Name: Yale Department of Psychiatry Grand Rounds, September 18, 2020: Alcohol Adaptations in Stress Circuits: Impact on Motivation, Intake and Treatment Outcomes
Uploaded: 2020-09-18T15:43:12.187Z
Duration: 55 min 44 s
Description: Rajita Sinha, PhD, Foundations Fund Professor of Psychiatry and Professor in the Child Study Center and of Neuroscience, Yale School of Medicine

Yale Department of Psychiatry Grand Rounds, September 18, 2020: Alcohol Adaptations in Stress Circuits: Impact on Motivation, Intake and Treatment Outcomes

September 18, 2020

Rajita Sinha, PhD, Foundations Fund Professor of Psychiatry and Professor in the Child Study Center and of Neuroscience, Yale School of Medicine

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00:00My. Time.
00:05Where it's time to start, I'd like to
00:08welcome everybody to our grand rounds.
00:11Lecture today, which is titled Alcohol
00:14adaptations and stress circuits.
00:17Impact on motivation and
00:20taken treatment outcomes.
00:22Our lecture today is Rajita Sinha,
00:25who's the foundation funds professor
00:27of psychiatry professor in the
00:29child study center in neuroscience.
00:32Director of the Yale Interdisciplinary
00:34stress center, chief of the psychology
00:36section in psychiatry and Co.
00:39Director of Education for the Yale
00:42Center for clinical investigation.
00:45I want to remind everybody that during
00:48the the grand rounds presentation,
00:52please keep your microphones muted and.
00:57If you would like to have
01:00continuing education credit,
01:02Please send in the code 22126.
01:06Two, the number that's on the screen 203.
01:114429435 26.
01:18That's right 22126.
01:23OK. I just wanted to say a little
01:26bit about Regina's background.
01:29Jeter got her bachelors at Delhi
01:31University and then went to the
01:34University of Oklahoma where she
01:36trained with Oscar Parsons are very.
01:39Famous cognitive neuro scientist
01:41and psychologist really wanted The
01:44Pioneers and the alcohol field in
01:47that area and then came to Yale.
01:52She's had an incredible record
01:55of accomplishment at Yale.
01:581st as clinical director Ann,
02:01then, director of the substance
02:03abuse treatment unit at the
02:05Connecticut mental Health Center,
02:08founding director of the score grants
02:10on sex differences in addiction.
02:13Then just a remarkable achievement.
02:16Director of an NIH road map initiative
02:18on stress of very interdisciplinary
02:22interdepartmental enormous initiative.
02:24Of which in its time was the largest
02:27grant ever awarded to a faculty member
02:30in the Department of psychiatry.
02:32And then and then from that
02:35was the founder of the Yale
02:37Interdisciplinary Stress Center,
02:39which continues today.
02:44Um? Ridgid's work is very much rooted
02:49in a clinical research on addiction.
02:53Going back to the 1990s,
02:55where she studied stress induced in cue
02:59induced craving for substances of abuse.
03:03Leading to a seminal paper
03:06that she wrote in 2001.
03:08Asking the question how does stress
03:11increase the risk of drug abuse
03:13and dependence can see this is
03:16been a theme throughout her career.
03:19And then in the era of neuroimaging
03:22to try to bring.
03:23This work to the brain by characterizing
03:29neural circuits involved in
03:32stress an in craving an other.
03:36Facets of self dysregulation.
03:41And then leading to a variety of important.
03:45Perspectives on treatment,
03:47including her work, going back to
03:51the 2000s of mindfulness training.
03:55And medications, including processing
03:57and guanfacine and other medications.
04:03Jesus really been a leader in the field
04:07serving on the NI AAA council she is.
04:11Been nominated for the night
04:13at Council and she served as an
04:15advisor in a variety of different
04:18variety of different organizations.
04:20She's also a very visible person.
04:24Often contacted by the press or for TV shows.
04:30She's received a number of honors.
04:33I just list 2 here.
04:34One is the chairman's award from
04:37the L Department of psychiatry.
04:40Now unbelievably,
04:4120 years ago for 20 years ago
04:45and and this year, of course,
04:48she received the Distinguished
04:51Researcher Award from the
04:53research society on alcoholism.
04:56So without further ado,
04:58then it's a tremendous pleasure to
05:02welcome Riggi to Sinha to present
05:05our Department grand rounds today.
05:10Thank you so much John.
05:12That was I didn't realize you would
05:15actually go back to the beginning.
05:17It does feel like a long time.
05:21Many of folks that are still here
05:24and others have not been our newer,
05:27but yeah, it has been 30 years,
05:30so it's a It's a pleasure
05:32to speak to you all today,
05:34even though it's unzoom.
05:36Guess I should share my screen.
05:38Let me see if I can.
05:44You don't see that.
05:46OK great. Well thank you.
05:48So let me get started.
05:50As John said, I've been sort of
05:52interested in the in studying the
05:55intersection of stress and addiction.
05:57An in fact as we consider this.
06:00So let me see why I'm not.
06:04Here we go.
06:05There has been it's well known
06:07that there is this bidirectional
06:09relationship between stress and
06:11addiction and really stress and reward.
06:13And one simple way of thinking about
06:16it is that when you have increased
06:19stress or a traumatic situation,
06:21there might be an increase in reward,
06:24particularly in vulnerable individuals.
06:25So by that I mean that high
06:28stress and anxiety states may
06:30enhance the sense of reward.
06:32If when you're engaging in.
06:34Any kind of rewarding behavior an
06:37and then a number of people started
06:40to look at and talk about the
06:42impact of drugs on stress as well,
06:45and therefore that bidirectional
06:47relationship, and in fact,
06:48as we think about number of
06:50rewarding substances and behaviors.
06:53This relate.
06:53Bidirectional relationship
06:54has been discussed.
06:55We are in the period of covid stress
06:58and there is increasing attention to the
07:01fact that Americans are drinking more
07:04amid the COVID-19 pandemic and experts
07:06warning that relief may be temporary,
07:09and there may be issues related
07:11to greater vulnerability,
07:13especially for those who
07:14have the susceptibility.
