Lucie Berkovitch, MD, PhD. September 2022

November 28, 2022

Information

Title: Psychedelics in the brain: An overview of neuroimaging studies

Description: This talk provides an exhaustive overview of neuroimaging data on psychedelics. It is divided in three parts: 1) from receptors to brain effects, 2) from brain to cognition, 3) from neurobehavioural effects to theoretical models.

In a first part, we describe psychedelic effects on brain networks, brain oscillations, signal complexity/entropy and on some specific functions such as emotional processing, social processing, surprise processing.

In the second part, we try to predict their cognitive effects based on their brain effects and compare those predictions to actual findings.

In the third part, we summarize existing models to explain psychedelic effects and propose another angle of description of their effects based on the theoretical models of consciousness.

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To CiteDCA Citation Guide

00:00Right. That was less difficulty with the
00:03technical aspects than I was expecting.
00:05So it's great to see everyone this is our.
00:11Restarted sent monthly seminar
00:14in psychedelic science,
00:17which we plan to continue to have
00:20every third Friday at 3:30 PM.
00:23We're going to do it hybrid as we are today.
00:25We've got a small number of people here
00:27in the room and a lot more on zoom,
00:29so it's great to see such a large group,
00:31and we'll continue to have it available
00:32in both formats if we can continue
00:34to make the technical stuff work.
00:36We do promise coffee and cookies
00:37if you come in person, so. Umm.
00:39So our presenter today is Lucy Berkovich,
00:43who's a postdoc in Allen Antiche lab.
00:46And she's in the early stages of
00:49putting together a very exciting
00:50study looking at the brain effects
00:53of psilocybin and ketamine.
00:54But what I've asked you to do
00:56is sort of a broader overview.
00:57I hope you'll talk about some of
00:58your own plans in your own work,
00:59but also a broader overview of the effects
01:01that the brain imaging literature and
01:04the effects of these substances on the brain.
01:07So Lucy,
01:08thank you so much for being here.
01:09It's great to have you join us and
01:10really looking forward to learn.
01:13Hi. Yeah, I'm very, I'm very glad
01:15to have been invited and I'm,
01:17I'm really happy in fact to
01:19to give this presentation. So
01:22I'm sorry, I did just realize,
01:24so just two housekeeping things.
01:26First of all, this is being
01:28recorded and eventually our
01:29plan is to post on the website.
01:31So just be aware that that that this
01:33is being recorded and second of all,
01:35in order to avoid the feedback we've
01:37turned off the speakers, which means
01:39we cannot hear people who are here.
01:43With this virtually we can
01:44try to figure out how to,
01:45I'll see if I can figure out
01:47how to make that work better.
01:48But yeah, if you're here virtually
01:49and you want to contribute,
01:51please raise your hand and
01:53or right into that.
01:54And I will try to keep an eye on the
01:55chat as the conference is going along.
01:57But if you just call out,
01:58I don't think we're going to hear you.
02:00All right.
02:01That's the last housekeeping I can think of.
02:02So go ahead.
02:05Well, so yes, so thank you
02:07for for this invitation.
02:08So in fact, I really try to provide
02:10an overview of the neuroimaging
02:13studies about psychedelics.
02:14So I decided not to focus
02:16on on psychedelic process.
02:18So I will not really address the
02:19ketamine aspect, but I would be
02:20really happy to talk about it too.
02:22And and I mean I can have a couple
02:24of slides on that also if you need.
02:26So just to provide like first,
02:29first of all maybe a few definitions,
02:31so everybody here I guess I
02:34know what it's like.
02:35But anyway,
02:36So what what I will talk about is
02:38uh psylocybe which is the the active
02:41compound of matching magic mushrooms,
02:43LSD DMT which is one of the chemical
02:47compound of iasca and also mescaline.
02:50But you will see that there
02:51is not in fact many studies,
02:53many neural imaging study about the Muslim.
02:56So all these molecules are
03:00serotonergic agonists,
03:01in particular in the vestibular
03:03receptors of the serotonin,
03:05but also on other receptors.
03:08And they have several subjective effects.
03:10And in fact This is why they are famous.
03:13And in particular they give a
03:16visual distortion that like you
03:18can see that are kind of moving,
03:21moving distortion or the impression
03:23that things are breathing or
03:26volute things like that.
03:27There is also time and
03:30space filling alterations,
03:31just academics and mystical spiritual
03:34experiences that are reported by users.
03:39And for all these effects,
03:43I've I've shown to also provide
03:45kind of promising results in
03:47different psychiatric disorders,
03:49and in particular in depression,
03:51anxiety and addiction.
03:53So all of this brings the question
03:56about brain mechanism and in fact how
04:00this brain mechanism can account for
04:02both these changes in perception,
04:04but also the therapeutic effects
04:07of these molecules.
04:08So first I will try to travel from
04:11the receptors to the brain effect
04:12and then to the cognitive and the
04:15theoretical aspects of the psychedelics.
04:17So regarding the receptors,
04:19maybe the first question is where
04:22are the 5-2 receptors in the brain?
04:24And in fact, as you can see here,
04:27I don't know if you can see my my mind,
04:28so I don't, I'm not sure.
04:30But you can see that they are quite
04:33broadly distributed across the brain
04:36and in particular they are located in.
04:39Region that corresponds to
04:41some important networks and in
04:43particular the default mode network
04:46and the task positive network.
04:49And these two networks are
04:52supposedly anticorrelated.
04:53The first one activate when you're
04:55doing nothing and the other one will
04:57activate when you are involved in the task.
05:00I just also highlighted on the
05:02left the five HT 1A receptor
05:04that is located more on the the
05:07the medial temporal lobe.
05:09And particularly the hippocampus,
05:10because there is more a kind of
05:13inhibitory effect of this receptor that
05:15is also activated by psychedelics.
05:20So what happens now when we activate
05:23this literary receptors in the brain?
05:26So here you can see a kind of schematic
05:28of different action of the psychedelic
05:31and we're going to review this
05:33progressively because it's kind of a
05:36complex complicated schematic, right.
05:38So here you can see the LSD on the
05:41left and on like the red receptors
05:44are the furnishings where receptors,
05:46so this LSD, but it's supposed
05:48to be the same with the others.
05:50Catholics will activate these
05:52pyramidal neurons that you can see
05:55here in layer 5 and layer six of the
05:58preferred the prefrontal cortex.
06:00So there will be a huge activation of
06:03these neuron just by a direct effect
06:06on the fiber structure receptors.
06:08There will be also an activation of
06:11these neurons through the appearance
06:13from other brain areas and in particular
06:17the telemus that also have these
06:19village tutorial receptors and this
06:22will result in a glutamate release
06:24in the prefrontal cortex still and
06:28an increased synaptic plasticity
06:30and you will see that.
06:32This is also a very important mechanism.
06:36But the father states where
06:38receptors are not only located on.
06:41Excitatory neurons,
06:42but also on inhibitory neurons and in
06:45particular these Gabaergic neurons here.
06:48And this will inhibit the pyramidal neuron.
06:51So there is a kind of balance
06:54between excitation and inhibition
06:55and there are also internal ones in
06:58the prefrontal cortex that would be
07:00activated and that will also inhibit,
07:03inhibit the the parent domains.
07:06But All in all,
07:08there is a neural activation
07:10of these pyramidal neurons,
07:12in particular in the layer of five,
07:14the prefrontal cortex,
07:16and this will lead to what has been
07:20observed as an hyper frontality or hyper
07:23activity in the prefrontal cortex.
07:27OK, so now if we turn to like
07:29the the brain effect of the
07:31psychedelics and what what we can
07:34observe with neuroimaging study.
07:36First of all there is a new
07:39state of connectivity at first.
07:41And this is characterized by a
07:44decreased within network connectivity.
07:46So it means that in several network
07:48you will have less connectivity of
07:50different parts of this network
07:51and this is particularly the case
07:53in the development network and
07:55here in this study also in the
07:57auditory network for the silo sibin.
08:00But we can see pretty much similar effect
08:03in the different network with LSD here.
08:06So what is in yellow is just the
08:08mapping of the the network and in
08:11blue-green it's the the decrease of
08:13the within network connectivity.
08:15You can see here also that in the
08:17visual network you have decreased
08:19connectivity and other networks can have
08:21this decrease within network connectivity.
08:24And we with AOS here we also have
08:27this decrease within connectivity
08:29within the in the different network.
08:32And you have another result that is not
08:35really observed with other psychedelics,
08:37which is an increase this time of
08:39the within network connectivity
08:41in the salience network.
08:43And we'll see that this is this
08:45belongs to some discrepancies that
08:47exist between the different molecules.
08:52On the other hand, there is an
08:54increased between network connectivity,
08:56which means that the network one
08:58with another will be more connected.
09:01And this can be seen here in this kind
09:04of metrics that shows the differences
09:07in fact between silybin and placebo.
09:09And what you can see in red is all
09:11the combination of networks that
09:13are more connected one to another.
09:16So there is really a kind of huge
09:18increase across the brain of this.
09:20Between network and activity.
09:23And this is also the case under LSD.
09:26Here in green we can see how these networks
09:28would be more connected to to each other.
