WEBVTT 00:00:03.537 --> 00:00:10.497 This is the Convergent Science Network podcast. Leading researchers in the domain 00:00:10.497 --> 00:00:16.737 of neuroscience, brain theory and technology are interviewed by Paul Vershoor and Tony Prescott. 00:00:20.457 --> 00:00:24.857 This is Paul Vershoor with the Convergent Science Network podcast together with 00:00:24.857 --> 00:00:29.717 my colleague and co-organizer of the BCBT Summer School, Tony Prescott. 00:00:30.017 --> 00:00:37.677 And we're talking with Marco Diona, who is one of the speakers in our school this year. 00:00:38.657 --> 00:00:46.137 And Marco, you spoke on the induction of a hypodogma-energic response through 00:00:46.137 --> 00:00:48.277 transcranial magnetic stimulation. 00:00:51.457 --> 00:00:56.617 So the question is, how did you end up leaking, if you want, 00:00:56.797 --> 00:01:01.897 transcranial magnetic stimulation in the treatment of addiction? 00:01:02.377 --> 00:01:10.817 So what was the trajectory that kept you there? Okay, let me make this thing straight first. 00:01:11.157 --> 00:01:20.937 The hypodipaminergic state contains, or the hypodipaminergic hypothesis, 00:01:21.457 --> 00:01:26.697 contains that the chronic use of drugs, 00:01:27.537 --> 00:01:33.337 several drugs, different drugs, drugs, alcohol, cocaine, opiates, 00:01:33.457 --> 00:01:41.157 psychostimulants in general, will produce a hypodopaminergic. 00:01:43.907 --> 00:01:49.087 From here, you can give a 00:01:49.087 --> 00:02:03.947 reason or a possible reason to justify all the changes that you observe in a drag art. 00:02:05.267 --> 00:02:11.327 Or not all the changes, but at least some changes. As we all know dopamine works 00:02:11.327 --> 00:02:18.067 in movement, is important in movement, is important in reward, 00:02:18.387 --> 00:02:20.147 is important in motivation, 00:02:20.567 --> 00:02:23.107 is important in a number of functions. 00:02:24.467 --> 00:02:27.947 The transcranial magnetic stimulation, 00:02:28.167 --> 00:02:38.467 in principle, may offer the cue by stimulating the prefrontal cortex. 00:02:38.887 --> 00:02:44.727 You can take advantage or you can exploit, 00:02:45.127 --> 00:02:49.307 if you will, a well-demonstrated 00:02:49.307 --> 00:02:56.067 anatomical pathway which goes from the prefrontal cortex monosynaptically to 00:02:56.067 --> 00:03:03.907 the ventral tegmental area and this neuron will impinge upon a dopamine neuron 00:03:03.907 --> 00:03:08.527 which in turn will project to the limbic areas. 00:03:09.367 --> 00:03:19.427 So if I apply transcranial magnetic stimulation in a stimulatory pattern, I should, in principle, 00:03:20.487 --> 00:03:25.687 potentiate a system that has been functioning less. 00:03:27.739 --> 00:03:37.539 Due to the chronic use of drugs. In fact, these are already being shown in healthy individuals. 00:03:38.259 --> 00:03:43.459 If you do apply TMS to the prefrontal cortex. 00:03:44.699 --> 00:03:51.059 You get an increase in dopamine release, as shown by PET studies by Antonio 00:03:51.059 --> 00:03:54.119 Straffella, essentially, and others. 00:03:54.479 --> 00:03:56.759 Right. So that's where you are today. 00:03:57.739 --> 00:04:04.739 But in some sense, we first have to inspect what is really the brain of an addict, right? 00:04:04.779 --> 00:04:07.979 How is the brain of an addict different from a healthy brain? 00:04:08.139 --> 00:04:16.079 So, and you very much emphasized the role of dopamine and dopamine reconfiguration. 00:04:16.979 --> 00:04:22.639 So, how should we think of the brain of an addict? There is another area that 00:04:22.639 --> 00:04:30.099 we did not emphasize today, but that requires and needs to be remembered. 00:04:30.479 --> 00:04:32.739 This is the prefrontal corpus. 00:04:33.499 --> 00:04:37.359 It has been shown by others, by the visual imagers, 00:04:37.359 --> 00:04:49.959 for instance, that the cortical mantle at various levels of the dorsolateral 00:04:49.959 --> 00:04:53.159 prefrontal cortex works less. 00:04:54.119 --> 00:04:58.459 I'm using very simple terms simply to be understood. to. 00:04:59.419 --> 00:05:02.439 For instance, Nora Volkow and 00:05:02.439 --> 00:05:07.979 Rita Goldstein they think that 00:05:07.979 --> 00:05:15.639 the lack of function or the reduction of function in the specific orbit of frontal 00:05:15.639 --> 00:05:26.259 cortex is then responsible for the impulsivity that characterizes the behavior of the addict. 00:05:27.739 --> 00:05:31.939 One of the key features of addiction is craving. 00:05:32.419 --> 00:05:36.659 Craving for the drug. It simply cannot resist. 00:05:37.599 --> 00:05:48.839 And so, many indications and many reports suggest that this is due to a malfunctioning 00:05:48.839 --> 00:05:51.839 of the prefrontal cortex. 00:05:51.839 --> 00:05:57.059 Specifically, in their idea, is the audit of frontal cortex. 00:05:57.359 --> 00:06:00.059 Other people think about the cingulate cortex. 00:06:00.399 --> 00:06:06.599 Some more think about the dorsolateral prefrontal cortex, also because in cortex 00:06:06.599 --> 00:06:10.139 there is a small problem to identify. 00:06:11.899 --> 00:06:18.059 The cortex does essentially always the same things. cognitive integration, 00:06:18.659 --> 00:06:22.719 decision-making, working memory, and so on. 00:06:23.159 --> 00:06:30.079 But it's very difficult to find the borders between preliminary cortex, 00:06:31.039 --> 00:06:37.899 singular cortex, orbital frontal, dorsolateral, dorsal medial, ventral lateral. 00:06:38.019 --> 00:06:45.679 There are no a priori boundaries. And when we apply a stimulus like the TMS, 00:06:46.059 --> 00:06:51.899 it's very difficult to contain that stimulus only to the preliminary cortex 00:06:51.899 --> 00:06:56.639 and not touching the infralimbic cortex, and so on and so forth. 00:06:56.859 --> 00:07:00.199 So the agreement exists only... 00:07:02.092 --> 00:07:09.372 Frontal lobe of the brain, which is not working properly and in many senses 00:07:09.372 --> 00:07:15.592 is unable to keep down pulsions. 00:07:15.612 --> 00:07:23.212 So it's unable to avoid dangerous behaviors. 00:07:23.632 --> 00:07:30.832 So the weak cognitive conditions for you, addiction is also a pathology of executive 00:07:30.832 --> 00:07:33.012 control. No, absolutely not. 00:07:33.292 --> 00:07:40.472 It's not only, let's say, as we'll see also later, an excessive manipulation of a reward system. 00:07:40.812 --> 00:07:45.132 No, no, no, no, no, absolutely not. But do you see it as an independent process 00:07:45.132 --> 00:07:49.272 or not as dependent on, again, what happens to the reward system? 00:07:49.512 --> 00:07:53.472 The key is, suddenly the reward system is damaged. 00:07:53.972 --> 00:07:59.872 Let's put it that way. And suddenly the reward system responds immediately. 00:08:01.332 --> 00:08:12.092 As the chronic treatment goes on, and the answer, the cognitive part will come into play later on. 00:08:13.212 --> 00:08:22.592 We'll know. Does not have the same timescale, the cognitive part as the emotional part. 00:08:23.072 --> 00:08:29.672 Emotion is beginning initially. Take drugs, dopamine goes up, he's happy, honeymoon. 00:08:29.672 --> 00:08:37.152 Then slowly the system adapts and the second system, the cognitive systems, 00:08:37.292 --> 00:08:42.372 mostly the cortex, will become involved. 00:08:42.872 --> 00:08:48.772 In other words, in spite of the fact that you are taking drugs from time zero. 00:08:50.686 --> 00:08:56.306 At time one, the limbic system is intervening and modifying your behavior. 00:08:56.566 --> 00:09:00.966 But at time 10, the cognition will come into play. 00:09:01.246 --> 00:09:10.106 The cognition means also that the addict becomes aware of the fact that he's an addict. 00:09:10.946 --> 00:09:13.686 He is an addict. 