07:16In fact,
07:17as we can imagine,
07:18because bars were closed and access
07:21was limited on side sales were down,
07:24but ecommerce profits have increased 30%.
07:26The beverage industry is sort of
07:29out there talking about the fact
07:31that their sales overall is not
07:34increased and so they should be
07:37some caution around worrying about.
07:39About these increases an.
07:41In fact the dialogue around that
07:44with them an at The Who level
07:47worldwide has been who's most
07:50susceptible to these increased
07:52drinking episodes an during covid.
07:55So I think this particular topic
07:58is particularly is especially
08:00relevant in the period of Covid.
08:04So let me just talk about what
08:06I want to cover today.
08:08Disruption of the stress circuits,
08:10particularly the coping stress
08:11resilient coping circuit as a
08:13target pathway for alcohol,
08:15compulsive seeking or drug
08:17compulsive seeking.
08:18Binge alcohol use and disruption
08:21of the neuroendocrine response
08:22to stress and to alcohol.
08:24Alcohol related changes in
08:26stress pathways that predict
08:27relapse and treatment outcome.
08:29And can we target this particular
08:31what I like to call stress
08:34pathophysiology of alcohol to address
08:36to improve our treatment outcomes.
08:39So we know of course,
08:41that there is this dopamine rich region
08:44circuitry that is called the reward
08:47circuitry in the brain going from
08:49the VTA to the comments to the Pfc,
08:52the nucleus comments,
08:53or ventral striatum is been sort
08:56of expanded into the dorsal
08:58striatum for the dopamine rich
09:00regions and the reward circuitry.
09:02So of course the and is beautiful
09:05data showing that this in fact
09:08circuit is activated when you.
09:10Participate in dude.
09:13Rewarding behavior whether it's
09:15in imbibing a substance or a
09:17rewarding behavior like gambling.
09:20What about stress related motivation?
09:22Before there were drugs of abuse,
09:24we obviously have this.
09:26This reward pathway in the brain.
09:29And what is it for really is one question,
09:32and in fact it's embedded hardwired for
09:35social reinforcement, social reward,
09:37natural rewards as well as if you
09:41have to run when you're faced with a.
09:44With the you know,
09:46aversive stimulus like large animal
09:48that looks like a Tiger perhaps,
09:50or something it really scared of.
09:53You need to mobilize.
09:54You need to know firstly that that this is.
09:58This is a difficult situation.
10:00Then you got to move and run and
10:02just this pathway is very involved
10:05in that it connects to the motor
10:07regions and is important in
10:09intent even in stress conditions.
10:11Well, I can say that but let me show
10:14you what we did and this is now a
10:17few years ago we wanted to understand
10:19what does this stress system have
10:22to do with this sort of coping and
10:24stress coping circuitry.
10:26So we designed a study where
10:28we showed really awful,
10:29aversive, threatening,
10:30challenging pictures in blocks.
10:32And those were the stress blocks compared
10:35it to relaxing non stressful pictures.
10:37And that was the neutral blocking
10:39these community volunteers and
10:41we got a very nice rise here.
10:43You can see in Stressfulness on a 9
10:45point scale that was sustained across
10:48the period from R1 to R6 years.
10:50The period of being exposed to
10:52the Stressor there was really high
10:54arousal and there was an increase
10:56in cortisol response.
10:58The main point I want to make here is
11:01there's a lot going on in the brain.
11:04At when you see red yellow,
11:05it means that those regions of the
11:08brain were activated an in addition to
11:10the amygdala in the in the hypothalamus.
11:12The key thing I want to show you
11:14is the striatum is really highly
11:16lit up and very much involved,
11:18as is the insula,
11:20because you're getting a lot of internal.
11:23Perceptual need coming up and signaling.
11:25Coming up from the body in terms of
11:29being stressed out and then what you
11:31see here in blue is this region of
11:34what we call the ventromedial Pfc.
11:37You're going to hear me talk about
11:39that quite a bit, so that going down,
11:42being blooming deactivated initially,
11:44and this is the dorsal ACC involved
11:47instead of intent, an action,
11:49and when because we were doing
11:51concurrent cortisol,
11:52you can see the circuitry.
11:54This is a whole brain cortisol.
11:56Map and what you can see is that
11:59in fact the ventral striatum
12:01extending into the dorsal striatum.
12:03The hypothalamus,
12:04amygdala are all positively correlated.
12:07Whoops with cortisol and the
12:10ventromedial Pfc that blunting is
12:12negatively correlated an then the
12:14key thing here that I wanted to
12:16show you is that there's actually
12:18a dynamic change going on during
12:20those runs that we had,
12:22and in fact the key regions
12:24where there was a
12:25mobilization and you might recall
12:27this was blue in the ventromedial Pfc.
12:30You start to see that start to
12:32come back up and the ventral
12:35striatum also coming back up.
12:37So really perhaps the region.
12:39The reward coping region is sort of
12:41mobilizing and we started to call
12:43this the resilient coping circuitry
12:45mainly because that dynamic change
12:47during stress was associated with
12:48active coping on the Cope scale
12:51which subjects had had completed
12:52that and also how they cope with
12:55stress in different questionnaires
12:57and what we found is that people who
12:59would not able to show the dynamic
13:01response in fact were those who are
13:04more likely to have higher scores
13:06on emotional eating or those who
13:08are reporting that they tend to.
13:10Have more arguments and fights sort of
13:13have emotion dysregulation and lashing out,
13:15and with those who happened
13:17to be binge drinkers,
13:19so that allowed us to sort of
13:21extend into our sort of speculation
13:23that this indeed is an active,
13:26resilient coping circuitry.
13:27So we identify this as yes,
13:29it's one that's activated by drugs
13:32of abuse and natural rewards,
13:34but it is really one that is an active
13:36coping motivation circuit that's important.
13:39Inflexible control of behavior.
13:41So we started to think
13:43more broadly about well,
13:44so the dopamine rich regions
13:46are activated by drugs of abuse.
13:49What about other regions?
13:50And of course other systems.
13:52And in fact, here's a data by Nancy Mellow.
13:56Put it put together in a review paper
13:59showing that high nicotine cigarette.
14:02Dramatically activates the HPA Axis.
