This is the Convergent Science Network podcast. Leading researchers in the domain
of neuroscience, brain theory and technology are interviewed by Paul Vershoor and Tony Prescott.
This is Paul Vershoor with the Convergent Science Network podcast together with
my colleague and co-organizer of the BCBT Summer School, Tony Prescott.
And we're talking with Marco Diona, who is one of the speakers in our school this year.
And Marco, you spoke on the induction of a hypodogma-energic response through
transcranial magnetic stimulation.
So the question is, how did you end up leaking, if you want,
transcranial magnetic stimulation in the treatment of addiction?
So what was the trajectory that kept you there? Okay, let me make this thing straight first.
The hypodipaminergic state contains, or the hypodipaminergic hypothesis,
contains that the chronic use of drugs,
several drugs, different drugs, drugs, alcohol, cocaine, opiates,
psychostimulants in general, will produce a hypodopaminergic.
From here, you can give a
reason or a possible reason to justify all the changes that you observe in a drag art.
Or not all the changes, but at least some changes. As we all know dopamine works
in movement, is important in movement, is important in reward,
is important in motivation,
is important in a number of functions.
The transcranial magnetic stimulation,
in principle, may offer the cue by stimulating the prefrontal cortex.
You can take advantage or you can exploit,
if you will, a well-demonstrated
anatomical pathway which goes from the prefrontal cortex monosynaptically to
the ventral tegmental area and this neuron will impinge upon a dopamine neuron
which in turn will project to the limbic areas.
So if I apply transcranial magnetic stimulation in a stimulatory pattern, I should, in principle,
potentiate a system that has been functioning less.
Due to the chronic use of drugs. In fact, these are already being shown in healthy individuals.
If you do apply TMS to the prefrontal cortex.
You get an increase in dopamine release, as shown by PET studies by Antonio
Straffella, essentially, and others.
Right. So that's where you are today.
But in some sense, we first have to inspect what is really the brain of an addict, right?
How is the brain of an addict different from a healthy brain?
So, and you very much emphasized the role of dopamine and dopamine reconfiguration.
So, how should we think of the brain of an addict? There is another area that
we did not emphasize today, but that requires and needs to be remembered.
This is the prefrontal corpus.
It has been shown by others, by the visual imagers,
for instance, that the cortical mantle at various levels of the dorsolateral
prefrontal cortex works less.
I'm using very simple terms simply to be understood. to.
For instance, Nora Volkow and
Rita Goldstein they think that
the lack of function or the reduction of function in the specific orbit of frontal
cortex is then responsible for the impulsivity that characterizes the behavior of the addict.
One of the key features of addiction is craving.
Craving for the drug. It simply cannot resist.
And so, many indications and many reports suggest that this is due to a malfunctioning
of the prefrontal cortex.
Specifically, in their idea, is the audit of frontal cortex.
Other people think about the cingulate cortex.
Some more think about the dorsolateral prefrontal cortex, also because in cortex
there is a small problem to identify.
The cortex does essentially always the same things. cognitive integration,
decision-making, working memory, and so on.
But it's very difficult to find the borders between preliminary cortex,
singular cortex, orbital frontal, dorsolateral, dorsal medial, ventral lateral.
There are no a priori boundaries. And when we apply a stimulus like the TMS,
it's very difficult to contain that stimulus only to the preliminary cortex
and not touching the infralimbic cortex, and so on and so forth.
So the agreement exists only...
Frontal lobe of the brain, which is not working properly and in many senses
is unable to keep down pulsions.
So it's unable to avoid dangerous behaviors.
So the weak cognitive conditions for you, addiction is also a pathology of executive
control. No, absolutely not.
It's not only, let's say, as we'll see also later, an excessive manipulation of a reward system.
No, no, no, no, no, absolutely not. But do you see it as an independent process
or not as dependent on, again, what happens to the reward system?
The key is, suddenly the reward system is damaged.
Let's put it that way. And suddenly the reward system responds immediately.
As the chronic treatment goes on, and the answer, the cognitive part will come into play later on.
We'll know. Does not have the same timescale, the cognitive part as the emotional part.
Emotion is beginning initially. Take drugs, dopamine goes up, he's happy, honeymoon.
Then slowly the system adapts and the second system, the cognitive systems,
mostly the cortex, will become involved.
In other words, in spite of the fact that you are taking drugs from time zero.
At time one, the limbic system is intervening and modifying your behavior.
But at time 10, the cognition will come into play.
