Yale Psychiatry Grand Rounds: January 14, 2022

January 14, 2022

"Attenuating the Traces of Trauma Memories With Ketamine"

Ilan Harpaz-Rotem, PhD, Associate Professor of Psychiatry, Yale School of Medicine

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00:00Question and dumb.
00:05I wanna give you one. It's an honor
00:07for me to be here and present my
00:10lab work to the department. And.
00:16I want to of course,
00:17acknowledge the tremendous help in
00:20this work for the National Center
00:22for PTSD with Jaune, Crystal,
00:24Steve Southwick, Andrew Peters.
00:26Like our collaborator and a large
00:29portion of the work that I'm doing,
00:31but particularly on those studies
00:33that I'm going to present,
00:34I wanna acknowledge my lab member doctor.
00:38All the work that he was a therapist
00:40and did a tremendous amount of analysis
00:43on the data and Charles Gordon,
00:45who is my lab manager.
00:47Erin O'Brien, who is the independent
00:50assessor and mark Laura Serena,
00:53Medicine and Rebecca,
00:55who are postgrad, did the heavy in.
00:58Lifting of organizing the data and
01:00you see them probably around in in
01:03the medical school all the time.
01:05So now they you know where they belongs to.
01:09Tremendous thanks to Shelly
01:11Ahmann and Bentyl Mandy,
01:13who worked the physician on my
01:15study doing the ketamine infusion
01:18and the medical examination.
01:20As John, of course noted,
01:24I'm collaborating with the levy
01:27decision making lab and to
01:30graduate student Ronan and Newton.
01:33And also assisting analysis and
01:35my collaborated Mount Sinai,
01:37Danielle Shiller and our postdoc
01:41Philip Pullman.
01:42At the time he was a postdoc.
01:44Now he back in Switzerland under the Swiss
01:48National Science Foundation Post Fellowship.
01:51So OK,
01:52PTSD,
01:53I want to really to dedicate this
01:57talk to my grandparents maternal
02:00grandparents to my grandmother,
02:02Tova and my grandfathers Ellie we
02:05we we do something for different
02:09reason and it's hard for me not to
02:13explain why I ended up doing PTSD.
02:17I realize I'm 20 years in yell and I
02:20never talked about this specifically.
02:22Person I grew up in a household
02:26that was really dumb.
02:29In trauma,
02:30especially around the Holocaust
02:32was over in 24/7 and I was born to
02:37single very young single mother.
02:40And that had to hold two jobs and she
02:43worked from 7:00 AM to 3:00 PM at
02:46one job and then another dorm from 3 to 7.
02:49So my maternal grandparents
02:51were my primary caretaker.
02:53Until the age of nine and then
02:56just to understand my grandmother.
03:01Lost her three sisters and parents in
03:04the Holocaust and I can't remember
03:06a day that she was not holding a
03:09picture of her three beautiful
03:11sister young sister and her parents.
03:13And then you know, it was the
03:16early 19 day to take a photo.
03:18It always was an event.
03:20You had to have a photographer
03:21about it dressed so nicely.
03:22So those picture was very magical in a way.
03:24It's not that everyone has a cell phone,
03:27so I remember her showing her sisters
03:29to me all the time as a young child,
03:31you don't understand this.
03:33As much as we understand it as adults,
03:37but then pain and agony,
03:39and she was spared because she because
03:42before the German invaded Poland,
03:44she went on a trip to Palestine
03:46and then parent.
03:47Her parents don't don't to come back and stay
03:49there and so she ended up in the age of 12.
03:52As a you know,
03:53out of school in in Palestine,
03:55my grandfather turned Grand Father.
03:59When Germany invaded Poland,
04:02they found themselves.
04:04In a situation that his parents made the
04:07decision to smuggle him his three sisters,
04:10his three,
04:10his brother,
04:11and one young sister out of Poland to safety.
04:15And this can be a whole lecture
04:17about this amazing journey across the
04:20entire Europe to France that they made
04:24and trying to avoid being captured.
04:26You know, can think like a group
04:28of my father was 13 at the time,
04:30but his brother ranged from 4 from 17 to.
04:3510 years old,
04:36little sister that had to care.
04:38Carry four in this adventure,
04:41eventually ended up in France.
04:42It was a probably not a very good
04:44place to end up because the Germany
04:47of course eventually took over France
04:49and and his brother and sister was
04:52sent to the concentration camp.
04:54My grandfather was able to escape
04:57prior to that and and made.
05:01And able to board a refugee boat.
05:06Went to Palestine and then at the
05:10time Palestine was occupied by UM.
05:13The British Empire and they
05:16refused to accept any boat refugee
05:18from the Second World War due
05:21to of course political reasons.
05:24And my grandfather and some other
05:26people were jumping the boat when
05:28it got closer to Tel Aviv shores.
05:30The usually boats were turned
05:33back to Cyprus to refugee camp
05:36eventually allowing later on after
05:39the UN resolution to come back.
05:42So you have two.
05:44People out of middle school have
05:47to fend for themselves and and
05:49live in a country without any and.
05:52Many parents and and working odd jobs.
05:56And and and.
05:58Eventually I think it just was
06:03a situation that always affected
06:06the hardly knew any Hebrew the
06:08language were skill was very poor
06:11and educational force limited.
06:13When I was nine years old,
06:15actually my dumb mother made a decision
06:17that she probably wants a better life.
06:20She took a job abroad in France and left me,
06:24but the social services and there
06:27was a decision that I'll be probably
06:29better off in foster care because my
06:32grandparents had really limited their,
06:35you know, education, skill,
06:36and language skill they were loving,
06:38caring and ever was ever felt.
06:40I I left.
06:41I felt as a child, extremely protective and.
06:44You know decision making.
06:46And so half of my life actually from
06:50age 9 to age 18I grew in foster care.