14:04ACTH cortisol as well as an origin ergic,
14:07Arousal Annuar,
14:08active steroids,
14:09and so this started to help us think about.
14:12Well,
14:12there's more going on than the
14:15dopamine rich regions.
14:16When you think about alcohol,
14:18some of this data is now published.
14:21What you see here is that heavy drinkers
14:24binge heavy drinkers in the light greys,
14:27a light, moderate,
14:28non bingers,
14:28but binge heavy drinkers just
14:30basically show a shift and.
14:32Increase in their cortisol levels
14:34so that starts to show that that
14:37by the biological stress response
14:39is adapting and changing as a
14:41function of active drinking.
14:43These folks are not stopping there,
14:45just regular binge heavy drinkers.
14:47They're not dependent,
14:48and you see that in two separate.
14:52Who has recommitted onescu so we
14:55then did a study where we expose
14:59people on three separate days
15:02to either stressed skew alcohol.
15:06Q Al correlated trigger or a neutral
15:08Q and then we presented them with
15:11what we call what we what is well
15:14known in the alcohol literature as
15:16the alcohol taste test which is
15:182 beers are shown and individuals
15:21are asked to taste them.
15:23To determine whether they are the
15:25same brand or the same type or different an,
15:28we call this an implicit
15:30alcohol motivation test.
15:31Alan Marlatt developed it and
15:33essentially what you find is that
15:35people and we tell them you can
15:37drink as much as you need to to
15:39make that determination,
15:40they get $10 for doing it,
15:42so there were three separate days where
15:45they got either alcohol Q or stress Q
15:48or neutral Q Context prior to the tray
15:50with the two drinks showing up and then.
15:53They get to drink it for 10 minutes
15:55and then we're monitoring them.
15:57The key thing is that quite reliably,
16:00now in two separate studies,
16:02we find that binge heavy drinkers
16:04in this is similar to what Alan
16:06Marlatt had shown will consume more
16:08to make the determination whether
16:10the two beers are same or different.
16:12So you see that across all three days
16:14is really high reliability that they
16:16were in fact drinking more to make that
16:19determination that binge heavy drinkers.
16:21And we see that post drinking.
16:23You see a rise in cortisol.
16:26Of course, they drank more,
16:28so you see the bench.
16:30Heavy drinkers have a
16:31bigger cortisol response.
16:33It's smiled because it's so
16:35small amounts of cortisol,
16:36I mean small amounts of alcohol,
16:39but nonetheless we see a significant
16:41increase in cortisol post consumption.
16:43Then the interesting thing was
16:45pre consumption when they folks
16:47were exposed to the cues we see.
16:50In fact, a blunted response in the
16:52binge heavy drinker,
16:54so remember.
16:55I showed you that baseline.
16:57They have high responses and
16:59then in response to stress,
17:01they're actually blunted
17:02compared to the bench compared
17:04to the light moderate drinkers.
17:06An in fact that blunted response in
17:08cortisol predicts how much they consume
17:11in this implicit motivation test.
17:13So cortisol is having an effect.
17:15I will say we have beautiful effects
17:18of craving in this paper that craving
17:21predicts intake across all three conditions.
17:23An cortisol in craving are not connected,
17:26so.
17:27We start to see separate pathways
17:29that are influencing motivation.
17:31Once through the subjective,
17:33wanting sailing sort of state,
17:35the other through the biological
17:37pathway of stress destruction.
17:38So we put out this notion that
17:41that would binge heavy drinking
17:43or with active alcohol you get
17:46a rise in your basil state.
17:48Sort of this.
17:49You'll start to hear and allostatic
17:52kind of model or explanation here
17:55that then there's when you get.
17:57When you actually consume alcohol,
17:59a standard alcoholic drink.
18:01Being heavy drinkers have a blunted response.
18:03I showed the same with,
18:06uh, stress manipulation.
18:07An in fact, then,
18:08in the face of being presented with queues,
18:12there is a need to drink more to
18:15perhaps bring back this response,
18:17bring back your Basil,
18:18State of responding or normalizing
18:20the stress response,
18:22so to speak with alcohol.
18:24So that's something we are we are.
18:27Pursuing and testing in different ways,
18:29but this was sort of our
18:31speculated heuristic model of
18:33the role of glucocorticoids.
18:35I should say here for those who are
18:37interested in whether we think that the
18:40peripheral glucocorticoids or cortisol
18:41is actually changing motivation.
18:44We do not think so.
18:46We think it's a marker.
18:48We think that that's really a
18:49marker of Central Activational
18:51central glucocorticoid pathways
18:52influencing the motivational circuits.
18:54So what about in alcohol use disorders?
18:57We have several treatments
18:59and alcohol use disorder.
19:01Treat alcohol use disorder, but.
19:04The treatment impact has been modest
19:06and we all here know this because
19:09naltrexone was developed here.
19:11There's been a lot of development
19:13in focus on treatment development
19:15in alcohol use disorders here,
19:18and so we started to think about how can
19:21we improve these treatments and wanted
19:23to go back to what happens to this
19:27stress pathway in alcohol use disorder,
19:30particularly as folks initiate
19:32treatment or start cutting back.
19:34And then the phase of abstinence,
19:36or early abstinence maintaining recovery.
19:38We know that there are high relapse rates.
19:41I'm going to show you some data
19:43of that for that an so we started
19:45to think about whether these
19:47different phases can be broken down.
19:50Could there be a need for as recovery starts?
19:53Perhaps this recovery in these in
19:55these pathways would there be a need
19:58for different types of treatment?
20:00Let me read to you. This pace.
20:02Someone who reached out as she
20:04was struggling with her recovery.
20:06Anne Rd about it and I thought
20:09it was very shows.
20:10Very articulate at 8 weeks without a drop.
20:13I really noticed I'm living
20:16less on instinct and habit.
20:18I can think much more clearly.
20:21And take time to process thoughts
20:24mature Lee before acting.
20:26I even notice I'm just talking less.
20:28I haven't had fully formed
20:30thoughts for so very long.
20:32It's kind of nice to have
20:35my faculties back again.
20:37In the past it's all been so
20:40superficial just to get me from A to B.
20:43Just to keep up the veneer of
20:45being a full human,
20:47but underneath I was just
20:49a slave to the bottle.
