Biology & Treatments for Compulsive Eating & Behaviors | Dr. Casey Halpern

1. 0:00 – 3:18

   Dr. Casey Halpern & Disordered Eating & Brain Stimulation

   1. AHAndrew Huberman0:00

      (uptempo music) Welcome to the Huberman Lab Podcast, where we discuss science and science-based tools for everyday life. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. Today my guest is Dr. Casey Halpern. Dr. Halpern is the Chief of Neurosurgery at the University of Pennsylvania School of Medicine. His laboratory focuses on bulimia, binge eating disorder, and other forms of obsessive-compulsive behaviors. Normally, when we hear about eating disorders or obsessive-compulsive disorders of other kinds, the conversation quickly migrates to pharmacologic interventions, and serotonin, or dopamine, or talk therapy interventions, many of which can be effective. The Halpern Laboratory, however, takes an entirely different approach. While they embrace pharmacologic and behavioral and talk therapy interventions, their main focus is the development and application of engineered devices to go directly into the brain and stimulate the neurons, the nerve cells, that generate compulsions, that cause people to want to eat more even when their stomach is full. In other words, they do brain surgery of various kinds, sometimes removing small bits of brain, sometimes stimulating small bits of brain with electrical current, and even stimulating the brain through the intact skull, that is, without having to drill down beneath the skull, in order to alleviate and indeed sometimes cure these conditions. Today's discussion with Dr. Halpern was an absolutely fascinating one for me because it represents the leading edge of what's happening in modification of brain circuits and the treatment of neurologic and psychiatric disease. For instance, they just recently published a paper in Nature Medicine, one of the premier journals out there, entitled Pilot study of responsive nucleus accumbens deep brain stimulation for loss-of-control eating. The nucleus accumbens is an area of our brains that we all have, in fact, we have two of them, one on each side of the brain, that is intimately involved in the release of dopamine for particular motivated behaviors. And while most often we think about dopamine for the release of behaviors that we want to engage in, in this context, they are using stimulation and control of neuronal activity in nucleus accumbens to control loss-of-control eating, something that when people suffer from it, despite knowing they shouldn't eat, despite not even wanting to eat, they find themselves eating. So again, this represents really the leading edge of where neuroscience is going and certainly is going to be an area of neuroscience that's going to expand in the years to come. And Dr. Halpern and the members of his laboratory are among a very small group of scientists in the world that are using the types of approaches that I described a minute ago and that you're going to hear more about in today's episode in order to resolve some of the most difficult and debilitating human conditions. During today's discussion, you will also learn about the use of deep brain stimulation and other approaches for the treatment of movement disorders such as essential tremor, Parkinson's disease, and various types of dystonias, which are challenges in generating particular types of movement. So whether or not you or somebody that you know suffers from an eating disorder, from obsessive-compulsive disorder, or from a movement disorder, today's episode is sure to teach you not only about what's happening in those arenas but also in the arenas of neuroscience generally. In fact, I would say today's episode is especially important for anyone that wants to understand how the brain works and what the future of brain modification really looks like

2. 3:18 – 7:19

   ROKA, Eight Sleep, InsideTracker

   1. AHAndrew Huberman3:18

      for all of us. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero cost to consumer information about science and science-related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast. Our first sponsor is ROKA. ROKA makes eyeglasses and sunglasses that are of the absolute highest quality. The company was founded by two All-American swimmers from Stanford, and everything about ROKA eyeglasses and sunglasses were created with performance in mind. Now I've spent a lifetime working on the biology of the visual system, and I can tell you that your visual system has to contend with a number of very important challenges in order for you to be able to see clearly, for instance, when you go from a sunny area to a more shaded area and then back out again. It's a very complex process. ROKA eyeglasses and sunglasses were built, that is engineered, with that sort of biology in mind. And as a consequence, no matter where you are wearing them and where you happen to be, you always see through them with crystal clarity. The aesthetic of ROKA eyeglasses and sunglasses is also worth mentioning. Unlike a lot of performance eyeglasses out there which only come in the kind of cyborg variety, ROKA eyeglasses and sunglasses come in those varieties but they also come in varieties that you would feel very comfortable wearing out to dinner or to work or to school, really anywhere that you go. If you'd like to try ROKA eyeglasses you can go to ROKA, that's ROKA.com, and enter the code Huberman to save 20% off on your first order. Again, that's ROKA, ROKA.com, and enter the code Huberman at checkout. Today's episode is also brought to us by Eight Sleep. Eight Sleep makes mattress covers with cooling, heating, and sleep tracking ability. I've talked many times before on this podcast about the close relationship between temperature and your ability to stay asleep and emerge from sleep. The way Eight Sleep mattress covers work is that they allow you to program the temperature of your mattress so that you can fall asleep quickly, get into deep sleep, stay in deep sleep, and emerge from that sleep feeling especially rested by dropping the temperature of that surface by one to three degrees at the beginning of the night-... dropping a little bit further into the night, and then raising the temperature towards morning, because waking up requires that one to three degree re-increase in body temperature. I've been sleeping on an Eight Sleep mattress cover for the last six months or so now and I can assert that it is the absolute biggest game changer in the quality and duration of my sleep. In fact, I don't really like traveling as much as I used to, because the Eight Sleep doesn't go with me and they don't seem to have them yet in Airbnbs and hotels. So, this is also a call to action. Airbnbs and hotels, please put Eight Sleep mattresses on your beds, and I'll be more apt to stay in those hotels and Airbnbs. With that said, if you'd like to try an Eight Sleep mattress cover, you can go to eightsleep.com/huberman. Check out the Pod 3 cover to save $150 at checkout. Again, that's eightsleep.com/huberman, and please note that Eight Sleep currently ships in the USA, Canada, UK, select countries in the EU, and Australia. Again, eightsleep.com/huberman to save $150 at checkout. Today's episode is also brought to us by InsideTracker. InsideTracker is a personalized nutrition platform that analyzes data from your blood and DNA to help you better understand your body and help you reach your health goals. Now, I've long been a believer in getting regular blood work done, for the simple reason that many of the factors that impact your immediate and long-term health can only be assessed with a quality blood test. One of the major issues with the various blood tests out there is that you get information back about lipids and hormones and metabolic factors, et cetera, but you don't know what to do with that information. With InsideTracker, they make knowing what to do with the information you get about your biological health extremely easy. They have this very easy to use dashboard, and that dashboard tells you, for instance, what to change in your nutrition, what supplements you may want or may not want to take, as well as other behavioral and other types of interventions that can allow you to move those numbers related to metabolic, hormone, and other factors into the precise range that's optimal for your immediate and long term health. If you'd like to try InsideTracker, you can go to insidetracker.com/huberman to get 20% off any of InsideTracker's plans. Again, that's insidetracker.com/huberman to get 20%

3. 7:19 – 8:28

   Momentous Supplements

   1. AHAndrew Huberman7:19

      off. On many episodes of the Huberman Lab Podcast, we talk about supplements. While supplements aren't necessary for everybody, many people derive tremendous benefit from them. Things like enhancing sleep and the depth of sleep, or for enhancing focus and cognitive ability, or for enhancing e- energy or adjusting hormone levels to optimal range for you. The Huberman Lab Podcast is now partnered with Momentous Supplements. We partnered with Momentous for a number of important reasons. First of all, the quality of their ingredients is exceptional. It's really second to none. Second of all, they ship internationally, and that was important to us because a number of you reside outside of the United States. Third, we've worked with Momentous very closely to develop single ingredient formulations. Now, this turns out to be very important, because if you're going to take supplements, you want to know what's working for you and what isn't. And of course, you want to optimize the cost efficiency and the biological efficiency of those supplements. To find the supplements we discuss on the Huberman Lab Podcast, you can go to Live Momentous, spelled O-U-S, livemomentous.com/huberman, and I should just mention that the library of those supplements is constantly expanding. Again, that's livemomentous.com/huberman. And now, for my discussion with Dr.

4. 8:28 – 13:05

   Neurosurgeon’s View of the Brain, Neurosurgery Specialization

   1. AHAndrew Huberman8:28

      Casey Halpern. Casey, I should say Dr. Halpern for those listening, welcome.

   2. CHCasey Halpern8:34

      Thank you. Great to be here.

   3. AHAndrew Huberman8:35

      Yeah, it's been a long time coming. We were colleagues at Stanford, and then recently, you moved, of course, to University of Pennsylvania, also an incredible institution. We're, we're sorry to lose you, so, uh-

   4. CHCasey Halpern8:46

      It's bittersweet for me too.