00:09:14.646 --> 00:09:18.766 It means he's a patient. He needs help. 00:09:18.766 --> 00:09:26.686 He needs somebody to rely on to come out from a situation that has slipped through 00:09:26.686 --> 00:09:31.406 his fingers, to put it in this romantic way. 00:09:32.266 --> 00:09:39.106 Can we know for sure that the people that become addicted to substances. 00:09:41.846 --> 00:09:46.266 Are already predisposed in some way towards addiction, 00:09:46.586 --> 00:09:52.926 so that other people may be given the same introduction to these substances 00:09:52.926 --> 00:09:54.286 might not become addictive, 00:09:54.466 --> 00:10:01.046 but these people may already have some aspect of frontal cortex dopamine function, 00:10:01.046 --> 00:10:06.526 which predisposes them towards this now there 00:10:06.526 --> 00:10:09.666 are studies of course 00:10:09.666 --> 00:10:19.606 which have indicated that there is a component a genetic component which will 00:10:19.606 --> 00:10:26.626 favor the the emergence of the full-blown phenomenon. 00:10:27.406 --> 00:10:32.446 It is a multifactorial disease, if you wish. 00:10:33.386 --> 00:10:41.086 I remember that a paper in Science by Jervik Piazza and his co-workers. 00:10:44.709 --> 00:10:56.109 Found that roughly of 100 people that will take drugs, roughly 17-18% will become addicts. 00:10:56.709 --> 00:11:01.389 Taking a drug does not mean to become an addict. 00:11:02.709 --> 00:11:08.049 The diagnosis is very clear. 00:11:08.329 --> 00:11:16.149 The DSM-50 will tell you exactly that You need to take drugs. 00:11:17.189 --> 00:11:18.809 You need to take continuously. 00:11:20.329 --> 00:11:28.549 You need to make attempts to stop. 00:11:28.729 --> 00:11:36.249 You know that you are doing bad to yourself, so you try to make attempts. 00:11:37.149 --> 00:11:40.589 And these attempts to quit, they fail. 00:11:41.609 --> 00:11:47.929 Okay? Another very important point is the fact that at one point, 00:11:48.049 --> 00:11:51.449 the drug is interfering with your life. 00:11:51.949 --> 00:12:00.249 It's not anymore a matter of physical, biological problems. 00:12:00.249 --> 00:12:09.469 It's a matter of interference with your normal social life, which means working 00:12:09.469 --> 00:12:12.909 life, which means familiar life, 00:12:13.289 --> 00:12:17.229 which means social life and many other things. 00:12:17.589 --> 00:12:30.009 So of 100 people that will take a drug, roughly a fifth will become real addicts. 00:12:30.249 --> 00:12:31.269 So, 00:12:32.790 --> 00:12:36.790 To bring it back to what you discussed earlier about prefrontal cortex. 00:12:38.750 --> 00:12:42.650 So, on the one hand, there's this idea, and we can also expand that later, 00:12:42.850 --> 00:12:47.630 that drug use, whether it's morphine or opioids or alcohol. 00:12:49.470 --> 00:12:53.750 Is targeting the dopamine system and leads to a dysregulation. 00:12:53.830 --> 00:12:56.010 It's one of the targets. Exactly. One. 00:12:56.650 --> 00:12:59.490 Absolutely not. So, that's not a debate yet. 00:12:59.910 --> 00:13:04.450 But now, I could argue, well, Now, since dopamine is changing, 00:13:04.750 --> 00:13:08.150 the targets of the dopamine system, including prefrontal cortex, 00:13:08.350 --> 00:13:10.490 is also changing its response. 00:13:10.770 --> 00:13:15.790 So the long-term changes are, in the end, a knock-on effect of manipulations 00:13:15.790 --> 00:13:17.110 of the neuromodulatory system. 00:13:17.990 --> 00:13:22.250 With an alternative interpretation to say, and I think the direction you were 00:13:22.250 --> 00:13:24.990 going, I have different functional subsystems. 00:13:24.990 --> 00:13:29.390 And these functional subsystems all have their own regulatory role in the control of behavior. 00:13:29.390 --> 00:13:32.670 Behavior, and you might have, let's say, a limbic system dealing with issues 00:13:32.670 --> 00:13:38.430 of satisfaction of immediate needs and craving that it tries to resolve in some 00:13:38.430 --> 00:13:42.110 ways, but when that remains unresolved, 00:13:42.350 --> 00:13:44.750 I have to start to use, 00:13:45.190 --> 00:13:47.890 let's say, cognitive resource to resolve that problem. 00:13:48.030 --> 00:13:51.630 And that's how I start to engage my executive control system in front of the cortex. 00:13:51.730 --> 00:13:56.950 So which of these two causal pathways do you see as being dominant in the development 00:13:56.950 --> 00:14:00.370 of a legal tool? I don't see any one of those dominant. 00:14:01.670 --> 00:14:07.930 Probably, if you stick a gun on my head and tell me only one, 00:14:08.090 --> 00:14:09.970 I will tell you about the cortex. 00:14:12.030 --> 00:14:16.590 Because another problem with the addict... Take out the gun, Tony. 00:14:19.290 --> 00:14:25.590 Another problem with the addict is he's a very difficult patient. 00:14:27.570 --> 00:14:34.270 All patients, they recognize their status as a patient. 00:14:34.730 --> 00:14:40.630 If I feel pain on my shoulder, I will come to you and I will tell you, I feel pain. 00:14:40.770 --> 00:14:45.510 Tell me what to do, what I have, what I should do to fix it. 00:14:46.090 --> 00:14:54.910 The other does not recognize that he is a patient. And that brings, 00:14:55.410 --> 00:14:59.210 elongates his pathology. 00:14:59.370 --> 00:15:07.670 He has to make efforts to realize that he needs treatment and treatment. 00:15:08.709 --> 00:15:14.629 Six treatment so so that form of anosmosia, or is it characterized differently? 00:15:15.169 --> 00:15:21.689 I Don't know. I don't know but I would say that this is a cortical pro Mm-hmm, 00:15:21.709 --> 00:15:24.929 I wouldn't say that this is a dopamine related protein. 00:15:25.049 --> 00:15:33.949 This is a good cognition Okay, it to one itself Awareness what what am I am 00:15:33.949 --> 00:15:36.189 I in a big and does the patient? 00:15:36.189 --> 00:15:42.869 Or am I simply a person having fun with cocaine and I'm rich enough and I don't care? 00:15:43.449 --> 00:15:48.929 For me, 3,000 euros every Friday is nothing. Right. 00:15:50.309 --> 00:15:55.989 So would the distinction be that the addict is actually suffering from pathology 00:15:55.989 --> 00:16:00.389 that also deforms the self, while in other cases, the patient, 00:16:00.509 --> 00:16:04.529 as a reference of, okay, in the past, the self, had the following characteristics, 00:16:05.069 --> 00:16:08.009 and today it has these characteristics, like I have pain in my shoulder, 00:16:08.229 --> 00:16:11.689 and this difference is now my particular... 00:16:11.689 --> 00:16:14.029 Yeah, so it is very difficult. 00:16:14.829 --> 00:16:21.889 I am not used to reasoning these terms, but certainly I would say that the self is affected. 00:16:23.489 --> 00:16:30.529 The self pre-drug is a different thing than the self post-drugs or during drugs. Okay. 00:16:30.849 --> 00:16:35.929 So the possibility exists then that the people that are taking a significant 00:16:35.929 --> 00:16:42.249 amount of these drugs on a regular basis, but not experiencing the same impact 00:16:42.249 --> 00:16:43.669 on these brain circuits, 00:16:44.009 --> 00:16:50.569 so they're therefore able to continue to live their life, more or less, 00:16:50.729 --> 00:16:56.189 and to take and leave the substance more effectively than somebody who's addicted. 00:16:56.189 --> 00:16:58.689 So they're not meeting the criteria. 00:16:59.169 --> 00:17:05.029 In your studies, do you use control groups who are cocaine users but are not 00:17:05.029 --> 00:17:10.929 alcohol users, who are not recognized as addicts? No, yet. 00:17:11.789 --> 00:17:20.749 My experience with humans, in spite of the fact that my degrees in medicine, I never did it. 00:17:21.934 --> 00:17:28.374 Clinical work i always did the robert's work and physiology so it is simply 00:17:28.374 --> 00:17:38.334 by seven eight years ago that i began and with these human studies and another 00:17:38.334 --> 00:17:40.554 thing is the point that we touched, 00:17:41.374 --> 00:17:44.614 briefly this morning is not easy 00:17:44.614 --> 00:17:48.574 yeah and i throw it when the patient recruitment is 00:17:48.574 --> 00:17:51.454 not an easy he does and he's very 00:17:51.454 --> 00:17:56.334 time and effort consuming and frequently 00:17:56.334 --> 00:18:00.354 frustrated so to find a 00:18:00.354 --> 00:18:03.194 group like that that you 00:18:03.194 --> 00:18:10.954 were saying it will take months and months so but it's it before we kind of 00:18:10.954 --> 00:18:16.634 conclude the differences we're seeing in the brains of people with addictions 00:18:16.634 --> 00:18:21.414 from those of the the controls who are Mokhbrok users, 00:18:22.354 --> 00:18:27.674 it's possible that some of those differences may predate their addiction and 00:18:27.674 --> 00:18:31.114 that they may already have a predisposition or a genetic. 