09:33Yeah. Are these two effects
09:35consistent with just an increase in noise?
09:39So if you just simply increase the noise,
09:41you're going to decrease the
09:42coherence within any given network
09:44that was coherent and baseline.
09:45You inject noise different less
09:47code and across networks if the
09:49networks are distinct in their
09:51patterns or even anti correlated
09:52because how we find them through ICA,
09:54then you're going to lose the anticorrelation
09:57which may read out as enhanced
09:59correlation or loss of anticorrelation.
10:02So all right,
10:02all it it's easy for me to see how the
10:05loss of within network connectivity
10:07could simply be the injection of noise.
10:09It's less obvious to me whether the
10:10second fight be increased in between.
10:12Never could be explained
10:13by just the injection.
10:18I I think that the fact that we
10:20find opposite pattern is like, yeah,
10:23less incoherence with the idea that
10:25we will have only a single like
10:28these are both relative to base.
10:31Find the different networks are non
10:33correlated or anticorrelated if not.
10:36It depends. For example,
10:37the different network and the
10:38science or the executive network.
10:40They are anticorrelated naturally.
10:41So the fact that
10:42there is a correlation between increased.
10:47This is the like this is the shortcut
10:48that is made in many studies.
10:50That diagram, what we called a
10:52loss of anticorrelation is an
10:54increasing connectivity between them,
10:56right? Yeah, but that's not true
10:57with all of these patterns.
11:00So what you can see here is that for
11:02between some networks you will have
11:04an increase but with between some
11:06other you will have like a decrease.
11:07I did not detail everything
11:09because like to cover everything.
11:11I could not go in every details.
11:13But indeed in fact the what you
11:16mentioned is a very important point
11:18and you will see and we will see for
11:21instance that what was taken as an
11:23hyper frontality or an increase in
11:25general activity in the brain could
11:27be in fact just related to the.
11:29Is the child rescue effect of the
11:31of the drugs and that when you
11:33when you correct that with for
11:35example global signal regression,
11:37you have very different pattern
11:39of activation.
11:42Is the increase within salience network
11:47effect that you showed on the last slide?
11:51Since that. By itself like generally
11:55to this increasing between network
11:56connectivity or is that like an outlier?
12:00Yeah, it's uh, something different.
12:01It's really the reason connectivity in the
12:04salience network and not just because it's
12:06connected to all the other. Like, yeah,
12:09it's just like an individual pattern.
12:13Umm. And so yes, so we're like this
12:17is what I was just saying like there
12:20is more coupling between the DMN
12:22and the task positive network under
12:24service saving and under iOS gas.
12:26So what you can see here in
12:29particular on the.
12:31On the bottom right is that when
12:33you choose a seed that belong
12:34to one of the two networks,
12:36you will see like a burst of
12:38activity on the other network.
12:40So it's also probably region
12:42dependent and some some parts
12:44of each of these network can
12:46be more connected to another.
12:48Yeah.
12:51Umm. So what we can see also during
12:54rest is a reduced associative but an
12:57increased sensory brain wide connectivity
12:59and this is what I was mentioning
13:01after our global senior regression.
13:03So you can see that for sale saving
13:06in this study with this increase in
13:10the particularity of capital area.
13:12And a decrease in the frontal area
13:14and you can and you have kind of
13:16a similar pattern that is quite
13:18striking how these two are are are
13:20really close to another with the very
13:23same increasing the exhibitor area,
13:25decrease in frontal and in this case
13:27also the somatomotor cortex that
13:29is also that has also an increased
13:31connectivity with the rest of the brain.
13:35Umm, the telem, the Telemus is also
13:38more connected to other areas and
13:41in particular to sensory areas.
13:43So there is a bit small,
13:45but what you can see here is that in
13:48this kind of ring graph is all the
13:51red lines corresponds to an increase
13:54in connectivity and it's and there
13:57is an increase that is kind of
13:59specific to the to the sensory areas
14:01compared to the associated areas.
14:05And finally, under iOS card,
14:08there is an increase of coupling
14:10between the visual area and
14:12the development network.
14:13But interestingly,
14:14I mean even if it's also like a
14:17correlate of what I presented before,
14:20there is a decreased coupling between
14:22the visual and the task positive network.
14:24And in this study the salience network
14:26has an increased within connectivity.
14:28So it may be related.
14:32So under Iowa schedule,
14:33I think that are quite specific
14:35and in particular there are there,
14:37there are changes in visual areas that
14:40really look like visual stimulation even
14:42if participants have their eyes closed.
14:46So this is what you can see here.
14:48So in fact there are like 4 condition
14:51like I close before and after iOS
14:54which on the blue and the red and the
14:58sorry yes before and after and and.
15:00Natural image which means visual
15:02stimulation before and after in
15:04in white and green and what you
15:05can see that there is a decrease.
15:07So this is the Brodmann areas
15:09corresponding to the visual cortex.
15:11There is a decrease in fact only.
15:15That was before I was camp.
15:16So in other words,
15:17after I was scared,
15:18you have the the I closed all the eyes open.
15:21You have the same activity
15:23in the visual areas,
15:25which is like kind of striking and you also
15:31relative to. Single track
15:34within trial baseline.
15:36So that's not comparing across conditions,
15:39just comparing each trajectory in
15:40each condition to its own, yeah?
15:44Then you can have also.
15:47So there is also an I I
15:48will go back to that later,
15:50a decreased feedback and an
15:52increased feed forward under iasca
15:54in eyes closed condition and this
15:57looks like a visual stimulation.
16:00So in fact you have like this increase
16:03that you can see of the blue line
16:05and the decrease of the red line.
16:06So it's like in a way visual eyes close.
16:13You have like similar pattern to.
16:15Uh, to visual estimation, the iOS can.
16:18Under LSD it's a bit different,
16:20but there isn't.
16:21It was observed that there was an
16:23increased activity in the visual cortex.
16:26And also an increased coordination between
16:29several subparts of the visual cortex.
16:33So this can be correlated to
16:35the visual imagery under LSD.
16:38But it's quite difficult in
16:39fact to compare because it's
16:41all these studies are different,
16:42are not necessarily using the same methods.
16:48Another effect that is uh quite
16:51reproducibly observed under psychedelic is
16:54a decrease of low frequency bands power.
16:58So you know that the different association
17:01carried like the vector of synchronization
17:04and information transfer across the brain.
17:07And what you can see on the second
17:09delic here for LG Stylo savings,
17:11that there is really a important
17:13decrease of alpha and beta bands.
17:16And for LS you have also decreased
17:18in Delta and data and also in gamma.
17:20So for LSD you have basically a decrease
17:23of all broadband decrease whereas for solo
17:26Sabine it would be more for alpha and beta.
17:30This is another way and from another
17:33study that confirms this results.
17:34And what you can see that yes indeed
17:37the decrease is higher under LSD
17:39and there is also a shift of alpha
17:42frequency toward higher frequency
17:43that you can see on the bottom left.
17:47And a decrease that is more specific
17:51to alpha and beta than under siding.
17:56For the,
17:56you also have a decrease of alpha
17:59and beta band that you can see here,
18:02but we'll see that there are different
18:04pattern and in particular that the
18:06feed forward or the Yammer bands
18:08are increased on the iOS and this
18:11is not something that is observed
18:13on the silo siding.
18:16For a decrease and so saving is more
18:19like no effect or really very light
18:23changes for this for this frequency.
18:26And I was scared.
18:28There are other accused that.
18:30Um,
18:31the there is a change in the
18:34feedforward connectivity and
18:35in particular there is here.
18:38So this study focused on information
18:40transfer and what you can see is
18:42that there is an increased postural
18:44entire information transfer,
18:45so from sensory areas to higher level areas,
18:49whereas there is a decrease in
18:51terrible posterior information from so.
18:52And this is the,
18:53the graph I just showed you before about
18:56the the mimicking of visual stimulation
18:58when eyes are closed and this is the same.
19:00Do that for a while.
19:01The previous increasing backlog is decreased.
19:04Lucy,
19:05I don't understand these
19:06data and that's my failing.
19:08Are you able to explain?
19:10Succinctly, how this the the data that
19:13you're showing the EEG connectivity data?
19:16Correspond to feedforward versus
19:18feedback information transfer or is
19:20that like a whole lecture by itself?
19:23So no like gamma was like regarding the
19:26association so it's a bit the shortcut.
19:29Alpha and beta were more associated with
19:32top down processing while gamma was more
19:35associated with both of our processing.
19:37OK. So these are inferences from
19:39relative power from changes in power
19:41in the different frequency bands
19:43like the. So this is for
19:45the gamma versus alpha beta,
19:47but for the like the study
19:49that is on the bottom left,
19:51it's really like the the
19:53measure the information transfer
19:55between different areas so.
19:59I think there's
20:00like a time 15 cross correlation.
20:03Yeah, they do like the I.
20:06They do a Granger causality,
20:08I think in this study.
20:10But in the earlier study,
20:11there wasn't featured personality.
20:13It's just based on an assumption
20:15based on what's been observed in
20:17visual processing for example,
20:19or something like that
20:20in the previous one with I like.