   5. AHAndrew Huberman8:47

      Stanford's loss is UPenn's gain, but, um, let's talk about your work, uh, past and present. As I've told the listeners already, you're a neurosurgeon, which I consider the astronauts of neuroscience, because you're in somewhat uncharted territory, or very uncharted territory, and yet precision is everything, right? The, the margins of error are, are very, very small. So, for those that aren't familiar with the differences between neurosurgery, neurology, psychiatry, if you could just educate us a bit. What does a neurosurgeon do, and what does the fact that you're a neurosurgeon do for your view of the brain? How do you think about and conceptualize the brain?

   6. CHCasey Halpern9:31

      Y- yeah, the scope of neurosurgery is quite broad. Uh, when I was in medical school, I, I was drawn to neurosurgery because of a procedure known as deep brain stimulation. Uh, when I was at Penn as a college student, I actually watched my first deep brain stimulation surgery performed by Gordon Baltuch, who t- to date is one of my career mentors. D- deep brain stimulation is, uh, one surgery that neurosurgeons offer, but it's actually sort of a, a very small minority of what neurosurgery does. Uh, uh, you know, we take out brain tumors. We clip aneurysms in the brain. Uh, we take care of patients that have had traumatic brain injury, um, concussion, um, spine surgeries, 90% of what neurosurgeons do around the country, uh, you know, taking care of herniated disks and lumbar fusions. So, you know, the, the scope is the entire central nervous system, includ- including the peripheral nervous system. We take care of patients with carpal tunnel syndrome and nerve disorders. Now, over the course of the past two decades or so, there's been a, a mission in the field to, to subspecialize, and so historically, neurosurgeons did everything in that domain. But now, we subspecialize, and I'm lucky to be at Penn Medicine, where we can focus on one of these areas, uh, so I'm, uh, Chief of Stereotactic and Functional Neurosurgery. All I do is deep brain stimulation surgery, and a complement to that is focused ultrasound or transcranial focused ultrasound, which is a non-invasive way to do an ablation in the brain, recently FDA approved, and it's FDA approved for tremor at the moment. Uh, these two procedures are, for me, my everyday, but, uh, still the minority of what neurosurgeons have to offer.The majority of neurosurgery, in my mind, is, is a bit more structural than it is physiology, or deeply rooted in, in how the brain functions. Uh, when we take out a brain tumor, we have to find a, a safe trajectory to get to the brain tumor, and then we remove it, and we help the patient recover in the ICU. Similar to a brain aneurysm. Often, we don't have to go into the brain to clip a brain aneurysm, but we go around the brain or under the brain to get there, and in my mind, those surgeries are a bit more structural. Deep brain stimulation, uh, the surgery that I do routinely, is, uh, a procedure where, yes, th- there is structure involved, of course. We have to place a, a, a very thin wire that's insulated deep into, uh, a part of the brain that's involved in Parkinson's disease, for example. Uh, but that's actually not the therapy. The therapy is delivering electrical stimulation through the tip of that wire, or one of the tips, as there actually are multiple contacts at the bottom of the wire. They're very small. Uh, but that's all done out of the operating room. You know, this stimulation wire is connected to a, a battery pack, or a pulse generator that's kind of like a pacemaker, and so we deliver this therapy... And I always tell patients, it's a bit more like I have to implant a, uh, a tool to, to deliver you a medication. Uh, but that medication is going to be in the form of electricity, and it's going to be delivered into a very small region of the brain. And it's that procedure that's, uh, inspired me to not just become a neurosurgeon, but, uh, has really defined the, uh, focus of my research laboratory as well.

5. 13:05 – 17:20

   Deep Brain Stimulation & Other Unexpected Positive Effects

   1. AHAndrew Huberman13:06

      Maybe by way of anecdote, you could tell us, uh, one of the more outrageous or surprising, or who knows, um, delightful and thrilling things about the brain that you've observed as a consequence of stimulating different brain areas. You know, in textbooks we always hear about, uh, kind of dark stuff, you know? Stimulate one brain area, somebody goes into a rage. Stimulate another brain area, a person starts laughing uncontrollably. First of all, um, given that some of the information, and let's hope not much, but some of the information in textbooks is incorrect, is, uh, are those sorts of statements true? Can one observe those in the clinic? And what are some of the more interesting, uh, and I don't necessarily mean entertaining, but, um, surprising things that you've seen when you've, uh, poked around in the brain, uh, deliberately of course, and, uh, what have you seen? What have you heard?

   2. CHCasey Halpern13:59

      I have to say, I, I, I am amazed by these effects, uh, every day. I'm very privileged to be able to interact with the human brain in this way. It's always in the, uh, uh, with the goal of trying to provide somebody with a meaningful therapy, but when we deliver electrical stimulation, you know, the, these electrodes, while they might be sitting in a very small region of the brain, there are regions within a few millimeters of where these electrodes are that, if stimulated could cause a temporary, very brief side effect. A, a moment of laughter, like you said, or a moment of panic. And of course we can just shut that electrode off, but often, these side effects could be therapeutic. And actually, that's how we have discovered ways to use deep brain stimulation, um, not just for movement disorders like Parkinson's disease, but for example, patients with Parkinson's disease that have, uh, a psychiatric, uh, uh, comorbidity like depression or obsessive compulsive disorder. A lot of these patients are highly compulsive, uh, uh, and impulsive, um... Sometimes these problems actually melt away, and we're trying to help their tremor, but the patients also tell us that their gambling issue has gotten better, or their mood has improved. And why is that? Well, you know, there's probably more than one reason, you know? You can help somebody's mood by making their tremor go away, of course, but we see laughter in the clinic sometimes, and, and why is that? And that's because we're stimulating parts of the brain that are not just involved in these motor circuits, but they're also involved in what we call a limbic circuit, or, or part of the brain involved in emotion. And if we learn how to modulate those areas therapeutically step by step, we can actually develop these therapies for other indications like depression. I would say the most impressive and consistent effect we have when we have a patient with tremor who has been trembling for the past 20 years, if we can deliver stimulation through that electrode in the clinic, we have immediate relief of tremor. And that is the effect that inspired me to be a neurosurgeon when I was in college. I've never really wanted to do anything else except help develop that type of therapeutic for an other, another kind of symptom. Uh, I'm very interested in obesity and related eating disorders, compulsive behavior, the urge to, uh, to, to have something that might be delicious but dangerous or unhealthy or, uh, a drug, uh, or a compulsion like we see in OCD or obsessive compulsive disorder. Uh, interestingly, like we see tremor melt away when we deliver electricity to a certain part of the brain, we can see these psychiatric, more psychiatric problems. They're not all psychiatric disorders, but let's say, uh, uh, disorders of the brain, we can see symptoms of those disorders also improve, and often immediately just like we do with tremor. So, uh, I see it all the time. To, to, to pick out one, uh, would be, would be a challenge because, uh, for me, this is my, my every day.

   3. AHAndrew Huberman16:56

      The speed of the relief that you describe for tremor is really, um, incredible. Uh, just thinking about drug therapies and there too there are side effects, but there are, uh, still a lot of mysteries as to, for instance, why SSRIs even work when they work.

   4. CHCasey Halpern17:13

      Yes.

   5. AHAndrew Huberman17:13

      And, uh-

   6. CHCasey Halpern17:14

      The timing is always a challenge.

   7. AHAndrew Huberman17:16

      Ti- timing, dosage. Yes, absolutely. Um, I'd

6. 17:20 – 25:40

   Obsessive Compulsive Disorder (OCD), Prescriptions & Cognitive Therapies

   1. AHAndrew Huberman17:20

      love to learn more from you about OCD. I, I have several reasons for asking this.... uh, first of all, I'm a somewhat obsessive person.

   2. CHCasey Halpern17:28

      (laughs)

   3. AHAndrew Huberman17:28

      Uh, I tend to be very- very narrowly focused, although I confess, it's not a step function. It takes me some time to turn off the chatter, but once I'm into a thought train or a mode of being, (laughs) uh, and thinking and work, it's very hard for me to exit that- that mode. It's like a deep trench. Adaptive in some circumstances, less adaptive in others, as you know. The other is that when I was a kid, uh, I had a little bit of a grunting tic.

   4. CHCasey Halpern17:52

      Oh.

