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Michael Fox: Addiction, Nicotine, Deep Brain Stimulation, Neurotechnology & Parkinson’s Disease

Updated: Jul 6, 2022

Full episode transcript below. Beware of typos!

Nick Jikomes

Dr. Michael Fox, thank you for joining me.

Michael Fox 4:08

Thank you so much for having me.

Nick Jikomes 4:10

Can you start off by just telling everyone who you are and what kind of research you do?

Michael Fox 4:15

Sure. My name is Michael Fox. I'm a neurologist at Brigham and Women's Hospital Harvard Medical School. I am the director of the Center for Brain circuit therapeutics. We focus on identifying therapeutic targets and administering neuromodulation treatments things like deep brain stimulation and transcranial magnetic stimulation.

Nick Jikomes 4:34

Yeah, I want to get into some of that stuff for folks who don't know what those techniques are. So can you just start by taking them one at a time? What is deep brain stimulation? And what are researchers and doctors are using it for?

Michael Fox 4:46

Yeah, so it's, I guess, starting with that therapy. So deep brain stimulation is a treatment where a surgeon implants, electrodes deep in the brain. There's then a wire that connects those electrodes to a battery pack in the chest, and you can turn on those electrodes and use them to modulate the activity within specific brain circuits. And it's used to treat certain symptoms, especially movement disorders. So it's very effective at suppressing tremor. It's very effective in improving most of the symptoms of Parkinson's disease. And then rarely it can also be used to treat things like obsessive compulsive disorder, or dystonia.

Nick Jikomes 5:27

So literally, a electrode a piece of metal is physically put deep in the brain, and you send electrical current into the brain. And this for some reason happens to help with things like Parkinson's disease.

Michael Fox 5:40

Correct. And it's, it's actually one of the most dramatic treatments that I've ever seen. You know, for a lot of brain diseases, we don't have dramatic treatments. Deep Brain Stimulation is the exception. Um, you can literally flip a switch and see someone's tremor stop.

Nick Jikomes 5:56

How was that even discovered?

Michael Fox 5:59

Yeah. For the most part, trial and error and serendipity, you know, patients with really severe Parkinson's tremor, for example, it's a, it's a resting tremor. So they have horrible tremor, just when they're sitting there watching TV, and it can be quite severe. And to the point where early on, a surgeon would go through, and lesion different parts of the nervous system, starting with the nerves that went from the spinal cord to the arm, just to try and stop the tremor. Now, obviously, if you severed the nerves that go from the spinal cord to the arm, you stop the tremor, but you also stop every nervous impulse to the arm, and then people have a paralyzed arm. And so that started this trial and error process of, you know, lesioning different parts of the nervous system to try and make the tremor stop. And many of these lesions made, the tremor stopped, but left patients paralyzed. And eventually they found places in the in the brain again through trial and error and serendipity that when lesion would stop the tremor, but not cause the arm to be paralyzed.

Nick Jikomes 7:04

And so there's that's a, that's a dramatic but but also invasive way to treat something like tremor. There's also this technique called transcranial magnetic stimulation. How does that work? And when did that start to get used?

Michael Fox 7:18

Yeah, so that's a non invasive form of stimulation, it's a electromagnet that you hold up to the side of someone's head. So outside their scalp, you discharge this electromagnet very rapidly, and that chain creates a rapidly changing magnetic field. And if you remember any old high school physics, anytime you have a wire sitting in a changing magnetic field will actually induce an electric current and the underlying wire. In the case of TMS for for treating neurological or psychiatric conditions, the underlined wires actually your brain cells. So as you discharge this magnet over and over again, you can modulate activity in different brain circuits. So just like dBs, you can modulate the activity and brain circuits. But with TMS, you do it non invasively, with an electromagnet outside of the scalp, and the primary clinical uses is depression, although it has other FDA approved indications as well, such as obsessive compulsive disorder, and actually smoking addiction.

Nick Jikomes 8:15

And so with something like TMS are the functional effects, are they happening in real time in the moment while you're doing this TMS stimulation? And do they actually outlast the treatment itself?

Michael Fox 8:28

So the answer to both is yes. So in real time, you are modulating the activity of these brain circuits. But when you do this day after day, and we actually do it for about six weeks, it creates a change in depression, that can last years after the end of the stimulation. So you can think of it as a circuit reset, you're helping people out of depression, and then that benefit can last well past the duration of the stimulation itself.

Nick Jikomes 8:55

Interesting. Yeah. So, you know, we're going to talk about brain damage brain lesions. And typically when we think about having damage to some part of the brain, we think about that causing a deficit. But in the case of deep brain stimulation, in some of those early interventions for Parkinson's, in the case of some of the stuff that we're going to talk about for addiction, there are examples of people who have brain damage that actually helps them in some way. And I'm hoping you can paint a picture for us of sort of what we knew before your recent study around lesions to different parts of the brain and how they impact things like addiction.