20:25Alpha represents top down ohh,
20:29so the alpha and the like.
20:31The correspondence between alpha and
20:33top down is more related to like other
20:36studies that they did not present here.
20:38It's like several studies showed that.
20:43You have like like object
20:44recognition for example is held by
20:46half hours and things like that.
20:47But it's a different feature.
20:48It's visual processing exactly, yeah, yeah.
20:56OK. And the last,
20:59the last part of the literature isn't?
21:04Interested about signal complexity or entry?
21:08So it's basically corresponds to the
21:11quantity of information in the brain
21:14and how how much this information
21:17is unpredictable in space and time.
21:20So this is an example for cytosine
21:22and how you can measure that.
21:24So you take the activity in different
21:27region and you can see how these
21:30different region are correlated and have
21:33connectivity at different time points.
21:35And you can measure I don't know what
21:39it is and you can measure the entropy
21:42by looking at the probability of
21:44changing of this pattern of connectivity
21:47in the across the run inference.
21:50And what it was found is that
21:52there is an increase of entropy.
21:55Leaving.
21:57And there are other way to
21:59measure the complexity,
22:00so these diversity of information
22:02in the brain and the diversity of
22:05pattern in the brain, for example.
22:09Complexity and you can see also that
22:12there is an increase in complexity
22:15under saving and LSD and that
22:18under LSD like it's a very general
22:22complexity that interest pretty
22:23much like all the posterior part
22:26of the brain, whether for like.
22:30The solar savings? More India.
22:34And this increase of Lymphoseek
22:36complexity was also observed and
22:38of Shannon entropy under iOS cap.
22:41So this is something that is quite.
22:45Like that seems to be shared
22:47between the different molecules.
22:50Lucy sorry again my my ignorance
22:52of some of the techniques.
22:55I have an intuition for what increased
22:57entropy means that's rough crudely
22:58analogous to more noise right?
23:00Injecting noise. What is?
23:01What is complexity?
23:02Does this measure of
23:04Flexity getting in is it on?
23:06The complexity and entropy are both
23:08going in the same direction and I
23:10think of complexity sort of amid a
23:12happy medium between between, you know,
23:14crystalline purity and total noise and.
23:16Like somewhere in the middle but.
23:19So, so complexity will be
23:20so I will just jump like.
23:22So this was more the title,
23:23but this slide is more about entropy.
23:25But the next slide will
23:26show about complexity.
23:27But complexity is basically like
23:32the diversity of information
23:34you can have in the brain.
23:36So it's like.
23:39I don't know exactly how to
23:40explain better than that,
23:41but it's not like with entropy.
23:43We have also the idea of
23:44a kind of a disorder,
23:46so also like a lot of changes across
23:48time and the complexity will be for
23:51example a more enhanced repertoire,
23:54like more diverse patterns of activation.
23:59Does it make sense?
23:59Yes. So they don't have to go in
24:01the same direction, but it's not
24:03contradictory that they do OK.
24:08So unless there is also more occurrence
24:12of global coherence phase log states, so.
24:15So here what the authors did is that
24:19so they took the the brain activity
24:23and they try to slice it according
24:26to like to define kind of phase lock
24:29states that corresponds in fact to
24:31activation patterns of activation and
24:34of connectivity between different areas.
24:36So this is not very obvious.
24:39Here but in fact so you have states
24:42where some region are connected one to
24:44the other and the first states that
24:46is that you can see the more frequent
24:48than this is in fact increased under
24:50sale siding is in fact a state where
24:52everything is connected to another.
24:54So there is no difference and not
24:56sub support that are more connected
24:58than other and that can corresponds
25:00to a specific network.
25:02And what is observed is that
25:04in fact on the same savings.
25:06So not only this Facebook state is.
25:09More frequent, but also there is uh,
25:11more probability to switch from any
25:13other states to this state of coherence,
25:16whereas like this frontoparietal state,
25:19the state three is less probable
25:21and there is less transition toward
25:24the states after something.
25:27Is this with global signal
25:28regression in the data?
25:31I'm not sure just state one is
25:34global signal, right? So it's state.
25:37So if you do it without global signal
25:39regression and the prominent state is global.
25:43If you if you did global signal
25:45regression and still saw that,
25:47that would mean something quite different.
25:49I think the control for that, but I
25:52cannot like yeah when I'm not 100% sure.
25:58And finally, you can also slice
26:02the like decompose the brain
26:04activity into harmonic states.
26:06So this is a bit tricky and
26:08I'm not an expert about that,
26:11but basically you will use the connectome
26:13and the structural connectivity
26:15of the brain and you will check
26:18how like the different harmonies,
26:21the different frequency of
26:24oscillation of this structural
26:26connectivity and you can then map.
26:28And analyze brain imaging according
26:31to a combination of these different
26:36patterns of connectome harmonics.
26:38So this is what these authors
26:41like developed and used for
26:44studying cellular Sabine and LSD.
26:46And basically what they find for
26:49silo sybian is that here the
26:51representation of the different
26:53energy like the different the
26:55probability of this harmonic pattern.
26:58And there is some changes where some
27:00of them will be more represented
27:03under and some of them will be less
27:06represented and interestingly when
27:07you plot the overall probability.
27:09You have different states.
27:10What you can see is that the more
27:12probable state will be a bit less
27:14probable underside of siding,
27:15while some states that are usually
27:18less represented in those possible
27:20will be more representative under
27:22set of sibling and they're the
27:24same pattern with LSD.
27:26So the main idea here is to say
27:28that in fact you will push some
27:30state that are usually quite rare
27:32and you will decrease maybe state
27:35that are more frequent.
27:38The brain when taking psychedelic
27:41and that that's qualitatively consistent
27:43with the increased complexity,
27:44right, because you have more,
27:46more states are being represented so
27:47there's a larger repertories, OK.
27:51And like there were also other,
27:53uh, quite technical studies using
27:55the fractal dimension in spatial
27:58or temporal dimensions or the
28:01directed international connectivity.
28:03But the main idea was that you
28:05have less constraints in the brain
28:07and more diverse and fluctuates
28:09fluctuation in the brain connectivity
28:12patterns under psychedelics.
28:17Different religions.
28:20So that's a very good question. In fact I I
28:24I think the people on zoom since we're
28:27hearing from from Luby's microphone.
28:29So I think they're having I loud
28:30and I'm close but I think they're
28:32having a little trouble hearing.
28:33So the question was how does this
28:35compare these these complexity
28:36findings compared to what might be
28:38seen with other psychoactive drugs.
28:40Are these unique to the psychedelic.
28:42So I did not see other study doing
28:46that for example for Kittanning so.
28:50Which is maybe one of the things that has
28:52the more closest pharmacological pattern
28:54by activating the neurons and algorithm.
28:58Or even just a more land drug likeness
29:01SSRI or some other drug, yeah,
29:03he's going to have some monoamines
29:04and compared the network. So
29:08I will go to that later.
29:09But there is like this,
29:11this study by character is team
29:15that compared for example the
29:17integration between different
29:18networks and we can think that
29:20this is also linked to this between
29:23connectivity across the brain and
29:25there is not a change in modularity.
29:28This is not exactly the same, but.
29:30We can imagine that this is a right not
29:34to put all these effects and also an
29:37important thing is that these effects
29:39are correlated to acute effects.
29:41So I mean it's,
29:42it's it could be quite specific in
29:45fact to the subjective effect but for
29:47ketamine it's a very good question.
29:48I mean yeah,
29:49because even if the subjective I'll be
29:52different maybe there are like just.
29:55As far as I know,
29:57it hasn't been explored so much,
29:59but these analysis could be done
30:00in the resting state F MRI datasets
30:02that exist, right? But yeah.
30:06This is so
30:06someone needs to figure out what
30:08it means and then do it, yeah?
30:14There are other important changes
30:16in those acrylic about emotion,
30:19social and software processing so.
30:23And there is overall decreased response,
30:25brain response during emotional processing.
30:28So what you can see here is
30:30that on the side of saving,
30:31there is a decrease for of the
30:34amygdala activity that is more
30:37important for negative emotion
30:39compared to neutral emotion.
30:41Here uh is uh under again like the
30:45network and small yellow you have
30:48the increase to shuffle places.
30:52And here and here is a ninja.
30:58Measure of the N 170 and which you can see
31:02is that there is a specific increase of.
31:05Of this wave this is associated with.
31:09I've just been thinking
31:10that you don't see at all,
31:11for it's important for neutral emotion.
31:16Question are they under the influence of?
31:20Yeah, for this, for this,
31:22it says it's, it's during the, the,
31:24it's during the acute effects.
31:31But this decrease of the and 170
31:34was also fined for neutral steam in
31:36another study and also for organiza
31:38steam that you know are these
31:40kind of triangle that you can see
31:42with the using visual integration.
31:44So maybe they are not very specific
31:47emotional processing. Umm.
31:49This is not observed under iowaska really,
31:53but there is less study for Iowa Aska.
31:54In fact, there was an increase of
31:58different region pertaining to the to
32:01the medial temporal lobe and increase
32:04connectivity again between the and the right.
32:08This confirms that the same
32:10study that they presented before,
32:11so it's difficult to generalize.