20:51Hungover hiding myself very much.
20:53A knee jerk reaction.
20:56But now I'm no longer feeling silence
20:58is nagging at my kids interrupting
21:01people while they're talking.
21:03I'm just listening.
21:04And not even planning how to
21:07react just sitting.
21:08With the moments and observing, hearing,
21:11feeling quiet and contented myself.
21:15I even think I found my chi.
21:18Without even knowing what that word
21:20meant a week ago, I felt something.
21:22Like a place inside my soul.
21:25Something I think I remember
21:27discovering as a child and teen
21:30before alcohol smothered it.
21:32A presence of myself.
21:35I thought she wrote this quite
21:37articulately about which.
21:39What are the struggles of that
21:41early recovery period.
21:42The first 8 weeks as she described an in.
21:46Really she's one of the lucky ones
21:48who makes it through eight weeks
21:51without without drop as she says and
21:54starts to notice the changes in a
21:57lot of which she's talking about.
21:59Is this higher executive function
22:01function this sense of self?
22:03The sense of feeling?
22:05Do controls.
22:05Building back herself control building back.
22:08Her ability to observe and notice
22:11people around you.
22:13Maybe even start to,
22:14of course, think clearly,
22:16but particularly emotional regulation.
22:18Emotional intelligence coming back.
22:20Thank you for some insight,
22:22which I thought was was a really
22:26interesting that capacity
22:27to have some insight and reflection.
22:30And these are components of
22:33higher order cognitive function
22:34that that folks in addiction.
22:37Our study is starting to characterize.
22:39And studies, so I thought it
22:41captured that pretty well.
22:43So we wanted to let me show you
22:45first our data from right here.
22:48The substance abuse treatment unit.
22:50In one year,
22:51data from 878 patients outpatients
22:53classified by different drugs of abuse.
22:55In the in the green is the alcohol.
22:58Of course,
22:59at tattoo we use the medications pretty
23:02religiously that are available for
23:04alcohol and so you see that effect.
23:06But critically,
23:07what I want to show you here on
23:10the X axis is time to discharge.
23:13And on the Y axis is sort of the
23:15proportion who remained abstinent
23:17or who were abstinent at discharge.
23:19So essentially it captures both at both
23:21the dropout rate as well as being abstinent.
23:24An weather weather at drop out,
23:25they were abstinent and so a lot of
23:28times when we think about recovery
23:30we think about this later period
23:32we kind of got obsessed with this
23:34beginning period 'cause there's
23:35this constant revolving door.
23:37When you're in addiction treatment
23:38you know about the revolving door.
23:40People who show up for one or two
23:43appointments and can show up after.
23:45That's what's represented here.
23:46You see a precipitous drop in the
23:48beginning and we really haven't
23:50understood that very well,
23:51and then there's this next phase of
23:54where people are falling off the wagon.
23:56And you see that in with alcohol as well,
23:59and so in some ways we wanted to
24:01ask the question if these are
24:03similar processes or could there
24:05be other things going on as people
24:08are initiating recovery.
24:09Many of you have seen this.
24:11This slide of ours where we started
24:13to bring what people are facing out
24:15in the real world as they struggling
24:18with early recovery into the laboratory.
24:20An provoking sort of their triggers to
24:23often talk about when I get stressed out.
24:25I don't know what happens.
24:27I start using.
24:28And so we started to in provoke stress,
24:31compared it to drug keyuan neutral
24:33in a tight experimental situation
24:35and just with five minutes of
24:37exposure you see sustained increases.
24:39And this is what became
24:41stress induced craving,
24:42which has been described numerous Times Now.
24:45And of course Q and use craving,
24:47which has been described an what we
24:50showed early on was that higher the
24:52stress induced stress induced craving,
24:54the provoke craving in the laboratory.
24:57So right here in the.
24:59Open.
25:01Squares here and hire
25:02the cue induced craving.
25:04The more quickly people respond,
25:05relapse on the X axis is time to relapse.
25:08You'll see a lot of these curves
25:11an on the Y axis is survival,
25:13so not relapsing and you
25:15see the precipitous drop.
25:16If you were a high Craver,
25:18so we identified that actually
25:20craving does have an impact,
25:22but what I wanted in coming back
25:24to this notion of where we are
25:26today with this and you're going
25:28to see me pointing this out so craving
25:31then is a predictor variable here,
25:33meaning it's a potential.
25:34Behavioral marker of relapse.
25:36But I want to show you the variability.
25:39OK not everybody craves and
25:41in fact we have 0 right here.
25:44People who were not craving and in fact
25:47about 30% of people when you provoke
25:50craving will not report craving.
25:52Maybe 20 to 25 under provocation states,
25:54but more so in if you're measuring it weekly.
25:58But most importantly there isn't good
26:00group of people who are reporting
26:03it an in fact it's not just.
26:06Amir rating it seems to have
26:08an impact on on relapse.
26:10These folks.
26:11By the way,
26:12these early studies were inpatient
26:14when we did the provocation and
26:16manipulations and then they
26:18were discharged to aftercare,
26:20outpatient aftercare and we followed
26:22them and so this is relapse.
26:24During aftercare we looked at
26:26their HPA access response and in
26:29fact they High Court ACTH ratio,
26:31which is a measure of adrenal sensitivity.
26:34This is the Basil measure.
26:37And it actually captures there that
26:39blunted responding during stress provocation.
26:41An that is well predicted relapse here,
26:45with high levels of the ratio
26:47leading to very precipitous drop in
26:50the ability to maintain abstinence.
26:52Again, we see variation in these responses,
26:55and frankly,
26:56with any neuro biological study
26:59that we're doing,
27:00all of us have been doing it.
27:03We have variation in there,
27:05and so the question is.
27:08How are we going to be able to
27:11capture variation?
27:12This is a structural analysis of
27:15voxel based morphometry showing the
27:18medial prefrontal cortical region
27:20is smaller the region the worst,
27:22the outcome in terms of time to
27:25relapse and then this disrupted
27:27functional activation where in
27:30the neutral condition we have
27:32activation or higher levels and
27:35inability to relax in this in this.