Michael Fox 9:32

Yeah. So as you mentioned, generally getting a stroke or damage to a focal part of the brain is not a good thing. And most strokes will cause negative symptoms, things like a paralyzed arm or inability to speak or depression. But there are certain cases where a lesion leads to functional benefit. And so I gave you an example of tremor earlier, and that was probably one of the most obvious examples where there are patients that had really bad tremor or had an incidental stroke. And the tremor got better without leaving them totally paralyzed. And so they got functional benefit from that lesion in the sense that the tremor improved. And again, those cases are telling us something really important about where our therapeutic target is, and where we should intervene in other patients to stop their tremor. And the same thing is true in addiction. So for a long time, ever since at least the late 90s, people have noticed that there are patients that are addicted, usually to cigarette smoking, because that's the big, big risk factor for stroke, they have a stroke, and then they're in the hospital, and they lost all craving for cigarettes. So it's not just that they stopped smoking. But they immediately had no interest in smoking, no withdrawal symptoms, they basically lost their addiction. And so some early studies, looked at these cases and said, Hey, these are really, really important cases, they're telling us something important about where we need to intervene to help addiction and other patients. And these early studies found that there was a statistical association with a brain region called the insula. If you had a stroke to the insula, you were more likely to lose your addiction than people that did not have a stroke to the insula. And so that set forth this focus on the insula is a therapeutic target for addiction. And in fact, the FDA approved TMS device that targets cigarette smoking, and addiction was designed to try and stimulate the insula. Based on these early studies. The problem is as time went on, and people tried to replicate this very exciting observation, they found that it didn't always line up, that most of the lesions that got rid of addiction didn't hit the insula. And most of the lesions that hit the insula, didn't get rid of addiction. And so while there was a statistical association there, we clearly were missing something, that it wasn't just all about the insula. And so that's what, that's what we set out to try and investigate. I see.

Nick Jikomes 12:01

So people were having strokes and things. In some cases, they had damage to this brain area called the insula, and their addiction was basically completely cured. But in other cases, you got similar effects with lesions to other places. And in other cases, still, you would have lesions to the insula that did not lead to that effect. So there is some kind of incomplete picture there. And that's where you guys pick things up? Before we get to your study. Can you talk a little bit more about the insula, where we're in the skull isn't located? And what do we already know about the types of things it tends to be involved in?

Michael Fox 12:36

Yeah, so it's a very deep region in the brain, kind of, I know, we have audio listeners or listeners hear. So if you go maybe a couple inches in front of your ear, and then you're gonna go straight in a few inches, you get to an area called the insula. So it's not on the surface of the brain, it's a little bit deep, which means it's hard to reach with a transcranial magnetic stimulation coil, because it's deep in the brain. This is a part of the brain that does a lot of different things involved in different types of body sensations, for example, and integrates, you know, body inflammation, cognitive control, you know, pain sensations. And so the insula does a lot of different things. But it does a lot of things that people have thought play a role in addiction.

Nick Jikomes 13:22

I see. And I often hear the insula mentioned, with a term called interoception. The idea being that, if the normal senses we think about, like seeing things with your eyes is exterior perception, detecting things outside the body, the infamous sort of doing a sensory integration or sensory detection function for the insides of our bodies, like what's going on in the body and in our viscera? And things like that? Is that the way that people often think about it?

Michael Fox 13:47

Correct? That's one of its many roles.

Nick Jikomes 13:51

And were there any other brain regions that were sort of top candidates or regions that you expected might also be involved in addiction that we might want to orient people towards before we dig into the study?

Michael Fox 14:05

Yeah, so So the insula was the number one region that came out of the stroke literature of lesions that hit the insula versus don't hit the insula. However, there are many, many other regions that either come out of animal research or functional neuroimaging studies of addiction, or in the case of my field lesioning or brain stimulation interventions. And so actually, there have been lesion trials for patients with addiction to the anterior cingulate. So it's a procedure called cingulate Atomy. And this is a procedure that people have used for depression, they've used it for pain. And actually, what they noticed is some of the patients where they did a single Atomy for pain. They also lost their addiction to the pain medications that they were on. And so the anterior cingulate or the idea that you could lesion the anterior cingulate to improve addiction had led to some controversial trials where they had taken people with addiction lesion the anterior cingulate to try and improve it. And these published trials reported some evidence of efficacy. But there were a lot of questions around both. Did they analyze the data correctly? Do they really hit their endpoint? And then ethical questions about this very vulnerable patient population? Is it okay to be be lesioning them to try and help their addiction. There's also been a number of different trials of different brain stimulation treatments, targeting lots of different regions. So there's trials that have targeted the front of the brain, the medial prefrontal cortex, the frontal polar cortex, there's trials that have targeted the dorsal lateral prefrontal cortex up on the top of the brain. And then there have been DBS trials, deep brain stimulation to the nucleus accumbens, for example. And so I'm giving you a flavor of all the different regions, because that's kind of the state of the field where everybody based on their evidence, their field, their type of brain stimulation, how they looked at the problem, they would identify a different region, a different target a different spot to go after. And again, there's signal there, you know, some of these trials were showing signals of efficacy, we have an FDA approved treatment for cigarette addiction with a TMS coil. But it was really unclear what we're actually targeting or what the therapeutic target is.

Nick Jikomes 16:21

I see. And, you know, I think probably everyone understands at this point, at least qualitatively, how big and how how much the problem of addiction is growing, especially in recent years. Can you put a little bit more meat on that for us? How big is that problem currently? And what's the trajectory trajectory that we're on?

Michael Fox 16:41

Now, so I don't, I don't think I can do it justice. So I want to make sure I give you my full disclosure, which I am not an addiction specialist. We did have multiple addiction specialists on the paper, including Nora Volkow, and clean Maasai. But I'm a Parkinson's doctor, I also do TMS for depression, we developed tools and techniques that we thought would be useful for studying addiction. But as far as the clinical problem of addiction, I just be quoting the New York Times papers, you know, articles, kind of describing how big of an issue it is, and, and how more of an issue it's become during the pandemic. But I think it's suffice to say that is a major, major problem. I think everybody agrees on that. And it's an increasing problem with addiction going up and with overdose death rates going up.