06:53And this is another very
06:56unique environment and.
06:58To grow because you know you are in
07:01someone else's home as much as they
07:04are loving and caring and and you
07:06know you always feel stranger in
07:08a way it's not a stranger is that
07:11when you open the fridge you take
07:13a yogurt or you open the candy bar.
07:16You have this big sensation that you're
07:18stealing something doesn't belongs to you.
07:20It's just something that
07:23it's very hard to describe.
07:25I don't know, but being like in a home.
07:29And there is of course biological
07:31child that you can.
07:32You are hyper.
07:34Are sensitive to those differences and then,
07:37but I I thankfully flourished at school.
07:40I flourished in sport.
07:42I did them well and everybody knows
07:45that the end of high school in Israel.
07:48There is also a service,
07:50so it's also a way to for me was to
07:55build some equity and money to afford.
08:00And my university and have a roof over
08:03my head so I I stayed in the military
08:05for 10 years as an officer, unfortunately.
08:08Israel at the time was.
08:13Occupying South Lebanon and it
08:15was the 82 invasion to Lebanon,
08:18Lebanon.
08:18The plus is almost till two 2002
08:221005 member correctly and 87 and
08:25my middle of my military service
08:28that was the Palestinian uprising.
08:32So a lot of service was done in in
08:35areas that was heavily populated and
08:38Lebanon is unique that the enemy is is not.
08:42You know,
08:43I I'm quite politically I
08:45was extremely active all my
08:47life, so in high school as a peace movement,
08:51trying to advocate for peace and
08:53Palestinian state that my political view,
08:55I couldn't afford myself not to go down.
08:57I could not do that because you can't,
08:59you're gonna end up in jail and
09:01I think something that I wanted.
09:02There's a trajectory, and of course,
09:05so you had a lot of internal conflict.
09:07You know, making right air raids
09:10into suspect house pulling people
09:13you have young kids screaming.
09:15And the wives are screaming
09:17and pulling a suspect that not
09:20necessarily is a real suspect,
09:22because intelligent can be
09:24deceived by local that have some.
09:28Internal reason I cannot go,
09:30but it's very taxing.
09:31Very hard to see young people that
09:34in my head in one hand are freedom
09:38fighters and so and and then you
09:40have to deal with this population,
09:44so that's kind of was very hard for me
09:46after I stayed just until I hated every
09:49day and I just wanted to build this enough.
09:52You know they have enough money when I leave
09:54to to at least manage myself through college.
09:58And and of course,
09:59I was the first one in my family to go
10:02to college and ended up here and here.
10:0620 years.
10:06This is the longest place that
10:08I ever lived in my life.
10:10And so here I am.
10:14What you learn when you study when
10:17you you in foster care it's you
10:20become hypersensitive to the in.
10:22Appreciate the kindness of others.
10:24Those who give you a hand and push
10:26you forward and and you know it's very
10:29hard when you don't have a family.
10:31So you really are dependent on
10:33others and some people make some
10:36small decisions that you don't
10:38understand how fundamentals and
10:40making change in people's life.
10:42So I want to thank Robert.
10:44Roseanne had,
10:45and he was my first research
10:48mentor here at Yale.
10:49He in Morris Bell brought me into yell.
10:53They convinced me to leave UC Davis
10:55and I was off for a post up there
10:57and actually also position and
10:59convince him to come to yellow.
11:01Last night I had a dream that I'm
11:03calling you see Davis ask for jobs.
11:05I'm not sure I made the right decision,
11:07but anyway, it's just he he.
11:10He taught me how to be a better researcher,
11:14Bob.
11:14And when I finished my postdoc,
11:18the I was offered a position amount,
11:20silent,
11:21but I was really interested in staying here.
11:25From variety of reason and I had
11:28some conversation with Mike Cyrnek
11:29that the at the time that almost 20,
11:32you know 1516 years ago there
11:34was no single psychologist on the
11:36PTSD specialty clinic at the VA,
11:39and I don't think even might remember that,
11:41but he he he then decided to it,
11:44was on his psychiatrist,
11:45nurses and social work on the unit
11:48and and he made this decision to,
11:50you know,
11:50seek a position for a psychologist
11:52which I was higher into it,
11:54and this is the. Place that they
11:57wanted to treat them and and and work,
11:59and this is really made a
12:01tremendous impact and I don't
12:03think even Mike was aware of this.
12:06How much it was impactful when I was at the
12:09National Center for PTSD at the PTSD clinic.
12:13Steve Southwick invited me into
12:15the National Center for PTSD.
12:18He and John managed this division of
12:21the neuroscience and they actually just
12:23Steve took care of me like a father.
12:26He made sure that all the resources
12:29and and and and the mentorship that
12:31needed for me to conduct my work
12:34at the National Center for PTSD.
12:37And this was tremendous support that
12:39was fundamental to my success and
12:41my work that I'm going to present
12:44today and then running off.
12:46Of course that hired me then.
12:47Two and not nap back to the be the
12:51director of the PTSD and treatment
12:54evaluation and for the entire system.
12:57So overseeing this is something that
13:00is really tremendous. So really.
13:05One of the things those people
13:06without them I will not be here today.
13:10So I'm gonna talk Johnny now.
13:12The work that being done in my lab and
13:15probably have to rush a little bit faster.
13:17And then I plan I'm going to talk about fuel,
13:20learning,
13:21extinction and PTSD about some
13:24issue with ambiguity in PTSD.
13:27And then the combination of exposure
13:30therapy and katamine so we know PTSD.
13:33There you need to be exposed
13:35to traumatic event.
13:37I can give a whole lecture how much
13:40criteria is problematic and how you define
13:43what's qualified as criteria and what isn't.
13:46We have the signature in.
