Dr. Veronica Alvarez and Dr. Bruno Averbeck — On the Pulse of Compulsive Behaviors

>> Diego (narration): I don’t love to admit this, but I’m a nail-biter. It’s a habit I’ve tried to break many times, but no matter what I do, I still find myself mindlessly picking and chewing my fingernails. The thing is, I know it’s not good for me, but for some reason that’s not enough to make me stop.

I recently learned nail-biting is considered a compulsive behavior, which makes sense because that’s how it feels, like this uncontrollable urge to do something that I know isn’t beneficial in the long-term. And while my compulsion is mostly cosmetic and manageable, there are others that aren’t. Ones with devastating consequences that trap people in vicious and self-destructive cycles.

>> Dr. Alvarez: You talk to the people that suffer from these disorders, and they want to stop. But they just can't stop.

>> Diego (narration): That’s Dr. Veronica Alvarez.

>> Dr. Alvarez: My name is Veronica Alvarez and I am an investigator in the intramural program of NIMH.

>> Diego (narration): For anyone not familiar, NIMH is NIH-speak for the National Institute of Mental Health. Together with Dr. Bruno Averbeck…

>> Dr. Averbeck: I’m Bruno Averbeck, similarly an investigator in NIMH.

>> Diego (narration): They run the NIH’s Center on Compulsive Behaviors, or the CCB to add another acronym to the mix. The CCB is not so much a place but a group of researchers, that work together to understand what drives these repetitive and often detrimental behaviors—behaviors that can range from hoarding, to overeating, and addiction.

>> Dr. Averbeck: It might not be obvious why those are all compulsive behaviors.

>> Diego (narration): Before talking with Dr. Averbeck and Dr. Alvarez, I used to think compulsive behaviors were largely associated with obsessive compulsive disorder, widely known as OCD and often portrayed in popular culture as excessive handwashing or an unrelenting urge to count or repeat certain words, phrases, or rituals. But compulsions can take many forms.

>> Dr. Averbeck: Not that long ago the field came up with a definition of compulsive behaviors, which is a repetitive behavior that you continue even though you're getting negative feedback or punishment. So, you're carrying out the behavior, it's causing distress in your life, maybe distress to people around you, but you continue to do the behavior.

>> Diego (narration): With this definition in mind, it’s clearer to see why substance abuse and addiction fall under compulsions and why saying that people who simply like to keep their space clean or are particular about the way they do certain things, can minimize the experience of someone who’s actually struggling with uncontrollable urges and involuntary behaviors that disrupt their lives.

>>Dr. Alvarez: It’s really the loss of total control over it, which is what you see in the case of the disorder that I study the most, that is substance use disorders. It’s just so damaging.

>> Diego (narration): According to Dr. Alvarez and Dr. Averbeck, it’s this loss of control that tips the scales and turns a person’s own ability to persevere—the very thing that helps them survive in the world—against them.

>> Dr. Alvarez: This behavior stands to be seen as bad. But truly if you think about it, you know, we couldn't do much and survive if we couldn’t things despite negative outcomes. It would be very hard, for example, to get through college, you know. We all display abilities to persevere and continue to do things despite, you know, sometimes punishment or negative feedback, because we know there's a better goal out there. And our ability to do that, is very important. Where it's wrong is where these behaviors are directed towards. So, we think that at the same time that we're trying to improve understanding of the disorders to improve treatment, we're also understanding better how it is that we can do these things that are essential for surviving and thriving in life.

>> Dr. Averbeck: Yeah, I mean, I think, I think people talk about a craving state, which I think is common to all these. And you can even think in OCD, you're craving, in other words, you're really highly motivated, for example, to wash your hands. And if you think about it, you might think, well, I've, you know, I actually have just washed my hands. But I feel like I really need to wash my hands again. So, it's a state that you enter into where you're really motivated to repeat some action. But it's not just a repetitive behavior.

If somebody wants to get access to a drug, they may carry out a very long sequence of very carefully planned behaviors to, for example, rob a pharmacy, or carry out some other acts, to get access to their drug. So, I think it's much more important to focus on the motivational aspects of these behaviors, and a little bit less on kind of the habitual aspects of them.

>> Diego (narration): So what drives this blind motivation that turns craving into compulsion? What makes someone more vulnerable to develop compulsions? And how is the CCB studying these behaviors to better understand and hopefully assuage them in the millions of people suffering from them every day?

For answers, stayed tune for the rest of my conversation with Dr. Alvarez and Dr. Averbeck.