The cognition means also that the addict becomes aware of the fact that he's an addict.
He is an addict.
It means he's a patient. He needs help.
He needs somebody to rely on to come out from a situation that has slipped through
his fingers, to put it in this romantic way.
Can we know for sure that the people that become addicted to substances.
Are already predisposed in some way towards addiction,
so that other people may be given the same introduction to these substances
might not become addictive,
but these people may already have some aspect of frontal cortex dopamine function,
which predisposes them towards this now there
are studies of course
which have indicated that there is a component a genetic component which will
favor the the emergence of the full-blown phenomenon.
It is a multifactorial disease, if you wish.
I remember that a paper in Science by Jervik Piazza and his co-workers.
Found that roughly of 100 people that will take drugs, roughly 17-18% will become addicts.
Taking a drug does not mean to become an addict.
The diagnosis is very clear.
The DSM-50 will tell you exactly that You need to take drugs.
You need to take continuously.
You need to make attempts to stop.
You know that you are doing bad to yourself, so you try to make attempts.
And these attempts to quit, they fail.
Okay? Another very important point is the fact that at one point,
the drug is interfering with your life.
It's not anymore a matter of physical, biological problems.
It's a matter of interference with your normal social life, which means working
life, which means familiar life,
which means social life and many other things.
So of 100 people that will take a drug, roughly a fifth will become real addicts.
So,
To bring it back to what you discussed earlier about prefrontal cortex.
So, on the one hand, there's this idea, and we can also expand that later,
that drug use, whether it's morphine or opioids or alcohol.
Is targeting the dopamine system and leads to a dysregulation.
It's one of the targets. Exactly. One.
Absolutely not. So, that's not a debate yet.
But now, I could argue, well, Now, since dopamine is changing,
the targets of the dopamine system, including prefrontal cortex,
is also changing its response.
So the long-term changes are, in the end, a knock-on effect of manipulations
of the neuromodulatory system.
With an alternative interpretation to say, and I think the direction you were
going, I have different functional subsystems.
And these functional subsystems all have their own regulatory role in the control of behavior.
Behavior, and you might have, let's say, a limbic system dealing with issues
of satisfaction of immediate needs and craving that it tries to resolve in some
ways, but when that remains unresolved,
I have to start to use,
let's say, cognitive resource to resolve that problem.
And that's how I start to engage my executive control system in front of the cortex.
So which of these two causal pathways do you see as being dominant in the development
of a legal tool? I don't see any one of those dominant.
Probably, if you stick a gun on my head and tell me only one,
I will tell you about the cortex.
Because another problem with the addict... Take out the gun, Tony.
Another problem with the addict is he's a very difficult patient.
All patients, they recognize their status as a patient.
If I feel pain on my shoulder, I will come to you and I will tell you, I feel pain.
Tell me what to do, what I have, what I should do to fix it.
The other does not recognize that he is a patient. And that brings,
elongates his pathology.
He has to make efforts to realize that he needs treatment and treatment.
Six treatment so so that form of anosmosia, or is it characterized differently?
I Don't know. I don't know but I would say that this is a cortical pro Mm-hmm,
I wouldn't say that this is a dopamine related protein.
This is a good cognition Okay, it to one itself Awareness what what am I am
I in a big and does the patient?
Or am I simply a person having fun with cocaine and I'm rich enough and I don't care?
For me, 3,000 euros every Friday is nothing. Right.
So would the distinction be that the addict is actually suffering from pathology
that also deforms the self, while in other cases, the patient,
as a reference of, okay, in the past, the self, had the following characteristics,
and today it has these characteristics, like I have pain in my shoulder,
and this difference is now my particular...
Yeah, so it is very difficult.
I am not used to reasoning these terms, but certainly I would say that the self is affected.
The self pre-drug is a different thing than the self post-drugs or during drugs. Okay.
So the possibility exists then that the people that are taking a significant
amount of these drugs on a regular basis, but not experiencing the same impact
on these brain circuits,
so they're therefore able to continue to live their life, more or less,
and to take and leave the substance more effectively than somebody who's addicted.
So they're not meeting the criteria.
In your studies, do you use control groups who are cocaine users but are not
alcohol users, who are not recognized as addicts? No, yet.
My experience with humans, in spite of the fact that my degrees in medicine, I never did it.