32:15And they'll say there is,
32:17there is also an increased interaction
32:19with the environment and in particular
32:22so there there were several studies
32:24using LSD during music listening.
32:27And what you can see is that there
32:29is an increased coupling between
32:31visual cortex and cortex and more
32:34particularly there is more influence of.
32:38Over the visual context.
32:39That can be linked to the visual imagery
32:42that you have when listening to music under.
32:46Because.
32:47That contrast there is listening
32:49to music without psychedelics,
32:51yes. In this case it's with and without.
32:53And they did also before,
32:55so this is the same on the right.
32:57This is the same alcohol
32:59that they did also before,
33:00during and after. So they compare,
33:02but they're always listening to music.
33:05No. Before listening to music,
33:07under secondary, before music,
33:08during and after music.
33:10So there is like 2
33:12crossover there is possible.
33:15These three moments before,
33:16during and after listening to me.
33:18So only one can only listen
33:20to music during one.
33:22And what they showed this couple in
33:24finding is the interactive effect.
33:25Exactly. Music and psychedelic. Yeah.
33:28Thank you. And there is also so.
33:32And an increase of um,
33:34um diversity under music that
33:37is more important than in the
33:39condition before and after music.
33:42So in the middle you have during music
33:44and so it's increased everywhere.
33:46But you have any direction between
33:48music and non music in this case.
33:54Then there is a music.
33:56Is there any differences?
33:58Also are there like
33:59connections between other?
34:03No there there is a like the
34:06it's mostly between like this
34:08visual cortex like hyper complex.
34:11I mean the rights against
34:13like the change in, yeah,
34:16of the global density of the brain,
34:18but it's not very like pop up.
34:24On those saving,
34:26there is a processing of social
34:28exclusion that you can see on the cortex.
34:31And on the reduced distinction
34:34between self and other and the
34:37posterior singulate cortex.
34:39So I put that all together.
34:40It's not exactly the same topic,
34:42but just to say that it can
34:45corresponds to this feeling of like
34:48connectedness with the environment.
34:50Yeah, ours.
34:52Like you think that
34:53was sort of like the?
34:58Like potentially like the
34:59Pro social effect vaccine.
35:01Yeah. So yeah.
35:02So I would I would talk about like the
35:05like the link between behavior and.
35:07So, but in fact it's not so easy to
35:09find the neural correlate of the solution,
35:12probably because it's a big entity that's
35:14very different aspect of the experience of.
35:19Business. So for social inclusion,
35:21what do they use?
35:22So the user, you know,
35:24this disable paradigm whereby people were
35:27and there we have a question in the
35:29chat, what kind of music was it?
35:31Oh, and general.
35:32So in this case exactly, I don't know.
35:35But they use a playlist
35:37that is quite control.
35:38So in the playlist there is Electro music,
35:40classic music and it's like,
35:42but it's a kind of control.
35:45In the clinical trials,
35:46the same the Hopkins playlist,
35:48the same one they use.
35:49I I'm not 100% sure that they use
35:52this very playlist in in this case,
35:54but this is a very good question.
35:56But I think it's the same.
35:57It's the same team, so it's
35:59probably the same kind of right? But
36:01it's not words and it's not.
36:05I don't know if there is no,
36:07maybe the place somewhere on the on
36:09the supplementary information that I
36:11don't have like the the lyrics. Sorry.
36:16There is also a decreased
36:18surprise processing,
36:19so a decreased mismatch negativity,
36:22that is this wave that appears when you
36:25have a sequence and and when you are
36:28processing a deviant team within a sequence.
36:31So this is decreased on the sybian
36:34and quite intriguingly, it's.
36:36It's even like it seems to be more pronounced
36:38for standard than deviant stimuli here,
36:41but it's only for tactile and it
36:44was not found for. Auditory system.
36:47Whereas for LSD it was finding
36:49the very classical overall,
36:51uh, paradigm, uh,
36:52where you are just a different tone
36:54and you can see that there is this
36:56decrease in mismatch negativity
36:58with the rain red red line that
37:00is not showing this since it's.
37:05OK. So I would just.
37:09Just shows a few data showing that it's
37:11it's it's probably all these effects
37:14probably depend on the five receptors
37:16because it could be also independent.
37:18But in fact Ketanserin,
37:20which is an antagonist of a further 2A,
37:25blocks many neural and behavioral
37:27effects of psychedelics.
37:29So here you can see that the
37:32contrast between LSD and placebo.
37:35Show pretty much the same
37:37pattern of differences as the
37:40contrast between LSD and LSD.
37:44Here it's the same ID, so uh,
37:46with ketanserin plus iOS call you,
37:48you have no more the decrease in the alpha
37:51that you could see with iOS scalone.
37:53And this has been shown in several
37:55studies that I will not list here,
37:57but it was regularly used and showed that
38:00it antagonized pretty much all the effects.
38:03Another way to check that.
38:06Involved in the effects of the
38:08of the psychedelic is to use the
38:11gene expression map and to see
38:14whether this gene expression map
38:16corresponds to the subjective,
38:17sorry to the to the neural
38:20effects in this case.
38:21So that is so.
38:22What you can see is there is kind of
38:25similarity in the expression map and
38:27the change in global brain connectivity
38:30observed under LSD and you can also
38:34correlate these maps across the time.
38:36So this is what the this thing did uh,
38:39with silybin on the right.
38:41And what you can see is that there is
38:43an increase of correlation between
38:45the neural effects of silybin
38:47and the 5H2 receptor gene map,
38:50whereas there is an inspiration
38:52for the 1A receptor map which is
38:55supposedly like as an opposite effect.
38:59There's a comment in the chat that gets
39:01answered isn't fully selected for two,
39:02and there is a more selective 1 available,
39:07MDL 100907. You know if anyone is
39:10following up with the more selective and
39:12I didn't see a study using
39:15a different antagonist,
39:16this is the one that is mostly used,
39:17but maybe there are like.
39:20Yeah. And and finally,
39:23you can also simulate what would be an
39:27excitatory gain modulation obtained by 5.
39:31Activation and you can reproduce
39:33again the empirical data.
39:35So you can see that there is
39:37a nice correlation between
39:38empirical change in global brain
39:40connectivity and the model changes.
39:44OK. So now I returned from rent
39:48recognition and So what I will try,
39:51but it's more hypothetical is to
39:54predict how what kind of cognitive
39:56effects we can have by the brain effects
39:59that we just have seen together.
40:01So the first part is about the
40:04reduction of the the the connectivity
40:07in the default mode network.
40:10And indeed what we can bet is that
40:13this change in connectivity can give
40:16the so-called equity solution or maybe
40:17you will be less self focused and
40:20more available to process external
40:21information because you have a
40:23deactivation of the of the default
40:25mode network that will be disrupted.
40:28The increased connectivity between
40:30network and the increased complexity
40:32slash diversity slash repertoire may
40:34corresponds to a more information
40:37sharing across the brain and also
40:40more fluctuation and more update
40:42of the content of the brain.
40:45What has been interpreted by several
40:47authors at a possible enhanced
40:49state of consciousness because
40:52information sharing and complexity
40:54has been also linked to different
40:56states of consciousness.
40:58And we can also think that the
41:00connectivity between different
41:01sensory areas can lead to the seizure,
41:04which is an effect that is regularly
41:07observed under psychedelic.
41:11On the other hand,
41:13so the reduced connectivity in
41:15associative several region but
41:17increased in sensory areas and the
41:20change in this alpha band or feedback.
41:22And for some molecules in particular
41:24they always get increased forward
41:27or the exchange in telemetry
41:29collectivity change from the LSD.
41:31All this may lead to so cognitive impairment
41:33is a really like broad prediction,
41:35but in fact it has been observed
41:37under secondary but more maybe
41:39more specifically to an increased
41:41sensory processing and maybe to
41:43less constraints that would be
41:44applied on this sensory processing.
41:49So now let's check whether this
41:51prediction can be observed in the data.
41:54So first of all,
41:55not all the neuroimaging studies
41:57explored the the correlation with
42:00subjective effect and it's quite
42:02difficult to prove that all together.
42:04But many of them explored
42:06whether a visual experience was
42:08correlated with several patterns,
42:11and in particular it has been found
42:13that the decrease of the N 170 was
42:15correlated with visual experience.
42:17So maybe there is less integration
42:21of visual information.
42:22That it was correlated to an increased
42:25activity in visual cortex increased
42:27connective connectivity between visual
42:28cortex and the rest of the brain.
42:31The decrease of alpha
42:32notably in posterior region,
42:34so notably those are pertaining
42:36to the visual cortex of the
42:40posterior different network.
42:42The connectivity between the
42:44telemus and the fusiform gyrus.
42:47And as I said earlier,
42:49like more influence of the parade book
42:51and book Cortex on the visual cortex.
42:53So all this data is kind of difficult
42:57to summarize in just one aspect.
43:00What we can see is that.
43:02Let's say generally like the change
43:04in visual cortex and disconnectivity
43:06seems to be associated with the the
43:09visual experience under psychedelic.
43:11The DMT,
43:12uh,
43:12there is a decrease of alpha and the
43:15increase of complexity that was also
43:17associated with visual experience and
43:20this change in feedforward feedback.