13:49Symptoms which are intrusive thoughts,
13:54flashbacks,
13:54the nightmares in my lab we are
13:58thinking about this mechanism,
14:00memory processing reconsolidation deficits.
14:02We have the avoidance of a reminder.
14:06People just try to avoid,
14:08and that's in order to avoid.
14:10Of course,
14:11this intrusive thoughts.
14:13There is alternation in modern
14:15communication this is very MDD,
14:17like cluster of PTSD symptoms there
14:19is dampening of the reward system and
14:23cognitive distortion that you know
14:25something is terribly wrong with me.
14:26It's my fault those those other people fault.
14:30And there is the hyper vigilance
14:33hyperarousal what we think of in the
14:36lab as the fear extinction deficits,
14:38the over generalization of fear.
14:41And the lifetime prevalence of PTSD.
14:44About 8% of the population will experience
14:47dramatic event in the life and meet
14:50PTSD diagnosis, lifetime diagnosis.
14:52However,
14:53we have lower emission in the monotherapy.
14:5630% remission in medication
14:59and 50% in psychotherapy,
15:02so they're in need for a new.
15:05And way of thinking of it.
15:08So fear is very hard to extinguish
15:11to extinction.
15:12Why?
15:12Because fear is learned instantly.
15:14You know you put your hand in a fire once.
15:16You don't have to do it more than
15:18once to know that it's not good
15:20idea and in the wild practice
15:22makes perfect is not an option.
15:24Fear is remember forever.
15:25So once you learn about danger,
15:27it is important not to have to relearn it.
15:31And that's the reason.
15:32It's so hard to change memories of
15:35fear because there are really in in in.
15:38Have a biological purpose?
15:40Is that you? You don't want to
15:43forget them when they study PTSD.
15:45The 90% of the studies are involved.
15:47What is called the Pavlovi and conditioning
15:51classical conditioning paradigm.
15:52Then in this paradigm,
15:55taking unconditional stimulus that causes
15:57aversive reaction like pain, fear.
16:00Here it will be like say my
16:02electric shock and you pair it
16:05with condition stimuli stimulus.
16:07Let's say sound so you.
16:09Play a song you see no effect on the animal.
16:12Then you pair the sound and the
16:15conditions stimulate with the electric
16:17show the unconditioned stimuli.
16:19When you take the shock away
16:21after several trial,
16:21the animal will respond to the
16:23tone as a conditional fear.
16:25You'll see increase blood pressure,
16:27heart rate, respiration,
16:28freezing behavior,
16:29and stress hormone release.
16:31When we're doing that in human,
16:34the most common paradigm is
16:37to pair like neutral.
16:39Stimulus like a square with a certain
16:42color with the electric shock and
16:45then to do an extinction trial.
16:50Tremendous amount of risk showed
16:51that individual was pretty bad.
16:53PTSD have impairment and extinction.
16:55Learning and recall,
16:57and dysregulation of the prefrontal cortex,
17:00amygdala, Circuit City.
17:01So the you see,
17:02the ventral medial prefrontal
17:04cortex in the extension trial,
17:06pressing the brakes and say,
17:08don't worry, it's safe, it's safe and,
17:11and reducing amygdala activation.
17:13Whereas you see hyperactivation of the
17:16ventral medial prefrontal cortex in PTSD?
17:19Failing to suppress amygdala?
17:22In response, hyper response to fear.
17:26Also,
17:27in PTSD there is a complete volume deficit.
17:30Smaller input campus in was
17:33shown in this population.
17:35It's not clear yet if it's a
17:37risk factor or consequences.
17:38I'm mentioning this brain area
17:40because there will be a part of
17:43the focus of my investigation.
17:45So in a study in my lab,
17:48we assess the ability to track changing
17:51contingency in the environment in
17:53post traumatic stress disorder,
17:54and we can think about it in in in
17:57a war zone, you are in a war zone.
17:59You hit by an IED.
18:01And then you know it was a garbage can,
18:06in very hypervigilant any garbage cans.
18:08You worried that will be.
18:11Dangerous consequences and then you
18:13have a friend that is a good friend.
18:17You he fights with you alongside with you.
18:20How are you going and coming back home?
18:22You don't want to continue to have
18:24this tremendous fear of a garbage can.
18:26You are and you Haven or whatever
18:28you are Tel Aviv and and.
18:30And this is something that you
18:33need to readjust yourself.
18:35However,
18:35your friend and you know started
18:38to ended up addicted to.
18:42Them.
18:43Substances become aggressive and
18:45causing you a lot of distress,
18:47so contingencies change in the
18:49environment and we need to update our
18:51perception of safety and dangerous
18:54because there is some level of of
18:58uncertainty in certain eventive life.
19:00It's not everything is fire or tiger.
19:03So we use what is called the reversal task.
19:06We have associated phase A with electric
19:10shock in the middle of the trial.
19:13We change the contingency and made people
19:16relearn what is safe and what is danger.
19:19It's about 24 trial for 12 each for each
19:23face in in the first half of the trial,
19:27and then we reverse another 16 trial
19:30for phase eight and B and half of
19:33them were associated with shocks.
19:37This is a combat veteran population,
19:41all exposed to trauma.
19:42Half of them were meeting criteria for PTSD,
19:45with of course, comorbid conditions
19:47of depression and anxiety.
19:49We excluded any substance
19:51use disorder in this study.
19:55So when we look at the population,
19:57regardless of the symptoms,
19:59we saw that the actually.
20:03Veterans exposed to trauma were laying.
20:07To differentiate between
20:09safety and unsafe faces,
20:12and if you look at the middle of the trial,
20:14where is the number 12?
20:17Trial, they successfully create a reverse
20:21cylinder and this is the most common
20:24analysis when you compare phase to Phase B.
20:27However, in psychiatry there is more
20:29advanced way to look about learning
20:32today and this is the Rescorla Wagner.