Nick Jikomes 17:30

Can you start describing for everyone at a very high level, what the basic design of your study was and how you guys went about conducting it?

Michael Fox 17:39

Yeah, so we started with these datasets that I told you about earlier. And in fact, we resurrected the original data sets that led to that insula observation. So Aaron, Bo's, one of my close collaborators at Iowa, had the original data set that led to that first insulin observation. And so he revitalized the dataset, but but analyzed it in a much, much more careful way, where he actually outline the exact location of every lesion from that original addiction study. So that was dataset, one where we had an outline of the exact lesion locations that either lead to addiction or a mission, or lead to people, you know, continuing to smoke. We then identified a second dataset from Rochester, where that was one of the trials where they had sought to replicate this original Iowa finding. And again, another data set of exact lesion locations all outlined and Atlas space, they either lead to addiction remission, or lead to people continuing to keep smoking. And we said, Okay, we've got two very valuable datasets here, one of them identified the insulin, although even in that original dataset, most of the lesions that lead to addiction remission were not in the insula. And then we had a second data set that failed to replicate the insula, fine, and we said, Okay, if we can make these two datasets line up, then we know we're on to something. And so we did something called lesion network mapping. And this is a technique that was developed by Aaron Bose and now at Iowa and others to look at not just where the lesion is located. But to look at what brain circuit, the lesion is intersecting. And so we turn to a wiring diagram of the human brain called the Human Connectome. You can think of this as an atlas of how every brain region is connected to every other brain region. And it's this really, really unique resource that for the first time, we can say, not just where is the lesion, but what is the lesion connected to what brain circuit is that lesion hitting? And so we can turn to these lesion datasets and then ask, okay, are all the lesions that lead to addiction remission are all they all hitting one specific brain circuit that the lesions that don't lead to addiction remission or avoiding it And sure enough, we sat we found a circuit data set one, we found the same circuit and dataset two.

Nick Jikomes 20:06

Okay, so So part of what I'm hearing here is, you had on the one hand, you had a, you had a kind of a puzzle, you had this dataset, this dataset is some brain anatomy data from human patients, some of whom had addiction to certain substances. And they had lesions to different parts of the brain. Sometimes those lesions were associated with remission from their addiction, sometimes it wasn't. But it's not like everyone that that got over their addiction had the same lesion in the same location. So they all had like different lesions in different locations. And it was a bit of a mystery what was going on. And from what you were saying, it sounds like, you know, one piece of the puzzle is, it's not enough just to know the sort of basic location of Allegiant, because one brain region might have multiple circuits inside of it that go to and from different locations in the brain. So there's this sort of really complicated map that you have to parse by comparing all of these people. And you use this thing called the Human Connectome to help do that. And that's just sort of an atlas that tells you where all of the where all the roads are connecting all of the different circuits and different sub regions of these patients.

Michael Fox 21:14

Yep, that's exactly right. That's, if you want to fix a stereo receiver, the first thing you do is you pull out the wiring diagram, and then you can figure out where the problem is coming from. But if you don't have that wiring diagram, it's very hard to make sense of where the where the problem or with a symptom or the change in behavior is coming from.

Nick Jikomes 21:31

Yeah, and I suppose that you know, because this wiring diagram is of the brain, it's so complex, and there's so many networks and circuits, there's a lot of different ways to cause the same kind of deficit. So there's a lot of different ways you could probably cure someone's addiction by by lesioning different different circuits going to different places, perhaps?

Michael Fox 21:51

Well, that that was the hypothesis, right? Is all we knew is that there was a mystery, as he articulated very nicely that there were lesions in different locations causing the same behavioral effect. And so the hypothesis was, maybe they're all hitting the same brain circuit. So that's the hypothesis we tested because it didn't have to be that way it could have been, each one of these lesions was in a different region. And each one of these lesions was, was hitting a completely different circuit, there might be multiple different ways to get rid of an addiction. And so that was the thing that the question that we wanted to answer is, are they actually hitting one consistent circuit? Are these lesions all connected to a consistent set of regions? Or are they all doing different things hitting different circuits?

Nick Jikomes 22:34

And for the patient population that you guys had data from? Were these patients all addicted to the same substance? Or was it different substances?

Michael Fox 22:43

Yeah, so the first two datasets that I described, every single patient was addicted to cigarette smoking, at the time they were enrolled in the study, so So every single patient, you know, to be enrolled in the study, you had to be drug addicted to cigarettes, and then you had to have a stroke. And then some of those patients that are addiction disappeared, some of those patients failed to quit smoking and kept smoking. And then there was also a middle group of people that they quit smoking, but they did it because their doctor told them to not because they suddenly lost their addiction.

Nick Jikomes 23:13

And, you know, when you when you compared what when you did your study, and you got into the weeds? What was the sort of basic overarching finding that you came to?

Michael Fox 23:23

Yeah. So the answer to the question that you articulated earlier is that, yes, these different lesions in different locations, did hit one common brain circuit, that there was a set of connections that were common to all these different lesions in different locations that got rid of addiction, that were different than the lesions that did not get rid of addiction.

Nick Jikomes 23:43

I see. So some people lost their addiction. And even though there was heterogeneity in the location of the legions, you were nonetheless able to find like a common core set of circuits that touched the most or all of the patients who actually went into remission.

