• 01:04:15Even when I try to internalize
• 01:04:18my father's lifelong model.
• 01:04:21I'm not OK. You're not OK.
• 01:04:23It's OK. I still felt pretty.
• 01:04:30In China.
• 01:04:32He asked if I would consider
• 01:04:35becoming a member of a COVID-19
• 01:04:37mental health task force.
• 01:04:39It's meaningful.
• 01:04:40And ask if I'm right joiner to give
• 01:04:43a talk about resilience to PA and,
• 01:04:46you know,
• 01:04:47interests.
• 01:04:50And I got married to them again.
• 01:04:53My partner is 20 years.
• 01:04:56I was back.
• 01:04:59That was my teenage.
• 01:05:00That was what we need since August.
• 01:05:03Perhaps I could contribute,
• 01:05:06even if in a small way.
• 01:05:09Which brings to mind Helen Keller's please.
• 01:05:13I longed to accomplish
• 01:05:15great and noble task,
• 01:05:17but it is my chief duty to
• 01:05:19accomplish small tasks as if
• 01:05:21they were great and noble.
• 01:05:26And recently I learned that the
• 01:05:29Yale Department of Psychiatry
• 01:05:31has been rated the number one
• 01:05:34department in the United States.
• 01:05:36Just thinking about it.
• 01:05:38You and I have the opportunity to work
• 01:05:42for great department whose clinical,
• 01:05:45educational and research mission is to help
• 01:05:49those who are suffering mental illness.
• 01:05:54What could be better than that?
• 01:05:57So this year, in a way,
• 01:05:59I rejoined the department
• 01:06:01by joining the task force,
• 01:06:03giving the talk with his meaning and
• 01:06:06also teaming up with colleagues to
• 01:06:09investigate the impact of the pandemic
• 01:06:12on frontline healthcare workers.
• 01:06:15Here's a passage from the manuscript
• 01:06:18that we recently published about
• 01:06:21frontline healthcare workers.
• 01:06:22I quote from that because it is relevant to
• 01:06:26how I personally experienced this past year.
• 01:06:32Quote. Baby seals and special forces
• 01:06:36teams often attribute their own courage
• 01:06:39and resilience to the power of team
• 01:06:42members who have each other's back and
• 01:06:45will even risk their life to one another.
• 01:06:49Message from healthcare leaders
• 01:06:51should be clear. Team, team, team,
• 01:06:54you are your brother and sisters.
• 01:06:58Team. We are all in this together.
• 01:07:01Fighting for a common mobile cause
• 01:07:04is a privilege to be working
• 01:07:06alongside such remarkable.
• 01:07:11For me, this year has been filled
• 01:07:15with distress and great concern
• 01:07:18for all those who have suffered
• 01:07:20from the devastating impact.
• 01:07:22Something came down.
• 01:07:24And for the toxic political
• 01:07:27divisions in our country.
• 01:07:28And for long standing and pervasive social,
• 01:07:32racial, economic,
• 01:07:34and healthcare disparities.
• 01:07:39This year has also been
• 01:07:41filled between no purpose.
• 01:07:43We just kind of resilient bonds.
• 01:07:4792 the privilege to work with
• 01:07:50him and care deeply about when
• 01:07:53wonderful colleagues who are both
• 01:07:56teenagers and cherished friends.
• 01:07:59Thank you for having my back.
• 01:08:07Absolutely amazing.
• 01:08:08Every time I watched the video
• 01:08:10I I think about the data and we
• 01:08:12see the same themes and and and
• 01:08:15how Steven bodied all of these
• 01:08:17resilience factors during the fight,
• 01:08:19fight for his life.
• 01:08:21Here are some remembrances from
• 01:08:22from Steve's many colleagues.
• 01:08:24I had an outpouring I probably
• 01:08:26about 200 emails that that I I I
• 01:08:29received after Steve had passed.
• 01:08:31The first is from Ilan Harpaz
• 01:08:33Rotem in our department,
• 01:08:34who said that Steve was more
• 01:08:36than an intellectual mentor.
• 01:08:37He cared for us like a father.
• 01:08:39I was lucky enough to have a FaceTime
• 01:08:41call with him several days before he passed.
• 01:08:43He was a fighter and reflected on resilience.
• 01:08:46He was an amazing mentor and spoke
• 01:08:48excitedly about the various projects.
• 01:08:51And was working on he valued
• 01:08:54his mentees tremendously.
• 01:08:55Lauren Pecoraro from Mount Sinai
• 01:08:57was involved in the COVID-19
• 01:08:59mental health research team.
• 01:09:01Said that Steve was a brilliant,
• 01:09:02kind and humble mentor and guide to us all.
• 01:09:05He generously gave of his
• 01:09:06time to help us in our work,
• 01:09:09even when he was ill and in pain.
• 01:09:11I know we will all greatly Miss
• 01:09:13Steve's calm and guiding presence.
• 01:09:16Rick for Keoni from Harvard,
• 01:09:17with whom Steve was developing resilience
• 01:09:19training programs in the past few years,
• 01:09:22remarked that Steve was a
• 01:09:24beautiful and inspiring person.
• 01:09:25He was always wanting to
• 01:09:26help in any way he could.
• 01:09:28There should be a picture of Steve in the
• 01:09:32dictionary next to the word resilience.
• 01:09:34And finally,
• 01:09:35Christine Olson,
• 01:09:36the Chief Wellness officer with whom
• 01:09:38Steve was working very closely during the
• 01:09:40pandemic and even prior to the pandemic,
• 01:09:42said that Steve made her feel seen,
• 01:09:44heard, valued, supported,
• 01:09:46developed, understood.