43:22And again like in this case,
43:24it's quite natural to think that
43:26the increase it corresponds to an
43:27increase of sensory processing.
43:31I got the solution so.
43:33What was found in several studies that
43:36it was correlated with the decreased
43:38alpha regulatory activity, and notably
43:40in the posterior cingulate cortex,
43:42which is part of the default network.
43:44So This is why it makes sense.
43:48But there were also, like many other
43:50correlate of the euro dissolution that
43:52are quite difficult to put together.
43:54So, for example,
43:55a disintegration of the salience network,
43:58a disconnection between the parietal
43:59lobes and the medial temporal lobes,
44:01decreased connectivity between parapro
44:03campus and retrosplenial cortex,
44:05change of increase of salience
44:07network connectivity.
44:08So many, many correlates that are not
44:13obviously a linkable to these effects.
44:16And regarding the overall subjective effects,
44:21the decreased network integrity
44:22and segregation was correlated
44:24to that and also connectivity
44:27with the somatomotor region, so.
44:30This is also quite, let's say,
44:33natural to think that's OK.
44:35When you when you change the the the
44:37integration of information across the brain,
44:39you will have this subjective effect.
44:42But they they could simply be correlated
44:45with the intensity effect specifically
44:47exactly in this in this study, it was
44:49not correlated to specific substrate.
44:54I mean it would be interested to, yeah,
44:56yeah, it would be interesting to have to
44:57have something that is more specific,
44:59but also all these phenomena are
45:01probably correlated one to another,
45:02so it's difficult to to separate them.
45:07Regarding emotions and mood.
45:10So we saw this decreased brain response to
45:15negative emotional stimuli and and this
45:18could lead to a bias toward positive emotion.
45:21And in fact it was not.
45:24It was found, but maybe not as expected.
45:27So here you can see that the decrease.
45:29So there is this decrease in the
45:32amygdala for negative that is more
45:34important than for neutral.
45:36Uh stimuli and and uh the reaction time
45:40that you can see uh uh under is increased,
45:44but it seems to be increased for everything.
45:46So negative, neutral and shapes.
45:47That is the control in these studies.
45:49So not very specific to an emotional aspect.
45:54Unfortunately,
45:54let's say or in other study,
45:56there is some specific bias
45:59toward positive emotion.
46:00So in this case it's like the the error
46:05rate in recognizing emotional faces.
46:07So what you can see is that there
46:10is more error for negative,
46:11so it's negative emotion is less recognized.
46:15And in this study also you can see that
46:17there is less recognition for fearful faces.
46:20You don't have it for other,
46:22it's not significant for the other emotions.
46:24And in this study they used 2 doses
46:27of LSD and there is not apparently
46:30a dose effect for this aspect.
46:35And what we may be interested in in
46:37particular as as psychiatrist as I
46:39am is the positive effect on mood.
46:42And for that even in the first study we
46:45have a significant positive effect on mood.
46:48And in the second one too that is
46:51like associated with stellar sibling
46:53index or in Africa controls here.
46:56And what you can see is that
46:58this positive effect change is
47:00correlated to the enterable change.
47:02So this is quite a.
47:04Grievance and are quite nice to see that
47:06it could be a like one of the neural
47:09substrates of this of this improvement.
47:12There's a comment in the chat.
47:16That the. Pointing out that these
47:18are all in healthy controls exactly,
47:21or perhaps general population.
47:22So it's possible that these would
47:24be qualitatively different findings
47:25into test subjects or in another.
47:27Thank you for this transition.
47:30So I'm going to the to the
47:33antidepressant effect.
47:34And uh, overall, uh,
47:35what was found is that the
47:37changes in magnitude were
47:39also alleviating depression in
47:41participant with depression.
47:44Just another comment please.
47:45Are acute effects.
47:49There's a bit of
47:50yeah, everything is acute I so
47:52there are several studies showing
47:55studying effects after one week,
47:57but I did not detail by
47:59mean I have like with time,
48:00so I did not detail everything.
48:02So this is really for acute effects.
48:06So for participants with depression,
48:09so quite strangely, there is an increased
48:12animal activity during phase processing.
48:15So this was interpreted by the others as
48:18being a moment where you are confronted,
48:21confronted to negative emotion and that it
48:24could be still positive for the people.
48:27But during rest there is a decreased
48:30amygdala activity that was in
48:32this study correlated with the
48:34improvement that was subsequently.
48:36Observed after service.
48:41There is also a decreased amygdala.
48:45Even from the personal cortex
48:48connectivity that was correlated
48:50with a decrease in ruminations and
48:53overall what is observed in this study
48:56where subjects with depression at the
49:00received signal savings that there
49:01is a better emotion recognition after
49:03the the the intake that is correlated
49:05with the improvement of the mood.
49:08When you say after is this.
49:11During these days, uh,
49:12in it's one week after I think I'm, yeah.
49:15Well beyond the period. It's.
49:17Yeah. It's their ability to
49:19recognize after the treatment.
49:20Yes, it's not during the treatment.
49:25So there there are two studies
49:28exploring how network integration
49:30changes the sailor saving could play a
49:34role in this antidepressant effects.
49:37So the first one we showed that there
49:39was a an increased connectivity between
49:42the entire single singular cortex and
49:44the posterior singulate cortex that
49:46are part of the respectively that's
49:49positive network and different network,
49:52so there is a better integration.
49:55Between these two regions pertaining
49:57to two different networks and they also
49:59studied like the cognitive flexibility,
50:01they found that both of them were increased.
50:03But quite strangely,
50:05these two measures were articulated,
50:07so the more changing in the connectivity
50:09and the less improvement in flexibility.
50:12So it was difficult to understand this
50:16result. And there is, uh, another um.
50:21Study uh where uh you can see that the
50:23higher integration between different
50:25networks, so the default network,
50:27executive network,
50:28salience network that you can see
50:30in this bar plot and the decrease
50:32recruitment of the default mode
50:35network was associated with a better
50:37outcome of of the depressive symptoms.
50:40And this seems to be specific to
50:42the Silo saving treatment because
50:44in this study they compared with
50:46the stellar prime and they did not
50:49observe this change of modularity.
50:50So what they called.
50:52If you like to use the inverse
50:55of integration.
50:56No,
50:56I mean yeah you understand so the
50:59when the network are correlated
51:02there is a less modularity and
51:06they find that it was correlated
51:08to the to the to the outcome.
51:11OK.
51:12Yeah, yeah. In the chat.
51:14Sharif so. These are. Let's see.
51:18Well, the comment is it's hard
51:20to have a placebo control.
51:25The changes are you know,
51:26they're, they're,
51:26they're changes in many of these cases.
51:29How much of that is attributable
51:31to suicide and versus other aspects
51:33of the experience that the patient,
51:35which I think is a an incredibly
51:37incredible challenge for this entire field,
51:41not in clinical outcome
51:43studies as well as study.
51:46It's also like I I'm not sure
51:48that the the rule is necessary to
51:51distinguish the like the subjective
51:53effects or let's say like I'm not
51:56sure if it's possible to have a
51:58very good placebo condition indeed.
52:01And I don't know like let's say
52:03my practical part is more like OK,
52:05it's like what you're interested
52:07in is the is the improvement.
52:09So of course you don't want to to
52:11put your patient with the like a
52:13risk that will be that's correlated
52:15to these improvements.
52:16But um, yeah and this is also one of
52:19the strong attack with to microdosing.
52:23But in fact yes,
52:24in all these studies of course people
52:26knows that they that they were they
52:28have psychedelic and not a placebo.
52:30So
52:31in this case these are
52:33within subject comparisons.
52:34So placebo question doesn't arise
52:35but it does for some of the other
52:38literature that you've reviewed.
52:40Think of this as the cordless
52:41of the overall experience. Yeah.
52:43Yeah. Significant component.
52:44Exactly. Yeah. Yeah.
52:46But I mean, the experience is
52:48also treated by the component.
52:49So I don't know if it's
52:50realistically satisfied.
52:52Yeah, yeah, exactly.
52:59So my last thought, if I have time,
53:01is to talk a bit about the
53:02theoretical models. It's fine.
53:03So, so there are few of them right now.
53:06The consequence theory,
53:09the relaxed belief under psychedelics,
53:12and the cortical posterior cortical models.
53:15So we will start with the the
53:19corticostriatal dynamic particle theory.
53:21So the main idea is that the
53:23teams will play a very important
53:25role in the psychedelic effects,
53:27and in particular it will.
53:32It, like the telemus,
53:33normally filter information and other
53:36psychedelic it will be less able
53:38to filter information, intercepts,
53:40even exceptive information.
53:42And um this uh will lead to um,
53:46uh kind of flooded uh information
53:48coming from the the sensory areas
53:50and it was shown also and I showed
53:53that before that there was an
53:56increased connectivity between the
53:57telemus and the sensory areas whereas
54:00there is a decreased connectivity
54:02probably with the associative areas.
54:05So overall this will the terms will
54:07be at the origin of this pattern that
54:10I already showed 2 whereby there is.
54:12The decreased connectivity for
54:15the associative areas,
54:17whereas there is an increased
54:19connectivity for the sensory
54:20cortices with the rest of the brain.