[MUSIC TRANSITION]

>> Diego (narration): To start, I think it’s important to acknowledge the question of vulnerability. Why do some people develop compulsive behaviors while others don’t? I mean, not everyone who is exposed to a drug becomes an addict. Just like two people who have a very similar experience, one can develop PTSD and one doesn't.

>> Dr. Alvarez: By looking at the epidemiological data, it becomes obvious that there are individual variabilities that contribute to some vulnerability to develop these disorders.

>> Diego (narration): I asked Dr. Alvarez what the science say about those variabilities.

>> Diego (interview): Are there specific genes or maybe other risk factors that make someone more likely to develop compulsive behaviors?

>> Dr. Alvarez: Yeah, that’s a really, you know, very very important question. It’s what’s driving the research that we do. Currently what we know is that it's complex. We know genes play an important role, that there are often in some of these disorders a significant heritability component. But we also know it's not all the answer. And for sure it's very hard to pinpoint this to individual genes. What we currently at least hypothesize is that it might be more a collection of genes that interact with environmental factors to then generate changes in development of the brain during adolescence, which is actually one of the things that Bruno is studying a lot. There are very significant alterations to the frontal parts of the brain, many of which are very involved in compulsive behaviors. And so the idea is that environmental and genetic factors contribute of how the brain finally rewires. And we now hypothesize that the wiring itself of the brain is what will determine vulnerability.

>> Diego (interview): Ooh ok. So let’s talk about that wiring in the brain. Maybe you can lay out for me, what parts of the brain are involved or what neurological circuits are compromised?

>> Dr. Averbeck: So when most people think of the brain, they probably think of the cortex, which is sort of the outside surface of the brain we see when we see a picture of a human brain. And in fact, cortex in Latin means shell, so it's basically the bark or the shell on the cerebrum. And there are parts of the cortex that are dedicated to primary sensory functions. So, in the back of the cortex, there's an area that's important for vision. There's an area that's important for audition, hearing things. There's areas that are important for motor control. If you get a stroke in motor cortex, you can become hemiparetic—it’s hard to control the opposite side of your body. We know a lot about all those areas. Between those areas are what we would call these kind of cognitive or association areas, like prefrontal cortex.

>> Diego (narration): Quick note: The prefrontal cortex is pretty much what it sounds like. It describes the front part of the cortex, roughly from behind the forehead to the back of the eyes.

>> Dr. Averbeck: And prefrontal cortex is connected to what we call a subcortical structure. So, we call it subcortical just because it's below the cortex, it's inside. And it's connected to a really, we think—for compulsive behaviors—a very, very important structure called the striatum.

>> Diego (narration): Chiming in again: The striatum is deeper inside the brain, near the area between your ears and it’s spiral in shaped, kind of like a snail shell. In tracking compulsive behaviors through the neural highways of the brain, most roads lead to the striatum, because it’s thought be important for learning.

>> Dr. Averbeck: Particularly learning the values of actions. So, not the kind of learning where you learn how to do math, for example, where you do a problem and somebody explains, oh, that's not right, you should have done it this way. But the kind of learning where sometimes you go to a new restaurant you haven't been to before…

[FADE IN NOISE FROM A BUSY RESTAURANT]

>> Diego (in scene): This place?

>> Diego’s friend (in scene): Is it open? Uh ok.

>> Dr. Averbeck: …and you order a new dish…

>> Diego (in scene): Oh this looks really good. I think I’m going to have this.

>> Dr. Averbeck: …and you really enjoy it…

>> Waiter (in scene): Enjoy.

>>Diego’s friend (in scene): That looks so good.

>> Dr. Averbeck: …and then a week later, you're like I want to go over to that restaurant again because I really enjoyed that dish.

>> Diego (in scene): This was delicious. We should definitely come back.

[FADE OUT RESTAURANT BACKGROUND]

>> Dr. Averbeck: So, we call it value learning, because you're learning to associate values to people, places, things. So you do something, and then you get a reward or a punishment following what you did, and you learn from those rewards and punishments to make better choices in the future. And we think that the striatum is really important for that kind of value based learning. And what Veronica actually studies a lot is how mechanisms at what we call the synaptic level, so at the connections between neurons in the striatum, how those can actually affect vulnerability to various—

>> Dr. Alvarez: Substance use disorders.

>> Dr. Averbeck: Yeah.

>> Dr. Alvarez: Yeah, that's actually a good segue. A large part of the research in my lab has been following up on clinical observations that show that individuals that abuse substances, like alcohol, and also with overeating, that they have low levels of one type of dopamine receptors in the brain.