Michael Fox 23:59

I correct, pretty, pretty close. I guess I would slightly restate it is that there were a set of connections that was common to all the lesions that got rid of addiction, that was statistically different from the lesions that did not get rid of addiction. So it was they were characterized not by their location, but by their connectivity profile, and what circuit they were hitting.

Nick Jikomes 24:25

I see. And can you talk about some of those connections and some of those circuits? What were some of the brain regions that were talking to each other that seemed to be a part of this network?

Michael Fox 24:34

Yeah. So so as we kind of expected would come out the insula was a major region. So they were all connected to the insula. They were all connected to the anterior cingulate that I mentioned earlier, that old lesion target for addiction. They're all connected to an area in the frontal cortex called the dorsolateral prefrontal cortex. And then interestingly, these lesions were also negatively connected. I'll go into a minute what that means, but they were also negatively connected to another set of regions in the ventral medial prefrontal cortex and in the frontal polar cortex. So they were positively connected to one set of regions negatively connected to another set of regions,

Nick Jikomes 25:13

I see does that basically mean that for some of these connections, it implies that if you break them, if you lesion them, the addiction will get better. And for other connections, if you were to stimulate them, the addiction would be expected to get better.

Michael Fox 25:27

That's a hypothesis that that, you know, stems from our data. So we weren't able to prove that right, we didn't actually lesion any patients, we didn't actually stimulate any patients. What we can say, based on our data is, this is the connectivity profile of a lesion that gets rid of addiction. What spot in the brain best matches this connectivity profile? Because in theory, that is the spot that you might want to lesion to get rid of addiction. Conversely, we could say, if you weren't going to lesion a spot in the brain, if you're actually going to stimulate or excite a spot in the brain, what would be the ideal spot that would have the opposite connectivity profile of a lesion that would get rid of addiction? Does that make sense?

Nick Jikomes 26:11

Yes, yes. And so is it possible for you guys to actually functionally test some of these things using DBS or using TMS or some of the other techniques that we discussed?

Michael Fox 26:20

Yeah. So I think that's the most exciting thing that came out of our paper, right is obviously we can make sense of these lesions in different locations. It was an interesting scientific study. But it directly leads to testable therapeutic targets, where we can say, hey, if there's one spot in the brain, we want to turn off, it's right there. If there's one spot in the brain, we want to excite, it's right there. And so again, we have to do the clinical trials, there's a lot of work to be done. But we come out with very testable hypotheses and testable therapeutic targets to find out if we're right or not.

Nick Jikomes 26:55

And so for the patients that went into remission, where their addiction symptoms got better, and they lost their cravings, and things did they have, were you able to? Did you have data on any other like psychological factors? Did they did any other psychological or emotional traits change after they had their lesion?

Michael Fox 27:15

Yeah, good question. So we didn't in everybody, but we did in a subset of patients. And that was certainly a concern, especially from our reviewers of you know, GE, you say you have a circuit for addiction, but maybe you just have a circuit for attention, they can no longer pay attention to what they're addicted to. Maybe that's why they lost their addiction. And so what we did is looked at a subset of patients where we did have extensive neuro psychological batteries done and we didn't see any huge differences in attention, or executive function or, or other major domains of cognitive function, the only big difference between the groups seem to be in terms of whether they lost their addiction or not.

Nick Jikomes 27:56

I see. Okay, so you at least had a subset of patients where you were able to look at other aspects of their cognition, and executive control and things and There didn't appear to be any other glaring differences. Correct. So getting into some of the brain regions that a little bit more detail. I know that, you know, part of the paper described some interesting patterns within a couple of general areas of the brain. One was the striatum, and one was the prefrontal cortex. So what did you find specifically? And how does this align with our functional knowledge of what the different sub regions of these areas are known to do?

Michael Fox 28:29

Yeah, it's a great question. So I'm speaking a little bit beyond my knowledge base right now, because I'm not an addiction expert. But but there is a lot of focus in the addiction field, especially in the animal studies of the dorsal versus ventral striatum, where the ventral striatum, including the nucleus accumbens, is thought to be, you know, the limbic part of the basal ganglia that's very focused on reward. And so there are a lot of abnormalities, again, both in animal studies and functional imaging of addicted patients that say, Hey, you know, this area of the basal ganglia that gets a lot of dopaminergic input is very, very involved in reward processing, and seems to be abnormal in multiple different ways in addiction. Where if, if you have a substance addiction, it tends to be underactive, when you go through your normal daily life, where you don't find things as rewarding as maybe other people would. But then when you encounter the substance that you're addicted to, it lights up like a light bulb, and you get this super surge of finding something that that's rewarding. And yet the dorsal striatum a different part, but but right adjacent to the ventral striatum tends to work very differently. It's more involved in the cognition or control part of addiction. And so, study after study after study scenes, a dissociation between what the ventral striatum is doing and what the dorsal striatum is doing. And so when we looked at our map, we saw that same dissociation In this this addiction circuit where the connectivity profile from the ventral striatum to the dorsal striatum to these lesions that got rid of addiction, it inverted itself, the connectivity profile to the ventral striatum was exactly opposite of the connectivity profile to the dorsal striatum. Again, it's a little bit complex, but suffice to say we were seeing signal in this area that aligned with a lot of other research on addiction from other sources.

Nick Jikomes 30:27

I see. I see. And so you had patients who were addicted to nicotine. You also had some patients that you had data for that were addicted to alcohol did the results, they're basically lined up, or were there differences between the two populations?