Clinical work i always did the robert's work and physiology so it is simply
by seven eight years ago that i began and with these human studies and another
thing is the point that we touched,
briefly this morning is not easy
yeah and i throw it when the patient recruitment is
not an easy he does and he's very
time and effort consuming and frequently
frustrated so to find a
group like that that you
were saying it will take months and months so but it's it before we kind of
conclude the differences we're seeing in the brains of people with addictions
from those of the the controls who are Mokhbrok users,
it's possible that some of those differences may predate their addiction and
that they may already have a predisposition or a genetic.
Something about their personality which is reflected in some of these findings.
I think that a portion is only in that way.
I think that there are There are several factors that contribute to the full blown syndrome.
In some case, maybe that is predisposed.
In some other case, even if it's not predisposed, but it comes across the drug situations.
And things, you may become addicted, even if you were not.
So there is not a single thing that you can identify and say,
okay, I know why you are getting addicted.
So now we have an idea of the phenomenon that we're looking at of addiction,
and it's different, let's say, medical, psychological, and also biological aspect.
Yes. But now in your research, you have dissected that down to a set of very
specific questions along what are the changes to the dopaminergic system and its targets.
This has really become, over many years, the main research trajectory that you
have followed, which I think is also very much representative for the field. divine development.
This is one of the targets that people look for.
So, in the first of the experiments, you looked at, let's say,
what's the effect of drug use and of withdrawal of drugs on the response of
adducting allergic cells.
And you report actually rather, and also that's confirmed by other experiments,
a rather dramatic impact on most of the baseline activity of these of these neurons, right?
So there may be users of actually different types of drugs.
But in some sense, even if it's not that related, right? It can be alcohol or
cannabis or opioids, right?
In all cases, you see a reduction in the baseline activity.
So, tell me, explain that. Where does it come from? Why is it targeting the brain?
A very simple way of providing a possible explanation relates to the acute effect of the drug.
All drugs of abuse, they do increase the activity of the dopamine system.
Once you take them chronically, there are various neuroplastic effects that take place over time.
Tolerance, sensitization, reverse tolerance. There are several.
In brief, what is happening is that the system,
the dopamine system is adapting to the new situation in which in the environment
there is always a molecule that stimulates its activity.
So when you take out this thing, the dopamine system becomes orphaned.
Actually, the drug may work as a constant pusher of the system.
You take out the drug and the system has adapted to a lower level to compensate
for the exogenous drug that is demanding an increase in activity.
Double neurons are also neurons that are very energy demanding.
So, to make a dopamine neuron firing is more costly in terms of energies.
Why is that? I don't know. Paul Balaam has done these studies.
He's an excellent, as you know, neuroanatomist. They are very branching neurons.
They have a huge number of axonolaterals.
But I remember that the conclusion was, that is, from an energetic standpoint,
to keep it going, it requires a lot of humor.
When it means that the first stage of the process,
you essentially describe it as some homeostatic system right,
that's self-regulatory now I'm in some sense overwriting an intrinsic drive
of the system with an external cue, which is a drug.
I'm overdriving the system so it starts to down-regulate so the system goes
down to accommodate for the drug and if now you take the drug Yeah, it looks lower.
OK, and those means if you then are not exposed to the drug long enough,
you should sort of bounce back to this initial baseline.
Is that true? Yes. OK, so it's like a self regulatory system and the drug now
sort of co-ops the system and it readjusts.
So are we optimistic then that you can make a full recovery or do you have some long term?
With TMS, you mean? No, I mean generally if you were to stop the drug.
If you stop the drug at the very first video, it is a painful period. Yeah. And we know that.
We know it for each single drug. Yeah. It is different.
But over six months, say, are you back to normal? Are you indistinguishable from it? Okay.
This is almost a joke. Right. But it is said that the diagnosis of a fully recovered Andy,
you make it only when he dies.
It's like a schizophrenia. Yeah.
He had fully recovered. Now, this is almost a joke, but to tell you,
it tells you how difficult it is.
So the answer is... You can say, this guy is 10 years that is not taking cocaine anymore.
But Marco, there is something though, physiologically, like physiologically,
do the neurons you measure from return to exactly the same baseline level?
Or do they go back to a somewhat different baseline level? That means as if
there's a memory system, right?
For the last question, I would say that there is a memory in the system.
There is a cellular memory as in every cell.
But this is my conviction.
There is only a memory. Let me go back to the first part.
It escapes me now. No, I was starting to unpack the whole addiction syndrome
by really now zooming in on this document.
Oh yeah, if it goes back to the three drugs left.