00:18:32.394 --> 00:18:37.774 Something about their personality which is reflected in some of these findings. 00:18:38.334 --> 00:18:43.074 I think that a portion is only in that way. 00:18:43.194 --> 00:18:52.954 I think that there are There are several factors that contribute to the full blown syndrome. 00:18:53.154 --> 00:18:57.974 In some case, maybe that is predisposed. 00:18:58.074 --> 00:19:05.674 In some other case, even if it's not predisposed, but it comes across the drug situations. 00:19:07.630 --> 00:19:13.110 And things, you may become addicted, even if you were not. 00:19:13.490 --> 00:19:18.950 So there is not a single thing that you can identify and say, 00:19:19.130 --> 00:19:23.070 okay, I know why you are getting addicted. 00:19:25.610 --> 00:19:32.470 So now we have an idea of the phenomenon that we're looking at of addiction, 00:19:32.470 --> 00:19:37.490 and it's different, let's say, medical, psychological, and also biological aspect. 00:19:37.730 --> 00:19:42.450 Yes. But now in your research, you have dissected that down to a set of very 00:19:42.450 --> 00:19:49.430 specific questions along what are the changes to the dopaminergic system and its targets. 00:19:49.690 --> 00:19:55.170 This has really become, over many years, the main research trajectory that you 00:19:55.170 --> 00:20:00.670 have followed, which I think is also very much representative for the field. divine development. 00:20:00.930 --> 00:20:02.750 This is one of the targets that people look for. 00:20:03.990 --> 00:20:08.170 So, in the first of the experiments, you looked at, let's say, 00:20:08.190 --> 00:20:15.110 what's the effect of drug use and of withdrawal of drugs on the response of 00:20:15.110 --> 00:20:16.190 adducting allergic cells. 00:20:17.030 --> 00:20:22.390 And you report actually rather, and also that's confirmed by other experiments, 00:20:22.610 --> 00:20:29.290 a rather dramatic impact on most of the baseline activity of these of these neurons, right? 00:20:29.290 --> 00:20:33.210 So there may be users of actually different types of drugs. 00:20:33.370 --> 00:20:36.950 But in some sense, even if it's not that related, right? It can be alcohol or 00:20:36.950 --> 00:20:38.790 cannabis or opioids, right? 00:20:39.130 --> 00:20:43.550 In all cases, you see a reduction in the baseline activity. 00:20:44.430 --> 00:20:48.330 So, tell me, explain that. Where does it come from? Why is it targeting the brain? 00:20:48.570 --> 00:21:01.030 A very simple way of providing a possible explanation relates to the acute effect of the drug. 00:21:01.470 --> 00:21:08.750 All drugs of abuse, they do increase the activity of the dopamine system. 00:21:10.270 --> 00:21:20.670 Once you take them chronically, there are various neuroplastic effects that take place over time. 00:21:20.670 --> 00:21:26.750 Tolerance, sensitization, reverse tolerance. There are several. 00:21:27.730 --> 00:21:31.610 In brief, what is happening is that the system, 00:21:31.750 --> 00:21:40.090 the dopamine system is adapting to the new situation in which in the environment 00:21:40.090 --> 00:21:45.030 there is always a molecule that stimulates its activity. 00:21:45.030 --> 00:21:53.870 So when you take out this thing, the dopamine system becomes orphaned. 00:21:55.351 --> 00:22:01.371 Actually, the drug may work as a constant pusher of the system. 00:22:01.471 --> 00:22:07.871 You take out the drug and the system has adapted to a lower level to compensate 00:22:07.871 --> 00:22:13.751 for the exogenous drug that is demanding an increase in activity. 00:22:14.171 --> 00:22:20.671 Double neurons are also neurons that are very energy demanding. 00:22:20.671 --> 00:22:28.351 So, to make a dopamine neuron firing is more costly in terms of energies. 00:22:28.951 --> 00:22:33.571 Why is that? I don't know. Paul Balaam has done these studies. 00:22:33.631 --> 00:22:39.831 He's an excellent, as you know, neuroanatomist. They are very branching neurons. 00:22:40.531 --> 00:22:48.151 They have a huge number of axonolaterals. 00:22:48.151 --> 00:22:56.391 But I remember that the conclusion was, that is, from an energetic standpoint, 00:22:56.611 --> 00:23:00.711 to keep it going, it requires a lot of humor. 00:23:00.711 --> 00:23:04.011 When it means that the first stage of the process, 00:23:04.291 --> 00:23:07.811 you essentially describe it as some homeostatic system right, 00:23:07.831 --> 00:23:13.831 that's self-regulatory now I'm in some sense overwriting an intrinsic drive 00:23:13.831 --> 00:23:18.391 of the system with an external cue, which is a drug. 00:23:19.251 --> 00:23:24.131 I'm overdriving the system so it starts to down-regulate so the system goes 00:23:24.131 --> 00:23:30.251 down to accommodate for the drug and if now you take the drug Yeah, it looks lower. 00:23:30.831 --> 00:23:34.891 OK, and those means if you then are not exposed to the drug long enough, 00:23:35.011 --> 00:23:38.551 you should sort of bounce back to this initial baseline. 00:23:38.811 --> 00:23:43.011 Is that true? Yes. OK, so it's like a self regulatory system and the drug now 00:23:43.011 --> 00:23:46.251 sort of co-ops the system and it readjusts. 00:23:47.131 --> 00:23:53.771 So are we optimistic then that you can make a full recovery or do you have some long term? 00:23:56.602 --> 00:24:01.022 With TMS, you mean? No, I mean generally if you were to stop the drug. 00:24:01.862 --> 00:24:07.902 If you stop the drug at the very first video, it is a painful period. Yeah. And we know that. 00:24:09.102 --> 00:24:14.162 We know it for each single drug. Yeah. It is different. 00:24:14.642 --> 00:24:19.962 But over six months, say, are you back to normal? Are you indistinguishable from it? Okay. 00:24:21.142 --> 00:24:32.982 This is almost a joke. Right. But it is said that the diagnosis of a fully recovered Andy, 00:24:33.682 --> 00:24:37.002 you make it only when he dies. 00:24:37.902 --> 00:24:39.702 It's like a schizophrenia. Yeah. 00:24:41.242 --> 00:24:48.562 He had fully recovered. Now, this is almost a joke, but to tell you, 00:24:48.662 --> 00:24:52.182 it tells you how difficult it is. 00:24:52.182 --> 00:24:59.362 So the answer is... You can say, this guy is 10 years that is not taking cocaine anymore. 00:24:59.802 --> 00:25:03.362 But Marco, there is something though, physiologically, like physiologically, 00:25:04.622 --> 00:25:10.742 do the neurons you measure from return to exactly the same baseline level? 00:25:11.282 --> 00:25:15.242 Or do they go back to a somewhat different baseline level? That means as if 00:25:15.242 --> 00:25:16.922 there's a memory system, right? 00:25:18.502 --> 00:25:22.562 For the last question, I would say that there is a memory in the system. 00:25:22.722 --> 00:25:28.482 There is a cellular memory as in every cell. 00:25:29.682 --> 00:25:33.402 But this is my conviction. 00:25:34.842 --> 00:25:39.762 There is only a memory. Let me go back to the first part. 00:25:39.982 --> 00:25:48.042 It escapes me now. No, I was starting to unpack the whole addiction syndrome 00:25:48.042 --> 00:25:50.982 by really now zooming in on this document. 00:25:51.182 --> 00:25:55.262 Oh yeah, if it goes back to the three drugs left. 00:25:56.142 --> 00:26:03.262 Yes, it will go back. And we have examples, we discussed this this morning at the lecture. 