>> Diego (narration): You’ll remember that dopamine is often called the “feel good molecule.” It signals pleasure when it’s released in the brain; but just like any message to get through, it must be appropriately received.

>> Dr. Alvarez: So, there are five different dopamine receptors, and they're labeled D1 to D5. But the D2 receptors are highly expressed in this region of the striatum that Bruno just mentioned. And the individuals that abuse stimulants, or alcohol, or obese individuals, tend to have low levels of these receptors. So, it wasn't clear why this was happening. And that's something that we have been following in the lab for the past 15 years using mice. Where we can actually control, you know, do genetic manipulations to lower the levels of D2 in animals that have never seen any substance. And then see how that alters the response to the substances, for example, either cocaine or alcohol, and then look whether, you know, this is creating vulnerability or not, which has been in itself also quite complicated to answer. But we can tell from our now over a decade of research that, in fact, pre-existing low levels of these receptors, specifically in some subsets of cells, leads to dramatic changes in how the brain is wired, changes that go beyond the cells that express the receptors.

>> Diego (interview): Ok, so then I’m assuming a dampened dopamine response affects the mechanics of the striatum, which then affects a person’s value learning ability and increases their susceptibility to develop compulsive behaviors? Am I getting that right? Is that how it all ties in?

>> Dr. Averbeck: Yeah, that's a very good question. We have very good hypotheses for how all of that is organized. So, the standard hypothesis for value learning, which I was referring to, is that when you make a choice, when you take some sort of action, after getting a reward or a punishment, you get a dopamine response to the reward or the punishment. And the response is called a reward prediction error, and it's literally just an error in your prediction of reward. So, the striatum contains an estimate of the value of choices.

So, this is where you would store the information about the fact that the pizza you had a couple weeks ago at the new restaurant was very good. Whereas a month ago, the soup that you had at a different restaurant wasn't that good. So, when you think about the pizza or the soup, you get a different response in your striatum. And depending on that response, it's either a high value response or a low value response. So, the way dopamine works is when you go back to the restaurant and have that pizza again, if it's better than expected, you get an increase in dopamine. It's called a positive reward prediction error. If it's worse than expected, you get a little dip in dopamine that's called a negative reward prediction error. If the pizza is exactly as you expected, you don't get any dopamine response, because, you know, it's good, but you expected it to be good. That dopamine response is thought to drive plasticity. In other words, a change in synaptic connections between two neurons. It's thought to drive plasticity between prefrontal cortex neurons and their inputs to the striatum, such that if you get a positive reward prediction error, you strengthen that connection. And so that next time when you go think about the pizza, you have a stronger connection, you drive stronger activity in the striatum when you have a stronger expectation of value. So, that’s kind of the overall theory for how this system works.

>> Diego (interview): Yeah, that seems very clearcut.

>> Dr. Averbeck: Yeah. And the standard hypothesis for what drugs of addiction do is that they hijack that system. So, that system is very important for day-to-day life. That's how you remember all the things that are valuable to you. It's there for is to drive cravings that you need to satisfy your basic physiological needs. So, you learn ways to make sure you have access to water and food and all the kinds of things, you know, to stay warm. But what drugs of abuse can do—substances of abuse, I guess—is fool that system into thinking that whatever you just did is very important to your survival.

They can actually create dopamine release in the absence of something that's really, let's call it intrinsically satisfying to you. So, you take a drug, and your brain has a response as if you just had the best pizza you've ever had in your life. And it was completely unexpected to you.

And because a lot of these processes have kind of these cyclical properties, where you have satiation, and then over time it comes back to craving, and then satiation, now you've created a system in your brain that says I haven't had that drug for a while, I probably really need that to survive, and that's what drives the compulsion.

>> Diego (interview): Well now I'm wondering if these components work the same in compulsions manifest themselves as avoidant behaviors, things like agoraphobia. Because so far you’ve talked about scenarios where a user is seeking something to boost their dopamine, but can the aversion of something do the same thing? 

>> Dr. Averbeck: Yeah, I mean we think that the same neural systems are involved. When people start thinking about fear and anxiety, that brings in the amygdala. The amygdala has really strong connections to the ventral striatum, so it's basically engaged in that same circuitry. So you can have anxiety for two reasons. One can be something you were born with. And in that case maybe you have social anxiety disorder or agoraphobia. And there you just have an implicit fear that you were born with that going out into public is potentially going to lead to negative consequences. And that just means that in this same system, so I mentioned the value representation in the striatum, that just means you're born with a pattern of synaptic connectivity, maybe between the amygdala and the striatum, that codes for a very negative outcome if you go out and engage in these behaviors.