Yes, it will go back. And we have examples, we discussed this this morning at the lecture.
Opiates, you have an opiate-dependent individual, fighting rate goes down,
the operator list goes down, TH goes down, everything goes down.
Then eventually, it will come to normal level, pre-drive level, in two weeks.
Remember that we are talking about roll-ins.
The time scale is different. So, by in roll-ins, in rats, in two weeks,
more or less, you have a system that is apparently working as it used to.
And we did this paper. We did publish the paper.
If you do administer morphine now to an opiate-dependent individual.
The reaction to morphine will be magnified enormously as compared to the first
shot of morphine in a, let's say, undrunk individual,
in spite of the fact that they have the same basic fighting rate.
So this experiment tells you some more.
Yes, it's going back. The mechanisms that sustain the spontaneous fighting rate,
But perhaps not every mechanism has gone back to normality.
It is known, for instance, that when they recover, one of the things that comes
back to normal later than others is the sleep-wake cycle. They don't sleep well.
Although they may be eight months without taking drugs.
And they have fixed the diarrhea the sympathetic imbalances the various things.
Pain kicking the monkey and all that kind of things in spite of that still they don't sleep well,
so every sign and symptom they have their own kind course right Right,
but that also indicates that you already indicated, I mean, we know we have
to look also beyond dopaminergic systems.
Exactly. Beyond. It's a global change.
But so what was it, what happened next? So now we see we have a huge impact
on the baseline firing of the dopaminergic system.
And then he showed, in also very great anatomical detail, that that in turn
has a huge impact on the targets of these dopaminergic cells.
And immediately the spine density along the targets of these dopaminergic cells,
and you look at it in accumbens, so your ventral cerium,
but supposedly it would happen on any cell that's targeting by these dopaminergic
cells. That's right, yes.
So the dynamics of these changes, if I lose all my spine, it also means I'm losing my side actions.
Yes. So is there any specific pattern to that, or is it a very non-specific effect?
We didn't even find it yet. Because that would mean that essentially there's
a massive disconnection somewhere.
There's a dramatic disconnection in the nervous system. Yes,
yes. Is that how you interpret it?
Yeah, yeah. In different words, I express the same thing. You are representing in very nice words.
There is a massive disconnection.
So if you would have to guesstimate, so if Tony pulls out the gun again,
And if you have to guesstimate how much of the circuit of the brain is disconnecting
as a result of this, just rough guess,
would you think like 1% or is it like 40% or even higher than that?
Well, I don't know, but between 1% is more, it's more than 1%, it's 40%.
Then if you say it's 40% or 80%, I would probably say 40%.
You know, it's difficult to put these things in numbers.
But this connection, believe me, the behavior changes.
The behavior changes. The best way to have a description...
Not a strictly scientific description, is to ask a mother.
Ask a mother that has a child that is taking drugs.
She will tell you, this is not my son anymore.
The whole behavior changes. It affects the relationships with loved and unloved,
the sleep-week cycle, feeding.
Everything changes more or less if someone would be interested in.
Opiate addiction I would never suggest him to read one of my papers but I would
suggest to read Confessions of an Opium Eater by Thomas de Kinse or if you want
to study memory you don't read,
Rokmalenka but you need the first to read
the French guy what's his
name now escapes me hmm the Lager
church a lumber of the left and
truth boost my land be free
you you get the idea what memory right
so so so so if a
disconnection somewhere citrus regret because it's an Alzheimer disease
is also described as a disconnection syndrome so in
terms of the symptomatology would you would you think overlap between addicts
chronic addicts and an alzheimer patient like you
have the hyper emotionality you have a lack of of cognitive control at least
overlaps explore this is like uh thought about that i I thought about the parallel
between psychostimulants,
abusers,
and schizophrenics, for instance.
I thought about cocaine addicts, you see, and paranoiacs.
Never thought about Alzheimer's.
His capability is extraordinary.
He knows how to solve a problem. He can do abstract thinking.
He can solve a puzzle. Actually, he solves puzzles every day because he doesn't
have money. And his problem every day is to get money, to get high,
and then to get money again.
And these are big puzzles when you don't have money.
So they steal, they do strange things, but their capacity to reason is not that cheap.
Or at least in some part. I mean,
one of the, we just mentioned one of the knock-on effects is on the D2 receptors
in the striatum that you discussed at length.
Okay, so just to be clear about what the effect is,
so what happens is that the overstimulation of the dopamine neurons by the drug
is flooding the striatum with dopamine and that's causing a reduction in the
D2 receptors, is that correct?