00:26:05.382 --> 00:26:10.622 Opiates, you have an opiate-dependent individual, fighting rate goes down, 00:26:10.622 --> 00:26:15.142 the operator list goes down, TH goes down, everything goes down. 00:26:15.922 --> 00:26:23.962 Then eventually, it will come to normal level, pre-drive level, in two weeks. 00:26:24.502 --> 00:26:27.142 Remember that we are talking about roll-ins. 00:26:27.722 --> 00:26:35.522 The time scale is different. So, by in roll-ins, in rats, in two weeks, 00:26:35.542 --> 00:26:42.042 more or less, you have a system that is apparently working as it used to. 00:26:43.122 --> 00:26:46.722 And we did this paper. We did publish the paper. 00:26:47.842 --> 00:26:52.962 If you do administer morphine now to an opiate-dependent individual. 00:26:55.162 --> 00:27:02.622 The reaction to morphine will be magnified enormously as compared to the first 00:27:02.622 --> 00:27:08.802 shot of morphine in a, let's say, undrunk individual, 00:27:09.062 --> 00:27:14.062 in spite of the fact that they have the same basic fighting rate. 00:27:14.262 --> 00:27:17.262 So this experiment tells you some more. 00:27:17.442 --> 00:27:24.682 Yes, it's going back. The mechanisms that sustain the spontaneous fighting rate, 00:27:25.162 --> 00:27:31.562 But perhaps not every mechanism has gone back to normality. 00:27:32.762 --> 00:27:38.202 It is known, for instance, that when they recover, one of the things that comes 00:27:38.202 --> 00:27:45.282 back to normal later than others is the sleep-wake cycle. They don't sleep well. 00:27:46.402 --> 00:27:50.402 Although they may be eight months without taking drugs. 00:27:51.462 --> 00:28:00.382 And they have fixed the diarrhea the sympathetic imbalances the various things. 00:28:01.782 --> 00:28:10.602 Pain kicking the monkey and all that kind of things in spite of that still they don't sleep well, 00:28:12.002 --> 00:28:17.622 so every sign and symptom they have their own kind course right Right, 00:28:17.642 --> 00:28:22.762 but that also indicates that you already indicated, I mean, we know we have 00:28:22.762 --> 00:28:25.642 to look also beyond dopaminergic systems. 00:28:25.842 --> 00:28:28.202 Exactly. Beyond. It's a global change. 00:28:28.502 --> 00:28:33.182 But so what was it, what happened next? So now we see we have a huge impact 00:28:33.182 --> 00:28:35.822 on the baseline firing of the dopaminergic system. 00:28:36.762 --> 00:28:43.422 And then he showed, in also very great anatomical detail, that that in turn 00:28:43.422 --> 00:28:47.302 has a huge impact on the targets of these dopaminergic cells. 00:28:47.302 --> 00:28:53.702 And immediately the spine density along the targets of these dopaminergic cells, 00:28:53.942 --> 00:28:57.122 and you look at it in accumbens, so your ventral cerium, 00:28:57.362 --> 00:29:03.022 but supposedly it would happen on any cell that's targeting by these dopaminergic 00:29:03.022 --> 00:29:03.862 cells. That's right, yes. 00:29:04.222 --> 00:29:13.222 So the dynamics of these changes, if I lose all my spine, it also means I'm losing my side actions. 00:29:14.102 --> 00:29:19.542 Yes. So is there any specific pattern to that, or is it a very non-specific effect? 00:29:21.188 --> 00:29:25.848 We didn't even find it yet. Because that would mean that essentially there's 00:29:25.848 --> 00:29:27.348 a massive disconnection somewhere. 00:29:28.048 --> 00:29:31.608 There's a dramatic disconnection in the nervous system. Yes, 00:29:31.728 --> 00:29:33.828 yes. Is that how you interpret it? 00:29:35.888 --> 00:29:42.908 Yeah, yeah. In different words, I express the same thing. You are representing in very nice words. 00:29:43.168 --> 00:29:45.108 There is a massive disconnection. 00:29:46.468 --> 00:29:50.088 So if you would have to guesstimate, so if Tony pulls out the gun again, 00:29:50.088 --> 00:29:57.088 And if you have to guesstimate how much of the circuit of the brain is disconnecting 00:29:57.088 --> 00:29:59.988 as a result of this, just rough guess, 00:30:00.228 --> 00:30:05.328 would you think like 1% or is it like 40% or even higher than that? 00:30:06.328 --> 00:30:16.248 Well, I don't know, but between 1% is more, it's more than 1%, it's 40%. 00:30:16.248 --> 00:30:22.008 Then if you say it's 40% or 80%, I would probably say 40%. 00:30:22.568 --> 00:30:25.728 You know, it's difficult to put these things in numbers. 00:30:26.248 --> 00:30:30.828 But this connection, believe me, the behavior changes. 00:30:31.948 --> 00:30:37.428 The behavior changes. The best way to have a description... 00:30:39.445 --> 00:30:45.745 Not a strictly scientific description, is to ask a mother. 00:30:46.525 --> 00:30:50.925 Ask a mother that has a child that is taking drugs. 00:30:51.185 --> 00:30:54.525 She will tell you, this is not my son anymore. 00:30:56.205 --> 00:31:05.265 The whole behavior changes. It affects the relationships with loved and unloved, 00:31:05.285 --> 00:31:08.945 the sleep-week cycle, feeding. 00:31:09.445 --> 00:31:17.065 Everything changes more or less if someone would be interested in. 00:31:18.745 --> 00:31:25.425 Opiate addiction I would never suggest him to read one of my papers but I would 00:31:25.425 --> 00:31:32.545 suggest to read Confessions of an Opium Eater by Thomas de Kinse or if you want 00:31:32.545 --> 00:31:34.625 to study memory you don't read, 00:31:36.085 --> 00:31:40.065 Rokmalenka but you need the first to read 00:31:40.065 --> 00:31:42.885 the French guy what's his 00:31:42.885 --> 00:31:46.145 name now escapes me hmm the Lager 00:31:46.145 --> 00:31:48.945 church a lumber of the left and 00:31:48.945 --> 00:31:53.685 truth boost my land be free 00:31:53.685 --> 00:31:57.405 you you get the idea what memory right 00:31:57.405 --> 00:32:00.065 so so so so if a 00:32:00.065 --> 00:32:03.005 disconnection somewhere citrus regret because it's an Alzheimer disease 00:32:03.005 --> 00:32:06.865 is also described as a disconnection syndrome so in 00:32:06.865 --> 00:32:10.645 terms of the symptomatology would you would you think overlap between addicts 00:32:10.645 --> 00:32:13.765 chronic addicts and an alzheimer patient like you 00:32:13.765 --> 00:32:21.185 have the hyper emotionality you have a lack of of cognitive control at least 00:32:21.185 --> 00:32:29.845 overlaps explore this is like uh thought about that i I thought about the parallel 00:32:29.845 --> 00:32:33.365 between psychostimulants, 00:32:33.365 --> 00:32:34.905 abusers, 00:32:34.945 --> 00:32:37.425 and schizophrenics, for instance. 00:32:38.914 --> 00:32:46.414 I thought about cocaine addicts, you see, and paranoiacs. 00:32:47.474 --> 00:32:49.954 Never thought about Alzheimer's. 00:32:51.174 --> 00:32:53.054 His capability is extraordinary. 00:32:54.374 --> 00:32:59.394 He knows how to solve a problem. He can do abstract thinking. 00:32:59.834 --> 00:33:06.374 He can solve a puzzle. Actually, he solves puzzles every day because he doesn't 00:33:06.374 --> 00:33:11.074 have money. And his problem every day is to get money, to get high, 00:33:11.214 --> 00:33:13.534 and then to get money again. 00:33:13.714 --> 00:33:17.954 And these are big puzzles when you don't have money. 00:33:18.134 --> 00:33:27.474 So they steal, they do strange things, but their capacity to reason is not that cheap. 00:33:29.274 --> 00:33:32.334 Or at least in some part. I mean, 00:33:33.074 --> 00:33:42.314 one of the, we just mentioned one of the knock-on effects is on the D2 receptors 00:33:42.314 --> 00:33:45.994 in the striatum that you discussed at length. 00:33:45.994 --> 00:33:51.134 Okay, so just to be clear about what the effect is, 00:33:51.934 --> 00:33:59.174 so what happens is that the overstimulation of the dopamine neurons by the drug 00:33:59.174 --> 00:34:05.114 is flooding the striatum with dopamine and that's causing a reduction in the 00:34:05.114 --> 00:34:07.434 D2 receptors, is that correct? 