27:38Coping circuit ventral striatal vetera,
27:40medial Pfc coping circuit and then
27:42distress conditions of blunted
27:44responding and once again that being
27:47important for predicting future
27:48relapse again we see variation.
27:50So this variation.
27:51So we have significant findings.
27:53We've got great data.
27:55What do we do clinically with this variation?
27:58So we again got very obsessed with
28:00this in terms of clinical translation.
28:03Who is most vulnerable to these changes?
28:06And can these bio behavioral
28:08markers help us identify?
28:10Those who are most vulnerable.
28:11We don't just want to show that
28:14alcohol leads to these changes
28:15and that it's a brain disease.
28:17Can we bring that translation back
28:19into the clinic to help us improve
28:21treatments for alcohol use disorder?
28:23And so you might start to think about,
28:26well, they should be moderate yrs of.
28:30These of our treatment outcomes
28:32an could we use that to enhance
28:34what we now know is it's called
28:37personalized medicine?
28:38No precision medicine.
28:39So in thinking about that,
28:41you could think about disease,
28:43pathophysiology,
28:44some of the things I've been showing you,
28:47perhaps severity,
28:47acute withdrawal,
28:48drug abstinence,
28:49the days that you can conjure up in
28:52terms of abstinence may contribute
28:54to the degree of these changes or
28:57the lack of recovery.
28:59The lack of normalization that may happen.
29:02As a function of initiating treatment,
29:04then there might be folks who,
29:06because of their predisposing factors
29:08such as only trauma or stress,
29:10May in fact be more vulnerable to some
29:13of the alcohol related adaptations.
29:15I was showing you earlier.
29:17It could be that comorbidities
29:19could in fact be playing an
29:22intersecting with those changes in
29:23the brain an in the stress circuit,
29:26and then gender plays a role which
29:29you're not going to hear me talk about,
29:32but it's a very important.
29:35Factor, and we've shown we've
29:37published data on that as well,
29:39and then they may be genetic.
29:42An Pharmaco Genomic effects.
29:43I'm just going to show you for in
29:47the interest of time and just to show
29:50you that these factors do matter,
29:52I'm going to stick with
29:54disease pathophysiology.
29:55So how much alcohol folks may have consumed?
29:58And how much does acute withdrawal
30:01in abstinence impact this?
30:02This circuitry so using again are newer?
30:06Approach to provoking stress.
30:08Q States we now added the
30:11alcohol an in drug studies.
30:14We've added drug block essentially.
30:16Now folks in addition to seeing averse,
30:19threatening awful images just
30:21coming at them continuously.
30:23They also have a block of
30:26alcohol images coming at them.
30:29An of course the neutral relaxing images.
30:32These blocks are randomized
30:34in counterbalanced,
30:35presented in various ways in.
30:38In specific, standardized ways,
30:39and the paper showed that,
30:41and again we are concurrently monitoring
30:43autonomic an HP access response.
30:45What I want to show you is distress
30:49response during and this is now P1 to P6,
30:52so six runs,
30:53provocation runs and the baseline period,
30:55and that folks is level of stress
30:57and what you see is that people
31:00are get highly stressed in the
31:02stress condition which is in red.
31:05Here an blue is the alcohol Q condition.
31:08And like as a neutral condition,
31:10what I want you to see,
31:12a udi's alcohol use disorder in the bench,
31:15heavy users here nondependent
31:16users is that there is a diss Basil
31:18shift in even the level of stress
31:20that the patients are feeling
31:22these at treatment entering folks,
31:24they haven't initiated treatment that
31:26Dave engages the intake period and they
31:28get scanned and he is craving in craving.
31:30You see a beautiful very little in the model.
31:33Drinkers are really more
31:35sustained craving in the bench,
31:36heavy drinkers an then a Basil
31:38shifting craving.
31:39Right, even at baseline,
31:40when it's assessed in a controlled way and
31:43then an increase in response to stress.
31:45And we see a stress induced
31:47craving and Acuna scraping,
31:49which you've seen previously.
31:50What happens in the brain?
31:52A lot of blunted responding in the
31:54in that resilient coping circuitry
31:56in our reward circuitry right there.
31:58Under stress neutral stress
32:00versus neutral conditions in the
32:02queue versus neutral conditions,
32:04much more so in the alcohol use disorder
32:08group relative to social drinkers.
32:10And once again,
32:11this hyperactivity in the
32:13neutral relaxed state.
32:15So really a disrupted respond
32:17disruption of the brain's functioning
32:20under under challenge States and as
32:23well as under relaxed States and
32:25here we just you see the beta weight,
32:28meaning the region of.
32:30Number of voxels activated and the
32:32difference between the AD or the AUD
32:34Group and the social drinking group
32:37for these target regions of in.
32:39Frustrate him, and the ventromedial Pfc.
32:43The reason why I wanted to show you
32:45that is that then we also measured very
32:48carefully how many days people were
32:50abstinent and you can see the those
32:53who had a short period of abstinence
32:55which is marked here by short abstinence.
32:58Really the mean being 5 days.
33:00They, um, relapse or continued
33:02with their heavy drinking during
33:04the early treatment phase.
33:05This is the first 14 days
33:07and you see that in fact,
33:09the number of days of abstinence is
33:12an important clinical marker and
33:13this is not surprising to clinicians.
33:15We know that if somebody drank
33:17yesterday or two days ago,
33:19they're going to have a hard time abstaining.
33:22Well,
33:22that's known across substances of abuse,
33:24and in fact,
33:25what we see here is that is the
33:28case they engage in heavy drinking.
33:30And the probability of no heavy
33:33drinking is much higher with
33:35longer days of abstinence.
33:37So we know that.
33:39And now when we look into the brain,
33:42in fact,
33:43that that pathophysiology I was
33:45showing you a blunted resilient coping
33:47pathway with the ventromedial Pfc and
33:50disruption in the neutral condition,
33:52both in the ventral striatum.
33:55An this extends into into the
33:57hypothalamus and then some heightened
34:00striedl activation as well.
34:02Is associated with a number of
34:04absence days actually predicts that,
34:06so this is an important clinical marker?