• 01:09:47He made me feel like I was
• 01:09:49somebody special and capable,
• 01:09:50showed me what it was to be resilient.
• 01:09:53I felt important because he shared
• 01:09:55himself and his life with me,
• 01:09:57led by example and generously
• 01:09:58gave of his time and wisdom.
• 01:10:01He was a rare,
• 01:10:02brilliant gem of a human being.
• 01:10:05I miss him so much and I know that I am
• 01:10:08sad and grieving because I was lucky.
• 01:10:10I was lucky to know him.
• 01:10:14And finally, these are reflections
• 01:10:16directly from Steve from.
• 01:10:17These are from the forthcoming
• 01:10:193rd edition of Steve and Doctor
• 01:10:22Charney's Book on Resilience.
• 01:10:25This is a direct quote from Steve,
• 01:10:26who said resilience has been defined
• 01:10:28as the ability to bounce back,
• 01:10:30but I can't bounce back.
• 01:10:33It's been defined as going
• 01:10:34through a traumatic situation
• 01:10:36without a drop in functioning,
• 01:10:37but I have had a drop in function.
• 01:10:40Does that mean I am not resilient?
• 01:10:44We can answer Steve's question for him.
• 01:10:46He was absolutely resilient.
• 01:10:48He inspired, supported,
• 01:10:50loved and lived fully.
• 01:10:52He let go of resentments and
• 01:10:54connected to sources of meaning.
• 01:10:56While Steve courageously fought his cancer,
• 01:10:58pain and physical limitations,
• 01:11:00he did bounce back with love,
• 01:11:03giving and service to others,
• 01:11:05the field colleagues, mentees and COVID
• 01:11:08frontline workers in his final months.
• 01:11:11Steve also reflected it on how he personally
• 01:11:15defined resilience toward the end of life.
• 01:11:17Everyone he knew well would
• 01:11:19agree that this is how he lived.
• 01:11:21Do the best you can with what you've got.
• 01:11:24Take it all success and failure and use it to
• 01:11:28the best you can in the service of others.
• 01:11:32In the end,
• 01:11:33what really matters is who and what you love.
• 01:11:36That's it.
• 01:11:37End of discussion.
• 01:11:38Love is the heart and soul of resilience.
• 01:11:46And finally, this is a Christmas card
• 01:11:49that I received last year from Steve May.
• 01:11:51May come across as a little unusual has the
• 01:11:54cover of Steve and Doctor Charney's book,
• 01:11:57as well as various pictures of Steve
• 01:11:59engaging and incredibly physically
• 01:12:01demanding activities of pushing up boulders,
• 01:12:04lifting trees, of boxing,
• 01:12:06and of course Bernadette.
• 01:12:07There as a cliffhanger and inside
• 01:12:10was this simple message that
• 01:12:13now when I reflect on it means.
• 01:12:16Much more than when I initially read it,
• 01:12:19it simply said hang in there you can do it,
• 01:12:22press on. And Bernadette,
• 01:12:25when I shared this slide with her,
• 01:12:28asked me to also add and don't
• 01:12:30take yourself too seriously.
• 01:12:31Steve always had a way to infuse humor,
• 01:12:34even in the darkest and and most
• 01:12:36challenging of life situations.
• 01:12:38And I think when I reflect on
• 01:12:40this really simple message,
• 01:12:41it's it's a message for all of us
• 01:12:43and and how Steve wanted to leave us
• 01:12:45with the encouragement to press on
• 01:12:47and forge ahead in what we're doing.
• 01:12:49And so, Steve,
• 01:12:50I'll try to say this without tearing up.
• 01:12:52Thank you for always having our backs.
• 01:12:56And for being an enduring shining
• 01:12:59light in our lives.
• 01:13:01We love you, we miss you,
• 01:13:02and we look forward to honoring
• 01:13:04and building on your extraordinary
• 01:13:06legacy for the rest of our lives.
• 01:13:09And thank you all for joining us today
• 01:13:11to honor our dear colleague and friend,
• 01:13:14Steve Southwick.
• 01:13:15This concludes our formal session today,
• 01:13:18and I'll turn it over now to Doctor
• 01:13:20Crystal for any final remarks.
• 01:13:24Thank you, rob. 1st. Rob,
• 01:13:29thank you for pulling all this together.
• 01:13:31Your. Your ability to draw on Steve's
• 01:13:36legacy with us and to share share this
• 01:13:40with us all is really greatly appreciated.
• 01:13:44As was the presentations from
• 01:13:46all the speakers today,
• 01:13:48from Doctor Charney and and from.
• 01:13:52Doctor Montalvo Ortiz.
• 01:13:55What a remarkable fortunate community we
• 01:13:59are to have known, worked with, learn from.
• 01:14:04Doctor Southwick. And. Um, I we will.
• 01:14:11He's he gives us a gift.
• 01:14:14That keeps us going at this really
• 01:14:17terribly difficult time in our culture,
• 01:14:20in our. You know,
• 01:14:22by challenging world that we live in.
• 01:14:26And. And. So thank you.
• 01:14:31To all the speakers,
• 01:14:34thanks to all who have joined us today.
• 01:14:38As we've had our respective backs.
• 01:14:42As we remember Steve and
• 01:14:45special thanks to the speakers,
• 01:14:47so take care of your buddy.