Michael Fox 30:42

Yes. So my minor correction is we actually did not have a dataset of people that were addicted to alcohol at the time of their stroke. We wish we had that data set. That would have been the ideal dataset to test whether our findings from cigarette smoking, generalized alcohol addiction. But we did have a data set that could allow us to broach the question, where are they we didn't have people that were addicted to alcohol at the time that they had a lesion. Instead, we had a database of lesion patients from Jordan graph, and this is the Vietnam penetrating head trauma study, the Jordan graph and is followed these patients that basically got shrapnel in their head in Vietnam. And then he followed them for many, many decades during a wide variety of different neuro psychological assays to understand the implications of their focal brain damage. And one of the tests that he did was an alcoholism risk score. So this is not, you know, patients that were alcoholic, but it's a battery that very tightly correlates with their risk of alcoholism. And so it gave us a proxy, right, it wasn't the ideal dataset to test of our results generalized, but it was a lot and allowed us to at least see, hey, if we look at the circuit that reduces your alcoholism risk, does that look like the circuit that led to addiction remission of cigarette smoking, I see. Okay, and the to lined up very, very nicely. And in fact, because Jordan Grafman had collected so much data on these Vietnam vets, we were also able to say, hey, does this line up with any other neuro psychological variables, and it really didn't addiction, what are sorry, the alcoholism risk score was the number one variable that looked like our addiction remission circuit, none of the other variables that he collected looked like that circuit.

Nick Jikomes 32:34

I see. So this is at least consistent with the idea that there could be sort of one core addiction circuit that might apply to addiction to in theory, anything or at least many substances, rather than distinct circuits that might be completely separate for alcohol versus nicotine versus whatever.

Michael Fox 32:51

Exactly. And I should mention, we also had three case reports of you know, we obviously scoured the literature, for any case, reports of patients that were addicted to anything that then had a lesion. And we did identify a few case reports of patients that were addicted to other substances like opiates. But again, at the case report level, but those few cases were able to find, they also lined up with this addiction remission circuit, and were addicted to other substances above me on cigarette smoking and alcohol. And so our data at least points to the possibility that there is one circuit for addiction remission across multiple different substances of abuse. I will say that's actually a very controversial finding, that was one of the ones that the reviewers really took us to task on. And there's still a lot of disagreement in the addiction field as to whether you know, addiction is one thing or addiction is something different for every different substance.

Nick Jikomes 33:46

I see. I see. And I suppose it doesn't have to be either or there could be common components that are common to all addictions, but also things that are specific to opioid addiction versus alcohol versus this or that.

Michael Fox 33:58

Correct. And our data suggests there's at least something in common, but that doesn't preclude the possibility that are also important differences.

Nick Jikomes 34:05

And so, you know, you mentioned some of these brain regions, like the insula, like the striatum and some other regions that you expected to come up and see in a study like this, just based on the prior, what was in the literature that had been done previously. Were there any brain regions that that were in your addiction or in remission, excuse me, addiction remission network that you were surprised to see, or that were unexpected?

Michael Fox 34:29

Yes, you know, but in retrospect, I shouldn't have been surprised. And it was just my lack of knowledge about the addiction field and all the brain stimulation trials that have been done. So I mentioned earlier that we looked for the spot that would have the ideal connectivity profile of a lesion that gets rid of addiction. And then we look for spots. So we'd have exactly the opposite connectivity profile, that might be a target of excitatory brain stimulation. And we were really hoping that we would get something that you know, lined up with the TM As literature and what we got was this area that we call the frontal polar cortex kind of right behind the forehead. And the first time we saw it, we kind of said all nuts, it's really too bad that we didn't get a spot that that lines up with what the TMS field is telling us is their target for addiction. I mentioned earlier that there was a giant TMS coil that had been designed to get the dorsal lateral prefrontal cortex in the insula. And, and neither of those regions were popping out as our ideal nodes for for excitatory TMS. And it wasn't until we actually looked at the electric fields from these TMS coils that were in use, and said, okay, the coil was designed to hit the dorsolateral prefrontal cortex in the insula, but where's it actually hitting. And we were shocked because it was the frontal polar cortex. And so it was a surprise to us when that brain region came out of our analysis. But when we looked back at the actual electric field models of what these different TMS coils were hitting, things lined up a whole lot better than we ever would have thought.

Nick Jikomes 36:07

Interesting. And what is, you know, we've talked about deep brain stimulation, and TMS. A lot of your career has been to do with things like Parkinson's disease, but then you did this collaboration about addiction. What is like the state of the art today for addiction treatment, how well does something like TMS or whatever works best actually work for addiction treatment and humans today?

Michael Fox 36:29

Yeah, so again, I should probably punt on this one. Because there are people that have dedicated their careers to this people like Colleen Hanlon. And, you know, I will mention that there is an FDA approved TMS coil for smoking cessation, and smoking addiction. And there are lots of research trials going on for TMS for other types of addiction as well, opiate addiction, alcohol addiction, cocaine addiction. And there's a lot of different trials, a lot of different stimulation targets. But the only one that has had the level of evidence that's led to FDA approval was this trial for smoking cessation.

Nick Jikomes 37:17

I see so so it is a TMS thing. So people probably go in for multiple sessions day by day for a period of weeks or something, they get the stimulation, and it has some level of efficacy and the FDA has approved it now.

Michael Fox 37:30

Correct. But but it's not yet covered by most insurance companies. And so while we run a TMS center here, we treat almost everybody with depression with our TMS, simply because that is FDA approved, but also insurance reimbursed versus right now smoking cessation is FDA approved, but not covered by most insurance companies.