34:08What about withdrawal in abstinence
34:10symptoms as we start to think
34:12about acute withdrawal,
34:13which are listed here,
34:15these are the withdrawal symptoms I've added.
34:17High craving as one of The Associated.
34:21Symptoms that that we see in folks
34:24during acute withdrawal,
34:25but also in early abstinence.
34:27And I'm going to show you data with
34:29folks again entering treatment if they
34:32were treated for acute withdrawal.
34:34Needed medical detox.
34:35They're entering treatment post that period,
34:37so everybody is coming in for
34:39outpatient treatment and we evaluate
34:41them for their alcohol withdrawal
34:43symptoms and their craving,
34:45and in fact all of us know this.
34:48Again,
34:48it from the treatment field that
34:50there is a pretty high bar for.
34:53Of being.
34:55For gaining getting medical detox,
34:57I think you need an 8 or more on
34:59the Siwa scale for as the criteria
35:02for qualifying at SDRC.
35:04So people are turned away and so
35:06of course they go back out and they
35:09drink and so and or there in the
35:12Ed and they go back out and they
35:15drink and you have this revolving
35:17door and that group.
35:18We tend to ignore when we think
35:20about recovery.
35:21Anne and we believe that in fact
35:24they are the most.
35:25Vulnerable and we need to target
35:27them for for sort
35:29of improving our treatment outcomes.
35:32Post withdrawal and during the relapse
35:34or during the early recovery phase.
35:37If you look at those
35:39alcohol withdrawal symptoms,
35:40they are actually quite correlated
35:42with other kinds of what we call
35:45abstinence symptoms in addiction,
35:47depression, depression, anxiety,
35:48craving, poor sleep quality.
35:50All of those are associated here
35:52with withdrawal because we wanted to
35:55put these together in the same the.
35:58Alcohol withdrawal scores.
35:59The Siwa scores were put
36:01on a Z score scale here,
36:03and you can see that those who have
36:06low SUA scores and this is really two
36:09or less versus 3 or more are quite
36:12different in these other abstinence symptoms.
36:15So right there we have a clinical
36:17profile or folks that I don't think
36:20we evaluate this these aspects
36:22very very thoroughly,
36:24thoroughly in outpatient treatment,
36:25and indeed the question would be,
36:27as I've shown you,
36:29some data already.
36:30That that the folks who have these
36:33higher or who are showing some
36:36symptoms of both craving an alcohol
36:39withdrawal and abstinence associated
36:41symptoms are in fact folks with
36:43the greatest neuro biological.
36:47Head so to speak or disruption,
36:49and can we target them for treatment.
36:51So Amy Arnsten Here in your
36:53science is a great collaborated
36:55with many of us and she's been.
36:58She's a prefrontal cortex physiologist
37:00Ann has put out this beautiful
37:02molecular mechanisms of how to
37:04protect the prefrontal cortex or
37:06rescue the prefrontal cortex under
37:08high levels of stress and some
37:10of the things she she put out.
37:12This is her work from the late
37:1590s and early 2000s.
37:16Word than origin ergic pathway
37:19in the northern ergic.
37:20Effects disruption,
37:21so to speak,
37:22in the cellular mechanisms that are
37:25driving stress related Pfc impairment.
37:27So we started to look at guanfacine
37:30and presence,
37:30and I'm just going to show you
37:33some of our process and data.
37:36We did a study with prazosin in
37:38just in our lab study provoking
37:40craving under stress in Q Conditions
37:43and found that process and
37:45decreases stress induced craving.
37:47Tracy Simpson and others.
37:49Did pilot studies 1st and then
37:51the largest study with prazosin
37:54for alcohol use disorder?
37:56This is with Murray Raskin and
37:58found some positive effects,
38:00but there's mixed data.
38:01Our own doctor Petrakis at the VA
38:04did a study with president in the
38:07treatment about call use disorder
38:09in found mixed, found no effects.
38:13And So what could be going on?
38:16Where, of course,
38:17treating everybody with the drug our
38:20data kept pointing to the fact that is
38:23targeting stress induced alcohol craving.
38:25It's helping with normalizing
38:27the disrupted HPA axis,
38:28and so we should focus on perhaps
38:31those who are most affected.
38:33Who could be most help,
38:36perhaps?
38:36So we managed to get a grant funded by an
38:40I AAA to look at president versus placebo.
38:43Initially we thought we would focus.
38:46This on anxiety and look
38:48at anxiety disorders,
38:49but we were really not convinced
38:52that it's really about comorbidity.
38:54We thought it was much more about
38:58alcohol related applications
38:59and so we wanted to look at the alcohol,
39:03abstinence and withdrawal related
39:04effect as a potential moderate are.
39:07So we recruited 112 patients.
39:09100 folks initiated the study we used
39:12to see what to assess withdrawal.
39:15Drinking outcomes are measured.
39:17The dose was tightened up,
39:19titrated up over 2 weeks,
39:21and we went up to 16 milligrams a day.
39:25Mixed effects models were used.
39:27Most importantly,
39:28a lot of alcohol use disorder treatment
39:31studies exclude people who are unable to
39:33stay abstinent for five days or three days,
39:36and naltrexone study early naltrexone
39:39studies did not include those who who
39:42could not be abstinent for five days.
39:44We required no abstinence days
39:46for treatment initiation,
39:47so if you were.
39:49Absent Today, you could get started
39:51and of course it was a titration.
39:54You know protocol,
39:55so it's not like they were
39:58getting full dose right away,
40:00or this was somehow treating
40:01their acute withdrawal symptoms.
40:03Nonetheless,
40:03they got engaged in treatment and
40:05were able to initiate treatment.
40:07I want to show you the significant
40:10moderation of processes benefit by
40:12alcohol withdrawal on the X axis.
40:14Here is the alcohol withdrawal
40:16scores at treatment entry in this
40:18is percent heavy drinking days Ann.
40:20Just any drinking days across
40:23the weeks of full dose 3 to 12.
40:26And you see here that are behavioral
40:29counseling platform of 12 step
40:31facilitation helped in everybody who
40:33was in low in the low category but
40:37just look at the placebo group just
40:39ramping up as as you look at those
40:42with higher withdrawal scores and in
40:44fact prazosin flattening that completely.