   5. AHAndrew Huberman17:52

      I used to, I had a (clears throat) this intense, intense desire to clear my throat, um, to the point where my- my dad said, like, "You need to stop that." And he used to squeeze my hand every time I do it, and I used to hide in the back seat of the car or in the closet to do it because it provided so much relief. Re- and then, it eventually passed.

   6. CHCasey Halpern18:10

      Yes.

   7. AHAndrew Huberman18:10

      I wasn't medicated, they never did anything about it. Every once in a while now if I'm, um, very fatigued, if I've been working a lot, I notice it starts to come back. (clears throat) I'll do this like kind of grunting.

   8. CHCasey Halpern18:21

      (laughs)

   9. AHAndrew Huberman18:21

      And so it's been sort of like a- a pet neurological symptom for me that reminds me that these- these circuits exist in all of us, and that sometimes they go haywire and sometimes they just have subtle, um, you know, over-excitation or something of that sort. And then, the third reason is that I get thousands of questions about OCD. Could you perhaps just tell us what is OCD?

   10. CHCasey Halpern18:45

       Sure.

   11. AHAndrew Huberman18:45

       Um, what are some brain areas involved? What are the current range of treatments? And what's the difference between someone who is obsessive and somebody who has true OCD?

   12. CHCasey Halpern18:57

       So a- a brief disclosure, as a- as a neurosurgeon, I do take care of patients with severe obsessive-compulsive disorder. Um, but my perspective on OCD may be a little bit different than a psychiatrist who- who lives and breathes OCD and sees patients every single day with OCD. Uh, I probably take care of three to five patients a year with deep brain stimulation for obsessive-compulsive disorder, so I don't see these patients as routinely, but my laboratory is geared... As a researcher, uh, I'm very focused on trying to improve outcomes of deep brain stimulation for- for OCD, so I- I do feel I have, um, expertise and- and a perspective to share, but just a- a brief disclosure. Uh, I- I do feel that, as a neurosurgeon, I am obligated to better understand where the obsessions in the brain come from and how we can interrupt them to stop the compulsion that's associated with the obsession, sort of the intrinsic most feature of OCD, uh, better than we're actually doing it. Uh, for example, if we were to offer a patient with tremor deep brain stimulation surgery, of course there's some risk to the procedure, but the outcome is so consistent and positive that many patients are willing to take on that risk. Uh, for obsessive-compuls- compulsive disorder, the surgery risk is about the same. However, the benefit is not quite as robust, and so a lot of patients and their referring psychiatrists are reluctant to refer these patients to us, and it's completely understandable. Uh, I've been, uh, leading an endeavor with a number of collaborators around the country to try to better understand these circuits in the brain, uh, study them in humans, both invasively and non-invasively, that would be with an electrode-based surgery, um, sort of like we do in epilepsy to understand where seizures come from. We want to understand better where obsessions come from. But we're also working with imaging experts and geneticists to understand OCD, uh, at a broader level as well. Uh, I- I'll- I consider OCD to be a- a spectrum disorder in a way, uh, and I- I- I apologize to those who- who might feel that I'm using that term incorrectly. I- I'm using it in a way to describe patients that have obsessions and even some related compulsions might not meet criteria for OCD. Um, it may be something, Andrew, that- that you have, and as a neurosurgeon, I'm really (laughs) obsessive about safety and compulsive about my surgical procedures. So, you know, I- I think that some aspect of OCD, which we often joke about, but we should, you know, consider seriously 'cause people do suffer from this, uh, some aspect of it helps us. Uh, there are, you know, famous, uh, CEOs that probably have some level of OCD, uh, surgeons and scientists alike. So, uh, perhaps if it can be controlled, it's an asset, and, uh, but if it goes awry and is uncontrollable, then it becomes obsessive-compulsive disorder. And, uh, I tend to see the patients that are the most severe, so they have failed medication, and there are multiple medications that are worth trying for OCD. Some can actually be very helpful. Uh-

   13. AHAndrew Huberman22:18

       Which- which neurotransmitter systems do they tend to poke at?

   14. CHCasey Halpern22:21

       Well, SSRIs are sort of the- the first, uh, line for OCD, but also tricyclics can be helpful, so this is still the serotonin system. Um, but as we know, the serotonin system interacts with the, you know, noradrenergic, uh, system and the dopamine system, so it's hard to, um, uh, be specific to one of these things. Uh, and I think that's also why it's hard for us to predict how these medications are going to- to work for these kinds of patients. But tricyclics and SSRIs can be very helpful and are definitely first line. Uh, and there's others. Um, exposure response prevention is, uh, probably the most effective option, which is kind of like cognitive behavioral therapy, but these are different and offered by psychologists, and this is a whole field. And there's a, uh, a field, uh, or I should say a whole clinic at my institution, um, uh, focused- it was started by Edna Foa, um, uh, uh, at Penn, who this is what they do for these patients, uh, is- is offer these types of cognitive therapies, exposure to the stressor, and to try to get patients to habituate to whatever it is that stresses them and causes these, uh, compulsions to help these patients live in every day and- and function. The- these are all...... fabulously helpful pa- uh, therapies for a variety of patients. But there's still about 30% of patients that still suffer from OCD, and some of them have severe OCD, sometimes it's moderate to severe, and those are the patients that I'm really motivated to try to help. Um, our therapies for those patients right now, uh, I would say are, are worth pursuing, but not optimal. Um, and so it's, it's one of those things that we have to balance as a researcher, because when you see patients like this you want to do everything you can to help them. And I think it's important to educate patients on the risk and benefits of them. This is deep brain stimulation surgery, but also capsulotomy, which is more of an ablation approach, a little bit like deep brain stimulation, but rather than delivering stimulation through an electrode, you can actually heat the tissue and even destroy it. Some would say this part of the brain is very safe to destroy, it's kind of like an appendix. Um, others would say it's safer to modulate. I have seen, uh, patients do very well with these ablations. And so, you know, you asked me earlier what, what I find so amazing about the brain, these effects that we can have, sometimes the lack of effect is what's so amazing. You can actually, uh, traverse parts of the brain without having any adverse effects on patients, um, function at least that you can test. Um, but you can also destroy small parts of the brain, we're talking three or four millimeters in size. These little ablations can be really helpful for patients, but have no obvious side effects that we can tell, perhaps after a short recovery from surgery. Uh, but nonetheless, despite how safe they might be, uh, these surgical procedures still are surgical procedures, and patients are hesitant to proceed, especially when they know that their chance of a transformative effect is quite low. We, we can generally, um, uh, achieve a responder rate of about 50%. Um, and responders still have symptomatic OCD. So I'm really, uh, uh, sort of inspired to, uh, really find a way to deliver these therapies in a more disease-specific or symptom-specific way. But, uh, we're years away probably from, from that therapy, since it's all part of a research study at the moment.

7. 25:40 – 31:11

   Brain Areas in OCD, Risk, Rewards & Addiction

   1. CHCasey Halpern25:40

   2. AHAndrew Huberman25:40

      What brain areas should I think about when I think about OCD? Years ago, I remember opening a textbook, I think I was an undergraduate still, and work from Judith Rappoport at the National Institutes of Mental Health, this would be late '80s, early '90s, was, um, had done some neuroimaging, or maybe it was PET, or s- uh, or some other imaging technique, and had identified portions of the basal ganglia-

   3. CHCasey Halpern26:04

      Sure.

   4. AHAndrew Huberman26:04

      ... um, caudate putamen type structures in OCD, and, um, maybe some differences in boys versus girls. So what brain areas ... Are there sex differences in terms of OCD? And were one to come into your clinic this, you know, for this sort of a work of ablations or stimulation, uh, where would you first start to probe in the brain?

   5. CHCasey Halpern26:28

      Yeah, you know, this is a, uh, a disorder of both cortex and the sub- subcortex, uh, the cortical control areas, areas that are involved in hi- inhibitory control, we have found to not function properly in patients with OCD, so areas like the orbital frontal cortex and the prefrontal cortex. If you image these areas, uh, or study them even in a, uh, a rodent model of OCD, which quite honestly these models, they model aspects of OCD, but OCD is a human condition. You can't really model this whole condition in a, in a mouse or a rat. But perhaps you can model compulsive behavior in a rat, sure. And that-

   6. AHAndrew Huberman27:10

      Pulling out their hair.