54:21So there will be a kind of switch from
54:25like a balance where you will have a
54:27lot of sensory processing and really
54:31degraded integrative processing.
54:33And this was fine,
54:35like with these two maps that
54:37are quite similar to each other,
54:39what is
54:39that gap in the middle
54:41lateral prefrontal cortex?
54:42There's an area of prefrontal there.
54:44It is not reduced.
54:47Still. Where? I'm sorry.
54:51So you've got this global reduction scroll
54:53this association protects. Except there.
54:58Uh, I like no,
55:00I don't know what it is exactly that,
55:01but this, so this study were also
55:04correlated with global signal regulation.
55:07So I mean this is the map of statistical.
55:11So it's it's maybe just a threshold effect
55:13and not necessarily something that is
55:15particularly not affected by this one.
55:17Yeah. Yeah, it's really, yeah.
55:21Freeze up and.
55:26So the second model.
55:29So the the main claim is that there is
55:31the under psychedelic there will be
55:33decreased prior and increased bottom up.
55:35So it starts from the irregular excitation
55:38of the of the layer 5 pyramidal neurons
55:41because of the receptor activation.
55:43According to the others,
55:45this is the cause of the decreased power.
55:49Because there is this kind of
55:51desynchronization and thereby less like
55:53the low frequency rhythm would be less
55:56synchronized and therefore decreased.
55:59And this is what is observed,
56:00of course, in the in the literature.
56:02And both of these will lead
56:05to disruption of integrity.
56:07Of last last scale networks and what
56:09we have seen about like this increased
56:13entropy diversity during rest.
56:16And this is also corroborated
56:19by empirical data.
56:20Uh, the other thing that all these
56:23corresponds to a decreased precision of
56:25high level priors or decrease in belief,
56:28because for them like this alpha
56:31rhythm and parameter neuron encodes
56:33the precision of the priors.
56:36So like it's not very easy to to
56:38to to fill this gap between like
56:41the computational aspect and the
56:43like the physical aspects.
56:45But this is what they propose and
56:47the consequence of that would be
56:49that there will be a liberation.
56:51The bottom up information that will slow
56:54and so and also a more as sensibility,
56:58sensitivity to updates and
57:00to prediction error.
57:01So you will have you will be more open to
57:04new information and update your models.
57:07And they propose that this is
57:08one of the crucial aspects of the
57:11therapeutical aspect of this molecule
57:12that you are able to update some rich,
57:15very rigid model,
57:16pathologically rigid model,
57:17for example in depression,
57:19anxiety or addictions.
57:23And finally there is the classic the
57:25cortical cluster cortical model.
57:27So. So this is the classroom,
57:31and what we know about it is that it is
57:34that it received input from the corpus.
57:37It expresses itself also 5H3 receptors.
57:42And uh, the role of the claustrum is to
57:45um to allow cortical synchronization and
57:47also it is activated during task switching.
57:51So it's a kind of.
57:53Then leader of different cortical network.
57:58So you should activate through receptors
58:00at these two location like the clustering
58:03directly and also in the prefrontal cortex.
58:05So the others think that it
58:07results in a decoupling.
58:09So it will not be synchronized because
58:10there will not be like this harmony
58:12between the two but they will work a bit
58:15separately and this will lead to aberrant
58:17cognitive control on network states.
58:19And in fact overall the the the customer
58:22will not be able to no more to to do
58:24these cortical synchronization and
58:25it will lead to a disruption and.
58:28And that's simulation of different
58:30cortical networks that are crucial
58:32for brain functioning.
58:33So in particular the different
58:35network by the continued work.
58:37And all this is supported by one study.
58:40So of course the recognizer
58:43techniques like further replication,
58:45but in this study,
58:46so there is a change of connectivity
58:49between the classroom and
58:51different different networks,
58:53in particular the development
58:55network and the frontal.
58:58Control, uh,
58:59network and there is also like change
59:02per se in the activity of the classroom.
59:05This isn't healthy.
59:07Yes,
59:08yes.
59:10And how well I know the
59:12classrooms like 1 voxel thing.
59:14Like how good is the site
59:15with modern methods?
59:16How good is imaging
59:17imaging in the classroom?
59:22OK, I would like to finish and I I
59:24hope that we may discuss about that.
59:26So I'm coming from the consciousness
59:28field of cognitive science and and I I
59:31get interested in psychedelic because for
59:33me it was quite obvious that subjectively
59:36there will be a strong impact of
59:38psychedelic and conscious perception.
59:39I just want to propose a link between
59:41what I know of conscious perception
59:43and the effect of psychedelic and
59:46like it's also a way to describe maybe
59:48the Rebus a bit differently because.
59:50Many of the premises of this will be common.
59:54So this is the model that I used a lot
59:57to to all my studies on consciousness.
01:00:00And this is the the model of the
01:00:02global neuronal workspace.
01:00:03So the main idea is that consciousness
01:00:06rely on the activation of a specific
01:00:08network that corresponds to like the
01:00:12connection between different brain
01:00:15area through a long distance neurons.
01:00:18And the main idea is that.
01:00:20So all the time you will have,
01:00:21you will unconsciously process
01:00:23information and few information will
01:00:25be amplified in particular by top
01:00:27down processing to enter this network
01:00:29and being shared and broadcasted
01:00:31across the brain.
01:00:32So it will bring like a kind of huge
01:00:34activation and this encoding of
01:00:36information shared by different brain
01:00:38areas would really corresponds to
01:00:40conscious perception of this information.
01:00:43Umm,
01:00:43and this top down could be linked
01:00:47to this alpha band or beta band.
01:00:49And as I said before,
01:00:51some studies showed that perception
01:00:54was helped by this particular vendor.
01:00:58Oscillations.
01:00:58And so there will be this kind
01:01:02of broadcasting in this network,
01:01:04but also filtering.
01:01:05So there are two roles of this
01:01:07amplification and of this top
01:01:08down processing.
01:01:09First of all to amplify so that you
01:01:11can perceive and you know that your
01:01:13attention plays a very important
01:01:14role in conscious perception,
01:01:15but also to determine and to
01:01:19disambiguate what you are exposed to.
01:01:22And of course,
01:01:24like this sharing of information
01:01:26really and like with the pyramidal
01:01:28neurons and also like just global
01:01:30connectivity across the brain.
01:01:34So if we start with the
01:01:37same idea as the Rebus,
01:01:39so the activity of the pyramidal neuron
01:01:42decrease low frequency rhythm and
01:01:45increased inter network connectivity.
01:01:47So let's see how this plays a
01:01:50role in consciousness.
01:01:51So the pyramid on the run have
01:01:54been shown to support information
01:01:57integration so and to allow
01:02:00coincidence detection between external
01:02:02data and internal prediction so.
01:02:05In fact, the computation between
01:02:07priors and and sensory input
01:02:09can can also occur directly
01:02:11injecting these neurons and not
01:02:13necessarily in a in a video area,
01:02:15but already at the neural level.
01:02:18But it has also been involved
01:02:20in conscious computations.
01:02:21And indeed there was a study
01:02:23showing that if you change the
01:02:25calcium activity in the dendrites,
01:02:27you can modulate threshold for
01:02:29perceptual detection and also that
01:02:31anesthesia decouples these neurons.
01:02:34And that's it can be one of the
01:02:36mechanism through which you lose
01:02:38consciousness during anesthesia.
01:02:42So as I said, like uh, alpha situation,
01:02:44we're shown to carry a part of the
01:02:47top down sensory prediction and this
01:02:50prediction will change your orientation
01:02:52of attention on the external world and
01:02:55also help to disambiguate sensor inputs.
01:02:58So This is why, for example,
01:03:00you can see that this you will have the
01:03:02impression that the left circle is convex,
01:03:05is convex while the right one is concave.
01:03:07And you will be pretty sure about that
01:03:09even if there is no like it could.
01:03:12Also be like uh the the opposite,
01:03:14but just because in general the light
01:03:16comes from the from the from the
01:03:19sky and not from the ground. Umm.
01:03:22And in fact it has been shown in several
01:03:24studies that the expectation correspond
01:03:26to kind of template of activation that
01:03:29you can decode in the brain and that is
01:03:31much to a sensory incoming evidence.
01:03:34So in fact you have a kind of ghost
01:03:37activation that corresponds to what
01:03:38you're expecting and there is a matching
01:03:41and this really sharpened perception by
01:03:43increasing the the signal to noise ratio.
01:03:49And finally like of course connectivity is
01:03:53crucial so that cortical region of high
01:03:57level region can constraint and like sensory
01:04:00region according to this expectation.
01:04:03And it was shown in this study that
01:04:07like the top down effects rely on
01:04:09recurrent and enhanced connectivity
01:04:11within some different areas and
01:04:13more broadly like the long distance
01:04:15connectivity has been shown to be.
01:04:18Related to contraception,
01:04:20uh threshold and information sharing too.
01:04:23So what I would like to propose here is that.