20:34I'm not going to go into computational
20:36psychiatrist because we are half
20:38of us is probably clinician,
20:40but the idea is that you can model.
20:41You know what you're going to do if you
20:45getting a shock to one square and then.
20:47You not getting and and you see,
20:49let's say that it's a Blue Square and then
20:51you being presented the blue score again
20:53and not getting shocked the next time
20:55that the Blue Square will be presented,
20:57you going to reduce your guards and
20:59expect your fear going to be lessened.
21:02However,
21:02if it's being followed by shock the
21:05next time you're going to update this
21:08so you can really calculate them.
21:10And here we using galvanic skin response
21:13response as a proxy for this stress,
21:16you can really.
21:18Measure those what you expected and
21:20then what you get and what the reaction
21:22is to each stimulus and build what is
21:25called the alpha the learning rate.
21:28So when we look at the learning rates
21:31and in this population that we we saw
21:34that hypothesis symptoms was associated
21:37with learning lower learning rate.
21:40OK, and that was very interesting,
21:42because amygdala tracks value
21:44less as a function of symptoms.
21:47When you look at it.
21:48When you're looking at better here,
21:50it's represent the contribution of
21:52expected value to the amygdala signal.
21:54So not just.
21:56In that they have a lower learning rate.
21:59This is really have a direct
22:01relationship to amygdala activation.
22:04In response to what you expect to get.
22:10More complicating mode,
22:11the computational psychiatry that
22:14flourish now, actually there is a
22:17learning rate in the original Rascal.
22:21Assume a constant learning like.
22:23Here we use what is called the hybrid
22:26model that take another Paris home
22:29model that allowed to prediction error.
22:31Wait, what does it mean that every
22:34time that we learn by mismatches,
22:36so you expect one things and
22:38get another thing, so you then?
22:40Correct your learning so the.
22:43Pierce Holes allows for, uh,
22:46this weight that everyone puts into that.
22:51At updating of the learning
22:53in the course of a trial.
22:56So and we when we tested model fit,
22:59it showed that the hybrid model
23:02fits the learning better and so we
23:05further look at that and what we
23:07found out was extremely interested.
23:10Interesting phenomena is that people with
23:13higher symptoms of PTSD actually put.
23:17Higher weights to the prediction error,
23:21so if there is a Mitch match
23:23they overcorrect.
23:23So let's say I'm expecting to get a shot.
23:26And I'm not getting the shock the next
23:28time that there will be the Blue Square.
23:30I will people with higher
23:32PTSD symptoms were lower.
23:33The expectation too much,
23:35and if they're gonna get a shock
23:38when they expect no shock,
23:39they're going to be overly anxious
23:42the next time that they go in to
23:46see this dangerous Blue Square.
23:49So kind of they were all over.
23:51In the learning.
23:53Paradigm so you can think about
23:55this as I'm getting a shock.
23:58I'm not getting a shock at
23:59some level of ambiguity.
24:00Uncertainty and uncertainty
24:02is very high in a battlefield.
24:06You know you never know what's gonna happen.
24:09I'm gonna be hit is gonna be the
24:11patrol gonna be relaxing and and
24:12you know it's nothing gonna be
24:14just another mundane and actually
24:16anyone that served long time a
24:18period even in a war zone sometimes
24:20it's boring you going and you're
24:22doing foot patrol on the same St.
24:23Over and over again,
24:25nothing happened and then one day
24:27something happened and it can be
24:29extremely unstable and environment.
24:33It's unclear, of course if.
24:39Answered if I'm untolerable until
24:41ability to being untolerable to
24:43uncertainty is a risk factor or
24:46it's a consequences of PTSD.
24:48That's something that of course in
24:50cross sectional study we cannot answer.
24:55Not not interesting.
24:57Thing is that similar brain area
25:00are implicated in decision making
25:02under uncertainty and fear learning,
25:04and those are of course medium prefrontal,
25:07cortex, striatum and amygdala.
25:08So here in this study we have looked
25:12at decision making and whereas in the
25:15fear conditioning you are passive,
25:18you're making assumption what's going to
25:20happen, but you don't have to act here.
25:21We stand instead of asking people.
25:24Our verse in a questionnaire that we
25:27use a task behavioral task and then
25:29you have to make active decision.
25:31You have to act upon your decision.
25:33I will.
25:34This is another economic task
25:37used by Levy Lab that uses PTSD
25:40patient and you have a lot.
25:41You have to choose either to
25:43play lottery or take the money.
25:45So you and and this is real money involved.
25:47People getting down money.
25:49The bags are in the lab,
25:50they can make it's real for
25:52them so you have a 100 chips.
25:54You have to choose.
25:55Either too, if you pull a red one,
25:57you're gonna get $5 if you or
25:59you don't wanna play the lottery,
26:00just take the $5 in destroy so
26:03of course doesn't make sense.
26:04You have only 50%, so you're gonna
26:06take the $5 Y to play the lottery.
26:09Then we're raising the beds.
26:10OK, do you wanna play the lottery for
26:13the chance to win $10 or take the five?
26:16So here like there is 50% chance to get $10.
26:19That's meaning that OK,
26:21theoretically have $5 in the
26:24bag if you're not risk taking.
26:26I said, let me take the file.
26:28If you like a little bit
26:29more with taking you say,
26:30let's let me play the lottery.
26:32Eventually you raise the amount and
26:34eventually at one point everybody
26:36will skip the lottery and then you
26:39can model the behavior about risk.
26:41And this can be done in gain and loss.
26:44However, there is 2 type of uncertainty.
26:47The Riskware probably are known.
26:49So if you have like,
26:50you're going to a medical procedure today,
26:52cancer treatment have really good.
26:56Prediction it was is a rate of success.
26:58You being described this as the treatment.
27:00This is what's gonna happen.