   7. CHCasey Halpern27:11

      Yeah, exactly. You know, that's, that's not necessarily obsessive compulsive disorder, but that is compulsive behavior, and perhaps if you can ameliorate that in a rat, that might be helpful for a patient with OCD. But we have to approach animal modeling of OCD thoughtfully. Uh, and I, and I ... and most scientists do, I think. Uh, and when we study OCD in, in models or in, in humans with imaging, and, and we're trying to do it i- invasively with, with electrodes, like we do in epilepsy patients, we, we find that areas in the cortex like the prefrontal and orbital frontal cortex are, are not functioning they w- the way they would in a non-OCD patient. They are often hyperfunctioning, um, such that while you might say, "Well, they're hyperfunctioning, so aren't these patients, you know, functioning better?" The, the-

   8. AHAndrew Huberman27:55

      Hyperfocused.

   9. CHCasey Halpern27:56

      Yeah, hyperfocused, exactly. (laughs) Um, no, I, I would say it's, it's not so much an up or a down, it's more that they're just dysfunctional, and we need to find a way to try to restore normal function to these areas. It's not so much directional really. Um, we, we tend to oversimplify brain function by thinking about it with directionality too much. Um, unfortunately, imaging studies sometimes demonstrate activation or hypoactivation, and that's where I think these kinds of things can be misconstrued. But what I would call the cortical areas of OCD is if they're dysregulated, um, and we need to find a way to try to normalize their function. So, uh, the frontal lobe is, is huge, but areas of the frontal lobe that are a bit more basal, like the OFC, or orbital frontal cortex, and the prefrontal cortex definitely consistently seem to be, uh, implicated in patients with, uh, OCD. And then there are projections to the subcortex. This is the basal ganglia, like you were saying, caudate putamen, or the dorsal striatum, and these are interconnected with the ventral striatum. This is an area of the brain that I, uh, focus a lot of my energy in. Um, this is the ventral striatum, which is not limited to but includes the nucleus accumbens. Um, this is an area of the brain that, uh, we know to be involved in gating reward-seeking behavior. When it's perturbed, it seems to gate compulsive behavior, meaning a rat will pursue a reward despite punishment, despite a foot shock, for example. And that can be, uh, similar to an OCD patient. They will, um, check their home for safety, uh, until 3:00 AM in the morning and not sleep that night, i- in a way that is similar to a rat seeking out a food reward, uh, despite a foot shock. Um, doing something because of the urge, but despite the risk. And perhaps there is some normal, uh, judgment there. Um, we all have to take risks to function in everyday society. Uh, to be successful, we have to take a risk. Um-... to take care of patients with surgery. There's some risk there. We make a judgment call, and, uh, that's not a condition. That, that's just normal. Um, but when our judgment is consistently, uh, sort of puts us at risk, that's where we have something like OCD. But OCD is also, you know, it's one of many conditions that suffer from these kinds of problems. We tend to label them, uh, because they tend to present in a consistent way. So, we have patients with OCD that have hyper checking behavior or, um, contamination behavior where they, if they c- feel contaminated, they will wash their hands for hours repeatedly, or if they drop their toothbrush on the floor, th- this will lead to a compulsive behavior of cleaning a toothbrush or brushing your teeth consistently. Very, very common symptoms that we see, uh, or signs that the patients report to us, or, or that we observe. But, you know, patients with eating disorders, they're, they tend to, if, if they have binge eating disorder, they'll overeat. If they have bulimia, they might purge, despite the risk of these things. And so, um, addiction is, is similar. We, we tend to drug seek if we're addicted. Um, uh, we'll, we'll pay off a, a dealer, uh, in order to get our fix, uh, despite the risk. And, and that type of urge, despite the risk, is something that I, I've always been really interested in, and, and it's a common denominator to all of these problems. And if you think about these problems, I mean, these are some of the most common conditions in our society

8. 31:11 – 32:27

   AG1 (Athletic Greens)

   1. CHCasey Halpern31:11

      today.

   2. AHAndrew Huberman31:12

      I'd like to take a quick break and acknowledge one of our sponsors, Athletic Greens. Athletic Greens, now called AG1, is a vitamin mineral probiotic drink that covers all of your foundational nutritional needs. I've been taking Athletic Greens since 2012, so I'm delighted that they're sponsoring the podcast. The reason I started taking Athletic Greens, and the reason I still take Athletic Greens once or usually twice a day, is that it gets me the probiotics that I need for gut health. Our gut is very important. It's populated by, uh, gut microbiota that communicate with the brain, the immune system, and basically all the biological systems of our body to strongly impact our immediate and long-term health. And those probiotics in Athletic Greens are optimal and vital for microbiotic health. In addition, Athletic Greens contains a number of adaptogens, vitamins and minerals that make sure that all of my foundational nutritional needs are met, and it tastes great. If you'd like to try Athletic Greens, you can go to athleticgreens.com/huberman, and they'll give you five free travel packs that make it really easy to mix up Athletic Greens while you're on the road, in the car, on the plane, et cetera. And they'll give you a year's supply of vitamin D3 K2. Again, that's athleticgreens.com/huberman to get the five free travel packs, and the year's supply of vitamin D3 K2. Yeah. I

9. 32:27 – 39:28

   Facial and Vocal Ticks, Stimulants, Stress & Superstition

   1. AHAndrew Huberman32:27

      really appreciate that you're building this bridge from OCD to nucleus accumbens, which is, of course, associated with reward in various forms, and we'll get to that. Um, I'll share a personal anecdote as a, as a form of question. When I was in college, um, and studying a lot, uh, I relied on caffeine as a stimulant. Uh, I've never really been into drugs or alcohol. I've been lucky in that sense. I don't drink, and I could care less if alcohol disappeared. Never really liked recreational drugs, so was never drawn to them. However, when I was in college, um, at the time, there were these little epinephrine pills that were, um, common in a lot of sports supplements.

   2. CHCasey Halpern33:07

      Oh.

   3. AHAndrew Huberman33:07

      These were like pre-workout type things.

   4. CHCasey Halpern33:09

      Yes.

   5. AHAndrew Huberman33:10

      Not unlike energy drinks now, which I completely avoid. Um, and I had this experience of taking one of these and drinking some coffee, and of course it gave me a lift in energy. These are very similar to amphetamine. They were legal over the counter at the time. They're now either banned or illegal. I do not recommend them. And I had a lot of energy, but what I noticed is that my grunting tic came back, and I had... I made one mistake. I still think of this as one mistake, which was, um, I engaged in a superstitious behavior. I knocked on wood, and then somehow it felt very rewarding. Like, it gave me some totally irrational, but internally rational sense of, of security around... I forget what I was knocking on wood about. And I found that I couldn't break that knock on wood compulsion. I felt I needed to knock on wood. And so then I started sneaking knock on woods like in mid-exam, and studying, and pretty soon, I was knocking on wood often. I developed a superstition. And so, I'm curious about the role of superstition and compulsion, and the crossover there. It makes sense logically to me, but I was equally shocked to learn that when I stopped taking this stimulant, which I was quite happy to, to stop, because it did make me feel too alert, couldn't sleep well, et cetera, that the superstition went away as well. And I'm guessing this has something to do with some of the reward circuitry, uh, as it's called, related to stimulants. Um, again, I am not encouraging anyone to take stimulants, although healthy use of caffeine or safe use of caffeine might be the one universally accepted stimulant. Um, it was really surprising to me how quickly this came on, how quickly it engaged my, my thinking and my behavior, the obsessions and the compulsions, and how quickly it turned off when I stopped taking this sports stimulant or whatever it was. I don't even remember. I think it was some form of epinephrine. Ephedrine.

   6. CHCasey Halpern34:58

      Sure.

   7. AHAndrew Huberman34:58

      Uh, some-

   8. CHCasey Halpern34:59

      Um-

   9. AHAndrew Huberman34:59

      It's not epinephrine. Excuse me. I misspoke. Eh- ephedrine.

   10. CHCasey Halpern35:02

       Sure.

   11. AHAndrew Huberman35:02

       Um, does what I describe sound totally outside the bounds of, of, uh, logic or is, or am-

   12. CHCasey Halpern35:10

       Uh-

   13. AHAndrew Huberman35:10

       ... I imagining it all? Um-

   14. CHCasey Halpern35:11

       No, I-

   15. AHAndrew Huberman35:11

       It did happen. I'm certain it happened.

   16. CHCasey Halpern35:13

       Yeah. No, I don't think you're imagining it at all. I... You know, this- the grunting that you, you mentioned to me, you know, first of all, I, I didn't, uh, comment, but you know, that, that sort of, not to put a label on it, but it sounds like a tic.