Nick Jikomes 37:54

I mean, not necessarily what I plan on talking about but but why is that what makes something like this not coverable versus coverable?

Michael Fox 38:01

Yeah, you'll have to ask the insurance companies. But it's not it's not uncommon, right? Not everything that gets FDA approved is something that's actually covered by insurance. There's different calculus that goes into an FDA approval versus whether there's a cost benefit to the insurance company to pay for that new intervention. It's it's not uncommon that there's a lag between when the FDA approves something when the insurance companies start paying. So for example, when TMS was FDA approved for depression, there was a lag of multiple years before insurance companies started paying for it. And in some other parts of the country just now our insurance companies beginning to pay for TMS for depression. So different insurance companies in different regions make different decisions. And exactly what enters into that decision is, you know, not not something that I've been involved in directly

Nick Jikomes 38:49

I see. And with TMS, I mean TMS is super interesting, because it is not invasive in the way that that deep brain stimulation is you don't actually have to cut open someone's skull and go inside the brain. Are there any? What is the risk profile for TMS look like? And how do you sort of calibrate how strong the signal is and what what the frequency is?

Michael Fox 39:10

Yeah, so we know a huge amount about the risk profile for TMS for depression. Just because you know, hundreds of 1000s of people have gotten TMS for depression at this point. And overall, it's extremely well tolerated. You know, one out of five patients will have a mild headache from the TMS one out of five patients will have a little mild discomfort. TMS kind of feels like somebody tapping you on the head, or it can cause very subtle muscle contractions like an eye twitch or jaw clench, but overall, it's very, very well tolerated. I'd say that the most concerning risk of TMS is something like a seizure, where our goal is to stimulate the brain. But unlike you know, electro convulsive therapy, for example, where you intentionally cause a seizure with TMS we want to stimulate the brain, but stopped short of actually causing the seizure. And we're very good at doing that there. risk of seizures about one out of 10,000 to one out of 30,000. So again, very rare. So it's a safe procedure, it's very well tolerated. Now again, that's TMS for depression. It's possible that if you switch the target, and you go after a brain circuit for addiction, the side effect profile could be different. But overall, TMS seems to be a pretty safe treatment for a variety different indications.

Nick Jikomes 40:25

Now, when we are discussing some of the brain areas involved in this addiction remission network that you've defined in your study, you mentioned for example, the insula is sort of in the brain a few inches, it's not right at the surface, does TMS work only right at the surface structures of the brain? Or can it kind of go in and stimulate some of those deeper structures? Like the insula?

Michael Fox 40:47

Yeah, good question. So, TMS will always maximally stimulate the part of the brain right under the TMS coil. So it's always going to be much, much better, and modulating something on the surface of the brain. Now with fancy engineering, you can design TMS coils, to try and penetrate a little bit deeper. And in fact, that's exactly what they did with the TMS coil that's FDA approved for smoking cessation. However, even those coils that are designed to penetrate a little deeper, are still stimulating something on the surface of the brain, way out of proportion to anything that they're stimulating deep in the brain. However, while the TMS coil stimulates something on the surface of the brain, that spots part of a circuit, and that stimulation doesn't stay on the surface of the brain, anytime you modulate a brain region, the effects are going to propagate to affect the brain circuit that that region is connected to. So the best way to think about it is that yes, TMS stimulate something on the surface of the brain. But it can still get deep based on what that brain region is connected to.

Nick Jikomes 41:53

I see. So when you have something like the human connectome, and you know, where all the connections to and from each region are going, you can be careful about, you know, in the decision about where to study, stimulate with TMS at the surface. And you can stimulate regions that literally reach down into the brain and go to different other areas and know that you're actually going to be hitting all of those, all of those places, because of the way that circuit is, is formed. That's exactly the idea. Interesting. And so, now that you guys have done this study, you've defined this addiction remission network, and you've got all these candidate locations for places that where you would either inhibit activity or increase activity to potentially treat addiction. What's what's next? Are you guys looking into using TMS or other things to go in and test some of these ideas?

Michael Fox 42:40

Yeah, very much. So. So your next step is obviously try and get funding. So clinical trials are, are expensive. So you know, just analyzing the location of brain lesions, you know, we can type on a computer at minimal expense and do the type of study that we did. But once you're starting about a major, randomized controlled trial to target a brain circuit for addiction remission, that's a big deal. And these are not easy patient populations to study. They're not easy palpation populations to treat and follow through part of a clinical trial. But that's exactly what we're prepping for. And, you know, one approach is, like you mentioned TMS, where we have a target on the surface of the brain that we think if we excite that target, you know, that that would be an ideal spot for addiction remission. And in fact, there's actually a webinar that I was just emailing with Colleen Hanlon and a group of other investigators to get, you know, all the people in the field that are experts in addiction, on a call together to say, Okay, how do we actually move this forward? How do we plan this out? What's the right way to do this? And this requires expertise that goes beyond what what I do. I've never run a clinical trial for addiction. But what is the TMS angle? We're very excited about that. Another one is people are beginning to plan out clinical trials of deep brain stimulation for addiction, and does at our circuit and the connectivity profile of our circuit, inform where you might want to think about deep brain stimulation. And then there are newer technologies around the corner that might allow us to shut off a brain region. Think of it as a temporary lesion. Is there a way that we can shut it down pilot the effects of a lesion and see if that helps addiction? And if it does, maybe that's the next step towards a lesion based treatment for addiction. How does

Nick Jikomes 44:32

that treatment work?