27:02This is the likelihood if you
27:04do this kind of treatment.
27:05This however, life is full of ambiguity.
27:08We don't know exactly what
27:10the probability are,
27:11and this is another time of
27:14uncertainty that we call ambiguity.
27:17And we can create ambiguity in this task too.
27:20So let's take here in again,
27:23we put some level of ambiguity.
27:25You don't know how many chips in the bag,
27:28so you can play the lottery.
27:30You can take $5 or play the
27:32lottery and get $20.
27:33However, you know,
27:34let's say I'm extremely risk averse.
27:37I say OK, they tricking me here.
27:39I think this long labs
27:42are going to screw me I.
27:45Imagining there is 75 in
27:47blue chip and only 25.
27:50I'm not going to play the lottery.
27:51I'm gonna take the $5.
27:53So in this subject head
27:54there is already created a
27:56situation. There is 75 blue, 25 red.
28:01However, when we change
28:03the contingency to laws.
28:04This subjects think maybe maybe
28:10I if there is actually 75 blue.
28:14It's better to play the lottery then
28:16you're not going to lose any money,
28:18but suddenly that change the mind and
28:20thinking maybe there is actually 275 red.
28:23I'm going to lose 20 bucks.
28:25So they decide not to play the lottery
28:27again and lose only $5 and we actually
28:30take the money away from them.
28:32So you can think about how in the
28:34same bag and that existed in the lab,
28:37can be the same time 75 blue if
28:40you playing on a game or 75 in in.
28:46Road if you playing under last condition,
28:48so this is in our head.
28:50Of course there is not 150 chips in there.
28:53It's only 100 so you change your perception.
28:56Depends on if you thinking it's
28:59a aversive or a positive outcome.
29:03So the study we manipulated different
29:06level of ambiguity and risk taking
29:08and what we found.
29:10It's extremely interesting that people.
29:16With post traumatic stress
29:18disorder versus averse storm,
29:20big,
29:20witty only under negative outcome
29:22and this is the time the proportion
29:25that people choose not to play the
29:29lottery in all other domain of risk
29:33under a gain and loss in the reward.
29:35There was no differences.
29:38Again,
29:39in the area of a competition psychiatry,
29:41you can really create what is called
29:43subjective value for each individual,
29:45so you can have a single number
29:48represent someone attitude or a loss.
29:51Either in the ambiguity in or risk condition,
29:56and again when we have examined this.
30:01Subjective value again,
30:03we found it on individual with PTSD had.
30:08We reversed one big witty,
30:09only under lost condition.
30:13So one last thing,
30:17when we took those combat exposure,
30:19the level of combat exposure was
30:23significantly associated with.
30:24PTSD symptom, and specifically
30:26with anxious arousal symptoms.
30:28Those are the hyper vigilance or
30:31exaggerated title response exactly.
30:33Those things that reflects in the
30:35fear conditioning and paradigm
30:37that we use early when we plug the.
30:41Subjective value for ambiguity under loss.
30:44It's totally mediated.
30:45The direct relationship between the level
30:48of combat exposure and the PTSD symptoms.
30:51Although we can,
30:53it's not a longitudinal standing.
30:54We know that hey happened before
30:57be thus can be what schedule,
31:00relationship and this schedule
31:02relationship you know.
31:05I'm fully mediated here by the level of.
31:10Aversive nastu ambiguous loss.
31:14So you can think.
31:18You can think about this PC population
31:22that we what we finding that they
31:25have hard time to deal with learning
31:27and updating when there is some level
31:30of ambiguity in the environment,
31:32and specifically when those
31:36decisions are involved.
31:38A negative outcome elect you know,
31:41mild shocks.
31:43And here we also show that it's can
31:47replicate it in in monetary losses and gain,
31:52whereas we didn't find anything.
31:55In the game domain.
31:59And so when we thinking all the study that
32:02my lab did and I was working as a clinician,
32:05and we I realized we're not dealing
32:08actually with the trauma, memory,
32:10trauma memory is very complex.
32:11It has connection to the self.
32:14It's part of who we are.
32:15We take our past present
32:17and we make interpretation.
32:19You know, the over over generalization fears,
32:22really, maybe express itself
32:25in our avoidance behavior.
32:26We are very jumpy.
32:28But the the the trauma memory
32:30and I did a lot of trauma,
32:33exposure and trauma focused
32:35psychotherapy and training it.
32:37And you realize when you are.
32:40Talking to patient, there is much more to it,
32:42just pure fear response.
32:46So trauma focused.
32:47Psychotherapy is effective.
32:49It's first line intervention recommended by
32:52all clinical guidelines published to date.
32:55It's ranging from 9 to 12 sessions.
32:58However,
32:59we know that there is high dropout rates,
33:01about 50% of the people drop out
33:04and remissions are only 50%,
33:06so there is a need for shift.
33:09There is a.
33:102 exposure 2 component to
33:12trauma focused psychotherapy.
33:14It's very possible is.
33:15That's why I like it.
33:16One is the exposure.
33:18Go out there, let's inhibit the
33:20over generalization of fear.
33:21You're gonna face a lot of garbage.
33:24Can make sure that you know you know
33:26they're safe and there will be an inhibition.
33:28However, there is other component.
33:30It's this really experiencing the memory.
33:32And when we conceptualize it as a
33:35failure to consolidate the memory,
33:38one memory consolidation is when
33:39you bring up the memory.
33:41Into label states.
33:43So consciousness.
33:44It's amendable to change,
33:45you can.
33:46It's like a material in the
33:49hands of the therapist to help
33:51the patient to rethink about it
33:53and put a new meaning to it.
33:56It's not an easy task,
33:57but however it it it's you you
34:00can think about and let's say
34:03for me like there was event.
34:06That we are hit by an IED
34:08and I remember that I was.