   17. AHAndrew Huberman35:24

       Mm-hmm.

   18. CHCasey Halpern35:25

       And, you know, tics in, in young males, extremely common, and they do tend to go away as-

   19. AHAndrew Huberman35:31

       Blinking tics.

   20. CHCasey Halpern35:31

       Exactly.

   21. AHAndrew Huberman35:32

       I have a good friend who, he actually a famous neuroscientist. I won't mention who it is. Who's worked very hard to suppress his, his blinking tic.

   22. CHCasey Halpern35:38

       Yes.

   23. AHAndrew Huberman35:39

       And when he gets fatigued, it comes back, and, and, um, he's very high functioning-

   24. CHCasey Halpern35:43

       Yes.

   25. AHAndrew Huberman35:43

       ... in his personal life and his professional life.

   26. CHCasey Halpern35:45

       Yes.

   27. AHAndrew Huberman35:45

       But, but when you're talking to him, and he starts doing this, you kind of start wondering-

   28. CHCasey Halpern35:49

       Yeah.

   29. AHAndrew Huberman35:49

       ... like, "What's going on?" (laughs)

   30. CHCasey Halpern35:50

       Yeah. (laughs) Yeah.
10. 39:28 – 47:18

    Nucleus Accumbens, Reward Circuits, Eating Disorders & Obesity

    1. AHAndrew Huberman39:28

       let's talk about nucleus accumbens, and reward circuitry, and the relationship between OCD, reward, addiction, uh, and to just give you a sense of where I'm headed with this is into the realm of- of food-related and eating-related beha- uh, behaviors and disorders-

    2. CHCasey Halpern39:45

       Yes.

    3. AHAndrew Huberman39:45

       ... 'cause I know you- you're doing, um, some very important work there. Uh, what is nucleus accumbens? Uh, I know we all have one. We- or two. (laughs)

    4. CHCasey Halpern39:53

       Yes.

    5. AHAndrew Huberman39:53

       Um, one on each side of the brain. Uh, what is it? Uh, what roles does it play, um, in healthy brain behavior and in pathology?

    6. CHCasey Halpern40:01

       Yeah, the nucleus accumbens is a part of the brain, part of our reward circuits, the hub of the reward circuits that I've always been most fascinated. Um, there are scientists around the world, some of the leading, uh, arguably some of the leading scientists in the world, the father of addiction neuroscience I call him, um, although he tells me I'm nuts, uh, Rob Malenka, who has studied the nucleus accumbens since the beginning of his career, and who I worked with when I was at Stanford. Um, fabulous scientist and mentor, taught me so much, um, taught the world so much.

    7. AHAndrew Huberman40:34

       Incredible-

    8. CHCasey Halpern40:35

       Yeah.

    9. AHAndrew Huberman40:35

       ... person, scientist, and phys- and physician as well.

    10. CHCasey Halpern40:38

        Yes, M- M- MD, PhD, and, uh, brilliant in both ways, and, um, very fatherly in a lot of way in terms of teaching people how to- how to do science and- and be good citizens as well. Um, but, uh, yeah, the nucleus accumbens is an area that is also very complicated because it has a lot of functions. Uh, it- it interconnects with many parts of the brain. Uh, but there are some things about the nucleus accumbens that are very consistent. Uh, so when I started getting interested in reward and what a- what I could do as a surgeon to try to improve how we manage rewards, and what I mean by that specifically is wha- if you have an urge for a reward, that- that's a normal phenomenon. That- that's not something we're trying to stop. The- the issue is if you have an urge for rewa- a reward that either puts you or somebody else at risk, it's probably a reward we shouldn't have. I suppose you could say, well, it depends on the size of the reward and the size of the risk and how that fits into your societal norms. Um, but for example, if you're, um, obese and, uh, you have a doctor who is advising that you lose weight and try to control your eating habits, uh, you know, perhaps...... uh, better food choices is an important way for you to be healthier. And, and not pursuing those better food choices, that's an urge that we probably need to treat. Uh, if you're a drug addict and you, uh, use heroin or opiate, considering the opiate crisis right now, uh, or cocaine, uh, uh, which is un- untreatable at the moment, um, you know, that- that cocaine might make you feel like you have s- some more energy that day to- to deal with your work, or that opiate might make you feel better 'cause life is stressful. But the risk of doing those things is really high, uh, in fact, potentially lethal. Uh, so, uh, that's an urge that's treatable. Um, if you have OCD and you can't sleep at night because you're so nervous that you didn't lock the door and you checked 30 times, um, that's a reality for some people with severe OCD. Um, that's an urge we gotta treat. Eating disorder is the same. Eating- eating disorders and obesity are obviously linked because of the relationship of a patient with food, but they're also quite distinct. Not everybody with obesity has an eating disorder, and obviously not everybody with an eating disorder has obesity. Um, I'm particularly interested in patients that have binge eating disorder as well as obesity because they're so heavily linked. N- not everybody with binge eating disorder has obesity, but, uh, on average, most are overweight. Um, we are doing a deep brain stimulation trial at Penn where we're trying to modulate the nucleus accumbens and understand it better in patients that have failed gastric bypass surgery, the most aggressive form of treatment for obesity, and we- and we believe they failed gastric bypass surgery because of binge eating disorder, meaning they just can't control how much they eat. So their obesity is either related or even due to overeating, not some predisposition to, um, that body habitus. You know, obesity is a phenotype, something that we can see. Not everybody is obese because of the same thing. So it's very important. I was taught this by a close mentor and friend, Tom Wadden, when he was the director of the, uh, obesity center at Penn, uh, or the Center for Weight and Eating Disorders, and- and he said to me, "You know, Casey, uh, you know, be careful with obesity. You're- you're interested in addiction, and I understand you're interested in the addictive tendencies of certain patients with obesity," uh, uh, "and- and- and their relationship with food, but not everybody with obesity has that problem." And- and in fact, it's- it's probably present in about 20% of patients with obesity. But now taking a step back, 20% of patients with obesity is still a massive problem, uh, of epidemic proportions, and perhaps some of these patients have either some form of binge eating disorder or- or I should say some degree of binge eating disorder, uh, or at least loss of control eating, which is common to both. Um, so that's a feature that I think eating disorder experts, obesity experts, neurosurgeons, uh, obesity m- uh, uh, m- m- obesity medicine experts would agree is common to eating disorders and obesity, and I also believe would- is common to addicts, um, and perhaps patients with OCD, is sort of a loss of control disorder. Um, it's actually not a disorder known by, like, the DSM-5, some diagnostic manual, but, uh, a feature, I should say, of these conditions that's common, and that common denominator, I believe, can be restored, or at least this problem can be ameliorated or improved upon by a better understanding and a tailored treatment to the nucleus accumbens specifically. Um, we have learned in mice, um, that if you expose a mouse ... Now this is just a model. If you expose a mouse to high-fat food, not food that they would normally eat, food that, um, is like 60% fat, high fat, it's like butter, um, we've learned that if you expose them to food like that, within two weeks their nucleus accumbens is not functioning like a mouse that was never exposed to that high-fat food. There's aspects of it that, uh, are hyperactive, I could say, and there's aspects of it that are hypoactive or decreased activity, but either way it's- it's not functioning properly, and most likely that function is pre- predisposing continued behavior, and then probably eventually leads to things like a habit that gets developed, and that's a whole nother area of these kinds of problems that is very complicated and poorly understood. But in any case, if we just focus on the behavior, uh, at hand, it seems that repeated exposure to something like high-fat food, a drug of abuse, or any type of reward that is a really strong reward, i- in a way, it- it can hijack normal functioning of the nucleus accumbens. So the goal of our, uh, invasive trial is to try to restore normal functioning to that nucleus accumbens. Uh, in mice there seems to be a- a signal that predicts when they're going to lose control, and we can use that signal to deliver a sort of a- a real-time therapy in the form of deep brain stimulation, just a brief amount of stimulation, and that actually blocks the behavior. And what's interesting is over time, that signal actually decreases in frequency, which suggests some level of restoring normal function to that circuit in a mouse, and we're trying to do that now in a human trial.

    11. AHAndrew Huberman47:16

        Fascinating. Where is

11. 47:18 – 49:49

    Stimulation of Nucleus Accumbens, Continuous vs. Episodic Stimulation

    1. AHAndrew Huberman47:18

       the stimulation provided? Because I would imagine that if one were to stimulate nucleus accumbens, you would see a reinforcement of whatever behavior coincided or preceded the stimulation.