00:34:08.674 --> 00:34:12.474 Well, I don't know if there is a causal role. 00:34:12.994 --> 00:34:22.154 Okay. I don't know if the dopamine receptors are decreasing in number because 00:34:22.154 --> 00:34:25.234 there is a lot of dopamine or... 00:34:26.842 --> 00:34:30.182 By an independent mechanism which goes in parallel. 00:34:31.102 --> 00:34:39.282 It could also be a neuro-adaptive mechanism as you are more or less suggesting. Lots of dopamine. 00:34:39.922 --> 00:34:46.402 Let's get down with this. It could be, but these are possibilities plus they 00:34:46.402 --> 00:34:54.122 are very academic possibilities in the sense that if you're looking for a therapy. 00:34:56.042 --> 00:34:59.222 Why is that? Or there is another reason. 00:34:59.902 --> 00:35:06.302 What I have to do is to fix that number and take it back up as it was. 00:35:06.642 --> 00:35:12.162 Yeah. Well, I mean, I think if it is an adaptation, then you would hope that 00:35:12.162 --> 00:35:17.102 that would, again, correct once you take out the excess dopamine. 00:35:17.102 --> 00:35:21.602 I mean, if the dopamine cells go back to firing at the normal levels, 00:35:22.262 --> 00:35:29.102 then you would hope the D2 receptors would also recover to the pre-addiction levels. Yes. 00:35:30.022 --> 00:35:33.222 But we don't know that. Still no good questions. Yes. 00:35:33.802 --> 00:35:39.082 Yes. Yeah. Would you expect any kind of specificity with respect to different 00:35:39.082 --> 00:35:42.842 receptor types, or do you think it's a very nonspecific effect? 00:35:44.302 --> 00:35:47.602 Within the dopamine system? It's non-specific, 00:35:47.802 --> 00:35:53.002 although there is some consistent literature, 00:35:53.122 --> 00:36:05.902 for instance, in rodents that tends to give to the D1 receptor a. 00:36:07.424 --> 00:36:17.984 Relatively major importance in rodents in humans so far cannot be studied because there is no label, 00:36:19.024 --> 00:36:27.104 right there is no radio light by richard wood is it and uh we did it ourselves also, 00:36:28.224 --> 00:36:35.804 and the mechanism in the population of the the middle spiny neurons can roughly 00:36:35.804 --> 00:36:37.604 be divided into two categories. 00:36:38.624 --> 00:36:46.304 One, that is the medial spiny neural that projects back to the substantia nigra parceria ticulata. 00:36:46.564 --> 00:36:53.344 And these neurons, they do contain predominantly D1 receptor. 00:36:54.624 --> 00:37:00.724 Then there is another population which projects to the palynus and then comes 00:37:00.724 --> 00:37:04.584 back. Okay, these are called the direct and indirect pathway. 00:37:06.184 --> 00:37:12.884 Virtually every study will tend to bring in the direct pathway. 00:37:13.844 --> 00:37:20.264 So you can block with the CH, which is the dopamine antagonist, 00:37:20.264 --> 00:37:28.384 and we did this, I was describing this morning, If you give L-DOPA to rats, 00:37:28.724 --> 00:37:36.184 you will have the spines growing back, you will have again your LTP mechanisms, 00:37:37.324 --> 00:37:39.564 and you will have also memory, 00:37:40.824 --> 00:37:45.324 the rodents performing well in emotional memory tasks. 00:37:46.564 --> 00:37:52.224 This can be blocked by SEH, but not by Sompi-R, which is D2N-DAP. 00:37:52.804 --> 00:38:01.364 And this is really invoking a D1 mechanism, but this is all. 00:38:01.824 --> 00:38:06.484 Okay. But if there's a differential effect on the direct and indirect pathway, 00:38:06.704 --> 00:38:12.184 then this again would imply that there's a modulation of executive control system, right? 00:38:12.244 --> 00:38:17.784 Because they will depend on these pathways again for the kind of competition 00:38:17.784 --> 00:38:19.364 that plays out at this cortical level. 00:38:19.364 --> 00:38:28.964 Yeah so when we move from rats to humans because this is in the end what you looked at there was so. 00:38:31.304 --> 00:38:36.704 What made you believe that the transcranial stimulation could actually help 00:38:36.704 --> 00:38:41.904 you to resolve the addiction problem what are the pieces of the puzzle that 00:38:41.904 --> 00:38:44.184 gave you confidence that this even made sense to do, 00:38:45.024 --> 00:38:50.164 to resolve the puzzle is certainly an overstatement. 00:38:51.104 --> 00:38:57.844 We won't resolve the puzzle. The transcranial magnetic stimulation has. 00:39:00.655 --> 00:39:12.135 Two main advantages the very first one is its physiological nature you're using a stimuli, 00:39:13.315 --> 00:39:20.035 let's forget a moment about electromagnetism and these things that are very 00:39:20.035 --> 00:39:23.895 confusing for some You are stimulating the cortex. 00:39:23.975 --> 00:39:31.815 You are able to modulate cellular activity in the cortical lane. 00:39:34.075 --> 00:39:42.775 This has to be contrasted with what you have available in the field today. 00:39:42.775 --> 00:39:46.955 Day for cocaine zero there 00:39:46.955 --> 00:39:54.655 is nothing there is not a single molecule why you have in an opiate and dictate 00:39:54.655 --> 00:40:01.755 you will say okay there is nothing else to do take methadone okay you are you 00:40:01.755 --> 00:40:03.735 are tobacco-dependent, 00:40:03.775 --> 00:40:05.615 here is varenicline, 00:40:06.055 --> 00:40:07.555 nicotine patches, 00:40:08.155 --> 00:40:13.635 gums, you have several therapeutic approaches. 00:40:13.935 --> 00:40:16.715 For cocaine and psychostimulants there is nothing. 00:40:18.915 --> 00:40:25.715 So this is the first part. The second part, we spoke about this also this morning 00:40:25.715 --> 00:40:32.275 the second part is this lack of possibility of therapeutic possibility, 00:40:33.235 --> 00:40:42.055 pushes the psychiatrist to find something to give to this guy and the standard 00:40:42.055 --> 00:40:49.535 things are and type the person oh he's taking cocaine because he's the the breast, it's obvious, 00:40:49.795 --> 00:40:56.255 you know, antidepressant, anxiolytics, and mood stabilizer. 00:40:57.015 --> 00:41:01.095 Now, as a pharmacologist, 00:41:01.175 --> 00:41:09.395 I am fully aware that while we do know the pharmacology of antidepressant, 00:41:09.455 --> 00:41:20.175 we know much about anxiolytics and problems and toxicology of this And we also 00:41:20.175 --> 00:41:25.675 know about the pharmacology of the mood stabilizers, 00:41:25.855 --> 00:41:27.695 whatever that means, 00:41:28.015 --> 00:41:36.335 because we don't know nothing about the pharmacology of these three molecules 00:41:36.335 --> 00:41:40.195 in a 50 years old individual, 00:41:40.455 --> 00:41:46.995 which is risking heart attacks, which takes blood lowering. 00:41:48.215 --> 00:41:51.655 Blood pressure pills, and eventually even other things. 00:41:52.500 --> 00:42:01.520 So, this combination of factors compared with the TMS tells me go ahead with TMS. 00:42:01.820 --> 00:42:06.320 At the very worst, you won't do anything, at least you won't do that. 00:42:07.120 --> 00:42:11.840 Right. While the drugs, they do that. So, you're having a very localized effect 00:42:11.840 --> 00:42:17.940 with the TMS, whereas you're rather in the systemic effect, which has got to be positive as well. 00:42:18.100 --> 00:42:22.920 Exactly. But, I mean, what's interesting about the TMS effect is that, 00:42:22.960 --> 00:42:27.920 as you said, you can't specifically localize one area of the cortex. 00:42:28.060 --> 00:42:34.240 So you could be rewiring some of the associations that we have in the frontal areas, 00:42:34.980 --> 00:42:39.920 and that could be a positive thing, and that you may be unlearning this link 00:42:39.920 --> 00:42:44.160 between dopamine release and alcohol or cocaine, 00:42:44.160 --> 00:42:50.920 cocaine and you may be learning something about dopamine release and TMS, but you know that's, 00:42:51.840 --> 00:42:54.040 maybe a better association to have. 00:42:54.260 --> 00:42:57.880 So that this thing when you see alcohol and you have to drink it or you see 00:42:57.880 --> 00:43:02.140 cocaine you have to have it, and learning that would be really powerful. Exactly. 