01:04:26So if we take this hypothesis of global
01:04:29neuronal workspace with this top down
01:04:32that is very crucial to amplify and and
01:04:34let's information enter this workspace,
01:04:37the decrease of alpha band will
01:04:39impair this top down processing
01:04:41and you will have therefore less
01:04:43selectivity on your sensory input.
01:04:46So this is quite close to what
01:04:48is proposed by characterized and
01:04:51and also in the talamo particles.
01:04:53Well, a looper proposal proposal.
01:04:56So what are the consequences of that is that
01:04:59you will have less filtering of information.
01:05:03But also because there is this increase
01:05:05in their network connectivity,
01:05:06you will have an amplification of the,
01:05:10we can say the neural vector
01:05:12encoding conscious percept.
01:05:13So we can imagine that there will
01:05:15be more amplification inside the
01:05:17workspace because there is a lot
01:05:19of sharing of information and this
01:05:21will lead to this may lead to.
01:05:23Maybe there is less information
01:05:25inside the workspace,
01:05:26but this seems to be
01:05:28subjectively very amplified.
01:05:29And it was also interesting he showed that
01:05:31when you were missing some information,
01:05:34you never you never detect that
01:05:35you're missing some information,
01:05:37you just complete with information.
01:05:39And generally you have the illusion
01:05:40to perceive everything.
01:05:41So the less you perceive and the
01:05:43more you can have the impression
01:05:44that you perceive correctly,
01:05:45and in fact you are just missing the
01:05:48gap with your own representation.
01:05:50Also,
01:05:50this can be linked to the temporal
01:05:53dilatation that was regularly
01:05:55described under a psychedelic.
01:05:59Japan, activity of pyramidal neurons.
01:06:02So I said that they were like
01:06:04kind of coincidence detectors.
01:06:05So maybe the feeling of epiphany or the
01:06:08feeling of coincidence is linked to this
01:06:10hyperactivity of these pyramidal neurons.
01:06:12And um,
01:06:13because you have less um uh,
01:06:16uh, prediction and you have
01:06:18less low uh frequency reason,
01:06:19you are less able to give a unique
01:06:21interpretation of your sensory input.
01:06:23So there is something that is
01:06:25maybe that can be more moving
01:06:27and maybe unstable in the way
01:06:29you represent the external world.
01:06:31But because you have this activity
01:06:33of the pyramidal neuron,
01:06:34maybe you will just match some
01:06:36available templates that are here with
01:06:38perception because they are activated
01:06:40and they are all used to integrate
01:06:43external information with prediction.
01:06:44So this may explain why why you
01:06:47match your sensory input with for
01:06:49example geometrical forms of faces
01:06:51are very like common patterns of
01:06:53activation that may be available
01:06:56and and and will be just hyper
01:06:58matched with this sensory inputs.
01:07:01And finally,
01:07:02but this is a more general statement,
01:07:04the increase of the uncertainty and the
01:07:07change in perception they have shown
01:07:09to be linked to like to to favor jumps
01:07:12to conclusion and delusional ideas.
01:07:15And there may be also, of course involved
01:07:18in the mental flexibility that have
01:07:21potential therapeutical effects. Yes.
01:07:27So that's the part that talks about.
01:07:29So less ability to give unique
01:07:31interpretation of sensory input.
01:07:33And I wonder if it is related with
01:07:36the sort of we have to decrease
01:07:39connectivity within networks.
01:07:41And I wonder if that also applies
01:07:43in terms of those interpretations
01:07:46that are so ingrained in different
01:07:48conditions or those associations that
01:07:50are ingrained in different conditions
01:07:53like making an association between one.
01:07:55Do you like and I'll draw on something
01:07:58in the environment and like having
01:08:00an obsessive thought or I wonder if
01:08:02part of the what we see with imagine
01:08:05like with less network connectivity,
01:08:08also more complexities is related
01:08:11with having that wider?
01:08:13Repertory in terms of associations
01:08:16or interpretation.
01:08:18Yeah, yeah,
01:08:19yeah. Yeah. So you write that this
01:08:22diffuse ability to to interpret
01:08:24uniquely and sensory input and we
01:08:26also due to like the disintegration
01:08:28of the network or the the increased
01:08:30connectivity of Internet work that can
01:08:32interfere with basically with the like
01:08:35like their regular functioning and
01:08:37and and their role to to distinguish
01:08:40between one thing and another.
01:08:42But what I like is in this idea
01:08:44and it's and and I didn't say
01:08:46but it's of course absolutely.
01:08:48Uh, compatible with the telemetry?
01:08:49Uh, hypothesis because the telemetry,
01:08:53the telemus also filtering information
01:08:54and allowed to to to choose between
01:08:57several interpretations too.
01:08:58So I think it's just another
01:09:01level of description.
01:09:02But yeah,
01:09:03because it's what I know it's,
01:09:04I feel more comfortable with this
01:09:06way of describing things.
01:09:07But of course it's it's not anemic
01:09:09with the the other proposals.
01:09:14I'm almost done I think I have
01:09:16two slides so please slide.
01:09:18So the limitation all of these studies
01:09:22so I took this summary that only
01:09:26talk about resting state of moral
01:09:28literature but I think it's it's
01:09:30quite obvious what are the problem
01:09:31with all this second indicator.
01:09:33So first of all what you can see is
01:09:36that there is many many reanalysis
01:09:39of few cohorts of data and.
01:09:42This is striking,
01:09:43like it's almost like half of
01:09:44the articles are in fact coming
01:09:46from the same data.
01:09:48So this is of course a
01:09:50problem for reproducibility.
01:09:52And I I, I mean,
01:09:53I also totally admit that it's very
01:09:55difficult to build such studies and
01:09:57I I know what I'm talking about.
01:09:59But of course this is a problem for
01:10:02interpretation and generalization.
01:10:04Second,
01:10:04so there are not so many participants
01:10:06in the study and we would like
01:10:08to have more important study,
01:10:09even if in cognitive psychology generally,
01:10:11like with.
01:10:1225 people you are you already have
01:10:14like substantial results, of course.
01:10:16So here are only resting state literature,
01:10:19but in fact it's like most of the
01:10:21literature in your imaging literature
01:10:22and psychedelic is using resting state.
01:10:24And this is a like kind of an
01:10:27issue because in fact we don't know
01:10:29exactly what people are doing during
01:10:31resting state and in particular
01:10:32during secret experience there
01:10:34may be totally attractive and
01:10:36fascinated by something and just
01:10:37processing one thing for a while.
01:10:39And we don't know if what we are analyzing
01:10:41is like really demanding resting or
01:10:44just focalizing on something special that.
01:10:47And the difference across participants.
01:10:49So I think that we really need to have
01:10:52more tasks because it's more constraining.
01:10:55So of course it also have its limits
01:10:57and but it it helps to compare
01:11:00different condition maybe in a
01:11:02more constrained manner.
01:11:03So as I said,
01:11:04so I did not mention there is just one.
01:11:09Study with muslin, but uh,
01:11:11so many of the study involved the
01:11:14SILYBIN and LSD a bit less for iasca.
01:11:18And what would be,
01:11:19I think really interesting is to
01:11:21compare the drug one to another and
01:11:24in particular with getting into
01:11:26because I did not highlight it.
01:11:28So yeah, yeah, someone should do that.
01:11:31So because as you can see,
01:11:33there are several aspects
01:11:35that are a bit different,
01:11:36in particular for the feed
01:11:38forward we talked about already.
01:11:40But also the condition are generally
01:11:42different and even in the use of
01:11:44people like I generally taken
01:11:45in a ritual way and things like
01:11:47that and we we really want to
01:11:49compare and to see what are the
01:11:52pharmacological difference and the
01:11:54the neuroimaging differences between
01:11:56several drugs in the very same.
01:12:00But I'm experimental paradigm.
01:12:03So we would also be very interested in
01:12:06comparing these different population
01:12:07because in general the study were either
01:12:10in control or in patient with depression.
01:12:13But there is not really comparison between
01:12:15the two for neuroimaging studies at least.
01:12:18Um, we talked about it also,
01:12:20but uh it would be quite interesting
01:12:22to see uh the long lasting effects or
01:12:25at least just some study explored the
01:12:27time dependent effect in the session.
01:12:29So they did several scan in the
01:12:31in the very same session.
01:12:32But it could be also interesting to
01:12:34see what is left after a session
01:12:37of psychedelic and also maybe
01:12:39to explore the different doses.
01:12:40So there are several study with Microdose,
01:12:42but it could be interesting within
01:12:44us the same study and within the same
01:12:46experimental guidance to have several doses.
01:12:48So to compare and to see what is
01:12:50dose dependent or not.
01:12:53OK, so as I should like psychedelic
01:12:56drastically change a brain state of
01:12:58activity and connectivity during rests,
01:13:00decreased within connectivity,
01:13:02increase entropy and
01:13:04internetwork connectivity,
01:13:05in particular in sensory areas.
01:13:08This decrease of low frequency problems
01:13:12that are probably involved in feedback.
01:13:15Some effects are quite consistently
01:13:17associated with subjective effects,
01:13:19and in particular the effect of Magdala,
01:13:21which showed that it were quite linked to the
01:13:25increased positive effects under psychedelic.