Michael Fox 44:34

Yeah, so so right now the the state of the technology is something called Focus ultrasound. So so it's a way to reach a little bit deeper into the brain and where we can go with TMS. And you can do things like transiently open the blood brain barrier. So people exploring this, for example, to deliver chemo agents to a tumor where you can transiently open the blood brain barrier around the area of the tumor and and let the chemo agents go directly to the tumor rather than just saturating the entire brain. But but there are ways where you might be able to temporarily release an anesthetic agent like propofol and a particular region of the brain and turn off a brain region. And there's monkey trials going on right now, for example, I don't know if there are any human trials yet. But I know that there are human trials planned for this kind of focus, ultrasound based temporary lesioning of the brain.

Nick Jikomes 45:31

I see. So it sounds like this is really the state of the art. And people are trying very hard to develop technologies that will work in humans that allow you to functionally manipulate specific areas of the brain in a reversible manner.

Michael Fox 45:43

Exactly. That would be the ideal is if you can go in and turn on or off different brain areas, kind of, there are people that do this in rodent models with technologies like optogenetics, where they can, you know, go in and and, you know, flexibly turn on or off different brain circuits and have a very powerful way to control behavior, again, in mice, but this requires genetically engineering, the mice and all kinds of invasive injections, things that might not be possible in humans, but but to be able to do that to go in and, you know, pilot these different therapeutic targets before you have to go in and make something like a permanent lesion, where if you if you do that, and you're wrong, or if you're in the wrong spot, you could have behavioral effects that are a major problem. And so to be able to transiently pilot the effect of a lesion, that would be a major step forward. And there's a lot of people looking at developing technologies that will allow us to do something like that.

Nick Jikomes 46:42

So this study was interesting for the reason, you know, also for the reason that, you know, you're you said you were a neurologist, and you specialize in things like Parkinson's and depression, you also had addiction experts on the study, and you had people from different institutions, it was a pretty major collaboration, how did this whole thing even come together?

Michael Fox 47:02

But bit by bit, because I want to say All in All told, it's like Dr. Utes or sorry, you would say, Yo, yo, yo, it's about six years to pull all these different datasets and analyses together. But But you notice that we had three co first authors, right. So Dr. Yotsuba, is a neurologist, Dr. Siddiqui as a sighted psychiatrist, Dr. Musawi is a neurologist, but then also was doing a specialized training in addiction. And then, on the paper itself, we had addiction experts, brain connectivity experts, lesion experts, psychiatrists, neurologists, it really was a a multidisciplinary effort. And I don't think the paper could have happened without any of those collaborators or any of those pieces. It was just too many different things that had to be brought together, to go ahead and find out or test the hypotheses that we had.

Nick Jikomes 47:58

Interesting. I would love to ask you a little bit about treatment resistant depression stuff, just because I know that a lot of people have interest in that area. And it's, there's been a lot of progress made, I think, in recent years in different ways. So can you just start out with some of the basics there? What is treatment resistant depression? And what would you say the? Why don't we start with like, since you specialize in this, I've heard many different people articulate many different things about this area. People have strong opinions, how effective what are the standard treatments? And how effective are they today? Let's start there.

Michael Fox 48:32

Yeah, so So again, full disclosure, I'm a Parkinson's doc. Okay, Parkinson's, and treatment resistant depression, but yeah, so but I do evaluate all of our patients that come into the TMS clinic here from a neurological standpoint for depression. And so, you know, first line treatment for depression is always medication, or psychotherapy, and a lot of patients will get better with that medication or that psychotherapy. However, if that doesn't work, you then move to oftentimes medication number two, and then medication number three, and then medication number four, but but once you've tried a few medications and failed a few medications, that's when we start using the term treatment resistant depression, and your chance of getting better to medication number four, once you've already failed three medications that starts going way down, as it get in, you get into the single digits at that point. And that's motivated people to start exploring alternative neuromodulation treatments for depression. Again, these different tools that we've been discussing, that allows us to go and directly intervene on the brain circuit we think is responsible for depression. And so TMS is one of those tools. DBS is one of those tools, even lesioning can be one of those tools.

Nick Jikomes 49:45

So when they actually lesion the brain for therapeutic reasons, how do they actually accomplish

Michael Fox 49:49

that? Yeah, so they, it's a surge, well, two technologies, right? The the traditional way is it's a surgery. Kind of like the DBS electric And then I described earlier where you put a small electrode into the head, but you use that electrode to actually burn a hole. And then you pull the electrode back out again, and now you have a small lesion. And that was actually the treatment that we use for decades for tremor and for Parkinson's disease, before they realized that they could put the electrode in, turn the electrode on, and the tremor would stop without actually having to burn the hole. That's actually where DBS came from. And so lesions are older than dBs, it's the original form of neuromodulation. Before we had dBs, before we had TMS people go in and create these lesions. And then there's obviously a very long history of lesion based therapies for psychiatric disease history that that some people would prefer to forget or better learn the lessons of the past to make sure we don't make the same mistakes in the future. Because some of these lesion induced therapies for psychiatric disorders, including bad depression, were very debilitating. Things like frontal lobotomies. But there are also much more focal lesion based treatments for psychiatric disease that didn't have the same level of side effects and comorbidity

Nick Jikomes 51:10

I see, I see. And when we think about, you know, one thing that occurs to me that's kind of interesting is, if your specialty is in Parkinson's, I know from from school that Parkinson's involves the death of dopamine neurons in the brain. But you know, addiction is also famously connected to the neuromodulator. Dopamine, is there any overlap in the symptoms between someone with Parkinson's and someone with a severe addiction, because it involves these dopaminergic neurons. Um,

Michael Fox 51:44

sort of so. So the medications that we use to treat Parkinson's disease are dopaminergic medications. And so some of the medications that that you can give patients can lead to things that look like addictive behavior. So people can get something called dopamine dysregulation syndrome, which is sort of like a form of addiction where they want more and more dopamine, right, I see. They can also get things like with certain medications, again, a rare side effect, but patients have developed gambling trouble with these these dopamine meds. And so it's not that Parkinson's and addiction as syndromes look the same. It's almost that the opposite, but some of the medications that we use to treat Parkinson's can give you syndromes that can look a little bit like addiction.