    2. CHCasey Halpern47:30

       So the stimulation, it's a, uh, a brief delivery of stimulation, anywhere between five and ten seconds, that is intended to just disrupt the perturbed signaling that's happening in the nucleus accumbens. There are disorders like depression, let's say, that I- I would describe as a bit more of a state disorder, and this is obviously oversimplified because we know that there's fluctuations in mood and depression as well, so don't let me oversimplify it too much. Um, but, um...... but, but for now, let's forgive the oversimplification. If we, if we accept that depression is a state disorder, or maybe Parkinson's disease is a state disorder ex- uh, recognizing that they do fluctuate, uh, these types of problems most likely, not, but not definitely, most (laughs) likely need a continuous therapy of some form, uh, a therapy that's consistent, uh, perhaps a therapy that fluctuates with the condition, but nevertheless still consistent. Uh, binge eating disorder or OCD or, uh, addiction, um, and- and binge eating disorder in the context of obesity, a lot of these patients are functioning quite normally every single day. It's just that intermittently throughout the day, there's brief interruptions in their normal functions such that they have thoughts about food or the drug of abuse that they're really longing to have. And so, we want to deliver a episodic therapy delivered at the right time and only at the right time, to try to interrupt the circuit aberration or the- the problem at hand that is going to lead to that dangerous behavior, and to kind of get the patient back on track to what they're doing. Um, I don't necessarily think that it leads to a reinforcement. Um, it's possible. Um, we have to study that more. But rather, the goal is to just disrupt perhaps what is kind of habitual, um, or- or at least this kind of recurring problem that is happening. You know, people that have binge eating disorder, at least at a severe level, they tend to binge about once a day, but they don't binge all day long, of course. They have a moment perhaps when they get home from work and they're stressed where they might have a bout of binge.

    3. AHAndrew Huberman49:48

       What constitutes

12. 49:49 – 53:02

    Binge Eating Disorder & Loss of Control Eating

    1. AHAndrew Huberman49:49

       a binge, and, uh, I also want to know, does binge eating disorder come on suddenly, uh, meaning as an entire disorder? D- one day, people wake up, suddenly they have binge eating disorder, or is this, you know, a few too many buffets, uh, and- and I'm being entirely serious here, you know, of kind of un- unlimited food?

    2. CHCasey Halpern50:07

       Yeah.

    3. AHAndrew Huberman50:07

       And a circuit gets flipped or kind of starts moving into the high RPMs, so to speak. Um, so how does it come on? And, um, I mean, I'm actually surprised to hear that it's once a day. I would think just hearing binge eating disorder, I assumed it's like OCD, which it probably fluctuates across the day as well, but, um, I would've thought anytime people are around food, they just simply can't control their intake of food.

    4. CHCasey Halpern50:31

       Yes.

    5. AHAndrew Huberman50:31

       Yeah. So- so what does this look like, uh, in terms of the onset of the disorder, and then what do you think underlies this once a day type of phenomena? That's pretty interesting.

    6. CHCasey Halpern50:40

       Yeah, so severe binge eating disorder, uh, these patients will binge about once a day. Could be a couple times a day, but in general, it's not more than that. Moderate is about three to four times a week, for example. The reason I think that that seems surprising to you, and i- if you think about it, it is surprising, but- but- but, um, and I- and I agree with you, but the reason for that is- is actually just in the definitions of the word, and as a neurosurgeon, in full disclosure, as I- as I mentioned, you know, I don't see these patients clinically. I see them for research trial purposes, and I try to s- understand the literature around eating disorders, and I obviously collaborate with fabulous eating disorders, uh, uh, in- in these problems that are- that are highly innovative people. Uh, but the word binge is a definition. There- there's a definition to that word, and y- you can't necessarily binge all day because our stomachs are not big enough, um, and so, uh, there's a limit to how much one can eat, and to meet criteria for a binge, you have to have a sense of loss of control, you have to eat an enormous amount of food in a brief period of time. And yes, generally, that doesn't happen more than about once a day i- in a patient with severe binge eating disorder. Uh, however, they can lose control quite often, and in fact, perhaps even at every meal they might meet criteria for a bout of loss of control where they, yes, they may have lost control, but they might not have eaten enough to constitute what we would define as a binge. Um, and that would be in a, uh, there- there's no specific number to that, by the way. It's- it's really just compared to their normal meal. You know, perhaps it's, uh, 50% of their daily calories in that one brief moment. Um, so, uh, that's- that's why I think it seems surprising that binges aren't happening more often than that. Uh, what I would say is if we s- re- re- replace the term binge with loss of control eating, loss of control eating could happen dozens of times a week, um, and in fact, you know, the patients that we're studying, you know, we've- we've seen patients that, uh, lose control 20, 30 times a week, um, and that's probably the- the term you have in mind when you say you're surprised that it's just one time a day. And it's specifically related to the fact that these patients have to eat such a large amount of food in such a brief period of time, um, so it's hard to do that more than once a day.

    7. AHAndrew Huberman53:00

       I see. Um, you

13. 53:02 – 1:02:07

    Developing Binge Eating Disorder: Predisposition, Environment, Stress

    1. AHAndrew Huberman53:02

       mentioned that some preexisting anxiety might bias somebody to have a binge. Um, I'm also fascinated by something I've observed before, which was when I was in college, my- my girlfriend had a roommate who we were aware was bulimic.

    2. CHCasey Halpern53:17

       Mm-hmm.

    3. AHAndrew Huberman53:17

       Um, and would binge and then purge, and often, uh, when she ingested alcohol, that would lead to a binge.

    4. CHCasey Halpern53:25

       Sure.

    5. AHAndrew Huberman53:26

       Which is kind of the opposite of anxiety when I think about alcohol as something that slightly reduces prefrontal activity, somewhat of a sedative or a- certainly a sedative at higher dosages. So this brings me to something that you said. I'm just gonna, uh, I won't say it as eloquently as you did, that it seems like it's n- neither the case that anxiety leads to binging nor that hypo, reduced activation of the forebrain and lower anxiety leads to binging. It's this- it's this dysregulation of circuitry.

    6. CHCasey Halpern53:56

       Mm-hmm.

    7. AHAndrew Huberman53:56

       That the- the seesaw could go either way and it- and it can throw things off, but it's off balance in both cases.

    8. CHCasey Halpern54:02

       Yes.

    9. AHAndrew Huberman54:02

       Uh, it's, uh, and that seems to be, uh, a-... that seems to pose a problem. It seems like it's a particularly tricky problem, and kind of explains to me, in my non-clinical awareness, why medication might be really hard to use as a way to treat this, but that being able to poke around in the brain and assay in real time, you know, how do you feel? Do you feel like binging now, or do you feel, um, further from the binge impulse? Is that what you do with these patients? Are they awake while you're stimulating the brain? 'Cause it's one thing to say, "I stimulate a brain area and the binging goes away," or, uh, partial relief or complete relief, but how do you know? Are they in there with a donut-

    10. CHCasey Halpern54:42

        (laughs)

    11. AHAndrew Huberman54:42

        ... um, and you're tempting them? So, how do you actually know (laughs) if it's- ablating a brain area is going to lead to, uh, relief or exacerbation or no impact on a- on this disorder?

    12. CHCasey Halpern54:54

        Yeah, so, uh, l- l- there's a lot to unpack there. Um, I- I'll try to go one step at a time, and if I, if I miss something, please remind me.

    13. AHAndrew Huberman55:00

        No, and I tend to ask these three-part questions-

    14. CHCasey Halpern55:02

        Yeah. (laughs)

    15. AHAndrew Huberman55:02

        ... specifically of neurosurgeons because I like to challenge you guys.

    16. CHCasey Halpern55:06

        (laughs) Yeah.

    17. AHAndrew Huberman55:06

        'Cause again, you are the astronauts of neuroscience. Also, I- I'm just gonna take a moment to poke at neurosurgeons-

    18. CHCasey Halpern55:10

        (laughs)

    19. AHAndrew Huberman55:10

        ... 'cause I have a couple close friends-

    20. CHCasey Halpern55:12

        Oh, here we go. (laughs)

    21. AHAndrew Huberman55:12

        ... um, who are neurosurgeons, and I consider Casey a friend. I don't know if he considers me a friend, but I-

    22. CHCasey Halpern55:16

        Of course.