You may also have something that came from PTSD, which not unlike experiencing a drug, you had one very, very strong emotional experience that led to strong plasticity in this circuitry that really hammered in this idea that whatever that event is that happened, you should avoid that in the future at all costs.

>> Diego (interview): So in that sense the feeling of relief from not doing something is the reward. And that reward reinforces the behaviors aimed towards not reliving the trauma.

>> Dr. Alvarez: Yeah, trauma, which is very highly linked to vulnerability. So, to bring back this to the low levels of D2 and how it can create vulnerability. And there are multiple levels at which I could try to relate what we have learned. One is, as Bruno was explaining, we believe that a lot of encoding of this learning with dopamine has, in fact, to do with this delta, you know, how much it changes from your expectation. And I think we all can relate to like when you have low expectations for something, and then it works out great, how exciting that is. And then how it's easier to get disappointed when you have high expectations. And what we are thinking is happening when you have low levels of these D2 receptors is that you're in some ways starting from a lower delta.

>> Diego (interview): Delta meaning the difference in reward prediction.

>> Dr. Alvarez: Yeah. So, one hypothesis is that the effect of these drugs, and raising dopamine, is even more robust in individuals that start from this lower levels. We see this in mice, that don't have low D2s, but they have low D2 receptor activation. They are slow at movement, and have trouble getting going, increased latency. And so the output of the striatum is highly restricted. And that might make these individuals more vulnerability to—more dependent on this dopamine boost that substance of abuse, for example, can create.

>> Diego (interview): Yeah. And just to bring it back, it’s not yet clear why someone’s D2 level starts out low or decrease over time. Like we discussed in the beginning, there could be environmental components, genetic factors—

>> Dr. Alvarez: Yeah. So, there could be genetic factors that contribute to that. But we have also very good evidence that the levels of D2 receptors change during development, actually as you age, they go clearly down. But we hypothesize also that that is under a lot of regulations. So, there could be epigenetic, but also translational regulations of the D2 receptors that play a role. So, it could be that, you know, conditions, such as stressful conditions, or other hormonal states, could also be modulating the levels of D2 receptors. So, both of those things can be happening.

>> Diego (interview): Wow, so many levels of complexity and nuance. But even if you can't exactly pinpoint the causes of vulnerability, or these glitches that lead to compulsive behaviors, the work you’re doing is very important in the way it helps destigmatize mental health by reassuring people that it’s not all about self-control. There are elements at play that are not a matter of willpower or mental fortitude. And in that sense, I would hope that it removes the guilt a person might feel, or you know, feel at fault for not being able to control their own behavior. Being able to point to the biology of the brain I think, or would hope, offers some solace. Just like being born with diabetes or an autoimmune condition, is just the way you’re built, not a character flaw or moral failing.

>> Dr. Alvarez: Absolutely. The issue is that they are actually very profound changes induced in the brain by the exposure to the substances. And once you are in the cycle, you're kind of trapped. So, it's very important to seek help. Currently combinations of psychotherapy and treatment with medication, I mean, it's showing to work effectively in some individuals. So, there’s a are a lot of reasons for hope, but I think it's very important to remove or lower the stigma to get people to come forward and ask for help.

>> Diego (interview): Definitely. And optimizing those treatments for patients was a huge motivation for creating the Center on Compulsive Behaviors. So let’s get into the CCB. What’s the story there? How did it get started and what are it’s main directions?

>> Dr. Averbeck: Yeah, I think it's been really interesting. I think we can talk about the structure of the CCB, as well as the content of the CCB. The structure has been a really interesting vehicle to build increased interaction across institutes. So, there really are no what I would call true barriers to interaction—it’s very easy to collaborate with other labs. On the other hand, for various reasons, we just don't always interact with people in other institutes. Maybe they're in a different building. In some cases, they're in a different campus. We have campuses in Baltimore, in Rockville. So, you don't necessarily run into people, you know, at the coffee machine, which is what you would like and it's a bit of a loss because we have really nice complementary expertise, particularly in neuroscience, we're really strongly represented in neuroscience, spread across many other institutes. And that's one of the things the CCB tries to do is we're in different buildings, but let's get together several times a year and talk. So, by bringing people together, we feel like we can tap into those sort of complementary areas of expertise, and, you know, improve our science.