40:47Let's look at that by average.
40:49Now here this is percent drinking days
40:53and heavy drinking days and you say
40:56see averaged across weeks 3 to 12.
40:58A whopping difference in those in the
41:01president group PR versus the placebo group.
41:04Right here in Week 12.
41:06Even more so,
41:08the placebo group going ramping back up.
41:11And of course, the president group
41:13maintaining their abstinence.
41:14Similarly, we looked at improvements.
41:16We looked at the other alcohol
41:19abstinence symptoms, anxiety,
41:20alcohol, craving and mood,
41:22and once again,
41:23alcohol withdrawal intersected and
41:25interacted with treatment prazosin
41:27and showed an impact on anxiety.
41:29Craving and mood and that's presented
41:31in the paper that is impressed
41:33and should be coming out soon.
41:36So in conclusion,
41:37I want to wrap it up to just.
41:41Conclude that I hope I've shown you.
41:44I know it's gone fairly quickly,
41:46but that we have evidence of putting
41:49alcohol related adaptations in
41:51the stress pathways autonomic,
41:53which I didn't show you much,
41:55but you want trust me on that.
41:58It looks quite like the HPA axis,
42:01disruption of the HPA axis
42:03neural circuit disruption,
42:05particularly targeting the instrumental
42:06learning reward motivation circuits
42:08that are important in resilient coping,
42:11important in reward.
42:13Assessment as well an that that's
42:17such disruption promotes relapse risk,
42:20jeopardizes alcohol recovery,
42:21but there are individual differences
42:24and we want to capture those individual
42:28differences and translate that into
42:31markers. Bio behavioral markers that can be
42:35clinical as well as neural or biological.
42:39So we want to utilize those moderate
42:41yrs and biobehavioral markers to
42:43identify and treat those who are most
42:46vulnerable for treatment failure.
42:47Apply them in the clinical setting.
42:50Of course, test whether
42:51that application works,
42:52whether it's severely abstinence.
42:54Daisy was scores,
42:55some of these people do clinically,
42:57but we haven't had treatment options
42:59as we identify those who are who
43:02are more severe and so we want to
43:04develop specific treatments to target
43:06those who are showing this kind of
43:09stress pathophysiology to improve.
43:11Treatment outcomes, so with that.
43:15I want to thank you for your attention.
43:18I'm happy to answer questions and.
43:21Then have a discussion.
43:23Thank you.
43:24I should also before I conclude I
43:27want to acknowledge that many other
43:30folks have done this work and I
43:33could not have done it without the
43:36amazing collaborators of the Elstra
43:38Center near Fogleman has done a lot
43:41of the more recent analysis you saw.
43:44Sarah Blaine's papers that were cited,
43:47Lizzie Goldfarb has is involved
43:49in number of the studies done.
43:52Juicio Stephanie Wham.
43:53Vera, Camilla Balvich, Helen Fox,
43:55who used to be here, of course,
43:58our imaging partners, constable and Dustin.
44:01She knows.
44:03New technology that seem ACC in
44:05are you staff and the CNR you for
44:07supporting my work over the years and
44:10all of the work that we've been doing,
44:12we could not have done the carefully
44:15controlled studies without the CNR.
44:16You being there.
44:17And of course,
44:18folks at the stress center and
44:20the NIH was supporting this work,
44:22so thank you.
44:28I'm happy to take questions.
44:38Yes, this is Stephanie.
44:39I just want to say that was
44:41a beautiful presentation.
44:42It was so great to see this really
44:44well integrated line of research
44:46that you've been pursuing for so
44:48many years and I think it's certainly
44:50interdigitate's with, as you say,
44:52some of the clinical information
44:54we know as you talked about it.
44:57Number of days absence prior to
44:59treatment entry is the strongest
45:00predictor of how people do,
45:02and so the fact that you can work
45:04on some treatments that could
45:06mitigate that risk for people in
45:07early absence is really terrific.
45:09So thank you very much for the
45:11talk and for the work you're doing.
45:14Regina, you might want to stop screen
45:17sharing. OK, great, thank you.
45:19Yeah, that helps. Thank you Stephanie.
45:23I was very,
45:24very kind of you to to put that
45:27in perspective and in fact you're
45:30right the naltrexone.
45:32I think it was the New England
45:34Journal paper or the JAMA paper that
45:36showed that strong predictor of days
45:38of abstinence on treatment outcome.
45:45Any other thoughts so questions? Regina
45:48this is this is Chris.
45:50I second stephanie's comments.
45:51It was beautiful to see
45:52though let work put together so nicely.
45:55I want to ask about the model that
45:58you presented about halfway through
45:59where the chronic drinkers have
46:01elevated elevated baseline court,
46:03but a reduced induction
46:05of court appan alcohol an.
46:07You hypothesize that that that they
46:09have they need repeated drinks
46:12to get a higher level of court.
46:15But are you implying that there's a
46:17homeostatic drive to a cheat to get
46:19back to that higher level of court?
46:21'cause that's not intuitive to me
46:22that there would be a homeostatic
46:24drive to get a higher stress signal,
46:26so I wonder if you could help me understand,
46:30yeah?
46:31How that would work as it's an intriguing
46:33model and it fits the data you have,
46:36but I don't understand that that
46:38that further out prediction.
46:39Yeah, thank you Chris, for asking.
46:41I know I went over that very quickly.
46:43Well, you know historically.
46:45The thinking was that we want a blunt or
46:48reduce stress response is a good thing.
46:50So if you don't have a stress response,
46:52that's a good thing.
46:53But in fact,
46:54all of the data that are coming
46:56out in the last 15 to 20 years.
46:59And as we are thinking about.
47:01Brazilian circuits what is coming
47:03to the fore is that in fact you
47:06want a good stress response.
47:08What we need is a robust stress response.
47:11When we are faced with stressors
47:13that central glucocorticoids are
47:15really important to to get the
47:17stress circuit going and then you
47:19will need it to come down and even
47:22outside of central mechanisms.
47:23If you look at peripherally
47:25and you look at folks,
47:27even their subjective and
47:29cognitive coping mechanisms,
47:30you see folks reporting stress.
47:32And then they come down.