01:13:29But some of the branches are
01:13:31changes are more difficult to link,
01:13:33or are maybe inconsistent across
01:13:36studies or across psychedelics,
01:13:38so it's difficult to really know what
01:13:41what are their subjective correlates.
01:13:45And finally the the current
01:13:47theoretical models agree on a
01:13:48decrease of filtering prior control.
01:13:50So there are different terms,
01:13:51but basically the idea is that there is
01:13:54less constraint on sensory processing
01:13:56and they kind of disagree on what is
01:14:00the main mechanism or stable region
01:14:02that is involved in in this effect.
01:14:07So the future direction,
01:14:08so for me like on top of all the proposal
01:14:12I made for having more maybe reliable or
01:14:16generalizable data for second imaging.
01:14:19I think that the two direction
01:14:22that we have is on the first
01:14:25hand like a better description,
01:14:27better description of the subjective
01:14:29effects and maybe one also of the aspect is
01:14:32that there is inter individual variation.
01:14:33So it will be very interesting and it's.
01:14:36It's in fact something that's our
01:14:38lab do to map the subjective effects
01:14:41to a neural individual map and not
01:14:44only to put everybody in the same.
01:14:49In the same group and it's important
01:14:53because if we if we are working on
01:14:57this individual neural effects,
01:14:59we will probably have more power to link
01:15:02the the subjective and the neural and
01:15:04the maybe the receptor also and better
01:15:07better understanding of the mechanistic.
01:15:10On the other hand,
01:15:11it will also be helpful to see
01:15:13what of these subjective effect
01:15:15may be helpful for patients.
01:15:18And once they see your addiction?
01:15:20And the second as aspect is in
01:15:25fact the using the psychedelic as a
01:15:29pharmacological model of psychosis.
01:15:31So in this case what we would like
01:15:33to do is rather to see what is the
01:15:36neural dysfunction in patients.
01:15:38So without taking them you can
01:15:40just doing brain imaging when they
01:15:42have like specific symptoms and
01:15:43try to link these symptoms to what
01:15:46we can observe under psychedelic
01:15:47and again if possible in the.
01:15:50Individual manner because in this case
01:15:52we may think for example that when
01:15:54patient is as a cerebral exhibition
01:15:56that is close to LSU response map
01:15:58and therefore that is mechanism is
01:16:00more a certain energetic logic.
01:16:04Yeah.
01:16:05Dysfunction,
01:16:05whereas another one may have for
01:16:07example a neural response map that is
01:16:09closer to look at anyone would have
01:16:12maybe more dissociative effects and
01:16:14things like that and the mechanistic
01:16:16of possible therapeutic drug may be
01:16:19different and this will really open
01:16:22the the field of individualized medicine.
01:16:24I finished.
01:16:25So thank you for your attention
01:16:29and of course I yeah,
01:16:31I see that there were so
01:16:32many questions in the chat.
01:16:33Sorry I could not do at the same time,
01:16:35but of course I would be happy to have
01:16:38your feedback and to answer your questions.
01:16:41Thank you, Lucy.
01:16:42That was a wonderful day.
01:16:44Thank you. We do have a couple of
01:16:47questions dangling in the chat.
01:16:49One thing for me to do,
01:16:50the collective findings, this is a big.
01:16:53Reconcile the phenomenon of a bad trip.
01:16:58And because, you know,
01:16:59to the extent that they did,
01:17:00the group data all looked pretty positive.
01:17:02So how do we understand the
01:17:03phenomenon of a bad trip?
01:17:04And relatedly,
01:17:05do we understand how or why
01:17:07some depressed individuals
01:17:08may be non responders despite
01:17:11having the second experience?
01:17:12It's not quite the same question,
01:17:14but both around how this negative affect.
01:17:16Yes, so. So there is one study exploring.
01:17:21So the difference between, but in fact
01:17:23it's not really the goal of the study,
01:17:25but they were exploring the level of
01:17:28glutamate in the brain and they find
01:17:30that the increasing glutamate in the
01:17:32prefrontal cortex was associated with bad
01:17:35trip and in the hippocampus was associated
01:17:37with good trip if my memory are good.
01:17:40So in fact there was a regional good trip or
01:17:43bad trip levels of mutants in this study,
01:17:46but otherwise it's.
01:17:47Yeah, I think there is a general bias
01:17:50from a researcher in psychedelic towards
01:17:52the good trip and a very good setting.
01:17:54So many people in fact in this in this study.
01:17:58Did not experience such a bad trip
01:18:01and so we don't have, I think,
01:18:03enough cases to really have the
01:18:06neural correlates of battrick.
01:18:08But this is a very interesting question,
01:18:10of course, because we. She started.
01:18:14Yeah, yeah. I'm sure you would
01:18:17have improvement for that, but
01:18:19can be interesting and at least, yeah.
01:18:24Risk benefit ratio. You know, like.
01:18:29To protect patients from that, we have
01:18:32to know what it is.
01:18:34Worked for a couple of days,
01:18:35but I think like anyways we do,
01:18:38if there's more and more study,
01:18:40we will have more. Yeah. I mean,
01:18:42yeah, it could turn into, yeah,
01:18:44if you start, you can evaluate
01:18:45exactly. And the second one was why?
01:18:49Depression do not respond.
01:18:51So yeah, I mean this is even a broader
01:18:53question like for for psychiatrists like
01:18:55why in some case you give a medicine it
01:18:58works and sometimes it doesn't work.
01:18:59So it's a very difficult question.
01:19:02Probably there is heterogeneity in
01:19:04patients with depression first of all.
01:19:06So of course they may not have the the
01:19:08same neural mechanisms of depression and
01:19:10and thereby not the same like a response
01:19:14to to treatment after like I can say
01:19:18from my experience with ketamine because.
01:19:20We were using a lot of ketamine to
01:19:23help people with a resistant depression
01:19:25and I don't know you manage afterward
01:19:28to to know a bit which patient will
01:19:31be will have a good trip or bad
01:19:33trip or will have a response.
01:19:34And in in particular I think one of
01:19:36the main aspect is really to accept
01:19:39the condition of the drug and to
01:19:41accept also to be high during a while.
01:19:43And this is something that is absolutely
01:19:45not easy to accept for many people and
01:19:48in particular patient because they are.
01:19:50Really afraid.
01:19:51And one of the questions for example
01:19:53is for people with trauma like whether
01:19:57the dissociative experience that they
01:19:59can really experience during during
01:20:02ketamine or I don't know exactly
01:20:04with psychedelic,
01:20:04we don't have a lot of data on that,
01:20:06but how it can be managed and will
01:20:08it be positive or negative for them.
01:20:11And also there is a decorrelation between
01:20:14the acute effect and the beneficial effects,
01:20:16OK.
01:20:17I mean it's quite striking straightening
01:20:18like some some of them will have very.
01:20:20Kind of battery backfilling,
01:20:21but afterward they will feel really
01:20:23good and some other will really
01:20:25enjoy the trip and they will have
01:20:26no room blasting with the effects.
01:20:28So there are several layers of
01:20:31response to that question, I think.
01:20:33Yeah.
01:20:36So it's still bad?
01:20:37Yeah. See this. Thanks.
01:20:40And measured by MRI like do you
01:20:43know approximately, I don't,
01:20:44I don't think the last and the reason
01:20:46I ask the question is thinking
01:20:48logistically in terms of but we
01:20:49have the best imaging as another
01:20:51tool not being able to measure.
01:20:53The occupancy of the party still
01:20:55do every sector and then getting
01:20:57a sense of how that occupancy
01:20:59in a specific area is related
01:21:01to what we see with the MRI.
01:21:03But I don't know if that's gonna
01:21:05be like along those effects last,
01:21:08is that something that we can
01:21:10see like 24 hours later or
01:21:11yeah, so most of the study that's
01:21:14explored the long lasting effect
01:21:16like they explored one week
01:21:18after or something like that.
01:21:20But I cannot remember something
01:21:22really long term in general the
01:21:25safety between two doses is so for
01:21:28study for example that are crossover.
01:21:31So for the clinical trial they
01:21:32really tried to have.
01:21:33Long time between the two,
01:21:35but for like from dental study
01:21:38usually they manage at least two
01:21:40weeks between 2 intake to be sure that
01:21:43they will not like the long lasting
01:21:45effect for the placebo or condition.
01:21:47But yeah it's I mean this question
01:21:49is not solved like we don't know
01:21:52exactly and we don't have enough
01:21:54data to to really answer how long
01:21:56does it last because you have like
01:21:58just the effect of the drug staying
01:22:00in the brain but also like I did not
01:22:02mention the effect on on synaptic.
01:22:04But it's probably also very important in
01:22:07particular for the beneficial effects,
01:22:09and this may be long lasting effects.
01:22:13We have a couple
01:22:14more questions in the chat,
01:22:15but we are at 5:00 o'clock.
01:22:18It was a wonderful presentation.
01:22:20I really covered a lot of ground.
01:22:21Thank you. Thank you.
01:22:30I mean people can send me
01:22:32emails and have discussion.
01:22:34I would be very happy to.
01:22:38Yeah. Qualitative
01:22:40analysis of different narratives
01:22:41in our seeking treatment study, OK.
01:22:45Say. You know. And the model.