00:43:02.380 --> 00:43:05.280 And perhaps that's one of the benefits of this training. 00:43:05.300 --> 00:43:11.100 Exactly. This is also possible where speculating is allowed to speculate. 00:43:11.500 --> 00:43:12.800 We are in these interviews. as we can. 00:43:14.680 --> 00:43:17.340 We can't hear because I feel it. 00:43:18.300 --> 00:43:23.640 That's why we're here. The TMS, there are studies, for instance, 00:43:23.900 --> 00:43:31.660 which are showing that TMS in certain cases and in certain areas of the brain 00:43:31.660 --> 00:43:35.020 are inducing connectivity strengthening. 00:43:36.140 --> 00:43:43.320 So with those methods that visual imagers do now, tractography and all these kind of things, 00:43:44.000 --> 00:43:48.860 they are able to tell you that after a stimulus, you have this bundle, 00:43:49.280 --> 00:43:53.920 it's thicker, thinner, and things like that. And these things are emerging. 00:43:55.290 --> 00:44:04.650 They also appear to be frequency dependent. So you can increase or decrease or modulate, 00:44:05.450 --> 00:44:12.070 not only transmitters but the real structure of the neuron. Okay? 00:44:12.970 --> 00:44:16.330 There are also other reports in the memory field. 00:44:18.450 --> 00:44:26.270 Which indicate that the TMS is able to modulate dendritic spines. 00:44:27.610 --> 00:44:32.010 The number, the shape, in vitro, in vivo. 00:44:32.250 --> 00:44:40.350 So, once again, these are not things that are established and well-established, 00:44:40.450 --> 00:44:41.910 but they let you speculate. 00:44:42.450 --> 00:44:46.330 Well, there are two things going on. One is, as you say, a direct effect that 00:44:46.330 --> 00:44:52.910 TMS could have on the sort of wiring of the brain, maybe a learning effect. 00:44:53.070 --> 00:44:56.950 There's also the effect that the releasing the dopamine has, 00:44:57.030 --> 00:44:59.470 because, of course, dopamine is a very powerful learning signal. 00:44:59.670 --> 00:45:04.450 So during the TMS episode, the dopamine release is stimulating you to learn 00:45:04.450 --> 00:45:09.650 something, which is possibly to have positive associations around TMS, 00:45:09.870 --> 00:45:13.290 if the dopamine release experience is plausible. 00:45:14.130 --> 00:45:17.950 But this is also the weakness of the method. Well, this is the risk of it. 00:45:18.050 --> 00:45:22.870 So isn't it really of a great priority. 00:45:23.970 --> 00:45:29.370 To find also a way to contextualize the stimulation, that you really allow this 00:45:29.370 --> 00:45:34.850 brain to reconfigure in a way that is less risky? 00:45:35.390 --> 00:45:41.550 So if you do TMS stimulation, you know you're going to drive dopamine, 00:45:41.550 --> 00:45:44.050 meaning on the drive, all sorts of associative learning processes. 00:45:44.490 --> 00:45:49.810 So maybe it's important that it happens in a context that is like a healthy, normal life. 00:45:50.530 --> 00:45:54.830 Yeah. So have you considered that? Have you included it? 00:45:55.070 --> 00:46:02.610 Because now you are conditioning people to really love the KVS device, right? 00:46:02.710 --> 00:46:09.470 And again, we are looking at all these things, and I appreciate very much this 00:46:09.470 --> 00:46:13.670 very stimulating talk because it gives you more ideas. 00:46:14.010 --> 00:46:20.510 The incumbent problem you have always, every day, with each one of these guys 00:46:20.510 --> 00:46:23.310 is, are you taking cocaine or not? 00:46:24.370 --> 00:46:26.090 If he's taking cocaine... 00:46:28.158 --> 00:46:34.578 You see, with those that are not taking cocaine, then you can go deeper in the 00:46:34.578 --> 00:46:41.458 conversation and ask those questions we were saying, but so tell me about cocaine now, here. 00:46:42.298 --> 00:46:45.318 You see, this is cocaine. What do you think? How do you feel? 00:46:46.378 --> 00:46:53.958 By only a portion, but our target is to lower the drug intake. 00:46:54.338 --> 00:46:58.118 Of course. So, one thing he considered… And then it will come with time. 00:46:58.498 --> 00:47:01.858 Well, there are interesting approaches that look much more at the associative 00:47:01.858 --> 00:47:08.818 processes, where you try to dissociate the drug-associated stimuli from the addiction. 00:47:09.058 --> 00:47:12.298 So you have simple conditioning paradigms, so behavioral therapy paradigms, 00:47:12.378 --> 00:47:17.258 where you try to dissociate alcoholics from beer bottles and wine bottles. 00:47:17.758 --> 00:47:20.618 This is what we do. This is what we do. Okay. 00:47:20.718 --> 00:47:25.658 And in your case, you can do something similar, right? It's not about dissociating. 00:47:25.658 --> 00:47:27.078 It's about forming new associations. 00:47:27.618 --> 00:47:33.798 So you project people into a context that is supposedly the healthy living context 00:47:33.798 --> 00:47:39.278 within which they are getting their conditions without seeing the TMS device. 00:47:39.978 --> 00:47:43.678 So don't suggest that you have to go to things like virtual reality to do that. 00:47:44.158 --> 00:47:48.698 This is another thing that is next to be investigated. 00:47:49.158 --> 00:47:50.558 Very good. That would be very good. 00:47:50.558 --> 00:47:59.018 So, you found a way to reactivate this under-activated dopamine system. 00:47:59.418 --> 00:48:02.658 Through that, you're able to reactivate the targets of the dopamine system. 00:48:02.778 --> 00:48:03.918 You allow the circuit to rebuild. 00:48:04.818 --> 00:48:10.818 And in some of your most recent papers, you also showed that it led to reduced cocaine intake. 00:48:11.178 --> 00:48:16.418 Correct. No? Correct. Would this just generalize without further adaptation 00:48:16.418 --> 00:48:17.898 to any other addiction? fiction? 00:48:19.138 --> 00:48:21.698 Like, can we go from alcoholics to the same thing? Only in theory. 00:48:22.938 --> 00:48:25.438 Only in theory. Would you believe it could? 00:48:26.682 --> 00:48:31.942 It could, but I'm also aware that drugs are not the same. 00:48:32.082 --> 00:48:39.082 Although all of them, they do increase the dopamine transmission and they do 00:48:39.082 --> 00:48:42.022 decrease dopamine transmission after withdrawal, 00:48:42.442 --> 00:48:50.202 there are drugs that are more difficult to draw, like nicotine, for example. 00:48:52.202 --> 00:48:56.182 Okay. So which one? So you think cocaine is one of the easier targets? 00:48:56.682 --> 00:49:01.762 I would say, absolutely, I would say that. Are there drugs that you think are 00:49:01.762 --> 00:49:03.142 completely beyond this method? 00:49:04.702 --> 00:49:09.702 No, I'm not a pessimistic individual. Okay, good. Yeah, that's good. 00:49:09.922 --> 00:49:12.902 But then, so now we're going to open up a little bit, right? 00:49:12.982 --> 00:49:19.682 So we already indicated and discussed that this is very much dopamine-centric, right? Absolutely. 00:49:20.102 --> 00:49:24.502 I admit that. No, and that's fine, right? Because, yeah, you need controllability, 00:49:24.642 --> 00:49:27.502 so we have to start to reduce complexity, And then you came a long way. 00:49:27.582 --> 00:49:31.802 It's fantastic that you see that a non-invasive method is actually having a 00:49:31.802 --> 00:49:33.182 big impact on drug intake. It's incredible. 00:49:35.562 --> 00:49:43.042 But what other systems would be on your wish list to start to include now in 00:49:43.042 --> 00:49:50.242 an understanding and also intervention for drug addiction, to counter drug addiction? 00:49:51.122 --> 00:49:57.202 What we are trying to do is still very difficult. very time-consuming. 00:49:58.062 --> 00:50:02.662 We are trying to do mainly two things. 00:50:03.522 --> 00:50:10.322 One is to couple these studies with functional magnetic resonance. 00:50:11.962 --> 00:50:18.222 Before, after drugs, cue-inducing, there are many things. 