Well, I don't know if there is a causal role.
Okay. I don't know if the dopamine receptors are decreasing in number because
there is a lot of dopamine or...
By an independent mechanism which goes in parallel.
It could also be a neuro-adaptive mechanism as you are more or less suggesting. Lots of dopamine.
Let's get down with this. It could be, but these are possibilities plus they
are very academic possibilities in the sense that if you're looking for a therapy.
Why is that? Or there is another reason.
What I have to do is to fix that number and take it back up as it was.
Yeah. Well, I mean, I think if it is an adaptation, then you would hope that
that would, again, correct once you take out the excess dopamine.
I mean, if the dopamine cells go back to firing at the normal levels,
then you would hope the D2 receptors would also recover to the pre-addiction levels. Yes.
But we don't know that. Still no good questions. Yes.
Yes. Yeah. Would you expect any kind of specificity with respect to different
receptor types, or do you think it's a very nonspecific effect?
Within the dopamine system? It's non-specific,
although there is some consistent literature,
for instance, in rodents that tends to give to the D1 receptor a.
Relatively major importance in rodents in humans so far cannot be studied because there is no label,
right there is no radio light by richard wood is it and uh we did it ourselves also,
and the mechanism in the population of the the middle spiny neurons can roughly
be divided into two categories.
One, that is the medial spiny neural that projects back to the substantia nigra parceria ticulata.
And these neurons, they do contain predominantly D1 receptor.
Then there is another population which projects to the palynus and then comes
back. Okay, these are called the direct and indirect pathway.
Virtually every study will tend to bring in the direct pathway.
So you can block with the CH, which is the dopamine antagonist,
and we did this, I was describing this morning, If you give L-DOPA to rats,
you will have the spines growing back, you will have again your LTP mechanisms,
and you will have also memory,
the rodents performing well in emotional memory tasks.
This can be blocked by SEH, but not by Sompi-R, which is D2N-DAP.
And this is really invoking a D1 mechanism, but this is all.
Okay. But if there's a differential effect on the direct and indirect pathway,
then this again would imply that there's a modulation of executive control system, right?
Because they will depend on these pathways again for the kind of competition
that plays out at this cortical level.
Yeah so when we move from rats to humans because this is in the end what you looked at there was so.
What made you believe that the transcranial stimulation could actually help
you to resolve the addiction problem what are the pieces of the puzzle that
gave you confidence that this even made sense to do,
to resolve the puzzle is certainly an overstatement.
We won't resolve the puzzle. The transcranial magnetic stimulation has.
Two main advantages the very first one is its physiological nature you're using a stimuli,
let's forget a moment about electromagnetism and these things that are very
confusing for some You are stimulating the cortex.
You are able to modulate cellular activity in the cortical lane.
This has to be contrasted with what you have available in the field today.
Day for cocaine zero there
is nothing there is not a single molecule why you have in an opiate and dictate
you will say okay there is nothing else to do take methadone okay you are you
are tobacco-dependent,
here is varenicline,
nicotine patches,
gums, you have several therapeutic approaches.
For cocaine and psychostimulants there is nothing.
So this is the first part. The second part, we spoke about this also this morning
the second part is this lack of possibility of therapeutic possibility,
pushes the psychiatrist to find something to give to this guy and the standard
things are and type the person oh he's taking cocaine because he's the the breast, it's obvious,
you know, antidepressant, anxiolytics, and mood stabilizer.
Now, as a pharmacologist,
I am fully aware that while we do know the pharmacology of antidepressant,
we know much about anxiolytics and problems and toxicology of this And we also
know about the pharmacology of the mood stabilizers,
whatever that means,
because we don't know nothing about the pharmacology of these three molecules
in a 50 years old individual,
which is risking heart attacks, which takes blood lowering.
Blood pressure pills, and eventually even other things.
So, this combination of factors compared with the TMS tells me go ahead with TMS.
At the very worst, you won't do anything, at least you won't do that.
Right. While the drugs, they do that. So, you're having a very localized effect
with the TMS, whereas you're rather in the systemic effect, which has got to be positive as well.
Exactly. But, I mean, what's interesting about the TMS effect is that,
as you said, you can't specifically localize one area of the cortex.
So you could be rewiring some of the associations that we have in the frontal areas,
and that could be a positive thing, and that you may be unlearning this link
between dopamine release and alcohol or cocaine,
cocaine and you may be learning something about dopamine release and TMS, but you know that's,
maybe a better association to have.