34:10Freezing,
34:11I don't know how long the freeze took.
34:13If it was one second or ten second.
34:16I remember just in my head it was running.
34:19I'm gonna die.
34:20I think this I remember this clearly
34:22it's like my my thought was I
34:24was not moving and I was thinking
34:27I'm gonna die in my head and then
34:29you snap out of that and and it's
34:31fight or flight instinct you you
34:34started to get engaged in combat.
34:37Eventually,
34:37you know we made it out of this
34:41situation, and then I
34:43started to talk about it.
34:45You know, to my friend and say I started
34:47to joke about how this freezing,
34:49you know, was really tremendous.
34:51Scary, But then I started to have
34:54some humor out injected into memory.
34:56So every time that I brought
34:58it to consciousness,
34:59it's stressful in a way and more manageable.
35:03It's happened to everyone in every time
35:04that you think about negative attribution.
35:06It seems like in PTSD.
35:08This memory is stuck in its original form.
35:11It doesn't go any transformation
35:13that every time that they have the
35:15flashbacks or some of the time,
35:17it's really recalling all the neural.
35:21Component of the smell, emotions,
35:24fear that was associated with the memory.
35:27It's like happening to them all over again.
35:30So the idea was here to use
35:33katamine to enhance new learning.
35:36I wanna talk about this study
35:39because Schiller and her mom
35:42made this very discovery.
35:45Interesting that if you create
35:48a reminder before an extinction,
35:51what is called you bring something into.
35:56Uh, the reconsolidation window.
35:58So they did like three groups.
36:00One of them did get no reminder
36:03for extinction.
36:04The two other Group One got 10
36:06minutes before the extinction,
36:07trying to reminder and the
36:09other one six hours so.
36:12And when they brought those people back
36:1424 hours after the extinction trial,
36:17they showed that the group that received a
36:19reminder 10 minutes before the extending.
36:22So before you,
36:23let's say you you were conditioned
36:25to a Blue Square.
36:26You've been shown only the Blue Square.
36:30Without anything else.
36:31You just brought this memory of Blue Square
36:33to a consciousness and only 10 minutes.
36:35After that you started
36:37with the extinction track.
36:38The Sumption was that the memory
36:40because you you evoke this memory
36:42of the Blue Square that allow it
36:45to be in label state and and so the
36:47group that had 10 minutes before the
36:50extinguisher had zero return of fear,
36:52whereas the group that had this reminder
36:546 hours or not reminder, had the return of.
36:57Dear friend nomina.
36:58So they concluded that the windows for
37:01reconsolidation is at least 10 minutes
37:03long but less than six hour long.
37:05We don't know exactly how long the
37:07memory stays in label label stay.
37:10They did an imaging study and it's
37:12extremely interesting result because
37:14what they show that in another reminder
37:17group in the extinction they need
37:19the ventral medial prefrontal cortex
37:21to inhibit the fear of the amygdala.
37:24However, in the reconsolidation,
37:25the group that had.
37:27The membrane label state there is no
37:30need to suppress mcdell activation with
37:33the ventral medial prefrontal cortex,
37:36thinking that is a new representation
37:38that doesn't need this inhibition
37:41activity of the ventral medial
37:44prefrontal cortex and that will
37:46link to our results later.
37:49So why can't I mean?
37:50Because we know that stress,
37:51overtime, create atrophy,
37:53and loss of dendrites, spines and branches,
37:57we know that.
37:58Katamine reverse this effect.
38:00So we know that and this
38:02tremendous amount of work
38:04done here at yell mostly.
38:07But later on Doom and lab work,
38:09and of course Jones and other people,
38:14discovery of Kitami Ketamin promote
38:18neurogenesis synaptogenesis cell
38:20proliferation studies here at Yale show
38:23that Ketamin reverse lower BDNF level
38:25in the hippocampus caused by stress get
38:27them in lower reactivation of theory,
38:30sports and animal alleviate.
38:32Is D like symptoms of
38:34animal models and inhuman?
38:36We know that it's lower depressive symptoms,
38:38that is transit if we using a single
38:41infusion and also in Mount Sinai,
38:44they show that ketamin show
38:46reduction in PTSD symptoms in adults,
38:50so that seems like that we have a
38:52window of opportunity 24 hours after
38:54infusion there is a pickup for the
38:57BDNF that lasts for seven days.
38:59After seven days BDNF levels come to.
39:03Baseline,
39:03so we thought let's try to use this
39:06window of opportunity to enhance the
39:09reconsolidation of the traumatic
39:11memory we did a screen patient
39:14with script them and we use Regina
39:18Sinha training opportunities and we
39:20learn how to script memory trauma.
39:23Said a neutral.
39:24We need a neutral because you need
39:27to compare activation to something.
39:29And the idea was to bring the trauma
39:31memory to the level of said memory,
39:33because we're not in the business
39:35of racing memory,
39:35but we want the trauma memory
39:37be said when I'm thinking about
39:38those events in the military.
39:40They said, you know, I can cry,
39:42but that isn't really.
39:45I'm not losing a day.
39:46I'm not losing an hour.
39:47I'm not losing like 3 minutes.
39:49It's gonna be, you know,
39:50transition of two seconds.
39:52I'm thinking about those events
39:54that happen to me and they are said
39:56and and we can acknowledge the
39:58sadness but they not paralyze me.
40:00And so we won't trauma memory to be kind
40:04of evoked in the level of other said memory.
40:07We randomized the group to ketamin,
40:10omit assalam.
40:11We had 14 in this pile of 14
40:15individual in the cat amine group
40:18and 14 in the medazzaland group.
40:21However, 1 participant in the
40:23middle and left after the infusion.
40:25She just said I came for
40:26the free drugs and left.
40:28We didn't lose a single
40:30participant to the intervention.