00:50:19.662 --> 00:50:26.002 In the wish list, you are asking me my wish list, so this is the dream book, we call it. 00:50:26.142 --> 00:50:30.822 The other thing are the protocol. 00:50:31.922 --> 00:50:41.782 We would like to investigate better, like Tentabarst, to see if beyond the obvious advantage, 00:50:42.122 --> 00:50:49.682 the practical advantage, that while one of these treatments with 10 hertz will cost you 27 minutes, 00:50:50.902 --> 00:50:52.802 Tentabarst will cost you 3 minutes. 00:50:54.502 --> 00:51:03.342 Beyond this, if it has a different effect on the drug intake, 00:51:03.562 --> 00:51:05.582 first of all, and eventually, 00:51:06.462 --> 00:51:13.962 in all those cognitive functions that can be measured or measured is a strong word. 00:51:16.699 --> 00:51:20.159 Through the tools we have tower of 00:51:20.159 --> 00:51:24.219 london and my gambling whatever 00:51:24.219 --> 00:51:34.019 okay in the wish list right i hope that god will keep me going in a life but 00:51:34.019 --> 00:51:40.539 then now with the current tms protocol on the on the cocaine users how much 00:51:40.539 --> 00:51:42.279 of a reduction can you accomplish. 00:51:43.159 --> 00:51:45.539 Right? It's nothing to zero. 00:51:46.359 --> 00:51:51.359 What's the modulation you get? Okay. First of all, 00:51:51.379 --> 00:52:01.779 we have 65-70% people that they do stop in the first month. 00:52:02.299 --> 00:52:07.259 Okay? This is more or less the success rate. 00:52:07.259 --> 00:52:14.739 We don't have data other than those published in the long range and this is 00:52:14.739 --> 00:52:17.799 the most important part yeah exactly 6, 00:52:18.359 --> 00:52:31.459 9, 12 months the relapse rate in our case is around 70% and normal addiction 00:52:31.459 --> 00:52:36.719 treatment service is around 98-99 null, soft, 00:52:36.939 --> 00:52:38.879 better than nothing. 00:52:39.039 --> 00:52:42.999 No, it's a substantial impact. Substantial impact. 00:52:43.779 --> 00:52:52.139 Tony? Yeah, we were talking about the sort of broader implications and uses of TMS. 00:52:52.439 --> 00:53:00.139 So there is evidence that nicotine, even cigarette smoking, can lower risk of Parkinson's disease. 00:53:00.759 --> 00:53:06.019 So, I don't know what the mechanism is that perhaps you do. and that involves 00:53:06.019 --> 00:53:08.119 stimulation of dopamine cells. 00:53:08.259 --> 00:53:12.279 So is there possible therapeutic benefit in Parkinson's. 00:53:14.574 --> 00:53:21.454 And Parkinson's has been tried and is being tried for several things, 00:53:21.774 --> 00:53:25.094 but not for the progression of the disease. 00:53:25.814 --> 00:53:37.114 So you try to reduce tremors, you try to reduce other aspects of the syndrome. 00:53:37.114 --> 00:53:46.034 The people in general believe that Parkinson's is a lack of dopamine, 00:53:46.294 --> 00:53:51.514 and so it gets cured by administering L-Dopa. 00:53:51.694 --> 00:53:54.674 Unfortunately, this is not the case. 00:53:54.994 --> 00:54:00.814 But what do we know about the mechanisms through which nicotine may have a protective effect? 00:54:02.034 --> 00:54:08.254 Well, nicotine pushes dopamine neurons. So it could be, could easily be. 00:54:09.554 --> 00:54:14.054 On dopamine neurons, you have nicotine receptors. 00:54:15.374 --> 00:54:20.734 So when you take a puff, it will go here, and the dopamine neuron will fire more. 00:54:21.734 --> 00:54:26.094 If you consider that you observe clinically Parkinson's, 00:54:26.754 --> 00:54:35.154 when the number of cells has fell 60% or something, thing, nicotine can help 00:54:35.154 --> 00:54:40.834 to push those minerals to make it moving, but this is a very, I can only say. 00:54:41.054 --> 00:54:45.074 But it's more, I think, the evidence is that it prevents it, 00:54:45.154 --> 00:54:47.774 so people are less likely to- Prevents? 00:54:48.174 --> 00:54:50.854 That people are at lower risk of Parkinson's. 00:54:51.794 --> 00:54:52.814 Smokers? Yes. 00:54:53.770 --> 00:54:57.650 I don't know i don't know 00:54:57.650 --> 00:55:01.430 no right no um but 00:55:01.430 --> 00:55:07.150 so one of the neurotransmitters which you put into the mix it if i told you 00:55:07.150 --> 00:55:15.950 cif okay so you see the control panel factor okay uh crf has a behavior that 00:55:15.950 --> 00:55:19.250 is just the mirror image of dopamine. 00:55:20.190 --> 00:55:27.450 Dopamine goes up, CRF goes down, and recently the people at Scripps, Olivier George, 00:55:27.990 --> 00:55:33.550 George Kub, and his group in Wendrúscula, a number of people, 00:55:33.690 --> 00:55:39.030 they are a very big and prominent group in the field, they found, 00:55:39.310 --> 00:55:47.150 in spite of the fact that George Kub is an anti-dopamine guy in general, but very nice. 00:55:49.330 --> 00:55:55.310 They found the link between CRF and dopamine neurons. 00:55:55.590 --> 00:56:03.050 They did studies in rodents and humans post-mortem, and they combined a nice 00:56:03.050 --> 00:56:06.510 and steadily standing story. 00:56:06.850 --> 00:56:09.330 Okay. That's a new frontier. year? 00:56:09.750 --> 00:56:14.250 Ah, in pharmacology, yes. I prefer to think of the TMS. 00:56:15.490 --> 00:56:20.930 But now you also made quite a strong statement about the whole opioid epidemic 00:56:20.930 --> 00:56:23.610 we're facing now, especially in the US. 00:56:24.430 --> 00:56:28.510 It will come here. Are you sure about that? We already see... 00:56:28.510 --> 00:56:31.410 I would love to be wrong. Okay, of course. 00:56:32.310 --> 00:56:41.970 I would love to be wrong, but I fear there will be because literally in that 00:56:41.970 --> 00:56:51.510 case there is a portion of medical malpractice first in the in the U.S. and, 00:56:52.807 --> 00:56:56.867 They are very easygoing with opioids. 00:56:57.567 --> 00:57:04.887 So you find over-the-counter pills for sore throat with codeine. 00:57:06.247 --> 00:57:11.207 Codeine is an opioid. It is an antitussive drug. 00:57:11.287 --> 00:57:15.267 It is employed as an anti-coughing drug. 00:57:16.547 --> 00:57:22.267 But an addict immediately understands that instead of taking one pill, 00:57:22.267 --> 00:57:25.227 it will take five pills and it 00:57:25.227 --> 00:57:28.327 will get high so this is one problem 00:57:28.327 --> 00:57:31.847 the other problem is 00:57:31.847 --> 00:57:35.767 it is not calling notice I 00:57:35.767 --> 00:57:44.007 mean it's harrowing or that matter but are the fentanyl derivatives the smugglers 00:57:44.007 --> 00:57:54.967 I don't know we go now into to the chronicles of drug barons and Escobar and El Chapo, 00:57:55.087 --> 00:57:57.087 I don't know if you follow, 00:57:57.287 --> 00:57:59.247 but to make it very brief, 00:57:59.467 --> 00:58:08.847 the Mexicans used to be the mules of the cocaine that was coming from Colombia and the United States. 00:58:10.067 --> 00:58:15.187 The Mexicans are not anymore that, are not anymore the mules. 00:58:15.187 --> 00:58:19.707 They are the directors of all operations. 00:58:20.007 --> 00:58:29.567 And they discovered that illicit labs can make amphetamines, 00:58:29.627 --> 00:58:34.647 make amphetamines and DMA and fentanyl derivatives. 00:58:35.767 --> 00:58:40.427 So the U.S. have been invaded by this very cheap. 00:58:41.852 --> 00:58:49.512 Powerful drug. And many people that get refused by the physician, 00:58:50.392 --> 00:58:59.092 they go to the street and with $5 they buy a shot of fentanyl and he dies because 00:58:59.092 --> 00:59:01.192 the drug is incredibly powerful. 00:59:01.692 --> 00:59:07.412 But how do you see the role of, let's say, the pharmaceutical industry and the 00:59:07.412 --> 00:59:16.572 standard medical practice in the U.S.? Because they push the physician to administer it. 00:59:17.412 --> 00:59:22.992 They do what they do everywhere. I mean, I don't want to talk badly about the 00:59:22.992 --> 00:59:30.452 companies, but I know for a fact this is a true thing. 