So that this thing when you see alcohol and you have to drink it or you see
cocaine you have to have it, and learning that would be really powerful. Exactly.
And perhaps that's one of the benefits of this training.
Exactly. This is also possible where speculating is allowed to speculate.
We are in these interviews. as we can.
We can't hear because I feel it.
That's why we're here. The TMS, there are studies, for instance,
which are showing that TMS in certain cases and in certain areas of the brain
are inducing connectivity strengthening.
So with those methods that visual imagers do now, tractography and all these kind of things,
they are able to tell you that after a stimulus, you have this bundle,
it's thicker, thinner, and things like that. And these things are emerging.
They also appear to be frequency dependent. So you can increase or decrease or modulate,
not only transmitters but the real structure of the neuron. Okay?
There are also other reports in the memory field.
Which indicate that the TMS is able to modulate dendritic spines.
The number, the shape, in vitro, in vivo.
So, once again, these are not things that are established and well-established,
but they let you speculate.
Well, there are two things going on. One is, as you say, a direct effect that
TMS could have on the sort of wiring of the brain, maybe a learning effect.
There's also the effect that the releasing the dopamine has,
because, of course, dopamine is a very powerful learning signal.
So during the TMS episode, the dopamine release is stimulating you to learn
something, which is possibly to have positive associations around TMS,
if the dopamine release experience is plausible.
But this is also the weakness of the method. Well, this is the risk of it.
So isn't it really of a great priority.
To find also a way to contextualize the stimulation, that you really allow this
brain to reconfigure in a way that is less risky?
So if you do TMS stimulation, you know you're going to drive dopamine,
meaning on the drive, all sorts of associative learning processes.
So maybe it's important that it happens in a context that is like a healthy, normal life.
Yeah. So have you considered that? Have you included it?
Because now you are conditioning people to really love the KVS device, right?
And again, we are looking at all these things, and I appreciate very much this
very stimulating talk because it gives you more ideas.
The incumbent problem you have always, every day, with each one of these guys
is, are you taking cocaine or not?
If he's taking cocaine...
You see, with those that are not taking cocaine, then you can go deeper in the
conversation and ask those questions we were saying, but so tell me about cocaine now, here.
You see, this is cocaine. What do you think? How do you feel?
By only a portion, but our target is to lower the drug intake.
Of course. So, one thing he considered… And then it will come with time.
Well, there are interesting approaches that look much more at the associative
processes, where you try to dissociate the drug-associated stimuli from the addiction.
So you have simple conditioning paradigms, so behavioral therapy paradigms,
where you try to dissociate alcoholics from beer bottles and wine bottles.
This is what we do. This is what we do. Okay.
And in your case, you can do something similar, right? It's not about dissociating.
It's about forming new associations.
So you project people into a context that is supposedly the healthy living context
within which they are getting their conditions without seeing the TMS device.
So don't suggest that you have to go to things like virtual reality to do that.
This is another thing that is next to be investigated.
Very good. That would be very good.
So, you found a way to reactivate this under-activated dopamine system.
Through that, you're able to reactivate the targets of the dopamine system.
You allow the circuit to rebuild.
And in some of your most recent papers, you also showed that it led to reduced cocaine intake.
Correct. No? Correct. Would this just generalize without further adaptation
to any other addiction? fiction?
Like, can we go from alcoholics to the same thing? Only in theory.
Only in theory. Would you believe it could?
It could, but I'm also aware that drugs are not the same.
Although all of them, they do increase the dopamine transmission and they do
decrease dopamine transmission after withdrawal,
there are drugs that are more difficult to draw, like nicotine, for example.
Okay. So which one? So you think cocaine is one of the easier targets?
I would say, absolutely, I would say that. Are there drugs that you think are
completely beyond this method?
No, I'm not a pessimistic individual. Okay, good. Yeah, that's good.
But then, so now we're going to open up a little bit, right?
So we already indicated and discussed that this is very much dopamine-centric, right? Absolutely.
I admit that. No, and that's fine, right? Because, yeah, you need controllability,
so we have to start to reduce complexity, And then you came a long way.
It's fantastic that you see that a non-invasive method is actually having a
big impact on drug intake. It's incredible.
But what other systems would be on your wish list to start to include now in
an understanding and also intervention for drug addiction, to counter drug addiction?
What we are trying to do is still very difficult. very time-consuming.