47:33And so number of folks have looked at this,
47:37and the newer thinking is that
47:39we need a robust stress response
47:41with all aspects of it working.
47:43The rise as well as the down and what
47:46we see now here is a disruption of
47:49that with chronic alcohol states.
47:51Now we have evidence that early trauma
47:53exposure an with repeated trauma,
47:55this stress response as we think
47:57of the HPA axis or the Autonomic
48:00Response Arousal under stress.
48:02Is disrupted and So what we see
48:05is a shift baseley.
48:07And then it blunted stress response,
48:09even if when you don't think of alcohol.
48:12Just think about the shift baseley
48:15and then a blunted stress response.
48:17And in fact,
48:18that's what we saw even with stress
48:21here in the in the bench heavy
48:24drinkers prior to drinking an.
48:26That is what led us to start
48:29thinking about a dysfunctional need.
48:31Because clearly,
48:32if your Basil is still up in,
48:35you are trying to get the response
48:38state backup.
48:39It's it's going to remain dysfunctional,
48:41but that there is, in fact a drive.
48:43We are starting to go back to the model
48:46of a drive to come back to have our response,
48:49because in fact having a
48:51response is is innately an.
48:53Instinctively the drive that
48:54should help us adapt and survive,
48:56and so that that's the way we're
48:58starting to think about it.
49:00Does that make sense? It
49:03does that. Thank you.
49:04It does make sense. The mechanisms
49:06whereby that drug might happen or going to
49:09be an interesting thing to tease apart.
49:12Those aren't clear,
49:13but but it makes more sense.
49:15Thank you. Yeah, we have evidence.
49:17I will say Well haven't shown this
49:19'cause this is all preliminary
49:21and not preliminary analysis and
49:23suddenly not put out there that
49:25that that blended responding is
49:27directly associated with the blunted
49:29response in the resilient coping
49:31circuit an in the ventromedial Pfc.
49:33And the straddle systems which
49:35do in fact show.
49:36And it's been written about the hypo
49:39dopaminergic state with heavy use.
49:41Heavy drug use,
49:42heavy alcohol use an in patients
49:44has been documented and we're
49:46picking it up here in various ways,
49:49and we're sort of thinking that
49:51that Central court mechanisms
49:53have something to do with that.
49:58Regina, you have a question in the chat
50:01from Sally's hotel says any speculation
50:04on what these patients or subjects
50:07looked like in terms of stress response
50:10before alcohol use was ever initiated.
50:14Yeah, thank you Sally.
50:15That's a great question.
50:17Those are sort of moderate
50:19yrs and risk factors.
50:20Sort of studies that were
50:22going down the road.
50:26I we have a sense of it,
50:29we have some sense of it.
50:32There are the sex differences start
50:34to come in 'cause the stress response
50:38is highly sexually dimorphic.
50:40So women, girls, an boys,
50:42are somewhat different in the way they
50:45are activating the striedl pathway,
50:47and this ventromedial Pfc and
50:50there's amygdala differences as
50:52well that are feeding into this sort
50:55of limbic striatal circuit that's
50:57critical for emotion regulation.
50:59So I don't have the data out
51:03ready to present,
51:04but I can say this that we're seeing
51:08really interesting parallels to pain.
51:10For example,
51:11emotional pain and physical pain,
51:14and blunted responding,
51:15particularly in women,
51:16seems to be a risk factor,
51:19so there are some,
51:21which is why I had that factor
51:25in that there are some sort of.
51:29Factors and the related biology
51:31that going into the phase of
51:33experimenting and drinking
51:34is going to make people more
51:36vulnerable towards addiction,
51:38but there's still a lot more
51:40work to be done in that area.
51:49You know, I, I really wanted us to talk.
51:51I mean, it's been really close to my heart.
51:55Work that that we start to really
51:57understand the drug related adaptations.
51:59If we can't sort that out,
52:01it's really hard when we start
52:03to do 2 by two or say, well,
52:06this person has trauma and the drugs
52:08we don't really know whether those are
52:10additive effects or synergistic effects.
52:12So if there are ways to design experiments,
52:15which is what we've been obsessed
52:16with to really kind of manipulate the
52:19drug related effects an then bring
52:21in other risk factors there maybe it
52:23might help us understand it better.
52:40The questions comments.
52:52Everything was clear.
52:57And there's a a comment that was a
53:00question that was made to be private.
53:03Can you speak to agent cognitive
53:05decline as moderators of treatment
53:06response in the early phase?
53:08How do these factors relate
53:10to the stress response?
53:14That's a great question.
53:16We don't know very much about it.
53:19We do know that age,
53:21an age related declines in in frontal
53:25systems could have an effect suddenly.
53:29I'm not aware of any studies that
53:32particularly look at the circuitry
53:34that we're identifying that are
53:36related to emotional regulation in
53:39self control is resilient coping
53:41circuitry that is relevant in sort of.
53:46Give having people gain better self control.
53:49I would expect though we control
53:51for age in all of our studies.
53:54We are interested in looking
53:56at the age effects,
53:58but we haven't done that as yet
54:00in in a direct way in terms of
54:04impact on treatment outcome,
54:06I know that Ed Sullivan and Alpha
54:08bomb and others have been looking
54:11at age related declines in cognitive
54:14function and its impact in recovery.
54:16But not so much in this early phase.
54:21John, you may be aware actually
54:23have some of that work as well.
54:24I'm not sure if you have
54:26anything to add there. No,
54:28but just the just the general comment that
54:32that that as executive cognitive control.
54:36Begins to decline in an advancing age
54:39that you begin to see emergence of a
54:42variety of impulsive behaviors again.
54:44Anne, and there's actually.
54:46Surge or increased risk for substance abuse.
54:50Again in later life that that people
54:53haven't really paid that much
54:56attention to that might be related to.
54:59What you've described in younger folks.
55:05Yeah.
55:18Last chance for questions.
55:25Alright, well Regina was a fantastic
55:27talk in an awesome amount of work
55:29and thought by by yourself and the
55:32people that you've brought together
55:34to work on these important questions.
55:36So thank you so much for sharing this.
55:39A wonderful lecture with us today.
55:41Much appreciated.
55:42Thank you, thanks for having me.