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

September 18, 2020

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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.