00:59:30.732 --> 00:59:36.132 So you think there's a market, just commercial market forces at work driving this epidemic? 00:59:37.592 --> 00:59:44.272 Contributing. certainly not putting obstacles certainly not putting obstacles 00:59:44.272 --> 00:59:47.052 I would never dream of accusing, 00:59:47.992 --> 00:59:51.152 Big Pharma of triggering this thing 00:59:51.152 --> 00:59:54.592 but certainly they don't do nothing against and 00:59:54.592 --> 01:00:02.012 we know that they do anything to sell their compounds an opiate cannot be sold 01:00:02.012 --> 01:00:07.532 over the counter to make it brief Italy is not sold I don't think it is sold 01:00:07.532 --> 01:00:12.832 in Spain and I don't think it is sold in Europe, throughout Europe, you know. 01:00:13.692 --> 01:00:17.172 But now, do you believe, so earlier we talked about cocaine and drugs of abuse, 01:00:17.492 --> 01:00:20.492 where you said it was something like, if you have 100 users, 01:00:20.632 --> 01:00:23.552 maybe 20 get addicted, something like this, right? Exactly. 01:00:24.152 --> 01:00:26.992 If it's fentanyl, would the number be higher? 01:00:27.672 --> 01:00:32.012 I don't think it will be higher. You will get more deaths. 01:00:32.372 --> 01:00:37.252 Oh, absolutely. Because they know this thing already happened. 01:00:37.252 --> 01:00:44.152 In the 80s there was a thing called China Y in California and there were. 01:00:45.606 --> 01:00:50.346 Numberless deaths in San Francisco and Los Angeles. 01:00:51.206 --> 01:00:57.026 Oh gee, this must be an opioid overdose. The guy at the needle here, 01:00:57.266 --> 01:01:03.046 he was cyanotic blue and so depression, respiratory depression. 01:01:03.146 --> 01:01:09.226 They went to see if there were morphine, like a couple of nights and morphine could not be found. 01:01:10.046 --> 01:01:19.246 After some time, they found phantom. religion yes China white was the name the 01:01:19.246 --> 01:01:23.866 street name of the drug it was composed by. 01:01:25.386 --> 01:01:33.406 Fentanyl and meperidine which is an opioid that has mostly peripheral actions 01:01:33.406 --> 01:01:41.546 so the addict feels that and he perceives the action the peripheral actions. 01:01:43.026 --> 01:01:46.806 And they were selling this as if it was heroin. 01:01:46.966 --> 01:01:49.866 They don't say this is fentanyl. 01:01:50.606 --> 01:01:54.926 This is very good. Give me $10. Be careful. 01:01:55.006 --> 01:01:59.366 Be careful because this is very good. So somebody was not careful. 01:02:00.486 --> 01:02:05.246 And many people died. It is occurring exactly the same thing. 01:02:05.466 --> 01:02:10.406 They use spreads and many more people will die. 01:02:11.546 --> 01:02:16.586 Okay. 62,000 is not bad as a number, unfortunately. That's scary. 01:02:16.766 --> 01:02:17.686 Yeah, that's really scary. 01:02:17.866 --> 01:02:25.286 So, Marco, we're close to the finish line, and so we went, we made quite a tour 01:02:25.286 --> 01:02:29.746 also through your career, which started quite a few decades ago by now, 01:02:29.866 --> 01:02:31.186 right, and it's all a business of addiction. 01:02:32.086 --> 01:02:35.826 So you are a diet in the wool neuroscientist and addiction researcher. 01:02:35.826 --> 01:02:41.026 So if you want to learn from your lessons or want to learn from you and your 01:02:41.026 --> 01:02:46.946 experience, what would be Marco's law we should adhere to to understand how the brain works? 01:02:48.208 --> 01:02:56.068 The brain works jesus this is tough you should have me we give this question to everybody. 01:02:58.748 --> 01:03:06.568 No i don't consider myself your advice to other researchers your students right 01:03:06.568 --> 01:03:10.608 your students what's the rule you would give them what's the codex that you 01:03:10.608 --> 01:03:17.388 would give give to your to your students to my students to to keep going in neuroscience, 01:03:18.208 --> 01:03:24.128 The most important ingredient to solve the problem, yeah, to make progress. Two things you need. 01:03:24.528 --> 01:03:30.288 You need an endless intellectual curiosity and enthusiasm. 01:03:31.848 --> 01:03:36.268 Enthusiasm. You don't need to be rich. You don't need to be nothing. 01:03:36.488 --> 01:03:37.868 You don't need to be smart. 01:03:38.288 --> 01:03:40.448 The brain is a smart organ. 01:03:41.368 --> 01:03:47.988 The brain, if you make it work, it will work. And the more you make it work, he enjoys that. 01:03:48.208 --> 01:03:55.768 This is called enthusiasm, I would say. I try to transmit this to the youngsters. 01:03:56.388 --> 01:04:02.688 Curiosity and enthusiasm. Curiosity could be an elixir of long life. 01:04:03.188 --> 01:04:05.808 Because I think we begin... 01:04:07.671 --> 01:04:11.211 Declining when we 01:04:11.211 --> 01:04:14.971 say oh I know that already when you 01:04:14.971 --> 01:04:18.451 believe that you have learned what I'm 01:04:18.451 --> 01:04:24.871 very impossible to be left so nice to think no I didn't let me think otherwise 01:04:24.871 --> 01:04:29.691 I'll be dead so how do you protect then your own curiosity net is just how do 01:04:29.691 --> 01:04:36.331 you protect it with TMS but doing something new moving from through physiology in rodents, 01:04:36.331 --> 01:04:39.651 through physiology in humans. So novelty, right? 01:04:40.071 --> 01:04:44.511 Novelty seeker, that's absolutely correct. And then the last question is that, 01:04:44.591 --> 01:04:47.651 so Tony still wants to go to Sassari, he hasn't been there yet. 01:04:48.471 --> 01:04:51.471 He hasn't been to Sardinia a lot anyway, right? And then once, 01:04:51.651 --> 01:04:55.151 just once. The four years from now, Tony will come visit your lab. 01:04:55.391 --> 01:04:59.951 Oh, sure. With a little notebook to check whether you actually have falsified 01:04:59.951 --> 01:05:06.051 your core hypothesis that you're gonna share with us today. What's the key hypothesis 01:05:06.051 --> 01:05:10.251 you want to see tested in the four-year time frame in your program? 01:05:11.931 --> 01:05:20.071 You know what I'm trying to do? I'm trying to develop a way to measure or to 01:05:20.071 --> 01:05:24.691 estimate dopamine in the human brain living, 01:05:25.711 --> 01:05:27.251 in the living human brain, which 01:05:27.251 --> 01:05:33.511 will not be PET scanning, nor will it be functional magnetic resonance. 01:05:36.811 --> 01:05:45.631 But, because I don't have those opportunities, it's not that I don't want, but we are pursuing, 01:05:46.231 --> 01:05:52.071 the electro-rectinal gap, let's call it, that is dopamine also in the right 01:05:52.071 --> 01:05:58.051 team, as there are D1 receptors, and there are studies which have indicated, 01:06:00.271 --> 01:06:07.751 that the blue cone wave apparently is not mediated by dopamine. 01:06:07.811 --> 01:06:10.171 Dopamine contributes to this. 01:06:11.091 --> 01:06:19.031 And this has been seen in cocaine antics, and it correlates with the dopamine metabolites in the CSF. 01:06:19.131 --> 01:06:25.351 So perhaps with the electroretinogram, which is a very simple thing to do, 01:06:26.171 --> 01:06:30.051 in four years I may have some results for Tom, if he comes. 01:06:30.271 --> 01:06:32.491 And if you count too. 01:06:32.831 --> 01:06:37.471 Wonderful. So for you, it is much easier with a serenio wine. 01:06:38.371 --> 01:06:41.131 So Marco Dianas, thank you very much for this. Thank you. Thank you. 01:06:43.651 --> 01:06:49.391 The CSN Podcast was produced by the Convergent Science Network of Biometrics 01:06:49.391 --> 01:06:55.831 and Biohybrid Systems, a project funded by the European 7th Research Framework Program. 01:06:57.491 --> 01:07:02.651 For more interviews, recorded lectures or upcoming conferences in the field 01:07:02.651 --> 01:07:08.891 of biometrics and biohybrid systems, go to csnnetwork.eu. 01:07:09.200 --> 01:07:16.400 Music. 01:07:09.711 --> 01:07:11.071 And thank you for listening.