40:32Myself in and we started the exposure therapy
40:3724 hours after the ketamine infusion.
40:40Those took 44 consecutive
40:42days of exposure therapy.
40:45So what we had done is they
40:47want we did psychoeducation.
40:49Of course, the day Zero was the screening.
40:52We do cycle education and we built
40:55some hierarchy of exposure where
40:56people will go and voluntarily expose
40:59them self to things that they avoid.
41:01We try to reduce avoidance behavior by that,
41:04but that's not the focus of
41:06this intervention.
41:07On day two we did an MRI scan to
41:10achieve base 911 of activation
41:12of memory to the third neutral.
41:15And the trauma.
41:17And then after we did,
41:21the baseline memory level activation,
41:24they receive an infusion.
41:2614 minutes of .5 milligram per
41:29kilogram for the ketimine or
41:31.045 of midazolam per kilogram
41:34for 40 minutes. Day 345 and six.
41:39Every day they came met with
41:41a therapist and they trauma.
41:44Exposure therapy,
41:45processing the trauma with the therapist,
41:48trying to bring new meaning.
41:51And you know more it was open
41:54to the public, the study.
41:56So we had about would say probably 50%
41:59will rape victims and and about 50% war.
42:05But veterans that participate
42:07in the study took place in New
42:09Haven Hospital a day seven.
42:11We did another MRI scan,
42:13the post treatment,
42:14Macdill activation for the memories
42:16and we did another clinical assessment.
42:19We did a follow up 30 days scans
42:22again for the memory activation
42:24and clinical assessment and another
42:27clinical assessment just to see how
42:30symptoms reductions stay all the time.
42:33So let me take you through
42:35the results of the study,
42:37and so we look at them.
42:40Macdill activation to the
42:43traumatic memory at baseline,
42:45there was no difference between the
42:47group and both of the same level
42:50of amygdala activation distress.
42:54In response to traumatic memory,
42:56however, at the end of the treatment,
42:57there was significant reduction in
42:59amygdala activation to the trauma script.
43:03And when compared to the
43:07Medazzaland group and.
43:09When we look at the hippocampus
43:11activation to the trauma memory,
43:13we also saw a significant reduction
43:17in trauma recall activation in
43:20the hippocampus in the ketamin
43:22group when compared to the middle.
43:28When we look at the ventral medial
43:31prefrontal cortex, we didn't see
43:33any differences between the group.
43:36And I just want to remind that
43:38both the hippocampus, amygdala,
43:40hippocampus, and VM Pfc.
43:41There was no significant difference
43:43between the group prior to the study,
43:45so those reduction in the amygdala.
43:49And hippocampus showed really strong
43:53biomarker for the effect of ketamin
43:56underrepresentation of the trauma memory.
43:59And this is really a shift on
44:01this square or monetary gain.
44:03This is a whole new ball game when
44:05we using the real trauma memory,
44:08what they define as the air criteria.
44:12Another thing is what we done.
44:13We wanted to look at them connectivity.
44:16We knew that you know in regular fear
44:20extinction and lab paradigm we see the
44:23importance of VM Pfc activation to reduce.
44:28Amygdala activation this is did not.
44:31Was that what we did?
44:34We did not, sorry,
44:35observed that in our study what we saw
44:38is the decoupling of the katamine and of
44:42the amygdala with the hippocampus indicator,
44:46mean group much significant, more.
44:49We see this decoupling of the connectivity
44:52between hippocampus and amygdala
44:54indicate groups compared to the middle,
44:57so when we're thinking about chillers.
45:01Result it's made really clear to
45:03us that what we are seeing is this.
45:06The new pathway for memory reconsolidation
45:09of the original traumatic memory.
45:11It seems that there is less distress
45:14being expressed by the neural signature
45:17of the trauma indicator mean group.
45:21Compared to me that slam and that that
45:24doesn't involve the inhibition of.
45:28Ventromedial performed aquatic.
45:29It seems that the memory is now
45:32represented in in a way that is
45:35less distressful to the patient and
45:37there is no need for this tremendous
45:39inhibition to say it's OK, it's safe.
45:42The memory itself already has this more.
45:48Inappropriate representation and we
45:50when we compared the memories of the
45:53trauma to the set of their treatment,
45:55there was no difference in activation.
45:57Exactly as we wanted it to be.
46:01In the original design. We did some.
46:04We play around with the data
46:06just to make sure that you know.
46:09If we can use machine learning to
46:12differentiate between the group and
46:15that receive katamine Ahmed Aslam,
46:17we took the those area of interest
46:20here that amygdala and we looked at
46:22Vauxhall activation, so the you know,
46:25the extra amount of voxels in
46:28the amygdala that respond each
46:30one in a different in a patterns.
46:33And it's like a dance of each voxel that,
46:36in response to the trauma memory,
46:40so we wanted to see if the.
46:41Information learning that we can
46:44reliably say this is the way that.
46:47The amygdala respond,
46:49then sore to the rhythm of ketamin,
46:53versus midazolam,
46:54and we show that the machine learning
46:57was we were able to differentiate the
46:59reliably between those patterns of
47:02activation in the amygdala between
47:04the cattlemen and gasoline groups
47:06that know that they are responding in
47:08different ways to the trauma memory.
47:11A definite treatment.
47:13The same pattern analysis of the
47:16hippocampus responds to the trauma
47:18memory was differentiated reliably
47:21much above chance.
47:24There saying this is the hippocampus
47:28response while this subject was
47:31receiving midazolam versus ketamine
47:33at the end of treatment.
47:36So we didn't talk about the PTSD symptoms,
47:39so when we look at the PTSD symptoms can
47:43four days intensive psychotherapy work?
47:47So this is the PTSD symptoms overtime
47:51and we put a cut off line here in blue.
47:55So on average of course not.