We are trying to do mainly two things.
One is to couple these studies with functional magnetic resonance.
Before, after drugs, cue-inducing, there are many things.
In the wish list, you are asking me my wish list, so this is the dream book, we call it.
The other thing are the protocol.
We would like to investigate better, like Tentabarst, to see if beyond the obvious advantage,
the practical advantage, that while one of these treatments with 10 hertz will cost you 27 minutes,
Tentabarst will cost you 3 minutes.
Beyond this, if it has a different effect on the drug intake,
first of all, and eventually,
in all those cognitive functions that can be measured or measured is a strong word.
Through the tools we have tower of
london and my gambling whatever
okay in the wish list right i hope that god will keep me going in a life but
then now with the current tms protocol on the on the cocaine users how much
of a reduction can you accomplish.
Right? It's nothing to zero.
What's the modulation you get? Okay. First of all,
we have 65-70% people that they do stop in the first month.
Okay? This is more or less the success rate.
We don't have data other than those published in the long range and this is
the most important part yeah exactly 6,
9, 12 months the relapse rate in our case is around 70% and normal addiction
treatment service is around 98-99 null, soft,
better than nothing.
No, it's a substantial impact. Substantial impact.
Tony? Yeah, we were talking about the sort of broader implications and uses of TMS.
So there is evidence that nicotine, even cigarette smoking, can lower risk of Parkinson's disease.
So, I don't know what the mechanism is that perhaps you do. and that involves
stimulation of dopamine cells.
So is there possible therapeutic benefit in Parkinson's.
And Parkinson's has been tried and is being tried for several things,
but not for the progression of the disease.
So you try to reduce tremors, you try to reduce other aspects of the syndrome.
The people in general believe that Parkinson's is a lack of dopamine,
and so it gets cured by administering L-Dopa.
Unfortunately, this is not the case.
But what do we know about the mechanisms through which nicotine may have a protective effect?
Well, nicotine pushes dopamine neurons. So it could be, could easily be.
On dopamine neurons, you have nicotine receptors.
So when you take a puff, it will go here, and the dopamine neuron will fire more.
If you consider that you observe clinically Parkinson's,
when the number of cells has fell 60% or something, thing, nicotine can help
to push those minerals to make it moving, but this is a very, I can only say.
But it's more, I think, the evidence is that it prevents it,
so people are less likely to- Prevents?
That people are at lower risk of Parkinson's.
Smokers? Yes.
I don't know i don't know
no right no um but
so one of the neurotransmitters which you put into the mix it if i told you
cif okay so you see the control panel factor okay uh crf has a behavior that
is just the mirror image of dopamine.
Dopamine goes up, CRF goes down, and recently the people at Scripps, Olivier George,
George Kub, and his group in Wendrúscula, a number of people,
they are a very big and prominent group in the field, they found,
in spite of the fact that George Kub is an anti-dopamine guy in general, but very nice.
They found the link between CRF and dopamine neurons.
They did studies in rodents and humans post-mortem, and they combined a nice
and steadily standing story.
Okay. That's a new frontier. year?
Ah, in pharmacology, yes. I prefer to think of the TMS.
But now you also made quite a strong statement about the whole opioid epidemic
we're facing now, especially in the US.
It will come here. Are you sure about that? We already see...
I would love to be wrong. Okay, of course.
I would love to be wrong, but I fear there will be because literally in that
case there is a portion of medical malpractice first in the in the U.S. and,
They are very easygoing with opioids.
So you find over-the-counter pills for sore throat with codeine.
Codeine is an opioid. It is an antitussive drug.
It is employed as an anti-coughing drug.
But an addict immediately understands that instead of taking one pill,
it will take five pills and it
will get high so this is one problem
the other problem is
it is not calling notice I
mean it's harrowing or that matter but are the fentanyl derivatives the smugglers
I don't know we go now into to the chronicles of drug barons and Escobar and El Chapo,
I don't know if you follow,
but to make it very brief,
the Mexicans used to be the mules of the cocaine that was coming from Colombia and the United States.
The Mexicans are not anymore that, are not anymore the mules.
They are the directors of all operations.
And they discovered that illicit labs can make amphetamines,
make amphetamines and DMA and fentanyl derivatives.
So the U.S. have been invaded by this very cheap.
Powerful drug. And many people that get refused by the physician,
they go to the street and with $5 they buy a shot of fentanyl and he dies because
the drug is incredibly powerful.