>> Dr. Alvarez: Absolutely, we all were very hungry for collaboration, knowing more what the other person, the other labs were doing, how we could work together. We all agreed that the way to get that done was to actually have post-docs do the bridging. That truly we could sit and talk how it would be nice to do that experiment together. But that that wouldn't happen unless we had a fellow interested. And so the idea came out to fund fellowships. And truly I think we started with like four fellowships on the first year, and now we have 30 fellows each year.

>> Diego (narration): Two of those fellows were Peter Manza and Renata Marchette. They hail from different institutes, Peter from NIAAA, that’s the National Institute on Alcohol Abuse and Alcoholism and Renata from NIDA, the National Institute on Drug Abuse. They were brought together by their shared interest in the neurobiology of addiction and right now, they’re collaborating on a study that looks at how the method of drug delivery—how a drug gets in a person’s system—can actually alter the potential for addiction.

Here's Peter with more.

>> Peter: We were interested in this observation that we’ve seen for a long a time; that the faster a drug enters your brain, the more addictive it is. For instance, if you take Ritalin, a very common drug that people use to treat ADHD, if you take it in pill form, it becomes slowly absorbed in the digestive tract and gets into the brain in a very slow and controlled way. And that is therapeutic for people with ADHD, it addresses some of the symptoms and there is a very low risk for misuse and addiction. But if you take that same drug and that same dose and you give it to someone in the form of an intravenous injection, that now becomes extremely rewarding and has high potential for misuse and addiction.

And so we were able to measure in the human brain, in real-time, changes in the way that different parts of the brain are communicating and talking with one another, and were really inspired when we saw that this one circuit in the brain—these two regions—tend to talk to one another much more readily after the intravenous dose but not in the oral dose. And so we think that this connection is assigning the fast drug delivery a particular salience. The brain is saying, “Wow this is really rewarding. This is really an intense experience.” And we think that this circuit might be partly responsible for the addictive potential of the fast drug delivery.

>> Diego (narration): While Peter studies brain circuits in the clinic, Renata is working on the preclinical side, developing animal models in which they can induce changes in those circuits and observe how it affects behavior.

>> Renata: I do all things with rodents so mice and rats. Of course, we cannot see the exact same things that we see in a person, but there is some translatability and we know that certain traits are conserved across species. Specifically for this study, we know how to measure in animals if they like the drug, if it has rewarding properties. So using this model we are going to manipulate this circuit that Peter found in his clinical research and see if we can modulate this preference for the drug on IV versus oral.

>> Diego (narration): Both Renata and Peter attribute the opportunity to collaborate to the environment fostered by the CBB. If it weren’t for the CBB they might have never met.

>> Renata: The CCB is a big part of this effort coming to happen, because by nature, since Pete works with clinical and I work in preclinical these things don’t cross paths normally. Like in the research environments we’re usually kept very separated physically. But from CCB is where I had the opportunity to meet clinical people, like Pete. Then from there we could develop this actual project that we’re collaborating on. So I think it helps bridge people together.

>> Peter: Renata summed that up perfectly. The opportunity to meet people from different regions doing different types of work, it really did bring us together. I think a lot of times researchers talk very hopefully, or optimistically, about these sorts of cross-institute, cross-discipline collaborations, but they rarely happen in practice. And the CCB gave us the time and the space to really make that possible. 

>> Diego (narration): And just as Dr. Alvarez and Dr. Averbeck hoped, the spirit of collaboration only radiates upwards.

>> Dr. Alvarez: The PIs, as a consequence of the fellows and the projects that they propose that are collaborative, have been interacting with other investigators that otherwise might have not thought of talking. So truly they are the glue to the program.

>> Diego (narration): Along with annual fellowships, the CCB also boasts a seed grant program which gives post-docs the opportunity to take on an official PI role in an NIH grant, and non-human primate physiology consortium that encourages different labs to work together in developing next-generation therapeutics. If you’re interested in learning more about these or the CCB in general, you can check out their website at the link in this episode’s description.

With collaboration at the core of the many resources and opportunities it offers, the CCB continues to grow. And as it pulls more scientists into its orbit, the center is gaining momentum in it’s mission to trace the shared circuitry of compulsive behaviors and develop treatments that will help patients regain control of their lives.

>> Dr. Averbeck: Compulsive behaviors is, it's just a really important problem for many reasons, right? We have the opioid epidemic, which is a big problem. But it does encompass behaviors that span a lot of institutes. You know, you mentioned at the beginning, obsessive compulsive disorder, which is normally considered a mental health disorder, but we think it's tapping into very similar neural mechanisms in the striatum. So, we can bring together people from different institutes and try to approach these problems and combine our knowledge and understanding. And we have a great group of people that we bring together; it’s very dynamic.