    23. AHAndrew Huberman55:16

        ... consider him a friend. I'm teasing there too, which is first of all, they all have incredible hands, right? They have- I'm not s- they all guard their hands with the kind of, um, uh, protection that you would guard the- the tools of- the most important tools of your trade. So, they're very careful with their hands. You're not going to see-

    24. CHCasey Halpern55:33

        Because, uh-

    25. AHAndrew Huberman55:33

        ... them doing heavy deadlifts.

    26. CHCasey Halpern55:35

        (laughs)

    27. AHAndrew Huberman55:35

        You're not because of the way that impacts the n- the-

    28. CHCasey Halpern55:37

        That's exactly true.

    29. AHAndrew Huberman55:37

        ... the motor neurons. They- it's all about fine control.

    30. CHCasey Halpern55:40

        Yes.
14. 1:02:07 – 1:11:41

    Electrodes in Nucleus Accumbens, Identifying “Craving Cells”

    1. CHCasey Halpern1:02:07

       you know, your second question, I, I sort of take that as, well, how do you study such a complicated problem in the operating room and, and in the clinic? Because, uh, I mentioned the operating room because that's sort of the first step here. Uh, first we want to, we have, uh, just to clarify, we have a, um, NIH-funded, uh, trial approved by the FDA for, for research to do this first-in-human study. Um, we've treated two patients. We have four more to come at Penn, and, um, and in this study, uh, it's something I've been working towards my entire career. Uh, what we don't know is where in the nucleus accumbens will we identify cells or regions that seem to be, um, involved in this sort of reward-seeking behavior. I would call it appetitive. It, it's kind of like appetite, but the word appetitive is, I think, a, a, a good word to use. What, what part of the nucleus accumbens is appetitive? Is the whole thing appetitive? Probably not. It's huge. In my world it's huge. As a (laughs) neurosurgeon, you know, I, I target parts of the brain that are three or four millimeters in size. The nucleus accumbens is almost a centimeter in size.

    2. AHAndrew Huberman1:03:22

       Wow.

    3. CHCasey Halpern1:03:22

       So-

    4. AHAndrew Huberman1:03:22

       I didn't realize it was that large.

    5. CHCasey Halpern1:03:24

       Yeah.

    6. AHAndrew Huberman1:03:24

       This sort of re- reminds me of discussions around the amygdala. Everyone thinks amygdala, fear.

    7. CHCasey Halpern1:03:28

       Yeah.

    8. AHAndrew Huberman1:03:28

       But the amygdala's got a lot of different sub-regions.

    9. CHCasey Halpern1:03:30

       Yes.

    10. AHAndrew Huberman1:03:31

        And stimulation of certain areas of the amygdala makes people feel great.

    11. CHCasey Halpern1:03:34

        That's right.

    12. AHAndrew Huberman1:03:35

        And other... Stimulation of other areas makes them feel terribly afraid.

    13. CHCasey Halpern1:03:38

        Exactly. And, and that shouldn't surprise us, because, you know, when we treat patients with Parkinson's disease, for tremor, you know, if we're in one part of the subthalamic nucleus, we'll help their tremor. If we're in another part of the subthalamic nucleus, the neurologist is looking at me like, "Why isn't this working?" And that shouldn't surprise us. We already know that, you know, two or three millimeters deviation or two or three millimeters away from where we want to be, and you might not have the result you want. And that's probably also true for these more limbic structures, like the amygdala and the nucleus accumbens. Uh, so, you know, regarding the nucleus accumbens, we traverse some of the nucleus accumbens, not all of it, in order to place the electrode that we want to use to detect when cravings are happening, for example, and to try to block the cravings from leading to the behavior related to the, the reward seeking, which is the overeating in this case. Uh, so what we decided to do i- in the operating room was to actually try to leverage a tool that we use all the time when we take care of patients with Parkinson's. So with Parkinson's, these, a lot of these patients, not all, have tremor. And so when we place an electrode into this motor structure to try to improve their movement disorder, uh, we often can hear tremor cells, and they sound... We, we convert their electrical signal to an audible signal, so we can actually hear it. Um, and it, and it sounds kind of like the tremor looks, like the frequency of the signal is the same as the hand shaking.

    14. AHAndrew Huberman1:05:07

        So

    15. CHCasey Halpern1:05:07

        zzz-zzz-zzz-zzz-zzz-zzz. Exactly.

    16. AHAndrew Huberman1:05:09

        And so the, the patient with Parkinson's is-

    17. CHCasey Halpern1:05:12

        Awake.

    18. AHAndrew Huberman1:05:12

        ... is trem- trembling.

    19. CHCasey Halpern1:05:13

        Yep.

    20. AHAndrew Huberman1:05:13

        They're awake, and you're poking around-

    21. CHCasey Halpern1:05:16

        Yep.

    22. AHAndrew Huberman1:05:16

        ... in a, in a dedicated, careful way, of course.

    23. CHCasey Halpern1:05:19

        Yes.

    24. AHAndrew Huberman1:05:19

        I don't want to-

    25. CHCasey Halpern1:05:19

        One poke at a time.

    26. AHAndrew Huberman1:05:20

        One poke at a time.

    27. CHCasey Halpern1:05:21

        Yeah.

    28. AHAndrew Huberman1:05:21

        Uh, with a very fine wire or set of wires.

    29. CHCasey Halpern1:05:23

        Yeah.

    30. AHAndrew Huberman1:05:23

        Listening to the electrical activity until you, uh, you encounter some cells that are sending out electrical activity-
15. 1:11:41 – 1:16:46

    Effects of Stimulation, Interrupting Craving, Intermediate Stimulation

    1. CHCasey Halpern1:11:41

       uh, sort of, um, strategy that we think is really important is, um, the effect of the stimulation. So a lot of patients, and this gets to sort of your question earlier about what kind of, what comes first, um, eh, you know, a lot of people, when they, when they binge or they lose control over food, um, or seek drugs, that moment of vulnerability is preceded by what we call a, a, a moment of sort of pre-meal negative affect, which basically means right before they binge, they're feeling down or they feel stressed or anxious, and they compensate for that momentary symptom by binging or losing control over food. Not everybody meets criteria for a binge, so I, I try to, uh, specify that we are, we are looking at loss of control eating specifically, just because the criterion of a binge is not as critical for us. Um...So, um, so what we want to be able to do is trigger stimulation when this craving is detected by the device. Uh, but we trigger it only when the craving is there, and we believe that if we can sort of temporarily elevate their mood, ever so briefly, again, this is about five to ten seconds of stimulation only, that perhaps that elevation in mood could actually sort of disrupt the craving to binge cycle. Maybe that's a habit, maybe it's not, but if you crave and then you binge, if we can interrupt that with this moment of feeling good, that might be a really good therapy for a patient. And in fact, when we do deep brain stimulation for obsessive compulsive disorder, we can fairly reliably induce a positive affect. The problem is that it's not sustained, and the reason it's likely not sustained is because with obsessive compulsive disorder, we treat that condition with continuous stimulation, and it's not surprising that over time the effect kind of goes away. So when they're in the clinic and we turn the device on, our patients feel great, and we feel like we've solved the problem, but they call us the next day and they're like, "You know, my, my depression came back." Or, "My OCD hasn't gotten better and my mood's back to where it was. Can you, can you get it back to where it was yesterday? 'Cause that felt great."

    2. AHAndrew Huberman1:14:05

       The brain loves homeostatic regulation.

    3. CHCasey Halpern1:14:07

       It does, and-

    4. AHAndrew Huberman1:14:08

       It does not like to shift patterns.

    5. CHCasey Halpern1:14:10

       Sort of regression to the norm.

    6. AHAndrew Huberman1:14:11

       Right.

    7. CHCasey Halpern1:14:11

       Um, and I think there's sort of a tolerance effect there, um, that, uh, is, is limiting the effect of continuous stimulation, and actually in a mouse if you do continuous stimulation, um, the, the sort of blockade of binge eating goes away. So actually in a mouse, we've actually demonstrated, um, we published this not too long ago, uh, in PNAS, that if you deliver stimulation intermittently, and only when sort of a craving signal is detected, so to speak, um, that, that ef- that effect will be the most robust and durable. Um, but if you deliver it continuously, actually the benefit goes away over time. So I've always encouraged my colleagues to consider more of an episodic stimulation approach rather than continuous deep brain stimulation. But of course that, that's for these more episodic conditions, whereas these more quote unquote state disorders (laughs) , uh, as I oversimplified earlier, they might need more of a continuous therapy. So that's definitely subject for a lot of research in the future. Um, so in any case, um, the goal in the operating room was to identify a craving cell, um, deliver stimulation safely, but also to capture a moment of elevated mood. We were able, uh, uh, to do that as we a- we are in our OCD patients as well, and also to get an intraoperative CAT scan. We have, uh, devices now in the operating room that allow us to get imaging in real time. Th- they're fabulous tools that we didn't have 10 years ago. Uh, so we can confirm accuracy. Um, s-

    8. AHAndrew Huberman1:15:41

       You know, where the el- you can see where the electrode is-

    9. CHCasey Halpern1:15:44

       Exactly.