47:57No one treatment works for everybody,
48:00but you see that at the end of
48:03treatment and this effects lasted.
48:06With 90 days and post treatment,
48:10the reduction of PTSD symptoms that
48:14were significantly and strong.
48:16This is the entire sample.
48:18If you look at the sample,
48:19even like in median level,
48:21it's more striking.
48:23You see that 50 the median score of the PCL.
48:27The PTSD checklist was 50 at the
48:30beginning of treatment at the end
48:32of treatment is was 32,
48:33remain 30 around 33 in 30 day follow up
48:40and down to 2790 day post treatment.
48:45However,
48:45we did not find any significant
48:48difference in the symptoms between
48:51the ketamine and medazzaland.
48:54And this is kind of raised a lot
48:56of questions because, you know,
48:58this is we when we ask subjective
49:01question about how people feel.
49:03It seems that they not reflect
49:06our biological biomolecule.
49:08And we don't know exactly how
49:10to reconcile it and and when I'm
49:13thinking about it,
49:14you can think about and this is
49:17significant move to move in NIH.
49:19We know the outlook into biomarkers
49:22and stay away from questionnaires
49:27and specifically the DSM file.
49:31And if I'm thinking about some
49:33two patient coming to emergency
49:35room with a cardiac arrest,
49:37they have both the same objective measure
49:42that indicated the medical condition.
49:46All the measure of the same,
49:47but one of them will say my chest
49:50pain is 9 and. Other one will
49:53say my chest pain is in level 6,
49:56so the subjective reporting of distress
49:59might be not always in full correlation
50:03with the biological bond market,
50:05and I don't know how to reconcile this.
50:08This is something that really interesting
50:13and needs further investigation we went.
50:15We also collected GSR and we say OK,
50:17GSR our behavioral biomarker that
50:20can reflect in level of distress and
50:25and when we look at the GSR data.
50:29In response to the trauma script.
50:34And compared baseline to end of treatment,
50:38we saw that people in the ketamine
50:40group had lower GSR response to the
50:43Trauma's group at the end of treatment.
50:44So we got another bomb of like a behavioral
50:47proxy that's also indicated that they are
50:51experienced something less than that.
50:54Less distressful, however,
50:55we didn't differentiate one able to
50:59differentiate on the symptom checklist.
51:01So this is something,
51:03of course, that.
51:06Is very.
51:07Important to think how and and what will
51:11be way to assess a successful treatment.
51:15Today there are 61 of course only
51:17require biomarker in order to move
51:20forward to an R33 for a clinical trial.
51:22They don't even interested in symptoms
51:24as long as you show the go no go
51:27criteria and this is the direction
51:28that we want to go with the study
51:30of course and our 61 or 33 combo.
51:35So to summarize.
51:39And I think what we showed that in
51:42our lab that individual was PTSD have
51:45really hard time learning safety and
51:48danger when there is a high level ambiguity.
51:51And we know that life,
51:53full of uncertainty,
51:54and this is in fact the way that
51:57how you you know you expect things
52:00and how you behave.
52:01In there in the environment and
52:04and that's something that we want
52:07to target through this window of
52:10opportunities that allow to get
52:12them in that catarman allows us.
52:15So we know that four days.
52:18Psychotherapy.
52:18Regardless,
52:19like controlling for medication works
52:21very well and there is like what
52:24is called written exposure therapy,
52:26that's another form of exposure therapy
52:29that people comes and write down the
52:32trauma and they do it five times once a week.
52:35So the idea is to evoke the re
52:40restart the reconsolidation process.
52:42We saw that four days seems to be a
52:47very meaningful intervention and has.
52:49All the potential and we can probably
52:51think about people coming and doing
52:54one week therapy.
52:55And taking a week off to deal
52:58with something like that,
52:59does ketamin enhance this
53:01effects of exposure therapy?
53:03Yes or no.
53:04So you know, it's not seems to be
53:07reported when we ask the symptoms.
53:09However,
53:09we when we look at the brain and the GSR we
53:13see a significant and meaningful effect here.
53:16In, in, in the cattleman group
53:19versus the MEDAZZALAND.
53:21So our design was tricky,
53:23and because if you remember
53:25when I showed the day
53:26two, we recall the memory,
53:29the trauma the said.
53:31And the neutral in the MRI.
53:35And after we finish doing it,
53:37we did a 40 minutes infusion.
53:40It was about you know half an hour
53:43between 15 minutes to half an hours.
53:48The range after we finish
53:50people listen to the memories.
53:52The question because we don't
53:54know how long memory we know that
53:56the reconciliation windows is
53:57already closed after six hours.
53:59But maybe those trauma memory we
54:01still in label state when they
54:04receive the middle and actually
54:06one single in middle and infusion
54:09maybe blocks the reconsolidation
54:11and we have some evidence to that.
54:14And had a positive therapeutic effect here,
54:18so that's why we see this
54:22symptoms improvement in the group.
54:25Maybe we need to change a placebo
54:27in the large clinical trial and
54:31there is a notion that.
54:34We are pushed by the NH officer here now
54:38to maybe to explore different those idols.
54:42.5 milligram of ketamin to kilogram
54:44and maybe going with a lower dose.
54:46That was the dose that toasted
54:48also by Charlie Abdalla and John
54:50Crystal in there in large clinical
54:53trial for KETAMIN for PTSD.
54:57And maybe we need more than one infusion.
54:59We know that seven days within seven
55:02days BDNF levels go back to the baseline.
55:05So maybe we need to increase the
55:07number of infusion and do two infusion
55:10within that week in order to really
55:12harvest the the positive neurogenesis.
55:17By created by the Ketamin group,
55:20so I want to thank everybody again.
55:24All the wonderful people at yelled at,
55:26you know,
55:27help me to do this research and
55:30my collaborator.
55:31And I'm open to questions now.