Nick Jikomes 52:34

I see. And those medications are basically boosting activity and dopamine circuits. Exactly. I see, I see.

Michael Fox 52:40

There's a relationship.

Nick Jikomes 52:43

And, you know, with, you know, with the state of the art today for treatment of Parkinson's, is it? Is it currently more of a symptom management thing? or can people get most of their quality of life back when they do something like dBs, or take some of these medications.

Michael Fox 53:02

So both in the sense that it is a symptom management thing, and I think it's important that people know, and when you start hearing about these exciting brain circuit treatments, and neuromodulation, that we're still treating the symptoms of the disorder. So we're not stopping the disease process, that's going to keep on going at the same rate, all of our treatments are targeting the symptoms. Now there's a lot of research going into stopping the disease or finding a quote unquote, cure for the disease. But with neuromodulation, for the most part, what we're finding is a very effective treatment for the symptoms of the disease. Now, if we're very good at treating the symptoms, right, that can let people have a wonderful quality of life and, and live a great quality of life because the symptoms are well controlled, even though we haven't cured the disease.

Nick Jikomes 53:53

And what's our current understanding of the cause of Parkinson's disease? Do we know why some of these neurons actually start to die?

Michael Fox 54:01

Short answer is no. Now there's certain things that can increase the risk of Parkinson's disease, but lots of people have those same risk factors and don't get Parkinson's disease. There are genetic factors that can make it a little bit more likely, but most people don't have those genes. And so that the short answer is no, we don't know what causes Parkinson's disease, just like we don't know what causes depression, or what predisposes someone to addiction.

Nick Jikomes 54:24

I see. I see. Yeah, so it's still very mysterious. The brain is complex. So it's really hard. What, um, how long does it take for Parkinson's to normally start to manifest? Like, is it something that happens quickly, like, like, some of these cells are dying and you notice right away? Or is it more of a slow progression? It's only when someone's relatively well into the disease state that you actually notice the symptoms and start treating them?

Michael Fox 54:47

Yeah, so very much the ladder. So you know, we think that the the dopamine neurons, for example, start to disappear many, many decades before patients will actually get diagnosed with Parkinson's. sees Wow.

Nick Jikomes 55:02

And what? You know how so you're an MD PhD? So you're, you're a medical doctor, and you're a scientist doing research. How much of your time do you spend doing the research side versus seeing patients and things like that?

Michael Fox 55:15

Yeah, so 80% research 20% clinical.

Nick Jikomes 55:19

Okay. And what are, what are some of the, you know, things that you're you're working on today that haven't been published yet? What are some of the questions that you're aiming for?

Michael Fox 55:30

I'm gonna leave that to the first authors to, to disclose, okay, okay. I, I've got a lot of fellows working on very, very exciting projects, some of which are under review at high profile journals. And I don't want to let the cat out of the bag prematurely. But But I would say that the same platform that we use to study the lesions that get rid of addiction, can be used to study a variety of other neurological or psychiatric symptoms. And so, you know, we've published on probably 20, or 30 of those, including things that you would think you couldn't study using, you know, neuroscience techniques, things like religion or freewill. But then also neurological and psychiatric diseases. And I think there's one thing that we've learned, which is, the brain works in terms of circuits. And so lesions causing the same symptom pretty much never hit the same brain region, but they almost always hit the same brain circuit. To is that there's really no fundamental difference between a neurological problem and a psychiatric problem, we can use exactly the same approach of lesions that cause that symptom to study either disease, and we can map it onto a brain circuit. And then three is is more and more we're seeing that, that this approach is lining up with what we know about effective therapeutic targets. And we've just got to take the next step to say, Okay, can we improve that target based on this lesion based localization?

Nick Jikomes 57:00

Excellent. Well, I think that's not a bad place to leave it. So Dr. Michael Fox, thank you once again, for joining me and and sharing your knowledge with us. I saw that study not that long ago. And I wanted to talk with someone who's on the paper, you know, soon after it came out. So thank you for getting back to me so soon. And if people want to check it out, can you just mention which journal is published in and maybe what the title is?

Michael Fox 57:24

Let me Nature Medicine. And then let me actually Google it to make sure I get the exact title. Through all the revisions we went through a fair number of

all right. So his brain lesion disrupt brain lesions, disrupting addiction map to a common human brain circuit? Again, the first authors are Dr. Yotsuba, Musawi and Siddiqui and that was published in Nature Medicine.

Nick Jikomes 57:55

Yeah, so it was a really interesting paper. I'll put a link to it in the episode description if anyone listening wants to check it out and get a sense for what the data actually looks like. But Michael Fox, thank you again for your time, and I look forward to talking to you again in the future.

Michael Fox 58:07

Yeah, thank you so much for your interest and it was a pleasure.

Unknown Speaker 58:09


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