    10. AHAndrew Huberman1:15:44

        ... precisely.

    11. CHCasey Halpern1:15:45

        Exactly. Um, you know, with 0.5 millimeters of error. So super precise, uh, or as precise as we think we need to be. Um, and we use connectomics. So there's a tool in, um, brain imaging called, uh, tractography, um, where we can actually measure circuit connections. It's, it's an indirect assay, but we believe it's powerful. It has its, uh, assumptions, but, um, like anything in, in science, but, uh, we can actually, uh, map out where the nucleus accumbens connects to, uh, the prefrontal cortex, sort of the cortical control, inhibitory control pathway, and where that pathway intersects with the nucleus accumbens, and we can target that area, um, structurally. Um, so those three goals of the surgery we, we aimed to set out to accomplish. Um, and we believed if we achieved two of those three, uh, that we would have a, a successful result in our, in our early trial.

    12. AHAndrew Huberman1:16:43

        Amazing. Given

16. 1:16:46 – 1:23:14

    Anorexia, Obesity & Compulsions, Potential Treatments for Anorexia

    1. AHAndrew Huberman1:16:46

       that at least to me, the non-clinician, that anorexia is the mirror image of binge eating disorder, and at least from what I learned, uh, one of the more deadly psychiatric conditions-

    2. CHCasey Halpern1:17:00

       Yeah.

    3. AHAndrew Huberman1:17:00

       ... um, but also quite common.

    4. CHCasey Halpern1:17:03

       Yes.

    5. AHAndrew Huberman1:17:03

       Um, is it possible that nucleus accumbens, this so-called reward circuit, is also involved in anorexia, but somehow it is the resistance to eating, the craving of the fasted state or something like that that's being reinforced?

    6. CHCasey Halpern1:17:20

       Yeah.

    7. AHAndrew Huberman1:17:20

       And, and I ask this for two reasons. One, because I'm genuinely curious about anorexia. I've observed anorexia in a number of people I know, and it's a striking thing to see somebody just resist food despite all better knowledge of the fact that they're getting quite ill and maybe even at risk of death. But the other reason is that if in fact nucleus accumbens i- is the site which can harbor cells to promote craving and craving of, uh, fasted states, so to speak, then that, I think, might tell us something fundamental about how the brain works, which is that structures don't control functions per se, structures control dynamics-

    8. CHCasey Halpern1:18:04

       Yes.

    9. AHAndrew Huberman1:18:04

       ... of interactions. Sort of like a, a orchestra conductor, um, has a certain number of operations that they perform, but really their main function is to coordinate the actions of a lot of things, not to make sure that the violins always play in-

    10. CHCasey Halpern1:18:18

        Yes.

    11. AHAndrew Huberman1:18:19

        ... a certain way, uh, alongside the oboes. You can tell I'm not a musician here. Um- (laughs)

    12. CHCasey Halpern1:18:23

        (laughs) . At least you have an appreciation for the oboes.

    13. AHAndrew Huberman1:18:25

        Yes.

    14. CHCasey Halpern1:18:26

        Those usually get left out.

    15. AHAndrew Huberman1:18:27

        What's that? The oboes?

    16. CHCasey Halpern1:18:27

        Yeah, they usually get ignored. (laughs)

    17. AHAndrew Huberman1:18:29

        Oh my... My partner plays the oboe, so yeah.

    18. CHCasey Halpern1:18:31

        Oh, wow.

    19. AHAndrew Huberman1:18:31

        So yeah, so-

    20. CHCasey Halpern1:18:32

        I, I think that's a great analogy, by the way. Um, you know, I, I, I make this statement, it's a little controversial, but I, I actually think people, uh, would understand where it's, where, where I'm coming from, um, across all of these sort of subspecialties, uh, of medicine. Um, but I, I actually think, especially with obesity, remember, it's a phenotype that's reflective, uh, often but not always of a behavior.

    21. AHAndrew Huberman1:18:53

        Mm-hmm.

    22. CHCasey Halpern1:18:53

        Uh...Um, but if you consider patients that have obesity and they, they exhibit some sort of compulsion towards food, so they, they overeat despite the risk of it, I think those kinds of patients are more similar to anorexics than they are different. Um, anorexia and obesity are both phenotypes that are, uh, at least in this specific case of obesity and in anorexia, um, a result of a compulsion to either over or under-eat despite the risk. Um, these types of compulsions are driven by societal pressures, um, uh, brain vulnerabilities that are probably more similar, uh, than, than they are different. They, they just happen to manifest differently. Um, why they manifest differently is probably related to each patient's predisposition or perhaps preference. Um, that's hard to know. Uh, like you, I, I have a, a personal connection to these eating disorders, anorexia included, and, uh, yeah, I, I think it's, um, it's very scary. Um, and it's a condition that, um, often instills fear in psychiatrists, uh, because I, I think, you know, not- not everybody by the way, I mean, I have some phenomenal, um, psychiatrists that I work with both at Stanford and at Penn, um, they're also involved in my obesity study that take care of these patients. I mean, these are heroes. But there's a lot of psychiatrists that are not in this domain that, that find anorexia scary for the reason you said. It has the highest mortality of all psychiatric conditions. That includes depression. Um, because not only can these patients die of suicide, but they die of metabolic complications of being underweight. Um, so it's a, uh, it is a- it is a scary condition. I, I relate with that. Um, I am trying over time to bridge what I'm doing in obesity and binging disorder to anorexia for, for two reasons. One, because I think these problems are more similar than they are different, and two, because of the need. Um, and I, I think we're well-positioned, um, to, to sort of tackle anorexia, um, uh, using similar approaches. Not identical, but, but similar approaches. Um, the nucleus accumbens has been studied in patients with anorexia, uh, in China. Actually, my post-doc, my first post-doc who, uh, I had the honor to train, uh, when I was at Stanford as a neurosurgeon in China when, uh, before he came to me, actually was involved in a- in a trial of anorexia that had some benefits. Um, and, uh, uh, there's studies in, uh, Europe, um, uh, and- and elsewhere that, uh, have examined preliminarily, uh, the effects of deep brain stimulation targeting the nucleus accumbens, uh, uh, for anorexia. Colleagues of mine in Canada, uh, Andres Lozado's a wonderful neurosurgeon scientist has been studying the effects of going after area 25, which is directly connected to the nucleus accumbens by, um, you know, it's- it's a monosynaptic connection. So in a lot of ways, you know, perhaps delivering stimulation there could- could be very similar to delivering stimulation with the nucleus accumbens. It's all part of one critical inhibitory control circuit. He's seen benefits as well. Um, so I, I definitely think there's some evidence that this is an area that we need to be studying. Um, I think our more episodic approach with responsive stimulation going after sort of a- a signal in the nucleus accumbens that seems to be related to the compulsion to withhold from eating I think is what we will be trying to accomplish, uh, in our study. It's, uh, right now just being conceived though. Uh, yeah, th- these studies, they move so slowly because you have to get a grant. That grant gets reviewed by the NIH six months after you submit it. Often gets rejected because it's too innovative and too high risk, so then you have to edit it and decrease the risk. So it takes... My obesity study took two years to get funded, and I worry about that timeframe because that's a lot of time for patients with anorexia to suffer that I might be able to help at least in a small sample of patients. So, um, but that- that is the nature of how these things go. You also have to get FDA approval to do these kinds of things. We try to do all of this in parallel. It's an enormous undertaking, and in a lot of ways we're starting from scratch, but in some ways we have some preliminary data to- to go after this. So my hope is in about a year we'll have a similar trial for anorexia at Penn, so, so more to come on that. Um, and, and I, we're not the only, uh, lab that's trying to go after it because of the- the clear need, so...

17. 1:23:14 – 1:32:27

    Non-Invasive Brain Stimulation, Transcranial Magnetic Stimulation

    1. CHCasey Halpern1:23:14

Episode duration: 2:14:34