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