But how do you see the role of, let's say, the pharmaceutical industry and the
standard medical practice in the U.S.? Because they push the physician to administer it.
They do what they do everywhere. I mean, I don't want to talk badly about the
companies, but I know for a fact this is a true thing.
So you think there's a market, just commercial market forces at work driving this epidemic?
Contributing. certainly not putting obstacles certainly not putting obstacles
I would never dream of accusing,
Big Pharma of triggering this thing
but certainly they don't do nothing against and
we know that they do anything to sell their compounds an opiate cannot be sold
over the counter to make it brief Italy is not sold I don't think it is sold
in Spain and I don't think it is sold in Europe, throughout Europe, you know.
But now, do you believe, so earlier we talked about cocaine and drugs of abuse,
where you said it was something like, if you have 100 users,
maybe 20 get addicted, something like this, right? Exactly.
If it's fentanyl, would the number be higher?
I don't think it will be higher. You will get more deaths.
Oh, absolutely. Because they know this thing already happened.
In the 80s there was a thing called China Y in California and there were.
Numberless deaths in San Francisco and Los Angeles.
Oh gee, this must be an opioid overdose. The guy at the needle here,
he was cyanotic blue and so depression, respiratory depression.
They went to see if there were morphine, like a couple of nights and morphine could not be found.
After some time, they found phantom. religion yes China white was the name the
street name of the drug it was composed by.
Fentanyl and meperidine which is an opioid that has mostly peripheral actions
so the addict feels that and he perceives the action the peripheral actions.
And they were selling this as if it was heroin.
They don't say this is fentanyl.
This is very good. Give me $10. Be careful.
Be careful because this is very good. So somebody was not careful.
And many people died. It is occurring exactly the same thing.
They use spreads and many more people will die.
Okay. 62,000 is not bad as a number, unfortunately. That's scary.
Yeah, that's really scary.
So, Marco, we're close to the finish line, and so we went, we made quite a tour
also through your career, which started quite a few decades ago by now,
right, and it's all a business of addiction.
So you are a diet in the wool neuroscientist and addiction researcher.
So if you want to learn from your lessons or want to learn from you and your
experience, what would be Marco's law we should adhere to to understand how the brain works?
The brain works jesus this is tough you should have me we give this question to everybody.
No i don't consider myself your advice to other researchers your students right
your students what's the rule you would give them what's the codex that you
would give give to your to your students to my students to to keep going in neuroscience,
The most important ingredient to solve the problem, yeah, to make progress. Two things you need.
You need an endless intellectual curiosity and enthusiasm.
Enthusiasm. You don't need to be rich. You don't need to be nothing.
You don't need to be smart.
The brain is a smart organ.
The brain, if you make it work, it will work. And the more you make it work, he enjoys that.
This is called enthusiasm, I would say. I try to transmit this to the youngsters.
Curiosity and enthusiasm. Curiosity could be an elixir of long life.
Because I think we begin...
Declining when we
say oh I know that already when you
believe that you have learned what I'm
very impossible to be left so nice to think no I didn't let me think otherwise
I'll be dead so how do you protect then your own curiosity net is just how do
you protect it with TMS but doing something new moving from through physiology in rodents,
through physiology in humans. So novelty, right?
Novelty seeker, that's absolutely correct. And then the last question is that,
so Tony still wants to go to Sassari, he hasn't been there yet.
He hasn't been to Sardinia a lot anyway, right? And then once,
just once. The four years from now, Tony will come visit your lab.
Oh, sure. With a little notebook to check whether you actually have falsified
your core hypothesis that you're gonna share with us today. What's the key hypothesis
you want to see tested in the four-year time frame in your program?
You know what I'm trying to do? I'm trying to develop a way to measure or to
estimate dopamine in the human brain living,
in the living human brain, which
will not be PET scanning, nor will it be functional magnetic resonance.
But, because I don't have those opportunities, it's not that I don't want, but we are pursuing,
the electro-rectinal gap, let's call it, that is dopamine also in the right
team, as there are D1 receptors, and there are studies which have indicated,
that the blue cone wave apparently is not mediated by dopamine.
Dopamine contributes to this.
And this has been seen in cocaine antics, and it correlates with the dopamine metabolites in the CSF.
So perhaps with the electroretinogram, which is a very simple thing to do,
in four years I may have some results for Tom, if he comes.
And if you count too.
Wonderful. So for you, it is much easier with a serenio wine.
So Marco Dianas, thank you very much for this. Thank you. Thank you.
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